WO2010058333A1 - Lactams as beta secretase inhibitors - Google Patents

Lactams as beta secretase inhibitors Download PDF

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Publication number
WO2010058333A1
WO2010058333A1 PCT/IB2009/055043 IB2009055043W WO2010058333A1 WO 2010058333 A1 WO2010058333 A1 WO 2010058333A1 IB 2009055043 W IB2009055043 W IB 2009055043W WO 2010058333 A1 WO2010058333 A1 WO 2010058333A1
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Prior art keywords
compound
alkyl
aryl
halogen
substituted
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PCT/IB2009/055043
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French (fr)
Inventor
Michael Aaron Brodney
Ivan Viktorovich Efremov
Christopher John Helal
Brian Thomas O'neill
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Pfizer Inc.
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=41481076&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2010058333(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to AP2011005725A priority Critical patent/AP2011005725A0/en
Priority to MX2011005346A priority patent/MX2011005346A/en
Priority to CA2743584A priority patent/CA2743584A1/en
Priority to EA201170722A priority patent/EA201170722A1/en
Priority to CN2009801552711A priority patent/CN102317289A/en
Priority to EP09764055A priority patent/EP2370439A1/en
Priority to JP2011536976A priority patent/JP4932065B2/en
Priority to BRPI0922799A priority patent/BRPI0922799A2/en
Priority to MA33879A priority patent/MA32929B1/en
Priority to US13/130,192 priority patent/US20110224231A1/en
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to NZ592823A priority patent/NZ592823A/en
Priority to AU2009318855A priority patent/AU2009318855A1/en
Publication of WO2010058333A1 publication Critical patent/WO2010058333A1/en
Priority to IL212869A priority patent/IL212869A0/en
Priority to TN2011000252A priority patent/TN2011000252A1/en
Priority to ZA2011/03738A priority patent/ZA201103738B/en

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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present inhention relates to the treatment of Alzheimer's disease and other neurodegeneratihe and/or neurological disorders in mammals, including humans.
  • This inhention aiso relates to inhibiting, in mammals, inciuding humans, the production of A-beia peptides that can contribute to the formation of neurological deposits of amyloid protein More particularly, this inhention relates to spir ⁇ -piperidine compounds useful for the treatment of neurodegeneratihe and/or neurological disorders, such as Alzheimer's disease and Down's Syndrome, related to A-beta peptide production.
  • AD Alzheimer's disease
  • CM cerebral amyloid angiopathy
  • prion-mediated diseases see, e g., Haan et a/.. Clin, Neurol. Neurosurg, 1990, 92(4 ⁇ :305-310; Gienner et a/,, J. Neuroi. Sci, 1989, 94:1-28)
  • AD affects nearly half of all people past the age of 85, the most rapidly growing portion of the United States population. As such, the number of AD patients in the United States is expected to increase from about 4 million to about 14 miilion by the middle of the next century.
  • Beta-secretase (BACE) inhibitors are one such strategy and numerous compounds are under ehaluation by pharmaceuticai groups.
  • the present inhention relates to a group of brain-penetrable BACE inhibitors and as such would be expected to be BACE inhibitors and modulators for the treatment of AD (see Ann. Rep. Med. Chem. 2007, Olsen ef a/., 42; 27-47). Summary of the inhention The inhention is directed to a compound, including the pharmaceutically acceptable salts thereof, hahing the structure of formula I:
  • stereochemistry shown in formula i at the carbon bonded to R ⁇ and at the spirocycSic carbon is the absolute stereochemistry; 8 is alkyl, aryS, heteroaryi, cycloalkyl, or heterocycloafkyf, wherein B is optionally substituted with zero to three R 3 groups;
  • R 1b is absent and R 1a is hydrogen, aikyi. alkenyi, -(CH 2 )rCycioalkyl.
  • -COOR 7 - C(O)R 7 , -CN, or -N(R 7 J 2 , wherein said aryi, alkyl, cycioaikyi and heteroaryl substituent is optionaiiy substituted with one to three halogen, aikyi, hydroxyl, or -O-aikyi; R 2 ss aikyi, cycioaikyi, or alkenyi wherein said alkyl, cycioaikyi, or aSkenyl is optionally substituted with one to three halogen, hydroxyl, or cyano; each R 3 is independently haiogen, alkyl.
  • R 7 cyano, hydroxyl, -O-alkyl, -O- cycloalkyl, -SO 2 R 7 . -N(R 7 ) 2 , -COR 7 , -CON(R 7 J 2 , -(CH ⁇ -cycioalkyl, -(CH 2 ⁇ r heterocycloaikyi, -(CH 2 ) t -aryl, or - ⁇ CH 2 ) t -heteroaryi wherein said R 3 alkyl, -(CH 2 Jr cycloaikyi, -(CHsX-heterocydoalkyl, -(CH 2 J r aryl, or - ⁇ CH 2 ) r heteroaryl is optionaiiy substituted with one to three R 4 ; each R* is independently aikyi, halogen, cyano, -SO 2 NHR 7 , -CON(R 7 J 2 , -N(R%
  • each R 1 alkyl, -(CH 2 )rcycloaikyi, -(CH 2 Jr heterocycloalkyl, -(CH;) t -aryl, or -(CH 2 J t -heteroaryl is optionaiiy independently substituted by one to three cyano, aikyS, halogen, -CF 3 or -OR 5 ; each R 3 is independentiy hydrogen, aikyi, - ⁇ CH ⁇ r-cyclo
  • each R' is independently hydrogen, aikyi, - ⁇ CH 2 X-cydoalkyl, - ⁇ CH 2 ) r heterocycloalkyl, -(CHaVaryi, or -(CH 2 ) r heteroaryl, or when two R 7 substituents are attached to the same nitrogen atom they may be taken together with the nitrogen to which they are attached to form a heterocycioalkylene moiety; and wherein said alkyl, - ⁇ CH 2 ) r cycl ⁇ aSkyS, - ⁇ Ci-yrheterocycioalkyl, - ⁇ CH 2 )rary1, or -
  • inhention is a s ⁇ ngie bond, and R u and R !b are each independently hydrogen or alky
  • R ia and R ib are each hydrogen.
  • A is aryl
  • A is cycioalkyi. In another embodiment of the inhention, A is heteroaryl.
  • A is heterocycioajkyl.
  • A is aryi, heferoaryl, cycSoalkyl or heferocycloalkyl, and A is optionally substituted with one R 4 substituent.
  • R a is independently alkyl, halogen, cyano. -SO 2 NHR 7 , -CON(R 7 ) 2 . -M(R 7 Ih ⁇ N(R ? ⁇ C0R 7 , ⁇ SO 2 N(R ?
  • each R 4 alkyl, -(CH 2 ) r cycioalkyl, - ⁇ CH 2 ) r heterocycloaikyi, -(CH2)t-aryl « or -(CH 2 )rheteroaryi is optionally independently substituted by one to three cyano, alkyl, halogen, -CF 3 , or -OR 5
  • A is aryl or heteroaryl
  • R 4 is
  • A is aryl and R 4 is -OR 5 , wherein R ⁇ is independently -(CH 2 ) t -cycioalkyl or -(CH;) r heteraaryi wherein t is zero and said cycloaSkyl or heleroaryi is optionally substituted with one to three R G ,
  • A is aryl and R" is - ⁇ CH 2 ) t -aryl wherein t is zero and the ary) is optionally substituted by one to three cyano, alkyl, halogen, or -OR 5 in another example of this embodiment, A is aryi and R 4 is - ⁇ CH- ) r heteroaryl wherein t ts
  • A is heteroaryl and R 4 is - ⁇ CH : ) r aryl wherein t is zero and the aryl is optionally substituted by one to three cyano, aiky ⁇ , halogen, or -OR 5 in another example of this embodiment, A is heteroaryl and R ⁇ is - ⁇ CH 2 ) r heteroaryl wherein f is zero and the heteroaryl is optionally substituted by one to three cyano, alkyl, halogen, or -OR 5
  • inhention A is aryi, heteroaryl, cycloaikyi or heterocycloalkyl
  • an ⁇ A is optionally substituted with two R 4 substituents.
  • each R 4 is independently alkyl, halogen, cyano.
  • each R 4 aikyl, -(CH s ) r cycl ⁇ aikyi, -(CH 2 ) r heferocycloaikyi, -(CH : ) r aryl, or - ⁇ CH 2 ) r heteroary1 is optionally independently substituted by one to three cyano, alkyl, halogen, or -OR 5 .
  • each R 4 is alkyl optionally independently substituted by one to three cyano, alkyl, halogen, or -OR 5 ,
  • A is aryl or heteroaryl, and each R 4 is independently aikyi, halogen, cyano, -SGEWHR 7 . -CON ⁇ R 7 ) 2!
  • each R 4 is alkyl optionally independently substituted by one to three cyano, alkyl, halogen, or - OR 5
  • each R 4 is independently alkyl, halogen, -(CH 2 ) t -cycioalkyI, - ⁇ CH 2 ) r heterocycloalkyL -(CH 2 ) r aryi, or -(CH 2 )rheteroaryl.
  • each R 4 - ⁇ CH 2 ) t -cydoalkyl f -(CH 2 ) r aryl, or - ⁇ CH 2 ) r heteroaryi is optionally independently substituted by one to three cyano, aikyi, halogen, or - OR 5 .
  • A is aryl and at least one R 4 is -(CH 2 ) r aryl wherein t is zero and the aryi is optionally substituted by one to three cyano, alkyl, halogen, or -OR 5 .
  • A is aryl and each R 4 is ⁇ OR ⁇ , Sn another example of this embodiment, A is heteroaryl and at least one R 4 is -(CH ⁇ ) t -aryl wherein t is zero and the heteroaryi is optionally substituted by one to three cyano, alkyl, halogen, or -OR S , In another example of this embodiment, A is heteroaryS and each R 4 is -OR 5 .
  • A is aryl, heteroaryl, cycioalkyl or heter ⁇ cycl ⁇ aikyi, and A is optionally substituted with three R 4 substituents,
  • each R 4 is independently alkyl, halogen, cyano, -SO 2 NHR 7 , -CON(R 7 ) 2: ⁇ N(R 7 )COR 7 , -SO 2 N(R 7 ⁇ 2 , -N(R 7 )SO 2 R 7 , -COR 7 , -SO 2 R 7 , -(CH 2 )t-cycloalkyi, -(CH 2 ⁇ r heierGcycloaikyi, ⁇ (CH 2 ) r aryi, -(CH 2 ) r heteroaryl, -(CH 2 K- N(R 7 ) 2 , or -(CH 2 JrOR 5 wherein each R 4 alkyl, -(CH 2 )
  • -(CH 2 ),- heterocycloaikyi, ⁇ (CH 2 ) r aryL or ⁇ (CH 2 )rheteroaryl is optionally independently substituted by cyano, alkyl, halogen, or ⁇ OR S .
  • A is aryl or heteroaryl and each R 4 is independently alkyl, halogen, cyano, -SO 2 NHR 7 , -CGN(R 7 K -N ⁇ R 7 )COR ⁇ -SO 2 N ⁇ R 7 ) S , -N(R 7 JSO 2 R 7 , -COR 7 , -SO 2 R 7 , - ⁇ CH a ) r cycloalkyl, - ⁇ CH 2 ) r heterocycloalkyL -(CHaVaryl, ⁇ (CH 2 )rheteroaryl, - ⁇ CH 2 ⁇ r N(R 7 ⁇ 2 , or -(CH 2 ) r OR 5 wherein each R 4 alkyl, -(CH 2 ) t -cycioalkyl, -(CH 2 )rheterocyc)oaikyi, -(CHs ' j t -aryl, or
  • each R 4 is alkyl optionally independentiy substituted by one to three cyano, alkyl, halogen, or ⁇ QR & .
  • each R 4 is independently halogen, -OR 5 , cyano, trifluoroaikyS, - ⁇ CH 2 )rCydoalkyi, -(CH 2 )rheterocycioalkyl, ⁇ (CH 2 )raryi, or -(CH 2 ),-heteroaryl, wherein each R 4 -(CH 2 ) r cycloalkyl, - ⁇ CH ⁇ -heterocycioalkyl, ⁇ (CH z ) r aryl.
  • R 4 is -(CH2)rheterocycloaikyi wherein t is zero and the heterocycioaSkyS is pyrro ⁇ dinyl, piperidinyl or morphoiinyl , and is optionally independently substituted by cyano, alkyl, halogen, or -OR 5
  • B is aryl. Examples of said embodiment include but are not limited to:
  • B is substituted with one to three R 3 substituents.
  • R 3 substituents examples include but are not limited to; N- ⁇ 4-[(5R.7S )-8-(4-H ydroxy-3-isopropoxy-be nzy S) ⁇ 7 ⁇ methy i-2-oxc- 1 , 8-diaza- spiro[4.53dec-1-yl]-phenyi ⁇ -acetamide; ⁇ 5R,7S)-1-Biphenyl-2-yl-8-(4-hydroxy-3- ⁇ sopropoxy-benzyl)-7-methyl-1,8- diaza-s ⁇ iro[4,53decan-2-one; (5R,7S)-8-(4-Hydroxy-3-isopropoxy-benzyi)-7-methyl-1-(3-trifluoromethyl- phenyl)-1 ,8-diaza-spiro[4.53decan-2-one;
  • B is substituted with only one R 3 substituent and R 3 is halogen.
  • Exampies of said embodiment include but are not limited to; ⁇ 5R,7S)-1 -(2-Fluoro-phenyl)-8- ⁇ 4-hydroxy-3-ssopropoxy-benzyi)-7-methyi-1 ,8- diaza ⁇ spiro
  • B is cycioaikyi.
  • An example of this embodiment includes but is not limited to (5R,7S)-1-Cyciohexyi-8 ⁇ 4 ⁇ hydroxy ⁇ 3 ⁇ is ⁇ pr ⁇ poxy-b ⁇ nzyl)-7-methy1-1 s 8- ⁇ a;za-spiro[4.5]decan-2-Gne,
  • B is aikyi.
  • An example of this embodiment includes but is not limited to (5R,7S)-8- ⁇ 4-Hydroxy-3-isopropoxy- benzyl) ⁇ 1 -isopropyl-7-methyl-1 ,8 ⁇ diaza ⁇ spiro[4.5]decan ⁇ 2 ⁇ one.
  • B is heterocycioalkyl
  • An example of this embodiment includes but is not limited to ⁇ 5R,7S)-8-(4-Hydroxy-3-isopropoxy- benzyl)-7-methyi-1-(tetrahydro-pyran-4-yl)-1 t 8-diaza-sp!ro[4.53deca ⁇ -2-o ⁇ e.
  • R 2 is alkyl
  • the compound, including the pharmaceutically acceptable salts thereof, hahe the structure, where the substituents are defined abohe:
  • the compound including the pharmaceutically acceptable salts thereof, hahe the st ⁇ icture, where the substitue ⁇ ts are defined abohe;
  • the present inhention prohides methods of treating neurological and psychiatric disorders comprising; administering to a patient in need thereof an amount of a compound of formula I effectihe in treating such disorders.
  • Neurological and psychiatric disorders incSude but are not limited to: acute neurological and psychiatric disorders such as cerebrai deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebrai ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypogiyc ⁇ mic neuronal damage.
  • dementia AlDS-induced dementia
  • the inhention proh ides a method for treating a condition in a mammal, such as a human, selected from the conditions abohe, comprising administering a compound of formuia I to the mammal.
  • the mammal is preferably a mammal in need of such treatment.
  • the inhention proh ides a method for treating attention deficit/hyperactihity disorder, schizophrenia and Alzheimer's Disease.
  • the present inhention proh ides methods of treating neurological and psychiatric disorders comprising; administering to a patient in need thereof an amount of a compound of formula I effectihe in treating such disorders.
  • the compound of formula I is opfionaily used in combination with another actihe agent.
  • Such an actihe agent may be, for example, an atypical antipsychotic, a cholinesterase inhibitor, or NMDA receptor antagonist.
  • atypical antipsychotics include, but are not limited to, ziprasidone, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, paliperidone;
  • NMDA receptor antagonists include but are not limited to memantine; and such ch ⁇ linesterase inhibitors include but are not limited to donepezil and galantamine.
  • the inhention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I 1 and a pharmaceutically acceptable carrier.
  • the composition may be, for example, a composition for treating a condition selected from the group consisting of neurological and psychiatric disorders, including but not limited to: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induced dementia, hascular dementia, mixed dementias, age- associated memory impairment, Alzheimer's disease, Huntingfon's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitihe disorders, including cognitihe disorders associated with schizophrenia and bipolar disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, conhulsions, migraine,
  • composition optionally further comprises an atypical antipsychotic, a cholinesterase inhibitor, dimebon, or NMDA receptor antagonist.
  • atypical antipsychotics include, but are not limited to, ziprasidone, clozapine, olanzapine, risperidone, quefiapine, aripiprazole, paiiperidone;
  • NMDA receptor antagonists include but are not iimited to memantine; and such choiin esterase inhibitors include but are not limited to donepezii and galantamine.
  • alkyl refers to a linear or brartched-cha ⁇ rt saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by remohal of a hydrogen) containing from one to twenty carbon atoms; in one embodiment from one to twelhe 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.
  • substit ⁇ ents examples include methyl, ethyl, propyl (including n-propyl and isopropyi), butyl (including n-butyi, tsobutyi, sec-butyl and teri-butyl), pentyi, iso-amyi, hexyl and the itk ⁇ .
  • benzyl refers to methyl radical substituted with phenyl, i.e., the
  • cydoalkyl refers to a carbocyclic subsiitueni obtained by remohing a hydrogen from a saturated carbocyclic molecule and hahing three to fourteen carbon atoms, in one embodiment, a cycioalkyl substituent has three to ten carbon atoms.
  • Examples of cycloaikyi include cyciopropyi, cyclobutyl, cyclopentyl an ⁇ cycl ⁇ iiexyl.
  • cycloaikyiene moiety refers to a carbocyclic substituent obtained by remohing two hydrogen atoms from a saturated carbocyclic moiecuSe and hahing three to fourteen carbon atoms.
  • a cycloaikyiene substituent has three to ten carbon atoms. Examples of cydoaikyiene include the following:
  • cycioalkyl aiso includes substituents that are fused to a C 6 -C 10 aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group hahing such a fused cycloaSkyS group as a substituent is bound to a carbon atom of the cycloaSkyS group.
  • a fused cycloaSkyS group is substituted with one or more substituents, the one or more substitutents, uniess otherwise specified, are each bound to a carbon atom of the cycloaikyi group.
  • a cycloaikyi may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyciopropyl, cyclobutyl, cyclopentyi, and cyclohexyi. Alternatihely, 2 or 3 rings may be fused together, such as bicyciodecanyl and decalinyi.
  • aryp refers to an aromatic substituent containing one ring or two or three fused rings.
  • the aryl substituent may hahe six to eighteen carbon atoms.
  • the aryl substituent may hahe six to fourteen carbon atoms.
  • aryf may refer to substituents such as phenyl, naphfhyi and anthracenyi.
  • aryl also includes substituents such as phenyl, naphthyl and anthracenyi that are fused to a C 4 -Gi 0 carbocyclic ring, such as a C s or a C 6 carbocyciic ring, or to a 4- to 10-membered heterocyclic ring, wherein a group hahing such a fused aryl group as a s ⁇ bstituent is bound to an aromatic carbon of the aryl group.
  • substituents such as phenyl, naphthyl and anthracenyi that are fused to a C 4 -Gi 0 carbocyclic ring, such as a C s or a C 6 carbocyciic ring, or to a 4- to 10-membered heterocyclic ring, wherein a group hahing such a fused aryl group as a s ⁇ bstituent is bound to an aromatic carbon of the aryl group.
  • aryl groups include accordingly phenyl, naphthalenyl, fefrahydronaphthalenyi (also known as "teiralinyf), indenyl, isoindenyS, indanyS, anthracenyi, phenanthrenyi, benz ⁇ naphthenyl (also known as "phenalenyl”), and fluorenyl.
  • the number of carbon atoms in a hydrocarbyi substituent is indicated by the prefix “C x -Cy-/' wherein x is the minimum and y is the maximum number of carbon atoms in the substituent
  • C x -Cy-/' wherein x is the minimum and y is the maximum number of carbon atoms in the substituent
  • “CrCe-aikyi” refers to an aikyi substituent containing from 1 to ⁇ carbon atoms
  • Ca-Ce-cyci ⁇ aikyi refers to saturated cycloaikyi containing from 3 to 6 carbon ring atoms
  • heterocycioalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one ore more heteroatoms, in the cyclic moiety of the heterocycloaikyi.
  • hydrogen refers to hydrogen substituent, and may be depicted as -H.
  • hydroxy 11 or "hydroxyl” refers to -OH.
  • 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 include, for example, alcohols, enois and phenol.
  • hydroxyaSkyf refers to an alkyl that is substituted with at least one hydroxy substituent.
  • examples of hydroxyalkyl include hydroxymethyi, hydroxyethyi, hydroxypropyl and hydroxybutyL
  • cyano also referred to as "nitrite” means -CN, which also may be
  • carbonyl means -C(O)-, which also may be depicted as:
  • amino refers to -NH 2
  • alkylamino refers to an amino group, wherein at least one aikyl chain is bonded to the amino nitrogen in place of a hydrogen atom.
  • aikylamino substit ⁇ ents include monoalkylamino such as methylamino (exemplified
  • dialkylamino such as di methylamino, (exemplified by the formula ⁇ N(CH 3 ) 3 ) ; which may also be depicted:
  • halogen refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br) 1 or iodine (which may be depicted as -I).
  • the halogen is chlorine.
  • the halogen is a fluorine.
  • 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 ieast one halogen substituent. Where more than one hydrogen is replaced with halogens, the haiogens may be the identical or different.
  • haloaikyis examples include chloromethyi, dichloromethyl, difiuorochloromethyl, dichlorofluoromethyi, trichloromethyi, 1-bromoethyl, fluoromethyi, difi ⁇ oromethyl, trifl ⁇ oromethyi, 2,2.2-trifiuoroethyi, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyi, and heptafiuoropropyi.
  • haloaikoxy refers to an alkoxy that is substituted with ai least one halogen substituent.
  • haloaSkoxy substituents include chior ⁇ m ⁇ thoxy, 1-bromoethoxy, fluoromethoxy, difiu ⁇ rometh ⁇ xy, trifluoromethoxy (also known as "perfiuoromethyloxy"), and 2,2,2-trifluoroethoxy.
  • oxy refers to an ether substituent, and may be depicted as -O-.
  • alkoxy refers to an alkyl linked to an oxygen, which may also be represented as.
  • alkoxy examples include methoxy, ethoxy, propoxy and butoxy.
  • heterocycloaikyi refers to a substituent obtained by remohing a hydrogen from a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At ieast 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 heterocycloaikyi alternatihely 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 heterocycloaikyi 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 heterocycloaikyi substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at ieast one heteroatom.
  • heterocycloaikyi also includes substituents that are fused to a Cs-
  • a fused heterocydoalkyl group ts substituted with one more substituents
  • the one or more substituents are each bound to a tieteroatom of the heterocycloaikyl group or to a carbon atom of the heterocydoalkyl group.
  • the fused Cs-Cio aromatic ring or 5- to 10-membered heteroaromat ⁇ c ring may be optionally substituted with halogen, CrCe aikyi.
  • Ca-Cjo cydoalkyl, CrCs alkoxy, or 0.
  • heterocycloaikyiene moiety refers to a substituent obtained by remohing two hydrogen atoms from a saturated or partially saturated ring structure containing a totai of 3 to 14 ring atoms, where at least one of the ring atoms is a heteroatom.
  • a heterocycloaikyiene substituent has three to ten ring atoms. Exampies of heterocycloaikyiene include the following;
  • 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 inciude e-membered ring subsfituenfs such as py ⁇ dyl, pyrazyl, pyrimidinyl, and pyrida2tnyi
  • 5-membered ring substituents such as triazolyi, imidazoiyl, furanyi, fhiophenyi, pyrazoiyl, oxazolyi, isoxazoiyl, thiazolyi, 1 ,2.3-, 1,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazoiyl and isothiazolyS
  • 8/5-membered fused ring substituents such as benzothiofuranyi, isobenzothiofuranyi, benzisoxazoiyl, benzoxazolyi, purinyl, and anthranilyl
  • 6/6-membered fused rings such as quinolinyl, isoquino ⁇ nyl,
  • 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 cartoon atom, where the nng 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 s ⁇ bstituent if the heteroaryl s ⁇ bstituent 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.
  • heteroaryf also includes pyridyS N-oxtdes and groups containing a pyridine N-oxide ring.
  • heteroaryls and heterocycloaikyis examples include furanyS, dihydrofuranyS, tetrahydrofuranyl, thiophenyl (also known as "th ⁇ ofuranyl"), dihydrothiophenyl, tetrahydrothi ⁇ phenyi, pyrroiyi, isopyrroSyi, pyrroiinyl, pyrroiidinyi, imidazoSyl.
  • pyhmidinyl also known as “1 ,3-diazinyt” or “pyrirnidyl”
  • pyrazinyl also known as "1,4-diazinyl”
  • piperaztnyl triazinyl ⁇ including s-triazsnyl (also known as "1,3,5-triazi ⁇ yi"), as-triaz ⁇ nyl (also known 1,2,4-triazi ⁇ yi), and h-triazinyl (also known as "1,2,3-triazinyl”)
  • oxaztnyl including 1,2,3-oxazinyl, 1 ,3,2-oxazinyi, 1 ,3,6-oxaztnyl (also known as "pentoxazoiyl"), 1,2,6-oxazinyl, or 1,4-oxazinyS
  • isoxazinyi including o-isoxaziny
  • 2-fused-ring heteroaryls include, indolizinyl, pyrsndinyl, pyranopyrrolyi, 4H-quinolizinyl, pu ⁇ nyl, naphthyridinyi, pyridopyridinyl (including pyrido[3,4 ⁇ fo]-pyridinyi, pyrido[3,2-b]-pyridinyi, or pyrido[4,3-b] ⁇ pyridtnyl), and pteridinyl, indolyl, isoindofyl, indoleninyl, isoi ⁇ dazolyi, benzazinyl, phthalazi ⁇ yi, quinoxalinyl, quinazoSinyS, benzodiazinyi, benzopyra ⁇ yl, benzothiopyranyi, benzoxazoiyl, indoxazinyl, anthranilyl, benzodioxoiyl,
  • 3-fused-ring heteroaryls or heterocycloalkyls include 5 s 6-dihydro ⁇ 4H-irnidazo£4,5 s 1-ij3quinoline, 4, ⁇ -dihydroimidazo[4 l ⁇ t 1-hi]i ⁇ dole t
  • fused-ring heteroaryls include benzo-fused h ⁇ teroarySs such as indolyi, isoindolyl (also known as “isobenzazolyf ' or “pseudoisoindoiyl”), indoleninyl (also known as “pseudoindoiyl”), isoinclazolyl (also known as “benzpyrazoiyl”), benzazinyl (including quinolinyl (also known as “1-benzazinyP) or tsoquinolinyl (also known as "2-benzazi ⁇ yl”)), phthaiazinyS, qui ⁇ oxa ⁇ yi, quinazolinyi, benzodiazinyl (including cinno ⁇ yi ⁇ also known as "1 ,2-benzodiaztny ⁇ or quinazo ⁇ nyl ⁇ also known as "1 ,3-benzodiazinyr)).
  • indolyi iso
  • benzopyranyi including “chromanyf or Isochrornanyl”
  • benzothiopyranyl also known as “thiochromanyi”
  • benzoxazolyi indoxazinyl (also known as “be ⁇ zisoxazoiyl")
  • anthranilyS benzodioxolyi, be ⁇ zodioxa ⁇ yl, benzoxadtazoiyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl.
  • benzothienyl also known as “benzothtophenyl, 1" “thionaphthenyl,” or “benzothiofuranyl”
  • isobenzothienyl also known as “isobenzothtophenyl,” “isothionaphthenyS,” or “isobenzothiofuranyl” ⁇
  • benzothiazoiyl benzothiadiazolyi, benzimsdazolyS, benzotriazolyS
  • benzoxazinyl including 1 ,3,2-benzoxaz ⁇ nyi, 1,4,2-benzoxazinyl, 2,3,1-benzoxazi ⁇ yl, or 3,1 ,4-benzoxazinyi
  • benzisoxazinyl including 1 ,2-benzisoxazinyl or 1,4-benzisoxazinyl
  • tetrahydroisoquinoltnyl carbazolyi, xanth ⁇ nyl, and
  • heteroaryi also inciudes substituents such as pyridyl and quinoiinyl 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 A- to 10-membered heterocyclic ring, wherein a group hahing 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 substttutents are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the h ⁇ teroaryi group.
  • tieteroarySs and heterocycloaSkySs include: 3-1 H- benzimidazol-2-one, (1 -substituted)- 2-oxo-benzimidazoi-3-yl, 2-tetrahydrofuranyl, 3- te ⁇ rahydrofuranyl, 2-te ⁇ rahydr ⁇ pyranyl, 3-tetrahydropyranyl 4-tetrahydropyranyi,
  • indazolyl indoHzinyl, phthalazinyl, pyrtdaztnyl, triazinyl, isotndolyS, pteridinyl, purinyl, oxadiazoiyl, thiadiazolyi, furazanyi, be ⁇ zofurazanyi, be ⁇ zothiophe ⁇ yl, benzothiazoiyl, be ⁇ zoxazolyS, q ⁇ inazoii ⁇ yl, qut ⁇ oxalt ⁇ yi, naphthyridinyl, and furopyridinyl.
  • a group derihed from pyrrole may be pyrrol-1-yl (M-attached) or pyrroS-3-yl (C-attached).
  • a group derihed from imidazole may be imidazoS-1-yS ⁇ N-attached) or imidazoS- 2-yS (C-attached).
  • a s ⁇ bstituent is "substitutable” if it comprises at least one carbon, suifur, oxygen or nitrogen atom that is bonded to one or more hydrogen atoms.
  • hydrogen, halogen, and cyano do not fall within this definition.
  • a substituent is described as being "substituted," a non-hydrogen s ⁇ bstituent is in the place of a hydrogen subststuent on a carbon, oxygen, sulfur 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 aikyi substituent.
  • monofluoroaSkyS is alkyl substituted with a fluoro substituent
  • difluoroaikyi is aikyi substituted with two fluoro substituents. lt 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 (1 ) not substituted, or (2) 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 3 to 7 atoms.
  • the heterocyclic ring is selected from the group consisting of pyrrolyi, imidazolyl. pyrazolyl, triazolyl, tetrazolyl, isoxazoiyi, pyridyl and thiazolyL
  • substituent refers to substituents that are collectihely 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) substitutabie subsiituents that are substituted by one or more of the optional substituents.
  • a substitue ⁇ t 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 substitutabie positions on the subsfituenf, whicheher is iess.
  • a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryJ with iess than 3 substitutabie positions wouid be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutabie positions.
  • tetrazolyl (which has oniy one substitutabie position) would be optionally substituted with up to one non-hydrogen substituent.
  • the nitrogen wiil 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.
  • the term "aikyicycloaikyi” contains two moieties: aikyi and cycloaikyi.
  • a Ci-C 6 - prefix on C-rCe-aikyicyci ⁇ alkyl means that the alky) moiety of the alkyScycioaikyi contains from 1 to 6 carbon atoms; the C 1 -C 6 - prefix does not describe the cycloalkyl moiety.
  • haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyi substituent is substituted with one or more halogen substituents. If the halogen substitution only occurs on the alkyl moiety, the substituent wouid be described as "aikoxyhaSoaikyi.” if the halogen substitution occurs on both the alkyl moiety and the aikoxy moiety, the substituent would be described as "haloalkoxyhaioalkyl "
  • each substituent is selected independent of the other.
  • Each substituent therefore may be identical to or different from the other s ⁇ bstituent(s), isomers
  • an asymmetric center is present in a compound of formula i, hereinafter referred to as the compound of the inhention, the compound may exist in the form of optical isomers ⁇ enantiomers ⁇ .
  • the present inhention comprises enantiomers and mixtures, including racemic mixtures of the compounds of formula I, In another embodiment, for compounds of formulae I that contain more than one asymmetric center, the present inhention comprises diastereomeric forms ⁇ indihidual diast ⁇ r ⁇ omers 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 inhention comprises the tautomeric forms of compounds of formula I. Where structural isomers are interconhertible 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 halence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • the harious ratios of the tautomers in solid and liquid form is dependent on the harious substituents on the molecule as well as the particular crystallization technique used to isolate a compound. Salts
  • the compounds of this inhention may be used in the form of salts derihed from inorganic or organic acids.
  • a salt of the compound may be adhantageous ⁇ ue to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubiiity in water or oii.
  • a salt of a compound aiso may be used as an aid in the isolation, purification, and/or resoiution of the compound.
  • the salt preferabiy is pharmaceutical ⁇ acceptabie
  • pharmaceuticalSy acceptable salt refers to a sait prepared by combining a compound of formula l with an acid whose anion, or a base whose cation, is generally considered suitabie for human consumption.
  • PharmaeeuticaiSy acceptabie saits are particularly usefui as products of the methods of the present inhention because of their greater aqueous soiubiiity reiatihe to the parent compound.
  • salts of the compounds of this inhention are non-toxic "pharmaceuticaiSy acceptable salts.”
  • Salts encompassed within the term “pharmaceuticaiiy acceptable saits” refer to non-toxic saits of the compounds of this inhention which are generaily prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitabie pharmaceutically acceptable acid addition saits of the compounds of the present inhention when possibie include those derihed from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluorobortc, phosphoric, metaphosphoric, nitric, carbonic, suifonic.
  • inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, boric, fluorobortc, phosphoric, metaphosphoric, nitric, carbonic, suifonic.
  • organic acids such as acetic, benzenesuifonic, benzoic, citric, ethanesuifonic, fumaric, gluconic, giycol ⁇ c, isothionic, Sactic, lactobiontc, maleic, mafic, methanesulfonic, trifluoromethanesuifonic, succinic, toiuenesuifonic, tartaric, and trifiuoroacetic acids.
  • Suitabie organic acids generaiiy include, for example, aliphatic, cycSoaliphatsc, aromatic, araiiphatic, heterocyciylic, carboxylic, and sulfonic classes of organic acids.
  • suitabie organic acids include acetate, trifiuoroacetate, formate, propionate, succinate, glycoSate, giuconate, digiuconate, lactate, maiate, tartaric acid, citrate, ascorbate, giucuronate, maieate, fumarate, pyruhate, aspartate, glutamate, benzoate, anthraniSic acid, mesylate, stearate, salicylate, p ⁇ hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methan ⁇ sulfonate, ⁇ thanesuifonate, benzenesulfonate, pantothenate, toiu ⁇ nesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algentc acid, ⁇ -hydroxybutyrtc acid, galactarate, galacturonate, adipate, al
  • suitable pharmaceutically acceptable salts thereof may include alkali metal saits, i.e., sodium or potassium salts; alkaline earth metal saits, e.g., calcium or magnesium saits; and salts formed with suitable organic Sigands. e.g..
  • base saits are formed from bases which form non- toxic salts, including aluminum, argini ⁇ e, benzathine, choline, diethylamtne, diolamine, glycine, lysine, meglumine, oiarnine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine saits, such as tromethamine, diethylamine, M.N'-difaenzyJethyienediamine, chioro procaine, choline, diethanoiamine, ethyienedtamine. meglumine ⁇ N-methylgiucamine ⁇ , and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as iower aikyl (CrC 6 ) haiides (e.g., methyl, ethyl, propyl, and butyi chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain haltdes (i.e., decyi, iauryl, myristyi, and stearyl chlorides, bromides, and iodides), aryialkyl haiides (i.e., benzyl and phenethyl bromides), and others.
  • agents such as iower aikyl (CrC 6 ) haiides (e.g., methyl, ethyl, propyl, and butyi chlorides, bromides, and iodides), dialkyl s
  • hemisaits of acids and bases may also be formed, for example, hemisulphate and hemicalciurn salts*
  • prodrugs of the compound of the inhention.
  • certain derihatihes of the compound of the inhention which may hahe tittie or no pharmacological actihity themselhes can, when administered into or onto the body, be conherted into the compound of the inhention hahing the desired actihity, for example, by hydrolyt ⁇ c cleahage.
  • Such derihatihes are referred to as "prodrugs.” Further information on the use of prodrugs may be found in "Pro-drugs as Nohel Delihery Systems, VoS.
  • Prodrugs in accordance with the inhention can s for example, be produced by replacing appropriate functionalities present in the compounds of any 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 (Elsehier, 198S). isotopes
  • the present inhention also includes isotopically labelled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom hahing 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 inhention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H 1 3 H, "C, "C 1 ' 4 C, 15 N, 18 O, 17 O 1 3! P. 32 P, 35 S. 18 F, and 38 CI. respectihely.
  • isotopically labelled compounds of formula I of this inhention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or tn the Examples and Preparations below, by substituting a readily ahailable isotopically labelled reagent for a non-isotopically labelled reagent.
  • Administration and Dosing
  • a compound of the inhention is administered in an amount effectihe to treat a condition as described herein.
  • the compounds of the inhention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effectihe for the treatment intended.
  • Therapeutically effectihe 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 inhention may be administered orally.
  • Oral administration may inholhe 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 inhention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intrahenous, intraarterial, intraperitoneal, intrathecal, intrahentricular, intraurethral, intrastemai, intracranial, intramuscular and subcutaneous.
  • Suitable dehices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the inhention may also be administered topically to the skin or mucosa, that is, derma ⁇ y or transdermaily.
  • the compounds of the inhention can also be administered intranasally or by inhalation, in another embodiment, the compounds of the inhention may be administered rectally or haginally. In another embodiment, the compounds of the inhention 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 hariety of factors, including the type, age, weight, sex and medical condition of the patient; the seherity of the condition; the route of administration; and the actihity of the particular compound employed. Thus the dosage regimen may hary widely. Dosage lehels 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 abohe-indicated conditions. In one embodiment, the total daily dose of a compound of the inhention (administered in single or dihided closes) is typicaiiy from about 0.01 to about 100 mg/kg.
  • total daily dose of the compound of the inhention 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 inhention 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 submuStipies thereof to make up the daily dose. In many instances, the administration of the compound will be repeated a pSuraiity of times in a day (typtcalSy no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • compositions may be prohided 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 actihe ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typicaiiy contains from about 0.01 mg to about 500 mg of the actihe ingredient, or in another embodiment, from about 1mg to about 100 mg of actihe ingredient, intrahenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • Suitabie subjects according to the present inhention include mammalian subjects. Mammals according Io the present inhention include, but are not limited to, canine, feline, bohine, caprine, equine, ohine, porcine, rodents, iagomorphs, primates, and the like, and encompass mammals in utero. in one embodiment, humans are suitabie subjects. Human subjects may be of either gender and at any stage of dehelopment. Use Jn the Preparation of a Medicament
  • the inhention comprises the use of one or more compounds of the inhention for the preparation of a medicament for the treatment of the conditions recited herein,
  • the compound of the inhention can be administered as compound per se.
  • acceptable salts are suitable for medical applications because of their greater aqueous solubility relatihe to the parent compound
  • the present inhention comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the inhention presented with a piiarmaceutically-acceptabie 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 96% by weight of the actihe compounds.
  • a compound of the inhention may be coupled with suitable polymers as fargefable drug carriers. Other pharmacologically actihe substances can also be present.
  • the compounds of the present inhention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effectihe for the treatment intended.
  • the actihe compounds and compositions for example, may be administered orally, rectally, parent ⁇ raiiy, 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 inhention.
  • 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 adjuhants.
  • Such capsules or tablets may contain a controlled-releas ⁇ formulation.
  • the dosage forms also may comprise buffering agentsor 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 (i.e., water). Such compositions also may comprise adjuhants, such as wetting, emulsifying, suspending, flahoring (e.g., sweetening), and/or perfuming agents.
  • the present inhention comprises a parenteral dose form.
  • Parenteral administration includes, for example, subcutaneous injections, intrahenous injections, intraperitoneal ⁇ , 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 agents, and/or suspending agents.
  • the present inhention comprises a topical dose form.
  • Topical administration includes, for example, transdermal administration, such as hia transdermal patches or iontophoresis dehices, 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 actihe 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, J, Pharm, ScL, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this inhention is dissolhed or suspended in suitable carrier.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a m ⁇ cronised 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 hesicular systems, such as niosomes or liposomes.
  • the actihe compounds of the inhention are conheniently delihered 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 nebuiizer, with the use of a suitable prope ⁇ ant.
  • 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 aerosoi spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebu ⁇ ser, with or without the use of a suitable propeilant, such as 1 ,1 ,1 ,2-tetrafiuor ⁇ ethane or 1,1 ,1 ,2,3,3,3-beptafiuoropropane.
  • the powder may comprise a bioadhesihe agent, for example, chitosan or cyciodextrin.
  • the present inhention comprises a rectal dose form.
  • rectai dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but harious aiternatihes may be used as appropriate.
  • compositions of the inhention may be prepared by any of the well-known techniques of pharmacy, such as effectihe formulation and administration procedures.
  • effectihe formulation and administration procedures are well known in the art and are descnbed tn standard textbooks.
  • Formulation of drugs is discussed in, for example, Hooher, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylhania, 1975; Uberrnan et a/., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y,, 1980; and Kibbe et a!,, Eds., Handbook of Pharmaceutical Excipients (3 rrJ Ed. ⁇ , American Pharmaceutical Association, Washington, 1999.
  • the compounds of the present inhention can be used, atone or in combination with other therapeutic agents, in the treatment of hanous conditions or disease slates.
  • the compound(s) of the present inhention and other therapeutic agent(s) may be may be administered simultaneousiy (either in the same dosage form or in separate dosage forms) or sequentially.
  • An exemplary therapeutic agent may be, for example, a metabotropic giutamate receptor agonist.
  • the administration of two or more compounds "in combination'" means that the two compounds are administered cSos ⁇ ly 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 present inhention further comprises kits that are suitable for use in performing the methods of treatment described abohe, in one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present inhention and a container for the dosage, in quantities sufficient to carry out the methods of the present inhention,
  • kit of the present inhention comprises one or more compounds of the inhention.
  • the inhention relates to the nohel intermediates useful for preparing the compounds of the inhention.
  • the compounds of the formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derihatisations that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are commercially ahailable 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-VI (published by Wiley-lnterscience)), Preferred methods include, but are not limited to, those described below.
  • Preferred methods include, but are not limited to, those described below.
  • conhentional protecting groups such as those described in T. W. Greene, Protectihe Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M.
  • Scheme 1 illustrates the synthesis of lactam derihatihes depicted by Formula I employing methods well known to one skilled in the art.
  • Formation of the keto-amide 5 is accompi ⁇ shed by base catalyzed closure of 4 foiiowed by decarboxylation/hydrolysis.
  • installation of R 13 ZR 1 ' ' to prohide compound 9 is accomplished using methods known to one skilled in the art Alternatihely, remohal of the protecting group of compound 6 (in the case of Cbz this is accomplished with 6N HCl) prohides enone 10.
  • reaction conditions may hary. In general reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate. Purifications may hary between experiments; in general, solhents and the solhent ratios used for eluants/gradtents were chosen to prohide appropriate R,s or retention times.
  • Preparation 1 Racemic (5R7S), ⁇ 5SJR)-1- ⁇ 3-fluoro ⁇ henyl ⁇ -7-methyl-1 ,8 ⁇ diazas ⁇ iro[4,53dec- 3-e ⁇ -2-one (Pt )
  • Methyl magnesium bromide (3,0 M in diethyl ether, 650 ml, 1.95 mol) was then added drop-wise at ⁇ 60"C - ⁇ 50"C.
  • the organic layer was separated and concentrated in vacuo, and the residue and the aqueous layer were extracted with ethyl acetate (2 x 2 L).
  • reaction mixture was stirred at 11O 0 C for 1 hour
  • the mixture was filtered through Ceitfe, the filtrate was concentrated in vacua, and the residue was diluted with water (2 L), and extracted with ethyl acetate ⁇ 3 L).
  • Dimethyipyridine (242 g, 2.28 mol) and ethyl 3-chioro ⁇ 3-oxopropanoate (255 g ⁇ 1.69 mol) were added to a solution of C3 (415.5 g, 1.13 moi) in anhydrous dichioromethane (2 L) at 10X.
  • the brown mixture was stirred at room temperature ohernight.
  • Step 6 Synthesis of racemic ⁇ 5R7S)(5SJR)-1-(3-fJyoro ⁇ heiiylV7-rnethyl- 1.8-diazaspirQf4.51decan ⁇ -2,4-dione hydrochloride (CS).
  • Compound C5 (217 g, 0.45 mol) was added portion-wise to 6 N aqueous hydrochloric acid (2 L) at room temperature, and the mixture was heated to reflux for 5 hours. The mixture was cooled to room temperature, and concentrated in vacuo to gihe crude C ⁇ as a brown solid, which was used in the next step without purification. Yield: 282 g, 2 batches.
  • Step 7 Synthesis of racemic benzyl (5R7S) ⁇ 5S,7/?)-1 -(3-fluoro ⁇ henhl)-7- methyl ⁇ 2,4-dioxo-t , ⁇ -diazaspirof4.51deca ⁇ - ⁇ -carbox ⁇ late (C7),
  • C6 racemic benzyl
  • the reaction mixture was cooled to 0 0 C and benzyl - 4Q ⁇
  • aqueous layer was then extracted with ethyl acetate (3 x 1 1) and the combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried oher sodium sulfate and concentrated in vacuo to gihe C7 as a y ⁇ iiow solid. Yield: 84 g, 2 batches, 0.205 moi, 23% oher two steps.
  • Step 8 Synthesis of racemic benzyl (5R7S)(5S,7/?)-1 ⁇ (3 ⁇ fluorQphenyl)-4 ⁇ hhdroxy-7-methyl-2-oxo-i .8-diazaspirof4.5
  • C7 racemic benzyl
  • methanoS/tetrahydrofuran 2500 mL/500 ml
  • sodium borohydride 23.3 g « 0.814 moi
  • Step 9 Synthesis of racemic benzyl (5R7$)(5S,7RV1-(3-fluorophenhl)-7- fflethy
  • Thio ⁇ yl chloride 73.88 g. 0.814 mol
  • the mixture was stirred at room temperature for 1 hour, then heated to 50 0 C for 5 hours.
  • Step 10 Synthesis of racemic (5R7$M5SJ/?H- ⁇ 3-fluorophenyQ-7-methhl- 1.8 ⁇ diazaspirof4.5]dec-3-en-2-one ⁇ F1 ).
  • methanol 20 mL
  • 6 N aqueous hydrochloric acid 200 mL
  • the reaction was then heated to reflux for 2 hours, during which time the brown solution became yellow.
  • Step 1 Synthesis of ⁇ ⁇ bengyi (2S,4R)-4-cyanp-4-f f,3-fluorophenyi)aniino1-2- methylp ⁇ eridine-1-carboxyiate (C1Q).
  • a soiution of benzyi (2S) ⁇ 2 ⁇ methyl ⁇ 4 ⁇ oxopiperidine-1-carboxylate see C. Cobum ei a/ .
  • reaction mixture was allowed to stir at room temperature for 18 hours, at which time it was cooled in an see bath and siowly basified with aqueous ammonium hydroxide soiution
  • the resuiting mixture was extracted three times with dichloromethane, and the combined organic iayers were dried and concentrated in vacuo.
  • Step 4 Synthesis of (5R7S)-1-(3-fluorophenhi)-7-methhi-1.8- diazaspjrof4..5]decane-2,4-cilpne hydrochloride .(CI 4), Compound C13 (8.0 g, 17 mmoi) was added in portions to an aqueous 6 N solution of hydrochloric acid (130 mL), and the yeilow suspension was heated at reflux for 28 hours. After cooling to room temperature, the mixture was azeotroped fihe times with toluene, then dried under high hacuum for 18 hours to prohide C14 as a gray-green solid.
  • the resulting material ⁇ 5,78 g) was identified as the enol benzyl carbonate by mass spectroscopic and NIhIR analysis.
  • the bulk of this material ⁇ 5.05 g) was dissolhed in tetrahydr ⁇ furan (about 80 ml) and stirred with aqueous sodium hydroxide solution ⁇ 1 N, 200 ml, 200 mmol) for 5 hours.
  • the reaction mixture was then acidified to pH 2 with aqueous 1 N hydrochloric acid, and extracted twice with dichioromethane.
  • the combined organic layers were dried oher sodium sulfate, and concentrated to afford C15 as a brown oil, contaminated with extraneous aromatic material Yield 4 g, ⁇ 9.7 mrnol.
  • Step 6 Synthesis of benzyl (5f?.7S)-1- ⁇ 3-fluorophenhl)-4-hhdP ⁇ xh-7-methhi-2- oxo-1.3-djazaspjrof4..51decane-8-cart)oxylate.(C16).
  • a solution of C15 (881 mg, 2.15 rnmoS) in methanol ⁇ 25 mL) and telrahydrofuran (5 ml) at 0 0 C was treated portion- wise with sodium borohydride (98%, 248 mg, 8.42 mmol), and the resulting yeilow solution was stirred at O 0 C for 2 hours.
  • Step 7 Synthesis of benzyl f5RJS)-1-(3-f)uorophenhi)-7-methhi-2-oxo-1.8- dia i zj i ⁇ p n i£g i f4J
  • a solution of C16 (510 mg, 1.24 mmoi) in pyridine (8.83 mL) was cooled to 0 0 C and treated with thionyl chloride (0.270 mL. 3.71 mmol). The reaction was stirred for 1 hour at room temperature, then at 5O 0 C for 18 hours.
  • Table 1 shows the structure of the compounds and relehant biological data that were measured in each case either on the compound as a free base or on the pharmaceutically acceptable salt of the compound disclosed in the Table. Each assay is disclosed in greater detaii hereinbelow.
  • Step 1 Synthesis of 3-isopropoxy-4-f ⁇ ethoxyben2aidehhde (C 18).
  • a solution of 3-hydroxy-4-m ⁇ thoxyb ⁇ nzald ⁇ hyd ⁇ (5,00 g, 32.9 mmoi) in dimeihyiformarnide (100 mL) was treated with potassium carbonate (9.08 g, 85.7 mm ⁇ l) and 2-iodopropane (8.57 ml, 65.7 mmol). The reaction was stirred for 4 hours and then additional 2 ⁇ iodopropane (3.29 mL, 32.9 mmol) was added and the mixture was allowed to react for an additional hour.
  • Step 3 Synthesis of ⁇ -h ⁇ drgx ⁇ J ⁇ iso ⁇ ro ⁇ gMbenzaldehyde ,( €20), Lithium wire (cut into smaii segments, 204 mg, 29.4 mmol) was added to a solution of chiorodiphenylphosphin ⁇ (2.17 mL, 11.7 mmoi) in tetrahydrofuran (18.7 ml), and the reaction was stirred for 1 hour, A solution of C19 (2,00 g, 8.39 mmoi) in tetrahydrofuran (5 ml) was then added drop-wise to the dark red mixture, and the reaction was stirred for 2 hours, it was then fiitered into an aqueous sodium hydroxide solution, and extracted with diethyl ether (3 x 15 mL); the combined organic layers were washed with 1N aqueous sodium hydroxide soiution, and the aqueous layers were combined and cooled in an ice bath.
  • Step 4 Synthesis of 87.
  • Compound C20 (20.7 mg, 0.1 15 mmol) in dichioroethane (0.5 mL) was combined with a solution of P3 (20 mg, 0.077 mmol) in dichioroethane (0.4 ml).
  • Acetic acid (4 ⁇ L, 0.07 mmol) was added.
  • the reaction was treated with sodium triacetoxyborohydride (32.6 mg, 0.154 mmoi), and the reaction mixture was ailowed to stir for 18 hours.
  • Aqueous sodium bicarbonate solution was then added, and the layers were separated.
  • aqueous iayer was extracted with dichloromethane (3 x 5 mL), and the combined organic iayers were dried oher sodium sulfate, fiitered and concentrated in vacuo.
  • the residue was purified by chromatography on siiica gel (Gradient: 20% - 70% ethyi acetate in heptane) to prohide the free base of 87 as an oil Yield: 7.8 mg, 0.018 mmoi, 23%.
  • the hydrochloride salt was prepared by dissolhing the free base of 87 in diethyl ether and treating the solution with a 1.0 M solution of hydrochloric acid in ether, followed by concentration in vacuo. Compound 87 was obtained as a solid. Yield: 8.6 mg, 0.18 mrool, 100%.
  • Compound 88 was prepared according to the general procedure for the synthesis of 87 in Example 87, except that P4 and 2'-rnethylbiphenyl-3-carbaSdehyde were used instead of PZ and C20, to prohide the free base of 88 as an oil.
  • the hydrochloride sait was prepared by dissolhing the free base of 88 in diethyl ether and treating the solution with a 1.0 M solution of hydrochloric acid in ether, followed by concentration in vacuo. Compound 57 was obtained as a solid. Yield: 18 mg. 0.037 rrtmoi, 100%.
  • the hydrochlonde salt was prepared by dissolhing the free base of 89 in diethyl ether and treating the solution with a 1.0 M solution of hydrochloric acid in ether, followed by concentration in vacuo.
  • Compound 8 ⁇ was obtained as a solid. Yield: 28 mg, 0.060 mmol, 100%,
  • Example 90 and 91 Racemic f SR 7S) ⁇ 5S,7R)-3-f luoro- 1 -(3-f iuprppheny I )-B-( 3-isoprop ⁇ x ⁇ benzyl )- 7- methyl- 1 t ⁇ -diazaspiro[4.5Jd ecan-2-o ⁇ e, formate salt (90) and Racemic (5f?,7SKSS.7ff)-3.3-difiuof ⁇ -1-(3-fl ⁇ QrQphenhi)-8-(3-isQpropoxhbenzyl)-7-methyl-1 , ⁇ - d jazasp.jrof4,51d ecan-2-one ,. formate salt (91 )
  • Example 91 A flame-dried flask under a nitrogen atmosphere was charged with dry THF (5 mL) and diisopropylamine (106 mg, 1.05 mmol) and was cooled to -78 0 C in a dry ice-acetone bath. n-Bu ⁇ (0.37 ml, 0,93 mmol ⁇ was added dropwise, then the solution was warmed to -55 0 C for 1 h and then cooled back to -78 C C. A solution of Example 45 ⁇ 240 mg, 0,58 rnmoS) in anhydrous THF (3 mL) was added dropwise, then the resulting mixture was stirred for 45 min at -78"C and allowed to warm to - 55 0 C.
  • Example 90 25 mg, 10%
  • Example 91 58 mg, 22%) as a white solid.
  • Example 91 1 H NMR (400 MHz, MeOD): ⁇ 7.54-7.49 ⁇ m, 1H), 7.28-7.23 (m, 1H) 1 7.17-7.13 (m, 1H), 7.09-7.06 (d, 2H), 6.78-6.75 (m, 3H), 4.55-4.51 (s, 1H), 3.60- 3.49 (m, 2H), 2.99-2.86 (m, 2H), 2.76-2.66 (d, 2H), 2.50-2.40 (m, 1 H), 2.13-2.05 (m, 2H), 1.84-1 ,77 ⁇ d, 2H), 1.28-1.26 ⁇ d, 6H), 1.19-1.18 ⁇ d, 3H).
  • Lithium bis ⁇ trimethylsilyl)amide ⁇ 1 M in tetrahydrofuran, 25.4 ml, 25.4 mmol) was added drop-wise oher 30 minutes, while keeping the internal temperature of the reaction below -72°C.
  • the reaction was stirred at -72 to -77°C for 4 hours, then allowed to warm to -15°C by transferring the flask to a wet ice-methanol bath. Alter one hour at -15°C, the reaction was slowly quenched with water (25 ml), then partitioned between water (75 ml) and ethyl acetate (150 mL).
  • the aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic extracts were washed with saturated aqueous sodium chloride solution (75 mL), dried oher magnesium sulfate, filtered and concentrated in vacuo.
  • the crude product was dissolhed in diethyl ether (30 ml), which caused a white precipitate to form; this mixture was stirred for 18 hours.
  • the s ⁇ iid was collected by filtration and rinsed with coid diethyl ether (10 mL) to prohide #C21 as a white solid.
  • Step 2 Synthesis of 1 -benzyl 4-methyl ⁇ 2$,4R)-4-azido-2-methylpiperidine- 1 ,4-dicarbQxylate (# €22), A suspension of benzyi (2S,4S)-4-hydroxy-2-rnethyl-4- (trichSoromethyl)pip ⁇ r ⁇ dine-i-carboxylate (#G21) (18.00 g, 49.09 mm ⁇ l), 18-crown-6 ether (2.00 g, 7.57 mmol) and sodium azicte (98%, 9.00 g, 138 mmoi) in methanol (130 ml) was stirred at room temperature for 1 hour.
  • Step 4 Synthesis of 1 -benzyl 4-methhi f2S,4/?)-4-f ⁇ 3-ethoxy-3- oxopropanoyl)amifio]-2-m ⁇ thylpiperidine-14-dicarboxylate (#C24).
  • N-[Z- (Dimethylamino)propyl]- ⁇ /'-ethylcarbodiimide hydrochloride (EDCI, 98%, 3.58 g, 18.3 rnmoS) was added to a solution of 1 -benzyl 4-methyl (2S,4/?)-4-amino-2- methylpiperidine-1 ,4-dicarboxyiate (#C23) (5.10 g, 18.6 mmol), 3-ethoxy-3- oxopropanoic acid (96%. 2.25 mL.
  • Step 5 Synthesis of ⁇ -benzyi 3-ethyi (5ft.7S)-7-methyl-2,4-dioxQ-1.8- diazaspj!ro
  • 4 ⁇ 51decane-3J-dicarbQxylat ⁇ (#C25), Sodium etnoxide powder (95%, 1 41 g, 19.7 mmol) was added to a solution of 1 -benzyl 4-metnyS (2S !
  • Step 6 Synthesis of be ⁇ zyi (5R7S)-7 ⁇ metnvi-2,4-dioxQ-1,8 ⁇ diazaspiro[4.51decane-8 ⁇ carpo ⁇ ylate (#C26).
  • 8-Ben2yl 3-ethyi ⁇ 5RJS ⁇ -7-meihyl-2,4- dioxo ⁇ 1 ,8-diazaspiro[4.5]decane-3,8-dicarboxyiate (#C25) (6.30 g « 16.2 mmol) was dissolhed in dioxane (90 ml) and water (10 ml_) and heated at reflux for 1 hour. After cooling to room temperature, the reaction was concentrated in vacuo.
  • Step 8 Synthesis of . benzyl ⁇ 5R,7S)-7-methyl-2-oxo-1 ,8-diazaspirof4,5
  • Step ..9 Synthesis of benzyl .(5R.7S)-I - ⁇ chcjoprQPVJ.rnethhl .)-?-methyl-2- ⁇ . ⁇ - IJ-diazaspiro ⁇ . ⁇ ldec-S-e ⁇ e-S-carboxyiate (#C29).
  • the reaction was heated to 60 l "C for 20 minutes, at which time sodium iodide ( ⁇ 5 mg) and 15 ⁇ crown-5 ether (1 drop from a Pasteur pipette, ⁇ 5 mg) were added.
  • the reaction mixture was maintained at 60 0 C for an additional 6 hours, then at room temperature for 18 hours.
  • Soihent was remohed under a stream of nitrogen, and the residue was partitioned between water ⁇ 1.5 mL) and ethyl acetate (3 mL).
  • the aqueous layer was extracted with ethyl acetate (2 mL), and the combined organic fayers were dried oher magnesium suifate. filtered and concentrated in vacuo.
  • the cartridge was flushed with dicbioromethane ⁇ 5 mL), and the fiStered solids and Celite were manually remohed from the cartridge.
  • the product was ⁇ iuted using a 2 M solution of ammonia in methanol ⁇ 5 mL). and the filtrate was concentrated in vacuo.
  • the residue was purified by preparatihe silica thin layer chromatography (Eiuant: 5% acetonitriie in ethyl acetate); the product band was extracted with 2:1 ethyl acetate; methanol (15 mL) and filtered.
  • Step 1 Synthesis of benzyl (5R,7S) ⁇ 7 ⁇ m ⁇ thyi ⁇ 2 ⁇ oxo ⁇ 1 ⁇ propyl-1 ,8- diazaspiro[4.5]dec-3-ene-8-carboxyIate (#C30).
  • Step 2 Synthesis of ⁇ 5R,7S) ⁇ 8 ⁇ (3 ⁇ isopropoxybenzyi) ⁇ 7-methyi ⁇ 1 ⁇ pr ⁇ pyl-1 ,8- diazaspiro[4.5
  • Step 1 Synthesis of benzyl ⁇ 5RJS)-t -cyclopropyl-7-methyi-2-oxo-1,8- diazaspiro[4.53dec-3-ene-8-carboxyiate (#C31).
  • Benzyl ⁇ 5R7$)-7-methyl-2-oxo-1,8- diazaspiro[4.53dec ⁇ 3 ⁇ ene-8-carboxylate (#C28) was conherted into the title product by reaction with cyclopropylboro ⁇ ic acid, according to the method of S. Benard et al. f J. Org, Chem. 2008, 73, 6441-6444.
  • the title compound was prepared according to the procedure described for the synthesis of #93 in Example @93, except that benzyi (5f?,7S)-1-cyclopropyl-7-methyi-2-oxo-1,8- diazaspiro[4.53ciec ⁇ 3-ene-8-carboxylate (#C31 ) was used instead of benzyl (5RJS ⁇ 1-(cyclopropylmethyl)-7-methyl-2-o ⁇ o-1.8-diazaspiro[4.5]dec-3-ene-8 ⁇ caft>oxyiate (#C29), the remohal of the protecting group was carried out oher 18 hours rather than 8 hours, and strong cation exchange (SCX) solid-phase extraction columns were used rather than MCX coiumns.
  • SCX strong cation exchange
  • the reaciion mixture was then diluted with ethyl acetate, and washed with water, then with saturated aqueous sodium chloride solution, dried oher magnesium sulfate, filtered and concentrated in vacuo. Purification was effected by chromatography on silica gel (Gradient 0% to 20% ethyl acetate in heptane), prohiding the product as a solid. Yield: 4.60 g, 12.1 mmol, 87%. The characterization data was obtained on a sample derihed from a similar reaction.
  • Diisobutyiaiuminum hydride (98%, 1 5 M soiution in toiuene, 5.8 ml, 8.5 mmol) was added drop-wise to a solution of ⁇ 2S,4R)-4-[(3-fluorophenyl5amino]-1 -(3-tsopropoxybe ⁇ zyl)-2- methylpiperidi ⁇ e-4-carbonitriie (#C33) (2.20 g, 5.77 mmol) at -78 0 C. The reaction was stirred at -78 " J C for 1 hour, then warmed to 0 0 C for 1 hour, then warmed to room temperature for 1 hour.
  • Step 4 Synthesis of ethyl 3-[ ⁇ 2S,4/?)-4-[ ⁇ 3-fl ⁇ oro ⁇ henyl)amtno]-1-(3- isopropoxybenzyi)-2 ⁇ methylpipe ⁇ din-4-yl3-2-methylacrylate (#C35).
  • Ethyl 2- ⁇ diethoxyphosphoryl)propa ⁇ oate (0.122 mL, 0.580 mmol) was added drop-wise to a mixture of sodium hydride (80% in oil. 20.6 mg, 0.516 mmol) in 1 ,2-dimethoxyethane ⁇ 0,9 ml) at 0 0 C. After being stirred at 0 0 C for 30 mi ⁇ , the reaction was warmed to room temperature.
  • Step 5 Synthesis of ethyl 3-[ ⁇ 2S,4R)-4-[ ⁇ 3-fluorophe ⁇ yi)amino]-1- ⁇ 3- isopropoxybenzyi)-2-methyipiper ⁇ din-4-yi] ⁇ 2 ⁇ methyipropanoate (#C36).
  • Step 2 Synthesis of benzyl ⁇ 5R,7S ⁇ -1-(3-fluorophenyl)-3-hydroxy-7-methyi-2- ox ⁇ -1 ,8-diazaspir ⁇ [4.5]decane-8-carboxylate (#C38).
  • Lithium bis(trimethyisilyl)amide (1 M in tetrahydrofuran, 1 .5 ml, 1.5 mmoS) was added to a solution of benzyl ⁇ SRJSJ-I ⁇ S-fluorophenyi ⁇ -methyf ⁇ -oxo-i ⁇ -diazaspiroH.SId ⁇ cane- ⁇ -carboxylate (#C37) (500 mg, 1 ,26 mmol ⁇ in tetrahydrofuran (6.3 mL) at -60 0 C, and the reaction mixture was maintained at this temperature for 1 hour.
  • a solution of 3-phenyl-2- (phenyfsulfonyi)oxaziridin ⁇ see L. C.
  • Step 3 Synthesis of benzyl (5R JS)-I - ⁇ 3-fluorophenyi)-7-methyl-2 ( 3-dioxo- 1 ( 8-diazaspir ⁇ [4.5Jdecane-8-carboxyiate (#C39).
  • Manganese(iV) oxide (85%, 124 mg, 1.21 mmol) was added to a solution of benzyl ⁇ 5R7S)-1-(3-fluorophenyl)-3- hydroxy ⁇ 7-methyl ⁇ 2 ⁇ oxo-1 ; 8 ⁇ diazaspir ⁇ [4.5]decane ⁇ 8 ⁇ carboxyiate (#C38) (50 mg, 0.12 mmol) in dichioromethane (0.61 mL), and the reaction was stirred at room temperature until no starting material was obserhed by thin iayer chromatography on silica gel (Eluant: 5% methanol in chSoroform), The reaction mixture was filtered through a ⁇ 1 ⁇ m filter, and soihent was remohed in vacuo.
  • Step 4 Synthesis of benzyl ⁇ 5R,7S)-1-(3-fl ⁇ orophenyl)-7-methyl-2-oxo-3- ⁇ [(tnf ⁇ uoromethyl)sulfonyl]oxy ⁇ -1 ,8-diazaspiro[4.5jdec ⁇ 3-ene-8-carboxyiat ⁇ (#C40).
  • Lithium bis(trimethylsilyl)amide (1 M in tetrahydrofura ⁇ , 0.067 mL, 0.067 mmol) was added drop-wise to a solution of benzyl (5R7S)-1-(3-fluorophenyi)-7-methyi-2,3- dioxo ⁇ 1 ,8 ⁇ diazaspiro[4.53decane-8 ⁇ carboxylat ⁇ (#C39) (25 mg, 0.001 mmoS) in tetrahydrofuran (0.61 ml) at -78 0 C.
  • Step 5 Synthesis of benzyl (5R,7S)-1-(3-fSuorophenyi)-7-methyl-2-oxo-3- phenyl ⁇ 1 I 8 ⁇ diazaspiro[4.5]dec-3-e ⁇ e-8 ⁇ carboxylate (#C41).
  • Step 6 Synthesis of ⁇ 5R7S)-1-(3-fiuoraphenyl)-7-methyi-3-phenyl-1 ,8- diazaspiro[4.5]d ⁇ c-3-e ⁇ -2-one (#C42).
  • the title compound was prepared according to the general procedure for the synthesis of P1 in Preparation 1, except that benzyl (5/?,7$)-1- ⁇ 3-fluofophenyl)-7-methyi-2-oxo-3-phenyl-1 ,8-diazaspiroJ4.5 ⁇ dec-3-ene-8- carboxylate (#C41) was used instead of racemic benzyl (5R,7S)(5S,7/? ⁇ 1 ⁇ (3 ⁇ fluorophenyl)-7-methyl-2-oxo-1 ,8-diazaspsro[4.5]dec ⁇ 3 ⁇ ene-8-carboxylate (C9).
  • the product was obtained as an oil.
  • the title product was prepared from (5R,7S)-1- ⁇ 3- fluorophe ⁇ yl)-7-r ⁇ ethyi-3-phe ⁇ yl-1 ,8-diazaspiro[4,5]dec-3-en-2-one (#C42) according to the general procedure for the synthesis of (5/?,7S)-1-(3-fluorophenyl)- ⁇ -(4- hydroxy-3-isopropoxybenzyl)-7 ⁇ methyl-1 l 8-diazaspiro[4. ⁇ Jdec-3-en-2-one hydrochloride (87) in Example 87, except that the purification was carried out by multiple silica gel chromatographies; 0% to 5% methanol in dichioromethane gradient, followed by 1% to 100% ethyl acetate tn heptane gradient, and finally diethyl ether eluant, prohiding the neutral form of the product as a solid.
  • Step 1 Synthesis of 1 -benzyl 4-methyS (2S,4/?)-4-K3-fluorofrfi ⁇ yl)amino]-2- methylpiperidine-1 ,4-dicarboxySate (#C43).
  • Step 2 Synthesis of benzyl ⁇ 2S,4R)-4-[(3-fluorophenyi)amino]-4- (hydroxymethyl)-2-methyl ⁇ iperidine-1-carboxylate (#C44).
  • 1 -Benzyl 4-methyl (2S l 4R)-4-[(3-fluorophenyi)aminoj-2-methyipipendine-1 ,4-dicarboxylate (#C43) from the prehious step was dissolhed in tetrahydrofuran (63.3 ml) and treated with a solution of lithium bor ⁇ hydride in tetrahydrofuran (2 M, 19.0 ml, 38,0 mmol). The resulting mixture was heated at refiux for 18 hours.
  • Step 3 Synthesis of benzyl (2S,4R)-4-[(3-fluorophenyl)amtno3-4-formyl-2- methylpiperidin ⁇ -1-carboxyiate (#C45).
  • Oxalyl chloride (99%, 0.39 mL, 4.4 mmol) was added drop-wise to a -78 °C solution of dimethyl sulfoxide (0.83 ml, 8.9 mmoi) in dichloromethane (5 mL).
  • Step 4 Synthesis of benzyl ⁇ 5R,7S)-1- ⁇ 3-flu ⁇ rophenyl)-3 l 7-dtmethyi-2-oxo- 1,8-diazaspiro[4.5]d ⁇ c-3- ⁇ ne-8-carboxylate (#C46).
  • Ethyl 2-[bis(2,2,2- triflu ⁇ r ⁇ ethoxy)piiosphoryl]propanoate (353 mg, 1.02 mmol) was added drop-wise to an ice-eooied mixture of sodium hydride (60% in oil, 40.8 mg, 1.02 mmoi) and 1 ,2- dimettioxyethan ⁇ (1.46 ml).
  • Step 5 Synthesis of (5R7S)-1-(3-f ⁇ uoro ⁇ heiiyO-3,7-dimethyl-1,8- diazaspiro[4.5ldec-3-en-2-one (#C47).
  • the ttti ⁇ compound was prepared according to the general procedure for the synthesis of Pi in Preparation 1, except that benzyl carboxyfate (#C4 ⁇ ) was used instead of racemic benzyi (5R,7S)(5S,7/?) ⁇ 1 ⁇ 3 ⁇ fluorophenyl)-7-methyi-2-oxo-1 ,8-diazaspiro[4.5]dec-3-ene-8-carboxylate (C9). Yieid: 55 mg, 0.20 mmol, 50%.
  • Tables 2 and 3 The structures of additional Examples are shown in Tables 2 and 3, which also gihe physical data, preparatihe information and biological data for these Examples.
  • Step 1 Synthesis of 1 -heteroaryi-substif ⁇ ted benzyl (5R,7S)-7-methyl-2-oxo- 1 ⁇ 8-diazaspiro[4.5]dec-3-ene-8 ⁇ carboxyiate (#C100).
  • the cartridge was flushed with dtchiorom ⁇ thane ⁇ 5 mL). and the filtered solids and Ceiite were manually remohed from the cartridge.
  • the product was eluted using a 2 M solution of ammonia in methanol ⁇ 5 rnL), and the filtrate was concentrated in vacuo.
  • a synthetic APP substrate that can be cleahed by beta-secretase and hahing N-termi ⁇ al bioli ⁇ is used to assay beta-secretase actihity in the presence or absence of the inhibitory compounds.
  • the substrate can contain either the wiidtype sequence around the BACE cleahage site or the Swedish mutation (Vassar, R. « B. D. Bennett Bt a/. (1999). "beta-secretase cleahage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.” Science, 286(5440): 736-741).
  • the substrate and test compounds are added to 384 well polypropylene plates.
  • the reaction is initiated by the addition of soluble BACE enzyme to a final holume of 12.5 ⁇ L per well.
  • Concentrated conditioned media from cells secreting human recombinant soluble BACE was titrated to prohide a source of BACE enzyme.
  • the cell media can be used as either a crude BACE prep or BACE can be purified using any number of techniques, including immobilized BACE inhibitor purification columns.
  • the assay mixture is incubated for 1 hour at 37 0 C, and the reaction is quenched by the addition of an equal holume of 0.1 M Iris, pH 8. Half of the quenched mix is incubated on clear streptahidin coated 384 well polystyrene plates for 1 hour.
  • An ELlSA is then performed using an in-house antibody that specifically recognizes the new C- terminus created after cleahage by BACE. Two in-house antibodies are ahailable; each is cleahage specific, but one is raised against the wiidtype sequence (APP 591— 596) while the other is raised against the Swedish mutation (APP 590-596).

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Abstract

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I) as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment methods of synthesis, and intermediates are also disclosed.

Description

LACTAMS AS BETA SECRETASE INHIBITORS
F ie i d of the inhent ion
The present inhention relates to the treatment of Alzheimer's disease and other neurodegeneratihe and/or neurological disorders in mammals, including humans. This inhention aiso relates to inhibiting, in mammals, inciuding humans, the production of A-beia peptides that can contribute to the formation of neurological deposits of amyloid protein More particularly, this inhention relates to spirø-piperidine compounds useful for the treatment of neurodegeneratihe and/or neurological disorders, such as Alzheimer's disease and Down's Syndrome, related to A-beta peptide production.
Background of the inhention
Dementia results from a wide hariety of distinctihe pathological processes. The most common pathological processes causing dementia are Alzheimer's disease (AD), cerebral amyloid angiopathy (CM) and prion-mediated diseases (see, e g., Haan et a/.. Clin, Neurol. Neurosurg, 1990, 92(4}:305-310; Gienner et a/,, J. Neuroi. Sci, 1989, 94:1-28), AD affects nearly half of all people past the age of 85, the most rapidly growing portion of the United States population. As such, the number of AD patients in the United States is expected to increase from about 4 million to about 14 miilion by the middle of the next century. At present there are no effectihe treatments for halting, prehenting, or rehersing the progression of Alzheimer's disease. Therefore, there is an urgent need for pharmaceutical agents capable of slowing the progression of Aizheimer's disease and/or prehenting it in the first place.
Seheral programs hahe been adhanced by research groups to ameliorate the pathological processes causing dementia, AD1 GM and prion- mediated diseases. Beta-secretase (BACE) inhibitors are one such strategy and numerous compounds are under ehaluation by pharmaceuticai groups. The present inhention relates to a group of brain-penetrable BACE inhibitors and as such would be expected to be BACE inhibitors and modulators for the treatment of AD (see Ann. Rep. Med. Chem. 2007, Olsen ef a/., 42; 27-47). Summary of the inhention The inhention is directed to a compound, including the pharmaceutically acceptable salts thereof, hahing the structure of formula I:
Figure imgf000004_0001
wherein the stereochemistry shown in formula i at the carbon bonded to R~ and at the spirocycSic carbon is the absolute stereochemistry; 8 is alkyl, aryS, heteroaryi, cycloalkyl, or heterocycloafkyf, wherein B is optionally substituted with zero to three R3 groups;
A is independently aryl, cycloalkyl, heterocycioalkyl or heteroaryi wherein said aryt cycloalkyl, heterocydoaikyl or heteroaryi is optionally substituted wsth one to three R4; when zzzzzzz is a single bond, RUΛ and R1b are each independently hydrogen, alkyl, aikeπyL -(CH2)rcycSoaikyl, -{CHs)i-heterocycloalkyl, -{CH=)raryl, -(CH2),- heteroaryl, -(CH2VOR5, -{CH2}tN(R7}2, -NH-(CH2}rcycioalkyl, -NH-(CH2),- heterocycioalkyl, -NH-(CH2)raryl. -NH-(CH2)rheteroaryl, -(CH2}rCOR5, -(CH2V SO^R5, or -(CHs)1-CO2R5; wherein said alkyl, aikenyl, -(CH2VcydoalkyJ, -(CH2V heterocycloaSkyS, -{CH2)raryi, or -(CH2)rheteroaryl R1a or R"J substituent is optionaily substituted with one to three hydroxyl. aryl, heteroaryi, halogen, aikyi, cycioaikyi, -SO2R7, -NR7COR7, -CON(R7 )2, -COOR7, -C(O)R7, -CM, or -N(R7J2 wherein said aryl, alkyl, cycioaikyi and heteroaryl substituent is opttonaily substituted with one to three halogen, alkyl, hydroxyl, or -O~alkyl; or Ru and R1Lh together with the carbon they are bonded to form a cycloalkylene moiety or a heterocycloaSkySene moiety, wherein said cycloaikyiene or heterocycioalkylene moiety is optionally substituted with one to three hydroxyl, aryl, heteroaryi, halogen, alkyl, cycloalkyl, -SO2R7 -NR7COR7, -CON(R7J2, -COOR7. -C(O)R7. -CN, or -N(R7J2, wherein said aryi, aikyi, cycloaikyi and heteroaryl substituent is optionally substituted with one to three halogen, aikyl, hydroxyl, or -G- alkyl; when rrrrrrr is a double bond. R1b is absent and R1a is hydrogen, aikyi. alkenyi, -(CH2)rCycioalkyl. -{CH2)rheterocycloalkyl, -{CHaJj-aryi, ~(CH2},~heterøaryi, -(CH2JrOR5, -(CH2JtN(R7J2, -NH-(CH2 JpCycloalkyl, -NH-(CH2Jrhθterocydoalkyl, -NH- (CH2Jt-aryl, -NH-(CH2)rhetβroaryl, -(CH2J1-COR5, -(CH2JrSO2R5, or -(CH2JrCO2R5, wherein said alkyl, aikenyl, -(CHaVcycloalkyl, -(CH2Jrheterocycloalkyl, -(CH2Jraryl, or ~{CHz)rhetβroaryl R] a substituent is optionaSiy substituted with one to three hydroxyl, aryl, heteroaryl, halogen, aikyi, cycloaikyi, -SO2R7 -NR7COR7, -CON(R7J2. -COOR7, - C(O)R7, -CN, or -N(R7 J2, wherein said aryi, alkyl, cycioaikyi and heteroaryl substituent is optionaiiy substituted with one to three halogen, aikyi, hydroxyl, or -O-aikyi; R2 ss aikyi, cycioaikyi, or alkenyi wherein said alkyl, cycioaikyi, or aSkenyl is optionally substituted with one to three halogen, hydroxyl, or cyano; each R3 is independently haiogen, alkyl. cyano, hydroxyl, -O-alkyl, -O- cycloalkyl, -SO2R7. -N(R7)2, -COR7, -CON(R7J2, -(CH^-cycioalkyl, -(CH2}r heterocycloaikyi, -(CH2)t-aryl, or -{CH2)t-heteroaryi wherein said R3 alkyl, -(CH2Jr cycloaikyi, -(CHsX-heterocydoalkyl, -(CH2Jraryl, or -{CH2)rheteroaryl is optionaiiy substituted with one to three R4; each R* is independently aikyi, halogen, cyano, -SO2NHR7, -CON(R7J2, -N(R% -N(R7JCOR7, -N(R7JCO2R7. -SO2N(R7J2, ~N(R7)SO2R7, -COR7, -SO2R7, -(CH2Jrcycioalkyi, -{CH2JrhβterocycloaikyK -{CH2Jraryl, -(CH2Jrheteroaryi, -(CH2Jr N(R7J2, or -(CH2)I-OR5; wherein each R1 alkyl, -(CH2)rcycloaikyi, -(CH2Jr heterocycloalkyl, -(CH;)t-aryl, or -(CH2Jt-heteroaryl is optionaiiy independently substituted by one to three cyano, aikyS, halogen, -CF3 or -OR5; each R3 is independentiy hydrogen, aikyi, -{CH^r-cycloaikyl, -(CH2Jr heterocycloaikyi, -(CH2Jraryl, or -(CH2Jr heteroary I; wherein said -( CH2}r cycloaikyi, -(CHsJrheterocycioalkyl, -(CH^Jraryi, or -(CH2Jrheteroaryl is optionally substituted with one to three R6; each Rs is independently aikyi. hydroxyl, alkoxy, halogen, cyano, ~(CH2)ιN(R7)2, ~{CH2)rcycloaikyi, -{CH^-heterocycloalkyl, -(C^^-aryl, or -(CH2Jr tieteroaryl; each R' is independently hydrogen, aikyi, -{CH2X-cydoalkyl, -<CH2)r heterocycloalkyl, -(CHaVaryi, or -(CH2)rheteroaryl, or when two R7 substituents are attached to the same nitrogen atom they may be taken together with the nitrogen to which they are attached to form a heterocycioalkylene moiety; and wherein said alkyl, -{CH2)rcyclαaSkyS, -{Ci-yrheterocycioalkyl, -<CH2)rary1, or -{Cr-ypheteroaryl are optionally substituted with one to three alkyl, halogen, cyano, hydroxyl, or -OR4; n is an integer selected from 1. 2 and 3; and each f is an integer independently selected from 0, 1, 2 and 3; or pharmaceutically acceptable salts thereof.
In another embodiment of the inhention, n - 1.
In a further embodiment of the inhention
Figure imgf000006_0001
is a sϊngie bond, and Ru and R!b are each independently hydrogen or alky), in one example of this embodiment, R] a and R11' together with the carbon they are bonded to form a cycloaikyiene moiety or a heterocycloaikyiene moiety. In another example of this embodiment, R1a and R'h together with the carbon they are bonded to form a cycloaikyiene moiety or a heterocycloaikyiene moiety, in another example of this embodiment, Ria and Rib are each hydrogen.
In another embodiment of the inhention
Figure imgf000006_0002
is a double bond, and R1β is absent,
In another embodiment of the inhention, A is aryl.
In another embodiment of the inhention, A is cycioalkyi. In another embodiment of the inhention, A is heteroaryl.
In another embodiment of the inhention, A is heterocycioajkyl.
In another embodiment of the inhention, A is aryi, heferoaryl, cycSoalkyl or heferocycloalkyl, and A is optionally substituted with one R4 substituent. In one example of this embodiment, Ra is independently alkyl, halogen, cyano. -SO2NHR7, -CON(R7)2. -M(R7Ih ~N(R?}C0R7, ~SO2N(R?}2, -N(R7ISO2R7, -COR7, -SO2R7, -(CH2),- cycioaSkyS, ~(CH2)rheterocycIoaikyi> -(CH:)raryl, -(CHa)rheteraaryl, -(CH2)rN(R7)2, or -(CHs)rOR5 wherein each R4 alkyl, -(CH2)rcycioalkyl, -{CH2)rheterocycloaikyi, -(CH2)t-aryl« or -(CH2)rheteroaryi is optionally independently substituted by one to three cyano, alkyl, halogen, -CF3, or -OR5 In one example of this embodiment, A is aryl or heteroaryl, and R4 is independently alkyl, halogen, cyano, -SG2NHR?, -CON(RT)2i -M(R7)2 -N{R7)CQR7. -SO2N(R7J2, -N(RT)SO2R\ -COR7, -SO2R7, -<CH2)r cyclαalkyl, -CCH2)rheterocycloaikyi, -(CH2)raryl, -{CH«)rheterøaryl, -(CH2)rN{R7)2, or -(CH^-OR5 wherein each R4 alkyl, -(CH^-cycioalkyl, -{CH^-heterocycloaikyi. -(CH;)raryl, or ~{CH2)rheteraaryl is optionally independently substituted by one to three cyano, alkyt halogen, -CF3, αr -0Rb in another example of this embodiment, R4 is halogen, alkyl, -GR5 ; cyano, trtfluoroalkyl, -(CH2).-cycSoaikyl, -(CH=)r heteroeycloalkyl, -(CH;)raryl, or -(CHs)rheieroaryl, wherein each R4 -{CH2)r cycloalkyl, -{CH2)rheterocycloalkyl. ~{CH2)raryi. or -(CHa)rheteroaryl, is optionally independently substituted by one to three -OR5, alkyl, cyano. or halogen, in an example of this embodiment, A is aryl and R4 is -OR5, wherein Rδ is independently -(CH2)t-cycioalkyl or -(CH;)rheteraaryi wherein t is zero and said cycloaSkyl or heleroaryi is optionally substituted with one to three RG, In another example of this embodiment, A is aryl and R" is -{CH2)t-aryl wherein t is zero and the ary) is optionally substituted by one to three cyano, alkyl, halogen, or -OR5 in another example of this embodiment, A is aryi and R4 is -{ CH- )r heteroaryl wherein t ts zero and the heteroaryl is optionally substituted by one to three cyano, alkyl, halogen, or -OR'' In another example of this embodiment, A is heteroaryl and R* is -GRS, wherein Rs is independently -{CH^rcyclαaSkyS or -(CH2)rheteroaryl wherein t is zero and said cycloalkyl or heteroaryl is optionally substituted with one to three Rδ. In another example of this embodiment, A is heteroaryl and R4 is -{CH:)raryl wherein t is zero and the aryl is optionally substituted by one to three cyano, aikyϊ, halogen, or -OR5 in another example of this embodiment, A is heteroaryl and R~ is -{CH2)rheteroaryl wherein f is zero and the heteroaryl is optionally substituted by one to three cyano, alkyl, halogen, or -OR5
In another embodiment of the inhention A is aryi, heteroaryl, cycloaikyi or heterocycloalkyl, anά A is optionally substituted with two R4 substituents. In one example of this embodiment, each R4 is independently alkyl, halogen, cyano. -SO2NHR7. -CON(R7)2> -N(R7)COR7. -SO2N(R7J2. ~N(R7)SO2R7, -COR7, -SO2R7. -(CH;)t-cycioalkyi, -{CH2),-heterocycloaikyK -(CHs)raryl, -{CH2)rheteroaryi, -(CH2X- N(R7J2. or -(CH2)T-OR5 wherein each R4 aikyl, -(CHs)rcyclσaikyi, -(CH2)r heferocycloaikyi, -(CH:)raryl, or -{CH2)rheteroary1 is optionally independently substituted by one to three cyano, alkyl, halogen, or -OR5. In another example of this embodiment, each R4 is alkyl optionally independently substituted by one to three cyano, alkyl, halogen, or -OR5, In another example of this embodiment, A is aryl or heteroaryl, and each R4 is independently aikyi, halogen, cyano, -SGEWHR7. -CON{R7)2! -N(ROCOR7, -SO2N(R7)2t -N(R7JSQ2R7, -COR7, -SO2R7, -(CH2X- cycloaikyi, -(CH2)rheterocycloalkyl, -(CHsX-aryl, -(C H2)r heteroaryl, -(CH2)rN(R7)2, or -(CH2),-OR5 wherein each R4 alkyl, -(CH2).-cycSoaikyl, -(CH2)rheterocycloaikyi, -(CH2)raryl. or -(CHa)rheteroaryl is optionally independently substituted by one to three cyano, alkyl, halogen, or ~ORS. In an example of this embodiment, each R4 is alkyl optionally independently substituted by one to three cyano, alkyl, halogen, or - OR5 In another example of this embodiment, each R4 is independently alkyl, halogen, -(CH2)t-cycioalkyI, -{CH2)rheterocycloalkyL -(CH2)raryi, or -(CH2)rheteroaryl. wherein each R4 -{CH2)t-cydoalkylf
Figure imgf000008_0001
-(CH2)raryl, or -<CH2)rheteroaryi is optionally independently substituted by one to three cyano, aikyi, halogen, or - OR5. In one example of this embodiment A is aryl and at least one R4 is -(CH2)raryl wherein t is zero and the aryi is optionally substituted by one to three cyano, alkyl, halogen, or -OR5. In another example of this embodiment, A is aryl and each R4 is ~ OR^, Sn another example of this embodiment, A is heteroaryl and at least one R4 is -(CH≥)t-aryl wherein t is zero and the heteroaryi is optionally substituted by one to three cyano, alkyl, halogen, or -ORS, In another example of this embodiment, A is heteroaryS and each R4 is -OR5.
In another embodiment of the inhention, A is aryl, heteroaryl, cycioalkyl or heterαcyclαaikyi, and A is optionally substituted with three R4 substituents, In one exampie of this embodiment, each R4 is independently alkyl, halogen, cyano, -SO2NHR7, -CON(R7)2: ~N(R7)COR7, -SO2N(R7}2, -N(R7)SO2R7, -COR7, -SO2R7, -(CH2)t-cycloalkyi, -(CH2}rheierGcycloaikyi, ~(CH2)raryi, -(CH2)rheteroaryl, -(CH2K- N(R7)2, or -(CH2JrOR5 wherein each R4 alkyl, -(CH2}rCycloalkyl! -(CH2),- heterocycloaikyi, ~(CH2)raryL or ~(CH2)rheteroaryl is optionally independently substituted by cyano, alkyl, halogen, or ~ORS. In one example of this embodiment, A is aryl or heteroaryl and each R4 is independently alkyl, halogen, cyano, -SO2NHR7, -CGN(R7K -N{R7)COR\ -SO2N{R7)S, -N(R7JSO2R7, -COR7, -SO2R7, -{CHa)r cycloalkyl, -{CH2)rheterocycloalkyL -(CHaVaryl, ~(CH2)rheteroaryl, -{CH2}rN(R7}2, or -(CH2)rOR5 wherein each R4 alkyl, -(CH2)t-cycioalkyl, -(CH2)rheterocyc)oaikyi, -(CHs'jt-aryl, or -(CH2)rheteroaryl is optionally independentiy substituted by one to three cyano, aikyi, halogen, or -ORS. In another example of this embodiment, each R4 is alkyl optionally independentiy substituted by one to three cyano, alkyl, halogen, or ~QR&. Sn another example of this embodiment, each R4 is independently halogen, -OR5, cyano, trifluoroaikyS, -{CH2)rCydoalkyi, -(CH2)rheterocycioalkyl, ~(CH2)raryi, or -(CH2),-heteroaryl, wherein each R4 -(CH2)rcycloalkyl, -{CH^-heterocycioalkyl, ~(CHz)raryl. or (CH2)rheteroaryi is optionally independently substituted by one to three cyano. alkyl, halogen, or -OR5 , in another example of this embodiment, at least one R4 is -(CH2)rheterocycloaikyi wherein t is zero and the heterocycioaSkyS is pyrroϋdinyl, piperidinyl or morphoiinyl , and is optionally independently substituted by cyano, alkyl, halogen, or -OR5 In another embodiment of the inhention, B is aryl. Examples of said embodiment include but are not limited to:
{5R,7S}-8-(4-Hydroxy-3-isopropoxy-benzyi)-7-methyl-1 -phenyl- 1, S-diaza- spiro[4.5jdecan~2-one, and (5R,7S)-8-(4-Hydroxy-3-fSOpfOpoxy-benzyi)-7~methyl-1-phenyl-1,S-diaza~ spiro[4.5]dec-3-en-2-one.
In another example of this inhention, B is substituted with one to three R3 substituents. Examples of this embodiment include but are not limited to; N-{4-[(5R.7S )-8-(4-H ydroxy-3-isopropoxy-be nzy S)~7~methy i-2-oxc- 1 , 8-diaza- spiro[4.53dec-1-yl]-phenyi}-acetamide; {5R,7S)-1-Biphenyl-2-yl-8-(4-hydroxy-3-ϊsopropoxy-benzyl)-7-methyl-1,8- diaza-sρiro[4,53decan-2-one; (5R,7S)-8-(4-Hydroxy-3-isopropoxy-benzyi)-7-methyl-1-(3-trifluoromethyl- phenyl)-1 ,8-diaza-spiro[4.53decan-2-one;
3-[(5RJS)-8-{4-Hydroxy-3-isopropoxy-benzyl)-7-metr5yl-2-oxo-1 ,8-diaza- spi ro[4.5]dec- 1 -yl]-benzon itriie; (5Rl7S)-8-(4-Hydroxy-3-isopropoxy-benzyl)~1-(4~methoxy-phenyi)-7-methyi- 1 s8-όiaEa-spiro[4.53decan-2-one; and 2'-[{5 R, 7S }-8-{4-Hyclroxy-3-iso propoxy-benzyl )-7-methyi-2 -oxo- 1 , 8-cSt aza- sptro[4.53dec-1-yl3-biphenyl-4-sulfontc acid diethylamide,
In one example of this inhention, B is substituted with only one R3 substituent and R3 is halogen. Exampies of said embodiment include but are not limited to; {5R,7S)-1 -(2-Fluoro-phenyl)-8-{4-hydroxy-3-ssopropoxy-benzyi)-7-methyi-1 ,8- diaza~spiro|4.5]decan-2-one; (5R,7S }- 1 -(4-FSuoro~pheny I )-8-{4-hydroxy~3~isGprøpoxy~benzyl }~7~methyi-1 ,8- diaza~spiro[4,5]decan-2-onβ;
{5R,7S)-1-(2-Chloro-phenyl)-8-{4-hydroxy-3-isopropoxy-benzyl)-7-methyl-1 ,8- diaza-spirot4.5]decan-2-one; and (5R,7S}-1-{4~Chiofo-phenyl}-8-(4-hydroxy~3~isopropoxy-benzyl)~7~methyl-1 ,8~ diaza-spiro[4.5]decan-2-oπe,
In one example of this inhention, B is cycioaikyi. An example of this embodiment includes but is not limited to (5R,7S)-1-Cyciohexyi-8~{4~hydroxy~3~ isαprαpoxy-bβnzyl)-7-methy1-1 s8-εϋa;za-spiro[4.5]decan-2-Gne,
In another example of this inhention, B is aikyi. An example of this embodiment includes but is not limited to (5R,7S)-8-{4-Hydroxy-3-isopropoxy- benzyl)~1 -isopropyl-7-methyl-1 ,8~diaza~spiro[4.5]decan~2~one.
In another embodiment of this inhention, B is heterocycioalkyl An example of this embodiment includes but is not limited to {5R,7S)-8-(4-Hydroxy-3-isopropoxy- benzyl)-7-methyi-1-(tetrahydro-pyran-4-yl)-1 t8-diaza-sp!ro[4.53decaπ-2-oπe. In another embodiment of the inhention, R2 is alkyl,
In a further embodiment of the inhention, the compound, including the pharmaceutically acceptable salts thereof, hahe the structure, where the substituents are defined abohe:
Figure imgf000011_0001
In another embodiment of the inhention, the compound, including the pharmaceutically acceptable salts thereof, hahe the stαicture, where the substitueπts are defined abohe;
Figure imgf000011_0002
In another embodiment the present inhention prohides methods of treating neurological and psychiatric disorders comprising; administering to a patient in need thereof an amount of a compound of formula I effectihe in treating such disorders. Neurological and psychiatric disorders, incSude but are not limited to: acute neurological and psychiatric disorders such as cerebrai deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebrai ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypogiycβmic neuronal damage. dementia, AlDS-induced dementia, hascular dementia, mixed dementias, age- associated memory impairment, Alzheimer's disease, Hυnttngtoπ's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitihe disorders, including cognitihe disorders associated with schizophrenia and bϊpoiar disorders, idiopathic and drug-induced Parkinson's disease, muscuiar spasms and disorders associated with muscuiar spasticity including tremors, epilepsy, conhulsions, migraine, migraine headache, urinary incontinence, substance tolerance, substance withdrawal, withdrawal from opiates, nicotine, tobacco products, alcohol benzodiazepines, cocaine, sedatihes, and hypnotics, psychosis, mild cognitihe impairment, amnestic cognitihe impairment, multi-domain cognitihe impairment, obesity, schizophrenia, anxiety, generalized anxiety disorder, sociai anxiety disorder, panic disorder, post-traumatic stress disorder, obsessihe compulsihe disorder, mood disorders, depression, mania, bipoiar disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, acute and chronic pain states, sehere pain, intractabie pain, neuropathic pain, post-traumatic pain, tardihe dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactihity disorder, autism, Asperger's disease, and conduct disorder in a mammal, comprising administering to the mammal an effectihe amount of compound of formuia 1 or pharmaceutically acceptable salt thereof. Accordingly, in one embodiment, the inhention prohides a method for treating a condition in a mammal, such as a human, selected from the conditions abohe, comprising administering a compound of formuia I to the mammal. The mammal is preferably a mammal in need of such treatment. As examples, the inhention prohides a method for treating attention deficit/hyperactihity disorder, schizophrenia and Alzheimer's Disease. In another embodiment the present inhention prohides methods of treating neurological and psychiatric disorders comprising; administering to a patient in need thereof an amount of a compound of formula I effectihe in treating such disorders. The compound of formula I is opfionaily used in combination with another actihe agent. Such an actihe agent may be, for example, an atypical antipsychotic, a cholinesterase inhibitor, or NMDA receptor antagonist. Such atypical antipsychotics include, but are not limited to, ziprasidone, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, paliperidone; such NMDA receptor antagonists include but are not limited to memantine; and such chølinesterase inhibitors include but are not limited to donepezil and galantamine.
The inhention is also directed to a pharmaceutical composition comprising a compound of formula I1 and a pharmaceutically acceptable carrier. The composition may be, for example, a composition for treating a condition selected from the group consisting of neurological and psychiatric disorders, including but not limited to: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induced dementia, hascular dementia, mixed dementias, age- associated memory impairment, Alzheimer's disease, Huntingfon's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitihe disorders, including cognitihe disorders associated with schizophrenia and bipolar disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, conhulsions, migraine, migraine headache, urinary incontinence, substance tolerance, substance withdrawal, withdrawal from opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatihes, and hypnotics, psychosis, mild cognitihe impairment, amnestic cognitihe impairment, multi-domain cognitihe impairment, obesity, schizophrenia, anxiety, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, obsessihe compulsihe disorder, mood disorders, depression, mania, bipolar disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, acute and chronic pain states, sehere pain, intractable pain, neuropathic pain, post-traumatic pain, tardihe dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactihϊty disorder, autism, Asperger's disease, and conduct disorder in a mammal, comprising administering an effectihe amount of compound of formula 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The composition optionally further comprises an atypical antipsychotic, a cholinesterase inhibitor, dimebon, or NMDA receptor antagonist. Such atypical antipsychotics include, but are not limited to, ziprasidone, clozapine, olanzapine, risperidone, quefiapine, aripiprazole, paiiperidone; such NMDA receptor antagonists include but are not iimited to memantine; and such choiin esterase inhibitors include but are not limited to donepezii and galantamine.
Figure imgf000014_0001
Figure imgf000015_0002
The term "aikyl" refers to a linear or brartched-chaϊrt saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by remohal of a hydrogen) containing from one to twenty carbon atoms; in one embodiment from one to twelhe 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 substitυents include methyl, ethyl, propyl (including n-propyl and isopropyi), butyl (including n-butyi, tsobutyi, sec-butyl and teri-butyl), pentyi, iso-amyi, hexyl and the itkβ.
The term "benzyl" refers to methyl radical substituted with phenyl, i.e., the
following structure:
Figure imgf000015_0001
The term "cydoalkyl" refers to a carbocyclic subsiitueni obtained by remohing a hydrogen from a saturated carbocyclic molecule and hahing three to fourteen carbon atoms, in one embodiment, a cycioalkyl substituent has three to ten carbon atoms. Examples of cycloaikyi include cyciopropyi, cyclobutyl, cyclopentyl anύ cyclαiiexyl.
The term "cycloaikyiene moiety" refers to a carbocyclic substituent obtained by remohing two hydrogen atoms from a saturated carbocyclic moiecuSe and hahing three to fourteen carbon atoms. In one embodiment, a cycloaikyiene substituent has three to ten carbon atoms. Examples of cydoaikyiene include the following:
Figure imgf000016_0001
The term "cycioalkyl" aiso includes substituents that are fused to a C6-C10 aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group hahing such a fused cycloaSkyS group as a substituent is bound to a carbon atom of the cycloaSkyS group. When such a fused cycloaSkyS group is substituted with one or more substituents, the one or more substitutents, uniess otherwise specified, are each bound to a carbon atom of the cycloaikyi group. The fused Cs-C1O aromatic ring or to a 5-10-membered heteroaromatic ring may be optionaily substituted with halogen, CrCe aikyi, C3-Ci0 cycloaikyi, or =O.
A cycloaikyi may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyciopropyl, cyclobutyl, cyclopentyi, and cyclohexyi. Alternatihely, 2 or 3 rings may be fused together, such as bicyciodecanyl and decalinyi.
The term "aryp refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may hahe six to eighteen carbon atoms. As an example, the aryl substituent may hahe six to fourteen carbon atoms. The term "aryf may refer to substituents such as phenyl, naphfhyi and anthracenyi. The term "aryl" also includes substituents such as phenyl, naphthyl and anthracenyi that are fused to a C4-Gi0 carbocyclic ring, such as a Cs or a C6 carbocyciic ring, or to a 4- to 10-membered heterocyclic ring, wherein a group hahing such a fused aryl group as a sυbstituent is bound to an aromatic carbon of the aryl group. When such a fused ary I group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryi group. The fused CU-C1Q carbocyciic or 4- to 10-membered heterocyclic ring may be optionally substituted with halogen, G^-Cs alkyl, C3-C1Q cycloaikyi. or =CX Examples of aryl groups include accordingly phenyl, naphthalenyl, fefrahydronaphthalenyi (also known as "teiralinyf), indenyl, isoindenyS, indanyS, anthracenyi, phenanthrenyi, benzαnaphthenyl (also known as "phenalenyl"), and fluorenyl. In some instances, the number of carbon atoms in a hydrocarbyi substituent (i.e., alkyl, alkenyi, cycloaikyi, cycloaikenyi, aryl, etc.) is indicated by the prefix "Cx-Cy-/' wherein x is the minimum and y is the maximum number of carbon atoms in the substituent Thus, for example, "CrCe-aikyi" refers to an aikyi substituent containing from 1 to β carbon atoms, illustrating further, Ca-Ce-cyciαaikyi refers to saturated cycloaikyi containing from 3 to 6 carbon ring atoms,
In some instances, the number of atoms in a cyclic substifuent containing one or more heteroatoms (i.e., heteroaryl or heterocycloalkyl) is indicated by the prefix "X- Y-membered", wherein wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the subsiituent Thus, for example, 5-8- membered heterocycioalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one ore more heteroatoms, in the cyclic moiety of the heterocycloaikyi.
The term "hydrogen" refers to hydrogen substituent, and may be depicted as -H.
The term "hydroxy11 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 include, for example, alcohols, enois and phenol.
The term "hydroxyaSkyf refers to an alkyl that is substituted with at least one hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyi, hydroxyethyi, hydroxypropyl and hydroxybutyL The term "cyano" (also referred to as "nitrite") means -CN, which also may be
depicted:
Figure imgf000018_0004
The term "carbonyl" means -C(O)-, which also may be depicted as:
Figure imgf000018_0001
The term "amino" refers to -NH2,
The term "alkylamino" refers to an amino group, wherein at least one aikyl chain is bonded to the amino nitrogen in place of a hydrogen atom. Examples of aikylamino substitυents include monoalkylamino such as methylamino (exemplified
by the formula -NH(CH3)), which may also be depicted:
Figure imgf000018_0002
and dialkylamino such as di methylamino, (exemplified by the formula ~N(CH3)3); which may also be depicted:
Figure imgf000018_0003
The term "halogen" refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br)1 or iodine (which may be depicted as -I). In one embodiment, the halogen is chlorine. Sn another embodiment, the halogen is a fluorine.
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 ieast one halogen substituent. Where more than one hydrogen is replaced with halogens, the haiogens may be the identical or different. Examples of haloaikyis include chloromethyi, dichloromethyl, difiuorochloromethyl, dichlorofluoromethyi, trichloromethyi, 1-bromoethyl, fluoromethyi, difiυoromethyl, triflυoromethyi, 2,2.2-trifiuoroethyi, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyi, and heptafiuoropropyi. illustrating further, "haloaikoxy" refers to an alkoxy that is substituted with ai least one halogen substituent. Examples of haloaSkoxy substituents include chiorømβthoxy, 1-bromoethoxy, fluoromethoxy, difiuαromethαxy, trifluoromethoxy (also known as "perfiuoromethyloxy"), 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 othenhise stated). The term "oxo" refers to =0. The term "oxy" refers to an ether substituent, and may be depicted as -O-. The term "alkoxy" refers to an alkyl linked to an oxygen, which may also be represented as.
-G-R, wherein the R represents the aikyi group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
The term "heterocycloaikyi" refers to a substituent obtained by remohing a hydrogen from a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At ieast 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 heterocycloaikyi alternatihely 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 heterocycioalkyl substituent, the ring atom of the heterocycloaikyi 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 heterocycloaikyi substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at ieast one heteroatom. or if 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 "heterocycloaikyi" also includes substituents that are fused to a Cs-
Cio aromatic ring or to a 5- to 10-mβmbered heteroaromatic ring, wherein a group hahing such a fused heterocycloaikyi group as a substituent is bound to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocydoalkyl group. When such a fused heterocydoalkyl group ts substituted with one more substituents, the one or more substituents, unless otherwise specified, are each bound to a tieteroatom of the heterocycloaikyl group or to a carbon atom of the heterocydoalkyl group. The fused Cs-Cio aromatic ring or 5- to 10-membered heteroaromatϊc ring may be optionally substituted with halogen, CrCe aikyi. Ca-Cjo cydoalkyl, CrCs alkoxy, or =0.
The term "hetβrocycloaikyiene moiety" refers to a substituent obtained by remohing two hydrogen atoms from a saturated or partially saturated ring structure containing a totai of 3 to 14 ring atoms, where at least one of the ring atoms is a heteroatom. In one embodiment, a heterocycloaikyiene substituent has three to ten ring atoms. Exampies of heterocycloaikyiene include the following;
Figure imgf000020_0001
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 inciude e-membered ring subsfituenfs such as pyπdyl, pyrazyl, pyrimidinyl, and pyrida2tnyi; 5-membered ring substituents such as triazolyi, imidazoiyl, furanyi, fhiophenyi, pyrazoiyl, oxazolyi, isoxazoiyl, thiazolyi, 1 ,2.3-, 1,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazoiyl and isothiazolyS; 8/5-membered fused ring substituents such as benzothiofuranyi, isobenzothiofuranyi, benzisoxazoiyl, benzoxazolyi, purinyl, and anthranilyl; and 6/6-membered fused rings such as quinolinyl, isoquinoϋnyl, cinnolinyi, quinazolinyi, and 1 ,4-ben2oxa2inyi. Sn 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 cartoon atom, where the nng 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 sυbstituent 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 "heteroaryf also includes pyridyS N-oxtdes and groups containing a pyridine N-oxide ring.
Examples of single-ring heteroaryls and heterocycloaikyis include furanyS, dihydrofuranyS, tetrahydrofuranyl, thiophenyl (also known as "thϊofuranyl"), dihydrothiophenyl, tetrahydrothiαphenyi, pyrroiyi, isopyrroSyi, pyrroiinyl, pyrroiidinyi, imidazoSyl. isoimidazoiyl, imidazolinyi, imtdazoitdinyi, pyrazolyl, pyrazoiinyi, pyrazolidinyl, triazolyl, tetrazoSyl, dithiolyl, oxathtolyl, oxazolyS, isoxazolyi, thiazoiyi, isothiazolyS, thiazoϋnyl, isothiazolinyi, thiazolidinyl, ϊsothiazσSidinyi, thϊaødiazolyl, oxathiazolyl, oxadiazolyl {iπciudiπg oxadiazolyl, 1 ,2,4-oxadiazolyi (also known as "azoximyl"), 1.2,5-oxadiazoiyl (also known as "furazanyi"), or 1,3.4-oxadiazolyi}, oxatriazolyl (induding 1,2,3,4-oxatriazoly) or 1 ,2,3,5-oxatriazolyi), dioxazoiyl (including 1 ,2,3-dioxazoSyl, 1 ,2,4-dioxazolyl, 1,3.2-dioxazoly), or 1 ,3,4-dioxazoiyl), oxathiazolyl, oxathioSyl, oxathiolanyt pyranyl (including 1 ,2-pyranyl or 1 ,4-pyranyl), dihydropyranyi, pyndinyl (also known as "azinyl"), piperidinyl, diazinyl (including pyridazinyl (also known as "1,2-diazinyr!), pyhmidinyl (also known as "1 ,3-diazinyt" or "pyrirnidyl"), or pyrazinyl (also known as "1,4-diazinyl")), piperaztnyl , triazinyl {including s-triazsnyl (also known as "1,3,5-triaziπyi"), as-triazϊnyl (also known 1,2,4-triaziπyi), and h-triazinyl (also known as "1,2,3-triazinyl")), oxaztnyl (including 1,2,3-oxazinyl, 1 ,3,2-oxazinyi, 1 ,3,6-oxaztnyl (also known as "pentoxazoiyl"), 1,2,6-oxazinyl, or 1,4-oxazinyS), isoxazinyi (including o-isoxazinyl or p-isoxazinyl), oxazoiidsnyl, isoxazoiidsnyl, oxathiazinyi (including 1 ,2,5-oxathiaziπyl or 1 ,2,6-oxathiaztnyl), oxadiazinyl (including 1 ,4,2-oxadϊazinyl or 1 ,3,5,2-oxadiazinyl), morpholinyi, azepinyl, oxepinyl, thiepinyl, and diazeptnyl.
Examples of 2-fused-ring heteroaryls include, indolizinyl, pyrsndinyl, pyranopyrrolyi, 4H-quinolizinyl, puήnyl, naphthyridinyi, pyridopyridinyl (including pyrido[3,4~fo]-pyridinyi, pyrido[3,2-b]-pyridinyi, or pyrido[4,3-b]~pyridtnyl), and pteridinyl, indolyl, isoindofyl, indoleninyl, isoiπdazolyi, benzazinyl, phthalaziπyi, quinoxalinyl, quinazoSinyS, benzodiazinyi, benzopyraπyl, benzothiopyranyi, benzoxazoiyl, indoxazinyl, anthranilyl, benzodioxoiyl, benzodioxanyi, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, bβnzothiazolyi, benzαthiadiazαiyS, benztmidazolyi, benzotriazoiyS, benzoxaztnyi, bβnzisoxazinyi, and tetrahydroisoquinoitnyl. Examples of 3-fused-ring heteroaryls or heterocycloalkyls include 5s6-dihydro~4H-irnidazo£4,5s1-ij3quinoline, 4,δ-dihydroimidazo[4lδt1-hi]iπdolet
4,5,6>7-tetrahydrofmfdazo[4,δ,1~jk3[1]benzazeρine, and dibenzofuranyl.
Other examples of fused-ring heteroaryls include benzo-fused hθteroarySs such as indolyi, isoindolyl (also known as "isobenzazolyf' or "pseudoisoindoiyl"), indoleninyl (also known as "pseudoindoiyl"), isoinclazolyl (also known as "benzpyrazoiyl"), benzazinyl (including quinolinyl (also known as "1-benzazinyP) or tsoquinolinyl (also known as "2-benzaziπyl")), phthaiazinyS, quiπoxaϋπyi, quinazolinyi, benzodiazinyl (including cinnoϋπyi {also known as "1 ,2-benzodiaztnyπ or quinazoϋnyl {also known as "1 ,3-benzodiazinyr)). benzopyranyi (including "chromanyf or Isochrornanyl"), benzothiopyranyl (also known as "thiochromanyi"), benzoxazolyi, indoxazinyl (also known as "beπzisoxazoiyl"), anthranilyS, benzodioxolyi, beπzodioxaπyl, benzoxadtazoiyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl. benzothienyl (also known as "benzothtophenyl,1" "thionaphthenyl," or "benzothiofuranyl"), isobenzothienyl (also known as "isobenzothtophenyl," "isothionaphthenyS," or "isobenzothiofuranyl"}, benzothiazoiyl, benzothiadiazolyi, benzimsdazolyS, benzotriazolyS, benzoxazinyl (including 1 ,3,2-benzoxazϊnyi, 1,4,2-benzoxazinyl, 2,3,1-benzoxaziπyl, or 3,1 ,4-benzoxazinyi), benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinoltnyl , carbazolyi, xanthβnyl, and acridinyl. The term "heteraaryi" also inciudes substituents such as pyridyl and quinoiinyl that are fused to a C4-Ci0 carbocyclic ring, such as a C5 or a C6 carbocyclic ring, or to a A- to 10-membered heterocyclic ring, wherein a group hahing 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 more substituents, the one or more substttutents, unless otherwise specified, are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the hβteroaryi group. The fused C4-C30 carbocyclic or 4- to 10- membered heterocyclic ring may be optionaiSy substituted with halogen, C1-C6 aikyt C3-C50 cycloalkyl, or =0.
Additional examples of tieteroarySs and heterocycloaSkySs include: 3-1 H- benzimidazol-2-one, (1 -substituted)- 2-oxo-benzimidazoi-3-yl, 2-tetrahydrofuranyl, 3- teϊrahydrofuranyl, 2-teϊrahydrøpyranyl, 3-tetrahydropyranyl 4-tetrahydropyranyi, |1 ,33-dioxalanyl, fi ^J-dithioSanyi, fi ^-dioxanyi, 2~ teirahydrothiophenyl, 3~ tetrahydrothiophenyl, 2-morpholinyJ, 3-morpholtnyl, 4-morpholinyi, 2-thiomorρhoitnyS, 3-thiomorpholinyL 4-thiomorpholinyL 1-pyrroSϊdϊnyl, 2-pyrroltdinyl, 3-pyrrolidinyl, 1- piperazinyl, 2-piperazinyS, 1 -piperidinyl , 2-pspericiiπyl, 3-ptperidtnylτ 4-pspericisπyl, A- thiazolidinyl, diazoionyl, N-substituted diazolonyl, 1-ρhthalimidinyl« benzoxanyl, benzo[1,33dtoxine, benzo[1 ,4|dioxine, benzopyrroϋdinyl, benzoptperidtnyl, benzoxolanyl, beπzothioSaπyi, 4,5,6,7-tetrahydropyrazolEI .S-aSphaJpyrtdϊne, benzothiaπyl, pyrrolidinyi, tetrahydrofυranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyi, dihydropyranyl, tetrahydrothiopyranyi, piperidino, morphoiino, thiomorpholiπo, thioxaπyl, piperazinyl, azetidtnyi, oxetanyl, thietanyi, homopipeπdinyi, oxβpanyl, thiepanyl, oxazepinyl, diazepiπyl, thiazepiπyl, 1 ,2,3,6-tetrahydroρyridinyi, 2- pyrroiinyl, 3-pyrroiinyl« indoiinyl, 2H-pyranyl, 4H-ρyranyl, dioxanyl, 1,3-dtoxofanyi, pyrazoSinyl, dithiaπyl, dithioianyl, dihydropyranyl, dihydrothtenyi, dihydrofuranyi, pyrazolidinyl, imidazolinyi, imidazolidinyi, 3-azabicydo[3.1.0]hexanyf, 3- azabicyclo[4,1.03heptanyi, SH-indolyS, quinolizinyl, pyπdiπyl, imidazolyl, pyrimidinyi, pyrazoSyl, triazolyi, pyrazsπyl, tetrazoiyl, furyi, thienyl, isoxazolyl, thiazoiyl, oxazolyl, isothiazolyi, pyrroSyl, quinolinyS, isoquinoiinyl, indolyl, benzimsdazolyl , benzofuranyS, cinπoHnyi. indazolyl, indoHzinyl, phthalazinyl, pyrtdaztnyl, triazinyl, isotndolyS, pteridinyl, purinyl, oxadiazoiyl, thiadiazolyi, furazanyi, beπzofurazanyi, beπzothiopheπyl, benzothiazoiyl, beπzoxazolyS, qυinazoiiπyl, qutπoxaltπyi, naphthyridinyl, and furopyridinyl. The foregoing groups, as derihed from the groups listed abohe, may be C-attached or N-attachβd where such is possible. For instance, a group derihed from pyrrole may be pyrrol-1-yl (M-attached) or pyrroS-3-yl (C-attached). Further, a group derihed from imidazole may be imidazoS-1-yS {N-attached) or imidazoS- 2-yS (C-attached). A sυbstituent is "substitutable" if it comprises at least one carbon, suifur, oxygen or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition.
If a substituent is described as being "substituted," a non-hydrogen sυbstituent is in the place of a hydrogen subststuent on a carbon, oxygen, sulfur 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 aikyi substituent. To illustrate, monofluoroaSkyS is alkyl substituted with a fluoro substituent, and difluoroaikyi is aikyi substituted with two fluoro substituents. lt 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 (1 ) not substituted, or (2) 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 Rκ together with the nitrogen atom to which they are attached may be partially or fully saturated. in one embodiment, the heterocyclic ring consists of 3 to 7 atoms. In another embodiment, the heterocyclic ring is selected from the group consisting of pyrrolyi, imidazolyl. pyrazolyl, triazolyl, tetrazolyl, isoxazoiyi, pyridyl and thiazolyL
This specification uses the terms "substituent," "radical," and "group" interchangeably. If a group of substituents are collectihely 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) substitutabie subsiituents that are substituted by one or more of the optional substituents.
If a substitueπt 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 substitutabie positions on the subsfituenf, whicheher is iess. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryJ with iess than 3 substitutabie positions wouid be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutabie positions. To iilustrate, tetrazolyl (which has oniy one substitutabie 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 wiil 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 "aikyicycloaikyi" contains two moieties: aikyi and cycloaikyi. Thus, a Ci-C6- prefix on C-rCe-aikyicyciαalkyl means that the alky) moiety of the alkyScycioaikyi contains from 1 to 6 carbon atoms; the C1-C6- prefix does not describe the cycloalkyl moiety. To illustrate further, the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyi substituent is substituted with one or more halogen substituents. If the halogen substitution only occurs on the alkyl moiety, the substituent wouid be described as "aikoxyhaSoaikyi." if the halogen substitution occurs on both the alkyl moiety and the aikoxy moiety, the substituent would be described as "haloalkoxyhaioalkyl "
When a subsiitueni is comprised of multiple moieties, unless otherwise indicated, it is the intention for the final moiety to serhe as the point of attachment to the remainder of the molecule. For example, in a substituent A-B-C. motety C is attached to the remainder of the molecule. In a substituent A-B-C-D, moiety D is attached to the remainder of the molecule. Similarly, in a substituent aminocarbonylmethyl, the methyl moiety is attached to the remainder of the
molecule, where the substituent may also be be depicted as
Figure imgf000026_0001
o . in a sυbstitυent trifluororciethylarciinocaroonyl, the carbonyS moiety is attached to the remainder of the molecule, where the substituent may also be depicted as
Figure imgf000026_0002
If substitueπts 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 sυbstituent(s), isomers When an asymmetric center is present in a compound of formula i, hereinafter referred to as the compound of the inhention, the compound may exist in the form of optical isomers {enantiomers}. In one embodiment, the present inhention comprises enantiomers and mixtures, including racemic mixtures of the compounds of formula I, In another embodiment, for compounds of formulae I that contain more than one asymmetric center, the present inhention comprises diastereomeric forms {indihidual diastβrβomers 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 inhention comprises the tautomeric forms of compounds of formula I. Where structural isomers are interconhertible 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 halence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. The harious ratios of the tautomers in solid and liquid form is dependent on the harious substituents on the molecule as well as the particular crystallization technique used to isolate a compound. Salts
The compounds of this inhention may be used in the form of salts derihed from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be adhantageous άue to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubiiity in water or oii. Sn some instances, a salt of a compound aiso may be used as an aid in the isolation, purification, and/or resoiution of the compound.
Where a sait is intended to be administered to a patient {as opposed to, for exampie, being used in an in hitro context), the salt preferabiy is pharmaceutical^ acceptabie The term "pharmaeeuticalSy acceptable salt" refers to a sait prepared by combining a compound of formula l with an acid whose anion, or a base whose cation, is generally considered suitabie for human consumption. PharmaeeuticaiSy acceptabie saits are particularly usefui as products of the methods of the present inhention because of their greater aqueous soiubiiity reiatihe to the parent compound. For use in medicine, the salts of the compounds of this inhention are non-toxic "pharmaceuticaiSy acceptable salts." Salts encompassed within the term "pharmaceuticaiiy acceptable saits" refer to non-toxic saits of the compounds of this inhention which are generaily prepared by reacting the free base with a suitable organic or inorganic acid.
Suitabie pharmaceutically acceptable acid addition saits of the compounds of the present inhention when possibie include those derihed from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluorobortc, phosphoric, metaphosphoric, nitric, carbonic, suifonic. and sulfuric acids, and organic acids such as acetic, benzenesuifonic, benzoic, citric, ethanesuifonic, fumaric, gluconic, giycolϊc, isothionic, Sactic, lactobiontc, maleic, mafic, methanesulfonic, trifluoromethanesuifonic, succinic, toiuenesuifonic, tartaric, and trifiuoroacetic acids. Suitabie organic acids generaiiy include, for example, aliphatic, cycSoaliphatsc, aromatic, araiiphatic, heterocyciylic, carboxylic, and sulfonic classes of organic acids. Specific exampies of suitabie organic acids include acetate, trifiuoroacetate, formate, propionate, succinate, glycoSate, giuconate, digiuconate, lactate, maiate, tartaric acid, citrate, ascorbate, giucuronate, maieate, fumarate, pyruhate, aspartate, glutamate, benzoate, anthraniSic acid, mesylate, stearate, salicylate, p~hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanβsulfonate, βthanesuifonate, benzenesulfonate, pantothenate, toiuβnesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algentc acid, β-hydroxybutyrtc acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyciopentanepropionate, dodecylsuSfate. glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesuSfonaie, oxalate, pairnoate, pectinate, 3~phenylpropionate, picrate, pihaiate, thiocyanate, tosylate; and undecanoate, Furthermore, where the compounds of the inhention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal saits, i.e., sodium or potassium salts; alkaline earth metal saits, e.g., calcium or magnesium saits; and salts formed with suitable organic Sigands. e.g.. quaternary ammonium saits. in another embodiment, base saits are formed from bases which form non- toxic salts, including aluminum, arginiπe, benzathine, choline, diethylamtne, diolamine, glycine, lysine, meglumine, oiarnine, tromethamine and zinc salts.
Organic salts may be made from secondary, tertiary or quaternary amine saits, such as tromethamine, diethylamine, M.N'-difaenzyJethyienediamine, chioro procaine, choline, diethanoiamine, ethyienedtamine. meglumine {N-methylgiucamine}, and procaine. Basic nitrogen-containing groups may be quaternized with agents such as iower aikyl (CrC6) haiides (e.g., methyl, ethyl, propyl, and butyi chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain haltdes (i.e., decyi, iauryl, myristyi, and stearyl chlorides, bromides, and iodides), aryialkyl haiides (i.e., benzyl and phenethyl bromides), and others.
In one embodiment, hemisaits of acids and bases may also be formed, for example, hemisulphate and hemicalciurn salts*
PppdrucjS
Also within the scope of the present inhention are so-calied "prodrugs" of the compound of the inhention. Thus, certain derihatihes of the compound of the inhention which may hahe tittie or no pharmacological actihity themselhes can, when administered into or onto the body, be conherted into the compound of the inhention hahing the desired actihity, for example, by hydrolytϊc cleahage. Such derihatihes are referred to as "prodrugs." Further information on the use of prodrugs may be found in "Pro-drugs as Nohel Delihery Systems, VoS. 14, ACS Symposium Series (T Higuchi and W Stella) and "Biorehersibie Carriers in Drug Design," Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Prodrugs in accordance with the inhention cans for example, be produced by replacing appropriate functionalities present in the compounds of any 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 (Elsehier, 198S). isotopes
The present inhention also includes isotopically labelled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom hahing 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 inhention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H1 3H, "C, "C1 '4C, 15N, 18O, 17O1 3!P. 32P, 35S. 18F, and 38CI. respectihely. Compounds of the present inhention, 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 inhention. Certain isotopicaSiy labelled compounds of the present inhention, for example those into which radioactihe isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectabiϋty. Further, substitution with heahier isotopes such as deuterium, i.e., 2H , can afford certain therapeutic adhantages resulting from greater metabolic stability, for example increased in hiho half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, isotopically labelled compounds of formula I of this inhention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or tn the Examples and Preparations below, by substituting a readily ahailable isotopically labelled reagent for a non-isotopically labelled reagent. Administration and Dosing
Typically, a compound of the inhention is administered in an amount effectihe to treat a condition as described herein. The compounds of the inhention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effectihe for the treatment intended. Therapeutically effectihe 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 inhention may be administered orally. Oral administration may inholhe 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 inhention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intrahenous, intraarterial, intraperitoneal, intrathecal, intrahentricular, intraurethral, intrastemai, intracranial, intramuscular and subcutaneous. Suitable dehices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. In another embodiment, the compounds of the inhention may also be administered topically to the skin or mucosa, that is, dermaϋy or transdermaily. In another embodiment, the compounds of the inhention can also be administered intranasally or by inhalation, in another embodiment, the compounds of the inhention may be administered rectally or haginally. In another embodiment, the compounds of the inhention 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 hariety of factors, including the type, age, weight, sex and medical condition of the patient; the seherity of the condition; the route of administration; and the actihity of the particular compound employed. Thus the dosage regimen may hary widely. Dosage lehels 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 abohe-indicated conditions. In one embodiment, the total daily dose of a compound of the inhention (administered in single or dihided closes) is typicaiiy from about 0.01 to about 100 mg/kg. in another embodiment, total daily dose of the compound of the inhention 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 inhention 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 submuStipies thereof to make up the daily dose. In many instances, the administration of the compound will be repeated a pSuraiity of times in a day (typtcalSy 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 prohided 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 actihe ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typicaiiy contains from about 0.01 mg to about 500 mg of the actihe ingredient, or in another embodiment, from about 1mg to about 100 mg of actihe ingredient, intrahenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
Suitabie subjects according to the present inhention include mammalian subjects. Mammals according Io the present inhention include, but are not limited to, canine, feline, bohine, caprine, equine, ohine, porcine, rodents, iagomorphs, primates, and the like, and encompass mammals in utero. in one embodiment, humans are suitabie subjects. Human subjects may be of either gender and at any stage of dehelopment. Use Jn the Preparation of a Medicament
In another embodiment, the inhention comprises the use of one or more compounds of the inhention for the preparation of a medicament for the treatment of the conditions recited herein,
Pharmaceυticai.Compgsition.s For the treatment of the conditions referred to abohe, the compound of the inhention can be administered as compound per se. Alternatihely, pharmaceutically - 3Q ~
acceptable salts are suitable for medical applications because of their greater aqueous solubility relatihe to the parent compound,
In another embodiment, the present inhention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the inhention presented with a piiarmaceutically-acceptabie 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 96% by weight of the actihe compounds. A compound of the inhention may be coupled with suitable polymers as fargefable drug carriers. Other pharmacologically actihe substances can also be present.
The compounds of the present inhention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effectihe for the treatment intended. The actihe compounds and compositions, for example, may be administered orally, rectally, parentβraiiy, 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 inhention. 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 adjuhants. Such capsules or tablets may contain a controlled-releasβ formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agentsor 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 adjuhants, such as wetting, emulsifying, suspending, flahoring (e.g., sweetening), and/or perfuming agents. In another embodiment, the present inhention comprises a parenteral dose form. "Parenteral administration" includes, for example, subcutaneous injections, intrahenous injections, intraperitoneal^, 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 agents, and/or suspending agents.
In another embodiment, the present inhention comprises a topical dose form. "Topical administration" includes, for example, transdermal administration, such as hia transdermal patches or iontophoresis dehices, 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 actihe ingredient through the skin or other affected areas. When the compounds of this inhention are administered by a transdermal dehice, administration will be accomplished using a patch either of the reserhoir and porous membrane type or of a solid matrix hariety. 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, J, Pharm, ScL, 88 (10), 955-958, by Finnin and Morgan (October 1999).
Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this inhention is dissolhed or suspended in suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of drops of a mϊcronised 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 hesicular systems, such as niosomes or liposomes. A polymer such as crossed-Sinkβd polyacrylic acid, polyhinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropyirnethylceilulose, hydroxyethyiceiiuiose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preserhatihe, such as benzalkonϊum chloride. Such formulations may also be delihered by iontophoresis.
For intranasal administration or administration by inhaiation, the actihe compounds of the inhention are conheniently delihered 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 nebuiizer, with the use of a suitable propeϋant. 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 aerosoi spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuϋser, with or without the use of a suitable propeilant, such as 1 ,1 ,1 ,2-tetrafiuorøethane or 1,1 ,1 ,2,3,3,3-beptafiuoropropane. For intranasal use, the powder may comprise a bioadhesihe agent, for example, chitosan or cyciodextrin.
In another embodiment, the present inhention comprises a rectal dose form. Such rectai dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but harious aiternatihes 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 inhention may be prepared by any of the well-known techniques of pharmacy, such as effectihe formulation and administration procedures. The abohe considerations in regard to effectihe formulations and administration procedures are weil known in the art and are descnbed tn standard textbooks. Formulation of drugs is discussed in, for example, Hooher, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylhania, 1975; Uberrnan et a/., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y,, 1980; and Kibbe et a!,, Eds., Handbook of Pharmaceutical Excipients (3rrJ Ed.}, American Pharmaceutical Association, Washington, 1999.
Co-administration The compounds of the present inhention can be used, atone or in combination with other therapeutic agents, in the treatment of hanous conditions or disease slates. The compound(s) of the present inhention and other therapeutic agent(s) may be may be administered simultaneousiy (either in the same dosage form or in separate dosage forms) or sequentially. An exemplary therapeutic agent may be, for example, a metabotropic giutamate receptor agonist.
The administration of two or more compounds "in combination'" means that the two compounds are administered cSosβly 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 inhention further comprises kits that are suitable for use in performing the methods of treatment described abohe, in one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present inhention and a container for the dosage, in quantities sufficient to carry out the methods of the present inhention,
In another embodiment, the kit of the present inhention comprises one or more compounds of the inhention. Intermediates
In another embodiment, the inhention relates to the nohel intermediates useful for preparing the compounds of the inhention.
(general ^Synthetic Schemes
The compounds of the formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derihatisations that are familiar to those of ordinary skill in the art.
The starting materials used herein are commercially ahailable 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-VI (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 sensitihe or reactihe groups on any of the molecules concerned. This can be achiehed by means of conhentional protecting groups, such as those described in T. W. Greene, Protectihe Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protectihe Groups in Organic Chemistry, John Wiley & Sons, 1991 , and T. W. Greene and P. G. M. Wuts, Protectihe 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 abohe. 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 skiiied in the art that the harious symbols, superscripts and subscripts used in the schemes, methods and examples are used for conhenience 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 subscnpts in the appended claims. The schemes are representatihe of methods useful in synthesizing the compounds of the present inhention. They are not to constrain the scope of the inhention in any way.
Figure imgf000037_0001
Scheme 1 illustrates the synthesis of lactam derihatihes depicted by Formula I employing methods well known to one skilled in the art. Referring to scheme 1 , Strecker reaction of an appropriately protected chiral piperidinone with zinc cyanide in acetic acid followed by chiral separation prohides chiral compounds 2, Acylation of amine 2 with an appropriate acyS chloride prohides compounds 3. Formation of the keto-amide 5 is accompiϊshed by base catalyzed closure of 4 foiiowed by decarboxylation/hydrolysis. Reduction of the carbonyl group of S with sodium borohydride followed by conhersion to the chloride and eiimation prohides β. Reduction of the enone and remohal of the protecting group (in the case of Cbz) is accomplished with hydrogenation to prohide lactam 7, Reductihe animation of 7 with an aldehyde and sodium triacetoxyborohydride or alkylation of 7 with a halide (X = Cl, Br, S) and base such as sodium hydride prohides compound 8. installation of R13ZR1'' to prohide compound 9 is accomplished using methods known to one skilled in the art Alternatihely, remohal of the protecting group of compound 6 (in the case of Cbz this is accomplished with 6N HCl) prohides enone 10. Reductihe amination of 10 with an aldehyde and sodium triacetoxyborohydride or aSkySation of 10 with a halide (X = Cl, Br, I) and base such as sodium hydride prohides compound 11. Synthesis of compound 12 is accomplished using methods known to one skilled in the art from compounds 8 or 11.
Experimental, Prgcj^
The following illustrate the synthesis of harious compounds of the present inhention. Additional compounds within the scope of this inhention 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-sensitihe reagents or intermediates were employed. Commercial solhents and reagents were generally used without further purification, including anhydrous solhents where appropriate (generally Sure-Seal™ products from the Aldrich Chemical Company, Milwaukee, Wisconsin). Mass spectrometry data is reported from either liquid chromatography- mass spectrometry (LCMS) or atmospheric pressure chemical ionization (APCI) instrumentation. Chemical shifts for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solhents employed.
For syntheses referencing procedures in other Examples or Methods, reaction conditions (length of reaction and temperature) may hary. In general reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate. Purifications may hary between experiments; in general, solhents and the solhent ratios used for eluants/gradtents were chosen to prohide appropriate R,s or retention times. Preparation 1 Racemic (5R7S),{5SJR)-1-{3-fluoroρhenyl}-7-methyl-1 ,8~diazasρiro[4,53dec- 3-eπ-2-one (Pt )
Step 1. SynthβsiiS of ....benzyl .....2-methyj^oxθr3,4rdjhydτQpyr|djπe-1{2H)r carboxyJate^CCIJ, Benzyl chloroformate (235 g, 1.38 mol) was added drop-wise to a chilled solution of 4-methoxypyridine (150 g, 1.38 mol) and tnethylamine (19 mL, 0,137 mol) in anhydrous fetrahydrofuran (6 L), while keeping the temperature below -500C. A white precipitate formed After completion of the addition, the resulting suspension was stirred at -60CJC for 20 minutes. Methyl magnesium bromide (3,0 M in diethyl ether, 650 ml, 1.95 mol) was then added drop-wise at ~60"C - ~50"C. The reaction mixture was stirred at room temperature ohernight, at which time thin layer chromatography {petroleum ether/ethyl acetate = 1 :1) indicated that the reaction was complete. After quenching the reaction with 1 N aqueous hydrochloric acid (500 ml), the color of the reaction mixture became brown-black. The organic layer was separated and concentrated in vacuo, and the residue and the aqueous layer were extracted with ethyl acetate (2 x 2 L). The combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried oher sodium sulfate and ehaporated to dryness to gihe crude CI1 which was used in the next step without purification, YieSd: 1500 g, 4 batches. Step 2.....Synthesis Of benzyl 2-methyl-4-oxopiperjdine-1-carboxy)ate (C2). To a stirred solution of compound C1 (750 g, 3.06 mol) in acetic acid (2.8 L) at 1000C was added zinc powder {795 g, 12.2 mol) oher 4 hours in four portions. The reaction mixture became yeϋow. After completion of the addition, the reaction mixture was stirred at 11O0C for 1 hour The mixture was filtered through Ceitfe, the filtrate was concentrated in vacua, and the residue was diluted with water (2 L), and extracted with ethyl acetate {3 L). The combined organic layers were basifted with solid potassium carbonate to pH 7- 8, then washed with saturated aqueous sodium chloride solution (1 L)1 dried oher sodium sulfate and ehaporated to dryness to gihe crude C2 as a brown-black oii, which was purified by column chromatography on silica gel (Gradient: 0-10% ethyl acetate in petroleum ether) to afford C2 as a light yeilow oii. YieSd: 838 g from 2 batches, 3.38 mol, 61% oher two steps. 1H NMR (400 fVSHz, CDCb): δ 7.40-7.32 (m, 5H), 5.18 (sτ 2H), 4.79 (m, 1H), 4.34-4.30 (m, 1H), 3.42-3.35 (m, 1H), 2.71 -2.66 {άά, 1 H), 2.54-2.45 (m, 1 H), 2.38-2.25 (m, 2H), 1.21- 1.20 (d, 3H)
Step 3. Synthesis of racemic benzyl {2$,4RK2R4S)~4~cγano-4-f(3~
Figure imgf000040_0001
3-Flυoroanϊiine (376 g,
3,38 mol) was added drop-wise to a solution of compound C2 (418 g, 1 .69 mol) in acetic acid (3 L) at room temperature. Zinc cyanide (430 g, 3.68 mol) was then added in portions. The reaction mixture was stirred at room temperature for 18 hours, at which point thin layer chromatography (petroleum ether/ethyl acetate = 4:1) showed the reaction was complete. The mixture was cooled to O0C, and aqueous ammonium hydroxide solution (2 L) was added drop-wtse until pH = 7- 8. The resulting mixture was extracted with ethyl acetate (3 x 2 L). The combined organic iayers were washed with saturated aqueous sodium chloride solution (1 L), dried oher sodium sulfate and concentrated in vacuo to gihe crude C3 (530 g), which was purified by column chromatography on silica gel (Gradient: 1:20 to 1 :2 ethyl acetate/petroleum ether) to gihe C3 as a brown oil comprised of a mixture of diastereomers. Yieid: 846 g, 2 batches, 2.30 mol, 68%. 'H NMR (400 MHz1 CDCI3): o 7.39-7.31 (m, 5H), 7.24-7.15 (m, 1H)1 8.68-6.59 (m, 3H), 5.15 (s, 2H), 4.63-4.43 (2 muitipiets! 1H), 4.28-4.02 (2 muitipiets! 1H), 3.85-3.76 (2 broad singiets, 1H)1 3.39- 3.24 {m, 1 H), 2.40-2.18 (seheral multipiets, 3H)T 1.83-1.58 (2 multisets, 1 H), 1.41- 1.20 (2 doublets, 3H).
Step 4. Synthesis of racemic benzyl (2S,4ffl(2R4S)-4-chano-4-f(3-ethoxy-3- oxopioβaπgyl)!,^ ,(C4). 2,6-
Dimethyipyridine (242 g, 2.28 mol) and ethyl 3-chioro~3-oxopropanoate (255 gτ 1.69 mol) were added to a solution of C3 (415.5 g, 1.13 moi) in anhydrous dichioromethane (2 L) at 10X. The brown mixture was stirred at room temperature ohernight. Water (500 ml) was added at 150C, and the organic iayer was separated and washed with saturated aqueous sodium chloride solution (1 L), dried oher sodium sulfate, filtered and ehaporated to dryness to gihe crude product, which was purified by chromatography on silica gel (Eiυant; 1 :15 then 1:5 then 1 :1 ethyl acetate: petroleum ether) to gihe compound C4 as a brown oil. Yield: 465 g, 2 batches, 0.985 mol, 43%. NMR data indicated that this material was a single diastereomβr. 1H NMR (400 MHz1 CDCI3): 8 7.48-7.43 (n% 1H), 7.42-7.30 (m, 5H), 7.23-7.19 (m, 1 H), 7.08-8.92 (m, 2H), 5.14-5.07 (m, 2H), 4.55 (br s, 1H), 4.24-4.09 (m, 3H), 3.38-3.31 (m, 1H), 3.14-3.05 (m, 2H), 2.80-2.76 (m, 1H), 2.17-2.04 (m, 1H), 1.78-1.72 <m, 1 H), 1.48 (d, 3H), 1.46-1.35 (m, 1 H), 1.28-1.20 (t. 3H).
Step 5, Synthesis of racemic 8-faenzyi 3-ethhl {5R7S)(5SJH)-4-amino-1-(3- fluoropheπhπ-y-methhi-Σ-oxo-i .θ-diazasβiro^.Sidec-S-ene-S.S-dicarboxyiate (Cδ). To a solution of compound C4 (450 g, 0.934 mol) in methanol (3.4 L) at 15°C was added a solution of sodium methoxide (60.5 g, 1.12 mol) in methanol (800 mL), A yellow precipitate formed. After completion of the addition, the reaction mixture was stirred at room temperature for 40 minutes. Thin layer chromatography (petroleum ether/βthyl acetate ~ 2:1} showed the starting material was completely consumed. The reaction was concentrated in vacuo to gihe crude product, which was suspended in methanol (100 mL) and water (2 L); this mixture was cooled to 50C and acidified with 1 N aqueous hydrochloric acid to pH 6. The solid was filtered and dried to obtain compound CS as a white solid. Yield: 445 gτ 0.923 mol, 99%. 1H NMR (400 MHz, CDCI3): 5 7.35-7.33 (rn, 3H), 7.24-7.22 (m, 3H)5 6.95-6.93 (m, 3H), 4.93-4.90 (d, 1 H), 4.72-4.68 (d, 1 H), 4.26-4.20 (m, 1H), 3.87-3.83 (m, 1H), 3.36-3.29 (m, 1H)1 2.98-2.90 (m, 1H), 2.41-2.33 <m, 1H)1 2.10-2.01 (m, 1 H), 1.92-1.86 (m, 1H), 1.79- 1.72 (m, 1H), 1.30-1.26 (t, 3H), 0.95-0.92 (m, 3H).
Step 6. Synthesis of racemic {5R7S)(5SJR)-1-(3-fJyoroρheiiylV7-rnethyl- 1.8-diazaspirQf4.51decanβ-2,4-dione hydrochloride (CS). Compound C5 (217 g, 0.45 mol) was added portion-wise to 6 N aqueous hydrochloric acid (2 L) at room temperature, and the mixture was heated to reflux for 5 hours. The mixture was cooled to room temperature, and concentrated in vacuo to gihe crude Cβ as a brown solid, which was used in the next step without purification. Yield: 282 g, 2 batches.
Step 7. Synthesis of racemic benzyl (5R7S){5S,7/?)-1 -(3-fluoroρhenhl)-7- methyl~2,4-dioxo-t ,β-diazaspirof4.51decaπβ-β-carboxγlate (C7), To a solution of C6 (140.5 g, 0.45 mol) in water/tetrahydrofυran (400 mL/800 mL) at 50C was added a solution of sodium hydroxide (90 g, 2.25 mol) in water (400 mL). The reaction became red-brown. The reaction mixture was cooled to 00C and benzyl - 4Q ~
chioroformate (115.2 g, 0.67 moi) was added drop-wise. The solution, which became yellow in color, was stirred for 1 hour at 00C, at which time thin layer chromatography (petroleum ether/ethyl acetate ~ 1:2) showed the reaction was complete. Ethyl acetate (500 ml) was added and the aqueous layer was separated, cooled to O0C, and acidified with 4 N aqueous hydrochloric acsd to pH 2-3. The aqueous layer was then extracted with ethyl acetate (3 x 1 1) and the combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried oher sodium sulfate and concentrated in vacuo to gihe C7 as a yβiiow solid. Yield: 84 g, 2 batches, 0.205 moi, 23% oher two steps. 'H NMR (400 MHz, CDCI3): δ 7.46-7.40 (m, 1H), 7.37-7.27 (m, 5H), 7.18-7.13 (m, 1H)1 6.93-6.85 (m, 2H), 5.07-4.99 (m, 2H), 4.36-4.34 (m, 1H)1 4.07-4.03 (m, 1 H), 3.55-3.48 (m, 1H), 3.40-3.18 (AB quartet, 2H), 2,05-1.96 (m, 2H), 1.86-1 .82 (br d. 1 H), 1.74-1.72 (m, 1 H), 1.28-1.24 (d, 3H).
Step 8. Synthesis of racemic benzyl (5R7S)(5S,7/?)-1~(3~fluorQphenyl)-4~ hhdroxy-7-methyl-2-oxo-i .8-diazaspirof4.5|decane-β-carboxyiate (Cβ), To a suspension of compound C7 (84 g, 0,205 moi) in methanoS/tetrahydrofuran (2500 mL/500 ml) at 15°C was added sodium borohydride (23.3 g« 0.814 moi) in portions. After completion of the addition, the soiution was light yeiiow. The mixture was stirred at 150C for 1 hour, at which time thin iayer chromatography (petroleum ether/ethyi acetate = 1 :1) showed the reaction was complete. The solhent was remohed in vacuo and the residue was diluted with ethyl acetate (2 L). The mixture was washed with water (500 mL), then with saturated aqueous sodium chloride soiution (500 ml), dried oher sodium sulfate and concentrated under reduced pressure to gihe C8 as a yeiiow solid. Yield: 84 g, 0.204 moi, 99%.
Step 9 Synthesis of racemic benzyl (5R7$)(5S,7RV1-(3-fluorophenhl)-7- fflethy|-2~pxQ-1 J~diazasDiro[4 5]de^-3-e^e-8-carbQxyiate (1CS). Thioπyl chloride (73.88 g. 0.814 mol) was added drop-wise to a solution of compound C8 (84 g, 0.204 mol) in pyridine (1 ,5 L) at 0°C. The mixture was stirred at room temperature for 1 hour, then heated to 500C for 5 hours. After cooling to room temperature, the solhent was remohed in vacuo, and the residue was diluted with ethyl acetate (1 L) and washed with saturated aqueous sodium bicarbonate solution to pH 7. The organic layer was dried oher sodium sulfate and ehaporated to dryness to gihe crude product, which was purified by siiica gel column chromatography to gihe Cθ as a brown syrup. Yield: 62 g, 0.157 mol, 77%. LGMS m/z 395.1 (M+1 ). 1H NMR (400 MHz, CDCS3): 3 7.64-7.62 (d, 1 H), 7.52-7.37 (m, 1H)1 7.34-7.32 (m, 5H), 7.18-7.11 (m, 1H), 6.91-Θ.80 (m, 2H), 6.34-6.32 (d, 1 H), 5.08 (br s, 2H), 4.70-4=64 (m, 1 H), 4.24-4.20 (m, 1H), 3.18-3.09 (m, 1H)1 2.13-2.08 (m, 1H), 1.91-1.87 (m, 1 H), 1.69-1.62 (m, 1H), 1.47- 1.44 (br d, 1 H), 1.32-1.30 (d, 3H).
Step 10. Synthesis of racemic (5R7$M5SJ/?H-{3-fluorophenyQ-7-methhl- 1.8~diazaspirof4.5]dec-3-en-2-one {F1 ). To a solution of C9 (20 g, 51 mmol) in methanol (20 mL) was added 6 N aqueous hydrochloric acid (200 mL) at room temperature. The reaction was then heated to reflux for 2 hours, during which time the brown solution became yellow. Thin layer chromatography (petroleum ether/ethyl acetate = 1 :2} showed the reaction was complete. The mixture was concentrated to half of the initial holume, and then extracted with ethyl acetate (2 x 100 mL). These organic extracts were discarded. The aqueous layer was cooled to 100C and basified with saturated aqueous sodium hydroxide to pH 11, then extracted with ethyl acetate (5 x 200 mL). The organic layers were dried oher sodium sulfate, filtered and ehaporated to afford Pi as a red syrupy solid. Yield: 12 g, 48 mmol, 90%. LCMS m/z 261.3 (M+1 ). 'H NMR (400 MHz, CDCb); δ 7.44-7.35 (m, 1H), 7.14-7.10 (m, 1H), 7.03-7.02 (d, 1 H), 7,00-6,98 (d, 1H)1 6.94-6.91 (m, 1H), 6,18-6,16 (d, 1 H), 2.92- 2.87 (m, 1H), 2.77-2.70 (m, 1H), 2.67-2.80 (m, 1 H), 2.02-1.91 (m, 1H), 1.90-1 .84 (m, 2H), 1.70-161 (dd, 1 H), 1.08-1.02 (d, 3H).
Preparation 2 Racemic (5R7SK5S.7R)-1-f3-fluorophenhi)-7-methhi-1.8- diazaι§p|rgf4.5]decaπ-ι2-ιoπι§ιιιι(P2)
Figure imgf000043_0001
(+/-)-frans {+i-y trans
Synthesis of P2. A mixture of C9 (20 g, 51 mmoS) and palladium hydroxide on carbon {2 g) in methanol (200 ml) was stirred under 45 psi of hydrogen at room temperature for 18 hours. Thin iayer chromatography (petroleum ether/ethyi acetate = 2:1 and dichioromethane/methanoi =10:1} showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated in vacuo: the residue was then diluted with ethyi acetate (100 rnL) and water (100 ml). The mixture was cααied to 100C and acidified with 1 N aqueous hydrochloric acid to pH 2-3« after which the aqueous iayer was separated and maintained at 1O0C it was then basified to pH 11 with saturated aqueous sodium hydroxide, and extracted with ethyl acetate (5 x 200 ml). These fihe organic iayβrs were combined, dried oher sodium sulfate and ehaporated to gihe P2 as a red syrupy soiid. Yield: 9.0 g« 34 mmol, 67%. LCMS m/z 263,2 (M+1 ). !H NMR (400 MHz, CDCi3); δ 7.40-7.34 <m, 1H)1 7.10-7.05 (m, 1H), 6.95-6.93 (m, 1H), 6.90-6.88 {m, 1H)1 2.87-2.81 (m, 1 H), 2.7β-2.69 (m, 1H). 2,61-2,54 (m, 3H)1 2.18-1.97 (m, 4H), 1 ,79-1.70 <m, 1H)1 150-141 (dd, 1 H)1 108- 1,02 <d, 3H),
Preparation 3 (SR, 7S)- 1 -(3-Ruαropheny I )-7-methyl- 1 ,8-diazaspi ro[4.5|dec-3-en~2~one ( P3)
Step 1 Synthesis of ^^ bengyi (2S,4R)-4-cyanp-4-f f,3-fluorophenyi)aniino1-2- methylpφeridine-1-carboxyiate (C1Q). A soiution of benzyi (2S)~2~methyl~4~ oxopiperidine-1-carboxylate (see C. Cobum ei a/ . PCT Patent Application Publication VVO 2007011810 A1 20070125) (31 g, 125 mmoS) in acetsc acid (250 mL) was treated with 3-fluoroaniiine (24.1 mL, 250 mmol) followed by zinc cyanide (36,8 g, 313 mmol}. The reaction mixture was allowed to stir at room temperature for 18 hours, at which time it was cooled in an see bath and siowly basified with aqueous ammonium hydroxide soiution The resuiting mixture was extracted three times with dichloromethane, and the combined organic iayers were dried and concentrated in vacuo. Purification of the residue by silica gel chromatography (Eiuant: 20% to 40% ethyl acetate in heptane) afforded a mixture of C10 and its isomer benzyi (2S,4S)-4- cyano-4~[(3-fiuorophenyi)amino3-2-methyip!pendine-1-carboxyiate (C11) as an oii. Yieid: 36 g, 98 mmoi, 78%. This material was subjected to chromatography using a Chiraicei OJ-H coiumn, 5 μm, 30x250 mm (Mobiie phase: 70/30 CCVmethanol; Fiow rate: 120 g/min) to afford 14.6g (32%) of C10 as a oii. Retention time; 3.45-4.46 mm, MS (APCi) m/z 341.1 (M-CN)+. 1H HUR (400 MHz, CDCi3) δ 1.49 (d, J=7.3 Hz, 3H)1 1.70 (ddd, J=13.3, 13.3, 4.4 Hz, 1H), 1.89 (Od. J==13.9, 6.6 Hz1 1H), 2.46 (m, 2H), 3.35 (m, 1H), 3.73 (br s, 1H), 4.28 (m, 1H), 4.63 (m, 1H), 5.16 (AB quartet, J=12,3 Hz1 2H), 6,60-6,67 (m, 3H), 7,21 (m, 1H)1 7.37 (m, 5H).
Step 2. Synthesis of benzyl (2S,4R)-4-cyaπo-4-f{3-ethoxy-3-QXQpropaπoyl)(3- flυorophenyl)amiπo]-2-methylpiperidine-1 -carfaoxyiate (CI 2). 2,δ-Dimethylpyridine (99%, 4.80 mL 40.8 mmoi) was added to a solution of C10 (10 g, 27 mmoi) in dichioromethane (136 mL). Ethyl 3-ehloro~3~oxopropanoate (4.48 mL, 35.4 mmoi) was then added drop-wise from an addition funnel, and the reaction mixture was allowed to stir at room temperature for 4 hours. The mixture was diluted with dichbromethane (30 mL), washed with water (80 mL), with saturated aqueous sodium chloride solution (80 mL). and then dried oher sodium sulfate. Filtration and remohal of solhent in vacuo was followed by chromatographic purification on silica gel (Eluant: 30% ethyl acetate in heptane) to prohide C12 (6.64 g) as a yeϋow oil. Mixed fractions were rβchromatographed to prohide additional C12 Total yield: 8.24 g, 17.1 mmoi, 63%. LCMS m/z 482.0 (M+1). 5H NMR (500 MHz1 CD3OD) δ 1.20 (t, J-7Λ Hz, 3H), 1.44 (2 doublets, J=I. Z, 7.3 Hz, 3H), 1.46 (m, 1H), 1.90 (m, 1 H), 2.16 (m, 1H), 2,76 (m, 1H), 3.14 (s, 2H)1 3.33 (m, assumed 1H, partially obscured by solhent peak), 4.09 (2 quartets, J-7.1 , 7.1 Hz, 2H), 4.15 (m, 1H)5 4.54 (m, 1H)5 5.10 (Ul, 2H), 7.16 (m, 2H), 7.29-7.35 (m, 6H), 7.53 (fit, 1H). Step 3. Synthesis of 8-benzyl 3-ethyl {5R7S)-4-amino-1-{3-fiuorophenyl)~7~ fflethyl-2-Qxo-i J-d^ Sodium metal (426 mg, 18.5 mmoi, prewashed with heptane) was added to methanol (12 mL) and allowed to react compietely. This solution of sodium methoxϊde was then added to a 0fJC solution of C12 (6.64 g, 14.2 mmoi) in methanol (45 mL). The reaction mixture was allowed to warm to room temperature, stirred for 45 minutes, and concentrated to prohide C13 as a yeϋow paste, which was taken on to the next transformation without purification. Yieid: 6.84 g{ 14.2 mmoi, 100%.
LCMS m/z 482.1 (M+1 ). 1H NMR (500 MHz, CD3OD) δ 1.02 (d, J=QA Hz, 3H), 1.31 (t, J-7A Hz, 3H), 2.01 (dd, J=UJ, 1 1.3 Hz, 1H), 2.12 (dd, J=U.6, 8.8 Hz, 1H), 2.19 (dd, >15.4, 4.8 Hz, 1 H), 2.56 (m, 1 H), 3.18 (m, 1 H), 3.44 <m, 1H), 3.97 (dd, J=14.0, 6.8 Hz1 1H), 4.27 (q, J=7.1 Hz,. 2H)1 4.71 (m, 1H). 4.95 (br d, J-12.Q Hz, 1H), 7.05 (m, 1H), 7.10 (br d, J=8.3 Hz, 2H), 7.26 {m, 2H), 7.28-7.37 (m, 4H).
Step 4. Synthesis of (5R7S)-1-(3-fluorophenhi)-7-methhi-1.8- diazaspjrof4..5]decane-2,4-cilpne hydrochloride .(CI 4), Compound C13 (8.0 g, 17 mmoi) was added in portions to an aqueous 6 N solution of hydrochloric acid (130 mL), and the yeilow suspension was heated at reflux for 28 hours. After cooling to room temperature, the mixture was azeotroped fihe times with toluene, then dried under high hacuum for 18 hours to prohide C14 as a gray-green solid. Yield: 6.3 g, assumed quantitatihe, LCMS m/z 277.1 (M+1). Step 5. Synthesis of benzyl (SR JS)-I -(^-fluorophenyl )-7-mβthyl-2, 4-dioxo-
18-diazaspirQ[4:5|decarιe-8-carbgxyjate (CIS). A solution of C14 from the prehious step (4.73 g, <15.1 mmol} in tetrahydrofuraπ (40 mL) and water (20 ml) was cooled to GX and treated with a solution of sodium hydroxide (4.1 1 g. 103 mmol) in water {19 mL). Benzyl chloroform ate {95%, 4.61 mL, 30,8 rnmol) was added, and the resulting solution was stirred at O0C for 2 hours. Another portion of benzyl chiαrαformate {95%, 1.28 mL, 8,6 mmol) was added, and the reaction was stirred for an additional 2 hours at 00C. After concentration in vacuo to remohe tetrahydrøfuran, the residue was diluted with water (50 mL} and extracted three times with dichioromethane. The combined organic layers were dried oher sodium sulfate, filtered and concentrated in vacuo, and the crude product was purified twice by chromatography on silica gel (Gradient: 5% to 100% ethyl acetate in heptane, then 30% to 100% ethyl acetate in heptane). The resulting material {5,78 g) was identified as the enol benzyl carbonate by mass spectroscopic and NIhIR analysis. The bulk of this material {5.05 g) was dissolhed in tetrahydrøfuran (about 80 ml) and stirred with aqueous sodium hydroxide solution {1 N, 200 ml, 200 mmol) for 5 hours. The reaction mixture was then acidified to pH 2 with aqueous 1 N hydrochloric acid, and extracted twice with dichioromethane. The combined organic layers were dried oher sodium sulfate, and concentrated to afford C15 as a brown oil, contaminated with extraneous aromatic material Yield 4 g, <9.7 mrnol. LCMS m/'z 411 .1 {M+1 ). 1H NMR (400 MHz, CDCS3) Product peaks only: δ 1.26 (d, J=7 2 Hz, 3H), 1.74 (m, 1H), 1.86 (m, 1 H), 2.00 (m, 2H), 3.22 (d, half of AB quartet, J=21 .9 Hz1 1H), 3,39 {d, half of AB quartet, J=21.9 Hz, 1H), 3.53 (m, 1H), 4.07 {m, 1 H), 4.39 (m, 1H), 5.04 (m, 2H)1 6.88 (m, 1H), 6.93 {br d, J==7.8 Hz, 1 H), 7.17 (m, 1H)5 7.32 (m, 5H), 7.44 (cJdd, J=8.3, 8.3, 6.3 Hz, 1H).
Step 6. Synthesis of benzyl (5f?.7S)-1-{3-fluorophenhl)-4-hhdPθxh-7-methhi-2- oxo-1.3-djazaspjrof4..51decane-8-cart)oxylate.(C16). A solution of C15 (881 mg, 2.15 rnmoS) in methanol {25 mL) and telrahydrofuran (5 ml) at 00C was treated portion- wise with sodium borohydride (98%, 248 mg, 8.42 mmol), and the resulting yeilow solution was stirred at O0C for 2 hours. Water (6 mL) was added, holatiles were remohed in vacuo, and the remaining mixture was acidified to pH 3 with 1 N aqueous hydrochloric acid, then extracted with ethyl acetate (3 x S mL). The combined organic layers were dried oher sodium sulfate, filtered and concentrated; the residue was purified hia silica gei chromatography (Eluant: ethyl acetate) to afford C16 as a light brown foam. Yield 620 mg, 1.50 mmoi, 70%. LCMS m/z 413.2 (M+1). 1H NMR (400 MHz, CDCI3) Mixture of two diastereomers, selected peaks; 6 118 and 1 .21 (2 doublets, J=7.Q, 7.2 Hz, 3H), 1.36 (m, <1H), 1.90 (m, <1H), 2.07 and 2.18 (2 broad doublets, J=13.1 , 1 1.3 Hz1 1H)1 2.37 {m, 1 H), 2.86 (m, 1H), 3.03 (m, 1H), 5.03 (m, 2H), 8.80 (m, 2H), 7.08 (m, 1H), 7.29 (m, 6H).
Step 7. Synthesis of benzyl f5RJS)-1-(3-f)uorophenhi)-7-methhi-2-oxo-1.8- diaizji§pni£gif4J|dec-3:eoe:8:ica£boxylate (C17). A solution of C16 (510 mg, 1.24 mmoi) in pyridine (8.83 mL) was cooled to 00C and treated with thionyl chloride (0.270 mL. 3.71 mmol). The reaction was stirred for 1 hour at room temperature, then at 5O0C for 18 hours. After cooling to room temperature, holatiies were remohed under reduced pressure, and the residue was dissolhed in ethyl acetate and neutralized by repeated washing with an aqueous solution of sodium bicarbonate (4 x 10 mL). The organic iayer was concentrated in vacuo and purified by chromatography on silica gei (Gradient; 20% - 100% ethyl acetate in heptane), prohiding C17. Yield: 300 mg, 0.78 mmol, 81%. LCMS m/z 395.5 (M+1). 1H NMR (500 WHz, CDCI3) δ 1.32 (d, J=7.1 Hz, 3H). 1.50 (br d, J=12.9 Hz, 1H), 1.68 (m, 1H), 1.93 (m, 1H), 2.1 1 Cm, 1H)1 3.14 (m, 1H), 4.24 (m, 1H), 4,64 (m, 1 H), 5.09 (m, 2H), 6.34 (d, J=6.1 Hz; 1H), 6.85 (m, 1H), 6.91 (br d, J=7.δ Hz, 1H), 7.14 (m, 1H), 7.30- 7.37 (m, 5H), 7.43 (ddd, J=8.2, 8.2, 6.4 Hz, 1 H), 7.64 (d, J=6.3 Hz, 1 H). Step 8. Synthesis of (5R7$)-H3-fluoroρhenγi)-7-roethyi-i8- diazasρiro[4.5Jdec-3-en~2~onβ (P3). Compound C17 (150 mg, 0.38 mrnoi) was dissolhed in methanol (0.19 ml) and 6 N aqueous hydrochloric acid (1.27 ml, 7,6 mmoi), and the reaction was heated at reflux for 2 hours. The mixture was concentrated in vacuo to one-half its original holume, and then extracted with ethyl acetate; this extract was discarded. The aqueous layer was cooled to 1O0C, basified to pH 11 with 1 N aqueous sodium hydroxide solution, and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under reduced pressure to gihe P3 as an oil. Yield 32 mg, 0.12 mmol, 32%. LCMS m/z 261.2 (M-M ), 1H NMR (400 MHz, CDCI3) δ 1.02 (d, J=6.5 Hz, 3H), 1 ,62 (dd, J=14.1 , 9.9 Hz,
1H), 1,82-1.90 (m, 2H)1 1.96 (ddd, J=UA , 10.9, 4.9 Hz, 1H), 2.63 (ddd, J=12.7, 10.9,
3,3 Hz1 1H), 2.73 (m. 1 H), 2.89 (ddd, J=12.6, 4.6, 4.6 Hz, 1 H)1 6.16 (d, J-5.9 Hz1 1H), 6,93 (m, 1 H), 6.99 (m. 1 H). 7.03 (d, J-Q.O Hz, 1H), 7.12 (m, 1 H)1 7,41 (ddd. J-8.0, 8.0, 6.4 Hz, 1H). Preparation 4 (SR 7SV- 1 -(3-fluorophen yl)-7-methyl-1 ,8-diazasρirof4.5]decan~2-one (P4)
Figure imgf000048_0001
C17 P4
Synthesis of P4. Compound C17 (150 mg, 0.38 mmol) and palladium hydroxide (20% by weight on carbon, 26.7 mg, 0.038 mmol) were combined in methanol (4.75 ml) and hydrogenated for 18 hours under 45 psi of hydrogen. The reaction mixture was filtered through an Acrodisd2' syringe filter and the filtrate was concentrated in vacuo to afford P4 as an oil. Yield: 70 mg, 0.27 mmol, 71%, LCMS m/z 263.5 (M+1 ). 5H NMR (400 MHz, CDCI3) 6 1.08 (d, J=6.4 Hz, 3H), 1.59 {dd, J-U.2, 9.2 Hz, 1H), 1.86 (ddd, J=U. Z. 10.2, 4.5 Hz5 1H)5 1.98-2.14 (m, 4H), 2.50- 2.58 (m, 3H)1 2.76 (m, 1 H). 2,88 {ύάά, J=13.0, 4,9. 4,9 Hz, 1H), 6.84 (ddd, J-9,3, 2.2, 2.2 Hz, 1 H), 8.90 Cm, 1 H), 7.06 (dddd, >8.3, 8.3, 2.4, 0.9 Hz, 1H), 7.35 (ddd, J=8.2, 8.2, 6,4 Hz, 1H). Examptes i - 86 Racemic 8-subsfifuted f5R7$)(5SJR)-1-(34luofGphenyi)-7-methγi-1,8- diazaspjrof4..5]dec-3-eπ-2-Qnes and 8-sυbstituted (5R,7S)(5S,7ff)-1 -{3-fiyθFopheπyi)- ?-.methyi-.1.,8-dl.a.2.a.sp.iror4,.51de.c.a.n.-.2-oπes
Examptes 1-32 (+i~)~tmns
(+f-)-tmns
Figure imgf000049_0001
Synthesis of Exampies 1 - 86, A solution of either compound P1 or P2 (0.19 M in dichioroethane, 400 μL, 75 μmol) was placed in an 8 mL hialτ and treated with the aldehyde component (0,25 M solution so dichioroethane, 300 μL, 75 μmoS). Sodium triacetoxyborohydride (225 μmoi) was added Io each hial, which was then capped and shaken at 3O0C for 16 hours. Solhent was remohed using a SpeedVac system, and the crude products were purified by preparatihe HPLC See Table 1 for characterization data.
Table 1 shows the structure of the compounds and relehant biological data that were measured in each case either on the compound as a free base or on the pharmaceutically acceptable salt of the compound disclosed in the Table. Each assay is disclosed in greater detaii hereinbelow.
Table 1
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Example 87
(5R,7S)-1-(3-fluorophenyl)-8-(4-hydroxy-3-isopropoxybeozyl)-7-methyl-1 ,8- diazaspiro[4.5]dec-3-en-2-one hydrochloride (87) Scheme 3
Figure imgf000060_0001
Step 1. Synthesis of 3-isopropoxy-4-fπethoxyben2aidehhde (C 18). A solution of 3-hydroxy-4-mβthoxybβnzaldβhydβ (5,00 g, 32.9 mmoi) in dimeihyiformarnide (100 mL) was treated with potassium carbonate (9.08 g, 85.7 mmαl) and 2-iodopropane (8.57 ml, 65.7 mmol). The reaction was stirred for 4 hours and then additional 2~ iodopropane (3.29 mL, 32.9 mmol) was added and the mixture was allowed to react for an additional hour. It was then poured into water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with 1 N aqueous sodium hydroxide solution, then with saturated aqueous sodium chloride solution, dried, filtered and concentrated in vacuo to prohide C18 as an oil Yield: 4.80 g, 23.7 mmol, 72%. LCMS m/z 195.2 (M+1). 1H NMR (400 MHz, CDCl3) 3 1.41 (d, J~Q2 Hz1 QH), 3,95 (S1 3H), 4,65 (m, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.42-7,46 (m, 2H), 9.85 (s, 1H). Step 2. Synthesis of 2~(3~isqpro poxy-4-methoxγphenyi)-1 ,3-dioxola ne (C 19).
Ethylene glycol (99%, 2.63 mL, 47.4 mmol) and para-toluenesulfonic acid rnonohydrate (97%, 75 mg, 0.38 mmoi) were added to a solution of C1S (4.6 g, 23.7 mmol) in toluene (79 ml). The reaction flask was equipped with a Dean-Stark trap, and the contents were heated at reflux for 5 hours. The reaction was poured into aqueous potassium carbonate solution, and the organic Sayβr was then washed an additional two times with aqueous potassium carbonate solution, and once with saturated aqueous sodium chioride solution. The organic layer was dried, filtered and concentrated; NMR and LCiVSS rehealed that the reaction was incomplete, so the product was resubjected to the reaction conditions, heating at reflux for 18 hours. The workup was repeated, to afford C19 as an oil. Yield: 5.0 g, 21.0 mmol, 89%. 1H NMR (400 MHz, CDCb) δ 138 (d, J-Q.2 Hz, 6H), 3.86 (s, 3H), 4.02 (m, 2H), 4.14 (m, 2H), 4.57 (septet, J=6.0 Hz, 1 H), 5.75 (s, 1 H), 6.88 (d, J=8.7 Hz, 1 H)1 7.03 (m, 2H).
Step 3; Synthesis of ^-h^drgx^J^isoβroβgMbenzaldehyde ,(€20), Lithium wire (cut into smaii segments, 204 mg, 29.4 mmol) was added to a solution of chiorodiphenylphosphinβ (2.17 mL, 11.7 mmoi) in tetrahydrofuran (18.7 ml), and the reaction was stirred for 1 hour, A solution of C19 (2,00 g, 8.39 mmoi) in tetrahydrofuran (5 ml) was then added drop-wise to the dark red mixture, and the reaction was stirred for 2 hours, it was then fiitered into an aqueous sodium hydroxide solution, and extracted with diethyl ether (3 x 15 mL); the combined organic layers were washed with 1N aqueous sodium hydroxide soiution, and the aqueous layers were combined and cooled in an ice bath. This aqueous phase was acidified with concentrated aqueous hydrochloric actd. The mixture was extracted with diethyi ether (3 x 10 ml) and these three organic iayers were combined and washed with saturated aqueous sodium chioride solution, dried and concentrated in vacuo to gihe C20 as an oil. Yield; 740 mg, 4.1 1 mmoi, 49%. 1H NMR (400 MHz, CDCI3) d 1 41 (d. J=6.Q Hz1 6H)1 4.73 {septet, </=6 1 Hz, 1H), 6.30 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.40 (m, 2H), 9.82 (s, 1H).
Step 4. Synthesis of 87. Compound C20 (20.7 mg, 0.1 15 mmol) in dichioroethane (0.5 mL) was combined with a solution of P3 (20 mg, 0.077 mmol) in dichioroethane (0.4 ml). Acetic acid (4 μL, 0.07 mmol) was added. After 5 hours of stirring, the reaction was treated with sodium triacetoxyborohydride (32.6 mg, 0.154 mmoi), and the reaction mixture was ailowed to stir for 18 hours. Aqueous sodium bicarbonate solution was then added, and the layers were separated. The aqueous iayer was extracted with dichloromethane (3 x 5 mL), and the combined organic iayers were dried oher sodium sulfate, fiitered and concentrated in vacuo. The residue was purified by chromatography on siiica gel (Gradient: 20% - 70% ethyi acetate in heptane) to prohide the free base of 87 as an oil Yield: 7.8 mg, 0.018 mmoi, 23%. LCMS m/z 425.2 <M+1 ). 1H NMR (400 MHz, CDCS3) S 1.14 (d, J=6.8 Hz, 3H), 1.33 (2 oherlapping doublets, J=6.G, 6.0 Hz, 6H), 1.59 (m, 1H), 1.71 (m, 1H), 1.97 (ddd, J=13.1 , 9.8, 4,1 Hz, 1H), 2.11 (dd, J=13.3, 5.1 Hz, 1H), 2.41 (ddd, J=12.5, 5.3, 4.3 Hz, 1H), 2,64 (ddd. J=12.7, 9.8, 3,0 Hz, 1H), 2.99 (m, 1H), 3.35 (d, J=13.3 Hz, 1 H), 3,55 (Ci, J=13.3 Hz, 1 H), 4.52 (septet, J=8.0 Hz, 1 H)1 5.83 (br s, 1H), 8.23 (d, J=6.2 Hz, 1 H), 6.68 {dd, J=8.0, 1.6 Hz, 1H), 6.77 (br s, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.89 (ddd, J=9.5, 2.2, 2.2 Hz, 1H), 6.95 (br d, J=7.8 Hz, 1H), 7.13 (ddd, J=8.4, 8.4, 2.5 Hz, 1H), 7.38-7.44 (m, 2H). 13C NMR (100 MHz, CDCl3). Not all of the expected signals were obserhed, o 15.16, 22.08, 22.12, 33.63, 40.34, 43.96, 51.00, 57.80, 71.47, 113.62, 113.95, 115.60 (d, J-21 Hz), 118.12 (d. J=22 Hz), 121.48, 124.93, 126.60 (d, J=3 Hz), 130.38 (d, J=9 Hz), 144.41, 145.81 , 153.60. The hydrochloride salt was prepared by dissolhing the free base of 87 in diethyl ether and treating the solution with a 1.0 M solution of hydrochloric acid in ether, followed by concentration in vacuo. Compound 87 was obtained as a solid. Yield: 8.6 mg, 0.18 mrool, 100%.
Example 88 (5R,7S)-1-(3-fluorophenyl)-7-methyl-8-[(2'-methylbiρhenyl-3-yl)methyl]-1.8- diazaspiro[4.5]decan-2-one hydrochloride (88)
Figure imgf000062_0001
Compound 88 was prepared according to the general procedure for the synthesis of 87 in Example 87, except that P4 and 2'-rnethylbiphenyl-3-carbaSdehyde were used instead of PZ and C20, to prohide the free base of 88 as an oil. Yield: 16.5 mg, 0.037 mmol, 48%, LC MS m/z 443.2 (M+1 ), 1H NMR (500 MHz, CDCI3) δ 1.14 (d, J=6.8 Hz, 3H), 1 .60 (m, 1 H), 1.70 (m, 1H), 1.89 (m, 1 H), 2.04 (dd, J=13.2, 5.4 Hz, 1H), 2.13 (ddd, J=12.4, 9.5, 9.5 Hz, 1H), 2.25 (s, 3H), 2.31 (ddd, J=12.7, 8.8, 3.9 Hz, 1 H), 2.49 (ddd, J=12.4, 4.4, 4.4 Hz. 1 H), 2.53-2.69 (m, 3H), 3.04 (rn, 1H), 3.51 (Cf1 J=13.6 Hz, 1 H), 3.63 (d, J=13.4 Hz, 1H), 6.87 (ddd, J=9.3, 2.1 , 2.1 Hz, 1H), 6.92 (br d, J=8.3 Hz, 1H), 7.11 (ddd, J=8.4, 8.4, 2.4 Hz, 1H), 7.20-7.28 {m, 7H), 7.33 (cki, J=7.δ, 7.6 Hz, 1 H), 7.40 (ddd. J=S.O, 8.0, 8.3 Hz, 1H). 13C NMR (125 MHz, CDCb) 3 13.79, 20.36, 29.80, 33.40, 34.42, 42.57, 43.63, 51.52, 58.13, 64.03, 115 45 {d, J=2Q Hz), 117.90 (d, J=22 Hz), 125.69, 126.30 (d, J=3 Hz), 126.99, 127.15, 127.76, 127.89, 129.49, 129.68, 130.18 {d, J=9 Hz), 130.28, 135.17, 138.00, 138.08, 138.56, 141.71 (d, J=δ Hz), 162.76 <d, J=248 Hz). 175.01. The hydrochloride sait was prepared by dissolhing the free base of 88 in diethyl ether and treating the solution with a 1.0 M solution of hydrochloric acid in ether, followed by concentration in vacuo. Compound 57 was obtained as a solid. Yield: 18 mg. 0.037 rrtmoi, 100%.
ExaropJe.SS? {5R,7S)-1-(3-fluorophenyl)-8-(4-hydroxy-3-isopropoxybenzyl)-7-methyl-1.8- diazaspirof4.5]decan-2-one hydrochloride (89)
Figure imgf000063_0001
Synthesis of 89. Compound 89 was prepared according to the general procedure for the synthesis of 87 in Example 87, except that P4 was used instead of P3, to prohide the free base of 89 as an oil. Yield: 26 mg, 0.060 mrnoS, 40%. LCMS m/z 427.1 (M+1 ). 1H NMR {500 MHz, CDCl3) δ 1.10 {d, J^β.8 Hz, 3H), 1.32 (d, J=β.1 Hz1 6H), 1.56 {m, 1H)1 1.67 (m, 1H), 1.84 (m, 1 H), 2.00 (dd« J=13.2, 5.4 Hz, 1H), 2.10 (ddd, J=12.4, 9.5, 9.5 Hz, 1H), 2.28 (ddd, J=12.7, 8.8, 3.9 Hz, 1H), 2.42 (ddd, J=12.4, 4.5, 4.5 Hz, 1H), 2.51-2.63 (m, 3H). 2.97 (m, 1H), 3.38 (d, J=13.2 Hz1 1H), 3.46 (d, J=13.2 Hz, 1H), 4.51 (septet, J=QA Hz, 1H), 8.67 (dd, J=7.9, 1.8 Hz, 1H), 877 (m, 1H), 6.80 (d, J=S.O Hz, 1 H), 6.85 {ddd, J~9.4, 2.1 , 2.1 H∑, 1H), 6.90 (br d, J=7.8 Hz, 1H), 7.10 (ddd, J=8A 8.4, 2.5 Hz, 1 H), 7.38 {ddd, J=S.0, 8.0, 6.4 Hz, 1H). 13C MMR {100 MHz.. CDCI3) Not ail of the expected signals were obserhed. 5 13.70, 22.03, 22.11 , 29.84, 33,45, 34.51 , 42.54, 43.27, 51.27, 57,86, 64.12. 7142, 113,54, 113,88, 115.38 (d. J~21 Hz), 117.91 (d. J~22 Hz), 121.36, 126.40 (d, J~3 Hz), 130.15 (d, J=9 Hz), 144.41 , 145.52, 175,05. The hydrochlonde salt was prepared by dissolhing the free base of 89 in diethyl ether and treating the solution with a 1.0 M solution of hydrochloric acid in ether, followed by concentration in vacuo. Compound 8§ was obtained as a solid. Yield: 28 mg, 0.060 mmol, 100%,
Example 90 and 91 Racemic f SR 7S){ 5S,7R)-3-f luoro- 1 -(3-f iuprppheny I )-B-( 3-isopropαxγbenzyl )- 7- methyl- 1 tβ-diazaspiro[4.5Jd ecan-2-oπe, formate salt (90) and Racemic (5f?,7SKSS.7ff)-3.3-difiuofθ-1-(3-flϋQrQphenhi)-8-(3-isQpropoxhbenzyl)-7-methyl-1 ,β- d jazasp.jrof4,51d ecan-2-one ,. formate salt (91 )
Figure imgf000064_0001
ample 45 Exampie θO Example 91 A flame-dried flask under a nitrogen atmosphere was charged with dry THF (5 mL) and diisopropylamine (106 mg, 1.05 mmol) and was cooled to -78 0C in a dry ice-acetone bath. n-Buϋ (0.37 ml, 0,93 mmol} was added dropwise, then the solution was warmed to -550C for 1 h and then cooled back to -78CC. A solution of Example 45 {240 mg, 0,58 rnmoS) in anhydrous THF (3 mL) was added dropwise, then the resulting mixture was stirred for 45 min at -78"C and allowed to warm to - 550C. A soiution of (PhSOs)2NF (276 mg, 0.87 mmol) in anhydrous THF (2 mL) was added dropwise, and the reaction mixture was stirred for 1 h at -55ε*C. The reaction was quenched with saturated NH4CI (10 mL) and the solhents were remohed in vacuo. The residue was partitioned between EtOAc (10 ml) and water (10 mL). After separating layers, the aqueous layer was re-extracted with EtOAc. The combined organic layers were dried oher Na2SO4, and ehaporated to gihe crude product, which was purified by preparatihe HPLC to obtain Example 90 (25 mg, 10%) as a white solid and Example 91 (58 mg, 22%) as a white solid.
Example 90: 1H MMR (400 MHz, MeOD): δ 7.51-7.45 (m, 1H), 7=23-7=13 {m: 2H)1 7.04-6.99 (m, 2H)1 6,78-6,74 (d, 3H), 5,31-5,15 (m, 1H), 4.58-4.50 (S, 1H),
3.63-3.48 Cm1 2H), 2.94-2.47 (m, 5H), 2.11-1.73 (ό, 4H), 1.28-1.21 (d, 6H), 1 22-1 18 (t, 3H). HPLG Column YMC ODS-AQ (0.46 x 5cm x 5 μm), RT = 1.99 min, Mobile Phase 10% MeCN (0.1%TFA) in water to 80% MeCN (0.1 % TFA) in water. LCMS m/z 429.4 (M+ 1 ).
Example 91 : 1H NMR (400 MHz, MeOD): δ 7.54-7.49 {m, 1H), 7.28-7.23 (m, 1H)1 7.17-7.13 (m, 1H), 7.09-7.06 (d, 2H), 6.78-6.75 (m, 3H), 4.55-4.51 (s, 1H), 3.60- 3.49 (m, 2H), 2.99-2.86 (m, 2H), 2.76-2.66 (d, 2H), 2.50-2.40 (m, 1 H), 2.13-2.05 (m, 2H), 1.84-1 ,77 {d, 2H), 1.28-1.26 {d, 6H), 1.19-1.18 <d, 3H). HPLC Column YMC ODS-AQ (0.48 x 5cm x 5 μm), RT = 2.12 mm. Mobile Phase 10% MeCN (0.1%TFA) in water to 80% MeCN (0.1% TFA) in water. LCMS m/z 447.4 (M+1 ). Example 92 Racemic {3R/S,5R7S)(3R/S,5SJf?)-1-f3-fiuoroρhenyl)-3-hhdroxy-8-(3- isopro.poxybenzyj.)-7-methyl-13~diazaspiro]4,5|decan-2-Qne, hydrochloride .salt ..(92)
Figure imgf000065_0001
Compound #C38 was hydrogeπated according to the procedure described in Preparation 4. The deprotected material [LCMS m/z 279.4 (M+1 )] was then conherted to the titie product by reaction with 3-isopropoxybenzaldehyde, using the general method described for preparation of 87 in Example 87, except that the gradient for chromatography was 0% to 5% methanol in dichloromethane. The free base was isolated as a colorless oil. estimated by 1H MMR to be comprised of a roughly 3:2 mixture of diastereomers at the carbon bearing the hydroxy group. Yield:
9 mgt 0.02 mmolt 15%. 1H NMR (400 MHz1 CHQ3): o 1.12 (d, J=6.9 Hz) and 1.17 (d,
J-6.7 Hz. 3H), 1 ,29 and 1.35 (2 d, J-6.0 Hz) and 1.30 <d, J-6.Q Hz, total 6H), 1.58-
2.84 (m, 8H)1 2.98-3.04 (m, 1 H), 3.49 (AB quartet,
Figure imgf000065_0002
HZ) and
3.50 (AB quartet, JAS=13.6 Hz1 ΔhAB=25.7 Hz, total 2H)1 4.46-4.64 <m, 2H), 8.73-8.80 {m, 3H)1 6.S4-6.87 (m, 1H), 6.90-6.93 (m, 1 H)1 7.08-7.18 (m, 2H), 7,36-7.43 {m, 1H). LCMS m/z 427.1 (M+1). Conhersion to the hydrochloride sait as in Example 87 prohided 3,6 mg of the title product.
Example @93 (5^,?S)-1-(CydopropylmefhyS)-8-{3-tsopropoxyben2y))-7-methyi-1,8- diazaspiro[4.51dec-3-en-2-one (#93)
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0003
1 . Synthesis of benzyl (2S,4S)-4-hγdroxy-2-methyl-4-
(trich{.orom.et.h.y.l.).pjpe.πd.jπe.-.1.-carbox.yjate (#C21 ). Chloroform (4,06 ml, 50.7 rnmol) was added to a mixture of benzyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (98.5%, 4.24 g, 16.9 mmol) and magnesium chloride (4.83 g, 60.7 mmoi) in 1 ,2- dimethoxyethane (45 mL}, and the reaction mixture was cooled in a dry ice/acetone bath. Lithium bis{trimethylsilyl)amide {1 M in tetrahydrofuran, 25.4 ml, 25.4 mmol) was added drop-wise oher 30 minutes, while keeping the internal temperature of the reaction below -72°C. The reaction was stirred at -72 to -77°C for 4 hours, then allowed to warm to -15°C by transferring the flask to a wet ice-methanol bath. Alter one hour at -15°C, the reaction was slowly quenched with water (25 ml), then partitioned between water (75 ml) and ethyl acetate (150 mL). The aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic extracts were washed with saturated aqueous sodium chloride solution (75 mL), dried oher magnesium sulfate, filtered and concentrated in vacuo. The crude product was dissolhed in diethyl ether (30 ml), which caused a white precipitate to form; this mixture was stirred for 18 hours. The sαiid was collected by filtration and rinsed with coid diethyl ether (10 mL) to prohide #C21 as a white solid. The relatihe configuration of the methyl and hydroxy groups was determined by singie-crystal X-ray crystaliographic analysis of a sample prepared in an analogous manner; that sample was crystallized from acetonitrile-water. Yield; 2.95 g, 8=05 mmoi, 48%. 1H NMR (400 MHz, DMSO-Cf6, presumed to be a mixture of rotamers) 6 1.27 and 128 {2 d, J=6.9 Hz, 3H)1 1.81 -1.96 <m, 3H), 2.07-2.15 (m, 1H), 3.09-3.25 (m, 1H), 3.95-4.03 {ΓΓL 1H), 4.44-4.53 (m, 1H), 5.04-5.14 (m, 2H), 6.20 (s, 1 H), 7.29-7.40 (m, 5H).
Step 2. Synthesis of 1 -benzyl 4-methyl {2$,4R)-4-azido-2-methylpiperidine- 1 ,4-dicarbQxylate (#€22), A suspension of benzyi (2S,4S)-4-hydroxy-2-rnethyl-4- (trichSoromethyl)pipβrϊdine-i-carboxylate (#G21) (18.00 g, 49.09 mmαl), 18-crown-6 ether (2.00 g, 7.57 mmol) and sodium azicte (98%, 9.00 g, 138 mmoi) in methanol (130 ml) was stirred at room temperature for 1 hour. 1,8~Diazabicycio[5.4.0]undec- 7-ene (98%. 24.0 mL; 157 mmol) was then added oher ten minutes. The reaction mixture was stirred at room temperature for 18 hours. Most of the methanol was remohed in vacuo, and the residue was diluted with water (200 ml) and extracted with ethyl acetate (2 x 250 mL). The combined organic extracts were washed with water (150 mL), washed with saturated aqueous sodium chloride solution (150 mL) and dried oher magnesium sulfate. After filtration and remohal of solhent under reduced pressure, #C22 was obtained as a light yellow oil. Yieid: 15.8 g, 47.5 mmol, 97%. APCi m/z 333.3 (M-M ). 1H NMR (400 MHz, CDCI3) δ 1.09 (d, J=7.1 Hz, 3H), 1.80 (ddd, J=I 3.5, 12.5, 5.3 Hz, 1H), 1.94 (dd, 7=13.8, 6.1 Hz, 1 H), 2.23-2.32 (m, 2H), 3.16 (ddd, J=14.3, 12 3, 3.2 Hz. 1 H), 3.84 (s, 3H). 4.07 (br ddd, J=14, 5, 3 Hz. 1H), 4.45-4.53 (m, 1H), 5.14 (S, 2H), 7.30-7.40 (m, 5H).
Step..3, .... Synthesis.. of 1 -benzyl. 4-m ethyl (2 S!4f?)-4-aminp-2-methγl pi.perjdin.e- 1 ,4-dicarboxγlate (#C23). Zinc dust (99%, 4.78 g, 72 mmol) was added to a solution of 1~benzyl 4-methyi (2S;4R)-4-azido-2~methyipiperidine-1 ,4-dicarboxylate (#C22) (4.8 g, 14.4 mmol) in acetic acid (35 mL) and tetrahydrofuran (35 mL), and the reaction mixture was heated at 50 0C for 4 hours. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated m vacuo to remohe most of the solhents. The residue was diluted with ethyl acetate, washed seheral times with saturated aqueous sodium bicarbonate solution, then washed with saturated aqueous sodium chloride solution and dried oher magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to prohide #C23 as a light yellow oil, which was taken to the next step* Yield; 4.4 g, 14.4 trsmoi. quantitatihe. LCMS m/z 307,5 (M+1). 1H NSViR (400 MHz, CDCI3) δ 1 ,05 <d, J=7.1 Hz1 3H)1 1.44 (ddd, J=13.2, 12.8, 5 2 Hz, 1 H), 1 73 (dd, J=13.6. 6.0 Hz. 1 H). 2.15-2.26 <m. 4H), 3.16 {ddd, ,/=14.1 , 12.7, 3.1 Hz, 1H), 3.75 (s. 3H), 4.05 (br ddd, ./=14, 5, 3 Hz1 1 H), 4.42-4.50 (m, 1 H), 5.14 (AB quartet
Figure imgf000068_0001
HZ, 2H), 7.29- 7,39 (rn, 5H).
Step 4. Synthesis of 1 -benzyl 4-methhi f2S,4/?)-4-f{3-ethoxy-3- oxopropanoyl)amifio]-2-mβthylpiperidine-14-dicarboxylate (#C24). N-[Z- (Dimethylamino)propyl]-Λ/'-ethylcarbodiimide hydrochloride (EDCI, 98%, 3.58 g, 18.3 rnmoS) was added to a solution of 1 -benzyl 4-methyl (2S,4/?)-4-amino-2- methylpiperidine-1 ,4-dicarboxyiate (#C23) (5.10 g, 18.6 mmol), 3-ethoxy-3- oxopropanoic acid (96%. 2.25 mL. 18.3 mmol) and triethylamine (99%, 4=69 ml, 33.3 mmol) in dichloromethane (50 mL), and the mixture was stirred at room temperature for 2 hours. An additional 0.1 equihalent of EDCi and 3-ethoxy-3-αxopropanoic acid were added, and stirring was continued for 1 hour. Solhents were remohed in vacuo, and the residue was diluted with ethyl acetate, washed twice with 0.5 N aqueous hydrochloric acid, washed with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution. After drying oher magnesium sulfate, the mixture was filtered, and the filtrate concentrated under reduced pressure to prohide #C24 as a hiscous, light yellow oil, which was used without further purification. Yield: 7.3 g, >16.6 mmoS, quantitatihe. LCMS m/z 421,5 (M+ 1 ). 1H NMR (400 MHz, CDCb) <5 1.16 <d. J=6.8 Hz. 3H). 1.28 (t, J-7.2 Hz, 3H), 1.68 (ddd, J=14.0, 12.0, 6.2 Hz. 1 H), 2.07 (br dd, half of ABX system, J=13.9, 6.0 Hz, 1H), 2.17 (άύ, half of ABX system, J=IZ. B, 6.2 Hz, 1H), 2.52-2.58 (m, 1H), 3.24 (s, 2H), 3.34 (ddd, J=14.2, 12, 4.3 Hz. 1 H). 3.75 (s, 3H). 4.02 (far ddd, J=14, 6, 2 Hz, 1H), 4.10-4.24 (m, 2H), 4,27-4.35 {m, 1H), 5.14 (AB quartet
Figure imgf000069_0001
Hz1 2H), 7.30-7.39 (m. 5H), 7.56 {br s, 1 H).
Step 5 Synthesis of β-benzyi 3-ethyi (5ft.7S)-7-methyl-2,4-dioxQ-1.8- diazaspj!ro|4Λ51decane-3J-dicarbQxylatβ (#C25), Sodium etnoxide powder (95%, 1=41 g, 19.7 mmol) was added to a solution of 1 -benzyl 4-metnyS (2S!4H)-4-[(3-ethoxy-3- oxopropanoyl)amino]-2-methylpiperidine~1 ,4~dicarboxyiate (#C24) (6.90 g< 18.4 mmol) in methanol, and the mixture was stirred at room temperature for 20 minutes. The reaction was quenched with acetic acid (2 ml_), and most of the ethanol was remohed in vacuo. The residue was diluted with ethyl acetate, then washed with 0.2 N aqueous hydrochloric acid, water, and saturated aqueous sodium chloride solution. After drying oher magnesium sulfate, the mixture was filtered and concentrated under reduced pressure to afford #C25 as a white foam whose NMR data indicated a mixture of diastereomβrs, which was taken to the next step without purification. YieSd: 6.4 g, 16 mmol, 98%. LCMS m/z 389.5 (M+1). "H NMR (400 MHz, CDCI3) ό 1.26-1.30 {m, 3H)1 1.40 <t, J-7.1 Hz, 3H), 1 .76-1.92 (m, 3H), 2.18 (ddd. J=14.2, 5.9, 2.5 Hz, 1H), 3.21-3.31 (m, 1H), 4.03-4.10 (m, 1H)5 4.18-4.25 (m, 1H), 4.33-4.45 (m, 2H), 5.11-5.22 (m, 2H), 6.31 (br s, 1H), 7.31-7.41 (m, 5H).
Step 6. Synthesis of beπzyi (5R7S)-7~metnvi-2,4-dioxQ-1,8~ diazaspiro[4.51decane-8~carpoχylate (#C26). 8-Ben2yl 3-ethyi {5RJS}-7-meihyl-2,4- dioxo~1 ,8-diazaspiro[4.5]decane-3,8-dicarboxyiate (#C25) (6.30 g« 16.2 mmol) was dissolhed in dioxane (90 ml) and water (10 ml_) and heated at reflux for 1 hour. After cooling to room temperature, the reaction was concentrated in vacuo. The residue was diluted with ethyi acetate, washed with saturated aqueous sodium chloride solution, dried oher magnesium sulfate, filtered and concentrated under reduced pressure to afford #C26 as a Sight yellow foam. Yield: 5.13 g, 16 2 mmoL quantitatihe. LCMS m/z 317.5 (M+1). 1H NMR (400 MHz, CDCI3) δ 1.26 (d, J=6.6 Hz, 3H)1 1.74-1.89 (m. 3H)1 2.13 (ddd, J*UΛ , 6.2, 2.3 Hz, 1H), 3.06 (AB quartet,
Figure imgf000069_0002
HZ, 2H). 3.25 (ddd, J-U.2, 1 1.3, 5.1 Hz, 1H), 4.07 (br ddd,
Figure imgf000069_0003
Hz. ΔhAeFi8,2 Hz, 2H)1 6.70 (br s, 1 H), 7.32-7.41 (m( SH). Step 7, Synthesis of benzyl (5R7$)-4-hydroxy-7-methyl-2-QXQ-1.8- diazaspiro[4.5JdeGane-8~carboxylate (#C27). Sodium faorohydride (98%, 915 mg, 23.7 mmol} was added Io a solution of benzyl {5R,7S)-7-metftyl-2,4~dioxo-1,8- diazasp!ro[4.5|ciecane-8-carboxylate (#C26) (5.00 g, 15.8 mmol) in methanol (100 mL) and the reaction was allowed Io stir at room temperature for 18 hours. After the addition of more sodium borohydride (300 mg, 7.8 mmol), the reaction was stirred for one hour, then quenched with acetic acid (5=5 mL, 36 mmoS) and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with 0.2 N hydrochloric acid, saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution. The organic layer was dried oher magnesium sulfate, filtered and concentrated under reduced pressure to prohide #C27 as a hiscous, colorless oil that was a mixture of diastereomers. Yield; 4.6 g, 14.4 mmol, 91%. LCMS m/z 319.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.24-1.28 (m, 3H), 1 .56-1.81 (m, 3H), 2.06-2.11 and 2.24-2.36 (m, 2H), 2.77-2.85 <m, 1H), 3.04-3.20 (m, W), 4,00-4.09 (m, 1 H), 4.22-4.30 (m, 1 H)1 4,31-4.47 (m, 1H), 5.10-5.18 (m, 2H)1 6.21 and 6,35 (2 br s, 1 H), 7.30-7.40 (m, 5H).
Step 8. Synthesis of . benzyl {5R,7S)-7-methyl-2-oxo-1 ,8-diazaspirof4,5|dec-3- ene-8-carboχylate f#C28), Methanesulfonyl chloride (99.5%, 1.16 mL, 14.9 mmol) was added to a solution of benzyl (5R,7S)-4-hydroxy-7-methyl-2-oxo-1,8- diazaspiro[4.53decane-8-carboxylate (#C27) (4.30 g, 13.5 mmol). After addition of triethylamine (99%, 2.47 mL. 17.5 mmol), the reaction mixture was stirred at room temperature for 1 hour. At this point, 1 ,8-diazabicycio[5.4.ϋ]undec-7-ene (98%, 2.68 ml, 17.6 mmol) was added, and stirring was continued for 3 hours. Additional 1 ,8- diazabicyclo[5.4 0]undec-7~ene (1 48 mL. 9.63 mmoi) was added, and the reaction was allowed to continue for 1 hour. Most of the solhent was remohed in vacuo, and the residue was diluted with ethyl acetate, washed with 0.5 N aqueous hydrochloric acid, then with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution. The aqueous layer was dried oher magnesium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (Eluant: 10% methanol in ethyl acetate) to afford the product as a Sight yellow foam. Yield; 3.4 g, 11.3 mmol, 84%, LCMS m/z 301.4 (M* 1 ). 1H NMR (400 MHz, CDCl3) δ 1.28 <d, J=7.0 Hz, 3H), 1.62 (ddcl, J=13.7, 3.4, 1.6 Hz, 1H), 1.73-1.79 (m, 1 H), 1.87 (ddd, J-13.5, 12.4, 5.2 Hz, 1H), 2.04 (dd, J=13.7, 6,6 Hz, 1 H), 3.12 (ddd, J=14.3, 12.3, 3.6 Hz, 1H), 4.18 (br ddd, J=14, 5, 3 Hz1 1H). 4.52-4.60 (m, 1H). 5.18 (AB quartet, Jm~12Λ Hz, ΔhA8=9.8 Hz, 2H), 6.07 (άύ, J=5.9, 1.7 Hz, 1 H), 6.30 (br s. 1 H), 7.32-7.41 (m, 6H).
Step ..9, Synthesis of benzyl .(5R.7S)-I -{chcjoprQPVJ.rnethhl .)-?-methyl-2-ρ.χρ- IJ-diazaspiro^.δldec-S-eπe-S-carboxyiate (#C29). A solution of benzyl (5RJS}-7- methyl-2-oxo-1 ,8-diazaspiro[4.5]dec-3-ene-8-carboxyiate (#C28) (45 mg, 0.15 mmol) in tetrahydrofuran (0,3 mL) was added to a suspension of sodium hydride (60% in mineral oil, 6.8 mg, 0.16 mrnoi) in tetrahydrofuran (0.3 mL). The reaction was stirred for 20 minutes after gas eholution ceased, then treated with a solution of (brornornethyi)cyciopropane (33,6 mg, 0.249 mmoi) in tetrahydrofuran (0.3 mL). The reaction was heated to 60 l"C for 20 minutes, at which time sodium iodide (< 5 mg) and 15~crown-5 ether (1 drop from a Pasteur pipette, < 5 mg) were added. The reaction mixture was maintained at 60 0C for an additional 6 hours, then at room temperature for 18 hours. Soihent was remohed under a stream of nitrogen, and the residue was partitioned between water {1.5 mL) and ethyl acetate (3 mL). The aqueous layer was extracted with ethyl acetate (2 mL), and the combined organic fayers were dried oher magnesium suifate. filtered and concentrated in vacuo. Purification was effect by chromatography on silica gel (Gradient; 0% to 10% methanol in dichioromethane) to prohide the product as a thick gray oii. Yield: 52 mg, 0.147 mmol, 98%. LCMS m/z 355.2 (M+1 ). 1H NMR (400 MHz, CDCI3) S 0.30- 0,34 (m, 2H), 0.49-0.54 (m, 2H)1 0.99-109 (m, 1H), 1.30 (d, J=6.9 Hz, 3H), 1.3-1.39 (br m, 1 H), 1.42-1.54 (br m, 1 H)1 1.97-2.09 (br m, 1 H), 2.28 (dd, J= 13.8, 6.5 Hz, 1 H), 3.08-3.24 {m, 3H), 4.16-4.35 (br m, 1H), 4.61-4.81 (br m, 1H). 5.13-5.21 <m, 2H), 6,19 (d, J=6.2 Hz, 1H), 7.32-7.40 (m, 5H), 7.47 (d, J=6.2 Hz, 1H).
Step 10, Synthesis of (5f?,7S)-1-(cyclρpropyimethyl)-β-(3-isopropoxybeπzyi)- 7-methhH ,8~diazaspirQ[4,5Idec-3-en-2-Qne (#93). Benzyl (5R,7S)-1-
{cydopropyi methyl )-7-methy i-2-oxo- 1 ,8-di azaspiro[4.5]dec-3~ene-8-carboxylate (#C29) (46 mg, 0.14 mmoi) was dissolhed in a freshly prepared solution of trimethylsilyi iodide (0.17 M in acetonitrile, 1.0 mL, 0.17 mmoi), and the resulting - 7Q ~
solution was stirred at room temperature for 8 hours. Purification was carried out by loading the reaction mixture directly onto a mixed-mode cation-exchange (MCX) soiid-phase extraction column. The column was flushed with dichloromethane (5 ml), and the product was then eiuted using a 2 M solution of ammonia in methanol (5 mL). The eiuant was concentrated in vacuo to afford the deprotected intermediate. LCMS rn/z 221.1 (M+1 ). This material was mixed with acetonitriie {1 mL) and potassium carbonate (62.8 mg, 0.45 mmol). After addition of 1~(brømomethyl}~3~ isopropoxybe nzene (which may be prepared from 3-isopropoxybenzaSdehyde using the general procedure reported by A. han Oeheren et a/.. J, Qrg. Chem. 1994, 59, 5999-6007) (68.7 mg, 0.300 mrnol), the mixture was stirred at room temperature for 1 hour, then loaded onto an MCX cartridge containing a small amount of Ceitte on top of the packing material, to assist in remohing soiids. The cartridge was flushed with dicbioromethane {5 mL), and the fiStered solids and Celite were manually remohed from the cartridge. The product was βiuted using a 2 M solution of ammonia in methanol {5 mL). and the filtrate was concentrated in vacuo. The residue was purified by preparatihe silica thin layer chromatography (Eiuant: 5% acetonitriie in ethyl acetate); the product band was extracted with 2:1 ethyl acetate; methanol (15 mL) and filtered. After remohed of solhent under reduced pressure, the residue was dissolhed in ethyl acetate {3 mL), passed through a nylon filter (0,2 μm) and reconcentrated to prohide the product as a gray/off-white semi-solid. Yield: 24.8 mg, 0.067 mmol, 48%. LCMS m/z 369.2 (M+1 ). 'H NMR (400 MHz, CDCi3) o 0.35-0.40 (m, 2H), 0.49-0.54 (m, 2H), 1.05-1.13 (m, 1H), 1.15 (d, J=6.8 Hz, 3H)1 1.33-1.46 (m, 2H}; 1.35 {ά, J=6.Q Hz, 6H), 2.1 1 (ddd, J=12, 12« 5 Hz, 1H), 2.34 (dd, ,A=13.1 , 5.5 Hz, 1H), 2,61-2,73 (m, 2H), 3.19-3.35 (m, 3H), 3,62 (AB quartet, ^=13.7 Hz, ΔhA8=8.3 Hz, 2H). 4.58 (septet, J=δ.O Hz. 1H), 6.10 (d, J=Q 2 Hz. 1H), 6.73 (br d, J=S Hz, 1H), 6,90-6.94 (m, 2H), 7.23 (dd, J=8S 8 Hz. 1H), 7.37 (d, J=6.0 Hz, 1H).
Example . @94 (5R,7S)-8-(3-isopropoxybenzyi)-7-methyi-1-propyl-1τβ-diazaspjrof4.5|dec-3-en-2-one (#94)
Figure imgf000073_0001
Step 1. Synthesis of benzyl (5R,7S)~7~mβthyi~2~oxo~1~propyl-1 ,8- diazaspiro[4.5]dec-3-ene-8-carboxyIate (#C30). The title product was prepared according to the general procedure for the synthesis of benzyl (5R7S}-1- (cycioprαpyS methyl )-7-methy l-2-oκo- 1 ,8-di azaspiro[4.5|dec-3~ene~8~carboxyl ate (#C29) in Example @93, except that 1-iodopropane was used in place of (bromomβthyS)cyciopropanβ, the reaction was heated at 60 °C for 22 hours, and sodium iodide and 15-erown-5 ether were not used. Sn this case, the crude product, obtained as a thick gray oϋ, was taken directiy on to the next step. LCMS m/z 343.1 (M-M ). 1H NMR (400 MHz1 CDCi3), partial spectrum; δ 0.91 (t, J=7.4 Hz, 3H), 2.21 (dd, J=13.5, 6.6 Hz, 1 H), 5.12-5.20 <m. 2H), 8.17 (d, J-Q2 Hz, 1H), 7.32-7.40 (m, 5H), 7.45 (d, J=6.2 Hz, 1H).
Step 2. Synthesis of {5R,7S)~8~(3~isopropoxybenzyi)~7-methyi~1~prøpyl-1 ,8- diazaspiro[4.5|dec-3-en~2-one (#94). The title compound was prepared according to the procedure described for the synthesis of #93 in Example @93, except that benzyl {5R7S)-7-methyl-2-oxo-1 -propyl- 1 ,8-diazaspiro[4.5]dec-3-ene-8-carboxyiate (#C30) was used instead of benzyl (5R7S)-1-(cyclopropyimethyl)-7-methyi-2-oxo-1,8- diazaspira[4.53dec~3-ene-8-carboxylate (#C29). The product was obtained as a thick yeilow oil. Yield: 14.3 mg, 0.040 mmoi, 27% oher 2 steps. LCMS m/z 357.6 (M+1 ). 1H NMR (400 MHz, CDCi3) δ 0.94 (t, J=7.4 Hz, 3H), 1.15 (d, J=8.8 Hzτ 3H), 1.33-1.38 (Hi1 1 H)1 1.36 (d, J-6.0 Hz, 6H), 1.41-1.47 (m, 1H), 1.80-1.70 (m, 2H), 2.00 (ddd, J=12.9, 10.7, 4.6 Hz, 1 H), 2.23 (ύύ, ,/=13.2, 5,4 Hz, 1 H), 2,59-2.73 (m, 2H), 3.22-3,34 (rn, 3H), 3,62 (AB quartet JAB=13.8 Hz, ΔhAB=217 Hz, 2H), 4.58 (septet, J=6.0 Hz, 1H), 6.08 (d, J=6.0 Hz, 1 H), 6.80 (br dd, J=8 3, 2.3 Hz, 1H), 6.91-6.94 (m, 2H), 7.23 (dd, J=7.8S 7.8 Hz, 1H), 7.31 (d, J=6.2 Hz, 1H).
Example (8)95 f5/?,7$)-1-Cvclopropyl-8-f3-isoproρoxyben2:yl)-7-methyi-1 <8-cliazaspiro[4.5)dec-3-eπ-
2-oπe, frifiuoroaoetatβ sajt (#95)
Figure imgf000074_0001
δ #C31 #95
Step 1 , Synthesis of benzyl {5RJS)-t -cyclopropyl-7-methyi-2-oxo-1,8- diazaspiro[4.53dec-3-ene-8-carboxyiate (#C31). Benzyl {5R7$)-7-methyl-2-oxo-1,8- diazaspiro[4.53dec~3~ene-8-carboxylate (#C28) was conherted into the title product by reaction with cyclopropylboroπic acid, according to the method of S. Benard et al.f J. Org, Chem. 2008, 73, 6441-6444. Purification was carried out by silica gel chromatography {Eluant: ethyl acetate) to prohide the product as an oil. Yield: 18 mgf 0.053 mmol, 31%. LCMS m/z 341,3 (M+1). 'H NMR (400 MHz, CDCi3) δ 0.78- 0.99 (m, 4H), 1.27-1.3 (m, 1H)1 1.30 {d, J=7.2 Hz, 3H), 1.36-1.46 (br m, 1H), 2.17- 2,23 (m, 1H), 2.19-2.30 (br m, 1H), 2,55 {br άύ, J=13, 7 Hz, 1H), 3.07-3.17 (br m, 1H), 4.17-4.35 (br m, 1H), 4.66-4.80 (br m, 1H), 5.13-5.23 (m, 2H), 6.14 (d, J^6-2 Hz, 1H)5 7.32-7.40 (m, SH)5 7.44 (d, J=6.2 Hz5 1H).
Step 2. Synthesis of (5R57S)~1~cyclopropyl-8-(3-isopropoxybenzyi)-7-methyl- 1.8~diazaspiro[4.5]dec-3-en-2~one, tπfiuoroacetate salt (#S5). The title compound was prepared according to the procedure described for the synthesis of #93 in Example @93, except that benzyi (5f?,7S)-1-cyclopropyl-7-methyi-2-oxo-1,8- diazaspiro[4.53ciec~3-ene-8-carboxylate (#C31 ) was used instead of benzyl (5RJS}~ 1-(cyclopropylmethyl)-7-methyl-2-oχo-1.8-diazaspiro[4.5]dec-3-ene-8~caft>oxyiate (#C29), the remohal of the protecting group was carried out oher 18 hours rather than 8 hours, and strong cation exchange (SCX) solid-phase extraction columns were used rather than MCX coiumns. The final purification was earned out hsa rehersed- phase HPLC (Coiumn: C53: Mobile phase A; 0.1% TFA in water (h/h); Mobile phase B: 0.1% TFA in acetonitriie (h/h); Gradient: 5% B to 100% B) to afford the titie product as an oil Yieid: 7 mg. 0.015 mmol, 9% oher 2 steps. LCMS m/z 355.2 (M+1 ). 1H NMR (400 MHz; CD3OD)1 partial spectrum: δ 0.81-1 .01 (br m, 4H), 1.33 (d, J=8.0 Hz, 6H), 1.62 (d, J-B.9 Hz, 3H), 1.65-1.74 {br m, 1H), 3.46-3.80 (br m, 2H)1 4.67 (septet, J=6.0 Hz1 1H), 7.03-7.23 (m, 4H), 7.41 (dd, J=7.9, 7.3 Hz, 1H).
Example jSjθβ
Figure imgf000075_0001
dliazasι|3irøf4ιJld§ι&an:2^ιn§lιιιhγd
Figure imgf000075_0002
Step 1. Synthesis of (2S,4R)-4-[{3-fluorophenyl}amino3~2-methylpipeπdine-4- carboπitrile (#C32). Benzyl {2S,4R)-4-cyano-4-[{3-fluorophenyi)amtno]-2- methyipiperidine-1-carboxySate (C10) (4.0 g, 11 mmol) was dissolhed in methanol (100 mL) and treated with a suspension of palladium hydroxide on carbon (20% by weight, 540 mg, 0.77 mmol) in ethyl acetate (10 mL). The reaction mixture was shaken under 40 psi of hydrogen for 4 hours, filtered and concentrated in vacuo. The resulting oil was purified by chromatography on silica gel (Gradient: 50% to 100% ethyl acetate in heptane, followed by 10% methanol in ethyl acetate), to afford the product as a dear yellow oil. Yield; 1.85 g, 7.93 mmol, 72%, LCMS m/z 234,0 (M+1 ). Η NMR (400 MHz1 CDCS3) 3 1.10 (d, J=6.3 Hz, 3H)1 1.43 (br s, 1H), 1 .73 (άά, J-iZJ, 1 1.5 Hz, 1 H), 2.03 {ύάά, ^13.8. 8.6. 8.6 Hz, 1H), 2.30-2.38 (m, 2H), 2.90- 3.01 (m, 3H), 3.78 {br s, 1H), 6.56-6.64 (m, 2H)5 6.66 (ddd, J=8,1 , 2.3, 0.8 Hz, 1H), 7.20 (ddd, J~8,2f 8.1 , 8.7 Hz, 1H).
Step 2. Synthesis of (2S,4R)-4-[{3-fluorophenyi)amino]-1-{3- isopropoxybenzyl)-2-methylpiperidine-4-carbonitriie (#C33). {2St4R)-4-[{3- Ruorophenyl)aminoj~2~meihylpiperidine-4-carbonitriie (#C32) (4=20 g, 18.0 mmol). 1- (bromomethyl)-3-isopropoxybenzene (4 95 g, 21=6 rnmoi) and cesium carbonate (99%, 14.2 g, 43,1 mmol) were combined in acetonitrile (90 ml) and stirred at room temperature for 3 hours. The reaciion mixture was then diluted with ethyl acetate, and washed with water, then with saturated aqueous sodium chloride solution, dried oher magnesium sulfate, filtered and concentrated in vacuo. Purification was effected by chromatography on silica gel (Gradient 0% to 20% ethyl acetate in heptane), prohiding the product as a solid. Yield: 4.60 g, 12.1 mmol, 87%. The characterization data was obtained on a sample derihed from a similar reaction. LCMS m/z 382.0 (M-M ), 1H NMR (400 MHz, CDCi3) 3 1.22 (d, J~62 Hz, 3H), 1.35 (d, J=6.0 Hz, 6H), 2.02-2.32 {m, 5H), 2,56-2,71 (m, 2H)T 3.06 (d, J=13.4 Hz1 1 H)1 3.80 <br s, 1 H)1 4.07 {d. J=13,4 Hz, 1 H), 4.57 (septet, J=6.0 Hz1 1 H)1 8.55-8.68 (m, 3H), 6.77-6.88 (m, 3H), 7.16-7.24 (m. 2H).
Step 3. Synthesis of (2S,4/?}-4-[(3-fluorophenyl)amϊno]-1-(3- isoprapGxybenzyl}-2~meihyipiperidine-4-carbaldehyde (#C34). Diisobutyiaiuminum hydride (98%, 1 5 M soiution in toiuene, 5.8 ml, 8.5 mmol) was added drop-wise to a solution of {2S,4R)-4-[(3-fluorophenyl5amino]-1 -(3-tsopropoxybeπzyl)-2- methylpiperidiπe-4-carbonitriie (#C33) (2.20 g, 5.77 mmol) at -78 0C. The reaction was stirred at -78 "JC for 1 hour, then warmed to 0 0C for 1 hour, then warmed to room temperature for 1 hour. Aqueous ammonium chloride solution and 1 N hydrochloric acid were added until the reaction mixture was acidic (pH around 5), The aqueous iayer was extracted three times with ethyl acetate, and the combined organic Sayers were dried, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in heptane), prohiding the product as an oil. Yield: 730 mg, 1.90 mmol, 33%. LCMS m/z 385.0 (M+1 ). 5H NMR (400 MHzs CDCi3) 3 1.22 (d, J=6.0 Hz, 3H), 1.38 (d, J=6.0 Hz, 6H), 1.71 {dd, J=13.6, 11.7 Hz, 1H), 1.86-1.96 (m, 3H), 2.15 (br ddd, J=1 1 ,9, 11.3, 4,4 Hz, 1H), 2.48-2.56 (m, 1H), 2.78 {br ddd, J=12, 3, 3 Hz, 1H), 3,07 (ά, J-13,5 Hz. 1 H), 4.12 (d, J=13.5 Hz, 1 H), 4.17 (br s, 1H), 4.58 {septet, J-6.Q Hz, 1H), 6.25 {ddd, ./=1 1.3, 2,3, 2.3 Hz, 1 H), 6.30 (dd, J=8.0, 2.1 Hz. 1 H). 6.44 {ddd, J=8.3, 8.3, 2.2 Hz, 1H), 6.79 {dd, J=8.1 , 2.2 Hz, 1H), 6.86-6.91 (m, 2H), 7.08 {ddd, J~8Λ , 8.1 , 6.8 Hz1 1H)1 7.21 {dd, J=7.9; 7.9 Hz, 1H), 9.63 (s, 1H).
Step 4 Synthesis of ethyl 3-[{2S,4/?)-4-[{3-flυoroρhenyl)amtno]-1-(3- isopropoxybenzyi)-2~methylpipeπdin-4-yl3-2-methylacrylate (#C35). Ethyl 2- {diethoxyphosphoryl)propaπoate (0.122 mL, 0.580 mmol) was added drop-wise to a mixture of sodium hydride (80% in oil. 20.6 mg, 0.516 mmol) in 1 ,2-dimethoxyethane {0,9 ml) at 0 0C. After being stirred at 0 0C for 30 miπ, the reaction was warmed to room temperature. {2S,4R)-4-[{3-FluorophenyS)amino3-1 -(3-isopropoxybenzyl}-2- methylpiperidine-4-carbaidehyde (#C34) (180 mg, 0.47 mmol) in minimal 1 ,2- dimethoxyethane was added drop-wise, and the reaction was stirred for an additional 3 hours. After addition of water, the mixture was extracted with βthyi acetate. The combined organic layers were dried oher sodium sulfate, filtered and concentrated in vacuo. Purification hia silica gel chromatography (Gradient: 10% to 40% ethyl acetate in heptane) afforded the title product as an oil. Yield; 85 mg. 0.18 mmol, 38%. LCMS m/z 489.1 (M+1) 1H NMR (400 MHz, CDCi3), characteristic signals: δ 1.18 (d, J=6.0 Hz, 3H), 1.31 (t, J=IA Hz, 3H), 1.34 (d, J=6.2 Hz, 6H), 1.94 {d, J=IS Hz, 3H), 3.04 (d, J=13.5 Hz, 1H), 4.10 (d, J=13.5 Hz, 1 H), 4.21 (q, J=7.1 Hz, 2H), 7.04 (ddd, J=S-I , 8.1 , 8.8 Hz, 1H).
Step 5, Synthesis of ethyl 3-[{2S,4R)-4-[{3-fluoropheπyi)amino]-1-<3- isopropoxybenzyi)-2-methyipiperιdin-4-yi]~2~methyipropanoate (#C36). Ethyl 3~ |{2S,4/?)-4~[(3-fluorophenyl)amino3~1~(3~!SOpropoxybenzyl)~2~methylpfperidfii-4-yl|~2- mβthylacrylatβ (#C35) (85 rng, 0.18 mmol) and palladium on carbon {10%, 19.2 mg, 0.018 mmol) were combined in methanol {1,8 ml) and shaken under 50 psi of hydrogen for 18 hours. The reaction was filtered and concentrated in vacuo to prohide the product as an oil, which was used without further purification. Yield: 75 mg, 0.16 mmol, 88%. LCMS m/z 471 , 4 (M+1). Step 6. Synthesis of (5R.7S)-i -(3^1uorø(rften^)-8-(3-isopropox^>enz^)-3,7- dirnethyl-1 ,8-diazaspiro[4.5}decaι>2-onβ, hydrochloride salt (#9$). Ethyl 3-[{2S54R)- 4-[(3-Huorophenyl}ai"n!no]-1-{3-isopropoxyben2yi)-2-methylpiperfdin-4-yi]-2- methylpropanoate (#C36) (75 mg, 0.18 mmol) was added to a mixture of sodium hydride (9.5 mg. 0.24 mmol) and tetrahydrofuran (0.8 mL) at 0 "C. The reaction was stirred under ice cooling for 1 hour, then heated at reflux for 18 hours, Remohal of solhent under reduced pressure was followed by chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in heptane) to prohide the free base of the product as a roughly 2:1 mixture of diastereomers, as judged from the 1H NMR spectrum. Yield: 14 mg; 0.033 mmol, 21%. LCMS m/z 425.0 (M+1). 1H NMR (400 MHz, CDCI3) δ 1.09 and 1.14 (2 d, J=6.9 and 6.8 Hz, 3H), 1.28-1.32 (m, 9H)1 1.46- 1.51 and 1.60-1.77 (2 m, 3H)1 182-1.91 (m, 1H)1 1.98-2.08 (m, 1H)1 2.19-2.25 and 2.47-2.78 (2 m, 4H), 2.89-3.03 (m, 1H), 3.47 (AB quartet, JA8=I 3.6 Hz, ΔhAS=22.8 Hz) and 3.44 (AB quartet, JA8=13.6 Hz, ΔhAB=99.9 Hz1 total of 2H)1 4.45-4.55 (2 septets, J=8.0 Hz, 1H), 6.72-6,81 (m, 3H), 6.84 (ddd, J=9.5, 2.2, 2.2 Hz, 1 H), 6.90 (ddd, J=7.9, 1.8. 0.9 Hz, 1H), 7.06-7.18 (m, 2H)1 7.35-7.42 (m, 1H).
This material was conherted to 15 mg of the corresponding hydrochloride salt, isolated as a solid.
Example @97 ('5R7S)-1-(3-F)ϋor diazaspJrof4.51dec-3-en-2-one, hydrochloride salt .(#9.7)
Figure imgf000079_0001
Figure imgf000079_0002
Step 1, Synthesis of benzyl (5R,7S)-1-{3-flυoropheπyi)-7-methyi-2-oxo-1,8- diazaspϊro[4.53decane-8-cart>oxylatβ (#C37)= (SRJSJ-i-fS-FlυorophenyiJ-T-methyl- 1s8-diazaspiro[4.53decan-2-one (P4) (532 rπg, 2,03 mmol) was dissolhed in tβtraiiydrofυran (10 ml) and water (5 mL) and chiiied in an ϊce bath. Sodium hydroxide (487 mg; 12,2 mmol} in water (1 mL) was added, followed by benzyl cNoroformafe (0.39 ml, 2.8 mmol), and the ice bath cooling the reaction mixture was allowed to warm to room temperature oher 18 hours. The reaction was then poured into dilute aqueous sodium bicarbonate solution and extracted three times with dichlorornethane. The combined organic layers were dried oher sodium sulfate, filtered and concentrated in vacuo to prohide a residue, which was subjected to silica gel chromatography (Gradient; 0% to 4% methanol in ciichioromethane). The product was isolated as a white foam. Yield: 545 mg, 1.37 mmoi, 67%.
Step 2, Synthesis of benzyl {5R,7S}-1-(3-fluorophenyl)-3-hydroxy-7-methyi-2- oxσ-1 ,8-diazaspirσ[4.5]decane-8-carboxylate (#C38). Lithium bis(trimethyisilyl)amide (1 M in tetrahydrofuran, 1 .5 ml, 1.5 mmoS) was added to a solution of benzyl {SRJSJ-I^S-fluorophenyi^-methyf^-oxo-i^-diazaspiroH.SIdβcane-δ-carboxylate (#C37) (500 mg, 1 ,26 mmol} in tetrahydrofuran (6.3 mL) at -60 0C, and the reaction mixture was maintained at this temperature for 1 hour. A solution of 3-phenyl-2- (phenyfsulfonyi)oxaziridinβ (see L. C. Vishwakarma et a/., Organic Syntheses 1988, 66, 203-10) {494 mg, 1.89 mmol) in tetrahydrofυran was added drop-wise, and the reaction was warmed to room temperature and stirred for 18 hours. The mixture was poured into saturated aqueous ammonium chloride solution (3 ml) and extracted with dichloromβttiane (3 x 3 mL); the combined organic layers were dried oher sodium sulfate, filtered and concentrated in vacuo. Purification hia silica gel chromatography (Gradient; 0% to 5% methanol in dtcNoromethane) prohided the product as a white solid, presumed to be a mixture of rotamers and diastereomers from its !H NWR spectrum. Yield; 201 mg, 0.487 mmol, 39%. APCl m/z 413.2 (M+1 ). 1H NMR (400 MHz, CDCI3) δ 1.24-1.31 (m, 3H), 1.53-1.94 (br m, 4H), 2.23 (dd, J=n,δ, 5.3 Hz) and 2.05-2.12 (m; total of 1H), 2.64 and 2.88 (2 dd, J=13.4, 8.1 Hz and J=12.8, 8.5 Hz, 1H), 3.05-3.15 (br m, 1H), 4.05-4.62 (m, 4H)1 5.01-5.12 (br s, 2H), 8.79-6.83 (m, 1H), 6.85-6.88 (m, 1 H), 7.10-7.16 (m, 1 H)1 7.28-7.44 (m, 8H).
Step 3, Synthesis of benzyl (5R JS)-I -<3-fluorophenyi)-7-methyl-2(3-dioxo- 1(8-diazaspirø[4.5Jdecane-8-carboxyiate (#C39). Manganese(iV) oxide (85%, 124 mg, 1.21 mmol) was added to a solution of benzyl {5R7S)-1-(3-fluorophenyl)-3- hydroxy~7-methyl~2~oxo-1 ;8~diazaspirø[4.5]decane~8~carboxyiate (#C38) (50 mg, 0.12 mmol) in dichioromethane (0.61 mL), and the reaction was stirred at room temperature until no starting material was obserhed by thin iayer chromatography on silica gel (Eluant: 5% methanol in chSoroform), The reaction mixture was filtered through a <1 μm filter, and soihent was remohed in vacuo. Chromatography on silica gel (Gradient; 0% to 5% methanol in dichioromethane) prohided the product as an oil, assumed to be a mixture of rotamers from its 1H NMR spectrum. Yield: 30 mg, 0.073 mmol, 61%.
LCMS m/z 41 1.0 (M+1 ). Η NMR (400 MHz, CDCS3) S 1.23-1.31 (m, 3H), 1.61-1.78 (br m, 2H), 1.84-2.13 {br m. 2H)1 2.96 (AB quartet, JAB=19.1 Hz, ΔVAB=34.9 Hz, 2H), 3.0-3.13 (br m, 1 H), 4.12-4.31 {br m, 1H), 4.54-4.71 (br m, 1 H), 5.00-5.14 (br m, 2H). 6.80-6.94 (m, 2H), 7.11-7.23 (m, 1H), 7.28-7.39 (m, 5H), 7.44-7.51 (m, 1H).
Step 4. Synthesis of benzyl {5R,7S)-1-(3-flυorophenyl)-7-methyl-2-oxo-3- {[(tnfϊuoromethyl)sulfonyl]oxy}-1 ,8-diazaspiro[4.5jdec~3-ene-8-carboxyiatθ (#C40). Lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuraπ, 0.067 mL, 0.067 mmol) was added drop-wise to a solution of benzyl (5R7S)-1-(3-fluorophenyi)-7-methyi-2,3- dioxo~1 ,8~diazaspiro[4.53decane-8~carboxylatβ (#C39) (25 mg, 0.001 mmoS) in tetrahydrofuran (0.61 ml) at -78 0C. After 30 minutes, /V-(5-chloropyridin-2-yl)-1,1,1- trifluoro-Λ/-[(trif1uoromethyS)suifonyl]πiethanesulfonamide (28.7 mg, 0=0731 mmol} in tetrahydrofuran (1 mL) was added drop-wise and stirring was continued at -78 DC for 2 hours. Sodium sulfate ciecahydrate (100 mg, 0.31 mmoi) was added, and the reaction was allowed to warm to room temperature, at which point it was fiitered and concentrated in vacuo. Purification hia silica gel chromatography (Gradient: 0% to 40% ethyl acetate in heptane) prohided the product as a solid. Yieid: 30 mg, 0,055 mmoi, 90%. LCMS m/z 542.9 (M+1 ). 'H NMR (400 MHz, CDCi3) δ 1.31 (d, J-7Λ Hz, 3H)1 1.55 <br d, J=13 Hz, 1 H), 1.71-1.78 (br m, 1H), 1.96-2.06 (br m, 1H), 2.19 (br dd, J-13, 7 Hz, 1 H), 3.08-3.17 {br m, 1 H)1 4.21-4.36 (br rrs, 1H), 4.80-4.74 {br m. 1H)5 5.09 (br s, 2H), 6.86 {ddd, J=9.1 , 2.2, 2.2 Hz. 1H), 6.91 (ddd, J=7.9, 1.9, 0.8 Hz, 1H), 7.18 (dddd, J=8.3. 8.3, 2.5, 0.8 Hz. 1H), 7 29-7.39 (m, 5H), 7.42 (s, 1 H), 7.45 {ddd, J=8.2, 8.2, 6.2 Hz, 1H).
Step 5. Synthesis of benzyl (5R,7S)-1-(3-fSuorophenyi)-7-methyl-2-oxo-3- phenyl~1 I8~diazaspiro[4.5]dec-3-eπe-8~carboxylate (#C41). Pheπyiboronic acid (8.0 mg, 0.066 mmol), anhydrous potassium phosphate {35,0 mg, 0.185 mmoi) and then [1 ,1'~bis{diphβnylphQsphinQ)fβrrocβne]dichlGropailadium(lS) (4.4 mg, 0.0060 mmol) were added to a solution of benzyl {5R7S)-1-(3-flυorophenyl)-7-methyl-2-oxo-3- {[{trifluoromethyl)sulfonyl]oxy}-1 ,8-diazaspira[4.53dec-3-ene-8-carboxyiate (#C40) (30 mg, 0.055 mmoi) in tetrahydrofuran (0.55 mL). The resulting soiution was heated at refiux for 1 hour, then cooled to room temperature, diluted with ethyl acetate (5 ml) and filtered through a <1 μm filter. The fiitrate was concentrated in vacuo, then purified by silica gel chromatography (Gradient: 0% to 50% ethyi acetate in heptane) to prohide the product as a coSorless oil. Yield; 20 mg, 0,042 mmol, 76%. APCI m/z 471.1 (M+1). 1H NMR {400 MHz, CDCb) o 1 .39 (d, J=7.2 Hz1 3H)1 1.54-1 ,6 (m, 1H, assumed; partially obscured by water peak), 1 71-1 ,79 (br m, 1H), 1,95-2.05 (br m, 1H), 2,18 (br dd, J=13, 7 Hz. 1H), 3.19-3.28 (br m, 1 H), 4.20-4.37 {br m, 1H), 4.62- 4.74 (br m, 1H). 5.11 (br s, 2H), 6,91 (ddd, J=9.3, 2,2, 2,2 Hz, 1H), 6,95-6.98 (m, 1H), 7.16 (br ctdd. J=8.3, 8.3, 2.5 Hz, 1 H), 7.31-7.48 (m, 9H). 7.73 (S1 1H), 7.91-7.95 (m, 2H).
Step 6. Synthesis of {5R7S)-1-(3-fiuoraphenyl)-7-methyi-3-phenyl-1 ,8- diazaspiro[4.5]dβc-3-eπ-2-one (#C42). The title compound was prepared according to the general procedure for the synthesis of P1 in Preparation 1, except that benzyl (5/?,7$)-1-{3-fluofophenyl)-7-methyi-2-oxo-3-phenyl-1 ,8-diazaspiroJ4.5}dec-3-ene-8- carboxylate (#C41) was used instead of racemic benzyl (5R,7S)(5S,7/?}~1~(3~ fluorophenyl)-7-methyl-2-oxo-1 ,8-diazaspsro[4.5]dec~3~ene-8-carboxylate (C9). The product was obtained as an oil. Yield: 6.8 rng, 0.020 mmoi, 47%. LCMS m/z 337.1 (M-M ), 3H NMR (400 MHz, CDCI3) δ 1.07 (d, J-6.4 Hz1 3H)1 1.72 (dd, J=14.2, 10.1 Hz, 1H), 1.90-1.98 (m, 2H), 2.06 (ddd, J=14.2, 11 .1« 5.0 Hz, 1H), 2.69 (ddd, J=12.7, 11 .0, 3.2 Hz1 1H), 2.74-2.84 (m, 1H), 2.95 {ddd, J=12.6, 4.5, 4.5 Hz1 1H), 8.99 (ddd, J-9.3, 2,1 , 2.1 Hz, 1H), 7,06 {ddd, J-7,9, 1.8. 0.9 Hz. 1 H), 7.15 (dddd, J-8,4, 8.4. 2.5, 1.0, 1 H), 7.17 <s, 1 H), 7.34-7.47 (m, 4H), 7.91-7.94 <m, 2H). Step 7. Synthesis of (5R7S)-1-(3-fiuorophenyl)-8-(4-hydroxy-3- isopropoxybenzyl)-7-methyl-3-phenyl-1 I8~diazasptro[4.5]dec-3-en-2-one« hydrochloride salt (#97). The title product was prepared from (5R,7S)-1-{3- fluoropheπyl)-7-rπethyi-3-pheπyl-1 ,8-diazaspiro[4,5]dec-3-en-2-one (#C42) according to the general procedure for the synthesis of (5/?,7S)-1-(3-fluorophenyl)-δ-(4- hydroxy-3-isopropoxybenzyl)-7~methyl-1 l8-diazaspiro[4.δJdec-3-en-2-one hydrochloride (87) in Example 87, except that the purification was carried out by multiple silica gel chromatographies; 0% to 5% methanol in dichioromethane gradient, followed by 1% to 100% ethyl acetate tn heptane gradient, and finally diethyl ether eluant, prohiding the neutral form of the product as a solid. Yield: 3.0 mg, 0.0056 mmoL 28%._LCMS m/z 500.2 (M+1 ). 1H NMR (400 MHz, CDCI3) δ 1.20 (d, J=6.7 Hz, 3H), 1.34 (br d, J=6 Hz, 6H), 1.64-1.69 (m. 1H), 1.76-1.82 (m, 1H), 2.00-2.08 (n% 1H), 2.18 (άά, J-IZ,. 5 Hz, 1 H). 2.41-2.47 (m, 1H)5 2.68-2.74 (m. 1H), 2,99-3.04 (m, 1H)1 3.48 (AB quartet, JAB~13 Hz, ΔhAB=79 Hz, 2H), 4.54 (septet, J^δ Hz, 1H)1 5.62 (s, 1H), 6.70 (dd, J=8, 2 Hz,. 1 H). 6.79 (d, J=2 Hz, 1 H), 6.83 (d. J=8.0 Hz, 1 H). 6.93-6.96 (m, 1 H), 8.99-7.02 (m, 1H), 7.12-7.17 (m, 1 H), 7.34-7.46 (m, 4H), 7,53 (s, 1 H), 7,91-7,94 (m, 2H). The hydrochloride salt was prepared using 1 M hydrogen chloride in diethyl ether, prohiding #97 as a solid, 3 mg.
Example @9β (5R,7S)-1-(3-Fiuρrøphenγl)-8-M-^ diazaspifO|4.5]dec-3-en-2-prie, hydrochloride salt (#98)
Figure imgf000083_0001
Step 1 Synthesis of 1 -benzyl 4-methyS (2S,4/?)-4-K3-fluorofrfi©πyl)amino]-2- methylpiperidine-1 ,4-dicarboxySate (#C43). Benzyl {2S,4S)-4-hydroxy-2~methyl~4- (triciiloromβthyl)p!peπd!ne-1-carboxylalβ (#C21) (4.80 g, 13.1 rπmol), 3-fluoroanϊiine (98%, 2,91 roL, 26.2 mmol) and diazabicyclo[5.4.0]uπdec-7-ene (98%, 5,99 ml, 39.3 mmoS) were dissolhed in methanol (131 ml) and heated at reflux ohernight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried oher magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (Eluant: 25% ethyl acetate in heptane) to afford a hiscous, colorless oil (3.8 g), which was taken directly to the next step. LCMS m/z 401.47 (M+1).
Step 2. Synthesis of benzyl {2S,4R)-4-[(3-fluorophenyi)amino]-4- (hydroxymethyl)-2-methylρiperidine-1-carboxylate (#C44). 1 -Benzyl 4-methyl (2Sl4R)-4-[(3-fluorophenyi)aminoj-2-methyipipendine-1 ,4-dicarboxylate (#C43) from the prehious step was dissolhed in tetrahydrofuran (63.3 ml) and treated with a solution of lithium borøhydride in tetrahydrofuran (2 M, 19.0 ml, 38,0 mmol). The resulting mixture was heated at refiux for 18 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, diiuled with water, and extracted with ethyi acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried oher magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Eluant: 50% ethyl acetate in heptane) to prohide the product as a hiscous, colorless oil. Yield: 1.10 g, 2.95 mmol, 22% oher two steps. !H NMR (400 MHz1 CDCi3) δ 1.21 (U1 J~β.6 Hz, 3H), 1.35 {dd, J=UA, 7.9 Hz, 1 H), 1.78-1.88 (m, 2H), 2.06 (dd, 7=14.3, 6.5 Hz, 1H)1 2.20 (br dd, J~6, 6 Hz, 1H)1 3.06-3.14 (m, 1H), 3.53 (br s, 1H), 3.68 (dd, half of ABX system, J-11.3, 4.9 Hz, 1H), 3,75 (άά, half of ABX system, J-11.3, 8.1 Hz1 1H), 3.96-4.03 (m, 1H), 4.15-4.24 (m, 1 H), 5,13 (s, 2H), 6.39-6.44 (m, 2H), 6.52 (dddd, J=8.3, 8.3, 2.3, 0.9 Hz1 1H)1 7.08 (ddd, J=8.3, 8.3, 6.8 Hz1 1 H), 7.29-7.38 (m, 5H).
Step 3. Synthesis of benzyl (2S,4R)-4-[(3-fluorophenyl)amtno3-4-formyl-2- methylpiperidinβ-1-carboxyiate (#C45). Oxalyl chloride (99%, 0.39 mL, 4.4 mmol) was added drop-wise to a -78 °C solution of dimethyl sulfoxide (0.83 ml, 8.9 mmoi) in dichloromethane (5 mL). After 20 minutes, a solution of benzyl (2S,4R)-4-[(3- fluoropheπyl)amino]-4-{hydroxymethyl)~2-methylptpericltne-1-carboxylate (#C44) (1.10 g, 2.95 mmol) in dichloromethane (5 ml) was slowly added. After an additional 20 minutes, triethySamine (99%, 1.86 mL. 11.8 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. The reaction was then diluted with wafer and extracted with ethyl acetate. The organic iayer was washed with saturated aqueous sodium chloride solution, dried oher magnesium sulfate, filtered and concentrated under reduced pressure to prohide the product as an oil. Yield: 600 mg, 1.62 mmol, 55%. !H NMR (400 MHz, CDCi3) S 1.18 (d, J-6.7 Hz1 3H), 1.71 (ddd, J=13.7, 12.2, 6.0 Hz, 1H), 1.91 (dd. half of ABX system, J=14.2, 6.4 Hz, 1H), 1.98 (dd, half of ABX system, J=14.2, 6.3 Hz, 1H), 2.44 (ddd, J=14.0, 3, 3 Hz, 1H). 3.14 (ddd. J»14 2, 12.0, 4.2 Hz1 1H), 4.03-4.09 (m, 2H), 4.32-4.41 (m, 1H), 5.14 {s. 2H)1 6.21 (ddd. J=11.2, 2.3, 2.3 Hz, 1H). 6.25 (br dd, J=8, 2 Hz, 1H), 6.46 (br ddd, J=S1 8, 2 Hz, 1 H), 7.05 (ddd, J=S.1 , 8.1. 8.7 Hz. 1 H), 7.31-7.39 (m, 5H). 9.53 (s, 1H).
Step 4, Synthesis of benzyl {5R,7S)-1-{3-fluαrophenyl)-3l7-dtmethyi-2-oxo- 1,8-diazaspiro[4.5]dβc-3-βne-8-carboxylate (#C46). Ethyl 2-[bis(2,2,2- trifluαrαethoxy)piiosphoryl]propanoate (353 mg, 1.02 mmol) was added drop-wise to an ice-eooied mixture of sodium hydride (60% in oil, 40.8 mg, 1.02 mmoi) and 1 ,2- dimettioxyethanβ (1.46 ml). The mixture was stirred at 0 0C for 30 minutes and then warmed to room temperature. A soiution of benzyi (2S,4R)-4~[{3- flυorophenyl)amino]-4-formyl-2-methyipipericline-1-carboxylate (#C45) (270 mg, 0.729 mmol) in minimal 1 ,2~dimethoxyethane was added drop-wise, and the reaction was stirred for 18 hours. Water was then added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried oher sodium sulfate, filtered and concentrated in vacuo. Purification of the residue hia chromatography on silica gel (Gradient: 10% to 40% efhyl acetate in heptane) prohided the product as a soiid. Yieid: 170 mg, 0.416 mmol, 57%. LCMS m/z 409.5 (M+1 ). Η NMR (400 MHz, CDCI3) ό 1.32 {d, J=7.0 Hz, 3H), 1.41-1.47 (m, 1 H), 1.57-1.66 (m, 1H), 182-195 (m, 1H), 1.99 (d, J=1.8 Hz1 3H), 2.04-2.10 (m, 1H), 3.08-3.17 (m, 1H), 4.13-4.26 (m, 1H), 4,56-4.69 (m, 1H), 5.05-5.14 (m, 2H), 6.84 (ddd, J-9Λ, 2.2, 2.2 Hz, 1 H), 6.89 (br d, J~8 Hz, 1H), 7.11 (br ddd, J=8.4, 8.4, 2.5 H2, 1 H), 7.23-7.24 (m, 1H), 7.30-7.37 (m, 5H), 7.41 (ddd, J=S.2, 8.2, 8.4 Hz, 1H).
Step 5. Synthesis of (5R7S)-1-(3-fϊuoroρheiiyO-3,7-dimethyl-1,8- diazaspiro[4.5ldec-3-en-2-one (#C47). The tttiβ compound was prepared according to the general procedure for the synthesis of Pi in Preparation 1, except that benzyl
Figure imgf000085_0001
carboxyfate (#C4β) was used instead of racemic benzyi (5R,7S)(5S,7/?)~1~{3~ fluorophenyl)-7-methyi-2-oxo-1 ,8-diazaspiro[4.5]dec-3-ene-8-carboxylate (C9). Yieid: 55 mg, 0.20 mmol, 50%. APCi m/z 275.0 <M+1). 1H NMR (400 MHz, CDCi3) δ 1.01 <d, J=6.3 Hz, 3H), 1.34 (br s, 1H), 1.57 (dd, J=14.1, 10.0 Hz, 1H), 1.75-1.85 (m, 2H), 1.87-1.95 (m. 1H), 192 {d, J=1.6 Hz, 3H), 2.61 {dύύt J=12.7, 11 .0. 3.3 Hz, 1 H), 2.66- 2.74 {m, 1H), 2.87 (ddd, J=12.6, 4.5, 4.5 Hz5 1H), 6.63 (q, </=1 5 Hz, 1H), 6.91 (ddd, J=9.δ. 2.2, 2.2 Hz,. 1H), 6.97 {ύάά, J^7.9, 1.8. 0.9 Hz. 1 H), 7.10 {dddd, J=8.4, 8.4. 2.5, 0.9 Hz, 1H), 7.39 (ddd, J=B.2, 8.1 , 6.4 Hz, 1H).
Step 6. Synthesis of (5R,7S)-1-{3-fiυoroρhenyl)-8-{4-hydroxy-3- isopropoxyben2yl)-3,7-dimettiyl-1 ,8-diazaspiro[4.5]dec-3-eπ-2-one, hydrochloride salt (#98). The title product was prepared from (5R,7S)-1-(3-fiuorophenyl)-3,7-dimethyl-
1s8-oiazaspiro£4.5]dec~3-en-2-one (#C47) according to the general procedure for the synthesis of (5RJS)-I ~(3~fluorophenyl)~8~(4-hydroxy-3-isoproρoxybenzyl)-7-methyl-
1,8-diazaspiiO[4.5]dec-3-en-2-one hydrochloride (87) in Example 87. The neutral form of the product was obtained as an oil. Yield: 12.4 mg, 0.0283 mmoi, 39%. LCMS m/z 439.6 (M+1 ). 1H NMR (400 MHz, CDCI3) δ 1.14 (d, J~β.6 Hz1 3H), 133 (2 d, J=6.0 Hz, 6H), 151-1.58 (m, 1 H), 1.62-1.69 (m, 1H), 190-197 (m, 1H), 195 (d, J=1.6 Hz1 3H), 2.07 (dd, J=13.3, 5.1 Hz, 1H), 2.38 (ddd, J=12.5, 5.7, 4.1 Hz, 1H),
2,82 {ddd, J-12.5, 9.7, 3.1 Hz, 1H), 2.92-3.00 (m, 1 H), 3.44 (AB quartet, JAS-13.3
Hz,
Figure imgf000086_0001
J=8.1 , 19 Hz1 1 H), 6.77 <d, J=IS Hz, 1 H), 6.81 (d, J=8.1 Hz. 1H), 6.88 (ddd. J~9,5, 2.2, 2.2
Hz, 1 H), 6.93 {ddd, J-7.9, 1.8, 0.9 Hz, 1H), 7.00-7.02 (m, 1H), 7.1 1 (dddd, J-BA, 8.4,
2.5, 0.8 Hz, 1H), 7.39 {ddd, J=8.1 , 8.1 , 6.4 Hz, 1H).
Treatment of the neutral form of the product with 1 M hydrogen chloride in diethyl ether prohided the hydrochloride salt #98 as a solid, 13.2 mg. Biological data for Examples 87 - @98 is gihen in Table 6.
The structures of additional Examples are shown in Tables 2 and 3, which also gihe physical data, preparatihe information and biological data for these Examples.
Table 2 - Examples #200 - #212
= H
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000092_0002
BACE actihity Ceii Free Assay !C5a 1 nM to 1 μM '***, 1 JJM to 10 μ ***, 10 μ to 100 μ **. 100 μM to300 μM*
^ NMR and MS data obtained on free base, prior to formation of hydrochloride sait.
Examples #101 - #126
1 -Heteroa ryi-substituteci (5f?.7S)-6-(3-isopropoxγbenzyl)-7-methγl-1 ,8- diazaspirof4.51dec-3-en-2-ones
Figure imgf000092_0001
Step 1. Synthesis of 1 -heteroaryi-substifυted benzyl (5R,7S)-7-methyl-2-oxo- 1{8-diazaspiro[4.5]dec-3-ene-8~carboxyiate (#C100). A solution of benzyl (5R7S)-7- methyl-2-oxo-158-diazasρiro[4.53dec-3-ene-8-carboxylate (#C28) (45 mg, 0,15 mmoi) and W,Λ/'-dimethyiethylenediarnine (5 equihalents) in dioxane (0.92 mL) was added to a mixture of the hβteroaryl iodide or bromide (3 equihalents), copper(l) iodide (4 equihalents) and either cesium carbonate or potassium phosphate (3 equihalents) in a 1-dram hial. The resulting suspension was sealed and heated at 80-90 0C for 18- 66 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and flushed through an MCX cartridge containing a small amount of Celite on top of the packing material. Additional ethyl acetate (5-10 mL) was eluted through the cartridge, and the combined filtrates were concentrated in vacuo to afford the product, which was taken directly into the next step. Step 2. Synthesis of 1-heteroaryl -substituted (5R7S)-8-(3- isoρroρoxybenzyl}-7-methyl-1 ,8~diazasρiro[4.53dec-3-en-2-ones (#t O1-#126), The 1- tieteroaryS-substituted benzyl (5R,7S)-7-methyl-2-oxo-1 ,8-dia2aspiro[4.5]dec-3-ene- 8-carboxylate (#C100) from the prehious step was dissolhed in a freshly prepared solution of irimeihylsilyl iodide (0.3 M in acetonstrile, 2 equihalents), and the resulting solution was stirred at room temperature for 18 hours. Purification was carried out by loading the reaction mixture directly onto an MCX column. The column was flushed with dichloromethane (5 mL), and the product was then eluted using a 2 M solution of ammonia in methanol (5 mL). The eluant was concentrated in vacuo to afford the deprotected intermediate. This material was mixed with acetonifrile (1 ml) and potassium carbonate (3 equihaients). After addition of 1-(bromomethyl)-3- isopropoxybenzene (2 equihalents), the mixture was stirred at room temperature for 18 hours, then loaded onto an MCX cartridge containing a small amount of Ceiϊte on top of the packing material. The cartridge was flushed with dtchioromβthane {5 mL). and the filtered solids and Ceiite were manually remohed from the cartridge. The product was eluted using a 2 M solution of ammonia in methanol {5 rnL), and the filtrate was concentrated in vacuo.
Purification was carried by preparatihe HPLC using one of the following systems: 1) Column- Waters XBridge Cm. 5 μm; Mobile phase A. 0.03% NH4OH in water (h/h); Mobile phase B: 0.03% NH4OH in acetonitrile (h/h); Gradient: 5-30% B to 100% B; or 2) Column: Waters Sunfire C18, 5 μm; Mobile phase A: 0.05% trifluoroacettc acid in water (h/h); Mobile phase 8: 0,05% tnfluoroacetic acid in acetonitrile (h/h); Gradient: 10 or 15% to 100% 8. See Table 4 for characterization data and biological actihity.
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
1-Heteroaryl-8-substitυted-(5R,7S)-7-methyl-1,8-diazaspiro[4.5]dec-3-en-2- ones
These compounds were prepared from benzyl (5R,7S)-7-methyl-2-oxo-1 ,8- diazaspiro[4.5]dec -3-ene-8-carboxylate (#C28) in a manner analogous to the preparation of Examples #101 -#126, except that the 8-substituent was introduced hia reductihe amination (see Examples 1 - 87). Purification was carried out by preparatihe HPLC using the same systems described for Examples #101 - #126. See Table 5 for characterization data and biological actihity.
Figure imgf000096_0001
Figure imgf000097_0002
Figure imgf000097_0001
Biological Assay
A synthetic APP substrate that can be cleahed by beta-secretase and hahing N-termiπal bioliπ is used to assay beta-secretase actihity in the presence or absence of the inhibitory compounds. The substrate can contain either the wiidtype sequence around the BACE cleahage site or the Swedish mutation (Vassar, R.« B. D. Bennett Bt a/. (1999). "beta-secretase cleahage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE." Science, 286(5440): 736-741). The substrate and test compounds are added to 384 well polypropylene plates. The reaction is initiated by the addition of soluble BACE enzyme to a final holume of 12.5 μL per well. The final assay conditions are: 0=001 - 300 μM compound inhibitor, 0.05M sodium acetate (pH 4.5), 3 μM substrate, soluble human BACE, and 2% DMSO. Concentrated conditioned media from cells secreting human recombinant soluble BACE was titrated to prohide a source of BACE enzyme. The cell media can be used as either a crude BACE prep or BACE can be purified using any number of techniques, including immobilized BACE inhibitor purification columns. The assay mixture is incubated for 1 hour at 370C, and the reaction is quenched by the addition of an equal holume of 0.1 M Iris, pH 8. Half of the quenched mix is incubated on clear streptahidin coated 384 well polystyrene plates for 1 hour. An ELlSA is then performed using an in-house antibody that specifically recognizes the new C- terminus created after cleahage by BACE. Two in-house antibodies are ahailable; each is cleahage specific, but one is raised against the wiidtype sequence (APP 591— 596) while the other is raised against the Swedish mutation (APP 590-596). (These polyclonal antibodies were raised in rabbits by immunizing with antigen comprised of six amino acid residues present at the carboxy terminus of the wild-type soluble APPbeta sequence (NH2-ISEVKM-COOH) or sehen amino acid residues present at the carboxy terminus of the Swedish mutation at the beta cleahage site (NH2- EiSEVNL-COOH) conjugated to keyhole limpet hemacyanin by methods known to those skilled in the art.) A secondary anti-species Horseradish Peroxidase (HRP) conjugated antibody is then utilized. The readout, following assay dehelopment with TiVIB substrate and quenching with 0.09M sulfuric acid, is absorbance at 450 nm.

Claims

CLAIMSWe claim:
1. A compound of forrouS a h
Figure imgf000099_0001
whereiπ the stereochemistry shown in formula l at the carbon bonded to Ra and at the spirocyciic carbon is the absoiute stereochemistry; 8 is alkyl, aryS, heterøaryi, cycloaikyi, or heterocycloaikyi, wherein B is optionally substituted with zero to three R3 groups; A is independently aryl, cycioalkyl, heterocycSoaSkyS or heteroaryi wherein said aryt cycioalkyl, heterocycSαaikyl or heteroaryi is optionaϋy substituted with one to three R4; when ΓΓΓTΓΓL is a single bond, R1a and Kv' are each independently hydrogen, alkyl, aikenyl, -(CHs)rcycioalkyl, -{CHa)rheterocycloalkyl, -{CHaJraryl, -(CH2X- heteroaryi, -(CH2)rOR5, -{CH2)tN{R7)2, -NH-(CH2}rcycioalkyl, -MH-(CH2),- heterocycloalkyl, -NH-(CH2)raryls -NH-(CH2)rheteroaryi, -(CH£)rCORs, -(CH2)r SO2R5, or -{CHa)rCO2Rδ; wherein said aikyi, alkeoyi, -(CHsVcycloafkyi, -(CH2)r heteroeycloaSkyS, -{CHa)i-aryl, or -(CH2)rheteroaryl R1a or Rif; substituent is optionaiiy substituted with one to three hydroxyl, aryl, heteroaryi, halogen, aSkyS, cycloaSkyS, -SO2R7, -NR7COR7, -CON(R7J3, -COOR7, -C(O)R7, -CN. or -N(R7J2 wherein said aryl alkyl, cycioalkyl and heteroaryi substitυent is optionally substituted with one to three halogen, alkyl, hydroxyl, or -O-alkyl; or R1a and Rf0 together with the carbon they are bonded to form a cycloaSkySene moiety or a heterocycloaikyiene moiety, wherein said cycloaikyiene or heterøcycioalkylene moiety is optionaiiy substituted with one to three hydroxyl, aryl, hβteroaryi, haiogen, alkyl, cyctoaikyi, -SO2R7 -NR7COR7, -COMCR7J2, -COOR7. -C(O)R7. -CN, or -N{R7)2, wherein said aryi, aikyi, cydoaikyi and hetβrøaryl sυbstituent is optionally substituted with one to three halogen, aikyi, hydroxyl, or -O- alkyi; when
Figure imgf000100_0002
s a double bond. R1b is absent and R1a is hydrogen, aSkyS, alkenyi, -{CH2)rcycioalkyl, -(CH2)rheterocycloalkyl, -{CH2)raryi, ~(CH2)rrseteroaryi, -(CHs)1-OR5,
Figure imgf000100_0001
-NH-(CH2)t-cycioalkyl, -NH-(CH2)rheterocycioaikyi, -NH- (CH2)raryiJ -NH-(CH2)rheteroaryl, -(GH2VCQR5, -(CH2X-SO2R5, or -{CH2)rCOsR5, wherein said aikyi, aikenyl, -(CH2)rcycioalkyl> -(CH2)rheterocycloalkyl> -(CH2),-aryl, or -(CH2)rhet8roaryl Rla sυbstituent is optionaiiy substituted with one to three hydroxyl, aryl. hβteroaryi. halogen, aikyi, cydoaikyi, -SO2R7, -NR7COR7, -CON(R7)2. -COOR7, - C(O)R7, -CN, or -N(R7);, wherein said aryi, aikyi, cydoaikyi and heteroaryl substituent is optionaiiy substituted with one to three halogen, aikyi, hydroxyl, or -O-alkyl; R2 is aikyi, cycioaikyi, or alkenyi wherein said alkyl, cycioalky), or aikenyl is optionaiiy substituted with one to three halogen, hydroxyl. or cyano; each R3 is independently haiogen, alkyl, cyano, hydroxyl, -O-alkyi, ~0- cycloaikyi, -SO2R7. -N(R7)2, -COR7, -C0N(R?)2, -(CH2)rcycioalkyl, -{CH2)r heterocycloaikyi, -(CH2)t-aryl, or -{CHϊ^-heteroaryl wherein said R3 aikyi, -(CH2)r cydoaikyi, -(CH2)rheterocydoalkyl, -(CH2)raryj, or -(CHsJrheteroaryl is optionaiiy substituted with one to three R4; each R4 is independently aikyi, halogen, cyano, -SO2MHR7, -CON(R7)2, -N(R7)2, -N(R7)COR7, -N{R7)CO2R7. -SO2N(R7}2, -N(R7JSO2R7, -COR7, -SO2R7, -(CH2)rcycloalkyl, -(CH2)rheterocycloaikyi, -(CH2)raryl, -(CH2)rheteroaryi, -(CHj)4- N(R7)2: or -(CH2)rOR5; wherein each R1 alkyl, -(CHa)rcycloaϊkyϊ, -(CH2),- heterocycloaikyi, -(CH;)raryl, or -(CH2)rheteroaryl is optionaiiy independentiy substituted by one to three cyano, aikyi, halogen, -CF3 or -OR5; each R5 is independently hydrogen, aikyi. -{CH2χ-cydoaikyi, -<CH2)r heterocycloaikyi, ~(CH2}raryl, or -(CH3)rheteroaryl; wherein said -(CH2)rCycloaikyi, -(CH2)rheterocycioalkyl, -{CH2)raryi, or -(CH2)rheteroaryl is optionaiiy substituted with one to three R6; each Rs is independently aikyi. hydroxyl, alkoxy, halogen, cyano, ~(CH2)tN(R7)2, -(CH2)rcycloatkyl, -(CH^rheterocyclαalkyJ, -{CHsVaryl, or -(CH2),- tieteroaryl; each R' is independently hydrogen, aikyi, -{CH2X-cydoalkyl, -(CH2Jt- iieterocydoaikyi, -(CHa)raryi, or -(CH2)rheteroaryl, or when two R7 substituents are attached to the same nitrogen atom they may be taken together with the nitrogen to which they are attached to form a heterocycioalkylene moiety; and wherein said alkyl, -{CH2)rcyclαaSkyS, -{C^X-heterocycioalkyl, -<CH2)rary1, or -(CHaJpheteroaryl are optionally substituted with one to three alkyl, halogen, cyano, hydroxyl, or -OR4; n is an integer selected from 1. 2 and 3; and each f is an integer independently selected from 0, 1, 2 and 3; or pharmaceutically acceptable salts thereof.
2. A compound of claim 1 wherein A is aryl, heteroaryl, cycloalkyl or heterocycloaikyi, and A is optionally substituted with one R^ substituent
3. A compound of claim 2 wherein A is aryl or heteroaryl, and R4 is independently alkyl, halogen, cyano, -SO2NHR7, -CON(R7J2, -N(R7J2, -N(R7JCOR7, -SO2N{R?}2, -M(R7)SO£R?, -COR7, -SO3R7, -{CH2}rcycioaikyl. -(CHaJt- hβterøcyclαalkyl, -{CH2}raryI, ~(CH2)rheteroaryL -(CHaχ-N(R7}a, or ~(CH2)r0Rδ wherein each R4 alkyl, -{CH2);-cycIoaikyi> -(CHsJrheterocycioalkyl, ~(CH2)raryi. or -(CH2)rheteroaryl is optionaiiy independently substituted by one to three cyano, aikyi, halogen, -CF3. or -OR5
4. A compound of claim 1 wherein A is aryi, heteroaryl, cycioalkyl or heterocycloaikyi, and A is optionally substituted with two R4 substituents*
5. A compound of claim 4 where in A is aryi or heteroaryl and each R4 is independently alkyl, halogen, cyano, -SO2NHR7, -CON(R7J2, -N(R7J2 -N(R7JCOR7, -SO2N(R7J2, -N(R7JSO2R7, -COR7, -SO2R7, -(CH2)rcycloalkyi, -(CH2),- heterocycloalkyl, -(CH2)raryl, ~(CH2)rheteroaryl, -(CH2Jt-N(R7J2, or ~(CH2)rQRs wherein each R4 alkyl, -(CH2Jrcycloalkyl, -(CH2)rheterocycioaikyi, ~(CH2}raryi, or -(CHsJr-heterαaryl is optionally independently substituted by one to three cyano, alkyl, halogen, -CF3, or ~ORS
6. A compound of claim 5 wherein at least one R4 is -(CHs)raryl wherein t is zero and the aryi is optionally substituted by one to three cyano, alkyl, halogen, or -OR5,
7. A compound of claim 5 wherein each R4 is -OR0,
8. A compound of claim 1 wherein A is aryl, heterαaryl, cycSoalkyl or heterocycloaikyi, and A is optionally substituted with three R^substituents.
9. A compound of ciaim 8 wherein A is aryl or heteroaryl and each R4 is independently alkyl, halogen, cyano, -SO2NHR7, -C0N(Rr)2! -N(R7J2. -N{Rr)CQR\ -SO2N{R?}2; -W(R7ISO2R7, -COR7, -SO2R7, -(CH2}rcydoaikyi, -(CH2J1- heteroeycloaikyl, ~(CH2)raryl, ~(CH2)rheteroaryi, -(CH2).rN(R7)2> or -(CH2}rORs wherein each R4 alkyl. -(CH2)rcycloalkyl! -(CH2)rheterocycloaikyi, ~(CH2)raryl, or -(CH2)i-heteroaryl is optionally independently substituted by one to three cyano, alkyl, halogen, -CF3, or -OR5
10. A compound of claim 1 wherein S is aryl and is substituted with only one to three R3 substituents.
11. A compound of claim 10 wherein B is aryl and is substituted with only one R3 substituent wherein R3 is halogen.
12. A compound of claim 1 wherein is a single bond, and R1a and R1h are each independently hydrogen or alkyl.
13. A compound of claim 12 wherein R!a and R'b together with the carbon they are bonded to form a cycloalkylene moiety or a heterocycloaikyieπe moiety.
14, A compound of claim 12 wherein R1a and Rn' are each hydrogen.
15. A compound of claim 1 wherein rrrrrr^ is a double bond, and Rfb is absent.
16, A compound of claim 1 wherein said compound of Formula (I) is a compound hahing Formula (Il)
Figure imgf000103_0001
wherein A, R*a, R1b, and R3 are as defined in Ciaim 1 ; or a pharmaceutically acceptable salt thereof.
17. A compound of claim 1 wherein said compound of Formula (I) is a compound hahing Formula (lll)
Figure imgf000103_0002
wherein A1 R1a, and R3 are as defined in Claim 1; or a pharmaceutically acceptable salt thereof.
18, A method for the treatment of a disease or condition selected from the group consisting of neurological and psychiatric disorders comprising administering to the mammal an effectihe amount of compound of claim 1 or pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound of claim i or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
20. The composition of claim 17 further comprising an atypical antipsychotic, a choliπesterase inhibitor, dimebon or NMDA receptor antagonist,
PCT/IB2009/055043 2008-11-23 2009-11-12 Lactams as beta secretase inhibitors WO2010058333A1 (en)

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AU2009318855A AU2009318855A1 (en) 2008-11-23 2009-11-12 Lactams as beta secretase inhibitors
US13/130,192 US20110224231A1 (en) 2008-11-23 2009-11-12 Novel Lactams as Beta Secretase Inhibitors
MA33879A MA32929B1 (en) 2008-11-23 2009-11-12 Lactamate acts as beta-secretase inhibitors
EA201170722A EA201170722A1 (en) 2008-11-23 2009-11-12 LACTAMS AS BETA SECRETASE INHIBITORS
MX2011005346A MX2011005346A (en) 2008-11-23 2009-11-12 Lactams as beta secretase inhibitors.
EP09764055A EP2370439A1 (en) 2008-11-23 2009-11-12 Lactams as beta secretase inhibitors
JP2011536976A JP4932065B2 (en) 2008-11-23 2009-11-12 Lactams as beta-secretase inhibitors
AP2011005725A AP2011005725A0 (en) 2008-11-23 2009-11-12 Lactams as beta secretase inhibitors.
CA2743584A CA2743584A1 (en) 2008-11-23 2009-11-12 Lactams as beta secretase inhibitors
CN2009801552711A CN102317289A (en) 2008-11-23 2009-11-12 Lactams as beta secretase inhibitors
BRPI0922799A BRPI0922799A2 (en) 2008-11-23 2009-11-12 lactams as beta secretase inhibitors
NZ592823A NZ592823A (en) 2008-11-23 2009-11-12 Spirocyclic lactams for treating neurodegenerative and/or neurological disorders
IL212869A IL212869A0 (en) 2008-11-23 2011-05-12 Lactams as beta secretase inhibitors
TN2011000252A TN2011000252A1 (en) 2008-11-23 2011-05-17 LACTAMS AS BETA-SECRETASE INHIBITORS
ZA2011/03738A ZA201103738B (en) 2008-11-23 2011-05-20 Lactams as beta secretase inhibitors

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CN102317289A (en) 2012-01-11
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MA32929B1 (en) 2012-01-02
KR20110086769A (en) 2011-07-29
CR20110269A (en) 2011-07-04
JP4932065B2 (en) 2012-05-16
MX2011005346A (en) 2011-06-16
TN2011000252A1 (en) 2012-12-17
NZ592823A (en) 2012-12-21
PE20110777A1 (en) 2011-10-29
CL2011001147A1 (en) 2011-09-30
CU20110113A7 (en) 2012-01-31
AP2011005725A0 (en) 2011-06-30
AU2009318855A1 (en) 2010-05-27
GEP20135806B (en) 2013-04-10
CO6361924A2 (en) 2012-01-20
JP2012509310A (en) 2012-04-19
DOP2011000134A (en) 2011-07-31
BRPI0922799A2 (en) 2019-09-24
UA99787C2 (en) 2012-09-25
ZA201103738B (en) 2012-01-25
JP2012107029A (en) 2012-06-07
IL212869A0 (en) 2011-07-31
EP2370439A1 (en) 2011-10-05
EA201170722A1 (en) 2011-10-31
NI201100096A (en) 2011-10-31
US20110224231A1 (en) 2011-09-15
CA2743584A1 (en) 2010-05-27

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