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WO2011058478A1 - Substituted triazolopyrimidines as pde8 inhibitors - Google Patents

Substituted triazolopyrimidines as pde8 inhibitors Download PDF

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Publication number
WO2011058478A1
WO2011058478A1 PCT/IB2010/054953 IB2010054953W WO2011058478A1 WO 2011058478 A1 WO2011058478 A1 WO 2011058478A1 IB 2010054953 W IB2010054953 W IB 2010054953W WO 2011058478 A1 WO2011058478 A1 WO 2011058478A1
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WIPO (PCT)
Prior art keywords
methyl
pyrimidin
amine
triazolo
morpholin
Prior art date
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PCT/IB2010/054953
Other languages
French (fr)
Inventor
Michelle Marie Claffey
Michael Paul Deninno
Robin Jean Kleiman
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Pfizer Inc.
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Publication of WO2011058478A1 publication Critical patent/WO2011058478A1/en

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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

Definitions

  • the present invention relates to the treatment of spinal cord injury, cognitive deficits associated with schizophrenia and/or Alzheimer's disease, and other neurodegenerative and/or neurological disorders in mammals, including humans. More particularly, this invention relates to substituted triazolopyrimidine inhibitors of the PDE8 enzyme, useful for the treatment of such disorders.
  • Adenosine and guanosine 3',5'-cyclic monophosphates are the second messengers that mediate the response of cells to a wide variety of hormones and neurotransmitters and modulate many metabolic processes.
  • Phosphodiesterases are the sole enzymes hydrolyzing these cyclic nucleotides and thus play pivotal roles in the physiological processes involving the nucleotide signaling pathway.
  • Phosphodiesterase-8 PDE8 is a family of cAMP-specific enzymes and plays an important role in many biological processes, including T-cell activation, testosterone production, adrenocortical hyperplasia, and thyroid function. See Wang et al., Biochemistry, 2008, 47 (48), 12760-8.
  • the present invention is directed to compounds of Formula I:
  • R is alkyl, haloalkyi, cycloalkyl, heterocycloalkyl, aminoalkyl, aryloxyalkyl, hydroxyalkyl, or alkoxyalkyl, wherein R may be optionally substituted with one or more substituents independently selected from halo, haloalkyi, alkyl, cycloalkyl, hydroxy, amino, and alkoxy;
  • R 2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein R 2 may be optionally substituted with one or more substituents independently selected from halo, haloalkyi, alkyl, cycloalkyl, hydroxy, amino, and alkoxy;
  • R 3 and R 4 are independently hydrogen, alkyl, or haloalkyi; and R 5 is a bond, methylene, or ethylene, wherein said methylene or ethylene may be substituted by a methyl or ethyl substituent;
  • This invention also includes pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites of compounds of Formula I.
  • This invention also includes all tautomers and stereochemical isomers of these compounds.
  • This invention also is directed, in part, to a method for treating a PDE8 mediated disorder in a mammal.
  • Such disorders include spinal cord injury, cognitive deficits associated with schizophrenia and/or Alzheimer's disease, and other neurodegenerative and/or neurological disorders.
  • the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeutically effective to treat the condition.
  • One embodiment of the present invention is a compound of Formula I as described above.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 5 is -(CH 2 ) n -, wherein n is 0, 1 , or 2.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyl, alkyl, cycloalkyl, hydroxy, amino, and alkoxy.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyl, alkyl, cycloalkyl, hydroxy, amino, and alkoxy; and R 4 is hydrogen; provided that when R 2 is oxazolyl, triazolyl, pyrazinyl, thiazolyl
  • R is alkyl, haloalkyi, or cycloalkyl
  • R 2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyi, and alkyl; and R 3 and R 4 are hydrogen.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyi, and alkyl, and wherein said oxazolyl or thiazolyl may be optionally substituted with one or two substituents independently selected from haloalkyi and alkyl.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R is methyl, trifluoromethyl, or cyclopropyl; and R 2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from fluoro, trifluoromethyl, and methyl.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R is methyl, cyclopropyl, or trifluoromethyl; R 2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl, oxazolyl, or thiazolyl may be optionally substituted with one or two substituents independently selected from ethyl, methyl, and trifluoromethyl; and R 3 and R 4 are hydrogen.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is 1 ; R is methyl, cyclopropyl, or trifluoromethyl; R 2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl, oxazolyl, or thiazolyl may be optionally substituted with one or two methyl substituents; and R 3 and R 4 are hydrogen.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from:
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • neurodegenerative disease or disorder the method comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • neurodegenerative disease or disorder the method comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease or disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, Huntington's disease, cognitive impairment associated with Alzheimer's disease, age-related cognitive decline, schizophrenia, or ADHD.
  • the neurodegenerative disease or disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, Huntington's disease, cognitive impairment associated with Alzheimer's disease, age-related cognitive decline, schizophrenia, or ADHD.
  • neurodegenerative disease or disorder the method comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease or disorder is spinal cord injury.
  • R is alkyl, haloalkyl, or cycloalkyi
  • R 2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyl, and alkyl; and R 3 is hydrogen.
  • R is methyl, trifluoromethyl, or cyclopropyl
  • R 2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from fluoro, trifluoromethyl, and methyl; and R 3 is hydrogen.
  • alkyl refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; in one embodiment from one to twelve carbon atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms.
  • substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n- butyl, isobutyl, sec-butyl and ieri-butyl), pentyl, isoamyl, hexyl and the like.
  • cycloalkyi refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule and having three to fourteen carbon atoms. In one embodiment, a cycloalkyi substituent has three to ten carbon atoms. Examples of cycloalkyi include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkyi also includes substituents that are fused to a C 6 -Ci 0 aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyi group as a substituent is bound to a carbon atom of the cycloalkyi group.
  • a fused cycloalkyi group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a carbon atom of the cycloalkyi group.
  • a cycloalkyi may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alternatively, 2 or 3 rings may be fused together, such as bicyclodecanyl and decalinyl.
  • aryl refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms.
  • aryl may refer to
  • aryl also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4 -Ci 0 carbocyclic ring, such as a C 5 - or a C 6 -carbocyclic ring, or to a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group.
  • fused aryl group When such a fused aryl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group.
  • aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, and benzonaphthenyl (also known as “phenalenyl”).
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -C y " or "C x-y ,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -C y or "C x-y ,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • Ci-C 6 alkyl and “Ci_ 6 alkyl” both refer to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C 3 -C 6 cycloalkyl and C 3 . 6 cycloalkyl refer to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.
  • the number of atoms in a cyclic substituent containing one or more heteroatoms is indicated by the prefix "X-Y-membered", wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent.
  • X-Y-membered the prefix "X-Y-membered”
  • x the minimum
  • y the maximum number of atoms forming the cyclic moiety of the substituent.
  • 5-8-membered heterocycloalkyi refers to a heterocycloalkyi containing from 5 to 8 atoms, including one or more heteroatoms, in the cyclic moiety of the heterocycloalkyi.
  • hydroxy refers to -OH.
  • prefix indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents.
  • Compounds bearing a carbon to which one or more hydroxy substituents are attached include, for example, alcohols, enols and phenol.
  • hydroxyalkyl refers to an alkyl that is substituted with at least one hydroxy substituent.
  • examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
  • cyano (also referred to as “nitrile”) means CN.
  • amino refers to NH 2 .
  • alkylamino refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom.
  • alkylamino substituents include monoalkylamino such as methylamino (exemplified by the formula NH(CH 3 )), and dialkylamino such as dimethylamino (exemplified by the formula -N(CH 3 ) 2 ).
  • halogen refers to fluorine (which may be depicted as F), chlorine (which may be depicted as CI), bromine (which may be depicted as Br), or iodine (which may be depicted as I).
  • the halogen is chlorine.
  • the halogen is fluorine.
  • the halogen is bromine.
  • halo indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents.
  • haloalkyl refers to an alkyl that is substituted with at least one halogen substituent. Where more than one hydrogen is replaced with halogens, the halogens may be identical or different.
  • haloalkyls examples include chloromethyl, dichloromethyl, difluorochloromethyl,
  • haloalkoxy refers to an alkoxy that is substituted with at least one halogen substituent. Examples of haloalkoxy substituents include chloromethoxy, 1 - bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as
  • alkoxy refers to an alkyl linked to an oxygen, which may also be represented as -OR, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
  • heterocycloalkyl refers to a substituent obtained by removing a hydrogen from a saturated or partially saturated ring structure containing a total of 4 to 14 ring atoms. At least one of the ring atoms is a heteroatom usually selected from oxygen, nitrogen, or sulfur.
  • a heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur).
  • the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • heterocycloalkyi also includes substituents that are fused to a C6-C 10 aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyi group as a substituent is bound to a heteroatom of the heterocyclocalkyi group or to a carbon atom of the heterocycloalkyi group.
  • a fused heterocycloalkyi group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a heteroatom of the heterocyclocalkyi group or to a carbon atom of the heterocycloalkyi group.
  • heteroaryl refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl substituents include: 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl; 6-/5-membered fused ring substituents such as benzothiofuranyl,
  • the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • heteroaryl also includes pyridyl /V-oxides and groups containing a pyridine /V-oxide ring. Examples of single ring heteroaryls include furanyl, thiophenyl (also known as
  • thiofuranyl pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl [including 1 ,2,4-oxadiazolyl (also known as “azoximyl”), 1 ,2,5-oxadiazolyl (also known as “furazanyl”), or 1 ,3,4-oxadiazolyl], pyridinyl (also known as "azinyl”), diazinyl [including pyridazinyl (also known as “1 ,2-diazinyl”), pyrimidinyl (also known as “1 ,3-diazinyl” or “pyrimidyl”), or pyrazinyl (also known as "1 ,4-diazinyl”)], and triaziny
  • 2-fused-ring heteroaryls examples include indolizinyl, pyrindinyl, purinyl,
  • naphthyridinyl pyridopyridinyl (including pyrido[3,4-£>]-pyridinyl, pyrido[3,2-£>]pyridinyl, or pyrido[4,3-j ]pyridinyl), and pteridinyl, indolyl, isoindolyl, isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, indoxazinyl, anthranilyl, benzoxadiazolyl, benzofuranyl,
  • 3-fused-ring heteroaryls or heterocycloalkyls include 5,6-dihydro-4/-/- imidazo[4,5,1-/y]quinoline, 4,5-dihydroimidazo[4,5,1-ft/]indole, 4,5,6J-tetrahydroimidazo[4,5,1- y ' /c][1]benzazepine, and dibenzofuranyl.
  • fused ring heteroaryls include benzo-fused heteroaryls such as indolyl, isoindolyl (also known as “isobenzazolyl” or “pseudoisoindolyl”), benzazinyl [including quinolinyl (also known as “1 -benzazinyl”) or isoquinolinyl (also known as “2-benzazinyl”)], phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl [including cinnolinyl (also known as “1 ,2- benzodiazinyl”) or quinazolinyl (also known as “1 ,3-benzodiazinyl”)], benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), benzoxadiazolyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzothieny
  • benzothiofuranyl isobenzothienyl (also known as “isobenzothiophenyl,” “isothianaphthenyl,” or “isobenzothiofuranyl”), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl), carbazolyl, and acridinyl.
  • heteroaryl also includes substituents such as pyridyl and quinolinyl that are fused to a C 4 -Ci 0 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group.
  • the one or more substituents are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group.
  • heteroaryls and heterocycloalkyls include: 3-1/-/-benzimidazol-2- one, (1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1 ,3]-dioxalanyl, [1 ,3]-dithiolanyl, [1 ,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4- morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 2-pipe
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-2-yl (C-attached).
  • a non-hydrogen substituent is in the place of a hydrogen attached to a carbon or nitrogen of the substituent.
  • a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated).
  • substituent may be either substituted or not substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent.
  • One exemplary substituent may be depicted as -NR'R", wherein R' and R" together with the nitrogen atom to which they are attached, may form a heterocyclic ring.
  • the heterocyclic ring formed from R' and R" together with the nitrogen atom to which they are attached may be partially or fully saturated.
  • the heterocyclic ring consists of 4 to 7 atoms.
  • the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, and thiazolyl.
  • substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1 ) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents.
  • a substituent is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent may be either (1 ) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • a substituent is described as a heteroaryl optionally substituted with up to 3 non- hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions.
  • tetrazolyl which has only one substitutable position
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.
  • alkylcycloalkyl contains two moieties: alkyl and cycloalkyl.
  • a C C 6 prefix on Ci-C 6 alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C 6 prefix does not describe the cycloalkyi moiety.
  • the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents.
  • each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
  • Form I may be hereinafter referred to as a "compound(s) of the invention.” Such terms are also defined to include all forms of the compound of Formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
  • CDCI 3 Deuterated chloroform
  • the compound may exist in the form of optical isomers (enantiomers).
  • the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of Formula I.
  • the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds.
  • geometric isomers may arise.
  • the present invention comprises the tautomeric forms of compounds of Formula I.
  • tautomeric isomerism 'tautomerism'
  • This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • the various ratios of the tautomers in solid and liquid form are dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound.
  • the compounds of this invention may be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • the salt preferably is pharmaceutically acceptable.
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound of Formula I with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • salts of the compounds of this invention are nontoxic "pharmaceutically acceptable salts.”
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,
  • toluenesulfonate 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, ⁇ -hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate,
  • glycerophosphate heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diethanolamine, glycine, lysine, meglumine, ethanolamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, ⁇ /, ⁇ /'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (/V-methylglucamine), and procaine.
  • secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, ⁇ /, ⁇ /'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (/V-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (Ci-C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
  • agents such as lower alkyl (Ci-C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e.,
  • hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the present invention also includes isotopically labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 3 C, C, 4 C, 5 N, 8 0, 7 0, 3 P, 32 P, 35 S, 8 F, and 36 CI, respectively.
  • Isotopically labeled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the invention also relates to prodrugs of the compounds of Formula I.
  • Certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as "prodrugs”. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series, 1975 (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include:
  • the compound of Formula I contains a primary or secondary amino functionality, or an amide which is functionalized into a suitably metabolically labile group, e.g., a hydrolyzable group (amide, carbamate, urea, phosphonate, sulfonate, etc.) on the compound of Formula I .
  • a suitably metabolically labile group e.g., a hydrolyzable group (amide, carbamate, urea, phosphonate, sulfonate, etc.) on the compound of Formula I .
  • a compound of the invention is administered in an amount effective to treat a condition as described herein.
  • the compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • the compounds of the invention can also be administered intranasally or by inhalation.
  • the compounds of the invention may be administered rectally or vaginally.
  • the compounds of the invention may also be administered directly to the eye or ear.
  • the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg.
  • the total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg body weight). In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient.
  • doses may range from about 0.01 to about 10 mg/kg/min during a constant rate infusion.
  • Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
  • the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment of the conditions recited herein.
  • the compound of the invention can be administered as compound per se.
  • pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
  • the present invention comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier.
  • the carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds.
  • a compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
  • the compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and compositions for example, may be administered orally, rectally, parenterally, or topically.
  • Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of Formula I are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain a controlled-release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art
  • compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • adjuvants such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • the present invention comprises a parenteral dose form.
  • Parenter administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations i.e., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting, and/or suspending agents.
  • Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated; see, for example, Finnin and Morgan, J. Pharm. Sci. , 1999, 88, 955-958.
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable carrier.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • a suitable propellant such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the present invention comprises a rectal dose form.
  • rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman ef a/., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe ef a/., Eds., Handbook of Pharmaceutical Excipients (3 rd Ed.), American Pharmaceutical Association, Washington, 1999.
  • the compounds of the present invention can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states.
  • the compound(s) of the present invention and other therapeutic agent(s) may be may be administered
  • An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist.
  • the administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
  • the two or more compounds may be administered
  • simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of
  • administering and “administered simultaneously” mean that the compounds are administered in combination.
  • kits that are suitable for use in performing the methods of treatment described above.
  • the kit contains a first dosage form comprising one or more of the compounds of the present invention and a container for the dosage, in quantities sufficient to carry out the methods of the present invention.
  • the kit of the present invention comprises one or more compounds of the invention.
  • the invention relates to the novel intermediates useful for preparing the compounds of the invention.
  • the compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art
  • Preferred methods include, but are not limited to, those described below.
  • any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 ; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
  • conventional protecting groups such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 ; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &
  • the compounds of Formula l(c) can be prepared as described in Scheme 1 starting from aminodichloropyrimidines II and amines III. Methods of preparing compounds II and compounds III are outlined later in Schemes 2 and 3. Compounds of Formula IV can be prepared from the corresponding aminodichloropyrimidine II by reacting with racemic or enantiomerically-enriched amines of the formula III.
  • Compounds II and III are combined in the presence of a base, such as diisopropylethylamine, triethylamine or sodium carbonate in a polar solvent such as N- methylpyrrolidinone at a temperature of about 50 °C to about 150 °C, preferably at about 125 °C for about 10 h to about 24 h, or in MeCN at a temperature of 80 °C for up to 36 h to yield compounds IV.
  • a base such as diisopropylethylamine, triethylamine or sodium carbonate
  • a polar solvent such as N- methylpyrrolidinone
  • triazolopyrimidines V are cyclized by treatment with a nitrosylating agent in acidic solution, to yield triazolopyrimidines V.
  • One method of triazole cyclization uses sodium nitrite in a solvent mixture of water, dichloromethane and acetic acid at a temperature of about 0 °C to about 30 °C, typically at ambient temperature for about 1 - 6 hours.
  • another method employs sodium nitrite in MeTHF with the addition of 1 N HCI at ambient temperature for about 1 hour.
  • the resulting chloropyrimidines V can then be reacted with a source of ammonia, such as ammonium hydroxide or anhydrous ammonia dissolved in organic solvents such as methanol, ethanol, THF, MeTHF or dioxane, at a temperature of about 40 °C to about 100 °C, preferably at about 75 °C for about 4 hours to 24 hours and typically in a sealed pressure vessel to provide compounds of formula l(a).
  • a source of ammonia such as ammonium hydroxide or anhydrous ammonia dissolved in organic solvents such as methanol, ethanol, THF, MeTHF or dioxane
  • Formula 1(a) compounds can be debenzylated to provide compounds of Formula 1(b).
  • the reduction is preferably carried out using a palladium catalyst, more preferably palladium hydroxide on carbon, and an acid catalyst, such as hydrochloric acid, sulfuric acid or acetic acid, in a solvent such as methanol, ethanol or MeTHF under between 1 and 4 atmospheres of hydrogen gas, preferably 3 atmospheres, at a temperature from ambient temperature to 50 °C, preferably at ambient temperature for about 2 hours to about 24 hours.
  • a compound of Formula l(b) wherein R is defined above is reacted with a heterocyclic halide in the presence of a base, preferably an amine base such as diisopropylethylamine in a polar solvent such as acetonitrile, 2-propanol or A/,A/-dimethylformamide at a temperature of 40 °C to the reflux temperature of the solvent, preferably at about 75 °C for about 1 -3 days.
  • a base preferably an amine base such as diisopropylethylamine
  • a polar solvent such as acetonitrile, 2-propanol or A/,A/-dimethylformamide
  • a compound of Formula l(b) wherein R is defined above is reacted with a heterocyclic halide in the presence of a palladium catalyst such as Pd 2 (dba) 3 , a phosphine ligand, such as xantphos, or X-Phos, and a base such as cesium carbonate, potassium hydroxide, or sodium ieri-butoxide, in a reaction-inert solvent such as dioxane, ieri-butanol, or ieri-amyl alcohol at a temperature of 50 °C to the boiling point of the solvent, preferably at about 100-1 10 °C for about one to about 24 hours.
  • a palladium catalyst such as Pd 2 (dba) 3
  • a phosphine ligand such as xantphos, or X-Phos
  • a base such as cesium carbonate, potassium hydroxide, or sodium ieri-butoxide
  • a reaction-inert solvent such as dioxan
  • the Formula l(b) compound and aldehyde are combined in a reaction-inert solvent such as dichloroethane, acetonitrile, THF, or MeTHF (or mixtures thereof), followed by the addition of a reducing agent, preferably sodium triacetoxyborohydride, at a temperature of about 0° C to about 50 °C, typically at ambient temperature for about one hour to about 24 hours.
  • a reducing agent preferably sodium triacetoxyborohydride
  • a base may be added to facilitate the reaction, preferably an amine base such as diisopropylethylamine.
  • the same Formula l(c) compounds can be prepared by reacting a Formula l(b) compound with an alkylating agent, such as an aryl alkyi halide or an aryl alkyi mesylate and the like.
  • an alkylating agent such as an aryl alkyi halide or an aryl alkyi mesylate and the like.
  • the Formula l(b) compound is reacted with an alkylating agent in the presence of a base, preferably an amine base such as triethylamine or diisopropylethylamine, in a solvent such as 1 -propanol, A/,/V-dimethylformamide, MeCN, or THF at a temperature of ambient temperature to 100 °C, preferably at about 75 °C for about 1 hour to about 24 hours.
  • the dichloropyrimidines of Formula II wherein R is defined above can be prepared according to Scheme 2 starting from the requisite amidines VI or esters VII.
  • Formula VI amidines can be prepared by numerous methods known to those skilled in the art. For example, the corresponding nitrile can be converted first to the imidate by the treatment of the nitrile with anhydrous hydrochloric acid in ethanol at ambient temperature for 24 hours, followed by the addition of anhydrous ammonia in ethanol at ambient temperature for 24 hours to provide amidines VI.
  • dihydroxypyrimidines of formula VIII Treatment of amidines VI with dimethylmalonate or diethylmalonate under basic conditions, preferably using an alkoxide base such as sodium methoxide, in alcohol solvent, preferably methanol, at ambient temperature for about 12 hours to about 48 hours, can provide dihydroxypyrimidines of formula VIII.
  • dihydroxypyrimidines VIII can be formed by reaction of esters VII with malonamide. Addition of esters VII to a mixture of malonamide and an alkoxide base such as n-butoxide, formed by treatment of n-butanol with sodium hydride, in solvents such as toluene at temperatures around 0 °C, followed by warming to about 40 °C and overnight stirring, can provide dihydroxypyrimidines of Formula VIII.
  • the pyrimidines of Formula VIII can be nitrated to provide nitropyrimidines of Formula
  • Formula VIII compounds are added in portions to a mixture of nitric acid and acetic acid at a temperature of between 20 °C to 30 °C for about 30 minutes to about 4 hours.
  • Formula VIII diols can be dissolved in TFA at ambient temperatures and then fuming nitric acid can be added dropwise, maintaining a temperature below 25 °C followed by overnight stirring to yield nitro compounds IX.
  • the Formula X compounds wherein R is defined above can be prepared from the corresponding Formula IX compounds by reaction with a chlorinating agent.
  • the chlorinating agent is phosphorus oxychloride.
  • the Formula IX compounds can be added to phosphorus oxychloride in the presence of an amine base, preferably an aniline base such as dimethylaniline.
  • an amine base preferably an aniline base such as dimethylaniline.
  • the mixture is heated at a temperature of about 50 °C to about 105 °C, for about one hour to about 6 hours to provide the desired dichloropyrimidines X.
  • a mixture of the Formula IX compounds in phosphorous oxychloride is stirred at ambient temperature and phosphoric acid is added followed by dropwise addition of an amine base such as diisopropylethylamine while maintaining the temperature below 40 °C.
  • an amine base such as diisopropylethylamine
  • the dichloroaminopyrimidines of Formula II can be prepared from the corresponding nitro compounds of formula X by reduction of the nitro group.
  • the reduction is generally carried out by the addition of a transition metal powder, such as iron or tin, to a solution of the Formula X compound in acidic solvent such as acetic acid or aqueous hydrochloric acid.
  • the reduction is performed at a temperature of about ambient temperature to about 75 °C, preferably about 50 °C, for about 2 to 10 hours.
  • the racemic amine of Formula lll(a) where R 4 equals hydrogen can be prepared as reported by S. Kato ef a/., J. Med. C em., 1990, 33, 1406-1413. It is most conveniently prepared from the corresponding Formula XIII nitrile through a reduction reaction.
  • the reduction can be achieved by a variety of reducing agents known to those skilled in the art for reducing nitriles selectively in the presence of /V-benzyl groups. These reducing agents include but are not limited to Raney nickel, lithium aluminum hydride, or Vitride®.
  • the nitrile of Formula XIII where R 4 equals hydrogen can be prepared in one step from 2-chloroacrylonitrile (XI) and 2- benzylaminoethanol XII as described by M. J. Cases-Thomas ef a/., Bioorganic Med. Chem. Lett. 2006, 16, 2022-2025 and F. D. King et ai , J. Med. Chem., 1993, 36, 683-689.
  • the chiral resolution of amine lll(a) where R 4 equals hydrogen can be accomplished as described by N. Sakurai et ai , Bioorganic Med. Chem. Lett., 1998, 8, 2185-2190.
  • reaction conditions length of reaction and temperature
  • reaction conditions may vary. In general, reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate.
  • Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluants/gradients were chosen to provide appropriate R f s or retention times.
  • Cyclopropylcarboxamidine hydrochloride (1) A solution of cyclopropanecarbonitrile (70 g, 1 .04 mol) in ethanol (50 mL) was added to a saturated solution of dry HCI gas in dry ethanol (93 g) along with slight cooling. The resulting mixture was then stirred at RT for 24 h. The thick suspension formed was diluted with ethanol (25 mL) and cooled with an ice-water bath. An ethanolic ammonia solution (103.2 g) was added slowly to the ethanol mixture over ⁇ 30 min. The cooling bath was then removed, and the mixture was stirred at 23 °C for another 24 h.
  • Examples 2-4 were prepared following the procedure for the preparation of (R)-3-((4- benzylmorpholin-2-yl)methyl)-5-cyclopropyl-3/-/-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7-amine (9) in Example 1 but using the appropriate starting materials: 4,6-dichloro-2-cyclopropylpyrimidin-5- amine (5) or 4,6-dichloro-2-methylpyrimidin-5-amine (10), commercially available from Sigma- Aldrich Chemical Company, St. Louis, Mo., and 1 -[4-benzylmorpholin-2-yl]methanamine (6), (6- S), or (6-R).
  • dichloronitropyrimidine 17 (21 .6 g, 82.4 mmol) in AcOH (344 mL) was added iron powder (21.6 g, 388 mmol) portion-wise.
  • the mixture was SLOWLY heated to 50 °C for 75 min and formed a very thick gray/brown sludge. After cooling to RT, the mixture was diluted with ethyl acetate, filtered through Celite and concentrated. The resulting material was dissolved in ethyl acetate, washed with water (3x), brine (2x), dried over MgS0 4 , filtered and concentrated to provide 17.1 g of 18 as a light brown solid.
  • LCMS m/z 230.0 (M+1 ). 9 F NMR (376 MHz, DMSO-d 6 ) ⁇ -67.82 (s, 3 F).
  • Benzyl morpholine 21 (16.6 g, 42.2 mmol) was dissolved in MeTHF (166 imL) in a hydrogenation vessel, charged with 10 % Pd(OH) 2 on carbon (1.66 g, 10 % w/w catalyst load), and placed under a hydrogen atmosphere (50 psi). The reaction mixture was heated to 55 0 C overnight. The catalyst was removed by filtration. The filtrate was concentrated to afford12.7 g of 23 as a light-colored solid.
  • Morpholine 29 (5.58 g, 22.38 mmol) was dissolved in water (0.4 mL), acetic acid (5.4 mL), and formaldehyde (2.55 mL of a 37% aqueous solution).
  • Zinc dust (2.99 g, 44.8 mmol) was added and the mixture was heated at 60 °C for 1 h, then cooled, filtered to remove the zinc, and rinsed with water.
  • Aqueous ammonia was added to the filtrate. Upon standing approximately 10 min, a white solid began to form in the flask. A stirbar was added and the mixture was stirred an additional 30 min. The resulting slurry was cooled in an ice/water bath for 30 min and then filtered to collect the solid.
  • Triethylamine 80 uL, 0.57 mmol was added to a solution of morpholine 27 (40 mg, 0.11 mmol) and 2-picolyl chloride hydrochloride (28.3 mg, 0.172 mmol) in 1-propanol (3 mL). The mixture was heated at 75 °C for 18 h. The mixture was cooled, diluted with saturated aqueous sodium bicarbonate solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Examples 17-21 are shown in Table 3 and were prepared according to the procedure described in Example 16 using the corresponding morpholine starting materials (23, 27, 28, or 30) and the requisite alkyl halide.
  • Triethylamine (352 ⁇ , 2.52 mmol) was added to a solution of morpholine 26 (139 mg,
  • Examples 23-25 are shown in Table 4 and were prepared according to the procedure described in Example 22 using the corresponding morpholine starting materials (27, 28, or 30) and the requisite heteroaryl halides.
  • Examples 27-58 are shown in Table 5 and were prepared according to the procedure described in Example 26 using the corresponding morpholine starting materials (26, 27, 28, or 30) and the requisite aldehydes.
  • Nitrile 80 (10 g, 49.44 mmol) was combined with concentrated HCI (50 imL) at RT in a sealed glass bottle with magnetic stirbar. The mixture was heated to 90 °C for 16 h and then cooled to RT. A precipitate formed and the slurry was concentrated and then azeotroped from toluene to provide 15.0 g of 81 as a light pink solid.
  • the diastereomers were separated by chiral HPLC using the following conditions: a Chiracel OJ-H column (250 mm x 21.0 mm), flow rate of 65 mL/min, and 10% ethanol in carbon dioxide.
  • the 4 diastereomers were separated but diastereomer 78 was contaminated with an impurity and required a second chiral chromatography using a ChiralPAK AD-H column (250 mm x 21 mm), a flow rate of 65 mL/min and 15% isopropanol in carbon dioxide.
  • the diastereomers are listed below in order of elution with the diastereomer with the shortest retention time listed first.
  • Diastereomer 76 LCMS m/z 408.3 (M+1). H NMR (400 MHz, CDCI 3 ) ⁇ 7.18-7.26 (m,
  • Diastereomer 78 LCMS m/z 408.3 (M+1). H NMR (400 MHz, CDCI 3 ) ⁇ 7.28-7.37 (m,
  • Morpholine 85 (135 mg, 0.42 mmol) was dissolved in water (2 imL) and acetic acid (0.1 imL, 1 .7 mmol). Formaldehyde solution (0.05 imL of a 37% aqueous solution) was added followed by zinc dust (56 mg, 0.85 mmol). The reaction mixture was heated at 60 °C overnight and then ammonium hydroxide (3 imL of 30 % aqueous solution) was added.
  • PDE8A SPA assay protocol Test compounds were solubilized in 100% dimethyl sulfoxide and diluted to the required concentrations in 15% dimethyl sulfoxide/water. The human PDE8A enzyme was thawed slowly and diluted in 50 imM Tris HCI buffer (pH 7.5 at RT) containing 1 .3 imM MgCI 2 . Incubations were initiated by the addition of enzyme solution to 384- well plates containing test drugs and radioligand (20 nM 3 H-cAMP). After a 30 min. incubation at RT, phosphodiesterase SPA beads (Amersham/GE) were then added to the assay plate at a concentration of 0.2 mg/well to stop the reaction.
  • test compounds were assessed by measuring the amount of 3 H-5'AMP resulting from enzyme cleavage of 3 H-cAMP radioligand.
  • Levels of 3 H-5'AMP bound to SPA beads were determined by paralux counting of the assay plates in a Microbeta Trilux Counter (PerkinElmer). Non-specific binding was determined by radioligand binding in the presence of a saturating concentration (10 ⁇ ) of a potent PDE8 inhibitor.
  • PDE8B SPA assay protocol Same as the PDE8A SPA assay protocol except that human PDE8B enzyme was used instead of the human PDE8A enzyme.
  • PDE8B fluorescence polarization (FP) assay protocol Test compounds were solubilized in 100% dimethyl sulfoxide and diluted to the required concentrations in 20% DMSO/assay buffer. The human PDE8B enzyme was thawed and diluted in assay buffer: 10 mM Tris HCI (pH 8.0 at RT), 10 mM Tris HCI (pH 7.0 at RT), 10 mM MgCI 2 and 0.007% Tween- 20. Enzyme and test compounds were added to a 384-well plate, followed by the TAMARA- cAMP substrate (Molecular Devices R7457) to initiate the reaction. After a 45 min.
  • TAMARA- cAMP substrate Molecular Devices R7457
  • binding reagent (Molecular Devices Original Binding System R8073) was added to the assay and allowed to incubate another 60 min. Plates were read on the Analyst GT. Activity of test compounds was assessed by calculating % inhibition, using total counts and background to determine the assay window.
  • IC 50 value concentration at which 50% inhibition of specific binding occurs

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Abstract

Compounds of Formula (I): wherein R1 , R2, R3, R4, and R5 are as defined herein, are disclosed.

Description

SUBSTITUTED TRIAZOLOPYRIMIDINES AS PDE8 INHIBITORS
FIELD OF THE INVENTION
The present invention relates to the treatment of spinal cord injury, cognitive deficits associated with schizophrenia and/or Alzheimer's disease, and other neurodegenerative and/or neurological disorders in mammals, including humans. More particularly, this invention relates to substituted triazolopyrimidine inhibitors of the PDE8 enzyme, useful for the treatment of such disorders.
BACKGROUND OF THE INVENTION
Adenosine and guanosine 3',5'-cyclic monophosphates (cAMP and cGMP) are the second messengers that mediate the response of cells to a wide variety of hormones and neurotransmitters and modulate many metabolic processes. Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing these cyclic nucleotides and thus play pivotal roles in the physiological processes involving the nucleotide signaling pathway. Phosphodiesterase-8 (PDE8) is a family of cAMP-specific enzymes and plays an important role in many biological processes, including T-cell activation, testosterone production, adrenocortical hyperplasia, and thyroid function. See Wang et al., Biochemistry, 2008, 47 (48), 12760-8.
Selective inhibitors of PDEs have been widely studied as therapeutics for treatment of various human diseases, including cardiotonics, vasodilators, smooth muscle relaxants, antidepressants, antiasthmatics, and agents for improvement of learning and memory.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula I:
Figure imgf000002_0001
wherein:
R is alkyl, haloalkyi, cycloalkyl, heterocycloalkyl, aminoalkyl, aryloxyalkyl, hydroxyalkyl, or alkoxyalkyl, wherein R may be optionally substituted with one or more substituents independently selected from halo, haloalkyi, alkyl, cycloalkyl, hydroxy, amino, and alkoxy;
R2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein R2 may be optionally substituted with one or more substituents independently selected from halo, haloalkyi, alkyl, cycloalkyl, hydroxy, amino, and alkoxy;
R3 and R4 are independently hydrogen, alkyl, or haloalkyi; and R5 is a bond, methylene, or ethylene, wherein said methylene or ethylene may be substituted by a methyl or ethyl substituent;
This invention also includes pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites of compounds of Formula I. This invention also includes all tautomers and stereochemical isomers of these compounds.
This invention also is directed, in part, to a method for treating a PDE8 mediated disorder in a mammal. Such disorders include spinal cord injury, cognitive deficits associated with schizophrenia and/or Alzheimer's disease, and other neurodegenerative and/or neurological disorders. The method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeutically effective to treat the condition.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention is a compound of Formula I as described above.
Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R5 is -(CH2)n-, wherein n is 0, 1 , or 2.
Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyl, alkyl, cycloalkyl, hydroxy, amino, and alkoxy.
Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyl, alkyl, cycloalkyl, hydroxy, amino, and alkoxy; and R4 is hydrogen; provided that when R2 is oxazolyl, triazolyl, pyrazinyl, thiazolyl, or imidazolyl, said optional substituent is not halo, and that when R2 is pyridazinyl, pyrazolyl, pyrimidinyl, or pyridinyl, and said optional substituent is halo, the ring carbon or carbons to which said halo substituent or substituents is attached is not adjacent to a ring N atom and/or ring O atom. For example, in this embodiment, when R2 is pyridazinyl substituted by one halo substituent, the halo substituent may only attach to the pyridazinyl ring as shown below:
Figure imgf000004_0001
R2 ring and -(CH2)n- in Formula I.
Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, haloalkyi, or cycloalkyl; R2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyi, and alkyl; and R3 and R4 are hydrogen.
Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyi, and alkyl, and wherein said oxazolyl or thiazolyl may be optionally substituted with one or two substituents independently selected from haloalkyi and alkyl.
Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R is methyl, trifluoromethyl, or cyclopropyl; and R2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from fluoro, trifluoromethyl, and methyl.
Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R is methyl, cyclopropyl, or trifluoromethyl; R2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl, oxazolyl, or thiazolyl may be optionally substituted with one or two substituents independently selected from ethyl, methyl, and trifluoromethyl; and R3 and R4 are hydrogen. Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is 1 ; R is methyl, cyclopropyl, or trifluoromethyl; R2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl, oxazolyl, or thiazolyl may be optionally substituted with one or two methyl substituents; and R3 and R4 are hydrogen.
Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from:
3-{[(2R)-4-benzylmorpholin-2-yl]methyl}-5-cyclopropyl-3H-[1 ,2,3]triazolo[4,5-c/]pyrimidin- 7-amine;
3-[(4-benzylmorpholin-2-yl)methyl]-5-cyclopropyl-3/-/-[1 ,2,3]triazolo[4,5-d]pyrimidin-7- amine;
3-{[(2R)-4-benzylmorpholin-2-yl]methyl}-5-methyl-3H-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7- amine;
3-{[(2R)-4-benzylmorpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
3-[(4-benzylmorpholin-2-yl)methyl]-5-(trifluoromethyl)-3H-[1 ,2,3]triazolo[4,5-c/]pyrimidin- 7-amine;
3-[(2R)-morpholin-2-ylmethyl]-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7- amine;
3-{[(2R)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/- [1 ,2,3]triazolo[4,5-d]pyrimidin-7-amine;
3-{[(2R)-4-methylmorpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
5-cyclopropyl-3-[(2R)-morpholin-2-ylmethyl]-3/-/-[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine; 5-methyl-3-{[(2R)-4-methylmorpholin-2-yl]methyl}-3H-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7- amine;
5-cyclopropyl-3-{[4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl}-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
5-cyclopropyl-3-{[4-(pyrimidin-2-ylmethyl)morpholin-2-yl]methyl}-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
5-methyl-3-{[4-(pyrimidin-2-ylmethyl)morpholin-2-yl]methyl}-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
3-{[4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3H-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine; 3-{[(2R)-4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-{[4-(pyrimidin-2-ylmethyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-cyclopropyl-3-{[(2R)-4-pyrimidin-2-ylmorph
c/]pyrimidin-7-amine;
5-cyclopropyl-3-[(4-pyrimidin-2-ylmorpholin-2-yl)methyl]-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
5-methyl-3-[(4-pyrimidin-2-ylmorpholin-2-yl)methyl]-3/-/-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7- amine;
3-[(4-pyrimidin-2-ylmorpholin-2-yl)methyl]-5-(trifluoromethyl)-3H-[1 ,2^]tr
c/]pyrimidin-7-amine;
5-cyclopropyl-3-{[(2R)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl}-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-cyclopropyl-3-{[4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl}-3/-/-[1 ,2,3]triazolo[4,5- cdpyrimidin-7-amine;
5-cyclopropyl-3-({4-[(4-ethyl-1 ,3-thiazol-2-yl)methyl]morpholin-2-yl}methyl)-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-methyl-3-{[4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl}-3H-[1 ,2,3]tri
cdpyrimidin-7-amine;
5-methyl-3-({4-[(1-methyl-1 H-imidazol-2-yl)methyl]morpholin-2-yl}methyl^
[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-{[4-(3,5-difluorobenzyl)morpholin-2-yl]methyl}-5-methyl-3H-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
3-{[(2R)-4-(3,5-difluorobenzyl)morp^
c/]pyrimidin-7-amine hydrochloride;
3-({4-[(4-ethyl-1 ,3-thiazol-2-yl)methyl]morpholin-2-yl}methyl)-5-methyl-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-({4-[(4-isopropyl-1 -thiazol-2-yl)methyl]morpholin-2-yl}methyl)-5-methyl-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-methyl-3-{[4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl}-3H-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
3-{[4-(1 ^-thiazol-2-ylmethyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine; 3-{[4-(3,5-difluorobenzyl)morpholi^
c/]pyrimidin-7-amine;
3-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-5-(trifluoro^
c/]pyrimidin-7-amine;
3-({4-[(4-ethyl-1 ,3-thiazol-2-yl)methyl]morpholin-2-yl}methyl)-5-(trifluoromethyl^
[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3H-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
3-({(2R)-4-[(4-Ethyl-1 ,3-thiazol-2-yl)methyl]morpholin-2-yl}methyl)-5-m
[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-methyl-3-{[(2R)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]meth
c/]pyrimidin-7-amine;
5-methyl-3-{[(2R)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]meth
c/]pyrimidin-7-amine ;
3-[1-(4-benzylmorpholin-2-yl)ethyl]-5-(trifluoromethyl)-3H-[1 ,2,3]triazolo[4,5-c^ 7-amine; and
3-[1-(4-methylmorpholin-2-yl)ethyl]-5-(trifluoromethyl)-3H-[1 ,2,3]triazolo[4,5- 7-amine;
or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Another embodiment of the present invention is a method of treating a
neurodegenerative disease or disorder, the method comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a method of treating a
neurodegenerative disease or disorder, the method comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease or disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, Huntington's disease, cognitive impairment associated with Alzheimer's disease, age-related cognitive decline, schizophrenia, or ADHD.
Another embodiment of the present invention is a method of treating a
neurodegenerative disease or disorder, the method comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease or disorder is spinal cord injury.
Another embodiment of the present invention is a compound of Formula I wherein R is alkyl, haloalkyl, or cycloalkyi; R2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyl, and alkyl; and R3 is hydrogen.
Another embodiment of the present invention is a compound of Formula I wherein R is methyl, trifluoromethyl, or cyclopropyl; R2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from fluoro, trifluoromethyl, and methyl; and R3 is hydrogen.
Abbreviations and Definitions
The term "alkyl" refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; in one embodiment from one to twelve carbon atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n- butyl, isobutyl, sec-butyl and ieri-butyl), pentyl, isoamyl, hexyl and the like.
The term "cycloalkyi" refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule and having three to fourteen carbon atoms. In one embodiment, a cycloalkyi substituent has three to ten carbon atoms. Examples of cycloalkyi include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cycloalkyi" also includes substituents that are fused to a C6-Ci0 aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyi group as a substituent is bound to a carbon atom of the cycloalkyi group. When such a fused cycloalkyi group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a carbon atom of the cycloalkyi group. The fused C6-Cio aromatic ring or 5-10-membered heteroaromatic ring may be optionally substituted with halogen, Ci-C6 alkyl, C3-Ci0 cycloalkyi, or =0. A cycloalkyi may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alternatively, 2 or 3 rings may be fused together, such as bicyclodecanyl and decalinyl. The term "aryl" refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms. The term "aryl" may refer to
substituents such as phenyl, naphthyl and anthracenyl. The term "aryl" also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C4-Ci0 carbocyclic ring, such as a C5- or a C6-carbocyclic ring, or to a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group. The fused C4-Ci0 carbocyclic or 4-10-membered heterocyclic ring may be optionally substituted with halogen, Ci-C6 alkyl, C3-Ci0 cycloalkyl, or =0. Examples of aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, and benzonaphthenyl (also known as "phenalenyl").
In some instances, the number of carbon atoms in a hydrocarbyl substituent (i.e., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix "Cx-Cy" or "Cx-y," wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Ci-C6 alkyl and "Ci_6 alkyl" both refer to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C3-C6 cycloalkyl and C3.6 cycloalkyl refer to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.
In some instances, the number of atoms in a cyclic substituent containing one or more heteroatoms (i.e., heteroaryl or heterocycloalkyi) is indicated by the prefix "X-Y-membered", wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent. Thus, for example, 5-8-membered heterocycloalkyi refers to a heterocycloalkyi containing from 5 to 8 atoms, including one or more heteroatoms, in the cyclic moiety of the heterocycloalkyi.
The term "hydroxy" or "hydroxyl" refers to -OH. When used in combination with another term(s), the prefix "hydroxy" indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds bearing a carbon to which one or more hydroxy substituents are attached include, for example, alcohols, enols and phenol.
The term "hydroxyalkyl" refers to an alkyl that is substituted with at least one hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
The term "cyano" (also referred to as "nitrile") means CN. The term "carbonyl" means C(O) or C=0.
The term "amino" refers to NH2.
The term "alkylamino" refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom. Examples of alkylamino substituents include monoalkylamino such as methylamino (exemplified by the formula NH(CH3)), and dialkylamino such as dimethylamino (exemplified by the formula -N(CH3)2).
The term "halogen" refers to fluorine (which may be depicted as F), chlorine (which may be depicted as CI), bromine (which may be depicted as Br), or iodine (which may be depicted as I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is bromine.
The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents. For example, haloalkyl refers to an alkyl that is substituted with at least one halogen substituent. Where more than one hydrogen is replaced with halogens, the halogens may be identical or different.
Examples of haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl,
dichlorofluoromethyl, trichloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl. Illustrating further, "haloalkoxy" refers to an alkoxy that is substituted with at least one halogen substituent. Examples of haloalkoxy substituents include chloromethoxy, 1 - bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as
"perfluoromethyloxy"), and 2,2,2-trifluoroethoxy. It should be recognized that if a substituent is substituted by more than one halogen substituent, those halogen substituents may be identical or different (unless otherwise stated).
The term "oxo" refers to =0.
The term "alkoxy" refers to an alkyl linked to an oxygen, which may also be represented as -OR, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
The term "heterocycloalkyl" refers to a substituent obtained by removing a hydrogen from a saturated or partially saturated ring structure containing a total of 4 to 14 ring atoms. At least one of the ring atoms is a heteroatom usually selected from oxygen, nitrogen, or sulfur. A heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). In a group that has a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heterocycloalkyi substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
The term "heterocycloalkyi" also includes substituents that are fused to a C6-C10 aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyi group as a substituent is bound to a heteroatom of the heterocyclocalkyi group or to a carbon atom of the heterocycloalkyi group. When such a fused heterocycloalkyi group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a heteroatom of the heterocyclocalkyi group or to a carbon atom of the heterocycloalkyi group. The fused C6-Ci0 aromatic ring or 5-10-membered heteroaromatic ring may be optionally substituted with halogen, Ci-C6 alkyl, C3-C10 cycloalkyl, Ci-C6 alkoxy, or =0.
The term "heteroaryl" refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include: 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl; 6-/5-membered fused ring substituents such as benzothiofuranyl,
isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl and purinyl; and 6-/6-membered fused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1 ,4-benzoxazinyl. In a group that has a heteroaryl substituent, the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. The term "heteroaryl" also includes pyridyl /V-oxides and groups containing a pyridine /V-oxide ring. Examples of single ring heteroaryls include furanyl, thiophenyl (also known as
"thiofuranyl"), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl [including 1 ,2,4-oxadiazolyl (also known as "azoximyl"), 1 ,2,5-oxadiazolyl (also known as "furazanyl"), or 1 ,3,4-oxadiazolyl], pyridinyl (also known as "azinyl"), diazinyl [including pyridazinyl (also known as "1 ,2-diazinyl"), pyrimidinyl (also known as "1 ,3-diazinyl" or "pyrimidyl"), or pyrazinyl (also known as "1 ,4-diazinyl")], and triazinyl [including s-triazinyl (also known as "1 ,3,5-triazinyl"), as-triazinyl (also known 1 ,2,4-triazinyl), and v- triazinyl (also known as "1 ,2,3-triazinyl")].
Examples of 2-fused-ring heteroaryls include indolizinyl, pyrindinyl, purinyl,
naphthyridinyl, pyridopyridinyl (including pyrido[3,4-£>]-pyridinyl, pyrido[3,2-£>]pyridinyl, or pyrido[4,3-j ]pyridinyl), and pteridinyl, indolyl, isoindolyl, isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, indoxazinyl, anthranilyl, benzoxadiazolyl, benzofuranyl,
isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl,
benzimidazolyl, benzotriazolyl, benzoxazinyl, and benzisoxazinyl.
Examples of 3-fused-ring heteroaryls or heterocycloalkyls include 5,6-dihydro-4/-/- imidazo[4,5,1-/y]quinoline, 4,5-dihydroimidazo[4,5,1-ft/]indole, 4,5,6J-tetrahydroimidazo[4,5,1- y'/c][1]benzazepine, and dibenzofuranyl.
Other examples of fused ring heteroaryls include benzo-fused heteroaryls such as indolyl, isoindolyl (also known as "isobenzazolyl" or "pseudoisoindolyl"), benzazinyl [including quinolinyl (also known as "1 -benzazinyl") or isoquinolinyl (also known as "2-benzazinyl")], phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl [including cinnolinyl (also known as "1 ,2- benzodiazinyl") or quinazolinyl (also known as "1 ,3-benzodiazinyl")], benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl," "thionaphthenyl," or
"benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl," "isothianaphthenyl," or "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl), carbazolyl, and acridinyl.
The term "heteroaryl" also includes substituents such as pyridyl and quinolinyl that are fused to a C4-Ci0 carbocyclic ring, such as a C5 or a C6 carbocyclic ring, or to a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. When such a fused heteroaryl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. The fused C4-Ci0 carbocyclic or 4-10- membered heterocyclic ring may be optionally substituted with halogen, Ci-C6 alkyl, C3-C10 cycloalkyl, or =0.
Additional examples of heteroaryls and heterocycloalkyls include: 3-1/-/-benzimidazol-2- one, (1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1 ,3]-dioxalanyl, [1 ,3]-dithiolanyl, [1 ,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4- morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, 2/-/-imidazol-2-one, 1-phthalimidinyl, benzoxanyl, benzo[1 ,3]dioxine,
benzo[1 ,4]dioxine, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, 4,5,6,7- tetrahydropyrazol[1 ,5-a]pyridine, benzothianyl, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, dihydropyranyl, tetrahydrothiopyranyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2/-/-pyranyl, 4/-/-pyranyl, dioxanyl, 1 ,3- dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3/-/-indolyl, quinolizinyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-2-yl (C-attached).
If a substituent is described as being "substituted," a non-hydrogen substituent is in the place of a hydrogen attached to a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated). If a substituent is described as being "optionally substituted," the substituent may be either substituted or not substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent. One exemplary substituent may be depicted as -NR'R", wherein R' and R" together with the nitrogen atom to which they are attached, may form a heterocyclic ring. The heterocyclic ring formed from R' and R" together with the nitrogen atom to which they are attached may be partially or fully saturated. In one embodiment, the heterocyclic ring consists of 4 to 7 atoms. In another embodiment, the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, and thiazolyl.
If a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1 ) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents.
If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent may be either (1 ) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non- hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen substituent. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.
A prefix attached to a multi-moiety substituent only applies to the first moiety. To illustrate, the term "alkylcycloalkyl" contains two moieties: alkyl and cycloalkyl. Thus, a C C6 prefix on Ci-C6 alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C6 prefix does not describe the cycloalkyi moiety. To illustrate further, the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents. If the halogen substitution only occurs on the alkyl moiety, the substituent would be described as "alkoxyhaloalkyl." If the halogen substitution occurs on both the alkyl moiety and the alkoxy moiety, the substituent would be described as "haloalkoxyhaloalkyl."
If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
As used herein the term "Formula I" may be hereinafter referred to as a "compound(s) of the invention." Such terms are also defined to include all forms of the compound of Formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
The following abbreviations are used herein:
ACN: Acetonitrile
br: Broad
CD3OD: Deuterated methanol
CDCI3: Deuterated chloroform
d: Doublet
DCM: Dichloromethane
dd : Dou blet of dou blets
DMF: Dimethylformamide
DMSO: Dimethyl sulfoxide
DMSO-cf6: Deuterated DMSO
EDCI: A/-(3-Dimethylaminopropyl)-/V-ethylcarbodiimide
Et20: Diethyl ether
EtOAc: Ethyl acetate
EtOH: Ethanol
g: Gram
h: Hour or Hours
HPLC: High pressure liquid chromatography
J: Coupling constant
LCMS: Liquid chromatography - mass spectrometry
m: Multiplet M: Molar
MeCN: Acetonitrile
MeOH: Methanol
MeTHF: 2-Methyltetrahydrofuran
mg: Milligram
MHz: Megahertz
min: Minutes
ml_: Milliliter
μΙ_: Microliter
mmol: Millimole
MS: Mass spectrometry
N: Normal
NMR: Nuclear magnetic resonance
Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
ppm: Parts per million
psi: Pounds per square inch
q: Quartet
RT: Room temperature
s: Singlet
t: Triplet
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
TLC: Thin layer chromatography Isomers
When an asymmetric center is present in a compound of Formula I, hereinafter referred to as the compound of the invention, the compound may exist in the form of optical isomers (enantiomers). In one embodiment, the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of Formula I. In another embodiment, for compounds of Formula I that contain more than one asymmetric center, the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds. When a compound of Formula I contains an alkenyl group or moiety, geometric isomers may arise. Tautomeric Forms
The present invention comprises the tautomeric forms of compounds of Formula I. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. The various ratios of the tautomers in solid and liquid form are dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound.
Salts
The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of Formula I with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this invention are nontoxic "pharmaceutically acceptable salts." Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,
toluenesulfonate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate,
glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diethanolamine, glycine, lysine, meglumine, ethanolamine, tromethamine and zinc salts.
Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, Λ/,Λ/'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (/V-methylglucamine), and procaine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (Ci-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
In one embodiment, hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
Isotopes
The present invention also includes isotopically labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 3C, C, 4C, 5N, 80, 70, 3 P, 32P, 35S, 8F, and 36CI, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 4C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 4C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The invention also relates to prodrugs of the compounds of Formula I. Certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series, 1975 (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
Some non-limiting examples of prodrugs in accordance with the invention include:
(i) where the compound of Formula I contains an alcohol functionality which is functionalized into a suitably metabolically labile group (ester, carbonate, carbamate, acetal, ketal, etc.) on the compound of Formula I; and
(ii) where the compound of Formula I contains a primary or secondary amino functionality, or an amide which is functionalized into a suitably metabolically labile group, e.g., a hydrolyzable group (amide, carbamate, urea, phosphonate, sulfonate, etc.) on the compound of Formula I .
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.
Administration and Dosing
Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
In another embodiment, the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrasternal, intracranial, intramuscular and subcutaneous.
Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear.
The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, the total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg body weight). In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
For oral administration, the compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.01 to about 10 mg/kg/min during a constant rate infusion.
Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
Use in the Preparation of a Medicament
In another embodiment, the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment of the conditions recited herein.
Pharmaceutical Compositions
For the treatment of the conditions referred to herein, the compound of the invention can be administered as compound per se. Alternatively, pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
In another embodiment, the present invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds. A compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and compositions, for example, may be administered orally, rectally, parenterally, or topically.
Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a
predetermined amount of at least one compound of the present invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of Formula I are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art
(i.e., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
In another embodiment, the present invention comprises a parenteral dose form.
"Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting, and/or suspending agents.
In another embodiment, the present invention comprises a topical dose form. "Topical administration" includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, Finnin and Morgan, J. Pharm. Sci. , 1999, 88, 955-958.
Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. In another embodiment, the present invention comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman ef a/., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe ef a/., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999. Co-administration
The compounds of the present invention can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states. The compound(s) of the present invention and other therapeutic agent(s) may be may be administered
simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist.
The administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds may be administered
simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of
administration.
The phrases "concurrent administration," "co-administration," "simultaneous
administration," and "administered simultaneously" mean that the compounds are administered in combination.
Kits
The present invention further comprises kits that are suitable for use in performing the methods of treatment described above. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention and a container for the dosage, in quantities sufficient to carry out the methods of the present invention. In another embodiment, the kit of the present invention comprises one or more compounds of the invention.
Intermediates
In another embodiment, the invention relates to the novel intermediates useful for preparing the compounds of the invention.
General Synthetic Schemes
The compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art
(such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-XII (published by Wiley-lnterscience)). Preferred methods include, but are not limited to, those described below.
During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 ; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
Compounds of Formula I, or their pharmaceutically acceptable salts, can be prepared according to the reaction Schemes discussed herein below. Unless otherwise indicated, the substituents in the Schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.
It will be understood by one skilled in the art that the various symbols, superscripts and subscripts used in the schemes, methods and examples are used for convenience of representation and/or to reflect the order in which they are introduced in the schemes, and are not intended to necessarily correspond to the symbols, superscripts or subscripts in the appended claims. The schemes are representative of methods useful in synthesizing the compounds of the present invention. They are not to constrain the scope of the invention in any way.
The compounds of Formula l(c) can be prepared as described in Scheme 1 starting from aminodichloropyrimidines II and amines III. Methods of preparing compounds II and compounds III are outlined later in Schemes 2 and 3. Compounds of Formula IV can be prepared from the corresponding aminodichloropyrimidine II by reacting with racemic or enantiomerically-enriched amines of the formula III. Compounds II and III are combined in the presence of a base, such as diisopropylethylamine, triethylamine or sodium carbonate in a polar solvent such as N- methylpyrrolidinone at a temperature of about 50 °C to about 150 °C, preferably at about 125 °C for about 10 h to about 24 h, or in MeCN at a temperature of 80 °C for up to 36 h to yield compounds IV.
Compounds IV are cyclized by treatment with a nitrosylating agent in acidic solution, to yield triazolopyrimidines V. One method of triazole cyclization uses sodium nitrite in a solvent mixture of water, dichloromethane and acetic acid at a temperature of about 0 °C to about 30 °C, typically at ambient temperature for about 1 - 6 hours. Alternatively another method employs sodium nitrite in MeTHF with the addition of 1 N HCI at ambient temperature for about 1 hour. The resulting chloropyrimidines V can then be reacted with a source of ammonia, such as ammonium hydroxide or anhydrous ammonia dissolved in organic solvents such as methanol, ethanol, THF, MeTHF or dioxane, at a temperature of about 40 °C to about 100 °C, preferably at about 75 °C for about 4 hours to 24 hours and typically in a sealed pressure vessel to provide compounds of formula l(a).
Scheme 1
Figure imgf000026_0001
Formula 1(a) compounds can be debenzylated to provide compounds of Formula 1(b). The reduction is preferably carried out using a palladium catalyst, more preferably palladium hydroxide on carbon, and an acid catalyst, such as hydrochloric acid, sulfuric acid or acetic acid, in a solvent such as methanol, ethanol or MeTHF under between 1 and 4 atmospheres of hydrogen gas, preferably 3 atmospheres, at a temperature from ambient temperature to 50 °C, preferably at ambient temperature for about 2 hours to about 24 hours.
Compounds of Formula l(c) wherein R is defined as above and n = 0 and R2 is a heterocyclic group can be prepared by various methods known to one skilled in the art. In one method, a compound of Formula l(b) wherein R is defined above, is reacted with a heterocyclic halide in the presence of a base, preferably an amine base such as diisopropylethylamine in a polar solvent such as acetonitrile, 2-propanol or A/,A/-dimethylformamide at a temperature of 40 °C to the reflux temperature of the solvent, preferably at about 75 °C for about 1 -3 days. If the heterocyclic halide is not sufficiently reactive, a palladium-catalyzed procedure can be employed. A compound of Formula l(b) wherein R is defined above, is reacted with a heterocyclic halide in the presence of a palladium catalyst such as Pd2(dba)3, a phosphine ligand, such as xantphos, or X-Phos, and a base such as cesium carbonate, potassium hydroxide, or sodium ieri-butoxide, in a reaction-inert solvent such as dioxane, ieri-butanol, or ieri-amyl alcohol at a temperature of 50 °C to the boiling point of the solvent, preferably at about 100-1 10 °C for about one to about 24 hours.
Compounds of Formula l(c) wherein R is defined above and n >0 and R2 is as defined above can be prepared by several methods known to one skilled in the art. One such method involves a reductive amination between a Formula l(b) compound and an aldehyde, which is either commercially available or readily synthesized by numerous methods known to those skilled in the art. Reductive amination reactions are well known in organic synthesis and to those skilled in the art (see for example A. F. Abdel-Magid ef a/., J. Org. C em. 1996, 61, 3849- 3862). Specifically, the Formula l(b) compound and aldehyde are combined in a reaction-inert solvent such as dichloroethane, acetonitrile, THF, or MeTHF (or mixtures thereof), followed by the addition of a reducing agent, preferably sodium triacetoxyborohydride, at a temperature of about 0° C to about 50 °C, typically at ambient temperature for about one hour to about 24 hours. Additionally, if the amine or aldehyde component is introduced as a salt, a base may be added to facilitate the reaction, preferably an amine base such as diisopropylethylamine.
Alternatively, the same Formula l(c) compounds can be prepared by reacting a Formula l(b) compound with an alkylating agent, such as an aryl alkyi halide or an aryl alkyi mesylate and the like. Specifically, the Formula l(b) compound is reacted with an alkylating agent in the presence of a base, preferably an amine base such as triethylamine or diisopropylethylamine, in a solvent such as 1 -propanol, A/,/V-dimethylformamide, MeCN, or THF at a temperature of ambient temperature to 100 °C, preferably at about 75 °C for about 1 hour to about 24 hours.
Scheme 2
Figure imgf000028_0001
VI VIII IX
Figure imgf000028_0002
The dichloropyrimidines of Formula II wherein R is defined above can be prepared according to Scheme 2 starting from the requisite amidines VI or esters VII. Formula VI amidines can be prepared by numerous methods known to those skilled in the art. For example, the corresponding nitrile can be converted first to the imidate by the treatment of the nitrile with anhydrous hydrochloric acid in ethanol at ambient temperature for 24 hours, followed by the addition of anhydrous ammonia in ethanol at ambient temperature for 24 hours to provide amidines VI. Treatment of amidines VI with dimethylmalonate or diethylmalonate under basic conditions, preferably using an alkoxide base such as sodium methoxide, in alcohol solvent, preferably methanol, at ambient temperature for about 12 hours to about 48 hours, can provide dihydroxypyrimidines of formula VIII. Alternatively dihydroxypyrimidines VIII can be formed by reaction of esters VII with malonamide. Addition of esters VII to a mixture of malonamide and an alkoxide base such as n-butoxide, formed by treatment of n-butanol with sodium hydride, in solvents such as toluene at temperatures around 0 °C, followed by warming to about 40 °C and overnight stirring, can provide dihydroxypyrimidines of Formula VIII.
The pyrimidines of Formula VIII can be nitrated to provide nitropyrimidines of Formula
IX. In one method of nitration, Formula VIII compounds are added in portions to a mixture of nitric acid and acetic acid at a temperature of between 20 °C to 30 °C for about 30 minutes to about 4 hours. In another method, Formula VIII diols can be dissolved in TFA at ambient temperatures and then fuming nitric acid can be added dropwise, maintaining a temperature below 25 °C followed by overnight stirring to yield nitro compounds IX. The Formula X compounds wherein R is defined above can be prepared from the corresponding Formula IX compounds by reaction with a chlorinating agent. Preferably, the chlorinating agent is phosphorus oxychloride. Thus the Formula IX compounds can be added to phosphorus oxychloride in the presence of an amine base, preferably an aniline base such as dimethylaniline. The mixture is heated at a temperature of about 50 °C to about 105 °C, for about one hour to about 6 hours to provide the desired dichloropyrimidines X. In another method of chlorination, a mixture of the Formula IX compounds in phosphorous oxychloride is stirred at ambient temperature and phosphoric acid is added followed by dropwise addition of an amine base such as diisopropylethylamine while maintaining the temperature below 40 °C. Upon completion of the addition of base, the reaction mixture is warmed to around 45 °C and stirred overnight to provide dichloropyrimidines X.
The dichloroaminopyrimidines of Formula II can be prepared from the corresponding nitro compounds of formula X by reduction of the nitro group. The reduction is generally carried out by the addition of a transition metal powder, such as iron or tin, to a solution of the Formula X compound in acidic solvent such as acetic acid or aqueous hydrochloric acid. The reduction is performed at a temperature of about ambient temperature to about 75 °C, preferably about 50 °C, for about 2 to 10 hours.
Scheme 3
Figure imgf000029_0001
The racemic amine of Formula lll(a) where R4 equals hydrogen can be prepared as reported by S. Kato ef a/., J. Med. C em., 1990, 33, 1406-1413. It is most conveniently prepared from the corresponding Formula XIII nitrile through a reduction reaction. The reduction can be achieved by a variety of reducing agents known to those skilled in the art for reducing nitriles selectively in the presence of /V-benzyl groups. These reducing agents include but are not limited to Raney nickel, lithium aluminum hydride, or Vitride®. The nitrile of Formula XIII where R4 equals hydrogen can be prepared in one step from 2-chloroacrylonitrile (XI) and 2- benzylaminoethanol XII as described by M. J. Cases-Thomas ef a/., Bioorganic Med. Chem. Lett. 2006, 16, 2022-2025 and F. D. King et ai , J. Med. Chem., 1993, 36, 683-689. The chiral resolution of amine lll(a) where R4 equals hydrogen can be accomplished as described by N. Sakurai et ai , Bioorganic Med. Chem. Lett., 1998, 8, 2185-2190.
Experimental Procedures and Working Examples
The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art.
Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification unless indicated otherwise, including anhydrous solvents where appropriate (generally Sure- Seal™ products from the Aldrich Chemical Company, Milwaukee, Wisconsin). Mass spectrometry data is reported from liquid chromatography-mass spectrometry (LCMS).
Chemical shifts for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents employed.
For syntheses referencing procedures in other Examples, reaction conditions (length of reaction and temperature) may vary. In general, reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate.
Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluants/gradients were chosen to provide appropriate Rfs or retention times.
Example 1 : Synthesis of 3-{r(2/?)-4-benzylmorpholin-2-yllmethyl}-5-cyclopropyl-3H-
Figure imgf000031_0001
1 2 3 4
Figure imgf000031_0002
Cyclopropylcarboxamidine hydrochloride (1) A solution of cyclopropanecarbonitrile (70 g, 1 .04 mol) in ethanol (50 mL) was added to a saturated solution of dry HCI gas in dry ethanol (93 g) along with slight cooling. The resulting mixture was then stirred at RT for 24 h. The thick suspension formed was diluted with ethanol (25 mL) and cooled with an ice-water bath. An ethanolic ammonia solution (103.2 g) was added slowly to the ethanol mixture over ~ 30 min. The cooling bath was then removed, and the mixture was stirred at 23 °C for another 24 h. The precipitated ammonium chloride by-product was filtered off, and washed with ethanol (25 mL). The filtrates were concentrated and diluted with methanol (25 mL). The product was precipitated from the methanol mixture by the addition of diethyl ether (100 mL). The suspension was stirred for 4 h, the precipitate was filtered off, washed with diethyl ether (50 mL), and dried under vacuum to afford 100 g (79.5%) of the amidine (1 ). LCMS m/z 85 (M+1 ). H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 2H), 8.72 (s, 2H), 1.84 (m, 1 H), 1.15-1 .06 (m, 4H).
2-Cyclopropylpyrimidine-4,6-diol (2) Sodium metal (5.83 g, 254 mmol) was added to anhydrous methanol (100 mL) cooled in an ice bath. Once sodium methoxide formation was complete (all sodium dissolved), cyclopropyl carboxamidine hydrochloride (10.0 g, 80 mmol) was added and reaction mixture was stirred for 15 min. Diethyl malonate (12.6 imL, 82.9 mmol) was added dropwise and the reaction mixture was warmed to RT and stirred overnight. The suspension was then concentrated under vacuum. The resulting residue was dissolved in water and the solution was acidified with concentrated HCI to pH 5. The resulting precipitate was collected via filtration and washed sequentially with water, ether, isopropanol, and finally ether. The solid was then dried under vacuum to afford 11 .69 g (96 %) of 2-cyclopropylpyrimidine-4,6- diol (2). LCMS m/z 153.4 (M+1 ). H NMR (400 MHz, DMSO-d6) δ 1 1 .87 (s, 2H), 5.03 (s, 1 H), 1.86 (m, 1 H), 0.98 (m, 4H).
2-Cyclopropyl-5-nitropyrimidine-4,6-diol (3) Fuming nitric acid (95 imL) was added to glacial acetic acid (263 imL) at 18-20 °C. To the mixture was added 2-cyclopropylpyrimidine-4,6- diol (2) (120 g, 789 mmol) in small portions, while keeping the internal temperature between 20- 30°C. The reaction mixture was stirred at that temperature for 30 min. It was poured onto crushed ice along with proper external cooling and continuous stirring. The precipitated product was filtered off, washed with water and dried under vacuum to afford 87 g (56%) of the title compound (3). LCMS m/z 196.2 (M+1 ). H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 2H), 1.95 (m, 1 H), 1.36 (m, 2H), 1 .26 (m, 2H).
4,6-Dichloro-2-cyclopropyl-5-nitropyrimidine (4) 2-Cyclopropyl-5-nitropyrimidine-4,6- diol (3) (37 g, 187.1 mmol) was added in one portion to phosphorus oxychloride (137.7 g, 898 mmol) with stirring, followed by an immediate addition of A/,/V-dimethylaniline (34 g, 281 mmol) within ~ 5 min. The reaction mixture was heated at reflux temperature for 2 h. The heating was terminated and the mixture was allowed to stand overnight. The excess phosphorus oxychloride was distilled off under vacuum and the residue was poured onto crushed ice. The product was extracted with diethyl ether (4 χ 200 imL). The combined extracts were washed with brine (3 χ 150 imL), dried over sodium sulfate, concentrated to a volume of 100 imL, and then decolorized with activated charcoal. After filtration, the solvent was removed in vacuo. The residue was diluted with hexane and cooled to -78 °C. The resulting solid was filtered cold and washed with cold hexane to afford 31 g (71 %) of the title compound (4). H NMR (400 MHz, DMSO-cf6) δ 2.08 (m, 1 H), 1 .23 (m, 2H), 1 .14 (m, 2H).
4,6-Dichloro-2-cyclopropylpyrimidin-5-amine (5) A flask was charged with acetic acid
(660 imL), heated to 50 °C and iron powder (44 g, 789.6 mmol) was added with efficient stirring. 4,6-Dichloro-2-cyclopropyl-5-nitropyrimidine (4) (44 g, 188 mmol) was then added to the flask in small portions within about 30 min while keeping the temperature between 45-55 °C. After the addition was complete, the mixture was stirred at 50-60 °C for another 2 h. The reaction was filtered through a bed of Celite® and the residue was washed thoroughly with ethyl acetate. The filtrate was neutralized with saturated sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography (5% ethyl acetate in hexane) to afford 33 g (86%) of the title compound (5). H NMR (400 MHz, DMSO-d6) δ 578 (s, 2H), 1.99 (m, 1 H), 0.95-0.87 (m, 2H), 0.83-0.80 (m, 2H).
1 -[(2S)-4-Benzylmorpholin-2-yl]methanamine (6-S), 1 -[(2/?)-4-benzylmorpholin-2- yl]methanamine {6-R), and 1 -[4-benzylmorpholin-2-yl]methanamine (6) were prepared according to the procedures described in Bioorganic Med. Chem. Lett. 1998, 8, 2185-2190, Bioorganic Med. Chem. Lett. 2006, 16, 2022-2025, and J. Med. Chem. 1993, 36, 683-689.
N4-{[(2S)-4-Benzylmorpholin-2-yl]methyl}-6-chloro-2-cyclopropylpyrimidine-4,5- diamine (7) Diisopropylethylamine (1.69 imL, 9.68 mmol) was added to a solution of 4,6- dichloro-2-cyclopropylpyrimidin-5-ylamine (5) (658 mg, 3.23 mmol) and 1-[(2S)-4- benzylmorpholin-2-yl]methanamine (6-S) (699 mg, 3.39 mmol) in dry 1 -methylpyrrolidin-2-one (6 imL) at RT. The mixture was heated at 124 °C for 18 h, cooled, diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed with water (2x) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (10-50% EtOAc/heptanes) to afford 1 .27 g (63%) of compound 7 as a colorless solid. LCMS m/z 374 (M+1 ). H NMR (400 MHz, CDCI3) δ 7.25 - 7.36 (m, 5H), 5.19 (t, J = 5.2 Hz, 1 H), 3.82 - 3.90 (m, 1 H), 3.60 - 3.78 (m, 3H), 3.45 - 3.56 (m, 2H), 3.27 - 3.37 (m, 1 H), 3.15 (br s, 2H), 2.77 (d, J = 1 1 .2 Hz, 1 H), 2.68 (d, J = 1 1.6 Hz, 1 H), 2.18 (td, J = 1 1.3, 3.1 Hz, 1 H), 1 .89 - 1 .99 (m, 2H), 0.80 - 0.98 (m, 4H).
3-{[(2 ?)-4-Benzylmorpholin-2-yl]methyl}-7-chloro-5-cyclopropyl-3H- [1,2,3]triazolo[4,5-cflpyrimidine (8) Sodium nitrite (178 mg, 2.58 mmol) was added to a mixture of N4-{[(2S)-4-benzylmorpholin-2-yl]methyl}-6-chloro-2-cyclopropylpyrimidine-4,5-diamine (7) (803 mg, 2.15 mmol) in dichloroethane (10 imL), water (10 imL) and acetic acid (1 imL) and the reaction was stirred at RT for 2.5 h. The mixture was carefully basified with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3x). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 827 mg (99%) of 8 as a colorless solid. LCMS m/z 385 (M+1 ). H NMR (400 MHz, CD3OD) δ 7.18 - 7.36 (m, 5H) 4.78 (dd, 1 H, J = 14.5, 7.9 Hz) 4.66 (dd, 1 H, J = 14.5, 4.6 Hz) 4.05 - 4.21 (m, 1 H) 3.78 (dt, 1 H, J = 1 1.1 , 3.1 , 2.8 Hz) 3.42 - 3.59 (m, 3H) 2.87 (d, 1 H, J = 1 1.2 Hz) 2.63 (d, 1 H, J = 1 1 .6 Hz) 2.28 - 2.41 (m, 1 H) 2.19 (dt, 1 H, J = 1 1 .2, 3.3 Hz) 2.06 (dd, 1 H, J = 1 1.4, 9.8 Hz) 1 .10 - 1.28 (m, 4H).
3-{[(2 ?)-4-Benzylmorpholin-2-yl]methyl}-5-cyclopropyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7 -amine (9) Concentrated ammonium hydroxide (1 .5 mL, 22 mmol) was added to a solution of 3-{[(2R)-4-benzylmorpholin-2-yl]methyl}-7-chloro-5-cyclopropyl-3/-/-
[1 ,2,3]triazolo[4,5-d]pyrimidine (8) (819 mg, 2.13 mmol) in dioxane (6 mL) in a sealed tube at RT. The mixture was heated at 74 °C for 18 h. The mixture was cooled and concentrated. Methanol was added and the mixture was reconcentrated until only ~1 mL of methanol remained. The product was precipitated by the addition of water and the solid was collected by vacuum filtration and washed with water. The solid was dissolved in chloroform and dried over magnesium sulfate, filtered and concentrated to afford 778 mg (98%) of product (9) as a colorless solid. LCMS m/z 366 (M+1 ). H NMR (500 MHz, CD3OD) δ 7.13 - 7.43 (m, 5 H), 4.65 (dd, J = 14.3, 7.5 Hz, 1 H), 4.52 (dd, J = 14.5, 4.7 Hz, 1 H), 4.04 - 4.19 (m, 1 H), 3.83 (d, J = 1 1 .4 Hz, 1 H), 3.57 (m, J = 1 1.4, 2.6 Hz, 1 H), 3.54 (AB quartet, JAB = 12.96 Hz, ΔνΑΒ = 14.83 Hz, 2 H), 2.83 (d, J = 1 1.4 Hz, 1 H), 2.21 (td, J = 1 1.3, 2.9 Hz, 1 H), 2.02 - 2.10 (m, 2 H), 1.1 1 - 1.15 (m, 2 H), 0.96 - 1 .02 (m, 2 H).
Examples 2-4 were prepared following the procedure for the preparation of (R)-3-((4- benzylmorpholin-2-yl)methyl)-5-cyclopropyl-3/-/-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7-amine (9) in Example 1 but using the appropriate starting materials: 4,6-dichloro-2-cyclopropylpyrimidin-5- amine (5) or 4,6-dichloro-2-methylpyrimidin-5-amine (10), commercially available from Sigma- Aldrich Chemical Company, St. Louis, Mo., and 1 -[4-benzylmorpholin-2-yl]methanamine (6), (6- S), or (6-R).
TABLE 1
Figure imgf000034_0001
Figure imgf000035_0001
Example 5: Synthesis of 3-{r(2 ?)-4-benzylmorpholin-2-yllmethyl>-5-(trifluoromethyl)-3H- ri,2,31triaz -cnpyrimidin-7 -amine (21)
Figure imgf000036_0001
2-(Trifluoromethyl)pyrimidine-4,6-diol (15) Sodium hydride (57 g of a 60% dispersion in mineral oil, 1430 mmol) was stirred in toluene under nitrogen and cooled with a wet ice bath. Butanol (130 mL, 1430 mmol) was added drop-wise and mixture was stirred for 30 min.
Malonamide (50 g, 480 mmol) was added in one portion followed by the drop-wise addition of methyl trifluoroacetate (14) (67.5 g, 475 mmol), which led to an immediate exotherm. When the addition was complete, the reaction mixture was stirred at 40 °C overnight and then cooled to RT. The reaction was diluted with 1 N HCI (300 mL) and then concentrated HCI was added until pH = 2. The layers were separated and the aqueous layer was extracted with ethyl acetate (3X), dried over magnesium sulfate, and concentrated. The resulting orange solid was triturated with 2:1 heptane: DCM (2 x 100 mL), collected by filtration, and dried under vacuum overnight to provide 28.1 g of 15 as a light orange solid. LCMS m/z 181.1 (M+1 ). H NMR (400 MHz, CD3OD) δ 5.90 (s, 1 H).
5-Nitro-2-(trifluoromethyl)pyrimidine-4,6-diol (16) Dihydroxypyrimidine 15 (1.0 g, 5.6 mmol) was dissolved in TFA (2 mL) and stirred for 15 min at RT. Fuming nitric acid (0.325 mL) was added drop-wise, maintaining the temperature <25°C, and the reaction was stirred overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate (2 x 20 mL). The organic extracts were dried over MgS04, filtered and concentrated to provide 851 mg of nitropyrimidine 16 as an off-white solid. LCMS m/z 224.1 (M+1 ). 9F NMR (376 MHz, DMSO-cfe) δ -70.45 (s, 3 F).
4,6-Dichloro-5-nitro-2-(trifluoromethyl)pyrimidine (17) To a mixture of pyrimidine 16 (22 g, 97 mmol) and POCI3 (46 mL, 489 mmol) under N2 at RT was added phosphoric acid (0.567 mL, 9.77 mmol), followed by the drop-wise addition of diisopropylethylamine (17 mL, 98 mmol) while keeping the reaction temperature below 40 °C. The reaction mixture was then heated at 45 °C overnight behind a blast shield. After cooling to RT, the reaction mixture was added slowly dropwise to water (750 mL) in a 2 L beaker with vigorous stirring. The mixture was extracted with diethyl ether (4 x 200 mL). The combined extracts were dried over MgS04, filtered and concentrated to provide 21.67 g of 17 as a light yellow solid. 9F NMR (376 MHz, DMSO-cf6) δ -70.73 (s, 3F).
4,6-Dichloro-2-(trifluoromethyl)pyrimidin-5-amine (18) To a mixture of
dichloronitropyrimidine 17 (21 .6 g, 82.4 mmol) in AcOH (344 mL) was added iron powder (21.6 g, 388 mmol) portion-wise. The mixture was SLOWLY heated to 50 °C for 75 min and formed a very thick gray/brown sludge. After cooling to RT, the mixture was diluted with ethyl acetate, filtered through Celite and concentrated. The resulting material was dissolved in ethyl acetate, washed with water (3x), brine (2x), dried over MgS04, filtered and concentrated to provide 17.1 g of 18 as a light brown solid. LCMS m/z 230.0 (M+1 ). 9F NMR (376 MHz, DMSO-d6) δ -67.82 (s, 3 F).
N4-{[(2S)-4-Benzylmorpholin-2-yl]methyl}-6-chloro-2-(trifluoromethyl)pyrimidine- 4,5-diamine (19) Amine 6-S (1 1.03 g, 53.47 mmol) was stirred in MeCN (0.3 M, 169 mL). Sodium carbonate (1 1.15 g, 100 mmol) was added, followed by dichloropyrimidine 18 (1 1 .78 g, 50.78 mmol). The reaction mixture was heated to 80 °C for 36 h and then cooled while stirring. The mixture was filtered, rinsing with diethyl ether, and the filtrate was concentrated to afford 21 g of 19, that was used without further purification. LCMS m/z 402.1 (M+1 ). H NMR (400 MHz, CDCI3) δ 7.22 - 7.42 (m, 5H), 5.40 (d, J = 5.0 Hz, 1 H), 3.89 (d, J = 1 1.2 Hz, 1 H), 3.74 - 3.86 (m, 2H), 3.65 - 3.74 (m, 1 H), 3.47 - 3.57 (m, 2H), 3.34 - 3.45 (m, 1 H), 2.81 (d, J = 1 1.2 Hz, 1 H), 2.70 (d, J = 1 1.2 Hz, 1 H), 2.20 (td, J = 1 1 .3, 3.1 Hz, 1 H), 1 .91 - 2.05 (m, 1 H), 1.79 (br s, 2H).
3-{[(2 ?)-4-Benzylmorpholin-2-yl]methyl}-7-chloro-5-(trifluoromethyl)-3H- [1,2,3]triazolo[4,5-cflpyrimidine (20) To a mixture of diaminopyrimidine 19 in MeTHF (1 10 mL) at RT was added a solution of sodium nitrite (3.97 g, 57.5 mmol) in water (25 mL). To the resulting mixture, 1 N HCI (131 imL, 2.5 eq) was added drop-wise over 25 min. The reaction mixture was stirred at RT for 45 min and then the pH of the mixture was adjusted to pH 9-10 by addition of sodium carbonate (7.99 g, 73.2 mmol). The layers were separated and the aqueous layer was extracted three times with MeTHF. The organic layers were combined, washed with brine, dried over MgS04, filtered and concentrated to provide 20 as an oil (21.38 g with -0.3 molar equivalents of residual 2-MeTHF). This material was used without further purification. LCMS m/z 413.1 (M+1). H N MR (400 MHz, CDCI3) δ 7.12 - 7.48 (m, 5H), 4.98 (dd, J= 14.1, 8.3 Hz, 1H),4.73 (dd, J= 14.1,3.7Hz, 1H), 4.19 - 4.30 (m, 1H), 3.81 -3.86 (m, 1H), 3.50 - 3.61 (m, 3H), 2.88 (d, J= 10.8 Hz, 1H), 2.63 (d, J= 11.6 Hz, 1H), 2.27 (td, J= 10.9,3.1 Hz, 1H), 2.12 -2.20 (m, 1H).
3-{[(2?)-4-Benzylmorpholin-2-yl]methyl}-5-(trifluoromethyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7-amine (21) Chloropyrimidine 20 (16.5 g, 40 mmol) was dissolved in 2-MeTHF (55 imL) in a sealed tube pressure vessel and aqueous ammonium hydroxide (65 imL) was added. The pressure vessel was capped and heated with stirring to 80 °C overnight. After cooling to RT, the vessel was opened and the MeTHF was removed in vacuo to provide a sticky solid in the aqueous layer, which was sonicated for 15 min to afford a granular suspension. After the suspension was stirred for 1 h, heptane (30 imL) was added to afford a fine suspension that was filtered, rinsing with water and heptane. The resulting solid was dried under vacuum to provide 17.78 g of 21 as an off-white solid. LCMS m/z 394 (M+1). H NMR (400 MHz, CDCI3) δ 7.26-7.36 (m, 5H), 6.71 (br s, 2H), 4.85 (dd, J = 14.3,8.1 Hz, 1H), 4.60 (dd, J = 14.2, 4.2 Hz,
1H), 4.18-4.24 (m, 1H), 3.88 (brddd, J= 11.3,2.9,2.9 Hz, 1H), 3.59 (brddd, J= 11, 11,2.5 Hz, 1H), 3.53 (s, 2H), 2.85 (brd, J= 11 Hz, 1H),2.63 (brd, J= 11.5 Hz, 1H),2.26 (brddd, J= 11, 11,3Hz, 1H), 2.13(dd, J= 11.1,9.4 Hz, 1H).
Example 6: Synthesis of 3-r(4-benzylmorpholin-2-yl)methyll-5-(trifluoromethyl)-3H- Γ1 ,2,31triazolor4,5-cnpyrimidin-7 -amine (22)
Prepared following the procedure for the preparation of (R)-3-((4-benzylmorpholin-2- yl)methyl)-5-(trifluoromethyl)-3/-/-[1,2,3]triazolo[4,5-c/]pyrimidin-7-amine (21) in Example 5 but using racemic 1-[4-benzylmorpholin-2-yl]methanamine (6) to provide 3-((4-benzylmorpholin-2- yl)methyl)-5-(trifluoromethyl)-3/-/-[1,2,3]triazolo[4,5-c/]pyrimidin-7-amine (22). LCMS m/z 394 (M+1). H NMR (400 MHz, CDCI3) δ 7.17 - 7.38 (m, 5H) 4.83 (dd, J = 14.1 , 7.9 Hz, 1H) 4.59 (dd, J= 14.3, 4.4 Hz, 1H) 4.15 -4.26 (m, 1H)3.87 (dt, J= 11.6, 2.9 Hz, 1H) 3.54 -3.64 (m, 1H)3.52 (s, 2H)2.84 (d, J= 11.2 Hz, 1H)2.62 (d, J= 11.6 Hz, 1H)2.25 (td, J= 10.9, 3.1 Hz, 1H)2.12 (dd, J= 11.2,9.5 Hz, 1H).
Figure imgf000039_0001
Example 7: Synthesis of 3-r(2/?)-morpholin-2-ylmethyll-5-(trifluoromethyl)-3H- ri,2,31triazolor4,5-cnpyrimidin-7 -amine hydrochloride (23)
Benzyl morpholine 21 (16.6 g, 42.2 mmol) was dissolved in MeTHF (166 imL) in a hydrogenation vessel, charged with 10 % Pd(OH)2 on carbon (1.66 g, 10 % w/w catalyst load), and placed under a hydrogen atmosphere (50 psi). The reaction mixture was heated to 550 C overnight. The catalyst was removed by filtration. The filtrate was concentrated to afford12.7 g of 23 as a light-colored solid. H NMR (400 MHz, CD3OD) δ 4.58 - 4.76 (m, 2H), 4.04 - 4.15 (m, 1H), 3.75-3.82 (m, 1H), 3.49 (ddd, 1H, J= 11.6, 10.2, 3.9 Hz), 3.00 (dd, 1H, J= 12.4, 2.9 Hz), 2.75 (d, 1H, J = 3.3 Hz), 2.72 -2.83 (m, 1H), 2.66 (dd, 1H, J= 12.6, 10.2 Hz).
Example 8: Synthesis of 3-{r(2?)-4-(1,3-thiazol-2-ylmethyl)morpholin-2-yllmethyl>-5- (trifluoromethyl)-3H-ri,2,31triazolor4,5-/lpyrimidin-7-amine (24)
In a dry round-bottomed flask under N2, morpholine 23 (100 mg, 0.29 mmol) was stirred in MeTHF (1.2 imL). Thiazole-2-carbaldehyde (43 mg, 0.38 mmol) was added and the reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (186 mg, 0.88 mmol) was added and the reaction was stirred at RT overnight. The reaction mixture was diluted with 1 N HCI. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc (3x). The combined extracts were dried over MgS04, filtered and concentrated. The resulting light yellow glass was purified by chromatography (gradient elution: 50% ethyl acetate/heptane to 100% ethyl acetate) to yield 84 mg of 24 as a white solid. LCMS m/z 401.1 (M+1). H NMR (400 MHz, DMSO-d6) δ 9.06 (br s, 1H), 8.82 (brs, 1H), 7.71 (AB quartet, JAB= 3.3 Hz, ΔνΑΒ= 18.1 Hz, 2H), 4.62-4.72 (m, 2H), 4.06-4.12 (m, 1H), 3.88 (s, 2H), 3.75-3.79 (m, 1H), 3.44 (brddd, J= 11, 11, 2 Hz, 1H), 2.95 (brd, J= 11 Hz, 1H), 2.67 (brd, J = 11 Hz, 1H), 2.28 (brddd, J = 11, 11,3Hz, 1H),2.22 (brdd, J= 11, 10Hz, 1H). Example 9: Synthesis of 3-{r(2?)-4-methylmorpholin-2-yllmethyl>-5-(trifluoromethyl)-3H- H ,2,31triazolor4,5-cnpyrimidin-7 -amine (25)
Figure imgf000040_0001
To a mixture of morpholine 23 (12.7 g, 41.9 mmol) in DCM (180 imL) and acetonitrile (360 ml_) at RT under nitrogen were added potassium carbonate (7.16 g, 50.3 mmol) and iodomethane (5.94 g, 41.9 mmol). The reaction mixture was stirred at RT overnight and concentrated. The resulting solid was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgS04, filtered and concentrated. The crude product was chromatographed (0-5%
MeOH: EtOAc) to afford 8.24 g of 25 as a white solid. LCMS m/z 318.2 (M+1). H NMR (400 MHz, DMSO-d6) δ 9.04 (br s, 1 H), 8.80 (br s, 1 H), 4.59-4.70 (m, 2H), 4.02-4.08 (m, 1 H), 3.73 (ddd, J= 11.3,2.7,2.7 Hz, 1H),3.40 (ddd, J= 10.9, 10.9, 2.5 Hz, 1H), 2.77 (br d, J = 11 Hz, 1H), 2.5-2.54 (m, 1H, assumed; partially obscured by solvent peak), 2.18 (s, 3H), 2.01 (ddd, J = 11.0, 11.0,3.2 Hz, 1H), 1.93 (dd, J= 11.1, 9.7 Hz, 1H).
Example 10: Synthesis of 5-cvclopropyl-3-r(2/?)-morpholin-2-ylmethyll-3H- ri,2,31triazolor4,5-cnpyrimidin-7 -amine hydrochloride (26)
Figure imgf000040_0002
Pd(OH)2/C (200 mg) was added to a nitrogen-flushed solution of (R)-3-((4- benzylmorpholin-2-yl)methyl)-5-cyclopropyl-3/-/-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7-amine (9) (759 mg, 2.08 mmol) in methanol (30 imL) and concentrated HCI (1.2 imL). The mixture was shaken under 43 psi of hydrogen gas for 18 h. The mixture was purged with nitrogen, filtered, and concentrated to afford 705 mg of the title compound as a colorless solid. LCMS m/z 289 (M+1 ) H NMR (400 MHz, CD3OD) δ 4.8 (m, 2H) 4.4 (m, 1H), 4.01 (dd, 1H, J = 13.4, 3.6 Hz) 3.8 (dt, 1H, J= 13.0,2.0 Hz) 3.58 (d, 1H, J= 13.0 Hz) 3.29 (d, 1H, J= 12.5 Hz) 3.18 (m, 2H) 2.22 (m, 1H) 1.4 (m,2H) 1.27 (m,2H). Examples 11-14 are shown in Table 2 and were prepared according to the procedure described in Example 10 using the corresponding benzylmorpholine starting materials: Example 2(11), 3(12), 4(13), and 6 (22).
TABLE 2
Figure imgf000041_0001
Example 15: Synthesis of 5-methyl-3-{r(2ff)-4-methylmorpholin-2-yllmethyl}-3H- ri,2,31triazolor4,5-cnpyrimidin-7 -amine (31)
Figure imgf000042_0001
Morpholine 29 (5.58 g, 22.38 mmol) was dissolved in water (0.4 mL), acetic acid (5.4 mL), and formaldehyde (2.55 mL of a 37% aqueous solution). Zinc dust (2.99 g, 44.8 mmol) was added and the mixture was heated at 60 °C for 1 h, then cooled, filtered to remove the zinc, and rinsed with water. Aqueous ammonia was added to the filtrate. Upon standing approximately 10 min, a white solid began to form in the flask. A stirbar was added and the mixture was stirred an additional 30 min. The resulting slurry was cooled in an ice/water bath for 30 min and then filtered to collect the solid. The solid was rinsed with water. The filtrate and aqueous wash were combined and extracted with MeTHF (3 x 80 mL). The combined extracts were washed with brine, dried over MgS04, filtered, and concentrated to give 4.85 g of 31 as a white solid. LCMS m/z 264.3 (M+1 ). H NMR (400 MHz, DMSO-d6) δ 8.24 (br s, 1 H), 7.94 (br s, 1 H), 4.57 (dd, half of ABX system, J = 14.3, 7.9 Hz, 1 H), 4.49 (dd, half of ABX system , J = 14.2, 4.7 Hz, 1 H), 3.99- 4.05 (m, 1 H), 3.73 (ddd, J = 1 1.2, 2.9, 2.4 Hz, 1 H), 3.40 (br ddd, J = 1 1 , 11 , 2 Hz, 1 H), 2.71 (br d, J = 11 Hz, 1 H), 2.5-2.55 (m, 1 H, assumed; partially obscured by solvent peak), 2.43 (s, 3H), 2.17 (s, 3H), 2.00 (br ddd, J = 1 1 , 11 , 3 Hz, 1 H), 1.89 (br dd, J = 11 , 10 Hz, 1 H).
Example 16: Synthesis of 5-cvclopropyl-3-{r4-(pyridin-2-ylmethyl)morpholin-2-yllmethyl>- 3H-ri,2,31triazolor4,5-cnpyrimidin-7 -amine hydrochloride (32)
Figure imgf000042_0002
Triethylamine (80 uL, 0.57 mmol) was added to a solution of morpholine 27 (40 mg, 0.11 mmol) and 2-picolyl chloride hydrochloride (28.3 mg, 0.172 mmol) in 1-propanol (3 mL). The mixture was heated at 75 °C for 18 h. The mixture was cooled, diluted with saturated aqueous sodium bicarbonate solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a gradient system (0 to 40% 1 :1 EtOAc-methanol/1 :1 EtOAc-dichloromethane) to afford 34 mg of the title compound 32 after conversion to the HCI salt by the addition of 17% HCI in diethyl ether. LCMS m/z 367 (M+1). H NMR (400 MHz, CD3OD) 58.79 (ddd, J = 5.1, 1.5,0.8 Hz, 1H), 8.17 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 7.80 (br d, J = 7.9 Hz, 1H), 7.69 (ddd, J = 7.6, 5.2, 0.9 Hz, 1H), 4.73-4.83 (m, 2H), 4.58 (s, 2H), 4.47-4.53 (m, 1H), 4.03 (brdd, J= 13, 3.5 Hz, 1H), 3.84-3.91 (m, 1H), 3.71 (brd, J= 12 Hz, 1H), 3.41 (brd, J = 12 Hz, 1H), 3.14-3.23 (m, 2H), 2.22-2.28 (m, 1H), 1.31-1.40 (m, 4H).
Examples 17-21 are shown in Table 3 and were prepared according to the procedure described in Example 16 using the corresponding morpholine starting materials (23, 27, 28, or 30) and the requisite alkyl halide.
TABLE 3
Figure imgf000043_0001
Figure imgf000044_0001
Example 22: Synthesis of 5-cvclopropyl-3-{r(2 ?)-4-pyrimidin-2-ylmorpholin-2-yllmethyl>- 3H-ri,2,31triazolor4,5-cnpyrimidin-7 -amine hydrochloride (38)
Figure imgf000044_0002
Triethylamine (352 μί, 2.52 mmol) was added to a solution of morpholine 26 (139 mg,
0.505 mmol) and 2-bromopyrimidine (161 mg, 1 .01 mmol) in dry acetonitrile (4 mL) at RT. The mixture was heated to 75 °C for 60 h. The mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with 1 :1 THF/EtOAc (2x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a gradient system (0 to 40% 1 : 1 EtOAc-methanol/1 : 1 EtOAc-dichloromethane) to afford 135 mg of 38 after conversion to the HCI salt by the addition of one equivalent of 1N HCI. LCMS m/z 354 (M+1). H NMR (500 MHz, CD3OD) δ 8.48 (d, J=4.7 Hz, 2 H), 6.83 (t, J=4.9 Hz, 1 H), 4.72 - 4.85 (m, 2 H), 4.66 (d, J=13.0 Hz, 1 H), 4.37 (d, J=13.5 Hz, 1 H), 4.08 - 4.23 (m, 1 H), 3.98 (dq, J=11.7, 1.8 Hz, 1 H), 3.60 (td, J=11.5, 2.9 Hz, 1 H), 3.21 (ddd, J=13.5, 11.4, 3.6 Hz, 2 H), 3.11 (dd, J=13.5, 10.4 Hz, 1 H), 2.20-2.26 (m, 1 H), 1.35- 1.43 (m,2H), 1.31 -1.35 (m, 2 H).
Examples 23-25 are shown in Table 4 and were prepared according to the procedure described in Example 22 using the corresponding morpholine starting materials (27, 28, or 30) and the requisite heteroaryl halides.
TABLE 4
Figure imgf000045_0001
Example 26: Synthesis of 5-cvclopropyl-3-{r(2/?)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-
Figure imgf000046_0001
Sodium triacetoxyborohydride (690 mg, 3.26 mmol) was added to a solution of morpholine 26 (350 mg, 1.09 mmol), thiazole-2-carboxaldehyde (172 mg, 1.52 mmol), diisopropylethylamine (378 μΙ_, 2.17 mmol) in acetonitrile (10 mL) at RT. After 18 h, the reaction was quenched by the addition of 1 N HCI and stirred for 15 min. The mixture was made basic with aqueous sodium bicarbonate solution and extracted with 1 :1 THF/EtOAc (2x). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography using a gradient system (0 to 40% 1 :1 EtOAc-methanol/1 : 1 EtOAc-dichloromethane) to afford 281 mg of 42 after conversion to the HCI salt by the addition of 1 equivalent of 1 N HCI. LCMS m/z 373 (M+1 ). H NMR (400 MHz, CD3OD) δ 8.0 (d, 1 H, J = 3.3 Hz) 7.8 (d, 1 H, J = 3.3 Hz) 4.8 (m, 4H) 4.42 (m, 1 H) 4.02 (dd, 1 H, J = 13.3, 2.9 Hz) 3.82 (m, 2H) 3.56 (d, 1 H, J = 12.5 Hz) 3.22 (m, 2H) 2.2 (m, 1 H) 1.2-1.15 (m, 4H).
Examples 27-58 are shown in Table 5 and were prepared according to the procedure described in Example 26 using the corresponding morpholine starting materials (26, 27, 28, or 30) and the requisite aldehydes.
TABLE 5
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Examples 59-62: Synthesis of 3-ri-(4-benzylmorpholin-2-yl)ethyll-5-(trifluoromethyl)-3H- n,2,31triazolor4,5-cnpyrimidin-7 -amine (75) and the individual diastereomers (76 rExample
Figure imgf000055_0002
80 81 82 83
Figure imgf000055_0003
separated via
chiral HPLC
4-Benzylmorpholine-2-carbonitrile (80) was prepared according to procedures described in Bioorganic Med. Chem. Lett. 2006, 16, 2022-2025, and J. Med. Chem. 1993, 36, 683-689.
4-Benzylmorpholine-2-carboxylic acid (81) Nitrile 80 (10 g, 49.44 mmol) was combined with concentrated HCI (50 imL) at RT in a sealed glass bottle with magnetic stirbar. The mixture was heated to 90 °C for 16 h and then cooled to RT. A precipitate formed and the slurry was concentrated and then azeotroped from toluene to provide 15.0 g of 81 as a light pink solid. LCMS m/z 222.1 (M+1 ). H NMR (400 MHz, CD3OD) δ 7.41 - 7.63 (m, 5H) 4.43 (q, 2H) 4.14 (br s, 11-1) 3.94 (d, J = 12.9 Hz, 1 H) 3.68 (br s, 1 H) 3.32 - 3.42 (m, 2H) 3.13 - 3.28 (m, 2H).
4-Benzyl-/V-methoxy-/V-methylmorphoNne-2-carboxamide (82) A mixture of carboxylic acid 81 (7.73 g, 30 mmol), /V-methylmorpholine (12.3 g, 120 mmol), and Ν,Ο- dimethyl hydroxylamine (8.96 g, 90 mmol) in DCM (200 mL) was treated with EDCI (17.6 g, 90 mmol)at RT. The reaction mixture was stirred for 16 h and then poured into saturated aqueous sodium bicarbonate solution and extracted with CH2CI2. The combined extracts were dried over MgS04, filtered, and concentrated to provide 7.90 g of 82 as a light yellow oil. LCMS m/z 265.1 (M+1 ). H NMR (400 MHz, CDCI3) δ 7.18 - 7.35 (m, 5H) 3.94 - 4.03 (m, 1 H) 3.68 - 3.77 (m, 2H) 3.65 (s, 3H) 3.48 - 3.59 (m, 2H) 3.17 (s, 3H) 2.91 (d, J = 1 1.2 Hz, 1 H) 2.66 (dd, J = 1 1.6, 2.1 Hz, 1 H) 2.19 - 2.34 (m, 2H).
1-(4-Benzylmorpholin-2-yl)ethanone (83) Weinreb amide 82 (7.9 g, 29.89 mmol) was dissolved in THF (200 mL) at RT under nitrogen and cooled to 0 °C. Methylmagnesium bromide (29.9 mL of a 3N solution in diethyl ether, 89.7 mmol) was added in portions. The reaction mixture was stirred at 0 °C for 1 h, allowed to warm to RT and then stirred for 16 h. The mixture was again cooled to 0 °C and saturated aqueous ammonium chloride solution was slowly added. The mixture was extracted with EtOAc, and the extracts were washed with brine, dried over MgS04, filtered and concentrated to provide 6.25 g of 83 as a yellow oil that was used without further purification.
1-(4-Benzylmorpholin-2-yl)ethanamine (84) A mixture of ketone 83 (6.25 g, 28.5 mmol), ammonium acetate (22.2 g, 285 mmol), sodium cyanoborohydride (2.83 g, 42.8 mmol), and 5 angstrom molecular sieves (10 g) in methanol was stirred at RT under nitrogen for 16 h. The sieves were removed by filtration and the filtrate was concentrated. A solution of 1 N NaOH was added until the pH reached 12. The mixture was extracted with CH2CI2 and the combined extracts were dried over MgS04, filtered and concentrated. The resulting light yellow oil (7.8 g) was purified by chromatography (elution with 5% MeOH in CH2CI2 followed by 30% MeOH in CH2CI2) to yield 3.0 g of 84 as a light yellow gum. LCMS m/z 221.2 (M+1 ). H NMR (400 MHz, CDCI3) δ 7.13 - 7.37 (m, 5H), 3.81 - 3.90 (m, 1 H), 3.60 - 3.71 (m, 1 H), 3.41 - 3.58 (m, 2H), 3.27 - 3.34 (m, 1 H), 3.02 - 3.09 (m, 1 H), 2.87 - 2.97 (m, 1 H), 2.79 (dd, J = 11.0, 5.2 Hz, 1 H), 2.57 - 2.68 (m, 1 H), 2.08 - 2.18 (m, 1H), 1.05 - 1.15 (m, 3H).
3-(1-(4-Benzylmorpholin-2-yl)ethyl)-5-(trifluoromethyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7 -amine as a mixture of diastereomers (75) and the individual diastereomers (76, 77, 78, and 79) Prepared according to the procedures in Example 1 starting from amine 84 and 4,6-dichloro-2-(trifluoromethyl)pyrimidin-5-amine (18) to provide a diastereomeric mixture (75). LCMS m/z 408.1 (M+1).
The diastereomers were separated by chiral HPLC using the following conditions: a Chiracel OJ-H column (250 mm x 21.0 mm), flow rate of 65 mL/min, and 10% ethanol in carbon dioxide. The 4 diastereomers were separated but diastereomer 78 was contaminated with an impurity and required a second chiral chromatography using a ChiralPAK AD-H column (250 mm x 21 mm), a flow rate of 65 mL/min and 15% isopropanol in carbon dioxide. The diastereomers are listed below in order of elution with the diastereomer with the shortest retention time listed first.
Diastereomer 76: LCMS m/z 408.3 (M+1). H NMR (400 MHz, CDCI3) δ 7.18-7.26 (m,
5H), 6.74 (brs, 2H), 5.12-5.20 (m, 1H), 4.11 (ddd, J = 9.3, 7.6, 2.3 Hz, 1H), 3.89 (ddd, J= 11.3, 2.7, 2.7 Hz, 1H),3.69 (brddd, J= 11, 11,2.5 Hz, 1H),3.41 (AB quartet, JAB = 13.0Ηζ,ΔνΑΒ = 43.9 Hz, 2H), 2.58 (brd, J= 11 Hz, 1H), 2.39 (brd, J= 11 Hz, 1H), 2.14 (br ddd, J = 11, 11,3 Hz, 1H), 2.02 (dd, J= 11.2,9.6 Hz, 1H), 1.79 (d, J = 7.0 Hz, 3H).
Diastereomer 77: LCMS m/z 408.3 (M+1). H NMR (400 MHz, CDCI3) δ 7.18-7.26 (m,
5H), 6.76 (brs, 2H), 5.12-5.19 (m, 1H), 4.11 (ddd, J = 9.4, 7.5, 2.3 Hz, 1H), 3.89 (ddd, J= 11.3, 3.0,2.5 Hz, 1H),3.69 (brddd, J= 11, 11,2.5 Hz, 1H),3.41 (AB quartet, JAB = 13.0Ηζ,ΔνΑΒ = 45.3 Hz, 2H), 2.56-2.61 (m, 1H), 2.40 (brd, J= 11 Hz, 1H), 2.14 (br ddd, J = 11, 11, 3.5 Hz, 1H), 2.02 (dd, J= 11.2, 9.6 Hz, 1H), 1.79 (d, J = 7.0 Hz, 3H).
Diastereomer 78: LCMS m/z 408.3 (M+1). H NMR (400 MHz, CDCI3) δ 7.28-7.37 (m,
5H), 6.96 (br s, 2H), 5.13-5.20 (m, 1H), 4.24 (br ddd, J = 8.9, 8.9, 2.2 Hz, 1H), 3.76 (ddd, J = 11.4, 2.8, 2.8 Hz, 1 H), 3.55 (AB quartet, JAB = 12.9 Hz, ΔνΑΒ = 43.4 Hz, 2H), 3.43-3.53 (m, 1 H), 2.95 (brd, J= 11 Hz, 1H), 2.58 (br d, J = 11 Hz, 1H), 2.22 (brddd, J= 11, 11, 3 Hz, 1H), 2.11 (dd, J= 10.8, 9.4 Hz, 1H), 1.64 (d, J = 7.0 Hz, 3H).
Diastereomer 79: LCMS m/z 408.3 (M+1). H NMR (400 MHz, CDCI3) δ 7.23-7.37 (m,
5H), 6.83 (br s, 2H), 5.12-5.20 (m, 1H), 4.24 (br dd, J = 9, 9 Hz, 1H), 3.74-3.79 (m, 1H), 3.55 (AB quartet, JAB = 12.8 Hz, ΔνΑΒ=43.8 Hz, 2H), 3.47-3.54 (m, 1H), 2.96 (brd, J= 11 Hz, 1H), 2.59 (brd, J= 11.5 Hz, 1H), 2.19-2.26 (m, 1H), 2.11 (dd, J= 10, 10 Hz, 1H), 1.64 (brd, J = 7.0 Hz, 3H). Example 63: Synthesis of 3-ri-(4-methylmorpholin-2-yl)ethyll-5-(trifluoromethyl)-3H- ri,2,31triazolor4,5-cnpyrimidin-7 -amine (86) as a single diastereomer (absolute
Figure imgf000058_0001
3-(1 -Morpholin-2-ylethyl)-5-(trifluoromethyl)-3H-[1,2,3]triazolo[4,5- /]pyrimidin-7- amine (85) Benzylmorpholine diastereomer 77 was dissolved in methanol to a concentration of 0.05 M and passed through an H-cube flow hydrogenator with a cartridge (cartridge brand ThalesNano CatCart30, 30 mm) of 20% palladium hydroxide on carbon at 75 °C and 10 bar with a flow rate of 1.0 imL/min and rinsing with methanol. The reaction mixture was concentrated to afford product 85. LCMS m/z 318.3 (M+1 ). H NMR (400 MHz, CD3OD) δ 4.89 - 5.05 (m, 1 H), 3.97 (ddd, J = 10.2, 7.6, 2.4 Hz, 1 H), 3.88 (dt, J = 1 1.5, 2.2 Hz, 1 H), 3.56 - 3.66 (m, 1 H), 2.68 - 2.77 (m, 2H), 2.56 (dd, J = 12.5, 10.3 Hz, 1 H), 2.40 - 2.50 (m, 1 H), 1 .73 (d, J = 7.0 Hz, 3H).
3-[1 -(4-Methylmorpholin-2-yl)ethyl]-5-(trifluoromethyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7 -amine (86) Morpholine 85 (135 mg, 0.42 mmol) was dissolved in water (2 imL) and acetic acid (0.1 imL, 1 .7 mmol). Formaldehyde solution (0.05 imL of a 37% aqueous solution) was added followed by zinc dust (56 mg, 0.85 mmol). The reaction mixture was heated at 60 °C overnight and then ammonium hydroxide (3 imL of 30 % aqueous solution) was added. Solid sodium chloride was added to saturate the solution and then the mixture was extracted with MeTHF (3 x 2 imL). The combined extracts were washed with brine (2 imL), dried over Na2S04, filtered, concentrated and chromatographed (eluted with gradient of 50-100% EtOAC in heptane) to afford 22 mg of 86 as a white solid. LCMS m/z 332.2 (M+1 ). H NMR (400 MHz, CD3OD) δ 5.04 (dt, J = 14.2, 7.0 Hz, 1 H) 4.02 - 4.12 (m, 1 H) 3.86 - 3.96 (m, 1 H) 3.67 (td, J = 1 1 .6, 2.5 Hz, 1 H) 2.55-267 (m, 1 H), 2.31 - 2.37 (m, 1 H), 2.20 (s, 3H) 2.1 1 (td, J = 1 1.5, 3.4 Hz, 1 H) 1 .92 (t, J = 10.6 Hz, 1 H) 1 .76 (d, J = 7.0 Hz, 3H).
PDE8 inhibition assays
PDE8A SPA assay protocol: Test compounds were solubilized in 100% dimethyl sulfoxide and diluted to the required concentrations in 15% dimethyl sulfoxide/water. The human PDE8A enzyme was thawed slowly and diluted in 50 imM Tris HCI buffer (pH 7.5 at RT) containing 1 .3 imM MgCI2. Incubations were initiated by the addition of enzyme solution to 384- well plates containing test drugs and radioligand (20 nM 3H-cAMP). After a 30 min. incubation at RT, phosphodiesterase SPA beads (Amersham/GE) were then added to the assay plate at a concentration of 0.2 mg/well to stop the reaction. The activities of test compounds were assessed by measuring the amount of 3H-5'AMP resulting from enzyme cleavage of 3H-cAMP radioligand. Levels of 3H-5'AMP bound to SPA beads were determined by paralux counting of the assay plates in a Microbeta Trilux Counter (PerkinElmer). Non-specific binding was determined by radioligand binding in the presence of a saturating concentration (10 μΜ) of a potent PDE8 inhibitor.
PDE8B SPA assay protocol: Same as the PDE8A SPA assay protocol except that human PDE8B enzyme was used instead of the human PDE8A enzyme.
PDE8B fluorescence polarization (FP) assay protocol: Test compounds were solubilized in 100% dimethyl sulfoxide and diluted to the required concentrations in 20% DMSO/assay buffer. The human PDE8B enzyme was thawed and diluted in assay buffer: 10 mM Tris HCI (pH 8.0 at RT), 10 mM Tris HCI (pH 7.0 at RT), 10 mM MgCI2 and 0.007% Tween- 20. Enzyme and test compounds were added to a 384-well plate, followed by the TAMARA- cAMP substrate (Molecular Devices R7457) to initiate the reaction. After a 45 min. incubation in the dark at RT, binding reagent (Molecular Devices Original Binding System R8073) was added to the assay and allowed to incubate another 60 min. Plates were read on the Analyst GT. Activity of test compounds was assessed by calculating % inhibition, using total counts and background to determine the assay window.
For all assays, the IC50 value (concentration at which 50% inhibition of specific binding occurs) of each compound tested was calculated by non-linear regression (curve fitting) of the concentration-response, and are reported in Table 6.
TABLE 6
PDE8A ICso (nM) PDE8B ICso (nM)
Ex. No.
SPA assay SPA assay FP assay
1 316 17.2
2 41.3 46.8
3 72.2
4 257 38.4
5 4.81
6 17.1
7 4.52
8 0.747 <0.316
9 141 <9.72
10 18.2
1 1 88.4 74.3
12 209
13 73.4 PDE8A ICso (nM) PDE8B ICso (nM)
Ex. No.
SPA assay SPA assay FP assay
14 66.1
15 549 24.6
16 5.19
17 9.93
18 23.9
19 1.8 1.69
20 5.4 <0.59
21 3.51 5.75
22 37.3
23 27.5 20.4
24 107
25 48.5
26 1.44
27 1.24 1.31
28 108
29 54
30 233
31 72.1
32 12.4
33 1 19
34 3.04
35 955
36 155
37 62.7
38 139
39 1 18
40 58.6
41 75.3
42 8.07
43 1 1.3 34.4
44 1450
45 5.78 5.36
46 3.67
47 83.3
48 7.48 8.87
49 0.512 0.702
50 80.2
51 43
52 50.3
53 5.49
54 50.8
55 6.23
56 394
57 1.93
58 2.27 <0.377
59 >1000 >1000
60 26.9 3.21 PDE8A ICso (nM) PDE8B ICso (nM)
Ex. No.
SPA assay SPA assay FP assay
61 >1000 >1000
62 837 2.92
63 134 1 1.9
When introducing elements of the present invention or the exemplary embodiment(s) thereof, the articles "a," "an," "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations to the invention, the scope of which is defined by the appended claims.

Claims

A compound of Formula I:
Figure imgf000062_0001
wherein:
R is alkyl, haloalkyi, cycloalkyl, heterocycloalkyl, aminoalkyl, aryloxyalkyl, hydroxyalkyl, or alkoxyalkyl, wherein R may be optionally substituted with one or more substituents independently selected from halo, haloalkyi, alkyl, cycloalkyl, hydroxy, amino, and alkoxy;
R2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein R2 may be optionally substituted with one or more substituents independently selected from halo, haloalkyi, alkyl, cycloalkyl, hydroxy, amino, and alkoxy;
R3 and R4 are independently hydrogen, alkyl, or haloalkyi; and
R5 is a bond, methylene, or ethylene, wherein said methylene or ethylene may be substituted by a methyl or ethyl substituent;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R5 is -(CH2)n-, wherein n is 0, 1 , or 2.
3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyi, alkyl, cycloalkyl, hydroxy, amino, and alkoxy.
4. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R2 is hydrogen, methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said methyl, phenyl, oxazolyl, triazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyi, alkyl, cycloalkyl, hydroxy, amino, and alkoxy;
provided that when R2 is oxazolyl, triazolyl, pyrazinyl, thiazolyl, or imidazolyl, said optional substituent is not halo, and that when R2 is pyridazinyl, pyrazolyl, pyrimidinyl, or pyridinyl, and said optional substituent is halo, the ring carbon or carbons to which said halo substituent or substituents is attached is not adjacent to a ring N atom and/or ring O atom; and
R4 is hydrogen.
5. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R is alkyl, haloalkyi, or cycloalkyl;
R2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyi, and alkyl; and
R3 and R4 are hydrogen.
6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl may be optionally substituted with one or two substituents independently selected from halo, haloalkyi, and alkyl, and wherein said oxazolyl or thiazolyl may be optionally substituted with one or two substituents
independently selected from haloalkyi and alkyl.
7. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein:
R is methyl, trifluoromethyl, or cyclopropyl; and
R2 is hydrogen, phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein said phenyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, or pyridinyl may be optionally substituted with one or two substituents independently selected from fluoro, trifluoromethyl, and methyl.
8. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R is methyl, cyclopropyl, or trifluoromethyl; R2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl, oxazolyl, or thiazolyl may be optionally substituted with one or two substituents independently selected from ethyl, methyl, and trifluoromethyl; and
R3 and R4 are hydrogen.
9. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein:
n is 1 ;
R is methyl, cyclopropyl, or trifluoromethyl;
R2 is hydrogen, phenyl, oxazolyl, or thiazolyl, wherein said phenyl, oxazolyl, or thiazolyl may be optionally substituted with one or two methyl substituents; and
R3 and R4 are hydrogen.
10. A compound according to claim 1 or claim 2 selected from:
3-{[(2R)-4-benzylmorpholin-2-yl]methyl}-5-cyclopropyl-3H-[1 ,2,3]triazolo[4,5-c/]pyrimidin-
7-amine;
3-[(4-benzylmorpholin-2-yl)methyl]-5-cyclopropyl-3/-/-[1 ,2,3]triazolo[4,5-d]pyrimidin-7- amine;
3-{[(2R)-4-benzylmorpholin-2-yl]methyl}-5-methyl-3H-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7- amine;
3-{[(2R)-4-benzylmorpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
3-[(4-benzylmorpholin-2-yl)methyl]-5-(trifluoromethyl)-3H-[1 ,2,3]triazolo[4,5-c/]pyrimidin- 7-amine;
3-[(2R)-morpholin-2-ylmethyl]-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7- amine;
3-{[(2R)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/- [1 ,2,3]triazolo[4,5-d]pyrimidin-7-amine;
3-{[(2R)-4-methylmorpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
5-cyclopropyl-3-[(2R)-morpholin-2-ylmethyl]-3/-/-[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine; 5-methyl-3-{[(2R)-4-methylmorpholin-2-yl]methyl}-3H-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7- amine; 5-cyclopropyl-3-{[4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl}-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
5-cyclopropyl-3-{[4-(pyrimidin-2-ylmethyl)m
c/]pyrimidin-7-amine;
5-methyl-3-{[4-(pyrimidin-2-ylmethyl)mor^
c/]pyrimidin-7-amine;
3-{[4-(pyridin-2-ylmethyl)morpholin-2-y^
c/]pyrimidin-7-amine;
3-{[(2R)-4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-{[4-(pyrimidin-2-ylmethyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-cyclopropyl-3-{[(2R)-4-pyrimidin-2-ylmorp
c/]pyrimidin-7-amine;
5-cyclopropyl-3-[(4-pyrimidin-2-ylmorpholin-2-yl)methyl]-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
5-methyl-3-[(4-pyrimidin-2-ylmorpholin-2-yl)methyl]-3/-/-[1 ,2,3]triazolo[4,5-c/]pyrimidin-7- amine;
3-[(4-pyrimidin-2-ylmorpholin-2-yl)methyl]-5-(trifluoromethyl)-3H-[1 ,2^]tr^
cdpyrimidin-7-amine;
5-cyclopropyl-3-{[(2R)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl}-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-cyclopropyl-3-{[4-(1 thiazol-2-ylmethyl^
c/]pyrimidin-7-amine;
5-cyclopropyl-3-({4-[(4-ethyl-1 ,3-thiazol-2-yl)methyl]morpholin-2-yl}methyl)-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-methyl-3-{[4-(1 thiazol-2-ylmethyl)morph^
c/]pyrimidin-7-amine;
5-methyl-3-({4-[(1-methyl-1 H-imidazol-2-yl)methyl]morpholin-2-yl}methyl)-3^
[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-{[4-(3,5-difluorobenzyl)morpholin-2-yl]methyl}-5-methyl-3/-/-[1 ,2,3]triazolo[4,5- cdpyrimidin-7-amine;
3-{[(2R)-4-(3,5-difluorobenzyl)morpholin-2-yl]methyl}-5-methyl-3H-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine hydrochloride; 3-({4-[(4-ethyl- 1 ,3-th iazol-2-yl )m ethyl]morpholin-2-yl}methyl)-5-methyl-3/-/- [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-({4-[(4-isopropyl-1 ,3-thiazol-2-yl)methyl]morpholin-2-yl}methyl)-5-methyl-3 - - [1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-methyl-3-{[4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl}-3H-[1 ,2,^
c/]pyrimidin-7-amine;
3-{[4-(1 ,3-thiazol-2-ylmethyl)morp^
[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-{[4-(3,5-difluorobenzyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3H-[1 ,^
c/]pyrimidin-7-amine;
3-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
3-({4-[(4-ethyl-1 ,3-thiazol-2-yl)methyl]morpholin-2-yl}methyl)-5-(trifluorometh
[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
3-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5- c/]pyrimidin-7-amine;
3-({(2R)-4-[(4-Ethyl-1 ,3-thiazol-2-yl)methyl]morpholin-2-yl}methyl)-5-methyl-3H^
[1 ,2,3]triazolo[4,5-cf]pyrimidin-7-amine;
5-methyl-3-{[(2R)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]meth
c/]pyrimidin-7-amine;
5-methyl-3-{[(2R)-4-(1 ,3-thiazol-2-ylmethyl)morpholin-2-yl]meth
cdpyrimidin-7-amine ;
3-[1-(4-benzylmorpholin-2-yl)ethyl]-5-(trifluoromethyl)-3/-/-[1 ,2,3]triazolo[4,5-cf]pyrimidin- 7-amine; and
3-[1-(4-methylmorpholin-2-yl)ethyl]-5-(trifluoromethyl)-3H-[1 ,2,3]triazolo[4,^
7-amine;
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A method of treating a neurodegenerative disease or disorder, the method comprising administering a compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.
13. A method according to claim 12 wherein the neurodegenerative disease or disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, Huntington's disease, cognitive impairment associated with Alzheimer's disease, age related cognitive decline, schizophrenia, or ADHD.
14. A method according to claim 13 wherein the neurodegenerative disease or disorder is spinal cord injury.
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CN112266386B (en) * 2020-10-20 2022-03-25 中山大学 2-chloroadenine derivative, preparation method and application
CN118206555A (en) * 2024-03-15 2024-06-18 海赋药业(海南)有限责任公司 3, 8-Disubstituted adenine derivative, preparation method and application thereof

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