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WO2024259241A1 - Modulateurs du récepteur 5-ht2a et leurs procédés d'utilisation - Google Patents

Modulateurs du récepteur 5-ht2a et leurs procédés d'utilisation Download PDF

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WO2024259241A1
WO2024259241A1 PCT/US2024/034016 US2024034016W WO2024259241A1 WO 2024259241 A1 WO2024259241 A1 WO 2024259241A1 US 2024034016 W US2024034016 W US 2024034016W WO 2024259241 A1 WO2024259241 A1 WO 2024259241A1
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hydrogen
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Paul Galatsis
Urjita H. SHAH
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Transneural Therapeutics Inc
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Transneural Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • Modulators of the 5-hydroxytryptamine 2A receptor are sought after as potential pharmaceuticals for a variety of psychiatric and neurological diseases and disorders including, but not limited to, depression, anxiety, post-traumatic stress disorder, obsessive compulsive disorder, substance abuse, eating disorders, migraine headaches, and/or cluster headaches, Alzheimer’s Disease, Parkinson’s Disease, and various somatic illnesses including, but not limited to, various inflammatory, cardiovascular, and/or pain disorders.
  • 5- HT2AR modulators have been developed, few are selective for this receptor over related subtypes, for example, the 5-HT2B receptor, a toxicology anti-target strongly implicated in serious side effects including drug-induced valvular heart disease.
  • the disclosure is directed, in part, to modulators of the 5-hydroxytryptamine 2A (5- HT2A) receptor.
  • pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.
  • A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, and phenyl; wherein ring A may be substituted on one or more substituents selected from R A ;
  • R A is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)- OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C 1 -C 6 alkyl,
  • R x and R Y are each independently selected from the group consisting of hydrogen and -C 1 -C 3 alkyl; or one R x and one R y are joined together to form -CH 2 -;
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CH 2 -phenyl, -CH 2 CH 2 -phenyl, and -CH 2 -(4-6 membered heteroaryl); wherein C 1 -C 6 alkyl, phenyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O- C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkeny
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy; and R a and R b are independently selected for each occurrence from the group consisting of hydrogen and C 1 -C 3 alkyl; wherein C 1 -C 3 alkyl may optionally be substituted by one or more halogens.
  • A is selected from the group consisting of
  • R c is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
  • R d is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C 1 -C 3 alkyl, and C 1 -C 3 alkoxy; wherein -C 1 -C 3 alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH 2 , - C(O)-NH 2 , and -OCH 3 ;
  • R e is selected from the group consisting of hydrogen, halogen, cyano, and -C 1 -C 3 alkyl;
  • R 1 is selected from the group consisting of hydrogen, -CH 3 ,
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)-N(CH 2 CH 3 ) 2 ; and m is 0, 1, 2, or 3.
  • R x and R Y are each independently selected from the group consisting of hydrogen and -C 1 - C 3 alkyl; or R x and R' are joined together to form -CH 2 -;
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and -SO 2 -phenyl; wherein C 1 -C 6 alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
  • R A is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)- OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 .C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C 1 -C 6 alkyl,
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C 3 -C 6 cycloalkyl, -CH 2 -phenyl, -CH 2 -CH 2 -phenyl, -CH 2 -(5-10 membered heteroaryl), and -CH 2 -(5-10 membered heterocyclyl); wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C 3 - C 6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C 1 -C 3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , - C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 - C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 .C 6 alkenyl, C 2
  • R 5 is selected from the group consisting of halogen, hydroxyl, cyano, -NR a R b , -C(O)- NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -CO 2 H, -C(O)- C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkeny
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1 . C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R a and R b are independently selected for each occurrence from the group consisting of hydrogen and C 1 -C 3 alkyl; wherein C 1 -C 3 alkyl may optionally be substituted by one or more halogens; and m is 0, 1, 2, or 3.
  • A is selected from the group consisting of
  • R w is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
  • R Y is hydrogen or -CH 3 ;
  • R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -CH 2 OH, -CH 2 NH 2 , - CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxi
  • R 1 is selected from the group consisting of hydrogen, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -
  • R 2 is selected from the group consisting of hydrogen, -CH 3 , and -CH 2 OH;
  • R 3 is selected from the group consisting of hydrogen, hydroxyl, -NH 2 , -CH 3 , -CH 2 OH, - CH 2 NH 2 , -CO 2 H, -NH-C(O)-N(CH 2 CH 3 ) 2 , phenyl, m-hydroxy phenyl, p-hydroxyphenyl, and p- aminophenyl; and m is 0, 1, 2, or 3.
  • compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions comprise at least one additional therapeutic agent that treats, ameliorates, and/or prevents a neurological disease and/or disorder.
  • a neurological disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of any of the compounds described herein, or a pharmaceutical composition thereof.
  • the neurological disease or disorder is selected from the group consisting of, for example, depression, anxiety, substance abuse, and headache.
  • methods of selectively modulating the 5 -hydroxy tryptamine 2A (5-HT2A) receptor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C 1-6 alkyl, C 1 -4 alkyl, and C 1-3 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2- ethyl-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C 1 -C 5 alkenyl, C 2 -C 6 alkenyl, and C 3 -C 4 alkenyl, respectively.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond.
  • exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C 2 -6 alkynyl, and C 3 -6 alkynyl, respectively.
  • exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
  • alkoxy refers to a straight or branched alkyl group attached to oxygen (alkyl-O-).
  • exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C 1 -C 5 alkoxy, C 1 -C 6 alkoxy, and C 2 -C 6 alkoxy, respectively.
  • Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • Examples of representative substituted aryls include the following wherein one of R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 -C 8 alkoxy, heteroaryl oxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 5X SOR ?9 NR 58 SO 2 R 59 , COO-alkyl, COO-aryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SO-alkyl, SO 2 -alkyl, S-
  • R 60 and R 61 are each independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.
  • carbonyl refers to the radical -C(O)-.
  • cyano refers to the radical -CN.
  • cycloalkyl or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C 3 -C 10 cycloalkyl, C 3-6 cycloalkyl or C4-6 cycloalkyl, respectively.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.
  • halo or halogen as used herein refer to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl radical in which the alkyl group is substituted with one or more halogens.
  • Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF 3 ), difluoromethyl, fluoromethyl, chloromethyl, di chloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.
  • haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br, and I), referred to herein as C 1-6 haloalkyl, C 1.4 haloalkyl, and C1-3 haloalkyl, respectively.
  • a halogen i.e., Cl, F, Br, and I
  • hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • alkyl e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • heteroaryl or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur.
  • the term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen.
  • heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.
  • heterocyclyl refers to saturated or partially unsaturated 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen.
  • the term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur.
  • heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc.
  • the heterocycle is a spiro heterocycle (e.g., 2,8-diazaspiro[4.5]decane).
  • the heterocycle is a bridged heterocycle (e.g., octahydro-lH-4,7-methanoisoindole).
  • “Spiro heterocyclyl,” or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O) m (wherein m is an integer of 0 to 2) as ring atoms.
  • hydroxy and “hydroxyl” as used herein refer to the radical -OH.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.
  • compositions refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and/or partial agonism.
  • the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-m
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.
  • the symbol — denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “£” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.
  • Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a preexisting one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a single polymorph.
  • the compound is a mixture of polymorphs.
  • the compound is in a crystalline form.
  • the disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • a compound of the disclosure may have one or more H atom replaced with deuterium.
  • C 6 rtain isotopically labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255).
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1 -s)alkyl, (C 2 - i2)alkyl carbonyl oxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl - l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy )ethyl having from 4 to 7 carbon atoms, 1-methyl- 1 -(alkoxycarbonyl oxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1-6 )alkylcarbonyloxymethyl, l-((C 1-6 )alkylcarbonyloxy)ethyl, l-methyl-l-((C 1 - 6)alkylcarbonyloxy)ethyl (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 )alkoxy carbonylaminomethyl, succinoyl, (C 1-6 )alkylcarbonyl, a-amino(C 1 -4)alkylcarbonyl, aryl alkyl carbonyl and a- aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a-aminoalkylcarbonyl, where each a- aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine.
  • the disclosure is directed to, in part, to compounds that are modulators of the 5- hydroxytryptamine 2A (5-HT2A) receptor.
  • the modulators of the disclosure exhibit selective functionality for, and/or binding to, the 5-HT2A receptor over the 5- HT2B and/or 5-HT2C receptor.
  • compounds of the disclosure can be used to treat a variety of neurological diseases and disorders including, but not limited to, depression, anxiety, substance abuse, migraine headaches, and/or cluster headaches.
  • R A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, and phenyl; wherein ring A may be substituted on one or more substituents selected from R A ;
  • R A is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)- OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2
  • R x and R Y are each independently selected from the group consisting of hydrogen and -C 1 - C 3 alkyl; or one R x and one R' are joined together to form -CH 2 -;
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CH 2 -phenyl, -CH 2 CH 2 -phenyl, and -CH 2 -(4-6 membered heteroaryl); wherein C 1 -C 6 alkyl, phenyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O- C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 .C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl; wherein C 1 .C 6 alkyl, C 1 -C 6 alkyl, C 2 .C 6 aC
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy; and
  • R a and R b are independently selected for each occurrence from the group consisting of hydrogen and C 1 -C 3 alkyl; wherein C 1 -C 3 alkyl may optionally be substituted by one or more halogens.
  • R 6 and R 7 are hydrogen. In other embodiments, R 2 and R 3 are hydrogen. In certain embodiments, a compound disclosed herein is represented by
  • R c is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
  • R d is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C 1 -C 3 alkyl, -C 1 -C 3 alkoxy, -C 3 -C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein -C 1 -C 3 alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH 2 , -C(O)-NH 2 , and - OCH 3 ;
  • R e is selected from the group consisting of hydrogen, halogen, cyano, and -C 1 -C 3 alkyl; and m is 0, 1, 2, or 3.
  • R c is selected from the group consisting of hydrogen and -CH 3 ;
  • R d is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -OCH 3 , -CH 2 C(O)NH 2 , and -OCH 2 CH 3 ;
  • R e is selected from the group consisting of hydrogen, fluoro, chloro, -CH 3 , and cyano.
  • R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , - CH 2 OH, -CH 2 NH 2 , -CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl,
  • R A is independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -OCH 3 , -CH 2 C(O)NH 2 , and -OCH 2 CH 3 .
  • A is selected from the group consisting of, for example,
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)-N(CH 2 CH 3 ) 2 .
  • R 4 is hydrogen.
  • R 5 is selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)-N(CH 2 CH 3 ) 2 .
  • R 3 is hydrogen or -CH 3 .
  • R 1 is hydrogen.
  • R 1 is selected from the group consisting of hydrogen, -CH 3 , and
  • A is selected from the group consisting of
  • R c is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
  • R d is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C 1 -C 3 alkyl, and C 1 -C 3 alkoxy; wherein -C 1 -C 3 alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH 2 , - C(O)-NH 2 , and -OCH 3 ;
  • R e is selected from the group consisting of hydrogen, halogen, cyano, and -C 1 -C 3 alkyl;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)-N(CH 2 CH 3 ) 2 ; and m is 0, 1, 2, or 3.
  • R d is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -OCH 3 , -CH 2 C(O)NH 2 , and -OCH 2 CH 3 ; and R e is selected from the group consisting of hydrogen, fluoro, chloro, -CH 3 , and cyano.
  • R 4 is hydrogen.
  • R 5 is selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)-N(CH 2 CH 3 ) 2 .
  • R 5 is hydrogen or -CH 3 .
  • R 1 is hydrogen.
  • the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.
  • R x and R Y are each independently selected from the group consisting of hydrogen and -C 1 - C 3 alkyl; or R x and R' are joined together to form -CH 2 -;
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and -SO 2 -phenyl; wherein C 1 -C 6 alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
  • R A is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)- OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 .C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C 1 -C 6 alkyl,
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C 3 -C 6 cycloalkyl, -CH 2 -phenyl, -CH 2 -CH 2 -phenyl, -CH 2 -(5-10 membered heteroaryl), and -CH 2 -(5-10 membered heterocyclyl); wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C 3 - C 6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C 1 -C 3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1 - C>, alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , - C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 .
  • R 5 is selected from the group consisting of halogen, hydroxyl, cyano, -NR a R b , -C(O)- NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -CO2H, -C(O)-C 1 .C 6 alkyl, C 1 .C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkeny
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1 - C& alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R a and R b are independently selected for each occurrence from the group consisting of hydrogen and C 1 -C 3 alkyl; wherein C 1 -C 3 alkyl may optionally be substituted by one or more halogens; and m is 0, 1, 2, or 3.
  • R 6 and R 7 are hydrogen.
  • a compound disclosed herein is represented by
  • R Y is hydrogen or -CH 3 .
  • R w is selected from the group consisting of hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH(CH 3 ) 2 .
  • R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -CH 2 OH, -CH 2 NH 2 , - CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholiny
  • R A is independently selected from each occurrence from the group consisting of fluoro, chloro, hydroxyl, cyano, phenyl, -CH 3 , -CHF 2 , -CH 2 OH, -CH 2 CH 3 , -OCH 3 , -CH 2 C(O)NH 2 , -CH 2 CH 2 OH, and -OCH 2 CH 3 .
  • R 2 is hydrogen.
  • R 3 is selected from the group consisting of hydrogen, -CH 3 , and -CH 2 OH.
  • R 4 is hydrogen.
  • R 5 is selected from the group consisting of hydrogen, hydroxyl, -NH 2 , -CH 3 , -CH 2 OH, -CH 2 NH 2 , -CO2H, -NH-C(O)-N(CH 2 CH 3 ) 2 , phenyl, m-hydroxyphenyl, p- hydroxyphenyl, andp-aminophenyl.
  • R 1 is selected from the group consisting of hydrogen, -CH 3 , -
  • A is selected from the group consisting of
  • R w is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
  • R v is hydrogen or -CH 3 ;
  • R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -CH 2 OH, -CH 2 NH 2 , - CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxi
  • R 1 is selected from the group consisting of hydrogen, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , - R 2 is selected from the group consisting of hydrogen, -CH 3 , and -CH 2 OH;
  • R 3 is selected from the group consisting of hydrogen, hydroxyl, -NH 2 , -CH 3 , -CH 2 OH, - CH 2 NH 2 , -CO2H, -NH-C(O)-N(CH 2 CH 3 ) 2 , phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p- aminophenyl; and m is 0, 1, 2, or 3.
  • the compound is a compound identified in Table 2 below or a pharmaceutically acceptable salt thereof.
  • the compound is a compound identified in Table 3 below or a pharmaceutically acceptable salt thereof.
  • enantiomer of a disclosed compound this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art.
  • diastereomeric derivatives such as salts
  • the diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt).
  • a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).
  • a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.
  • disclosed compounds may also comprise one or more isotopic substitutions.
  • hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium); carbon may be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may be, for example, 15 N, and the like.
  • a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.
  • Another aspect of the disclosure provides methods of treating patients suffering from a neurological disease or disorder.
  • the disclosure provides a method of treating the below medical indications comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.
  • a method of treating a neurological disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II.
  • a method of treating a neurological disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein, e g., a compound of Formula I or Formula II, and a pharmaceutically acceptable excipient.
  • Non-limiting examples of a neurological disease or disorder include depression, anxiety, substance abuse, and headaches. Headaches that can be treated with the methods herein include, but are not limited to, migraine headaches and cluster headaches.
  • the methods described herein may include treating a depressive disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the depressive disorder may be major depressive disorder.
  • the depressive disorder may include treatment resistant depressions.
  • the methods described herein may include treating an anxiety disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the anxiety disorder may be generalized anxiety disorder. In other embodiments, the anxiety disorder may be social anxiety disorder.
  • the methods described herein may include treating a trauma and/or stress disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a disorder may be post-traumatic stress disorder.
  • such a disorder may be an adjustment disorder.
  • the methods described herein may include treating obsessive compulsive disorder, for example, body dysmorphic disorder, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • obsessive compulsive disorder for example, body dysmorphic disorder
  • the methods described herein may include treating an eating disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the eating disorder may be anorexia. In other embodiments, the eating disorder may be bulimia.
  • the methods described herein may include treating a sleep-wake disorder, for example, insomnia, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a sleep-wake disorder for example, insomnia
  • the methods described herein may include treating a psychotic disorder, for example, insomnia, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the psychotic disorder may be schizophrenia.
  • the psychotic disorder may be schizoaffective disorder.
  • the psychotic disorder may be schizotypal personality disorder.
  • the methods described herein may include treating substance-related disorders and/or addictive disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a disorder may be alcohol use disorder.
  • such a disorder may be opioid use disorder.
  • such a disorder may be tobacco use disorder.
  • a compound disclosed herein may be useful in facilitating smoking cessation.
  • the methods described herein may include treating a neurocognitive disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the neurocognitive disorder may include those due to a primary neurodegenerative disease, for example, Alzheimer’s disease or Parkinson’s disease.
  • the methods described herein may include treating a personality disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the methods described herein may include treating an autism spectrum disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the methods described herein may include treating a bipolar disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the bipolar disorder may be bipolar I disorder.
  • the bipolar disorder may be bipolar II disorder.
  • the methods described herein may include treating a pain disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the pain disorder may be neuropathic pain.
  • the pain disorder may be migraine.
  • the pain disorder may be cluster headache.
  • the pain disorder may be trigeminal neuralgia. In still further embodiments, the pain disorder may be cancer pain. In certain embodiments, the pain disorder may be regional pain disorder. In yet other embodiments, the pain disorder may be phantom limb pain. In some embodiments, a contemplated pain disorder may be a chronic pain.
  • a compound disclosed herein may exhibit anxiolytic, anti-depressive, and anti-drug abuse actions, without exhibiting substantial psychedelic actions, for example, hallucinogenic actions.
  • a contemplated (5-HT2A) receptor modulator of the present disclosure may confer anti-depressant like activities without incurring psychedelic drug-like actions.
  • a compound disclosed herein may be safe and effective for use in a method described herein, yet lack the hallucinogenic effects of known psychedelics such as, for example, DMT and psilocybin.
  • This disclosure also provides a method of selectively modulating the 5- hydroxytryptamine 2A (5-HT2A) receptor.
  • the method includes administering to a patient a compound disclosed herein, e.g., a compound of Formula I or Formula II, a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein the compound selectively modulates the 5- HT2A over the 5-HT2B and/or 5-HT2C receptor.
  • the method of selectively modulating the 5- HT2A receptor can be used to treat, ameliorate, and/or prevent diseases or disorders that are affected by, associated with, or would benefit from selective modulations at the 5-HT2A receptor.
  • the method provides, for example, reduced side effects such as, but not limited to, drug-induced valvular heart disease associated with modulating the 5-HT2B receptor.
  • a method described herein further comprises administering to the patient an additional therapeutic agent that treats a neurological disease or disorder, or that treats a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.
  • Contemplated patients include not only humans, but other animals such as companion animals (e.g., dogs, cats), domestic animals (e g., cow, swine), and wild animals (e g., monkeys, bats, snakes).
  • Compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein.
  • contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic.
  • a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient.
  • a disclosed compound and one additional therapeutic agent is administered.
  • a disclosed compound as defined herein and two additional therapeutic agents are administered.
  • a disclosed compound as defined herein and three additional therapeutic agents are administered.
  • Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately.
  • a disclosed compound and an additional therapeutic agent can be formulated and administered separately.
  • Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents.
  • a disclosed compound and an additional therapeutic agent can be administered in a single formulation.
  • Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present within the patient's body at the same time, this need not be so.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y- Y, etc.
  • the methods described herein include administering to the patient a therapeutically effective amount of at least one compound of Formula I or Formula II, as described herein, which is optionally formulated in a pharmaceutical composition.
  • a therapeutically effective amount of at least one compound described herein, e.g., a compound of Formula I or Formula II, present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition.
  • the method further comprises administering to the patient an additional therapeutic agent that treats a neurological disease or disorder or that treats a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.
  • the methods described herein can include administering to the patient one or more additional therapeutic agents in combination with a compound disclosed herein.
  • the one or more additional therapeutics agents that may be administered in combination with a compound disclosed herein may be a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • the selective serotonin reuptake inhibitor may be selected from the group consisting of, for example, fluoxetine, paroxetine, sertraline, citalopram and escitalopram.
  • the one or more additional therapeutics agents may be a serotonin and norepinephrine reuptake inhibitor (SNRI).
  • the serotonin and norepinephrine reuptake inhibitor may be selected from the group consisting of, e.g., duloxetine, venlafaxine, desvenlafaxine, and levomilnacipran.
  • the one or more additional therapeutics agents may be selected from the group consisting of, for example, trazodone, mirtazapine, vortioxetine, vilazodone and bupropion.
  • the one or more additional therapeutics agents may be a tricyclic antidepressant.
  • the tricyclic antidepressant may be selected from the group consisting of, e.g., imipramine, nortriptyline, amitriptyline, doxepin and desipramine.
  • the one or more additional therapeutics agents may be a monoamine oxidase inhibitor (MAOI).
  • MAOI monoamine oxidase inhibitor
  • the monoamine oxidase inhibitor may be selected from the group consisting of, e.g., tranylcypromine, phenelzine and isocarboxazid.
  • the one or more additional therapeutics agents may be, for example, a lithium compound, e.g., a lithium salt, e.g., lithium carbonate, lithium acetate, lithium sulfate, lithium citrate, lithium orotate, or lithium gluconate.
  • the one or more additional therapeutics agents may be, for example, ketamine or esketamine.
  • the one or more additional therapeutics agents may be, for example, dextromethorphan.
  • the one or more additional therapeutics agents may be, for example, D-methadone.
  • administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and/or preventing a neurological disease or disorder or in treating, ameliorating, and/or preventing a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor in the patient.
  • the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.
  • the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I or Formula II.
  • compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier.
  • pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, intranasal, 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.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be 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 may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com 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 compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium
  • 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) fdlers 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 may also comprise buffering agents.
  • Solid compositions of a similar type may also be 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 may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be 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 may be 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, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceuticalformulating 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 may contain 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, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • 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
  • Suspensions in addition to the subject composition, may 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 may be presented as a suppository, which may be 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 may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may 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 may 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 may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds of the present disclosure may alternatively be 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 may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • 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.
  • non-ionic surfactants Teweens®, 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 of this disclosure 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 may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may 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 examples 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.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be 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.
  • 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 (ELPMCAS), 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 resin
  • kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . ” etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, and phenyl; wherein ring A may be substituted on one or more substituents selected from R A ;
  • R A is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)- OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C 1 -C 6 alkyl,
  • R x and R Y are each independently selected from the group consisting of hydrogen and -C 1 - C 3 alkyl; or one R x and one R Y are joined together to form -CH 2 -;
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CH 2 -phenyl, -CH 2 CH 2 -phenyl, and -CH 2 -(4-6 membered heteroaryl); wherein C 1 -C 6 alkyl, phenyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1 - G, alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 4 and R ? are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O- C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alken
  • C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, - NR a R b , and C 1 -C 3 alkoxy;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy; and
  • R a and R b are independently selected for each occurrence from the group consisting of hydrogen and C 1 -C 3 alkyl; wherein C 1 -C 3 alkyl may optionally be substituted by one or more halogens.
  • E4 The compound of any one of E1-E3, wherein R 2 and R 3 are hydrogen.
  • E5. The compound of any one of E1-E4, wherein the compound is represented by
  • E6 The compound of any one of E1-E5, wherein A is selected from the group consisting of
  • R c is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
  • R d is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -C 3 -C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein -C 1 -C 3 alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH 2 , -C(O)-NH 2 , and - OCH 3 ;
  • R e is selected from the group consisting of hydrogen, halogen, cyano, and -C 1 -C 3 alkyl; and m is 0, 1, 2, or 3.
  • E7 The compound of any one of E1-E6, wherein:
  • R c is selected from the group consisting of hydrogen and -CH 3 ;
  • R d is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -OCH 3 , -CH 2 C(O)NH 2 , and -OCH 2 CH 3 ;
  • R e is selected from the group consisting of hydrogen, fluoro, chloro, -CH 3 , and cyano.
  • E8 The compound of any one of E1-E5, wherein R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , - CHF 2 , -OCF 3 , -OCHF 2 , -CH 2 OH, -CH 2 NH 2 , -CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl,
  • E9 The compound of any one of E1-E5 and E7, R A is independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -OCH 3 , -CH 2 C(O)NH 2 , and -OCH 2 CH 3 .
  • E10 The compound of any one of E1-E9, wherein A is selected from the group consisting of
  • El l The compound of any one of El -El 0, wherein R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)- N(CH 2 CH 3 ) 2
  • E12 The compound of any one of El-El 1, wherein R 4 is hydrogen.
  • R 5 is selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)-N(CH 2 CH 3 ) 2 .
  • E14 The compound of any one of E1-E13, wherein R 5 is hydrogen or -CH 3
  • E15 The compound of any one of E1-E14, wherein R 1 is selected from the group consisting of hydrogen, -CH 3 ,
  • E16 The compound of any one of E1-E15, wherein R 1 is hydrogen.
  • A is selected from the group consisting of
  • R c is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
  • R d is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C 1 -C 3 alkyl, and C 1 -C 3 alkoxy; wherein -C 1 -C 3 alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH 2 , - C(O)-NH 2 , and -OCH 3 ;
  • R e is selected from the group consisting of hydrogen, halogen, cyano, and -C 1 -C 3 alkyl;
  • R 1 is selected from the group consisting of hydrogen, -CH 3 ,
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)-N(CH 2 CH 3 ) 2 ; and m is 0, 1, 2, or 3.
  • R d is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -OCH 3 , -CH 2 C(O)NH 2 , and -OCH 2 CH 3 ;
  • R e is selected from the group consisting of hydrogen, fluoro, chloro, -CH 3 , and cyano.
  • E19 The compound of E17 or E18, wherein R 4 is hydrogen.
  • E20 The compound of any one of E17-E19, wherein R 5 is selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, -NH 2 , and -NH-C(O)-N(CH 2 CH 3 ) 2 .
  • E21 The compound of any one of E17-E20, wherein R 5 is hydrogen or -CH 3 .
  • E22 The compound of any one of E17-E21, wherein R 1 is hydrogen.
  • E24 A compound represented by Formula III: or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein is a single bond, X is CR X , and Y is C(R Y ) 2 ; or is a double bond, X is C, and Y is C(R Y );
  • R x and R Y are each independently selected from the group consisting of hydrogen and -C 1 - C 3 alkyl; or R x and R Y are joined together to form -CH 2 -;
  • R w is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and -SO 2 -phenyl; wherein C 1 -C 6 alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
  • R A is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)- OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 .C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 .C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -Cs-C 6 cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C 1 -C 6 alkyl, C
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 .C 6 alkynyl, -C 3 -C 6 cycloalkyl, -CH 2 -phenyl, -CH 2 -CH 2 -phenyl, -CH 2 -(5-10 membered heteroaryl), and -CH 2 -(5-10 membered heterocyclyl); wherein C 1 -C 6 alkyl, C 2 .C 6 alkenyl, C 2 .C 6 alkynyl, -C 3 - C 6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C 1 -C 3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , - C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 - C 6 alkyl, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 .C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 .C 6 alkenyl, C 2
  • R 5 is selected from the group consisting of halogen, hydroxyl, cyano, -NR a R b , -C(O)- NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C 1 -C 6 alkyl, -CO 2 H, -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -C 3 -C 6 cycloalkyl, and phenyl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkeny
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1 - C 6 alkyl; wherein C 1 -C 6 alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 3 alkoxy;
  • R a and R b are independently selected for each occurrence from the group consisting of hydrogen and C 1 -C 3 alkyl; wherein C 1 -C 3 alkyl may optionally be substituted by one or more halogens; and m is 0, 1, 2, or 3.
  • E26 The compound of E24 or E25, wherein R 6 and R 7 are hydrogen.
  • E27 The compound of any one of E24-E26, wherein the compound is represented by
  • E28 The compound of any one of E24-E27, wherein R Y is hydrogen or -CH 3
  • E29 The compound of any one of E24-E28, wherein R w is selected from the group consisting of hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH(CH 3 ) 2
  • E30 The compound of any one of E24-E29, wherein R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , - CHF 2 , -OCF 3 , -OCHF 2 , -CH 2 OH, -CH 2 NH 2 , -CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl,
  • E31 The compound of any one of E24-E30, wherein R A is independently selected from each occurrence from the group consisting of fluoro, chloro, hydroxyl, cyano, phenyl, -CH 3 , -CHF 2 , -CH 2 OH, -CH 2 CH 3 , -OCH 3 , -CH 2 C(O)NH 2 , -CH 2 CH 2 OH, and -OCH 2 CH 3
  • E32 The compound of any one of E24-E31, wherein R 2 is hydrogen.
  • E33 The compound of any one of E24-E32, wherein R 3 is selected from the group consisting of hydrogen, -CH 3 , and -CH 2 OH.
  • E34 The compound of any one of E24-E33, wherein R 4 is hydrogen.
  • E35 The compound of any one of E24-E34, wherein R ? is selected from the group consisting of hydrogen, hydroxyl, -NH 2 , -CH 3 , -CH 2 OH, -CH 2 NH 2 , -CO2H, -NH-C(O)- N(CH 2 CH 3 ) 2 , phenyl, m-hy droxypheny 1, p-hydroxy phenyl, and p-aminophenyl.
  • E36 The compound of any one of E24-E35, wherein R 1 is selected from the group consisting of hydrogen, -CH 3 , -CD 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 -phenyl. cyclopropyl, or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein
  • A is selected from the group consisting of
  • R w is selected from the group consisting of hydrogen and C 1 -C 3 alkyl
  • R 3 is hydrogen or -CH 3 ;
  • R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -CH 2 OH, -CH 2 NH 2 , - CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, pipe
  • R 1 is selected from the group consisting of hydrogen, -CH 3 , -CD3, -CH 2 CH 3 , -CH(CH 3 ) 2 , -
  • R 2 is selected from the group consisting of hydrogen, -CH 3 , and -CH 2 OH;
  • R 3 is selected from the group consisting of hydrogen, hydroxyl, -NH 2 , -CH 3 , -CH 2 OH, - CH 2 NH 2 , -CO 2 H, -NH-C(O)-N(CH 2 CH 3 ) 2 , phenyl, /n-hydroxy phenyl, p-hydroxyphenyl, and p- aminophenyl; and m is 0, 1, 2, or 3.
  • E40 A pharmaceutical composition comprising a compound of any one of E1-E39 and a pharmaceutically acceptable excipient.
  • E41 A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of E1-E39.
  • E42 A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of E1-E39 and a pharmaceutically acceptable excipient.
  • E43 The method of E41 or E42, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.
  • Example 1 Synthesis of 3-[(3R)-piperidin-3-yl]-2,l-benzoxazole and 3-[(3S)- piperidin-3-yl]-2,l-benzoxazole (Compounds 109 and 110)
  • reaction mixture was stirred at -78 °C for 30 min before a solution of tert-butyl 3-(2-methoxypropanoyl) piperi dine- 1 -carboxylate (11.97 g, 44.1 mmol) in 2 mL THF was added dropwise. After an addition 30 min, the reaction mixture was quenched with NH4CI (aq) and then extracted with EtOAc (5 x 100 ml). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na?SO4, and concentrated under reduced pressure.
  • tert-Butyl 3-formyl-5,6-dihydro-2H-pyridine-l-carboxylate A solution of tert-Butyl 3-(hydroxymethyl)-5,6-dihydro-277-pyridine-l-carboxylate (1.60 g, 7.50 mmol) and MnCL (9.78 g, 112.60 mmol) in DCM (20 mL) was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was filtered, and the residue was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure.
  • tert-Butyl 3-(2,l-benzoxazol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate To a stirred solution of tert-butyl 3-(2-nitrobenzoyl)-5,6-dihydro-2H-pyridine- l -carboxylate (80.0 mg, 0.24 mmol) in MeOH (0.5 mL) and EtOAc (0.5 mL) was added SnCh.2H 2 O (163.0 mg, 0.72 mmol). The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction was quenched with sat. NaHCO.i (aq.) at room temperature.
  • tert-butyl 3- formyl-5,6-dihydro-2H-pyridine-l-carboxylate 600.0 mg, 2.84 mmol
  • the reaction was quenched with sat. NH 4 CI (aq.) at room temperature.
  • the resulting mixture was extracted with CH 2 CI 2 . (3 x 50 mL)
  • the combined organic extracts were washed with water (3 x 10 mL) and dried over anhydrous Na 2 SO 4 . After fdtration, the fdtrate was concentrated under reduced pressure.
  • the crude product (70.0 mg) was purified by Prep-HPLC with the following conditions, Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (lOmmol/L NH4HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 42% B in 7 min; Wave Length: 254nm/220nm nm; RTl(min): 7.18 to afford the desired product as a white solid (51.8 mg, 49.2% yield).
  • the mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL) and basified to pH 9 with saturated Na2CC>3 (aq ).
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol/L NH4HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 30 min; Wave Length: 254nm/220nm nm; RTl(min): 7.19) to afford the desired product as a yellow solid (27.8 mg, 38.9%) yield.
  • the mixture was basified to pH 8 with saturated Na2CC>3 (aq.).
  • the mixture was purified by Prep-HPLC with the following conditions (Column: YMC- Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water(10 mmol/L NH4HCO 3 ), Mobile
  • Example 12 Synthesis of 3-(4,7-dichloro-5-fluoro-l-benzofuran-3-yl)-l,2,5,6- tetrahydropyridine (Compound 135)
  • the mixture was neutralized to pH 7 with saturated Na2CCh (aq.).
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol/L NH4HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18 % B to 37 % B in 7 min; Wave Length: 254 nm/220 nm; RTl(min): 7.07) to afford the desired product as a white solid (66.6 mg, 63.7% yield).
  • the crude product was purified by Prep- HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water ( l Ommol/L NH4HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 18% B to 37% B in 7 min; Wave Length: 254nm/220nm nm; RTl(min): 7.07) to afford the desired product as a white solid (30.8 mg, 34.6% yield).
  • Example 17 Synthesis of tert-butyl 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl)- 5,6-dihydro-2H-pyridine-l-carboxylate (Compound 146)
  • tert-butyl (E)-3-(2-ethoxy-2-oxoethylidene)piperidine-l-carboxylate Under N2 atmosphere, a stirred solution of NaH (2.41 g, 100.37 mmol) in THF (20 mL) was treated with triethyl phosphonoacetate (11.25 g, 50.19 mmol) for 30 min at 0 °C. Then tert-butyl 3- oxopiperidine-1 -carboxylate (5.00 g, 25.1 mmol) was added dropwise while maintaining the temp at 0 °C. The final reaction mixture was stirred overnight at rt before concentrating under reduced pressure.
  • tert-butyl (3E)-3-[2-(5-fluoro-2-iodophenoxy)ethylidene]piperidine-l -carboxylate A solution of tert-butyl (3Z)-3-(2-hydroxyethylidene)piperidine-l-carboxylate (600.0 mg, 2.64 mmol), 5-fluoro-2-iodophenol (628.2 mg, 2.64 mmol) and triphenylphosphine (1.04 g, 3.96 mmol) in THF (10.0 mL) was stirred for 10 min at rt under a N2 atmosphere before the of diisopropyl azodicarboxylate ( 1.60 g, 7.92 mmol) dropwise at rt.
  • 6-fluoro-l-benzofuran-3-yl trifluoroniethanesulfonate To a stirred solution of 6- fluoro-27/-l-benzofuran-3-one (1.00 g, 6.60 mmol) and TEA (2.00 g, 19.70 mmol in DCM (15 mL) was added Tf20 (2.80 g, 9.90 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at rt before being diluted with water. The resulting mixture was extracted with CH 2 CI2 (3 x 50 mL) and the combined organic extracts were concentrated under reduced pressure.
  • tert-butyl 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl)piperidine-l-carboxylate To a stirred solution of tert-butyl 3-(6-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate (210.0 mg, 0.67 mmol) in MeOH (5 mL) was added PtCh (0.08 g, 0.33 mmol) in portions at rt. The resulting mixture was stirred overnight at rt under a H 2 atmosphere before the mixture was filtered through celite. The filter cake was washed with MeOH and the filtrate concentrated under reduced pressure.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: water(10 mmol/L NH4HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 2% B to 2% B in 5 min, 2% B to 20% B in 20 min, 20% B to 41% B in 30 min; Wave Length: 254nm/220nm nm; RTl(min): 8.9) to afford the desired product as a yellow solid (25.0 mg, 35.4% yield).
  • the mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (1 mL) and basified to pH 9 with saturated Na2COs (aq.).
  • the mixture was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: water (10 mmol/L NH4HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 47% B in 9 min; Wavelength: 254 nm /220 nm nm; RTl(min): 9.3) to afford the desired product as a white solid (49.6 mg, 70.1% yield).
  • 6-bromo-3-methoxy-2-nitropyridine A solution of 6-bromo-2-nitropyridin-3-ol (6.00 g, 27.5 mmol), iodomethane (11.72 g, 82.6 mmol) and cesium carbonate (26.9 g, 82.6 mmol) in acetone (50 mL) was stirred overnight at 60 °C under a N2 atmosphere. The reaction mixture was filtered through celite, the filter cake was washed with di chloromethane (4 x 20 mL), and the filtrate concentrated under reduced pressure.
  • tert-butyl 3-(lH-imidazo[4,5-b]pyridin-l-yl)piperidine-l-carboxylate A solution of tert-butyl 3-[(2-aminopyridin-3-yl)amino]piperidine-l-carboxylate (430.0 mg, 1.47 mmol) in 10 mL of tri ethyl orthoformate was stirred at 110 °C under N 2 atmosphere. After 2 hr, the reaction mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous Na 2 SO4, filtered, and the filtrate concentrated under reduced pressure.
  • Example 28 Synthesis of 7-(l-methyl-l,2,3-triazol-4-yl)-3-(l,2,5,6- tetrahydropyridin-3-yl)-lH-indazole; formic acid (Compound 309)
  • the resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column 30*150 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL/min mL/min; Gradient: 2% B to 15% B in 9 min; Wave Length: 254 nm/220 nm; RTl(min): 8.68/9.42) to afford the desired product as a white solid (14.8 mg, 14.3% yield).
  • the mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL) and it was basified to pH 9 with saturated Na2CCh (aq.).
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water(10mmol/L NH4HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 3% B in 1 min, 3% B to 20% B in 2 min, 20% to 38% B in 10 min; Wave Length: 254 nm/220 nm nm; RTl(min): 8.52) to afford the desired product as a white solid (43.4 mg, 61.5% yield).
  • 6-Fluoro-3-iodo-lH-indazole-7-carbonitrile To a stirred solution of 6-fluoro-l/T- indazole-7-carbonitrile (350 mg, 2.17 mmol) in DMF (10 mL) were added KOH (365.6 mg, 6.52 mmol) and I2 (826.9 mg, 3.26 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature, diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL), the combined organic extracts were concentrated under reduced pressure.
  • Example 36 Synthesis of 7-chloro-l-isopropyl-3-(l,2,5,6-tetrahydropyridin-3- yl) indole (Compound 525)
  • Example 38 Synthesis of 7-chloro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indol- 5-ol (Compound 529)
  • 7-Chloro-5-methoxy-lH-indole To a stirred solution of 2-chloro-4-methoxy-l- nitrobenzene (2.00 g, 10.662 mmol) in THF (20 mL) was added bromo(ethenyl)magnesium (37.4 mL, 1 M in THF) dropwise at -40 °C and the resulting mixture was stirred for 0.5 h at -40 °C under an N2 atmosphere.
  • Example 40 Synthesis of 5,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indole (
  • the mixture was basified to pH 8 with saturated Na2CCE (aq.).
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: 10 mmol/L NH 4 HC03+0.05%NH3H 2 0, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 1 min, 5% B to 47% B in 2 min, 47% to 60% B in 10 min; Wave Length: 254nm/220nm; RTl(min): 8.48) to afford the desired product as a white solid (38.6 mg, 51.8% yield).
  • the crude product (100.0 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol/L NH4HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 5% B to 5% B in 1 min, 5% B to 17% B in 15 min, 17% to 32% B in 30 min; Wave Length: 254nm/220nm nm; RTl(min): 8.03) to afford the desired product as a yellow solid (27.1 mg, 38.7% yield).
  • Example 43 Synthesis of 2- ⁇ [(3/?)-3-(lH-Indazol-3-yl)piperidin-l- yl]methyl ⁇ phenol and 2- ⁇ [(35)-3-(lH-indazol-3-yl)piperidin-l-yl]methyl ⁇ phenol (Compounds 523 and 524)
  • tert-Butyl 3-(lH-indazol-3-yl)piperidine-l-carboxylate A solution of terz-butyl 3- (l//-indazol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (800.0 mg, 2.67 mmol) and Pd/C (142.1 mg, 1.33 mmol, 0.5 equiv) in MeOH (10 mL) was hydrogenated for 5 h at room temperature under hydrogen atmosphere. After filtration, the filtrate was concentrated under vacuum.
  • 6-Fluoro-3-iodo-lH-indole-7-carbonitrile To a stirred solution of 6-fhioro-l //- indole-7-carbonitrile (300.0 mg, 0.87 mmol) in A,A-dimethylformamide (2 mL) was added NIS (843.0 mg, 3.74 mmol) at room temperature. The resulting mixture was stirred for 30 min. The resulting mixture was filtered, the residue was washed with EtOAc (5 x 10 mL). The filtrate was concentrated under reduced pressure.
  • tert-Butyl 3-(7-cyano-6-fluoro-lE/-indol-3-yl)-5,6-dihydro-2ZT-pyridine-l- carboxylate To a solution of 6-fluoro-3-iodo-lJ/-indole-7-carbonitrile (200.0 mg, 0.69 mmol) and K2CO 3 (193.2 mg, 1.39 mmol) in dioxane (1.6 mL) and H 2 O (0.4 mL) were added terZ-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (259.4 mg, 0.83 mmol) and Pd(dppf)C12 (102.3 mg, 0.14 mmol).
  • Example 47 Synthesis of 4-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indole- 7-carbonitrile (Compound 539)
  • Example 48 Synthesis of 4,7-dichloro-5-fluoro-3-(l,2,5,6-tetrahydropyridin-3- yl)-lH-indole (Compound 541)
  • the resulting mixture was concentrated under reduced pressure.
  • the crude product (20.0 mg) was purified by Prep-HPLC with the following conditions, Column: XB ridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: 10mmolNH 4 HC03+0.05%NH 3 H 2 0, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 48% B in 8 min; Wave Length: 254/220 nm; RTl(min): 10.15 to afford the desired product as a white solid (5.0 mg, 6.7% yield).
  • the mixture was basified to pH 9 with saturated Na2CC>3 (aq.).
  • the crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*100 mm, 5pm; Mobile Phase A: Water(10mmol/L NH4HCO 3 ), Mobile Phase B: MEOH; Flow rate: 60 mL/min mL/min; Gradient: 23% B to 38% B in 8 min; Wave Length: 254/220 nm; RTl(min): 8.1) to afford the desired product as a yellow oil (46.6 mg, 66.8% yield).
  • Example 50 Synthesis of 7-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indole-
  • tert-Butyl 3-(2-carbamoyl-7-fluoro-lH-indol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate Into a 40 mL vial were added ethyl 3-[l-(tert-butoxycarbonyl)-5,6-dihydro-277- pyridin-3-yl]-7-fluoro-l//-indole-2-carboxylate (400 mg, 1.03 mmol) and NH3 (g) in MeOH (15 mL) and stirred overnight at 70 °C under an N 2 atmosphere. The resulting mixture was concentrated under vacuum.
  • tert-Butyl 3-(2-cyano-7-fluoro-lH-indol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate A solution of tert-butyl 3-(2-carbamoyl-7-fluoro-177-indol-3-yl)-5,6-dihydro-2J7- pyridine-1 -carboxylate (150 mg, 0.42 mmol) in DCM (5 mL) was treated with TFAA (175.3 mg, 0.83 mmol) for 5 min at room temperature under an N 2 atmosphere followed by the addition of TEA (126.7 mg, 1.25 mmol) dropwise and stirred for 1 h at room temperature under an N 2 atmosphere.
  • Example 51 Synthesis of 2- ⁇ [(3S)-3-(lH-indol-3-yl)piperidin-l- yl] methyl] phenol and 2- ⁇ [(3R)-3-(lH-indol-3-yl)piperidin-l-yl]methyl ⁇ phenol (Compounds 546 and 547)
  • reaction mixture was purified by reversed-phase flash chromatography with the following conditions: column, C 1 s silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 20 min; UV 254 nm to afford the desired product as a white solid (150 mg, 39.2% yield).
  • C 2 0H 2 2N2O calcd 306.17; Found LCMS 48 (Method H) (ESI) [M+H] + :307.
  • Example 54 Synthesis of 7-ethyl-6-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)- IH-indole ( [00509] 7-Bromo-6-fluoro-l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ indole.

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Abstract

L'invention concerne des composés, par exemple, des composés de formule I, et leur utilisation dans le traitement de maladies ou de troubles médicaux, tels que des troubles psychiatriques et neurologiques. L'invention concerne des compositions pharmaceutiques et des procédés de fabrication de divers composés de benzisoxazole et de benzoisothiazole. Les composés sont envisagés pour être des modulateurs du récepteur de la 5-hydroxytryptamine 2A (5-HT2A).
PCT/US2024/034016 2023-06-16 2024-06-14 Modulateurs du récepteur 5-ht2a et leurs procédés d'utilisation Pending WO2024259241A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196425A (en) * 1988-09-02 1993-03-23 Janssen Pharmaceutica N.V. Antihypertensive 3-piperidinyl-indazole derivatives
WO2022067165A1 (fr) * 2020-09-28 2022-03-31 Yale University Agonistes sélectifs du récepteur 5-ht2a et procédés d'utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196425A (en) * 1988-09-02 1993-03-23 Janssen Pharmaceutica N.V. Antihypertensive 3-piperidinyl-indazole derivatives
WO2022067165A1 (fr) * 2020-09-28 2022-03-31 Yale University Agonistes sélectifs du récepteur 5-ht2a et procédés d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE 15 December 2022 (2022-12-15), ANONYMOUS: "3-(piperidin-3-yl)-1H-indazole", XP093259962, retrieved from PUBCHEM Database accession no. 473545396 *
JAYAKODIARACHCHI NAVODA, MAURER MALLORY A., SCHULTZ DANIEL C., DODD CAYDEN J., THOMPSON GRAY ANALISA, CHO HYEKYUNG P., BOUTAUD OLI: "Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists", ACS MEDICINAL CHEMISTRY LETTERS, vol. 15, no. 2, 8 February 2024 (2024-02-08), US , pages 302 - 309, XP093259995, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.3c00566 *

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