WO2016100349A2 - Composés azahétérocycliques bicycliques utilisés comme antagonistes des récepteurs nmda nr2b - Google Patents

Composés azahétérocycliques bicycliques utilisés comme antagonistes des récepteurs nmda nr2b Download PDF

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WO2016100349A2
WO2016100349A2 PCT/US2015/065829 US2015065829W WO2016100349A2 WO 2016100349 A2 WO2016100349 A2 WO 2016100349A2 US 2015065829 W US2015065829 W US 2015065829W WO 2016100349 A2 WO2016100349 A2 WO 2016100349A2
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mmol
chemical entity
alkyl
methyl
carboxylate
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WO2016100349A3 (fr
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Gideon Shapiro
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Rugen Holdings (Cayman) Limited
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    • 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
    • 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
    • A61P25/24—Antidepressants
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • Non-selective NMDA receptor antagonists originally developed in stroke and head trauma, have more recently shown clinical efficacy in treating depression.
  • the non-selective NMDA receptor antagonist, ketamine has been shown to have rapid onset and efficacy in depression resistant to standard monoamine reuptake inhibitor therapy (Mathews and Zarate, 2013, J. Clin. Psychiatry 74:516-158).
  • non-selective NMDA receptor antagonists such as ketamine have a range of undesirable pharmacological activities which limit application in humans. In particular dissociative or psychogenic side effects are particularly prominent for non-selective NMDA receptor antagonists.
  • N 2B subtype selective NMDA receptor antagonists have demonstrated potential in a wide range of clinical indications.
  • NR2B antagonists have also demonstrated antidepressant activity in early stage clinical trials (Ibrahim et al., 2012, 7. Clin. Psychopharmacol. 32, 551-557; Preskorn et al., 2008, J. Clin. Psychopharmacol. 28, 631-637).
  • selective NR2B antagonists have advantages over unselective NMDA receptor antagonists such as ketamine due to greatly diminished dissociative side effects.
  • NR2B antagonists described to date have generally exhibited drawbacks with regard to other drug properties which have limited potential use in human drug therapy.
  • NR2B subtype selective antagonists are needed.
  • the present invention addresses the need for NR2B receptor antagonists that are improved in one or more aspects exemplified by pharmacokinetic performance, oral activity, cardiovascular safety, and in vitro and in vivo therapeutic safety index measures.
  • the present invention encompasses the insight that chemical entities of Formula (I):
  • R 1 and Z are NR2B subtype selective receptor antagonists.
  • Chemical entities of Formula (I), and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases and disorders associated with NR2B receptor antagonism. Such diseases and disorders include those described herein.
  • FIG. 1 shows results of the Forced Swim Test as described in Example 2.2 with the compound El-1.2 ((3S,4 ?)-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-8-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate).
  • FIG. 2 shows results of the Forced Swim Test as described in Example 2.2 with the compound El-2.2 ((3S,4 ?)-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-5-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate).
  • the present invention provides chemical entities of Formula I:
  • R 1 is alkyl, cycloalkyi, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, (aryl)alkyl, heteroaryl or (heteroaryl)alkyl, wherein each of cycloalkyi, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, (aryl)alkyl, heteroaryl and (heteroaryl)alkyl is independently optionally substituted with 1 to 3 groups independently selected from -F, -CI, C C alkyl, cyclopropyl, -C ⁇ CH, -CFH 2 , -CF 2 H, -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , -Q alkoxy, -OCFH 2 , -OCF 2 H, -OCF 3 , -CN, -N(R 2 )
  • Z is 9- or 10-membered bicyclic ring system having ring carbon atoms, 1 nitrogen ring atom and 0-3 additional ring heteroatoms independently selected from N, O and S, wherein said ring system : is a heteroaromatic ring system, which ring system is optionally substituted with 1 or 2 R x groups and optionally substituted with 1 R a group, wherein each R x is attached to a ring carbon atom and R a is attached to a ring nitrogen atom; or is a 5- or 6-membered heteroaryl in which two adjacent ring atoms are linked to form a 5- or 6- membered heterocycle, which ring system is optionally substituted with 1 or 2 R x groups and optionally substituted with 1 R b group, wherein each R x is attached to a ring carbon atom and R b is attached to a ring nitrogen atom; wherein: each instance of R x independently is -F, -CI, -CH 3 , -CFH 2
  • R a is Ci_4 alkyl, C 3 . 4 cycloalkyi or -S(0) 2 -C!_ 4 alkyl;
  • R b is Ci_ 4 alkyl, C 3 . 4 cycloalkyi, -C(0)-Ci_ 4 alkyl, -C(0)0-Ci_ 4 alkyl or -S(0) 2 -Ci_ 4 alkyl.
  • the term “chemical entity” refers to a compound having the indicated structure, whether in its “free” form (e.g., “free compound” or “free base” or “free acid” form, as applicable), or in a salt form, particularly a pharmaceutically acceptable salt form, and furthermore whether in solid state form or otherwise.
  • a solid state form is an amorphous (i.e., non-crystalline) form; in some embodiments, a solid state form is a crystalline form. In some embodiments, a crystalline form is a polymorph, pseudohydrate, or hydrate. Similarly, the term encompasses the compound whether provided in solid form or otherwise. Unless otherwise specified, all statements made herein regarding "compounds" apply to the associated chemical entities, as defined.
  • A can be a halogen, such as chlorine or bromine
  • A can be, but is not limited to, chlorine or bromine.
  • Chemical entities of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein.
  • alkyl used alone or as part of a larger moiety, means a substituted or unsubstituted, linear or branched, univalent hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation.
  • alkyl groups contain 1 to 7 carbon atoms ("Ci-Cy alkyl”). In some embodiments, alkyl groups contain 1 to 6 carbon atoms ("Ci-Q alkyl”). In some embodiments, alkyl groups contain 1 to 5 carbon atoms ("Ci-Cs alkyl”). In some embodiments, alkyl groups contain 1 to 4 carbon atoms (“Ci-C 4 alkyl”). In some embodiments, alkyl groups contain 3 to 7 carbon atoms (“C 3 -C 7 alkyl”).
  • saturated alkyl groups include methyl, ethyl, n- propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more carbon- carbon double bonds or carbon-carbon triple bonds.
  • Examples of unsaturated alkyl groups include allyl, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the like.
  • the term "lower alkyl” refers to alkyl groups having 1 to 4 (if saturated) or 2 to 4 (if unsaturated) carbon atoms.
  • Exemplary lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl and the like.
  • alkenyl refers to alkyl groups having at least two carbon atoms and at least one carbon-carbon double bond.
  • alkynyl refers to alkyl groups having at least two carbon atoms and at least one carbon-carbon triple bond.
  • cycloalkyl used alone or as part of a larger moiety, e.g., "(cycloalkyl)alkyl”, refers to a univalent monocyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic; or bicyclo[2.2.1]heptanyl (also called norbornyl) or bicyclo[2.2.2]octanyl.
  • cycloalkyl groups contain 3 to 8 ring carbon atoms ("C 3 -C 8 cycloalkyl").
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like, as well as bicyclo[2.2.1]heptanyl and bicyclo[2.2.2]octanyl.
  • alkoxy used alone or as part of a larger moiety, refers to the group -O-alkyl.
  • halogen or halo
  • aryl used alone or as part of a larger moiety, e.g., "(aryl)alkyl” refers to a univalent monocyclic or bicyclic carbocyclic aromatic ring system. Unless otherwise specified, aryl groups contain 6 or 10 ring members. Examples of aryl include phenyl, naphthyl, and the like.
  • heteroaryl used alone or as part of a larger moiety, e.g., "(heteroaryl)alkyl”, refers to a univalent monocyclic or bicyclic group having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms, having 6, 10, or 14 ⁇ electrons shared in a cyclic array, and having, in addition to ring carbon atoms, from one to four ring heteroatoms.
  • heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and the like.
  • heterocyclyl used alone or as part of a larger moiety, e.g., "(heterocyclyl)alkyl”, refers to a univalent stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to ring carbon atoms, one to four heteroatoms.
  • heterocycyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, and the like.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci_4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement hydrogen, carbon, nitrogen, oxygen, chlorine or fluorine with 2 H, 3 H, n C, 13 C, 14 C, 1 3 N, 15 N, 17 0, 18 0, 36 CI or 18 F, respectively, are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • incorporation of heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase in vivo half-life, or reduced dosage requirements.
  • the present invention provides chemical entities of Formula (I):
  • R 1 and Z are as described above.
  • R 1 is optionally substituted alkyl.
  • R 1 is optionally substituted cycloalkyl or optionally substituted (cycloalkyl)alkyl. In some embodiments, R 1 is optionally substituted cycloalkyl. In some embodiments, R 1 is optionally substituted cyclohexyl. In some embodiments, R 1 is cyclohexyl. In some embodiments, R 1 is 4,4-difluorocyclohexyl. In some embodiments, R 1 is 4,4-dimethyl- cyclohexyl. In some embodiments, R 1 is 4-methylcyclohexyl. In some embodiments, R 1 is 4-ethyl- cyclohexyl.
  • R 1 is 4-cyclopropylcyclohexyl. In some embodiments, R 1 is optionally substituted norbornanyl. In some embodiments, R 1 is optionally substituted (cycloalkyl)alkyl. In some embodiments, R 1 is bicyclo[2.2.1]heptan-2-ylmethyl. In some embodiments, R 1 is optionally substituted cyclohexylmethyl. In some embodiments, R 1 is cyclohexylmethyl. In some embodiments, R 1 is (4,4-dimethylcyclohexyl)methyl. In some embodiments, R 1 is (4,4-difluorocyclohexyl)methyl.
  • R 1 is optionally substituted heterocyclyl or optionally substituted (heterocyclyl)alkyl. In some embodiments, R 1 is optionally substituted heterocyclyl. In some embodiments, R 1 is optionally substituted tetrahydropyranyl. In some embodiments, R 1 is tetrahydropyran-4-yl. In some embodiments, R 1 is optionally substituted (heterocyclyl)alkyl. In some embodiments, R 1 is optionally substituted tetrahydropyranylmethyl. In some embodiments, R 1 is tetrahydropyran-4-ylmethyl.
  • R 1 is optionally substituted aryl or optionally substituted (aryl)alkyl. In some embodiments, R 1 is optionally substituted (aryl)alkyl. In some embodiments, R 1 is optionally substituted benzyl. In some embodiments, R 1 is 4-methylbenzyl. In some embodiments, R 1 is 4- ethylbenzyl. In some embodiments, R 1 is 4-isopropylbenzyl. In some embodiments, R 1 is 4-(2,2,2-tri- fluoroethyl)benzyl. In some embodiments, R 1 is 4-(l,l-difluoroethyl)benzyl. In some embodiments, R 1 is 4-t-butylbenzyl.
  • R 1 is 4-chlorobenzyl. In some embodiments, R 1 is 4- fluorobenzyl. In some embodiments, R 1 is 4-difluoromethylbenzyl. In some embodiments, R 1 is 4- trifluoromethylbenzyl. In some embodiments, R 1 is 4-difluoromethoxybenzyl. In some embodiments, R 1 is 4-trifluoromethoxybenzyl. In some embodiments, R 1 is 4-methylthiobenzyl. In some embodiments, R 1 is 4-ethylthiobenzyl. In some embodiments, R 1 is 4-methylsulfonylbenzyl. In some embodiments R 1 is 4-ethylsulfonylbenzyl. In some embodiments, R 1 is 4-trifluoromethyl- sulfonylbenzyl.
  • R 1 is optionally substituted heteroaryl or optionally substituted (heteroaryl)alkyl. In some embodiments, R 1 is optionally substituted (heteroaryl)alkyl. In some embodiments, R 1 is optionally substituted (pyridin-2-yl)methyl. In some embodiments, R 1 is optionally (5-chloro-pyridin-2-yl)methyl. In some embodiments, R 1 is optionally (5-methyl-pyridin-2- yl)methyl. In some embodiments, R 1 is optionally substituted (pyridin-3-yl)methyl. In some embodiments, R 1 is (5-methyl-pyridin-3-yl)methyl.
  • Z is 9-membered optionally substituted bicyclic heteroaromatic ring system having ring carbon atoms, 1 nitrogen ring atom and 0-3 additional ring heteroatoms independently selected from N, O and S.
  • Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms, 1 nitrogen ring heteroatom and 1 oxygen ring heteroatom.
  • Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 2 nitrogen ring heteroatoms.
  • Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 3 nitrogen ring heteroatoms.
  • Z is a 9-membered optionally substituted bicyclic heteraromatic ring system having ring carbon atoms and 4 nitrogen ring heteroatoms.
  • Z is a 9-membered optionally substituted bicyclic ring system in which two adjacent atoms on a 6-membered heteroaryl are linked to form a 5-membered heterocycle.
  • Z is a 9-membered optionally substituted bicyclic ring system in which two adjacent atoms on a 6-membered heteroaryl having 1 ring nitrogen atom are linked to form a 5- membered heterocycle having 1 oxygen ring atom.
  • Z is a 9-membered optionally substituted bicyclic ring system in which two adjacent atoms on a 5-membered heteroaryl are linked to form a 6-membered heterocycle.
  • Z is a 9-membered optionally substituted bicyclic ring system in which two adjacent atoms on a 5-membered heteroaryl having 2 or 3 ring nitrogen atoms are linked to form a 6-membered heterocycle having 1 nitrogen ring atom and 1 additional ring heteroatom selected from N and O.
  • Z is one of Formulas Z1-Z33, wherein Z is optionally substituted with 1 or 2 x groups, wherein each R x is attached to a ring carbon atom:
  • each instance of R x independently is -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -OH, -OCH 3 , -OCF 3 or
  • R b is Ci -4 alkyl, C 3 . 4 cycloalkyl, -C(0)-Ci -4 alkyl, -C(0)0-C 1 alkyl or -S(0) 2 -Ci -4 alkyl;
  • R a is Ci_ 4 alkyl, C 3 . 4 cycloalkyl or -S(0) 2 -Ci_ 4 alkyl.
  • Z is Zl, 12, 13, Z4, 15, 16, 17, 111, 112, 113, Z14, Z15, Z16, Z17, Z19, 120, 121, 122, 123, Z24, Z25, Z26, Z27, Z28, Z29 or 130.
  • Z is Z17. In some embodiments, Z is Zll, Z12, Z23 or Z28. In some embodiments, Z is Z3, Z4, 16, 113, 115, 116, 119, 120, 121, 122, Z24, Z25, Z27, Z29 or Z30. In some embodiments, Z is Zl, Z2, 15, 17, 114 or Z26.
  • Z is Z18. In some embodiments, Z is Z8, Z9, Z10, Z31, Z32 or Z33.
  • Z is Zl, Z2, Z3, 15, 16, 17, 125 or Z26. In some embodiments, Z is Zl or Z2.
  • Z is Zl. In some embodiments, Z is Z2.
  • each instance of R x independently is -F, -CI, -CH 3 , -CF 3 or -CN. In some embodiments, each instance of R x independently is -CH 3 or -CF 3 .
  • R a is -CH 3 .
  • R b is -CH 3 .
  • a chemical entity of Formula (I) is a chemical entity of Formula (I I):
  • R 5 , R 6 and R 7 independently are -H, -F, -CI, C1-C4 alkyl, cyclopropyl, -C ⁇ CH, -CFH 2 , -CF 2 H, -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , C1-C4 alkoxy, -OCFH 2 , -OCF 2 H, -OCF3, -CN, -N( 2 )( 3 ), -N0 2 , C1-C4 alkylthio, Ci-C 4 alkylsulfonyl or -S(0) 2 CF 3 ; wherein each instance of R 2 and R 3 independently is -H or C1-C4 alkyl, or
  • Z is selected from formulas Z1-Z33, wherein: R x , R a and R b are as described in embodiments of formulas Z1-Z33, supra, or described in embodiments herein, both singly and in combination.
  • a provided chemical entity is a chemical entity of Formula (II), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, tert- butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 .
  • a provided chemical entity is a chemical entity of Formula (II), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH.
  • a provided chemical entity is a chemical entity of Formula (II), wherein:
  • R 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 .
  • a provided chemical entity is a chemical entity of Formula (II), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, tert- butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 ; and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26.
  • Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2. [052] in some embodiments, a provided chemical entity is a chemical entity of Formula (II), wherein each of 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Z is Zl. In some embodiments, Z is Z2.
  • a provided chemical entity is a chemical entity of Formula (II), wherein:
  • R 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 ;
  • Z is Zl, Z2, Z3, Z5, Z6, 11, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a chemical entity of Formula (II) is a chemical entity of Formula (Ila):
  • -C 4 alkyl cyclopropyl, -C ⁇ CH, -CFH 2 , -CF 2 H, -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , C C 4 alkoxy, -OCFH 2 , -OCF 2 H, -OCF 3 , -CN, -N(R 2 )(R 3 ), -N0 2 , Ci-C 4 alkylthio, Ci-C 4 alkylsulfonyl or -S(0) 2 CF 3 ; whe H or C1-C4 alkyl, or [055] Designation of the cis configuration indicates that the cis isomer is present in greater amount than the corresponding trans isomer.
  • the cis isomer can be present in a diastereomeric excess of 50%, 60%, 70%, 80%, 85%, 90%, 92%, 94%, 96% or 98% relative to the trans isomer.
  • Z is selected from formulas Z1-Z33, wherein: R x , R a and R b are as described in embodiments of formulas Z1-Z33, supra, or described in embodiments herein, both singly and in combination.
  • a provided chemical entity is a chemical entity of Formula (lla), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, tert- butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 .
  • a provided chemical entity is a chemical entity of Formula (lla), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH.
  • a provided chemical entity is a chemical entity of Formula (lla), wherein:
  • R 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 .
  • a provided chemical entity is a chemical entity of Formula (lla), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, tert- butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 ; and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a provided chemical entity is a chemical entity of Formula (lla), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl.
  • a provided chemical entity is a chemical entity of Formula (lla), wherein: 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 ;
  • Z is Zl, 12, 13, 15, 16, 17, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a chemical entity of Formula (lla) is a chemical entity of Formula (lla-1):
  • R 5 , R 6 and R 7 independently are -H, -F, -CI, Ci-C 4 alkyl, cyclopropyl, -C ⁇ CH, -CFH 2 , -CF 2 H, -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , C1-C4 alkoxy, -OCFH 2 , -OCF 2 H, -OCF 3 , -CN, -N(R 2 )(R 3 ), -N0 2 , C C 4 alkylthio, C ⁇ alkylsulfonyl or -S(0) 2 CF 3 ; wherein each instance of R 2 and R 3 independently is -H or C ! -C 4 alkyl,
  • Designation of the (3S,4 ?) configuration indicates that the (3S,4 ?) isomer is present in greater amount than the corresponding (3 ?,4S) isomer.
  • the (3S,4 ?) isomer can be present in an enanteomeric excess of 50%, 60%, 70%, 80%, 85%, 90%, 92%, 94%, 96% or 98% relative to the (3 ?,4S) isomer.
  • Z is selected from formulas Z1-Z33, wherein: R x , R a and R b are as described in embodiments of formulas Z1-Z33, supra, or described in embodiments herein, both singly and in combination.
  • a provided chemical entity is a chemical entity of Formula (lla-1), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, ferf-butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 .
  • a provided chemical entity is a chemical entity of Formula (lla-1), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH.
  • a provided chemical entity is a chemical entity of Formula (lla-1), wherein:
  • R 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 .
  • a provided chemical entity is a chemical entity of Formula (lla-1), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, ferf-butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 ; and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a provided chemical entity is a chemical entity of Formula (lla-1), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl.
  • a provided chemical entity is a chemical entity of Formula (lla-1), wherein: 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 ;
  • Z is Zl, 12, 13, 15, 16, 17, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a chemical entity of Formula (lla) is a chemical entity of Formula (lla-2):
  • R 5 , R 6 and R 7 independently are -H, -F, -CI, Ci-C 4 alkyl, cyclopropyl, -C ⁇ CH, -CFH 2 , -CF 2 H, -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , C1-C4 alkoxy, -OCFH 2 , -OCF 2 H, -OCF 3 , -CN, -N(R 2 )(R 3 ), -N0 2 , C C 4 alkylthio, C ⁇ alkylsulfonyl or -S(0) 2 CF 3 ; whe H or C1-C4 alkyl, or
  • Designation of the (3 ?,4S) configuration indicates that the (3 ?,4S) isomer is present in greater amount than the corresponding (3S,4 ?) isomer.
  • the (3 ?,4S) isomer can be present in an enanteomeric excess of 50%, 60%, 70%, 80%, 85%, 90%, 92%, 94%, 96% or 98% relative to the (3S,4R) isomer.
  • Z is selected from formulas Z1-Z33, wherein: R x , R a and R b are as described in embodiments of formulas Z1-Z33, supra, or described in embodiments herein, both singly and in combination.
  • a provided chemical entity is a chemical entity of Formula (lla-2), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, ferf-butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 .
  • a provided chemical entity is a chemical entity of Formula (lla-2), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH.
  • a provided chemical entity is a chemical entity of Formula (lla-2), wherein:
  • R 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 .
  • a provided chemical entity is a chemical entity of Formula (lla-2), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, ferf-butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 ; and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a provided chemical entity is a chemical entity of Formula (lla-2), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl.
  • a provided chemical entity is a chemical entity of Formula (lla-2), wherein: 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 ;
  • Z is Zl, Z2, Z3, Z5, Z6, 11, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a chemical entity of Formula (II) is a chemical entity of Formula (lib):
  • R 5 , R 6 and R 7 independently are -H, -F, -CI, Ci-C 4 alkyl, cyclopropyl, -C ⁇ CH, -CFH 2 , -CF 2 H, -CF 3 , -CF 2 CH 3 , -CH 2 CF 3 , alkoxy, -OCFH 2 , -OCF 2 H, -OCF 3 , -CN, -N(R 2 )(R 3 ), -N0 2 , Ci-C 4 alkylthio, Ci-C 4 alkylsulfonyl or -S(0) 2 CF 3 ; whe H or C1-C4 alkyl, or
  • Z is selected from formulas Z1-Z33, wherein: R x , R a and R b are as described in embodiments of formulas Z1-Z33, supra, or described in embodiments herein, both singly and in combination.
  • a provided chemical entity is a chemical entity of Formula (lib), wherein each of 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, tert- butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 .
  • a provided chemical entity is a chemical entity of Formula (lib), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH.
  • a provided chemical entity is a chemical entity of Formula (Mb), wherein:
  • R 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H,
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 .
  • a provided chemical entity is a chemical entity of Formula (lib), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , isopropyl, tert- butyl, cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -SCH 2 CH 3 , -S(0) 2 CH 3 , -S(0) 2 CH 2 CH 3 or -S(0) 2 CF 3 ; and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a provided chemical entity is a chemical entity of Formula (lib), wherein each of R 5 , R 6 and R 7 independently is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH and Z is Zl, Z2, Z3, Z5, Z6, Z7, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • a provided chemical entity is a chemical entity of Formula (Mb), wherein: 5 is -H, -F, -CI, -CH 3 , -CFH 2 , -CF 2 H, -CF 3 , -CH 2 CH 3 , -CF 2 CH 3 , -CH 2 CF 3 , cyclopropyl, -OCF 3 , -OCF 2 H, -SCH 3 , -S(0) 2 CH 3 or -C ⁇ CH;
  • R 6 is -H or -F
  • R 7 is -H, -F, -CI or -CH 3 ;
  • Z is Zl, 12, 13, 15, 16, 17, Z25 or Z26. In some embodiments, Z is Zl or Z2. In some embodiments, Z is Zl. In some embodiments, Z is Z2.
  • Glutamate is a fundamental excitatory neurotransmitter in the mammalian brain and central nervous system (CNS). The effects of this endogenous neurotransmitter are mediated through binding to and activation of GLU to glutamate receptors (GLURs), which are broadly classified into metabotropic G-protein coupled (mGluRs) and ligand gated ion channels or ionotropic GluRs.
  • GLURs glutamate receptors
  • the ionotropic GLURs are pharmacologically classified into three main types based on the actions of selective receptor agonists: NMDA (N-methyl D-aspartate selective), KA (kainic acid selective) and AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors whose structure and pharmacological function has been recently reviewed in detail (S. F. Traynelis et al. Pharmacology Reviews, 2010, 62, 405-496). Electrophysiology studies have demonstrated NMDARs to be cation ion channels that are subject to voltage-dependent channel block by endogenous Mg 2+ .
  • NMDARs Activation of NMDARs by glutamate in the presence of glycine as a co-agonist results in opening of the receptor ion channel. This in turn allows for the flow of Na + and Ca 2+ into the cell generating excitatory postsynaptic potentials (EPSPs) and Ca 2+ activated second messenger signaling pathways in neurons. By virtue of their permeability to Ca 2+ , activation of NMDA receptors regulates long-term changes in neuronal communication such as learning and memory and synaptic plasticity. [091] Since the original pharmacological characterization with selective ligands, molecular biology and cloning studies have enabled detailed characterization of NMDARs at the molecular level (Paoletti et al., 2013, Nat. Rev.
  • NMDARs are heterotetramers comprised of two NR1 subunits and two NR2 subunits.
  • NR1 subunits contain the binding site for the glycine co-agonist while NR2 subunits contain the binding site for glutamate.
  • the existence of multiple splice variants for NR1 and four isoforms of NR2 (NR2A, NR2B, NR2C and NR2D) from different genes results in a diverse molecular array and of NMDARs.
  • the pharmacological and electrophysiological properties of NMDARs vary depending on the particular NR1 isoform and NR2 subtype composition.
  • NR2 subtype isoforms are differentially expressed across cell types and brain regions.
  • compounds that interact selectivity with NR2 subunits can exert specific pharmacological effects in particular brain regions and have potential to treat CNS diseases with a high degree of specificity and selectivity (e.g. vz side effects).
  • vz side effects e.g. vz side effects.
  • the low expression of the NR2B subtype in the cerebellum relative to other brain structures indicated lower motor side effects for this subtype.
  • NMDA receptor antagonism has been extensively investigated for its potential to treat a variety of CNS diseases including stroke, epilepsy, pain, depression Parkinson's Disease and Alzheimer's disease (Paoletti et al., Nat. Rev. Neurosci 14:383-400; Sancora, 2008, Nature Rev. Drug Disc, 7, 426- 437).
  • the NMDA receptor offers a number of pharmacological entry points for developing receptor inhibitors.
  • Direct blockers of the NMDAR ion channel pore represent one family of antagonist compounds for which efficacy could be demonstrated in diverse in vitro and in vivo CNS disease models including, epilepsy, pain and neurodegeneration/stroke.
  • compounds from this class as exemplified by phencyclidine (PCP), MK-801, and ketamine, are generally categorized as unselective across the diversity of NMDA receptor subtypes.
  • ketamine has an essentially immediate onset compared to approximately six weeks required for standard serotonin reuptake inhibitor (SSRI) drug therapy.
  • SSRI serotonin reuptake inhibitor
  • intravenous administration of the drug has shown rapid onset and prolonged efficacy that can be maintained with continued intermittent administrations (Zarate et al., 2006, Arch. Gen. Psychiatry 63, 856-864).
  • ketamine has been shown to be effective in cases of depression resistant to standard drug therapies (Murrough et al., 2013, American J. Psychiatry, 170, 1134-1142) including bipolar depression (Zarate et al. 2012, Biol. Psychiatry, 71, 939-946).
  • ketamine therapy is of limited utility and restricted to acute or intermittent administration.
  • orally active selective NMDA antagonists with reduced side effects are needed that can be administered chronically.
  • Ifenprodil a vasodilator a adrenergic antagonist drug, was determined to have a novel allosteric modulator mechanism of action at the NR2B NMDA receptor subtype (Reynolds et al. 1989, Mol. Pharmacol., 36, 758-765). This new mechanism held promise for a new class of NMDA antagonist drugs having therapeutic efficacy without the limiting side effects of subtype unselective ion channel blockers. Following this discovery, NR2B selective antagonist analogs of ifenprodil (Borza et al., 2006, Current Topics in Medicinal Chemistry, 6, 687-695; Layton et al.
  • CP-101,606 has suboptimal pharmacokinetic properties and requires limiting intravenous administration.
  • a slow intravenous infusion protocol was required for optimal results in the aforementioned antidepressant clinical study (Preskorn et al. 2008, Journal of Clinical Psychopharmacology, 28, 631-637).
  • NR2B antagonists including ones that have been subjected to human studies have been described in a review by K.B. Ruppa et al., Annual Reports in Medicinal Chemistry 2012, 47:89-103). These include MK-0657, (Intl. Appl. Publ. No. WO 2004/108705; U.S. Patent No. 7,592,360), EVT-101 and RGH-896.
  • NR2B selective antagonists are needed, as also noted in K.B. Ruppa et al., Annual Reports in Medicinal Chemistry 2012, 47:89-103.
  • NR2B antagonist compounds which are improved in one or more aspects exemplified by pharmacokinetic, absorption, metabolism, excretion (ADME, e.g., oral activity), improved efficacy, off-target activity, improved therapeutic safety index relative and compatibility with chronic oral therapy.
  • NR2B receptor Provided chemical entities are antagonists of the NR2B receptor and have technical advantages with regard to one or more pharmaceutical drug properties, such as oral bioavailability, pharmacokinetic parameters, ADME properties (e.g., CYP inhibition, metabolite formation), in vivo and/or in vitro pharmacological safety.
  • pharmaceutical drug properties such as oral bioavailability, pharmacokinetic parameters, ADME properties (e.g., CYP inhibition, metabolite formation), in vivo and/or in vitro pharmacological safety.
  • a provided chemical entity has NR2B functional NMDA receptor selectivity versus NR2A ("NR2B selectivity", determined as the ratio NR2A IC 50 /NR2B IC 50 , in which the IC 50 values are measured according to the procedure of Example 2.1) > 400.
  • a provided chemical entity has NR2B selectivity > 300.
  • a provided chemical entity has NR2B selectivity > 200.
  • a provided chemical entity has NR2B selectivity > 100.
  • a provided chemical entity has NR2B selectivity > 50.
  • a provided chemical entity has NR2B selectivity > 20.
  • the invention provides a composition comprising a chemical entity of the invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of chemical entity in compositions of this invention is such that is effective to measurably inhibit NR2B, in a biological sample or in a patient.
  • the amount of chemical entity in compositions of this invention is such that is effective to measurably inhibit NR2B, in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the chemical entity with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers
  • a "pharmaceutically acceptable derivative” means any non-toxic ester, salt of an ester or other derivative of a chemical entity of this invention (e.g., a prodrug) that, upon administration to a recipient, is capable of providing, either directly or indirectly, a chemical entity of this invention or an inhibitorily active metabolite or residue thereof.
  • inhibitors as used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of N 2B.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon a variety of factors, including the host treated and the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • N R2B receptor antagonists [0116] Human therapeutic applications of N R2B receptor antagonists have been summarized in reviews by Traynelis et al. (S. F. Traynelis et al., Pharmacology Reviews, 2010, 62:405-496), Beinat et al. (C. Beinat et al., Current Medicinal Chemistry, 2010, 17:4166-4190) and Mony et al. (L. Mony et al., British J. of Pharmacology, 2009, 157:1301-1317).
  • Antagonism of NR2B can be useful in the treatment of diseases and disorders including depression, pain, Parkinson's disease, Huntington's disease, Alzheimer's disease, cerebral ischaemia, traumatic brain injury, epilepsy and migraine.
  • the activity of a chemical entity utilized in this invention as an antagonist of N R2B or a treatment for a disease or disorder of the central nervous system (CNS) may be assayed in vitro or in vivo.
  • An in vivo assessment of the efficacy of the compounds of the invention may be made using an animal model of a disease or disorder of the CNS, e.g., a rodent or primate model.
  • Cell-based assays may be performed using, e.g., a cell line isolated from a tissue that expresses N R2B, or a cell line that recombinantly expresses NR2B.
  • biochemical or mechanism-based assays e.g., measuring cAM P or cGM P levels, Northern blot, RT-PCR, etc.
  • In vitro assays include assays that determine cell morphology, protein expression, and/or the cytotoxicity, enzyme inhibitory activity, and/or the subsequent functional consequences of treatment of cells with chemical entities of the invention.
  • Alternate in vitro assays quantify the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/target molecule complex and determining the amount of radiolabel bound.
  • inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands.
  • Detailed conditions for assaying a compound utilized in this invention as an antagonist of N 2B are set forth in the Examples below.
  • the aforementioned assays are exemplary and not intended to limit the scope of the invention. A person skilled in the art can appreciate that modifications can be made to conventional assays to develop equivalent assays that obtain the same result.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of a CNS disease or disorder.
  • the chemical entities and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease or disorder associated with NR2B.
  • the chemical entities and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a CNS disease or disorder.
  • the disease or disorder is depression with or without concomitant anxiety disorder, e.g., single episode and recurrent depressive disorder, dysthymic disorder, treatment-resistant depression (T D, i.e., major depressive disorder that has not responded to other drug therapies).
  • the disease or disorder is an acute affective disorder, e.g., selected from bipolar disorders including bipolar I and bipolar II manic disorders.
  • the disease or disorder is pain, e.g., selected from pain states arising from a variety of sources including inflammation, nerve damage, diabetic neuropathy and postherpetic neuralgia.
  • the disease or disorder is associated with intractable, such as migraine, fibromyalgia, and trigeminal neuralgia.
  • the disease or disorder is selected from sleep disorders and their sequelae including insomnia, narcolepsy and idiopathic hypersomnia.
  • the disease or disorder is selected from CNS disorders characterized by neuronal hyperexcitablity, such as epilepsy, convulsions and other seizure disorders.
  • the disease or disorder is Parkinson's disease.
  • the disease or disorder is Huntington's disease.
  • the disease or disorder is cognitive dysfunction associated with disorders including schizophrenia, Alzheimer's disease, fronto-temporal dementia, Pick's disease, Lewy body disease, and other senile dementias (e.g., vascular dementia).
  • disorders including schizophrenia, Alzheimer's disease, fronto-temporal dementia, Pick's disease, Lewy body disease, and other senile dementias (e.g., vascular dementia).
  • the present invention provides a method of treating a disorder described herein, comprising administering a chemical entity of the invention in conjunction with one or more pharmaceutical agents.
  • Suitable pharmaceutical agents that may be used in combination with the chemical entities of the present invention include selective serotonin reuptake inhibitors (SSRIs), e.g., in the treatment of depression; dopamine replacement therapy regimens and dopamine agonists, e.g., in the treatment of Parkinson's disease; typical antipsychotics; atypical antipsychotics; anticonvulsants; stimulants; Alzheimer's disease therapies; anti-migraine agents; and anxiolytic agents.
  • SSRIs selective serotonin reuptake inhibitors
  • Suitable SSRIs include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, vilazodone and zimelidine.
  • Suitable dopamine replacement therapy regimens include replacement of L-DOPA with a DOPA decarboxylase inhibitor such as carbidopa.
  • Suitable dopamine receptor agonists include aplindore, apomorphine, bromocriptine, cabergoline, ciladopa, dihydroergocryptine, lisuride, pardoprunox, pergolide, piribedil, pramipexole, ropinirole and rotigotine.
  • Suitable typical antipsychotics include chlorpromazine, thioridazine, mesoridazine, levomepromazine, loxapine, molindone, perphenazine, thiothixene, trifluoperazine, haloperidol, fluphenazine, droperidol, zuclopenthixol, flupentixol and prochlorperazine.
  • Suitable atypical antipsychotics include amisulpride, aripiprazole, asenapine, blonanserin, clotiapine, clozapine, iloperidone, llurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine, bifeprunox, pimavanserin and vabicaserin.
  • Suitable anticonvulsants include carbamazepine, lamotrigine, topiramate and divalproex.
  • Suitable stimulants include Adderall (amphetamine, dextroamphetamine mixed salts), methylphenidate, dextroamphetamine, dexmethylphenidate and lisdexamfetamine.
  • Suitable Alzheimer's disease therapies include acetylcholinesterase inhibitors such as rivastigmine, donepezil, galanthamine and huperazine; alpha-7 nicotinic agonists such as encenicline; and drugs that reduce ⁇ 42 such as BACE inhibitors, gamma secretase modulators and beta amyloid peptide antibodies.
  • acetylcholinesterase inhibitors such as rivastigmine, donepezil, galanthamine and huperazine
  • alpha-7 nicotinic agonists such as encenicline
  • drugs that reduce ⁇ 42 such as BACE inhibitors, gamma secretase modulators and beta amyloid peptide antibodies.
  • Suitable anti-migraine drugs include ergotamine and 5-HT1D agonist triptans such as sumitriptan.
  • Suitable anxiolytic drugs include benzodiazepine receptor modulators such as diazepam, alprazolam, lorazepam and clonazepam.
  • Suitable agents for use in conjunction with a chemical entity of the invention include memantine and modafinil.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the chemical entities of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the chemical entities and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific chemical entity employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific chemical entity employed; the duration of the treatment; drugs used in combination or coincidental with the specific chemical entity employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the chemical entities of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • 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 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, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of chemical entity release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the chemical entity in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the chemical entities of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active chemical entity.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active chemical entity.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active chemical entity is mixed with at least one inert, pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as
  • 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 sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions that can be used include polymeric substances and waxes.
  • 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 sugar as well as high molecular weight polethylene glycols and the like.
  • the active chemical entities can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active chemical entity may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a chemical entity of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active chemical entity is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of the invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a chemical entity to the body.
  • Such dosage forms can be made by dissolving or dispensing the chemical entity in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the chemical entity across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the chemical entity in a polymer matrix or gel.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a chemical entity of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a chemical entity of Formula (I), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of both, a provided chemical entity and additional therapeutic agent in those compositions which comprise an additional therapeutic agent as described above, that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a provided chemical entity can be administered.
  • compositions which comprise an additional therapeutic agent that additional therapeutic agent and the chemical entity of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 100 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention provides a medicament comprising at least one chemical entity of Formula (I) and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the present invention provides the use of a chemical entity of Formula (I) in the manufacture of a medicament for the treatment of a CNS disease or disorder.
  • LG Br or CI
  • R 1 ' R 1 or Boc leaving group
  • Z is a bicyclic ring system as defined above, and LG is a suitable leaving group for the coupling reaction such chlorine or bromine.
  • the coupling reaction can be conducted as a base-mediated nucleophilic aromatic substitution reaction.
  • the coupling reaction can be conducted as a Buchwald reaction mediated by palladium catalysis.
  • Aromatic substitution coupling reactions can be conducted in suitable protic solvents (e.g., isopropanol, n- butanol) or aprotic solvents (e.g., CH 2 CI 2 , DMF, DMSO, CH 3 CN) solvents at temperatures from ambient to 160 °C, e.g., between 50 °C and 120 °C, with intermediates of formula Z-CI in the presence of a suitable base (e.g., triethylamine, diisopropylethylamine).
  • suitable protic solvents e.g., isopropanol, n- butanol
  • aprotic solvents e.g., CH 2 CI 2 , DMF, DMSO, CH 3 CN
  • Buchwald coupling reactions can be conducted in suitable protic solvents (e.g., n-butanol) or aprotic solvents (e.g., toluene, DMF, DMSO, CH 3 CN) in the presence of a suitable palladium catalyst (e.g., Pd(PPh 3 )) 4 , Brettphos/Brettphos precatalyst) at elevated temperatures from 70 °C to 150 °C, e.g., between 80 °C and 130 °C, with intermediates of formula Z-Br, in the presence of a suitable base (e.g., Cs 2 C0 3 ) under inert atmosphere (e.g., nitrogen).
  • suitable protic solvents e.g., n-butanol
  • aprotic solvents e.g., toluene, DMF, DMSO, CH 3 CN
  • a suitable palladium catalyst e.g., Pd(PPh 3
  • compounds of formula XII are compounds of the invention of formula I.
  • R 1 R 1
  • intermediate compounds of formula XII can be converted to intermediate compounds of formula XIII using deprotection conditions known in the art.
  • R 1 is a t-butyloxycarbonyl (Boc) protecting group
  • intermediate compounds of formula XII can be converted to intermediate compounds of formula XIII using a number of known methods.
  • Boc deprotection is conducted under acidic conditions using either HCI (e.g., 1-4N HCI in ether or dioxane) in a suitable organic solvent (e.g., dichloromethane, methanol or THF) at a temperature between 0 and 50 °C, or using trifluoroacetic acid in an aprotic solvent (e.g,. dichloromethane) at a temperature between 0 °C and room temperature.
  • HCI e.g., 1-4N HCI in ether or dioxane
  • a suitable organic solvent e.g., dichloromethane, methanol or THF
  • trifluoroacetic acid e.g,. dichloromethane
  • aprotic solvent e.g,. dichloromethane
  • Intermediate compounds of formula XIII can be can be converted by one skilled in the art to compounds of the invention of formula I by carbamoylation reaction with a carbamoylating reagent of general Formula R ⁇ CfOjX wherein X is a suitable leaving group (e.g., CI, imidazolyl, hydroxysuccinyl).
  • X is a suitable leaving group (e.g., CI, imidazolyl, hydroxysuccinyl).
  • Reagents of general Formula R ⁇ CfOjX can be implemented in pure isolated form or generated in situ.
  • an alcohol of formula R ⁇ H can be treated with carbonyldiimidazole in an aprotic organic solvent at between 0 °C and room temperature to first form the R ⁇ CiOjimidazolyl carbamoylating reagent.
  • XIV cis (XIV-c/s) or trans (XlV-trans) diastereomeric form as also described by Koudih (Koudih et al. Eur. J. Med. Chem. 2012, 53, 408-415).
  • XIV-c/s cis
  • XlV-trans trans diastereomeric form
  • Koudih Koudih et al. Eur. J. Med. Chem. 2012, 53, 408-415
  • Suitable leaving groups include sulfonyl leaving groups (e.g., mesylate, triflate, tosylate and nosylate) as well as halide leaving groups (e.g., chloride, bromide and iodide).
  • sulfonates of formula XV may be prepared by treatment of XIV with an appropriate sulfonylchloride (e.g., methanesulfonylchloride as described by Koudih et al.) in a suitable aprotic organic solvent (e.g., dichloromethane, toluene, THF) in the presence of a tertiary amine base (e.g., trimethylamine or diisopropylethylamine) at temperatures from -30 °C to room temperature.
  • an appropriate sulfonylchloride e.g., methanesulfonylchloride as described by Koudih et al.
  • a suitable aprotic organic solvent e.g., dichloromethane, toluene, THF
  • a tertiary amine base e.g., trimethylamine or diisopropylethylamine
  • XlVa XVa e.g., OS0 2 CH 3 , OSO
  • amino group or an amino equivalent group e.g., for an azide amino equivalent group (AE), sodium azide, DMF solvent with heating up to 90 °C, e.g., for direct amine formation, aqueous ammonium hydroxide in a miscible aprotic organic solvent e.g., acetonitrile with heating as needed;
  • conversion of amino equivalent group to an amino group e.g., by catalytic hydrogenation of an azido group with 5% Pd/C in an organic solvent such as ethanol 2]
  • Examples of such amino group equivalents include azido and phthalimido groups.
  • Such amino group equivalents may be introduced by reacting intermediates of formula XV under conditions established in the art.
  • compounds of formula XVI wherein the amine equivalent is an azido group may be prepared by reacting intermediates of formula XV with sodium azide in an aprotic organic solvent (e.g., dimethylformamide) at temperatures ranging from room temperature to 80 °C.
  • aprotic organic solvent e.g., dimethylformamide
  • Compounds of formula XVI wherein the amine equivalent is a phthalimido group can be prepared by standard Gabriel reaction using potassium phthalimide in a suitable solvent at temperatures ranging from room temperature to 120 °C.
  • unmasking the amino group in compounds of formula XVI under known conditions in the art gives the compounds of formula X.
  • compounds of formula XVI wherein the amine equivalent is azide may be unmasked by hydrogenation reaction in an organic solvent in the presence of a 5% palladium on carbon catalyst at room temperature.
  • Phthalimido groups may be unmasked under conditions standard in the art e.g by hydrazinolysis reaction in ethanolic solvent to give compounds of formula X.
  • XW-trans X-trans 3 The individual cis or trans diastereomers of compounds of formula X can be prepared from corresponding pure starting material diastereomers.
  • the 1 group is t-butyl for the Boc-protected intermediate Xa
  • the chromatographic separation of a mixture of XlVa- cis I XlVa-trans isomer starting materials has been described (Koudih et al. Eur. J. Med. Chem. 2012, 53, 408-415).
  • the individual cis or trans diasteromers of compounds of formula I, l-c/s and ⁇ -trans can be prepared from corresponding pure X-c/s and X-trans diastereomers using the methods described above and generally represented in Scheme 3.
  • the individual enantiomers of l-c/s and ⁇ -trans racemic mixtures can be prepared by chiral HPLC or other chiral chromatography separation methods known in the art.
  • the individual (3S,4/?)-l-c/s and (3/?,4S)-l-c/s enantiomers and (3S,4S)- ⁇ -trans and (3R,4R)- ⁇ -trans enantiomers of the invention can be prepared from the respective l-c/s and ⁇ -trans racemic mixtures.
  • pure enantiomers of compounds of formula I of the invention can be prepared by using starting materials or intermediates in the methods described above which have sufficiently high chiral purity with respect to the two stereocenters.
  • enantiomer intermediates such as X (e.g., (3S,4/?)-X) and XIV (e.g., (3S,4/?)-XIV) can be implemented in the methods described above to yield enantiomers of formula I (e.g., (3S,4/?)-l).
  • enantiomer intermediates can be prepared by resolution methods or by chiral or asymmetric synthesis methods known in the art.
  • racemic cis or trans intermediate diastereomers of formula X can be resolved into the individual enantiomers by chiral acid addition salt formation and recrystallization (e.g., using a chirally pure tartaric acid) or by formation of an amide with a chiral acid (e.g., an amino acid) followed by standard separation (e.g., by chromatography or recrystallization) and hydrolysis of the of the amide to yield individual enantiomers of formula X.
  • Enantiomer intermediates can also be prepared by asymmetric synthesis. For example the asymmetric hydrogenation of the intermediate XX with chiral catalysts has been described by Krska et. al (Krska S. W.
  • the individual (3/?,4S)-l-c/s enantiomers can be prepared by methods analogous to the above starting from the (3/?,4S)-XXI intermediate prepared by asymmetric hydrogenation of XX using the enantiomeric (S)-(-)-l-[(S)-2-(2'-(diphenylphosphino)phenyl]ferrocenylethyldicyclohexylphosphine (CA number 849925-19-5, available from Solvias as Walphos # SL-W003-2) as the chiral ligand in the hydrogenation catalyst system.
  • a multistep synthesis of intermediate XX has also been described by Krska et al. (Krska W. W. et al Tetrahedron 2009, 65, 8987-8994).
  • the heteroaryl chloride or bromide coupling reagents Z-LG are either commercially available, can be prepared according to known literature procedures for the exact compound or can be prepared using methods known in the art for synthesizing heteroaryl chlorides and bromides.
  • the unsubstituted heteroaryl compound Z can be brominated or chlorinated using methods known in the art (e.g., by treatment with bromine or N-bromosuccinimide or another brominating reagent, or treatment with a chlorinating reagent such as sulfurylchloride).
  • the desired Z-Br or Z-CI heteroaryl coupling reagent can then be isolated by the appropriate procedure (e.g., by chromatography as needed to separate regioisomers).
  • Heteroaryl coupling reagents Z-CI wherein the chloro group is part of an iminochloride substructure can be prepared under standard conditions (e.g., using phosphorus oxychloride at elevated temperature as solvent itself or in a suitable aprotic organic solvent) from the corresponding Z-OH starting material which has the corresponding amido tautomeric substructure.
  • Other heteroaryl coupling reagents can be prepared from the corresponding Z-NH 2 starting material under Sandmeyer reaction type conditions which are well established in the art (i.e., diazotization reaction followed by chlorination or bromination with CuCI or CuBr).
  • the appropriate Z, Z-OH or Z-NH 2 starting materials can be prepared using methods known in the art for synthesizing heteroaryl compounds.
  • a "pure" material is one sufficiently pure for its intended purpose.
  • a diastereomerically pure material means that the desired diastereomer is in a diastereomeric excess of 60%, 70%, 80%, 85%, 90%, 92%, 94%, 96% or 98% relative to the undesired diastereomer(s).
  • an enantiomerically pure or chirally pure material means that the desired enantiomer is in an enantiomeric excess of 60%, 70%, 80%, 85%, 90%, 92%, 94%, 96% or 98% relative to the undesired enantiomer.
  • chemical entities are prepared according to the following procedures. It will be appreciated that, although the general methods depict the synthesis of certain chemical entities of the present invention, the following methods, and other methods known to persons skilled in the art, can be applied to all chemical entities and subclasses and species of each of these chemical entities, as described herein.
  • reaction mixture was then warmed to -10 °C, and H 2 0 (1.1 Kg, 62 mol) was added.
  • Sodium borohydride (234 g, 6.18 mol) was then added in two portions over several minutes at 0 °C with stirring.
  • 6 M HCI (5.6 L) was added over 1 h while maintaining the reaction quenching temperature between 0-25 °C.
  • the reaction mixture was then heated to 40 °C and stirred at this temperature overnight.
  • 6 M NaOH was then slowly added at 0-15 °C to adjust the pH to 12.
  • the aqueous layer was extracted with isopropylacetate (500 m L x 1, 1 L x 3).
  • Step 1 (3S, 4 ?)-tert-butyl 3-fluoro-4-(hydroxymethyl)piperidine-l-carboxylate
  • Step 2 (3S,4 ?)-tert-butyl 3-fluoro-4-((methylsulfonyloxy)methyl)-piperidine-l-carboxylate
  • Step 3 (3S, 4 ?)-tert-butyl 4-(azidomethyl)-3-fluoropiperidine-l-carboxylate
  • Step 4 (3S,4 ?)-tert-butyl 4-(aminomethyl)-3-fluoropiperidine-l-carboxylate
  • Step 2 N-(((3S,4 ?)-3-fluoropiperidin-4-yl)methyl)-[l,2,4]triazolo[4,3-a]pyrazin-5-amine
  • EXAMPLE 1.4a (3S,4 ?)-4-chlorobenzyl 4-(([l,2,4]triazolo[4,3-o]pyrazin-8-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate methanesulfonate (El-1.3a).
  • EXAMPLE 1.5a (3S,4 ?)-4-fluorobenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-8-ylamino)methyl)-3- fluoropiperidine-l-carboxylate methylsulfonate (El-1.4a).
  • Step 2 (4-(difluoromethyl)phenyl)methanol
  • a solution of methyl 4-(difluoromethyl)benzoate (1.00 g, 5.37 mmol) in THF (dried) was added dropwise to a stirred suspension of LiAIH 4 in dry THF (25 mL) at 0 °C under N 2 atmosphere.
  • the reaction mixture was stirred for 1 h, then quenched by addition of Na 2 SO 4 .10H 2 O under ice-water bath cooling.
  • the mixture was stirred at rt for 30 min and filtered through celite. The filter mass was washed with EtOAc.
  • EXAMPLE 1.12a (3S,4 ?)-4-ethyl benzyl 4-(([l,2,4]triazolo[4,3-o]pyrazin-5-ylamino)methyl)-3- fluoropiperidine-l-carboxylate mesylate (El-2.5a).
  • Step 2 (3S,4/?)-2-fluoro-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-o]pyrazin-5-ylamino)-methyl)-3- fluoropiperidine-l-carboxylate
  • Step 3 (3S,4R)-4-cyclopropylbenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-5-ylamino)-methyl)-3- fluoropiperidine-l-carboxylate
  • EXAMPLE 1.18a (3S,4 ?)-4-cyclopropylbenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-8-ylamino)methyl)-3- fluoropiperidine-l-carboxylate methanesulfonate (El-l.lla).
  • Step 2 (3S,4 ?)-4-chloro-2-fluorobenzyl 4-(([l,2,4]triazolo[4,3-o]pyrazin-5-ylamino)-methyl)-3- fluoropiperidine-l-carboxylate
  • EXAM PLE 1.20a (3S,4 ?)-4-ethyl benzyl 4-(([l,2,4]triazolo[4,3-o]pyridin-3-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate methanesulfonate (El-6.5a).
  • Step 1 (3S,4/?)-ferf-butyl 3-fluoro-4-((2-(pyridin-2-yl)hydrazinecarboxamido)methyl) piperidine- 1-carboxylate
  • Step 2 (3S, 4/?)-ferf-butyl 4-(([l,2,4]triazolo[4,3-a]pyridin-3-ylamino)methyl)-3-fluoropiperidine- 1-carboxylate
  • Step 3 N-(((3S, 4 ?)-3-fluoropiperidin-4-yl)methyl)-[l,2,4]triazolo[4,3-o]-pyridin-3-amine
  • Step 4 (3S, 4/?)-4-(difluoromethyl)benzyl 4-(([l,2,4]triazolo[4,3-o]pyridin-3-ylamino)methyl)-3- fluoropiperidine-l-carboxylate
  • Step 1 methyl 4-(l,l-difluoroethyl)benzoate
  • Step 3 (3S,4 ?)-4-(l,l-difluoroethyl)benzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-8-ylamino)-methyl)- 3-fluoropiperidine-l-carboxylate
  • Step 4 (3S,4R)-4-methylbenzyl 3-fluoro-4-((3-(trifluoromethyl)-[l,2,4]-triazolo[4,3-a]pyrazin-8- ylamino)methyl)piperidine-l-carboxylate
  • EXAMPLE 1.28a (3 ?,4S)-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-8-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate methanesulfonic acid (E2-1.2a).
  • EXAMPLE 1.30a (3 ?,4 ?)-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-5-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate methanesulfonate (E2-2.2a).
  • Step 1 c/s-4-methylbenzyl 3-fluoro-4-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-d]pyrim- idin-4-ylamino)methyl)piperidine-l-carboxylate
  • Step 2 c/s-4-methylbenzyl 4-((lH-pyrazolo[3,4-d]pyrimidin-4-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate
  • EXAMPLE 1.31a c/s-4-methylbenzyl 4-((lH-pyrazolo[3,4-d]pyrimidin-4-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate methanesulfonate (C-5.1a).
  • Step 2 (3S,4/?)-4-methylbenzyl 3-fluoro-4-((2-(pyridin-2-yl)hydrazinecarboxamido)methyl)- piperidine-l-carboxylate
  • Step 3 (3S,4 ?)-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-o]pyridin-3-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate
  • EXAMPLE 1.33a (3S,4 ?)-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-o]pyridin-3-ylamino)methyl)-3-fluoro- piperidine-l-carboxylate methanesulfonate (El-6.2a).
  • Step 2 (3S,4/?)-3-fluoro-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-8-ylamino)methyl)-3- fluoropiperidine-l-carboxylate
  • EXAMPLE 1.36a (3S,4/?)-3-fluoro-4-methylbenzyl 4-(([l,2,4]triazolo[4,3-a]pyrazin-8-ylamino)-methyl)-3- fluoropiperidine-l-carboxylate methanesulfonate (El-1.28a).
  • Step 3 6-bromo-2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate
  • Step 2 (3S, 4 ?)-4-methylbenzyl-3-fluoro-4-((l-methyl-l/-/-pyrazolo-[3,4-d]pyrimidin-6-ylamino)- methyl)piperidine-l-carboxylate
  • EXAM PLE 1.40a (3S, 4 ?)-4-methylbenzyl 3-fluoro-4-((l-methyl-lH-pyrazolo-[3,4-d]pyrimidin-6-ylamino)- methyl)piperidine-l-carboxylate methanesulfonate (El-19.26a).

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Abstract

L'invention concerne des entités chimiques de formule (I), dans laquelle R1 et Z sont tels que définis dans la description, utilisées comme antagonistes sélectifs du sous-type NR2B des récepteurs. L'invention concerne également des compositions pharmaceutiques comprenant une entité chimique de formule (I), et des méthodes de traitement de diverses maladies et divers troubles associés à l'antagonisme NR2B, par ex., de maladies et troubles du système nerveux central, tels que la dépression, par l'administration d'une entité chimique de formule I.
PCT/US2015/065829 2014-12-16 2015-12-15 Composés azahétérocycliques bicycliques utilisés comme antagonistes des récepteurs nmda nr2b WO2016100349A2 (fr)

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Cited By (6)

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US10221182B2 (en) 2015-02-04 2019-03-05 Rugen Holdings (Cayman) Limited 3,3-difluoro-piperidine derivatives as NR2B NMDA receptor antagonists
US10294230B2 (en) 2015-06-01 2019-05-21 Rugen Holdings (Cayman) Limited 3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists
US10420768B2 (en) 2014-09-15 2019-09-24 Rugen Holdings (Cayman) Limited Pyrrolopyrimidine derivatives as NR2B NMDA receptor antagonists
US11000526B2 (en) 2016-11-22 2021-05-11 Rugen Holdings (Cayman) Limited Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders
CN114213424A (zh) * 2021-12-30 2022-03-22 杭州澳赛诺生物科技有限公司 一种呋喃[3，2-b]并吡啶衍生物的合成方法
US11376258B2 (en) 2019-06-04 2022-07-05 Boehringer Ingelheim International Gmbh Purine derivatives and the use thereof as medicament

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US6476041B1 (en) * 1999-10-29 2002-11-05 Merck & Co., Inc. 1,4 substituted piperidinyl NMDA/NR2B antagonists
DK1379520T3 (da) * 2001-02-23 2006-08-21 Merck & Co Inc N-substituerede ikke-aryl-heterocykliske NMDA/NR2B-antagonister
US7592360B2 (en) * 2003-06-04 2009-09-22 Merck & Co., Inc. 3-fluoro-piperidines as NMDA/NR2B antagonists
WO2007099828A1 (fr) * 2006-02-23 2007-09-07 Shionogi & Co., Ltd. Derives heterocycliques azotes substitues par des groupes cycliques

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US10420768B2 (en) 2014-09-15 2019-09-24 Rugen Holdings (Cayman) Limited Pyrrolopyrimidine derivatives as NR2B NMDA receptor antagonists
US10221182B2 (en) 2015-02-04 2019-03-05 Rugen Holdings (Cayman) Limited 3,3-difluoro-piperidine derivatives as NR2B NMDA receptor antagonists
US10294230B2 (en) 2015-06-01 2019-05-21 Rugen Holdings (Cayman) Limited 3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists
US10584127B2 (en) 2015-06-01 2020-03-10 Rugen Holdings (Cayman) Limited 3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists
US11136328B2 (en) 2015-06-01 2021-10-05 Rugen Holdings (Cayman) Limited 3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists
US11000526B2 (en) 2016-11-22 2021-05-11 Rugen Holdings (Cayman) Limited Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders
US11752155B2 (en) 2016-11-22 2023-09-12 Rugen Holdings (Cayman) Limited Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders
US11376258B2 (en) 2019-06-04 2022-07-05 Boehringer Ingelheim International Gmbh Purine derivatives and the use thereof as medicament
CN114213424A (zh) * 2021-12-30 2022-03-22 杭州澳赛诺生物科技有限公司 一种呋喃[3，2-b]并吡啶衍生物的合成方法

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