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WO2009158393A1 - 1, 2 disubstituted heterocyclic compounds - Google Patents

1, 2 disubstituted heterocyclic compounds Download PDF

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Publication number
WO2009158393A1
WO2009158393A1 PCT/US2009/048426 US2009048426W WO2009158393A1 WO 2009158393 A1 WO2009158393 A1 WO 2009158393A1 US 2009048426 W US2009048426 W US 2009048426W WO 2009158393 A1 WO2009158393 A1 WO 2009158393A1
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WIPO (PCT)
Prior art keywords
compound
optionally substituted
cycloalkyl
alkyl
phenyl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2009/048426
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French (fr)
Inventor
Amy Ripka
Gideon Shapiro
Richard Chesworth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Forum Pharmaceuticals Inc
Original Assignee
EnVivo Phamaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by EnVivo Phamaceuticals Inc filed Critical EnVivo Phamaceuticals Inc
Priority to MX2011000175A priority Critical patent/MX2011000175A/en
Priority to EP09770926.5A priority patent/EP2297133B1/en
Priority to AU2009262241A priority patent/AU2009262241B2/en
Priority to JP2011516574A priority patent/JP5658664B2/en
Priority to RU2011102569/04A priority patent/RU2506260C2/en
Priority to CA2729259A priority patent/CA2729259A1/en
Priority to BRPI0914772A priority patent/BRPI0914772A2/en
Priority to CN200980133288.7A priority patent/CN102131801B/en
Publication of WO2009158393A1 publication Critical patent/WO2009158393A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the disclosure relates to 1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10.
  • the disclosure further relates to processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function.
  • CNS central nervous system
  • the disclosure also relates to methods for treating neurological, neurodegenerative and psychiatric disorders including but not limited to those comprising cognitive deficits or schizophrenic symptoms.
  • Cyclic phosphodiesterases are intracellular enzymes which, through the hydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels of these mono phosphate nucleotides which serve as second messengers in the signaling cascade of G- protein coupled receptors.
  • PDEs also play a role in the regulation of downstream cGMP and cAMP dependent kinases which phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis.
  • eleven different PDE families have been identified which are encoded by 21 genes. The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS.
  • PDElO is primarily expressed in the brain (caudate nucleus and putamen) and is highly localized in the medium spiny neurons of the striatum, which is one of the principal inputs to the basal ganglia. This localization of PDEl O has led to speculation that it may influence the dopaminergic and glutamatergic pathways both which play roles in the pathology of various psychotic and neurodegenerative disorders.
  • PDElO has a fivefold greater V max for cGMP than for cAMP and these in vitro kinetic data have lead to the speculation that PDElO may act as a cAMP-inhibited cGMP phosphodiesterase in vivo (Soderling and Beavo "Regulation of cAMP and cGMP signaling: New phosphodiesterases and new functions," Curr. Opin. Cell Biol., 2000, 12, 174-179).
  • PDElO is also one of five phosphodiesterase members to contain a tandem GAF domain at their N-terminus. It is differentiated by the fact that the other GAF containing PDEs (PDE2, 5, 6, and 1 1) bind cGMP while recent data points to the tight binding of c AMP to the GAF domain of PDElO (Handa et al. "Crystal structure of the GAF-B domain from human phosphodiesterase 1OA complexed with its ligand, cAMP" J. Biol. Chem. 2008, May 13 th , ePub).
  • PDElO inhibitors have been disclosed for the treatment of a variety of neurological and psychiatric disorders including Parkinson's disease, schizophrenia, Huntington's disease, delusional disorders, drug-induced psychoses, obsessive compulsive and panic disorders (US Patent Application 2003/0032579).
  • Studies in rats (Kostowski et. al "Papaverine drug induced stereotypy and catalepsy and biogenic amines in the brain of the rat" Pharmacol. Biochem. Behav. 1976, 5, 15-17) have showed that papaverine, a selective PDElO inhibitor, reduces apomorphine induced stereotypies and rat brain dopamine levels and increases haloperidol induced catalepsy.
  • Antipsychotic medications are the mainstay of current treatment for schizophrenia.
  • Conventional or classic antipsychotics typified by haloperidol, were introduced in the mid-1950s and have a proven track record over the last half century in the treatment of schizophrenia. While these drugs are effective against the positive, psychotic symptoms of schizophrenia, they show little benefit in alleviating negative symptoms or the cognitive impairment associated with the disease.
  • drugs such as haloperidol have extreme side effects such as extrapyramidal symptoms (EPS) due to their specific dopamine D2 receptor interaction.
  • EPS extrapyramidal symptoms
  • atypical antipsychotics typified by risperidone and olanzapine and most effectively, clozapine.
  • These atypical antipsychotics are generally characterized by effectiveness against both the positive and negative symptoms associated with schizophrenia, but have little effectiveness against cognitive deficiencies and persisting cognitive impairment remain a serious public health concern (Davis, J.M et al. "Dose response and dose equivalence of antipsychotics.” Journal of Clinical P sychopharmacology, 2004, 24 (2), 192-208; Friedman, J.H. et al "Treatment of psychosis in Parkinson's disease: Safety considerations.” Drug Safety, 2003, 26 (9), 643-659).
  • atypical antipsychotic agents while effective in treating the positive and, to some degree, negative symptoms of schizophrenia, have significant side effects.
  • clozapine which is one of the most clinically effective antipsychotic drugs shows agranulocytosis in approximately 1.5% of patients with fatalities due to this side effect being observed.
  • Other atypical antipsychotic drugs have significant side effects including metabolic side effects (type 2 diabetes, significant weight gain, and dyslipidemia), sexual dysfunction, sedation, and potential cardiovascular side effects that compromise their clinically effectiveness.
  • Described herein are 1 ,2-disubstituted heterocyclic compounds of Formulas (I), (II) or (III) that are inhibitors of at least one phosphodiesterase 10 (e.g., human PDE-IOA):
  • at least one phosphodiesterase 10 e.g., human PDE-IOA
  • HET is a heterocyclic ring selected from Formulas A1-A26 and A29-42 below
  • W is selected from halogen, cyano, nitro, alkoxy, amino, alkylamino, dialkylamino, carboxy, amido, alkylamido, and dialkylamido;
  • X is selected from C 3 -C 8 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;
  • Y is a bond or a divalent linker group selected from -CH 2 -, -0-, -SO 2 -, -CH 2 O-, -OCH 2 - and -CH 2 CH 2 - with the rightmost radical of the Y group connected to the Z substituent;
  • Z is optionally substituted heteroaryl
  • Ri a is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;
  • Rib is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;
  • Each R 2 is independently selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl; or two R 2 groups taken together form a 3-6 membered cycloalkyl ring;
  • R 3 and R 4 are independently selected from CpC 4 alkyl, CF 3 , optionally substituted cycloalkyl; or R 3 and R 4 taken together form a 3-6 membered cycloalkyl ring;
  • R5 is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;
  • n is independently selected from 1 and 2;
  • R 7 is selected from hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl; In one embodiment, alkyl groups are fully saturated whether present on their own or as part of another group (e.g., alkylamino).
  • substituent groups are not further substituted. In other embodiements, substituent groups are not further substituted.
  • any group that is defined as being optionally substituted can be independently singly or multiply optionally substituted.
  • a group that is defined as being optionally substituted is not substituted.
  • a compound of Formula (I) is selected.
  • a compound of Formula (II) is selected.
  • a compound of Formula (III) is selected.
  • HET is selected from Formulas Al, A2, A7, A8, AH, A15, A19, A25, A29, A30, A31, A32, A35, A37, A38, A39, A40.
  • HET is selected from Formulas A7, A8, A25, A29, A30, A31, A32, A35, A37 and A38.
  • HET is selected from Formulas A7, A8, A25, A29, A30, A35, A37 and A38.
  • HET is selected from Formulas A7, A8, A17 A18, A25, A29, A30 and A34. In a further embodiment, HET is selected from Formulas Al, A2, A7, A8, A 14, A 15 and A19.
  • HET is selected from Formulas A5, A6, A9 AlO, A20 and A24.
  • HET is selected from Formulas Al, A2, A7 and A8.
  • HET is selected from Formulas A22, A23, A25 and A26.
  • HET is selected from Formulas A29, A30, A31 and A32.
  • HET is selected from Formulas A7, A8, A29 and A30.
  • HET is selected from Formulas A25, A26, A35 and A36.
  • HET is selected from Formulas A25, A29, A35 and A38.
  • HET is selected from Formulas A7, A8, A29 and A31.
  • HET is selected from Formulas A29, A31, A37 and A38. In another embodiment, HET is selected from Formulas A25, A35, A37 and A38. In another embodiment, HET is selected from Formulas A25, A29, A30 and A35. In another embodiment, HET is selected from Formulas A7 and A8. In another embodiment, HET is selected from Formulas A25 and A26. In another embodiment, HET is selected from Formulas A29 and A30. In another embodiment, HET is selected from Formulas A35 and A36.
  • HET is selected from Formulas A29 and A31.
  • HET is selected from Formulas A31 and A32.
  • HET is selected from Formulas A37 and A38.
  • HET is Formula Al.
  • HET is Formula A2.
  • HET is Formula A3.
  • HET is Formula A4.
  • HET is Formula A5.
  • HET is Formula A6.
  • HET is Formula A7.
  • HET is Formula A8.
  • HET is Formula A9.
  • HET is Formula AlO.
  • HET is Formula Al l.
  • HET is Formula A 12. In another embodiment, HET is Formula A13. In another embodiment, HET is Formula A 14. In another embodiment, HET is Formula Al 5. In another embodiment, HET is Formula A 16. In another embodiment, HET is Formula Al 7. In another embodiment, HET is Formula A 18. In another embodiment, HET is Formula A 19. In another embodiment, HET is Formula A20. In another embodiment, HET is Formula A21. In another embodiment, HET is Formula A22. In another embodiment, HET is Formula A23. In another embodiment, HET is Formula A24. In another embodiment, HET is Formula A25. In another embodiment, HET is Formula A26. In another embodiment, HET is Formula A29. In another embodiment, HET is Formula A30.
  • HET is Formula A31.
  • HET is Formula A32.
  • HET is Formula A33.
  • HET is Formula A34.
  • HET is Formula A35.
  • HET is Formula A36.
  • HET is Formula A37.
  • HET is Formula A38.
  • HET is Formula A39.
  • HET is Formula A40.
  • HET is Formula A41.
  • HET is Formula A42.
  • W is selected from nitro, carboxy, amido, alkylamido, and dialkylamido.
  • W is selected from amino, alkylamino and dialkylamino. In another embodiment, W is selected from halogen, cyano and alkoxy.
  • W is selected from halogen and cyano.
  • W is halogen
  • W is cyano
  • W is alkoxy
  • X is selected from C 3 -C8 alkyl, cycloalkyl and cycloalkylalkyl.
  • X is selected from cycloalkyl and cycloalkylalkyl. Examples include, but are not limited to, cyclohexyl and cyclohexylmethyl.
  • X is C3-C8 alkyl. Examples include, but are not limited to, isopropyl, t-butyl and isopentyl.
  • X is heterocycloalkyl
  • X is heterocycloalkyl having only 6 ring atoms.
  • examples include, but are not limited to, morpholinyl, piperidinyl, piperazinyl N-Me-piperazinyl and pyranyl.
  • X is heterocycloalkyl having only 5 ring atoms. Examples include, but are not limited to, tetrahydrofuranyl and pyrrolidinyl.
  • X is a heterocycloalkyl group selected from Formulas B1-B16 depicted below:
  • R 6 is selected from hydrogen and Cj-C ⁇ alkyl, C 3 -C 6 cycloalkyl and C 4 -C 7 cycloalkylalkyl, all of which can be optionally substituted.
  • X is selected from morpholinyl, pyranyl and tetrahydrofuranyl.
  • X is selected from morpholinyl (having Formula Bl) and 4-pyranyl (having Formula B2).
  • X is heteroaryl
  • X is selected from a monocyclic aromatic ring having 5 ring atoms selected from C, O, S and N provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur, and a monocyclic aromatic ring having 6 atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from Ci-C 4 alkyl, cycloalkyl, cycloalkyloxy, Ci- C 4 alkoxy, CF 3 , carboxy, alkoxyalkyl, C 1 -C 4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro.
  • Examples include but are not limited to lH-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3, 5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1 ,2,3,5-thiatriazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-
  • X is a monocyclic aromatic ring having 6 ring atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from C 1 -C 4 alkyl, cycloalkyl, cycloalkyloxy, C 1 -C 4 alkoxy, CF3, carboxy,-alkoxyalkyl, C 1 -C 4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro.
  • Examples include but are not limited to 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
  • X is a monocyclic aromatic ring having 5 ring atoms selected from C, O, S, and N, provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur and where said ring may be optionally and independently substituted with up to two groups selected from Ci-C 4 alkyl, cycloalkyl, cycloalkyloxy, C1-C 4 alkoxy, CF3, carboxy, alkoxyalkyl, C 1 -C 4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro.
  • Examples include but are not limited to lH-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3, 5-oxatriazolyl, 1 ,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl.
  • X is selected from 2-pyridinyl, 3-pyridinyl and 4-pyridinyl optionally substituted with one group selected from C
  • X is 3-pyridinyl optionally substituted with one group selected from Ci-C 4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, Ci-C 4 alkoxy, CF 3 , amino, alkylamino, dialkylamino, thioalkyl, halogen and cyano.
  • X is 4-pyridinyl optionally substituted with one group selected from Ci-C 4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C 1 -C 4 alkoxy, CF 3 , amino, alkylamino, dialkylamino, thioalkyl, halogen and cyano.
  • X is selected from 3-pyridinyl and 4-pyridinyl.
  • X is 3-pyridinyl.
  • X is 2-methoxy-5-pyridinyl.
  • X is 4-pyridinyl.
  • X is 2-methoxy-4-pyridinyl.
  • X is a heterobicyclic ring system.
  • X is a heterobicyclic ring system where one ring is aromatic.
  • X is a heterobicyclic ring system where both rings are aromatic.
  • X is a heterobicyclic ring system containing exactly 9 ring atoms. In another embodiment, X is a heterobicyclic ring system containing exactly 10 ring atoms.
  • X is selected from benzo[d]oxazoyl, benzo[c][l,2,5]oxadiazyl, benzo[c][l,2,5]thiadiazolyl, benzo[d]isoxazolyl, lH-benzo[d]imidazoyl, benzo[d]thiazoyl, benzo[c]isothiazolyl, benzo[d]isothiazoryl, benzo[c]isoxazolyl, imidazo[l,2-a]pyridinyl and imidazo[l,5-a]pyridinyl
  • X is selected from benzo[c][l ,2,5]oxadiazyl and benzo[c][l,2,5]thiadiazolyl.
  • X is selected from benzo[d]oxazoyl, lH-benzo[c/]imidazoyl and benzo[d]thiazoyl.
  • X is benzo[d]oxazoyl.
  • X is lH-benzo[d]imidazoyl.
  • X is benzo[d]thiazoyl.
  • X is benzo[c][l,2,5]oxadiazoyl.
  • X is benzo[c][l,2,5]thiadiazolyl
  • X is benzo[d]isoxazolyl.
  • X is benzo[d]isothiazolyl.
  • X is benzo[c]isothiazolyl.
  • X is benzo[c]isoxazolyl. In another embodiment, X is imidazo[l,2- ⁇ ]pyridinyl.
  • X is imidazo[l,5- ⁇ ]pyridinyl.
  • X is aryl
  • X is selected from phenyl and pyridinyl.
  • X is phenyl
  • X is phenyl optionally substituted with one or more substituents selected from F, Cl, CN, NO 2 , CF 3 , OCF 3 , OCHF 2 , CH 2 CF 3 and OMe.
  • X is restricted phenyl
  • X is selected from a 3,4-disubstituted phenyl, 3-substituted phenyl and 4-substituted phenyl.
  • X is selected from 3,4-disubstituted phenyl and 4-substituted phenyl.
  • X is 3-chloro-4-methoxyphenyl
  • X is 3-cyano-4-methoxyphenyl
  • X is 3-chloro-4-difluoromethoxyphenyl
  • X is 3-cyano-4-difluoromethoxyphenyl
  • X is 4-substituted phenyl. In another embodiment, X is 4-nitrophenyl.
  • X is 4-methoxyphenyl.
  • X is 4-chlorophenyl.
  • X is 4-cyanophenyl.
  • X is 4-trifluoroethylphenyl.
  • X is 4-trifluoromethoxyphenyl.
  • X is 3-substituted phenyl.
  • X is 3-nitrophenyl
  • X is 3-trifluoromethoxyphenyl.
  • X is 3-methoxyphenyl.
  • X is 3-chlorophenyl.
  • X is 3-cyanophenyl
  • X is 3-trifluoroethylphenyl.
  • X is 3-trifluoromethoxyphenyl.
  • Y is -CH 2 O- or -OCH 2 - with the rightmost radical connected to the Z substituent.
  • Y is -CH 2 CH 2 - with the rightmost radical connected to the Z substituent.
  • Y is -CH 2 O- with the rightmost radical connected to the Z substituent.
  • Y is -OCH 2 - with the rightmost radical connected to the Z substituent.
  • Z is selected from heteroaryl having only 6 ring atoms and a heterobicyclic ring system.
  • Z is a heterobicyclic ring system.
  • Z is a heterobicyclic ring system where one ring is aromatic.
  • Z is a heterobicyclic ring system where both rings are aromatic.
  • Z is a heterobicyclic ring system containing exactly 9 ring atoms.
  • Z is a heterobicyclic ring system containing exactly 10 ring atoms.
  • Z is selected from benzimidazolyl, quinolinyl, tetrahydroquinolyl, imidazo[l,2- ⁇ ]pyridin-2-yl, tetrahydroisoquinolyl, 5-methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl, 6-fluoroquinolyl and isoquinolinyl, all of which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is selected from benzimidazolyl, quinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and isoquinoHnyl, all of which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro.
  • Z is selected from quinolinyl, imidazo[l,2- ⁇ ]pyridin-2-yl, 5- methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl and 6-fluoroquinolin-2-yl, all of which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is selected from quinolinyl and isoquinoHnyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is selected from 2-quinolinyl and 2-benzimidazolyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is 2-quinolinyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is 6-fluoroquinolin-2-yl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is 3,5-dimethylpyridin-2-yl substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is 5-methylpyridin-2-yl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is selected from 2-quinolinyl and 2-benzimidazolyl.
  • Z is selected from 2-quinolinyl and 5-methylpyridin-2-yl.
  • Z is selected from 2-quinolinyl and 3,5-dimethylpyridin-2-yl.
  • Z is selected from 2-quinolinyl and 6-fluoroquinolin-2-yl.
  • Z is 2-quinolinyl
  • Z is heteroaryl consisting of 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two; said ring is optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is heteroaryl consisting of 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two.
  • Z is pyridinyl optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
  • Z is 2-pyridinyl optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro.
  • any Z is substituent may be unsubstituted.
  • a is selected from cycloalkyl and alkyl .
  • Ri a is cycloalkyl. %
  • Ri 3 is alkyl
  • R1 a is fully saturated C 1 -C 4 alkyl.
  • R 1b is selected from cycloalkyl and alkyl .
  • R 1b is cycloalkyl
  • R 1b is alkyl .
  • Rib is fully saturated C1-C4 alkyl.
  • each R 2 is independently selected from cycloalkyl, alkyl or two R2 groups taken together form a 3-6 membered cycloalkyl ring.
  • each R 2 is independently selected from cycloalkylalkyl and alkoxyalkyl.
  • each R 2 is independently selected from cycloalkyl and alkyl. In another embodiment, each R 2 is independently selected from cycloalkyl.
  • each R 2 is independently selected from alkyl.
  • each R 2 is independently selected from fully saturated Ci-C 4 alkyl.
  • two R 2 groups taken together form a 3-6 membered cycloalkyl ring.
  • two R 2 groups taken together form a three membered ring.
  • R3 and R 4 are independently selected from C 1 -C 4 alkyl or R3 and R 4 taken together form a C3-C6 cycloalkyl ring.
  • R3 and R 4 are independently selected from C 1 -C 4 alkyl and cycloalkyl.
  • R 3 and R 4 are independently selected from C 1 -C 4 alkyl and CF3.
  • R 3 and R 4 are Ci-C 4 alkyl.
  • R 3 and R 4 are methyl.
  • R 5 is selected from cycloalkylalkyl and alkoxyalkyl.
  • R 5 is cycloalkyl. In another embodiment, R 5 is alkyl.
  • R 5 is selected from cycloalkyl and alkyl.
  • n 1
  • n is 2.
  • R 7 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and alkoxyalkyl.
  • R 7 is selected from alkyl, cycloalkyl, cycloalkylalkyl and alkoxyalkyl.
  • R 7 is selected from hydrogen, alkyl, cycloalkyl and cycloalkylalkyl.
  • R7 is selected from alkyl, cycloalkyl and cycloalkylalkyl.
  • R 7 is selected from cycloalkyl and cycloalkylalkyl.
  • R 7 is selected from alkyl and cycloalkyl.
  • R 7 is alkyl
  • R 7 is cycloalkyl
  • R 7 is cycloalkylalkyl.
  • R 7 is hydrogen.
  • Compounds of the disclosure may contain asymmetric centers and exist as different enantiomers or diastereomers or a combination of these therein. All enantiomeric, diastereomeric forms of Formulas (I), (II) and (III) are embodied herein.
  • compositions in the disclosure may be in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids.
  • Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc.
  • Salts derived from organic bases include ammonia, primary, secondary and tertiary amines, and amino acids.
  • Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric, hydrobromic.
  • Salts derived from organic acids include Ci -6 alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, proprionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as ⁇ ra-tolouene sulfonic acid and benzene sulfonic acid.
  • Compounds in the disclosure may be in the form of a solvate. This occurs when a compound of Formulas (I) or (II) or (III) has an energetically favorable interaction with a solvent, crystallizes in a manner that it incorporates solvent molecules into the crystal lattice or a complex is formed with solvent molecules in the solid or liquid state.
  • solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone.
  • Polymorphism is the ability of a substance to exist in two or more crystalline phases that have different arrangements and/or conformations of the molecule in the crystal lattice.
  • Compounds in the disclosure may exist as isotopically labeled compounds of Formulas (I) or (II) or (III) where one or more atoms are replaced by atoms having the same atomic number but a different atomic mass from the atomic mass which is predominantly seen in nature.
  • isotopes include, but are not limited to hydrogen isotopes (deuterium, tritium), carbon isotopes ( 11 C, 13 C, 14 C) and nitrogen isotopes ( 13 N, 15 N).
  • substitution with heavier isotopes such as deuterium ( 2 H) may offer certain therapeutic advantages resulting from greater metabolic stability which could be preferable and lead to longer in vivo half-life or dose reduction in a mammal or human.
  • Prodrugs of compounds embodied by Formulas (I) or (II) or (III) are also within the scope of this disclosure. Particular derivatives of compounds of Formulas (I) or (II) or (III) which may have little to negligible pharmacological activity themselves, can, when administered to a mammal or human, be converted into compounds of Formulas (I) or (II) or (III) having the desired biological activity.
  • Compounds in the disclosure and their pharmaceutically acceptable salts, prodrugs, as well as metabolites of the compounds may also be used to treat certain eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders, diabetes, metabolic syndrome, neurodegenerative disorders and CNS disorders/conditions as well as in smoking cessation treatment.
  • the treatment of CNS disorders and conditions by the compounds of the disclosure can include Huntington's disease, schizophrenia and schizo-affective conditions, delusional disorders, drug-induced psychoses, panic and obsessive compulsive disorders, post-traumatic stress disorders, age-related cognitive decline, attention deficit/hyperactivity disorder, bipolar disorders, personality disorders of the paranoid type, personality disorders of the schizoid type, psychosis induced by alcohol, amphetamines, phencyclidine, opioids hallucinogens or other drug-induced psychosis, dyskinesia or choreiform conditions including dyskinesia induced by dopamine agonists, dopaminergic therapies, psychosis associated with Parkinson's disease, psychotic symptoms associated with other neurodegenerative disorders including Alzheimer's disease, dystonic conditions such as idiopathic dystonia, drug-induced dystonia, torsion dystonia, and tardive dyskinesia, mood disorders including major depressive episodes, post-stroke depression, minor depressive disorder, premen
  • compounds of the disclosure may be used for the treatment of eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders as well as in smoking cessation treatment.
  • compounds of the disclosure may be used for the treatment of obesity, schizophrenia, schizo-affective conditions, Huntington's disease, dystonic conditions and tardive dyskinesia.
  • compounds of the disclosure may be used for the treatment of schizophrenia, schizo-affective conditions, Huntington's disease and obesity.
  • compounds of the disclosure may be used for the treatment of schizophrenia and schizo-affective conditions.
  • compounds of the disclosure may be used for the treatment of Huntington's disease.
  • compounds of the disclosure may be used for the treatment of obesity and metabolic syndrome.
  • Compounds of the disclosure may also be used in mammals and humans in conjuction with conventional antipsychotic medications including but not limited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol, Aripiprazole, Sertindole and Quetiapine.
  • conventional antipsychotic medications including but not limited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol, Aripiprazole, Sertindole and Quetiapine.
  • the combination of a compound of Formula (I) or (II) or (III) with a subtherapeutic dose of an aforementioned conventional antipsychotic medication may afford certain treatment advantages including improved side effect profiles and lower dosing requirements.
  • Alkyl is meant to denote a linear or branched saturated or unsaturated aliphatic Ci-C 8 hydrocarbon which can be optionally substituted with up to 3 fluorine atoms. Unsaturation in the form of a double or triple carbon-carbon bond may be internal or terminally located and in the case of a double bond both cis and trans isomers are included. Examples of alkyl groups include but are not limited to methyl, trifluoromethyl, ethyl, trifluoroethyl, isobutyl, neopentyl, cis- and trans- 2-butenyl, isobutenyl, propargyl. C 1 -C 4 alkyl is the subset of alkyl limited to a total of up to 4 carbon atoms.
  • C x -Cy includes all subsets, e.g., Ci -C 4 includes C 1 -C 2 , C 2 - C 4 , C 1 -C3 etc.
  • Acyl is an alkyl-C(O)- group wherein alkyl is as defined above.
  • Examples of acyl groups include acetyl and proprionyl.
  • Alkoxy is an alkyl-O- group wherein alkyl is as defined above.
  • C 1 -C 4 alkoxy is the subset of alkyl-O- where the subset of alkyl is limited to a total of up to 4 carbon atoms.
  • alkoxy groups include methoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxy
  • Alkoxyalkyl is an alkyl-O-(Ci-C 4 alkyl)- group wherein alkyl is as defined above.
  • alkoxyalkyl groups include methoxymethyl and ethoxymethyl.
  • Alkoxyalkyloxy is an alkoxy-alkyl-O- group wherein alkoxy and alkyl are as defined above.
  • alkoxyalkyloxy groups include methoxymethyloxy (CH3OCH 2 O-) and methoxyethyloxy (CH 3 OCH 2 CH 2 O-) groups.
  • Alkylthio is alkyl— S- group wherein alkyl is as defined above.
  • Alkylsulfonyl is alkyl-SO2- wherein alkyl is as defined above.
  • Alkylamino is alkyl-NH- wherein alkyl is as defined above.
  • Dialkylamino is (alkyl>2-N- wherein alkyl is as defined above.
  • Alkylamido is alkyl-NHC(O)- wherein alkyl is as defined above.
  • Dialkylamido is (alkyl) 2 -NC(0)- wherein alkyl is as defined above.
  • Aromatic is heteroaryl or aryl wherin heteroaryl and aryl are as defined below.
  • Aryl is a phenyl or napthyl group.
  • Aryl groups may be optionally and independently substituted with up to three groups selected from halogen, CF 3 , CN, NO 2 , OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, -OCH 2 CH 2 OCH 3 , -OC(O)R a , -OC(O)OR a -OC(O)NHR a , -OC(O)N(R a ), -SR a , -S(O)R a , -NH 2 , -NHR a , -N(R a )(R b ), -NHC(O)R a ,
  • Aryloxy is an aryl-O- group wherein aryl is as defined above.
  • Arylalkoxy is an aryl -(Ci -C 4 alky I)-O- group wherein aryl is as defined above.
  • Carboxy is a CO 2 H or CO 2 R c group wherein R 0 is independently chosen from, alkyl, Ci- C4 alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl, CF 3 , and alkoxyalkyl, wherein alkyl is as defined above.
  • Cycloalkyl is a C 3 -C 7 cyclic non-aromatic hydrocarbon which may contain a single double bond and is optionally and independently substituted with up to three groups selected from alkyl, alkoxy, hydroxyl and oxo.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.
  • Cycloalkyloxy is a cycloalkyl-O- group wherein cycloalkyl is as defined above. Examples include cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. C 3 -C O cycloalkyloxy is the subset of cycloalkyl-O- where cycloalkyl contains 3-6 carbon atoms.
  • Cycloalkylalkyl is a cycloalkyl-(Ci -C 4 alkyl)- group. Examples include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl.
  • Cycloalkylalkoxy is a cycloalkyl-(Cj-C 4 alkyl)-O- group wherein cycloalkyl and alkyl are as defined above.
  • Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclopentylmethoxy and cyclohexylmethoxy.
  • Halogen is F, Cl, Br or I.
  • Heteroaryl is a tetrazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, a mono or bicyclic aromatic ring system, or a heterobicyclic ring system with one aromatic ring having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C.
  • heteroaryl groups include but are not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl, imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyl and benzimidazolyl.
  • Heteroaryl groups may be optionally and independently substituted with up to 3 substituents independently selected from halogen, CF 31 CN, NO 2 , OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, -OCH 2 CH 2 OCH 31 -OC(O)R a1 -OC(O)OR a1 -OC(O)NHRa, -OC(O)N(R 3 ), -SR 2 , -S(O)R 3 , -NH 2 , -NHR 3 , -N(R 3 )(Rb), -NHC(O)R 3 , -N(R 8 )C(O)Rb, -NHC(O)OR 3 , -N(
  • Heteroarylalkyl is a heteroaryKCi-C t alkyl)- group wherein heteroaryl and alkyl are as defined above.
  • heteroarylalkyl groups include 4-pyridinylmethyl and 4- pyridinylethyl.
  • Heteroaryloxy is a heteroaryl-0 group wherein heteroaryl is as defined above.
  • Heteroarylalkoxy is a heteroaryl-(Ci-C 4 alkyl)-O- group wherein heteroaryl and alkoxy are as defined above.
  • heteroarylalkyl groups include 4-pyridinylmethoxy and 4-pyridinylethoxy.
  • Heterobicyclic ring system is a ring system having 8-10 atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than carbon and provided that at least one of the rings is aromatic; said bicyclic ring may be optionally and independently substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, C 3 -C 6 cycloalkyloxy, cycloalkylalkyl, halogen, nitro, alkylsulfonyl and cyano.
  • Examples of 8-10 membered heterobicyclic ring systems include but are not limited to 1,5-naphthyridyl, l,2,3,4-tetrahydro-l,5-naphthyridyl 1,6- naphthyridyl , l,2,3,4-tetrahydro-l,6-naphthyridyl 1,7-naphthyridyl, 1,2,3,4-tetrahydro- 1,7-naphthyridinyl 1,8-naphthyridyl, l,2,3,4-tetrahydro-l,8-naphthyridyl, 2,6- naphthyridyl , 2,7-naphthyridyl, cinnolyl , isoquinolyl , tetrahydroisoquinolinyl, phthalazyl , quinazolyl , 1,2,3,4-tetrahydroqui
  • Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated or partially unsaturated ring system comprising 5-10 ring atoms selected from C, N, O and S, provided that not more than 2 ring atoms in any single ring are other than C.
  • the nitrogen may be substituted with an alkyl, acyl, -C(O)O-alkyl, -C(O)NH(alkyl) or a -C(O)N(alkyl) 2 group.
  • Heterocycloalkyl groups may be optionally and independently substituted with hydroxy, alkyl and alkoxy groups and may contain up to two oxo groups.
  • Heterocycloalkyl groups may be linked to the rest of the molecule via either carbon or nitrogen ring atoms.
  • heterocycloalkyl groups include tetrahydrofuranyl, tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl, pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl, thiomorpholin-3-one, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydro-lH-pyrido[l,2-a]pyrazine, 3-thia-6- azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[
  • Heterocycloalkylalkyl is a heterocycloalkyl-(Ci-C4 alkyl)- group wherein heterocycloalkyl is as defined above.
  • Heterocycloalkyloxy is a heterocycloalkyl-O- group wherein heterocycloalkyl is as defined above.
  • Heterocycloalkylalkoxy is a heterocycloalkyl-(Ci-C 4 alkyl)-0- group wherein heterocycloalkyl is as defined above.
  • Oxo is a -C(O)- group.
  • Phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF 3 CN, NO 2 , OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, -OCH 2 CH 2 OCH 31 -OC(O)Ra 1 -OC(O)ORa, -OC(O)NHR 3 , -OC(O)N(R 3 ), -SR 3 , -S(O)R 3 , -NH 2 , -NHR 3 , -N(Ra)(Rb), -NHC(O)R 3 , -N(R 9 )C(O)Rb, -NHC(O)OR 3 ,
  • Restricted phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF 3 CN, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, -OCH 2 CH 2 OCH 3 , -OC(O)R 3 , -OC(O)OR 3 , -OC(O)N(R 3 ), -N(R 3 )(Rb), -NHC(O)R 3 , -N(R 8 )C(O)Rb, -NHC(O)OR 3 , -N(R a )C(O)OR b , - C(O)N(R 3 )(R b ), -COR 3 wherein R 3 and R b are independently chosen from alkyl, alkoxyalkyl, -CH 2 CH 2
  • PhNTf 2 1 1,1 -trifluoro-N-phenyl-N-
  • the 1,2 disubstituted heterocyclic compounds of Formula I may be prepared from multi-step organic synthesis routes from commercially available starting materials by one skilled in the art of organic synthesis using established organic synthetic procedures.
  • Non-commercially available phenyl acetic acids can be made from commercially available starting materials via methods known by one skilled in the art of organic synthesis. Such methods include synthesis from the corresponding aryl acids via. the Wolff rearrangement using diazomethane.
  • HET HET
  • A3, A5, A7, A8, A9, AH, A 15, A 16, A 18, A 19, A24, A29, A30, A31, A35 and A39 may be prepared generally as depicted in Schemes 1-18 below.
  • Compounds of the disclosure where HET is Al, A2, A4, A6, AlO, Al l, A12, A13, A17, A20, A21, A22, A23, A25, A26, A32, A33, A34, A36, A37, A38, A40, A41 and A42 may be prepared by methods known to one skilled in the art of organic synthesis.
  • Reactive groups not involved in the above processes can be protected with standard protecting groups during the reactions and removed by standard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley-Interscience) known to those of ordinary skill in the art.
  • Presently preferred protecting groups include methyl, benzyl, MEM, acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC, Cbz, trifluoroacetamide and benzyl for the amino moiety, methyl, ethyl, tert-buty] and benzyl esters for the carboxylic acid moiety.
  • the reaction mixture was quenched with HCl (1 N), aqueous layer was basified with NaHCO 3 solution and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water, dried over Na 2 SO 4 and concentrated in vacuo to obtain the crude product.
  • the crude product was purified via silica gel column chromatography eluting with 25% EtOAc in hexanes to afford 4- (pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl) furan-2(5H)-one (600 mg, 15 %) as a solid.
  • the reaction mixture was re fluxed for 3 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography to afford 2, 2-dimethyl-5- (pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (0.29 g, 74 %) as a solid.
  • reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain crude material.
  • the crude material was purified via silica gel column chromatography eluting with 5 % EtOAc in hexanes to afford 1 -(4-methoxyphenyl)-4-methylpent-2-yne- 1, 4-diol (6.3 g, 78 %) as an oil.
  • the reaction mixture was refluxed for 3 h, filtered through a pad of Celite®.
  • the filtrate was diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL), dried over Na 2 SO ⁇ filtered and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography to afford 5-(4-methoxyphenyl) -2, 2-dimethyl- 4-(4-(quinolin-2- ylmethoxy) phenyl) furan-3(2H)-one (2.3 g, 74 %) as solid.
  • reaction mixture was then quenched with a saturated NH4CI solution and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (30% ethyl acetate in hexanes) to afford 4-methyl-l -(4-nitrophenyl) pent-2-yne-l, 4-diol (8 g, 65 %) as a yellow solid.
  • the reaction mixture was quenched with a saturated NH 4 Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography eluting with 5-7 % EtOAc in hexanes to afford l-(4- chlorophenyl)-4-methyl-4-(trimethylsilyloxy) pent-2-yn-l-one (3.8 g, 57 %) as a light green oil.
  • the reaction mixture was quenched with a saturated NH 4 Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried OVCr Na 2 SO 4 , filtered, and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography eluting with 15 % EtOAc in hexanes to afford 4-(4- methyl-4-(trimethylsilyloxy) pent-2-ynoyl) benzonitrile (3.8 g, 68 %) as a yellow oil.
  • reaction mixture was stirred for 30 min at -78 °C, and then a solution of N-methoxy -N- methylbenzo[c][l,2,5]oxadiazole-5-carboxamide (0.557 g, 3.550 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at -78 0 C.
  • the reaction mixture was quenched with a saturated NH 4 Cl solution and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product.
  • the reaction mixture was quenched with a saturated NH 4 Cl solution and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography eluting with 5 % EtOAc in hexanes to afford 2- methoxy-5-(4-methyl-4-(trirnethylsilyloxy) pent-2-ynoyl) benzonitrile (0.8 g, 56%) as a pale yellow oil.
  • the reaction mixture was then quenched with a saturated NH 4 Cl solution and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography eluting with 2-4 % EtOAc in hexanes to afford l-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-l, 4-diol (0.69 g, 26%) as a yellow syrup.
  • reaction mixture was quenched with a saturated NH 4 Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (80 mL), brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated
  • 6-Fluoro-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline may be prepared in manner analogous to 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline using 2-(chloromethyl)-6-fluoroquinoline instead of 2- (chloromethyl)quinoline.
  • 5-Methyl-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine may be prepared in a manner analogous to 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-
  • 3,5-Dimethyl-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy) methyl)pyridine may be prepared in a manner analogous to 2-((4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline using 2-(chloromethyl)-3,5- dimethylpyridine instead of 2-(chloromethyl)quinoline.
  • reaction mixture was quenched with a saturated NH4CI solution and extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography eluting with 5 % EtOAc in Hexane to afford 1- (pyridin-4-yl)-3-(l-(trimethylsilyloxy) cyclopentyl) prop-2-yn-l -one (1.0 g, 32%) as an oil.
  • reaction mixture was cooled to RT, and the volatiles were evaporated in vacuo to obtain the crude product.
  • the crude product was extracted in EtOAc (25 mL), washed with water (2 x 10 mL), brine and dried over anhydrous Na 2 SO,). After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford 5-(4-aminophenyl)-2, 2-dimethyl-4-(4- (quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (400 mg, 71%), as a yellow solid.
  • Example 819 N-acetyl-N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2- ⁇ imethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)acetamide, (30 mg, 18 .0%) as an off white solid
  • the reaction mixture was quenched with a saturated NH 4 CI solution and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product.
  • the crude material was purified via silica gel column chromatography eluting with 2-4 % EtOAc in Hexane to afford 4-methyl-l- (thiazol-4-yl)-4-(trimethylsilyloxy) pent-2-yn-l-one (0.15 g, 31.44 %) as an oil.

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Abstract

1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10 are described. Also described are processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. Among the disorders which may be treated are neurological, neurodegenerative and psychiatric disorders including, but not limited to, those associated with cognitive deficits or schizophrenic symptoms.

Description

1,2-Disubstituted Heterocyclic Compounds
The disclosure relates to 1,2-disubstituted heterocyclic compounds which are inhibitors of phosphodiesterase 10. The disclosure further relates to processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of mammals, including human(s) for central nervous system (CNS) disorders and other disorders which may affect CNS function. The disclosure also relates to methods for treating neurological, neurodegenerative and psychiatric disorders including but not limited to those comprising cognitive deficits or schizophrenic symptoms.
Background
Cyclic phosphodiesterases are intracellular enzymes which, through the hydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels of these mono phosphate nucleotides which serve as second messengers in the signaling cascade of G- protein coupled receptors. In neurons, PDEs also play a role in the regulation of downstream cGMP and cAMP dependent kinases which phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis. To date, eleven different PDE families have been identified which are encoded by 21 genes. The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS.
The discovery of a new PDE family, PDElO, was reported simultaneously by three groups in 1999 (Soderling et al. "Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDElOA" Proc. Natl Sci. 1999, 96, 7071-7076; Loughney et al. "Isolation and characterization of PDElOA, a novel human 3', 5'-cyclic nucleotide phosphodiesterase" Gene 1999, 234, 109-1 17; Fujishige et al. "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDElOA)1V. Biol. Chem. 1999, 274, 18438-18445). The human PDElO sequence is highly homologous to both the rat and mouse variants with 95% amino acid identity overall, and 98% identity conserved in the catalytic region.
PDElO is primarily expressed in the brain (caudate nucleus and putamen) and is highly localized in the medium spiny neurons of the striatum, which is one of the principal inputs to the basal ganglia. This localization of PDEl O has led to speculation that it may influence the dopaminergic and glutamatergic pathways both which play roles in the pathology of various psychotic and neurodegenerative disorders.
PDElO hydrolyzes both cAMP (Km= 0.05 uM) and cGMP (Km= 3uM) (Soderling et al. "Isolation and Characterization of a dual-substrate phosphodiesterase gene family: PDElO." Proc. Natl ScL USA 1999, 96(12), 7071-7076). In addition, PDElO has a fivefold greater Vmax for cGMP than for cAMP and these in vitro kinetic data have lead to the speculation that PDElO may act as a cAMP-inhibited cGMP phosphodiesterase in vivo (Soderling and Beavo "Regulation of cAMP and cGMP signaling: New phosphodiesterases and new functions," Curr. Opin. Cell Biol., 2000, 12, 174-179).
PDElO is also one of five phosphodiesterase members to contain a tandem GAF domain at their N-terminus. It is differentiated by the fact that the other GAF containing PDEs (PDE2, 5, 6, and 1 1) bind cGMP while recent data points to the tight binding of c AMP to the GAF domain of PDElO (Handa et al. "Crystal structure of the GAF-B domain from human phosphodiesterase 1OA complexed with its ligand, cAMP" J. Biol. Chem. 2008, May 13th, ePub).
PDElO inhibitors have been disclosed for the treatment of a variety of neurological and psychiatric disorders including Parkinson's disease, schizophrenia, Huntington's disease, delusional disorders, drug-induced psychoses, obsessive compulsive and panic disorders (US Patent Application 2003/0032579). Studies in rats (Kostowski et. al "Papaverine drug induced stereotypy and catalepsy and biogenic amines in the brain of the rat" Pharmacol. Biochem. Behav. 1976, 5, 15-17) have showed that papaverine, a selective PDElO inhibitor, reduces apomorphine induced stereotypies and rat brain dopamine levels and increases haloperidol induced catalepsy. This experiment lends support to the use of a PDElO inhibitor as an antipsychotic since similar trends are seen with known, marketed antipsychotics. Antipsychotic medications are the mainstay of current treatment for schizophrenia. Conventional or classic antipsychotics, typified by haloperidol, were introduced in the mid-1950s and have a proven track record over the last half century in the treatment of schizophrenia. While these drugs are effective against the positive, psychotic symptoms of schizophrenia, they show little benefit in alleviating negative symptoms or the cognitive impairment associated with the disease. In addition, drugs such as haloperidol have extreme side effects such as extrapyramidal symptoms (EPS) due to their specific dopamine D2 receptor interaction. An even more severe condition characterized by significant, prolonged, abnormal motor movements known as tardive dyskinesia also may emerge with prolonged classic antipsychotic treatment.
The 1990s saw the development of several new drugs for schizophrenia, referred to as atypical antipsychotics, typified by risperidone and olanzapine and most effectively, clozapine. These atypical antipsychotics are generally characterized by effectiveness against both the positive and negative symptoms associated with schizophrenia, but have little effectiveness against cognitive deficiencies and persisting cognitive impairment remain a serious public health concern (Davis, J.M et al. "Dose response and dose equivalence of antipsychotics." Journal of Clinical P sychopharmacology, 2004, 24 (2), 192-208; Friedman, J.H. et al "Treatment of psychosis in Parkinson's disease: Safety considerations." Drug Safety, 2003, 26 (9), 643-659). In addition, the atypical antipsychotic agents, while effective in treating the positive and, to some degree, negative symptoms of schizophrenia, have significant side effects. For example, clozapine which is one of the most clinically effective antipsychotic drugs shows agranulocytosis in approximately 1.5% of patients with fatalities due to this side effect being observed. Other atypical antipsychotic drugs have significant side effects including metabolic side effects (type 2 diabetes, significant weight gain, and dyslipidemia), sexual dysfunction, sedation, and potential cardiovascular side effects that compromise their clinically effectiveness. In the large, recently published NIH sponsored CATIE study, (Lieberman et al "The Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome." Schizophrenia Research, 2005, 80 (1), 9-43) 74% of patients discontinued use of their antipsychotic medication within 18 months due to a number of factors including poor tolerability or incomplete efficacy. Therefore, a substantial clinical need still exists for more effective and better tolerated antipsychotic mediations possibly through the use of PDElO inhibitors.
Brief Summary
Described herein are 1 ,2-disubstituted heterocyclic compounds of Formulas (I), (II) or (III) that are inhibitors of at least one phosphodiesterase 10 (e.g., human PDE-IOA):
Figure imgf000005_0001
(I) (H) (III)
Wherein:
HET is a heterocyclic ring selected from Formulas A1-A26 and A29-42 below
Figure imgf000005_0002
A1 A2 A3 A4 A5 A6
Figure imgf000005_0003
A7 A8 A9 A10 A11 A12
Figure imgf000006_0001
A13 A14 A15 A16 A17 A18
Figure imgf000006_0002
A19 A20 A21 A22 A23 A24
Figure imgf000006_0003
A25 A26
Figure imgf000006_0004
A31 A32 A33 A34 A35 A36
Figure imgf000006_0005
A37 A38 A39 A40 A41 A42
and the left most radical is connected to the X group;
W is selected from halogen, cyano, nitro, alkoxy, amino, alkylamino, dialkylamino, carboxy, amido, alkylamido, and dialkylamido; X is selected from C3-C8 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;
Y is a bond or a divalent linker group selected from -CH2-, -0-, -SO2-, -CH2O-, -OCH2- and -CH2CH2- with the rightmost radical of the Y group connected to the Z substituent;
Z is optionally substituted heteroaryl;
Ri a is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;
Rib is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;
Each R2 is independently selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl; or two R2 groups taken together form a 3-6 membered cycloalkyl ring;
R3 and R4 are independently selected from CpC4 alkyl, CF3, optionally substituted cycloalkyl; or R3 and R4 taken together form a 3-6 membered cycloalkyl ring;
R5 is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;
n is independently selected from 1 and 2;
R7 is selected from hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl; In one embodiment, alkyl groups are fully saturated whether present on their own or as part of another group (e.g., alkylamino).
In certain embodiments, substituent groups are not further substituted. In other embodiements, substituent groups are not further substituted.
In various embodiments, any group that is defined as being optionally substituted can be independently singly or multiply optionally substituted.
In varius embodiments, a group that is defined as being optionally substituted is not substituted.
In one embodiment, a compound of Formula (I) is selected.
In another embodiment, a compound of Formula (II) is selected.
In another embodiment, a compound of Formula (III) is selected.
In one embodiment, HET is selected from Formulas Al, A2, A7, A8, AH, A15, A19, A25, A29, A30, A31, A32, A35, A37, A38, A39, A40.
In one embodiment, HET is selected from Formulas A7, A8, A25, A29, A30, A31, A32, A35, A37 and A38.
In another embodiment, HET is selected from Formulas A7, A8, A25, A29, A30, A35, A37 and A38.
In another embodiment, HET is selected from Formulas A7, A8, A17 A18, A25, A29, A30 and A34. In a further embodiment, HET is selected from Formulas Al, A2, A7, A8, A 14, A 15 and A19.
In another embodiment, HET is selected from Formulas A5, A6, A9 AlO, A20 and A24. In an additional embodiment, HET is selected from Formulas Al, A2, A7 and A8. In another embodiment, HET is selected from Formulas A22, A23, A25 and A26. In another embodiment, HET is selected from Formulas A29, A30, A31 and A32. In another embodiment, HET is selected from Formulas A7, A8, A29 and A30. In another embodiment, HET is selected from Formulas A25, A26, A35 and A36. In another embodiment, HET is selected from Formulas A25, A29, A35 and A38. In a further embodiment, HET is selected from Formulas A7, A8, A29 and A31. In another embodiment, HET is selected from Formulas A29, A31, A37 and A38. In another embodiment, HET is selected from Formulas A25, A35, A37 and A38. In another embodiment, HET is selected from Formulas A25, A29, A30 and A35. In another embodiment, HET is selected from Formulas A7 and A8. In another embodiment, HET is selected from Formulas A25 and A26. In another embodiment, HET is selected from Formulas A29 and A30. In another embodiment, HET is selected from Formulas A35 and A36.
In another embodiment, HET is selected from Formulas A29 and A31.
In a further embodiment, HET is selected from Formulas A31 and A32.
In another embodiment, HET is selected from Formulas A37 and A38.
In another embodiment, HET is Formula Al.
In another embodiment, HET is Formula A2.
In another embodiment, HET is Formula A3.
In another embodiment, HET is Formula A4.
In another embodiment, HET is Formula A5.
In another embodiment, HET is Formula A6.
In another embodiment, HET is Formula A7.
In another embodiment, HET is Formula A8.
In another embodiment, HET is Formula A9.
In another embodiment, HET is Formula AlO.
In another embodiment, HET is Formula Al l.
In another embodiment, HET is Formula A 12. In another embodiment, HET is Formula A13. In another embodiment, HET is Formula A 14. In another embodiment, HET is Formula Al 5. In another embodiment, HET is Formula A 16. In another embodiment, HET is Formula Al 7. In another embodiment, HET is Formula A 18. In another embodiment, HET is Formula A 19. In another embodiment, HET is Formula A20. In another embodiment, HET is Formula A21. In another embodiment, HET is Formula A22. In another embodiment, HET is Formula A23. In another embodiment, HET is Formula A24. In another embodiment, HET is Formula A25. In another embodiment, HET is Formula A26. In another embodiment, HET is Formula A29. In another embodiment, HET is Formula A30.
In another embodiment, HET is Formula A31.
In another embodiment, HET is Formula A32.
In another embodiment, HET is Formula A33.
In another embodiment, HET is Formula A34.
In another embodiment, HET is Formula A35.
In another embodiment, HET is Formula A36.
In another embodiment, HET is Formula A37.
In another embodiment, HET is Formula A38.
In another embodiment, HET is Formula A39.
In another embodiment, HET is Formula A40.
In another embodiment, HET is Formula A41.
In another embodiment, HET is Formula A42.
In one embodiment, W is selected from nitro, carboxy, amido, alkylamido, and dialkylamido.
In another embodiment, W is selected from amino, alkylamino and dialkylamino. In another embodiment, W is selected from halogen, cyano and alkoxy.
In an additional embodiment, W is selected from halogen and cyano.
In another embodiment, W is halogen.
In a further embodiment, W is cyano.
In an additional embodiment, W is alkoxy.
In one embodiment, X is selected from C3-C8 alkyl, cycloalkyl and cycloalkylalkyl.
In a further embodiment X is selected from cycloalkyl and cycloalkylalkyl. Examples include, but are not limited to, cyclohexyl and cyclohexylmethyl.
In another embodiment X is C3-C8 alkyl. Examples include, but are not limited to, isopropyl, t-butyl and isopentyl.
In an additional embodiment, X is heterocycloalkyl.
In a further embodiment X is heterocycloalkyl having only 6 ring atoms. Examples include, but are not limited to, morpholinyl, piperidinyl, piperazinyl N-Me-piperazinyl and pyranyl.
In another embodiment X is heterocycloalkyl having only 5 ring atoms. Examples include, but are not limited to, tetrahydrofuranyl and pyrrolidinyl.
In another embodiment, X is a heterocycloalkyl group selected from Formulas B1-B16 depicted below:
Figure imgf000014_0001
B1 B2 B3 B4
Figure imgf000014_0002
Figure imgf000014_0003
B9 B10 B11 B12
Figure imgf000014_0004
B13 B14 B15 B16
wherein R6 is selected from hydrogen and Cj-Cβ alkyl, C3-C6 cycloalkyl and C4-C7 cycloalkylalkyl, all of which can be optionally substituted.
In another embodiment X is selected from morpholinyl, pyranyl and tetrahydrofuranyl.
In another embodiment X is selected from morpholinyl (having Formula Bl) and 4-pyranyl (having Formula B2).
In another embodiment X is heteroaryl.
In another embodiment, X is selected from a monocyclic aromatic ring having 5 ring atoms selected from C, O, S and N provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur, and a monocyclic aromatic ring having 6 atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from Ci-C4 alkyl, cycloalkyl, cycloalkyloxy, Ci- C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro. Examples include but are not limited to lH-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3, 5-oxatriazolyl, 1,2,3,4-thiatriazolyl, 1 ,2,3,5-thiatriazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
In a further embodiment, X is a monocyclic aromatic ring having 6 ring atoms selected from C and N provided that not more than 3 ring atoms are N, and where said ring may be optionally and independently substituted with up to two groups selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy,-alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro. Examples include but are not limited to 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
In a further embodiment, X is a monocyclic aromatic ring having 5 ring atoms selected from C, O, S, and N, provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms is oxygen or sulfur and where said ring may be optionally and independently substituted with up to two groups selected from Ci-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro. Examples include but are not limited to lH-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, 1,2,3,4-oxatriazolyl, 1,2,3, 5-oxatriazolyl, 1 ,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl. In a further embodiment, X is selected from 2-pyridinyl, 3-pyridinyl and 4-pyridinyl optionally substituted with one group selected from C|-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C|-C4 alkoxy, CF3, amino, alkylamino, dialkylamino, thioalkyl, halogen and cyano.
In a further embodiment, X is 3-pyridinyl optionally substituted with one group selected from Ci-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, Ci-C4 alkoxy, CF3, amino, alkylamino, dialkylamino, thioalkyl, halogen and cyano.
In a further embodiment, X is 4-pyridinyl optionally substituted with one group selected from Ci-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C1-C4 alkoxy, CF3, amino, alkylamino, dialkylamino, thioalkyl, halogen and cyano.
In a further embodiment, X is selected from 3-pyridinyl and 4-pyridinyl.
In a further embodiment, X is 3-pyridinyl.
In another embodiment, X is 2-methoxy-5-pyridinyl.
In a further embodiment, X is 4-pyridinyl.
In another embodiment, X is 2-methoxy-4-pyridinyl.
In another embodiment X is a heterobicyclic ring system.
In another embodiment X is a heterobicyclic ring system where one ring is aromatic.
In a further embodiment, X is a heterobicyclic ring system where both rings are aromatic.
In another embodiment, X is a heterobicyclic ring system containing exactly 9 ring atoms. In another embodiment, X is a heterobicyclic ring system containing exactly 10 ring atoms.
In another embodiment X is selected from benzo[d]oxazoyl, benzo[c][l,2,5]oxadiazyl, benzo[c][l,2,5]thiadiazolyl, benzo[d]isoxazolyl, lH-benzo[d]imidazoyl, benzo[d]thiazoyl, benzo[c]isothiazolyl, benzo[d]isothiazoryl, benzo[c]isoxazolyl, imidazo[l,2-a]pyridinyl and imidazo[l,5-a]pyridinyl
In another embodiment X is selected from benzo[c][l ,2,5]oxadiazyl and benzo[c][l,2,5]thiadiazolyl.
In a further embodiment, X is selected from benzo[d]oxazoyl, lH-benzo[c/]imidazoyl and benzo[d]thiazoyl.
In a further embodiment, X is benzo[d]oxazoyl.
In a further embodiment, X is lH-benzo[d]imidazoyl.
In a further embodiment, X is benzo[d]thiazoyl.
In another embodiment X is benzo[c][l,2,5]oxadiazoyl.
In a further embodiment X is benzo[c][l,2,5]thiadiazolyl
In a further embodiment, X is benzo[d]isoxazolyl.
In another embodiment, X is benzo[d]isothiazolyl.
In another embodiment, X is benzo[c]isothiazolyl.
In another embodiment, X is benzo[c]isoxazolyl. In another embodiment, X is imidazo[l,2-α]pyridinyl.
In another embodiment, X is imidazo[l,5-α]pyridinyl.
In an additional embodiment, X is aryl.
In another embodiment, X is selected from phenyl and pyridinyl.
In a further embodiment, X is phenyl.
In another embodiment, X is phenyl optionally substituted with one or more substituents selected from F, Cl, CN, NO2, CF3, OCF3, OCHF2, CH2CF3 and OMe.
In another embodiment, X is restricted phenyl.
In a further embodiment, X is selected from a 3,4-disubstituted phenyl, 3-substituted phenyl and 4-substituted phenyl.
In another embodiment, X is selected from 3,4-disubstituted phenyl and 4-substituted phenyl.
In another embodiment, X is 3-chloro-4-methoxyphenyl
In another embodiment, X is 3-cyano-4-methoxyphenyl
In a further embodiment, X is 3-chloro-4-difluoromethoxyphenyl
In a further embodiment, X is 3-cyano-4-difluoromethoxyphenyl
In an additional embodiment, X is 4-substituted phenyl. In another embodiment, X is 4-nitrophenyl.
In a further embodiment, X is 4-methoxyphenyl.
In another embodiment, X is 4-chlorophenyl.
In another embodiment, X is 4-cyanophenyl.
In another embodiment, X is 4-trifluoroethylphenyl.
In a further embodiment, X is 4-trifluoromethoxyphenyl.
In a further embodiment, X is 3-substituted phenyl.
In another embodiment, X is 3-nitrophenyl.
In another embodiment, X is 3-trifluoromethoxyphenyl.
In a further embodiment, X is 3-methoxyphenyl.
In another embodiment, X is 3-chlorophenyl.
In another embodiment, X is 3-cyanophenyl.
In another embodiment, X is 3-trifluoroethylphenyl.
In a further embodiment, X is 3-trifluoromethoxyphenyl. In one embodiment, Y is -CH2O- or -OCH2- with the rightmost radical connected to the Z substituent.
In another embodiment, Y is -CH2CH2- with the rightmost radical connected to the Z substituent.
In an additional embodiment, Y is -CH2O- with the rightmost radical connected to the Z substituent.
In a further embodiment, Y is -OCH2- with the rightmost radical connected to the Z substituent.
In one embodiment, Z is selected from heteroaryl having only 6 ring atoms and a heterobicyclic ring system.
In another embodiment, Z is a heterobicyclic ring system.
In another embodiment, Z is a heterobicyclic ring system where one ring is aromatic.
In a further embodiment, Z is a heterobicyclic ring system where both rings are aromatic.
In another embodiment, Z is a heterobicyclic ring system containing exactly 9 ring atoms.
In another embodiment, Z is a heterobicyclic ring system containing exactly 10 ring atoms.
In an additional embodiment, Z is selected from benzimidazolyl, quinolinyl, tetrahydroquinolyl, imidazo[l,2-α]pyridin-2-yl, tetrahydroisoquinolyl, 5-methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl, 6-fluoroquinolyl and isoquinolinyl, all of which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro. In an additional embodiment, Z is selected from benzimidazolyl, quinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and isoquinoHnyl, all of which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro.
In an additional embodiment, Z is selected from quinolinyl, imidazo[l,2-α]pyridin-2-yl, 5- methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl and 6-fluoroquinolin-2-yl, all of which may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
In an additional embodiment, Z is selected from quinolinyl and isoquinoHnyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
In a further embodiment, Z is selected from 2-quinolinyl and 2-benzimidazolyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
In a further embodiment, Z is 2-quinolinyl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
In a further embodiment, Z is 6-fluoroquinolin-2-yl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro. In a further embodiment, Z is 3,5-dimethylpyridin-2-yl substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
In a further embodiment, Z is 5-methylpyridin-2-yl substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
In an additional embodiment, Z is selected from 2-quinolinyl and 2-benzimidazolyl.
In an additional embodiment, Z is selected from 2-quinolinyl and 5-methylpyridin-2-yl.
In an additional embodiment, Z is selected from 2-quinolinyl and 3,5-dimethylpyridin-2-yl.
In an additional embodiment, Z is selected from 2-quinolinyl and 6-fluoroquinolin-2-yl.
In an additional embodiment, Z is 2-quinolinyl.
In another embodiment, Z is heteroaryl consisting of 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two; said ring is optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
In another embodiment, Z is heteroaryl consisting of 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two.
In a further embodiment, Z is pyridinyl optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro. In a further embodiment, Z is 2-pyridinyl optionally substituted with up to 2 substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro.
In a further embodiment, any Z is substituent may be unsubstituted.
In one embodiment, R|a is selected from cycloalkyl and alkyl .
In an additional embodiment, Ria is cycloalkyl. %
In another embodiment, Ri3 is alkyl.
In another embodiment, R1a is fully saturated C1-C4 alkyl.
In one embodiment, R1b is selected from cycloalkyl and alkyl .
In another embodiment, R1b is cycloalkyl.
In a further embodiment, R1b is alkyl .
In another embodiment, Rib is fully saturated C1-C4 alkyl.
In one embodiment, each R2 is independently selected from cycloalkyl, alkyl or two R2 groups taken together form a 3-6 membered cycloalkyl ring.
In another embodiment, each R2 is independently selected from cycloalkylalkyl and alkoxyalkyl.
In an additional embodiment, each R2 is independently selected from cycloalkyl and alkyl. In another embodiment, each R2 is independently selected from cycloalkyl.
In another embodiment, each R2 is independently selected from alkyl.
In another embodiment, each R2 is independently selected from fully saturated Ci-C4 alkyl.
In another embodiment, two R2 groups taken together form a 3-6 membered cycloalkyl ring.
In another embodiment, two R2 groups taken together form a three membered ring.
In one embodiment, R3 and R4 are independently selected from C1-C4 alkyl or R3 and R4 taken together form a C3-C6 cycloalkyl ring.
In another embodiment, R3 and R4 are independently selected from C1-C4 alkyl and cycloalkyl.
In another embodiment, R3 and R4 are independently selected from C1-C4 alkyl and CF3.
In an additional embodiment, R3 and R4 taken together form a C3-C6 cycloalkyl ring.
In an additional embodiment, R3 and R4 taken together form a C3 cycloalkyl ring.
In a further embodiment, R3 and R4 are Ci-C4 alkyl.
In a further embodiment, R3 and R4 are methyl.
In one embodiment, R5 is selected from cycloalkylalkyl and alkoxyalkyl.
In another embodiment, R5 is cycloalkyl. In another embodiment, R5 is alkyl.
In an additional embodiment, R5 is selected from cycloalkyl and alkyl.
In one embodiment n is 1.
In another embodiment n is 2.
In one embodiment, R7 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and alkoxyalkyl.
In another embodiment, R7 is selected from alkyl, cycloalkyl, cycloalkylalkyl and alkoxyalkyl.
In another embodiment, R7 is selected from hydrogen, alkyl, cycloalkyl and cycloalkylalkyl.
In another embodiment, R7 is selected from alkyl, cycloalkyl and cycloalkylalkyl.
In another embodiment, R7 is selected from cycloalkyl and cycloalkylalkyl.
In another embodiment, R7 is selected from alkyl and cycloalkyl.
In another embodiment, R7 is alkyl.
In another embodiment, R7 is cycloalkyl.
In another embodiment, R7 is cycloalkylalkyl.
In a further embodiment, R7 is hydrogen. Compounds of the disclosure may contain asymmetric centers and exist as different enantiomers or diastereomers or a combination of these therein. All enantiomeric, diastereomeric forms of Formulas (I), (II) and (III) are embodied herein.
Compounds in the disclosure may be in the form of pharmaceutically acceptable salts. The phrase "pharmaceutically acceptable" refers to salts prepared from pharmaceutically acceptable non-toxic bases and acids, including inorganic and organic bases and inorganic and organic acids. Salts derived from inorganic bases include lithium, sodium, potassium, magnesium, calcium and zinc. Salts derived from organic bases include ammonia, primary, secondary and tertiary amines, and amino acids. Salts derived from inorganic acids include sulfuric, hydrochloric, phosphoric, hydrobromic. Salts derived from organic acids include Ci-6 alkyl carboxylic acids, di-carboxylic acids and tricarboxylic acids such as acetic acid, proprionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid and citric acid, and alkylsulfonic acids such as methanesulphonic, and aryl sulfonic acids such as ^αra-tolouene sulfonic acid and benzene sulfonic acid.
Compounds in the disclosure may be in the form of a solvate. This occurs when a compound of Formulas (I) or (II) or (III) has an energetically favorable interaction with a solvent, crystallizes in a manner that it incorporates solvent molecules into the crystal lattice or a complex is formed with solvent molecules in the solid or liquid state. Examples of solvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, and acetone.
Compounds in the disclosure may exist in different crystal forms known as polymorphs. Polymorphism is the ability of a substance to exist in two or more crystalline phases that have different arrangements and/or conformations of the molecule in the crystal lattice.
Compounds in the disclosure may exist as isotopically labeled compounds of Formulas (I) or (II) or (III) where one or more atoms are replaced by atoms having the same atomic number but a different atomic mass from the atomic mass which is predominantly seen in nature. Examples of isotopes include, but are not limited to hydrogen isotopes (deuterium, tritium), carbon isotopes (11C, 13C, 14C) and nitrogen isotopes (13N, 15N). For example, substitution with heavier isotopes such as deuterium (2H) may offer certain therapeutic advantages resulting from greater metabolic stability which could be preferable and lead to longer in vivo half-life or dose reduction in a mammal or human.
Prodrugs of compounds embodied by Formulas (I) or (II) or (III) are also within the scope of this disclosure. Particular derivatives of compounds of Formulas (I) or (II) or (III) which may have little to negligible pharmacological activity themselves, can, when administered to a mammal or human, be converted into compounds of Formulas (I) or (II) or (III) having the desired biological activity.
Compounds in the disclosure and their pharmaceutically acceptable salts, prodrugs, as well as metabolites of the compounds, may also be used to treat certain eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders, diabetes, metabolic syndrome, neurodegenerative disorders and CNS disorders/conditions as well as in smoking cessation treatment.
In one embodiment the treatment of CNS disorders and conditions by the compounds of the disclosure can include Huntington's disease, schizophrenia and schizo-affective conditions, delusional disorders, drug-induced psychoses, panic and obsessive compulsive disorders, post-traumatic stress disorders, age-related cognitive decline, attention deficit/hyperactivity disorder, bipolar disorders, personality disorders of the paranoid type, personality disorders of the schizoid type, psychosis induced by alcohol, amphetamines, phencyclidine, opioids hallucinogens or other drug-induced psychosis, dyskinesia or choreiform conditions including dyskinesia induced by dopamine agonists, dopaminergic therapies, psychosis associated with Parkinson's disease, psychotic symptoms associated with other neurodegenerative disorders including Alzheimer's disease, dystonic conditions such as idiopathic dystonia, drug-induced dystonia, torsion dystonia, and tardive dyskinesia, mood disorders including major depressive episodes, post-stroke depression, minor depressive disorder, premenstrual dysphoric disorder, dementia including but not limited to multi-infarct dementia, AIDS-related dementia, and neurodegenerative dementia,
In another embodiment, compounds of the disclosure may be used for the treatment of eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders as well as in smoking cessation treatment.
In a further embodiment, compounds of the disclosure may be used for the treatment of obesity, schizophrenia, schizo-affective conditions, Huntington's disease, dystonic conditions and tardive dyskinesia.
In another embodiment, compounds of the disclosure may be used for the treatment of schizophrenia, schizo-affective conditions, Huntington's disease and obesity.
In a further embodiment, compounds of the disclosure may be used for the treatment of schizophrenia and schizo-affective conditions.
In an additional embodiment, compounds of the disclosure may be used for the treatment of Huntington's disease.
In another embodiment, compounds of the disclosure may be used for the treatment of obesity and metabolic syndrome.
Compounds of the disclosure may also be used in mammals and humans in conjuction with conventional antipsychotic medications including but not limited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol, Aripiprazole, Sertindole and Quetiapine. The combination of a compound of Formula (I) or (II) or (III) with a subtherapeutic dose of an aforementioned conventional antipsychotic medication may afford certain treatment advantages including improved side effect profiles and lower dosing requirements. Definitions
Alkyl is meant to denote a linear or branched saturated or unsaturated aliphatic Ci-C8 hydrocarbon which can be optionally substituted with up to 3 fluorine atoms. Unsaturation in the form of a double or triple carbon-carbon bond may be internal or terminally located and in the case of a double bond both cis and trans isomers are included. Examples of alkyl groups include but are not limited to methyl, trifluoromethyl, ethyl, trifluoroethyl, isobutyl, neopentyl, cis- and trans- 2-butenyl, isobutenyl, propargyl. C1-C4 alkyl is the subset of alkyl limited to a total of up to 4 carbon atoms.
In each case in which a size range for the number of atoms in a ring or chain is disclosed, all subsets are disclosed. Thus, Cx-Cy includes all subsets, e.g., Ci -C4 includes C1-C2, C2- C4, C1-C3 etc.
Acyl is an alkyl-C(O)- group wherein alkyl is as defined above. Examples of acyl groups include acetyl and proprionyl.
Alkoxy is an alkyl-O- group wherein alkyl is as defined above. C1-C4 alkoxy is the subset of alkyl-O- where the subset of alkyl is limited to a total of up to 4 carbon atoms. Examples of alkoxy groups include methoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxy
Alkoxyalkyl is an alkyl-O-(Ci-C4 alkyl)- group wherein alkyl is as defined above. Examples of alkoxyalkyl groups include methoxymethyl and ethoxymethyl.
Alkoxyalkyloxy is an alkoxy-alkyl-O- group wherein alkoxy and alkyl are as defined above. Examples of alkoxyalkyloxy groups include methoxymethyloxy (CH3OCH2O-) and methoxyethyloxy (CH3OCH2CH2O-) groups.
Alkylthio is alkyl— S- group wherein alkyl is as defined above. Alkylsulfonyl is alkyl-SO2- wherein alkyl is as defined above.
Alkylamino is alkyl-NH- wherein alkyl is as defined above.
Dialkylamino is (alkyl>2-N- wherein alkyl is as defined above.
Amido is H2NC(O)-
Alkylamido is alkyl-NHC(O)- wherein alkyl is as defined above.
Dialkylamido is (alkyl)2-NC(0)- wherein alkyl is as defined above.
Aromatic is heteroaryl or aryl wherin heteroaryl and aryl are as defined below.
Aryl is a phenyl or napthyl group. Aryl groups may be optionally and independently substituted with up to three groups selected from halogen, CF3, CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, -OCH2CH2OCH3, -OC(O)Ra, -OC(O)ORa -OC(O)NHRa, -OC(O)N(Ra), -SRa, -S(O)Ra, -NH2, -NHRa, -N(Ra)(Rb), -NHC(O)Ra, -N(Ra)C(O)Rb, -NHC(O)ORa, -N(Ra)C(O)ORb, -N(Ra)C(O)NH(Rb), -N(Ra)C(O)NH(Rb)2, -C(O)NH2, -C(O)NHRa, -C(O)N(Ra)(Rb), -CO2H, -CO2Ra, -CORa wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, -CH2CH2OH, -CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, 'Pr, tBu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon- carbon or carbon-nitrogen or carbon-oxygen single bonds; or R3 and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring. Arylalkyl is an aryl-alkyl- group wherein aryl and alkyl are as defined above.
Aryloxy is an aryl-O- group wherein aryl is as defined above.
Arylalkoxy is an aryl -(Ci -C4 alky I)-O- group wherein aryl is as defined above.
Carboxy is a CO2H or CO2Rc group wherein R0 is independently chosen from, alkyl, Ci- C4 alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl, CF3, and alkoxyalkyl, wherein alkyl is as defined above.
Cycloalkyl is a C3-C7 cyclic non-aromatic hydrocarbon which may contain a single double bond and is optionally and independently substituted with up to three groups selected from alkyl, alkoxy, hydroxyl and oxo. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.
Cycloalkyloxy is a cycloalkyl-O- group wherein cycloalkyl is as defined above. Examples include cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. C3-CO cycloalkyloxy is the subset of cycloalkyl-O- where cycloalkyl contains 3-6 carbon atoms.
Cycloalkylalkyl is a cycloalkyl-(Ci -C4 alkyl)- group. Examples include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl.
Cycloalkylalkoxy is a cycloalkyl-(Cj-C4 alkyl)-O- group wherein cycloalkyl and alkyl are as defined above. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclopentylmethoxy and cyclohexylmethoxy.
Halogen is F, Cl, Br or I.
Heteroaryl is a tetrazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, a mono or bicyclic aromatic ring system, or a heterobicyclic ring system with one aromatic ring having 5 to 10 ring atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than C. Examples of heteroaryl groups include but are not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl, imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyl and benzimidazolyl. Heteroaryl groups may be optionally and independently substituted with up to 3 substituents independently selected from halogen, CF31CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, -OCH2CH2OCH31 -OC(O)Ra1-OC(O)ORa1 -OC(O)NHRa, -OC(O)N(R3), -SR2, -S(O)R3, -NH2, -NHR3, -N(R3)(Rb), -NHC(O)R3, -N(R8)C(O)Rb, -NHC(O)OR3, -N(R3)C(O)ORb, -N(R3)C(O)NH(Rb), -N(R3)C(O)NH(Rb)2, -C(O)NH2, -C(O)NHR8, -C(O)N(R3)(Rb), -CO2H, -CO2R3, -COR3 wherein Ra and Rb are independently chosen from alkyl, alkoxyalkyl, -CH2CH2OH, -CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, 1Pr, 1Bu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon- carbon or carbon-nitrogen or carbon-oxygen single bonds; or R3 and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
Heteroarylalkyl is a heteroaryKCi-Ct alkyl)- group wherein heteroaryl and alkyl are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethyl and 4- pyridinylethyl.
Heteroaryloxy is a heteroaryl-0 group wherein heteroaryl is as defined above.
Heteroarylalkoxy is a heteroaryl-(Ci-C4alkyl)-O- group wherein heteroaryl and alkoxy are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethoxy and 4-pyridinylethoxy. Heterobicyclic ring system is a ring system having 8-10 atoms independently selected from C, N, O and S, provided that not more than 3 ring atoms in any single ring are other than carbon and provided that at least one of the rings is aromatic; said bicyclic ring may be optionally and independently substituted with up to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, C3-C6 cycloalkyloxy, cycloalkylalkyl, halogen, nitro, alkylsulfonyl and cyano. Examples of 8-10 membered heterobicyclic ring systems include but are not limited to 1,5-naphthyridyl, l,2,3,4-tetrahydro-l,5-naphthyridyl 1,6- naphthyridyl , l,2,3,4-tetrahydro-l,6-naphthyridyl 1,7-naphthyridyl, 1,2,3,4-tetrahydro- 1,7-naphthyridinyl 1,8-naphthyridyl, l,2,3,4-tetrahydro-l,8-naphthyridyl, 2,6- naphthyridyl , 2,7-naphthyridyl, cinnolyl , isoquinolyl , tetrahydroisoquinolinyl, phthalazyl , quinazolyl , 1,2,3,4-tetrahydroquinazolinyl, quinolyl , tetrahydroquinolinyl, quinoxalyl, tetrahydroquinoxalinyl, benzo[c(][l,2,3]triazyl, benzo[e][l,2,4]triazyl , pyrido[2,3-b]pyrazyl, pyrido[2,3-c]pyridazyl, pyrido[2,3-d]pyrimidyl, pyrido[3,2- b]pyrazyl, pyrido[3,2-c]pyridazyl , pyrido[3,2-ύT]pyrimidyl, pyrido[3,4-ft]pyrazyl, pyrido[3,4-c]pyridazyl , pyrido[3,4-d]pyrimidyl , pyrido[4,3-b]pyrazyl , pyrido[4,3- cjpyridazyl, pyrido[4,3-d]pyrimidyl, quinazolyl, lH-benzo[d][l,2,3]tπazoyl, IH- benzo[d]imidazoyl, lH-indazoyl, lH-indoyl, 2H-benzo[d][l,2,3]triazoyl , 2H- pyrazolo[3,4-6]pyridinyl , 2H-pyrazolo[4,3-6]pyridinyl , [l,2,3]triazolo[l,5-a]pyridinyl , [l ,2,4]triazolo[l ,5-a]pyridinyl , [l,2,4]triazolo[4,3-a]pyridinyl , benzo[b]thienyl , benzo[c][l,2,5]oxadiazyl , benzo[c][l,2,5]thiadiazolyl , benzo[</]isothiazoyl , benzo[d]isoxazoyl , benzo[d]oxazoyl , benzo[d]thiazoyl , benzofuryl , imidazo[l,2- a]pyrazyl , imidazo[l,2-a]pyridinyl, imidazo[l,2-α]pyrimidyl , imidazo[l,2-ό]pyridazyl , imidazo[l,2-c]pyrimidyl , imidazo[l,5-a]pyrazyl, imidazo[l,5-α]pyridinyl , imidazo[l,5- a]pyrimidyl , imidazo[l,5-b]pyridazyl , imidazo[l,5-c]pyrimidyl , indolizyl , pyrazolo[l ,5-a]pyrazyl , pyrazolo[l,5-«]pyridinyl , pyrazolo[l,5-α]pyrimidyl, pyrazolo[l ,5-b)]pyridazine , pyrazolo[l,5-c]pyrimidine , pyrrolo[l,2-α]pyrazine , pyrrolo[l,2-a]pyrimidyl , pyrrolo[l,2-b]pyridazyl , pyrrolo[l,2-c]pyrimidyl, IH- imidazo[4,5-b]pyridinyl, lH-imidazo[4,5-c]pyridinyl , lH-pyrazolo[3,4-ό]pyridinyl , IH- pyrazolo[3,4-c]pyridinyl , lH-pyrazolo[4,3-6]pyridinyl , lH-pyrazolo[4,3-c]pyridinyl , lH-pyrrolo[2,3-b]pyridinyl , lH-pyrrolo[2,3-c]pyridinyl , lH-pyrrolo[3,2-b]pyridinyl , lH-pyrrolo[3,2-c]pyridinyl , 2H-indazoyl , 3H-imidazo[4,5-b>]pyridinyl , 3H-imidazo[4,5- c]pyridinyl , benzo[c]isothiazyl , benzo[c]isoxazyl , furo[2,3-Z>]pyridinyl , furo[2,3- c]pyridinyl , furo[3,2-6]pyridinyl , furo[3,2-c]pyridiyl , isothiazolo[4,5-6]pyridinyl , isothiazolo[4,5-c]pyridinyl , isothiazolo[5,4-ύ]pyridinyl , isothiazolo[5,4-c]pyridinyl , isoxazolo[4,5-b]pyridinyl , isoxazolo[4,5-c]pyridinyl , isoxazolo[5,4-b]pyridinyl , isoxazolo[5,4-c]pyridinyl , oxazolo[4,5-Z>]pyridinyl , oxazolo[4,5-c]pyridinyl , oxazolo[5,4-6]pyridinyl , oxazolo[5,4-c]pyridinyl , thiazolo[4,5-ό]pyridiyl, thiazolo[4,5- cjpyridinyl , thiazolo[5,4-ft]pyridinyl , thiazolo[5,4-c]pyridinyl, thieno[2,3-£]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-ό]pyridinyl and thieno[3,2-c]pyridinyl.
Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated or partially unsaturated ring system comprising 5-10 ring atoms selected from C, N, O and S, provided that not more than 2 ring atoms in any single ring are other than C. In the case where the heterocycloalkyl group contains a nitrogen atom the nitrogen may be substituted with an alkyl, acyl, -C(O)O-alkyl, -C(O)NH(alkyl) or a -C(O)N(alkyl)2 group. Heterocycloalkyl groups may be optionally and independently substituted with hydroxy, alkyl and alkoxy groups and may contain up to two oxo groups. Heterocycloalkyl groups may be linked to the rest of the molecule via either carbon or nitrogen ring atoms. Examples of heterocycloalkyl groups include tetrahydrofuranyl, tetrahydrothienyl, tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl, pyrrolidinyl, pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl, thiomorpholin-3-one, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydro-lH-pyrido[l,2-a]pyrazine, 3-thia-6- azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]heptanyl
Heterocycloalkylalkyl is a heterocycloalkyl-(Ci-C4 alkyl)- group wherein heterocycloalkyl is as defined above.
Heterocycloalkyloxy is a heterocycloalkyl-O- group wherein heterocycloalkyl is as defined above. Heterocycloalkylalkoxy is a heterocycloalkyl-(Ci-C4 alkyl)-0- group wherein heterocycloalkyl is as defined above.
Oxo is a -C(O)- group.
Phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF3 CN, NO2, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, -OCH2CH2OCH31 -OC(O)Ra1 -OC(O)ORa, -OC(O)NHR3, -OC(O)N(R3), -SR3, -S(O)R3, -NH2, -NHR3, -N(Ra)(Rb), -NHC(O)R3, -N(R9)C(O)Rb, -NHC(O)OR3, -N(R3)C(0)0Rb, -N(R3)C(O)NH(Rb), -N(R3)C(O)NH(Rb)2, -C(O)NH2, -C(O)NHR3, -C(O)N(R3)(Rb), -CO2H, -CO2R3, -COR3 wherein R3 and Rb are independently chosen from alkyl, alkoxyalkyl, -CH2CH2OH, -CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, 1Pr, 1Bu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon- carbon or carbon-nitrogen or carbon-oxygen single bonds; or R3 and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
Restricted phenyl is a benzene ring which may be optionally and independently substituted with up to three groups selected from halogen, CF3 CN, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, -OCH2CH2OCH3, -OC(O)R3, -OC(O)OR3, -OC(O)N(R3), -N(R3)(Rb), -NHC(O)R3, -N(R8)C(O)Rb, -NHC(O)OR3, -N(Ra)C(O)ORb, - C(O)N(R3)(Rb), -COR3 wherein R3 and Rb are independently chosen from alkyl, alkoxyalkyl, -CH2CH2OH, -CH2CH2OMe, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionally and independently substituted with up to three groups selected from only halogen, Me, Et, 'Pr, 1Bu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, ClM, NO2, NH2, CF3, NHMe, NMe2, OMe, OCF3, each of which are attached via carbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or R3 and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
Abbreviations used in the following examples and preparations include:
Ac Acyl (Me-C(O)-)
AcN Acetonitrile
BINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl
Bn Benzyl
Celite® Diatomaceous earth
DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
DCC N.N', Dicyclohexylcarbodiimide
DCM Dichloromethane
DIEA Di-isopropylethyl amine
DIPEA Di-isopropylethyl amine
DMAP 4-Dimethylaminopyridine
DMF Dimethylformamide
DMP Dess Martin Periodinane
DMSO Dimethyl sulfoxide
Dppf 1,4-Bis(diphenylphosphino) ferrocene
EDC l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride
Et3N Triethylamine g gram(s) h Hour(s) hr Hour(s)
HATU 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
HMDS Hexamethyldisilazide
HOBt 1-Hydroxybenzotriazole
HPLC High Pressure Liquid Chromatography
HRMS High resolution mass spectrometry i.v. Intravenous
KHMDS Potassium Hexamethydisilazide
LDA Lithium Di-isopropylamide m Multiplet m- meta
MEM Methoxyethoxymethyl
MeOH Methyl Alcohol or Methanol min Minute(s) mmol millimoles mmole millimoles
Ms Mesylate
MS Mass Spectrometry
MW Molecular Weight
NBS N-Bromosuccinamide
NIS N-Iodosuccinamide
NMR Nuclear Magnetic Resonance
NMM N-Methyl Morpholine
NMP N-Methyl-2-pyrrolidone o ortho o/n overnight p para
PCC Pyridinium Chlorochromate
PEPPSI l ,3-Bis(2,6-diisopropylphenyl)imidazolidene)( 3- chloropyridinyl) palladium(II) dichloride
PhNTf2 1 , 1,1 -trifluoro-N-phenyl-N-
(trifluoromethylsulfonyl)methanesulfonamide
POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp) palladate
(2-) p.s.i. Pounds per square inch
PPA Polyphosphoric acid
PPAA 1 -Propanephosphonic Acid Cyclic Anhydride PTSA p-Toluenesulfonic acid
PyBOP® Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate RT (or it) room temperature (about 20-250C)
S Singlet sat. Saturated t Triplet
TBAF Tetra-butyl ammonium fluoride
TEA Triethylamine
TFA Trifluoroacetic Acid
THF Tetrahydrofuran
TLC Thin layer chromatography
TMS Trimethylsilyl
Tf Triflate
Tof-MS Time of Flight Mass Spectrometry
Ts Tosylate v/v volume/volume wt/v weight/volume
Detailed Description of the Disclosure
The 1,2 disubstituted heterocyclic compounds of Formula I may be prepared from multi-step organic synthesis routes from commercially available starting materials by one skilled in the art of organic synthesis using established organic synthetic procedures. Non-commercially available phenyl acetic acids can be made from commercially available starting materials via methods known by one skilled in the art of organic synthesis. Such methods include synthesis from the corresponding aryl acids via. the Wolff rearrangement using diazomethane.
Compounds of the disclosure where HET is A3, A5, A7, A8, A9, AH, A 15, A 16, A 18, A 19, A24, A29, A30, A31, A35 and A39 may be prepared generally as depicted in Schemes 1-18 below. Compounds of the disclosure where HET is Al, A2, A4, A6, AlO, Al l, A12, A13, A17, A20, A21, A22, A23, A25, A26, A32, A33, A34, A36, A37, A38, A40, A41 and A42 may be prepared by methods known to one skilled in the art of organic synthesis.
Compounds of the disclosure of Formulas (I), (II) or (III) in which X= phenyl, restricted phenyl, aryl, heteroaryl or a heterobicyclic ring are as described previously and thus having general Formula XIV may be prepared generally as depicted in Scheme 1.
Scheme 1
Figure imgf000039_0001
Compounds of the disclosure of Formulas (I), (II) or (III) in which X= heterocycloalkyl are as described previously and thus having general Formula XXIV may be prepared generally as depicted in Scheme 2.
Scheme 2 ma
Figure imgf000040_0001
Compounds of the disclosure of Formula (I) in which X= phenyl or restricted phenyl are as described previously and thus having general Formula XXXIV may be prepared generally as depicted in Scheme 3:
Scheme 3
Figure imgf000040_0002
XXXII
Figure imgf000040_0003
XXXIII
Compounds of the disclosure of Formulas (1), (II) or (III) in which X= phenyl, restricted phenyl or heteroaryl are as described previously and thus having general Formula XLlV and XLVmay be prepared generally as depicted in Scheme 4: Scheme 4
Figure imgf000041_0002
XL XLI
Figure imgf000041_0001
Figure imgf000041_0003
XLIII XLIV
Figure imgf000041_0004
XLV
Compounds of the disclosure of Formulas (I), (II) or (III) in which X= phenyl, restricted phenyl, aryl or heteroaryl are as described previously and thus having general Formula LIV may be prepared generally as depicted in Scheme 5:
Figure imgf000042_0001
LI LII
Figure imgf000042_0002
Compounds of the disclosure of Formula I in which X= phenyl, restricted phenyl, aryl, heteroaryl, heterocycloalkyl or a heterobicyclic ring are as described previously and thus having general Formula LXV may be prepared generally as depicted in Scheme 6:
Figure imgf000042_0003
Compounds of the disclosure of Formulas (I), (II) and (III) in which X= phenyl or heteroaryl are as described previously and thus having general Formula LXXIV may be prepared generally as depicted in Scheme 7:
Figure imgf000043_0001
Compounds of the disclosure of Formulas (I), (II) and (III) in which X= aryl, phenyl or heteroaryl are as described previously and thus having general Formula LXXXIV may be prepared generally as depicted in Scheme 8:
Figure imgf000043_0002
Compounds of the disclosure of Formula (I), (II) or (III) in which X= aryl, heteroaryl or heterocycloalkyl are as described previously and thus having general Formula XCIII may be prepared generally as depicted in Scheme 9: Scheme 9
Figure imgf000044_0001
Compounds of the disclosure of Formula (I), (II) or (III) in which X= phenyl, heteroaryl or heterocycloalkyl are as described previously and thus having general Formula CIII may be prepared generally as depicted in Scheme 10:
Scheme 10
Figure imgf000044_0002
Compounds of the disclosure of Formula (I), (II) or (III) in which X= phenyl or heteroaryl are as described previously and thus having general Formula CXII may be prepared generally as depicted in Scheme 11 :
Scheme 11
Figure imgf000044_0003
Compounds of the disclosure of Formula (I) in which X= aryl or phenyl are as described previously and thus having general Formula CXXIII may be prepared generally as depicted in Scheme 12. Other compounds of Formula CXXIII may be synthesized by further modification of the OMe group into other functional groups via methods standard in the art of organic chemistry.
Scheme 12
Figure imgf000045_0001
CXXIl CXXIII
Compounds of the disclosure of Formula (I) in which X= aryl or heteroaryl are as described previously and thus having general Formula CXXXIII may be prepared generally as depicted in Scheme 13.
Scheme 13
Figure imgf000046_0001
CXXXII CXXXIII PG: MEM, etc.
PG removal :PTSA etc.
Compounds of the disclosure of Formula (I) in which X= aryl or heteroaryl are as described previously and thus having general Formula CXLIII may be prepared generally as depicted in Scheme 14.
Scheme 14
PG-O
Figure imgf000046_0002
Figure imgf000046_0003
etc. Compounds of the disclosure of Formula (I) in which X= aryl or heteroaryl are as described previously and thus having general Formula CLIV may be prepared generally as depicted in Scheme 15.
Scheme 15
O Br2, CHCI3 O EtOH
CL CLI 1 O CLII
Figure imgf000047_0001
CLlIl CLIV
Compounds of the disclosure of Formula (I) in which X= aryl or heteroaryl and R7 is hydrogen are as described previously and thus having general Formula CLXIV may be prepared generally as depicted in Scheme 16.
Scheme 16
Figure imgf000047_0002
CLXIII CLXIV Compounds of the disclosure of Formula (I) in which X= aryl or heteroaryl are as described previously and thus having general Formula CLXXIV may be prepared generally as depicted in Scheme 17.
Scheme 17
Figure imgf000048_0001
CLXX CLXXI CLXXII
Figure imgf000048_0002
CLXXlV
CLXXIII
Compounds of the disclosure of Formula (I) in which X= phenyl or restricted phenyl are as described previously and thus having general Formula XXXIV may be prepared generally as depicted in Scheme 18:
Scheme 18
Figure imgf000048_0003
CLXII CLXIII
Reactive groups not involved in the above processes can be protected with standard protecting groups during the reactions and removed by standard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley-Interscience) known to those of ordinary skill in the art. Presently preferred protecting groups include methyl, benzyl, MEM, acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC, Cbz, trifluoroacetamide and benzyl for the amino moiety, methyl, ethyl, tert-buty] and benzyl esters for the carboxylic acid moiety.
Experimental Procedures
The synthesis of N-methoxy-N-methylcarboxamides from their corresponding carboxylic acids is known by those of ordinary skill in the art. A representative procedure is described below, where is selected from
Figure imgf000049_0001
HOγE O O
To a stirred solution of carboxylic acid (1 eq., 3 mmol) in DCM (50 mL) was added HATU (1.5 eq , 4.5 mmol), N-methoxy methylamine(1.5eq, 4.5 mmol) and TEA (3 eq., 9 mmol) at RT under nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h. The reaction mixture was diluted with water and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the corresponding N-methoxy-N-methylcarboxamide.
HPLC Conditions
Condition -A:
Column: Hypersil BDS C8 250X 4.6 mm, 5um (SHCL06E001)
Mobile Phase: AcN (A): 0.1 % TFA in Water. (B).
Flow rate: 1.5ml/min (Gradient) Condition -B:
Column: Zobrax SB- Cl 8 25OX 4.6 mm, 5um Mobile Phase: AcN (A): 0.1 % TFA in Water. (B). Flow rate: 1.5ml/min (Gradient)
Condition -C:
Column: Targa C-18 250 X 4.6 mm, 5um Mobile Phase: AcN (A): 0.1 % TFA in Water. (B). Flow rate: 1.5ml/min (Gradient)
Condition -D:
Column: Targa Cl 8 250X 4.6 mm, 5um (SHCL-12)
Mobile Phase: AcN (A): 5M Ammonium Acetate in Water. (B).
Flow rate: l .Oml/min (Gradient
Condition -E:
Column: Higgins- Cl 8 250X 4.6 mm, 5um Mobile Phase: AcN (A): 0.1 % TFA in Water. (B). Flow rate: 1.5ml/min (Gradient)
Condition -F:
Column: Chiralpak AD
Mobile Phase: n-Hexane: Ethanol (50:50)
Flow rate: 0.6ml/min (Gradient)
Condition -G:
Column: Venusil C8, 250 X 4.6 mm, 5um. Mobile Phase: AcN (A): 0.1 % TFA in Water. (B). Flow rate: 1.5ml/min (Gradient)
Condition -H: Column: Eclipse XDB- Cl 8, 150 X 4.6 mm, 5um. Mobile Phase: 0.1 % TFA in Water. (A).ACN (B) Flow rate: 1.5ml/min (Gradient)
Condition -I:
Column: Acquity BEH- C18, (50 X 2.1 mm, 1.7um.)
Mobile Phase: AcN (B)
Flow rate: 0.5ml/min (Gradient)
Condition -J:
Column: Zobrax C18, (150 X 4.6 mm, 5um.) Mobile Phase: AcN (A): 0.1 % TFA in Water. (B). Flow rate: l .Oml/min (Gradient)
Synthesis of l-Methyl-3-(pyridin-4-yl)-4-(4-(quinoIin-2-ylmethoxy)phenvD-lH- pyrrole-2,5-dione (Example 11)
Ethyl 2-(4-(quinolin-2-ylmethoxy) phenyl) acetate
Figure imgf000051_0001
To a stirred solution of ethyl 2-(4-hydroxyphenyl) acetate (30 g, 0.16 mol) in acetonitrile (300 mL) was added K2CO3 (114.9 g, 0.83 mol) and 2-(chloromethyl) quinoline (42.7 g, 0.19 mol) at RT. The reaction mixture was refluxed for 16 h. The reaction mixture was then filtered and the solid residue was extracted with EtOAc (2x100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy) phenyl) acetate (50 g, 93.4%) as a solid.
2-(4-(Quinolin-2-ylmethoxy) phenyl) acetic acid
Figure imgf000052_0001
To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy) phenyl) acetate (8 g, 0.02 mol) in MeOH: THF (300 mL; 1 :1) was added LiORH2O (5.21 g, 0.124 mol) and the mixture was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude compound. The crude material was acidified with HCl (IN), filtered and dried in vacuo to afford 2-(4-(quinolin-2-ylmethoxy) phenyl) acetic acid (7.0 g, 95%) as a solid.
2-Bromo-l-(pyridin-4-yl) ethanone hydro bromide
Figure imgf000052_0002
To a stirred solution of l-(pyridin-4-yl)-ethanone (10 g, 0.08 mol) in CCl4 (150 mL) was added Br2 (3.99 mL, 0.02 mol) dropwise at 00C and the mixture was then refluxed for 1 h. The reaction mixture was filtered and dried in vacuo to afford 2-bromo-l -(pyridin-4- yl)-ethanone hydrobromide (22 g, 94%) as a solid.
4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl) furan-2(5H)-one
Figure imgf000052_0003
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl) acetic acid (3.0 g, 0.01 mol) in acetonitrile (40 mL) were added TEA (1.3 mL, 0.01 mol) and 2-bromo-l-(pyridin-4-yl) ethanone hydrobromide (2.86 g, 0.01 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 1 h followed by addition of DBU (46.6 g, 0.03 mol) at 0 0C and stirring was continued for another 2 h at 0 0C. The reaction mixture was quenched with HCl (1 N), aqueous layer was basified with NaHCO3 solution and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude product was purified via silica gel column chromatography eluting with 25% EtOAc in hexanes to afford 4- (pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl) furan-2(5H)-one (600 mg, 15 %) as a solid.
(Z)-4-Hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy) phenyl) but- 2-enamide
Figure imgf000053_0001
A solution of 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl) furan-2(5H)-one (1.0 g, 0.002 mol) and MeNH2 in MeOH (25 mL) was refluxed for 1 h. The reaction mixture was concentrated in vacuo to afford (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4- (quinolin-2-ylmethoxy)-phenyl) but-2-enamide (920 mg, 86 %) as a solid.
1- Methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl)-lH-pyrrol-2(5H)- one
Figure imgf000053_0002
To a solution of (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy) phenyl)-but-2-enamide (430 mg, 1.01 mmol) in Ether: DCM (20 mL; 1 : 1) was added PBr3 (0.114 mL, 1.21 mol) dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was then diluted with DCM and basified with NaHCO3 solution. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford l-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylrnethoxy) phenyl)-lH-pyrrol-2(5H)-one (350 mg, 85%) as a solid. 1H NMR (500 MHz, CD3OD): δ 8.81 (d, J = 7.8 Hz, 2 H), 8.24-8.19 (m, 2 H), 8.11- 7.94 (m, 3 H), 7.85-7.80 (m, 1 H), 7.59 (d, J= 7.2 Hz, 2 H), 7.44 (s, 2 H), 7.21 (d, J= 7.2 Hz, 2 H), 5.61 (s, 2 H), 3.38 (s, 2 H), 3.09 (s, 3 H). MS: M+H: m/z = 408.2. HPLC: 89%, (Condition-B).
l-Methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-lH-pyrrole-2,5-dione (Example 11)
Figure imgf000054_0001
To a stirred solution of l-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl)- lH-pyrrol-2(5H)-one (200 mg, ,0.49 mmol) in AcN (10 mL) was added DBU (224.5 mg, 1.47 mmol) dropwise and then the reaction mixture was stirred for 6 h under a continuous flow of oxygen. The reaction mixture was quenched with IN HCl and extracted with EtOAc (2 x 20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO,), and concentrated in vacuo to afford l-methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2- ylmethoxy)phenyl)-lH-pyrrole-2,5-dione (100 mg, 48 %) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.18-8.09 (m, 1 H), 8.0-7.95 (m, 3 H), 7.65-7.59 (m, 3 H), 7.48-7.39 (m, 1 H), 7.28-7.18 (m, 4 H), 7.1-7.09 (m, 2 H), 5.25 (s, 2 H), 2.86 (s, 3H); MS: MΗ: m/z = 420.1.
Synthesis of 4-f4-methoxyphenvD-5, 5-dimethyl-3-(4-(quinolin-2-ylmethoxy) phenyl) furan-2(5HVone (Example 33)
4-Hydroxy-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one
Figure imgf000055_0001
To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (2.0 g, 0.006 mol) in THF (10 mL), were added methyl 2-hydroxy-2-methylpropanoate (1.4 g, 0.012 mol) and /-BuOK (1 N, 50 mL) at RT under an inert atmosphere. The mixture was then stirred for 16 h at RT. The reaction mixture was diluted with water, acidified with HCl (IN), and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 4-hydroxy-5,5-dimethyl-3- (4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (1.0 g, 45%) as a yellow solid.
2,2-Dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate
Figure imgf000055_0002
To a solution of 4-hydroxy-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan- 2(5H)-one (500 mg, 1.3 mmol) in DCM (50 mL) were added TEA (410 mg, 4.1 mmol) and triflic anhydride (780 mg, 2.7 mmol) at 0 0C under an inert atmosphere. The mixture was then stirred for 2 h at 0 0C. The reaction mixture was diluted with water and extracted with DCM (2 x 100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2,2-dimethyl-5-oxo-4-(4- (quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (250 mg, 37 %) as a white solid.
4-(4-Methoxyphenyl)-5, 5-dimethyl-3-(4-(quinolin-2-ylmethoxy) phenyl) furan- 2(5H)-one (Example 33)
Figure imgf000056_0001
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5- dihydrofuran-3-yl trifluoromethanesulfonate (250 mg, 0.5 mol) in 1, 4-Dioxane (10 mL) were added 4-methoxyphenylboronic acid (92 mg, 0.6 mol), Na2CO3 (127 mg, 1.5 mol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min followed by addition of Pd(PPh3)4 (58 mg, 0.05 mol) and then refluxed for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5, 5-dimethyl-3-(4-(quinolin-2- ylmethoxy) phenyl) furan-2(5H)-one- (40 mg, 18 %) as a yellow solid. 1H NMR (500 MHz, de-DMSO): δ 8.43-8.41 (m, 1 H), 8.02-7.98 (m, 2 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.68-7.52 (m, 2 H), 7.25-7.21 (m, 4 H), 7.02-6.98 (m, 4 H), 5.40 (s, 2 H), 5.25 (s, 2 H), 3.79 (s, 3 H). MS: M+H: m/z =452.2; M+Na: m/z= 474.3. HPLC: 91%, (Condition-B).
Synthesis of 5, 5-dimethyl-4-(pyridin-4-vD-3-(4-(quinolin-2-ylmethoxy) phenyl) furan-2(5H)-one (Example 23)
5, 5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl) furan-2(5H)-one (Example 23)
Figure imgf000056_0002
Following the procedure for the preparation of 4-(4-methoxyphenyl)-5, 5-dimethyl-3-(4- (quinolin-2-ylmethoxy) phenyl) furan-2(5H)-one (Example 33) using pyridine-4-yl boronic acid provided the title compound.
Yield: 76 %. 1H NMR (500 MHz, (I6-DMSO): δ 8.68 (d, /= 7.2 Hz, 2 H), 8.40 (d, J = 7.6 Hz, 1 H), 8.06-7.95 (m, 2 H), 7.62-7.58 (m, 2 H), 7.38 (d, J= 7.8 Hz, 2 H), 7.33 (d, J = 7.6 Hz, 2 H), 7.0-6.96 (m, 3 H), 5.39 (s, 2 H), 1.54 (s, 6 H). MS: M+H: m/z = 423.1. HPLC: 99%, (Condition-B).
Synthesis of 5, 5-dimethyl-4-(pyridin-4-v0-3-(4-(quinolin-2-ylmethoxy) phenvO-lH- pyrrol-2(5H)-one (Example 63)
Methyl 2-amino-2-methylpropanoate
\^
M2N CO2IVIe
To a solution of 2-amino-2-methylpropanoic acid (5.0 g) in MeOH (15 mL) was added SOCb (4 mL) at 0 0C under an inert atmosphere. The mixture was then stirred for 2 h. The reaction mixture was concentrated in vacuo and washed with ether to afford methyl 2-amino-2-methylpropanoate (4.8 g, 82.7 %) as a white solid.
2-(4-(Quinolin-2-ylmethoxy) phenyl) acetic acid
Figure imgf000057_0001
To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (25 g, 0.07 mol) in 1 : 1 (MeOH: THF) (400 mL) were added LiORH2O (6.3 g, 0.38 mol) and water (50 mL). The mixture was then stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo. The residue was then acidified with aqueous HCl (IN) and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy) phenyl) acetic acid (9.0 g, 40 %) as a solid. Methyl 2-methyl-2-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetamido)propanoate
Figure imgf000058_0001
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy) phenyl) acetic acid (5.0 g, 0.017 mol) in DCM (50 mL) were added DIPEA (6.6 g, 0.05 mol), HOBT (3.4 g, 0.02 mol) and EDC (4.9 g, 0.02 mol) at RT under an inert atmosphere. After 10 minutes, 2-amino-2- methylpropanoate (3.9 g, 0.02 mol) was added to the reaction mixture and stirring was continued for 4 h. The reaction mixture was diluted with water and extracted with DCM (2 x 200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4. Evaporation of organic solvents in vacuo afforded methyl 2-methyl- 2-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetamido)propanoate (5.0 g, 74 %) as a white solid.
4-Hydroxy-5, 5-diniethyl-3-(4-(quinolin-2-ylmethoxy) phenyl)-lH-pyrrol-2(5H)-one
Figure imgf000058_0002
To a stirred solution of methyl 2-methyl-2-(2-(4-(quinolin-2- ylmethoxy)phenyl)acetamido)propanoate (5.0 g, 0.01 mol) in DMF (100 mL) was added NaH (913 mg, 0.03 mmol) at 0 0C under an inert atmosphere. The reaction mixture was then stirred for 2 h, diluted with ice water and then extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SU4 and concentrated in vacuo to afford 4-hydroxy-5, 5-dimethyl-3-(4-(quinolin-2- ylmethoxy) phenyl)-! H-pyrrol-2(5H)-one (2.0 g, 44 %) as a white solid. 2, 2Dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy) phenyl)-2, 5-dihydro-lH-pyrrol-3-yl trifluoromethanesulfonate
Figure imgf000059_0001
To a solution of 4-hydroxy-5, 5-dimethyl-3-(4-(quinolin-2-ylmethoxy) phenyl)-lH- pyrrol-2(5H)-one (500 mg, 1.3 mmol) in DCM (15 mL) were added TEA (422 mg, 4.1 mmol) and triflic anhydride (785 mg, 2.7 mol) at 0 0C under an inert atmosphere. The mixture as then stirred for 2 h., diluted with water and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water, dried over Na2SCU and then concentrated in vacuo to afford 2, 2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy) phenyl)-2, 5-dihydro-lH-pyrrol-3-yl trifluoromethanesulfonate (400 mg, 58 %) as a white solid.
5, 5-Dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl)-lH-pyrrol- 2(5H)-one (Example 63):
Figure imgf000059_0002
To a solution of 2, 2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy) phenyl)-2, 5-dihydro- lH-pyrrol-3-yl trifluoromethanesulfonate (2.0 g, 0.004 mol) in 1,4-dioxane (50 mL) were added pyridin-4-yl boronic acid (598 mg, 4.8 mol), Na2CCb (1 O g, 0.012 mol) and water (20 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (468 mg, 0.4 mol) was added. The mixture was then heated at 80 0C for 16 h, diluted with water, and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 5, 5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl)-lH- pyrrol-2(5H)-one (250 mg, 15%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.74-8.68 (m, 1 H), 8.66-8.56 (m, 2 H), 8.06-7.94 (m, 2 H), 7.78 (t, J= 7.2 Hz, 1 H), 7.66-7.56 (m, 3 H), 7.30-7.18 (m, 4 H), 6.98-6.88 (m, 3 H), 5.36 (s, 2 H), 1.36 (s, 6 H). MS: M+H: m/z = 422.1; M+Na: m/z = 444.1. HPLC: 89%, (Condition-I).
Synthesis of 4-(4-Methoxyphenyl)-5, 5-dimethyl-3-(4-(quinolin-2-ylmethoxy) phenvn-lH-pyrrol-2(5H)-one (Example 823):
4-(4-Methoxyphenyl)-5, 5-dimethyl-3-(4-(quinolin-2-ylmethoxy) phenyl)-lH-pyrrol- 2(5H)-one (Example 823)
Figure imgf000060_0001
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5- dihydro-lH-pyrrol-3-yl trifluoromethanesulfonate (500 mg, 1.01 mmol) in 1, 4-dioxane (20 mL) were added 4-methoxyphenylboronic acid (185 mg, 1.2 mmol), Na2CO3 (256 mg, 3.04 mmol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (117 mg, 0.1 mmol) was added. Stirring was continued at 80 °C for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (2x200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SC^ and concentrated in vacuo to afford 4-(4- methoxyphenyl)-5, 5-dimethyl-3-(4-(quinolin-2-ylrnethoxy) phenyl)- lH-pyrrol-2(5H)- one (30 mg, 7 %) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.20-8.01 (m, 2 H), 7.87-7.62 (m, 2 H), 7.61-7.51 (m, 2 H), 7.38-7.30 (m, 2 H), 7.16-7.09 (m, 2 H), 6.91 6.80 (m, 4 H), 5.96 (bs, 1 H), 5.39 (s, 2 H), 3.81 (s, 3 H), 1.43 (s, 6 H). MS: M+H: m/z = 451.2 and HPLC: 94%, (Condition-I). Synthesis 4-(4-methoxyphenyI)-l, 5, 5-trimethyl-3-(4-(qiiinolin-2-ylmethoxy) phenvn-lH-pyrrol-2(5H)-one (Example 73):
4-(4-Methoxyphenyl)-l, 5, 5-trimethyl-3-(4-(quinolin-2-ylmethoxy) phenyl)-lH- pyrrol-2(5H)-one (Example 73)
Figure imgf000061_0001
To a solution of 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)- lH-pyrrol-2(5H)-one (150 mg, 0.35 mmol) in DMF (10 mL) were added NaH (15 mg, 0.7 mmol) and CH3I (100 mg, 0.7 mmol) at 0 0C under an inert atmosphere. The mixture was then stirred for 4 h, diluted with cold water and filtered. The resulting residue was dried to afford 4-(4-methoxyphenyl)-l, 5, 5-trimethyl-3-(4-(quinolin-2-ylmethoxy) phenyl)- lH-pyrrol-2(5H)-one (50 mg, 37 %) as a white solid. 1H NMR (500 MHz, d6- DMSO): δ 8.04 (d, J= 7.2 Hz, 1 H), 8.02-7.98 (m, 2 H), 7.81-7.78 (m, 1 H), 7.62-7.58 (m, 2 H), 7.31-7.28 (m, 2 H), 7.19-7.16 (m, 2 H), 6.99-6.84 (m, 4 H), 5.36 (s, 2 H), 3.89 (s, 3 H), 2.96 (s, 3 H), 1.24 (s, 6 H). MS: M+H: m/z = 465.2; M+Na: m/z = 487.2. HPLC: 92%, (Condition-I).
Synthesis 4-(4-methoxyphenvO-2, 2-dimethyl-5-(4-(quinolin-2-ylmethoxy') phenyl) furan-3(2HVone (Example 262)
Ethyl 2-(4-methoxyphenyl) acetate
Figure imgf000061_0002
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile
(100 mL) were added K2CO3 (15.3 g, 0.11 mol) and dimethyl sulfate (8.4 g, 0.06 mol) under an inert atmosphere. The reaction mixture was stirred at 80 0C for 2 h and then extracted with EtOAc (2 x 300 mL), The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-methoxyphenyl) acetate (8 g, 74 %) as a white solid.
2-(4-MethoxyphenyI) acetic acid
Figure imgf000062_0001
To a solution of ethyl 2-(4-methoxyphenyl) acetate (12 g, 0.06 mol) in MeOH (150 mL) was added dropwise a solution of NaOH (9.8 g, 0.24 mol) in water (50 mL). The mixture was then stirred at RT for 1 h and concentrated in vacuo, the residue was acidified with HCl (IN) and extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4- methoxyphenyl) acetic acid (10 g, 67 %) as a yellow oil.
l-(4-Hydroxyphenyl)-2-(4-methoxyphenyl) ethanone
Figure imgf000062_0002
To a solution of 2-(4-methoxyphenyl)acetic acid (1O g, 0.06 mol) in PPA (20 mL) was added dropwise phenol (5.6 g, 0.06 mol) under an inert atmosphere. The mixture was then stirred at 80 °C for 1 h, quenched with cold water and extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over Na2Sθ4 and concentrated in vacuo to obtain the crude product which was purified via silica gel column chromatography to afford l-(4-hydroxyphenyl)-2-(4-methoxyphenyl)-ethanone (3 g, 20 %) as a pale yellow solid
l-(4-(Benzyloxy) phenyl)-2-(4-methoxyphenyl) ethanone
Figure imgf000063_0001
To a O0C solution of l-(4-hydroxyphenyl)-2-(4-methoxyphenyl) ethanone (3.0 g, 0.01 mol) in acetonitrile (60 mL) under an inert atmosphere was added potassium carbonate (3.4 g, 0.02 mol) followed by benzyl chloride (1.8 mL, 0.014 mol). The reaction mixture was brought to 80 0C and stirred for 2 h. The reaction was quenched with cold water, filtered and the filtrate was extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford l-(4-(benzyloxy) phenyl)-2-(4-methoxyphenyl) ethanone (1.0 g, 24 %) as a white solid.
5-(4-(Benzyloxy)phenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one
Figure imgf000063_0002
To a pre-cooled O0C solution of l-(4-(benzyloxy) phenyl)-2-(4-methoxyphenyl)-ethanone (2 g, 6.02 mmol) in THF (20 mL) under an inert atmosphere was added J-BuOK (8 mL, 1.0 N solution in THF). The mixture was then stirred for 30 minutes. 2-Bromo-2- methylpropanoyl cyanide (2 g, 12 mmol) was then added to then reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was then quenched with cold water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), and then dried over Na2SO4 concentrated and purified via silica gel column chromatography (10-15% Ethyl acetate in hexanes) to afford 5-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran- 3(2H)-one (100 mg) as a white solid.
5-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one
Figure imgf000064_0001
To a stirred solution of 5-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-2,2- dimethylfuran-3(2H)-one (1.0 g, 3.0 mmol) in methanol (50 mL) was added Pd(OH)2 (150 mg, 1.07 mmol) at RT under an inert atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen for 1 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford 5-(4-hydroxyphenyl)-4-(4- methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one (600 mg, 64 %) as a pale yellow solid
4-(4-Methoxyphenyl)-2, 2-dimethyl-5-(4-(quinolin-2-ylmethoxy) phenyl) furan- 3(2H)-one (Example 262)
Figure imgf000064_0002
To a stirred solution of 5-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran- 3(2H)-one (600 mg, 1.93 mol) in acetonitrile (50 mL) was added K2CO3 (800 mg, 5.8 mol). 2-Chloromethyl quinoline (500 rrig, 2.32 mol) was added dropwise under an inert atmosphere. The reaction mixture was stirred at 80 °C for 16 h and then partitioned between water and EtOAc (200 mL). The organic layer was separated, washed with water, dried over Na2SO4 and then concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography to afford 4-(4-methoxyphenyl)-2, 2- dimethyl-5-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (0.51 g, 58 %) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.45 (d, J= 7.2 Hz, 1 H), 8.02-7.97 (m, 2 H), 7.85-7.77 (m, 1 H), 7.76-7.68 (m, 2 H), 7.59-7.51 (m, 2 H), 7.19-7.1 1 (m, 4 H), 6.95 (d, J = 7.4 Hz, 2 H), 5.41 (s, 2 H), 3.75 (s, 3 H), 1.45 (s, 6 H). MS: M+H: m/z = 452.1. HPLC: 97%, (Condition-I). Synthesis of 2, 2-Dimethyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 125):
Trimethyl (2-methylbut-3-yn-2-yloxy) silane
Figure imgf000065_0001
To a stirred solution of 2-methylbut-3-yn-2-ol (20 g, 0.23 mol) in HMDS (42.3 g, 0.261 mol) was added LiClO4 (38.03 g, 0.35 mol) at RT. The reaction mixture was then stirred for additional 30 minutes, diluted with water (100 mL) and then extracted with ether (3 x 200 mL). The combined ether layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO and filtered. The ether was distilled off at 800C to afford trimethyl (2-methylbut-3-yn-2-yloxy) silane (25 g) as an oil.
4-Methyl-l-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-l-one
Figure imgf000065_0002
To a pre-cooled -780C stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (5.0 g, 0.03 mol) in dry THF (150 mL), H-BuLi (23.82 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over a period of 10 minutes under an inert atmosphere. The reactions was stirred for 30 minutes at -780C and then a solution of N-methoxy-iV- methylisonicotinamide (6.34 g, 0.03 mol) in dry THF (30 mL) was added to the reaction mixture and stirring was continued for an additional 40 min at -78 0C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and finally concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography eluting with 5 % EtOAc in hexanes to afford 4-methyl-l-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-l-one (2.2 g, 27 %) as oil. 4-Hydroxy-4-methyl-l-(pyridin-4-yl) pent-2-yn-l-one
Figure imgf000066_0001
To a stirred solution of 4-methyl-l-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-l- one (0.5 g, 1.915 mmol) in DCM (10 mL) was added PTSA (0.47 g, 2.49 mmol) at RT and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with DCM (50 mL). The organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl- l-(pyridin-4-yl) pent-2-yn-l-one (0.35 g, 96 %) as an oil.
2, 2-Dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
Figure imgf000066_0002
To a stirred solution of 4-hydroxy-4-methyl-l-(pyridin-4-yl) pent-2-yn-l-one (1.49 g, 0.0O7 mol) in ethanol (15 mL), diethylamine (0.51 1 g, 0.007 mol) in EtOH (15 mL) was added dropwise at RT. The mixture was then stirred for additional 40 min. The EtOH was evaporated and the mixture was diluted with EtOAc (100 mL). The organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.4 g)-
4-Bromo-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
Figure imgf000066_0003
To a stirred solution of 2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.81 g, 4.28 mmol) in CHCl3 (20 mL), NBS (1.3 g, 7.28 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (100 mL). The organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2, 2-dimethyl-5- (pyridin-4-yl) furan-3(2H)-one (0.25 g, 21%) as a solid
2, 2-Dimethyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 125)
Figure imgf000067_0001
A mixture of 4-bromo-2, 2-dimethyl-5-(pyridin-4-yl)-furan-3(2H)-one (0.25 g, 0.93 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.37 g, 1.026 mmol), and Cs2CO3 (1.52 g, 4.664 mmol) in 5:1 toluene/ water (12 mL) was degassed. Pd(dppf)Cl2 (152.2 mg, 0.18 mmol) was then added under an inert atmosphere and the mixture was again degassed. The reaction mixture was re fluxed for 3 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2, 2-dimethyl-5- (pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (0.29 g, 74 %) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.78 (d, J= 7.2 Hz, 1 H), 8.56-8.50 (m, 2 H), 8.15- 8.05 (m, 2 H), 7.78-7.72 (m, 1 H), 7.63-7.59 (m, 1 H), 7.56-7.47 (m, 2 H); 7.18-7.09 (m, 2 H), 7.02-6.96 (m, 3 H), 5.40 (s, 2 H), 1.50 (s, 6 H). MS: M+H: m/z = 423.1. LC MS: 98%, Column: Eclipse XDB- C 18, 150 X 4.6 mm, 5um. Mobile Phase: 0.1 % TFA in Water (A), AcN (B), Flow rate: 1.5ml/min (Gradient) Synthesis of 5-(4-methoxyphenvD -2, 2-dimethyl- 4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 138):
l-(4-Methoxyphenyl)-4-methylpent-2-yne-l, 4-diol
Figure imgf000068_0001
To a pre-cooled, -780C stirred solution of 2-methylbut-3-yn-2-ol (4.3 g, 0.04 mol) in dry THF (150 mL) n-BuLi (39.9 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The mixture was stirred for 30 min at -78 0C, and then a solution of 4-methoxy-benzaldehyde (5 g, 0.037 mol) in dry THF (30 mL) was added to reaction mixture and stirring was continued for an additional 40 min at -78 0C. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain crude material. The crude material was purified via silica gel column chromatography eluting with 5 % EtOAc in hexanes to afford 1 -(4-methoxyphenyl)-4-methylpent-2-yne- 1, 4-diol (6.3 g, 78 %) as an oil.
4-Hydroxy-l-(4-methoxyphenyl)-4-methylpent-2-yn-l-one
Figure imgf000068_0002
To a room temperature, stirred solution of l-(4-methoxyphenyl)-4-methylpent-2- yne-1, 4-diol (6.3 g, 0.029 mol) in DCM (50 mL), Dess Martin periodinane (31.2 g, 0.07 mol) was added and the reaction mixture was stirred for 3 h. The reaction mixture was then diluted with DCM (50 mL) and the combined organic layers were washed with a saturated NaHCO3 solution and water, dried OVCrNa2SO,), filtered and then concentrated in vacuo to afford 4-hydroxy-l-(4-methoxyphenyl)-4-methylpent-2-yn-l -one (6 g, 96 %) as an oil. 5-(4-Methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one
Figure imgf000069_0001
To a stirred solution of 4-hydroxy-l-(4-methoxyphenyl)-4-methylpent-2-yn-l-one (6 g, 0.027 mol) in ethanol (100 mL) diethyl amine (2.86 g, 0.027 mol) in EtOH (15 mL) was added dropwise at RT and the reaction mixture was stirred for additional 4 h. The EtOH was then removed and the mixture diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 5-(4-methoxyphenyl)-2, 2-dimethylfuran- 3(2H)-one (5.5 g, 92%).
4-Bromo-5-(4-methoxyphenyI)-2, 2-dimethylfuran-3(2H)-one
Figure imgf000069_0002
To a stirred solution of 5-(4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one (5.5 g, 0.025 mol) in CHCl3 (100 mL) NBS (6.733 g, 0.038 mol) was added portionwise at RT and the reaction mixture was stirred for 2 h. The mixture was then diluted with DCM (100 mL), washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-5-(4-methoxyphenyl)-2, 2- dimethylfuran-3(2H)-one (4.6 g, 65 %) as a solid.
5-(4-Methoxyphenyl) -2, 2-dimethyl- 4-(4-(quinolin-2-ylmethoxy) phenyl) furan-
3(2H)-one (Example 138)
Figure imgf000069_0003
A mixture of 4-bromo-5-(4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one (2 g, 0.0067 mol), 2-((4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (2.43 g, 0.0067 mol), and Cs2CO3 (1 1 g, 0.034 mol)' in toluene (25 mL) and water (8 mL) was degassed. Pd(dppf)Cl2 (l.lg, 0.0013 mol) was then added under an inert atmosphere and the mixture was degassed again. The reaction mixture was refluxed for 3 h, filtered through a pad of Celite®. The filtrate was diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL), dried over Na2SO^ filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-methoxyphenyl) -2, 2-dimethyl- 4-(4-(quinolin-2- ylmethoxy) phenyl) furan-3(2H)-one (2.3 g, 74 %) as solid. 1H NMR (500 MHz, d6- DMSO): δ 8.42 (d, J= 7.6 Hz, 1 H), 8.06-7.99 (m, 2 H), 7.95 (t, J= 7.2 Hz, 1 H), 7.72 (t, J= 7.2 Hz, 1 H), 7.63 (t, J = 7.8 Hz, 1 H), 7.56 (d, J= 7.2 Hz, 2 H); 7.18 (d, J= 7.4 Hz, 2 H), 7.12 (d, J= 7.2 Hz, 2 H), 6.89 (d, J= 7.2 Hz, 2 H), 5.38 (s, 2 H), 3.79 (s, 3 H).1.42 (s, 6 H). MS: M+H: m/z = 452.1; M+Na: m/z= 474.2. HPLC: 96%, Column: Eclipse XDB- C 18, 150 X 4.6 mm, 5um. Mobile Phase: 0.1 % TFA in Water (A), AcN (B), Flow rate: 1.5ml/min (Gradient)
Synthesis of 5-(4-hvdroxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2- ylmethoxy)phenyl)furan-3(2H)-one (Example 813):
5-(4-hydroxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-yImethoxy)phenyl)furaα-3(2H)- one (Example 813)
Figure imgf000070_0001
To a stirred O0C solution of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2- ylmethoxy)phenyl)furan-3(2H)-one (1.0 g, 2.61 mmol) in THF (10 mL), aqueous HBr (908 mg, 5.2 mmol) was added under a nitrogen atmosphere. The reaction mixture was then stirred for 12 h at RT, diluted with water and extracted with hexane (2 x 50 mL). The organic layers were concentrated in vacuo to afford 5-(4-hydroxyphenyl)-2,2- dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (100 mg) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 10.25 (s, 1 H), 8.48 (d, J= 7.8 Hz, 1 H), 8.16-8.00 (m, 2 H), 7.95 (t, J= 7.8 Hz, 1 H), 7.72 (t, J= 7.8 Hz, 1 H), 7.63 (t, J= 7.2 Hz, 1 H), 7.56 (d, J= 7.2 Hz, 2 H); 7.18 (d, J= 7.2 Hz, 2 H), 7.12 (d, J= 7.2 Hz, 2 H),6.89 (d, J= 7.6 Hz, 2 H), 5.32 (s, 2 H), 1.37 (s, 6 H). MS: M+H: m/z = 438.2; and LC MS: 88%, (Condition-H).
Synthesis of 7-(pyridin-4-vO-6-(4-(quinolin-2-ylmethoxy) phenvD-4-oxaspiro [2.41 hept-6-en-5-one (Example 26):
Methyl l-(2-(4-(quinolin-2-ylmethoxy) phenyl) acetoxy) cyclopropane carboxylate
Figure imgf000071_0001
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy) phenyl) acetyl chloride (2.0 g, 6.557 mmol) in DCM (50 mL), DMAP (1.4 g, 13.114 mmol) was added followed by methyl 1- hydroxycyclopropanecarboxylate (1.1 g, 9.836 mmol) under a nitrogen atmosphere at RT and the mixture was stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were washed with a saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude methyl l-(2-(4-(quinolin-2-ylmethoxy) phenyl) acetoxy) cyclopropanecarboxylate (2.0 g,) as a solid.
7-Hydroxy-6-(4-(quinolin-2-ylmethoxy) phenyl)-4-oxaspiro [2.4] hept-6-en-5-one
Figure imgf000072_0001
To a O0C solution of methyl l-(2-(4-(quinolin-2-ylmethoxy) phenyl) acetoxy) cyclopropanecarboxylate (2.0 g, 6.825 mmol) in DMF (20 mL) NaH (49 mg, 20.477 mol) was added and the mixture stirred at RT for 12 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice water (3 mL) and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (30 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude 7-hydroxy-6-(4-(quinolin-2- ylmethoxy) phenyl)-4-oxaspiro [2.4] hept-6-en-5-one (2.0 g, 83 %) as a light yellow color solid..
5-Oxo-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-7-yl trifluoromethanesulfonare
Figure imgf000072_0002
To a O0C solution of 7-hydroxy-6-(4-(quinolin-2-ylmethoxy)-phenyl)-4- oxaspiro[2.4]hept-6-en-5-one (400 mg, 1.1 mmol) in DCM (15 mL) TEA (226 mg, 3.36 mmol) and triflic anhydride (631 mg, 2.2 mol) were added under an inert atmosphere and the reaction mixture was stirred for 2 h at O0C. The reaction mixture was then diluted with water and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 5-oxo-6-(4- (quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-7-yl trifluoromethanesulfonate (400 mg, 73 %) as an ash-colored solid. 7-(Pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy) phenyl)-4-oxaspiro [2.4] hept-6-en-5- one (Example 26)
Figure imgf000073_0001
To a stirred solution of 5-oxo-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6- en-7-yl trifluoromethanesulfonate (200 mg, 0.4 mmol) in 1, 4-dioxane (10 mL) were added pyridin-4-ylboronic acid (74 mg, 0.6 mmol), Na2CU3 (102 mg, 1.2 mmol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 minutes, and then Pd(PPh3)4 (46 mg, 0.04 mmol) was added and the reaction mixture was then refluxed for 16 h, diluted with water and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water and brine, dried over Na2SU4 and concentrated in vacuo to afford 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy) phenyl)-4- oxaspiro [2.4] hept-6-en-5-one (30 mg, 18 %) as white solid. 1H NMR (500 MHz, d6- DMSO): δ 8.64-8.61 (m, 2 H), 8.40 (d, J= 12 Hz, 1 H), 8.02 - 7.99 (m, 2 H), 7.81-7.77 (m, 1 H), 7.67- 7.51 (m, 3 H), 7.38-7.24 (m, 5 H), 5.36 (s, 2 H), 1.88-1.85 (m, 2 H), 1.24- 1.21 (m, 2 H). MS: M+H: m/z = 421.2; M+Na: m/z = 443.2. HPLC: 92%, (Condition-I).
Synthesis of 7-(4-methoxyphenvD-6-(4-(quinolin-2-ylmethoxy) phenyl)-4-oxaspiro T2.41 hept-6-en-5-one (Example 885):
7-(4-Methoxyphenyl)-6-(4-(quinolin-2-ylmethoxy) phenyl)-4-oxaspiro [2.4] hept-6- en-5-one (Example 885)
Figure imgf000074_0001
Following the procedure for the preparation of 7-(pyridin-4-yl)-6-(4-(quinolin-2- ylmethoxy) phenyl)-4-oxaspiro [2.4] hept-6-en-5-one (Example 26) using 4- methoxyphenylboronic acid provided the title compound.
Yield: 18 %. 1H NMR (500 MHz, d6-DMSO): δ 8.38 (d, J= 7.8 Hz, 1 H), 8.16-8.0 (m, 2 H), 7.73 (t, J= 7.8 Hz, 1 H), 7.66 (d, /= 7.2 Hz, 2 H), 7.28 (d, J= 7.2 Hz, 2 H), 7.22 (d, /= 7.2 Hz, 2 H), 6.99-6.92 (m, 4 H), 5.36 (s, 2 H), 3.76 (s, 3 H), 1.72-1.66 (m, 2 H), 1.25-1.18 (m, 2 H). MS: M+H: m/z = 450.2; M+Na: tn/z= 472.1. HPLC: 96%, (Condition-I).
Synthesis of 4-(4-methoxyphenyl)-l,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)- lH-imidazol-2(3H)-one (Example 822):
2-Hydroxy-l, 2-bis (4-methoxyphenyl) ethanone
Figure imgf000074_0002
To a stirred solution of 4-methoxybenzaldehyde (2 g, 14.6 mmol) in EtOH (50 mL) was added a solution of NaCN (0.8 g, 16.3 mmol) in water (5 mL) and the reaction mixture was refluxed for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, dried over Na2Sθ4, filtered and then concentrated in vacuo to yield a crude material which was purified via silica gel column chromatography eluting with 40% EtOAc in hexanes to afford 2-hydroxy-l, 2-bis (4-methoxyphenyl) ethanone (1.3 g, 65%) as a solid. 4,5-bis(4-methoxyphenyl)-l,3-dimethyl-lH-imidazol-2(3H)-one
Figure imgf000075_0001
A mixture of 2-hydroxy-l , 2-bis (4-methoxyphenyl) ethanone (1 g, 3.6 mmol) and 1 ,3- dimethylurea (1.29 g, 14.7 mmol) in ethylene glycol (10 mL) was refluxed at 180 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and then concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 80% EtOAc in hexanes to afford 4,5-bis(4-methoxyphenyl)- l,3-dimethyl-lH-imidazol-2(3H)-one (0.8 g, 67%) as a solid.
4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-l,3-dimethyl-lH-imidazol-2(3H)-one
Figure imgf000075_0002
To a stirred -4O0C solution of 4,5-bis(4-methoxyphenyl)-l,3-dimethyl-lH-imidazol-
2(3H)-one (0.6 g, 1.84 mmol) in DCM (10 mL), BBr3 (0.7 mL, 7.38 mmol) was added dropwise and the reaction mixture was then stirred for 48 h at RT, quenched with 6 N HCl and washed with water. The combined organic layers were then dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-(4-hydroxyphenyl)-5-(4- methoxyphenyl)-l,3-dimethyl-lH-imidazol-2(3H)-one (0.38 mg, 66 %) as a solid.
4-(4-Methoxyphenyl)-l,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)-lH- imidazol-2(3H)-one (Example 822)
Figure imgf000076_0001
To a stirred solution of 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-l,3-dimethyl-lH- imidazol-2(3H)-one (0.35 g, 1.12 mmol) in AcN (20 mL) was added K2CO3 (0.46 g, 3.3 mmol) at RT. The reaction mixture was heated to 8O0C for 30 min, and then 2- (chloromethyl)quinoline hydrochloride (0.29 g, 1.35 mmol) was added and the mixture stirred for an additional 3 h at 800C. Then the mixture was concentrated in vacuo and the residue was dissolved in EtOAc (30 mL). The organic layer was washed with water, dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 80% EtOAc/20% hexanes to afford 4-(4-methoxyphenyl)-l,3-dimethyl-5-(4-(quinolin-2- ylmethoxy)phenyl)-lH-imidazol-2(3H)-one (0.2 g, 39%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.21 (d, J= 7.2 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.84 (d, J= 7.2 Hz, I H), 7.74-7.72 (m, 1 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.59-7.56 (m, 1 H), 7.11-7.05 (m, 4 H), 6.93 (d, J = 7.2 Hz, 2 H), 6.82 (d, J= 7.6 Hz, 2 H), 5.39 (s, 2 H), 3.81 (s, 3 H), 3.19 (s, 6 H). MS: M+H: m/z = 452.2 and HPLC: 97%, (Condition-H).
Synthesis of 2, 2-dimethyl-4-(pyridin-4-vD-5-(4-(quinolin-2-vImethoxy) phenyl) furan-3(2HVone (Example 249)
l-(4-(Benzyloxy) phenyl)-4-methylpent-2-yne-l, 4-diol
Figure imgf000076_0002
To a precooled -780C solution of 2-methylbut-3-yn-2-ol (4.71 g, 0.05 mol) in THF (250 mL), »-BuLi (51.2 mL, 0.08 mol) was added under an inert atmosphere, and the mixture stirred for 30 min. Then, 4-(benzyloxy)benzaldehyde (8.0 g, 0.037 mol) in THF was added and the mixture was stirred for an additional 3 h at RT, quenched with a saturated NH4CI solution and concentrated in vacuo. The residue was acidified with HCl (1 N) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford l-(4- (benzyloxy) phenyl)-4-methylpent-2-yne-l, 4-diol (6 g, 54%) as a solid.
l-(4-(Benzyloxy) phenyl)-4-hydroxy-4-methylpent-2-yn-l-one
Figure imgf000077_0001
To a solution of l-(4-(benzyloxy) phenyl)-4-methylpent-2-yne-l, 4-diol (3.0 g, 0.01 mol) in DCM (30 mL) were added Celite® (1.0 g) followed by PCC (2.61 g, 0.01 mol) at RT. The reaction mixture was stirred for 1 h, filtered through a pad of Celite® and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford l-(4-(benzyloxy) phenyl)-4-hydroxy-4- methylpent-2-yn-l-one (1.5 g, 51 %) as a solid.
5-(4-(BenzyIoxy) phenyl)-2, 2-dimethylfuran-3(2H)-oπe
Figure imgf000077_0002
To a RT solution of l-(4-(benzyloxy) phenyl)-4-hydroxy-4-methylpent-2-yn-l-one (1.5 g, 0.005 mol) in EtOH (10 mL) was added a solution OfEt2NH (0.86 mL) in EtOH (10 mL) under an inert atmosphere. The reaction mixture was stirred for 1 hr and then concentrated in vacuo to obtain the crude product. The crude material was partitioned between water and DCM and the organic layer was separated, washed with water, dried over Na2SO4 and then concentrated in vacuo to afford 5-(4-(benzyloxy) phenyl)-2, 2- dimethylfuran-3(2H)-one (1.4 g, 98 %) as a solid.
5-(4-(Benzyloxy) phenyl)-4-bromo-2, 2-dimethylfuran-3(2H)-one
Figure imgf000078_0001
To a room temperature solution of 5-(4-(benzyloxy) phenyl)-2, 2-dimethylfuran-3(2H)- one (1.5 g, 0.005 moi) in CHCl3 (50 mL), NBS (1.37 g, 0.007 mol) was added portionwise. The reaction mixture was stirred for 2 h at RT and then concentrated in vacuo to obtain the crude product. The residue was partitioned between water and DCM. The organic layer was separated, washed with water, dried over Na2SCH, and concentrated in vacuo to afford 5-(4-(benzyloxy) phenyl)-4-bromo-2, 2-dimethylfuran-3(2H)-one (2.0 g) as a solid. This material was used in the next step without further purification.
5-(4-(Benzyloxy) phenyl)-2, 2-dimethyI-4-(pyridin-4-yl) furan-3(2H)-one
To a solution of 5-(4-(benzyloxy) phenyl)-4-bromo-2, 2-dimethylfuran-3(2H)-one (1.0 g, 2.67 mmol) in toluene (10 mL) were added pyridin-4-ylboronic acid (362 mg, 2.94 mmol), Cs2CO3 (4.3 g, 13.3 mmol) followed by water (5 mL) under an inert atmosphere. The reaction mixture was stirred for 15 minutes and then Pd(dppf)Cl2 (430 mg, 0.0005 mmol) was added. This mixture was refluxed for 16 h and then filtered through a pad of Celite®. The filtrate was extracted with EtOAc (2 x 40 mL) and the combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 40% EtOAc in hexanes to afford 5-(4-(benzyloxy) phenyl)-2, 2-dimethyl-4- (pyridin-4-yl) furan-3(2H)-one (620 mg, 62 %).
5-(4-Hydroxyphenyl)-2, 2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one
Figure imgf000079_0001
To a stirred solution of 5-(4-(benzyloxy) phenyl)-2, 2-dimethyl-4-(pyridin-4-yl) furan- 3(2H)-one (620 mg, 0.001 mmol) in MeOH (15 mL) was added Pd (OH) 2 (120 mg, 0.85 mmol) at RT under an inert atmosphere. The reaction mixture was stirred under a hydrogen atmosphere for 1 h. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4- hydroxyphenyl)-2, 2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (280 mg, 60 %) as a solid.
2, 2-dimethyl-4-(pyridin-4-yl)-5-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 249)
Figure imgf000079_0002
To a room temperature solution of 5-(4-hydroxyphenyl)-2, 2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (280 mg, 0.9 mol) in DMF (5 mL), K2CO3 (413 mg, 2.98 mol) was added and the reaction mixture was stirred for 30 min. 2-Chloro methyl quinoline (235 mg, 1.09 mol) was then added to the reaction and stirring was continued for 2 h at 85 °C. The reaction mixture was then quenched with cold water and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2, 2-dimethyl-4-(pyridin-4-yl)-5-(4-(quinolin- 2-ylmethoxy) phenyl) furan-3(2H)-one (240 mg, 57 %) as a solid. 1H NMR (500 MHz, dβ-DMSO): δ 8.58-8.54 (m, 2 H), 8.42 (d, J= 7.8 Hz, 1 H), 8.04-7.98 (m, 2 H), 7.80 (t, J = 7.6 Hz, 1 H), 7.68 (d, J= 7.4 Hz, 1 H), 7.64 (t, J= 7.6 Hz, 1 H), 7.58 (d, J= 7.4 Hz, 2 H), 7.30-7.24 (m, 2 H), 7.19 (d, J= 7.2 Hz, 2 H), 5.43 (s, 2 H), 1.50 (s, 6 H). MS: M+H: m/z = 423.0. HPLC: 96%, (Condition-I).
Synthesis of 5-(4-methoxypheny0-2, 2-dimethyI-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 138):
Ethyl 2-(4-(quinolin-2-ylmethoxy) phenyl) acetate
Figure imgf000080_0001
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile (150 mL) were added K2CO3 (23 g, 0.16 mol) and 2-(chloromethyl) quinoline (14.2 g, 0.06 mol) under an inert atmosphere. The reaction mixture was then heated at 80 0C for 16 h, diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2- ylmethoxy) phenyl) acetate (19 g, 95 %) as an oil.
2-(4-(Quinolin-2-ylmethoxy) phenyl) acetic acid
Figure imgf000080_0002
To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy) phenyl) acetate (20 g, 0.05 mol) in MeOH (200 mL), a solution of KOH (12.6 g, 0.22 mol) in water (50 mL) was added dropwise and the reaction mixture was stirred for 1 h at RT. The methanol was then removed, and the reaction mixture was washed with EtOAc (2 x 100 mL) and acidified to pH ~ 3 with 1 N HCl at 0 0C. The precipitated solid was filtered and dried to afford 2-(4-(quinolin-2-ylmethoxy) phenyl) acetic acid (15 g, 92 %) as a white solid.
2-(4-(Quinolin-2-ylmethoxy) phenyl) acetyl chloride
Figure imgf000081_0001
A mixture of acid 2-(4-(quinolin-2-ylmethoxy) phenyl) acetic acid (2.0 g, 6.8 mmol) in SOCb (10 mL) was stirred at RT for 2 h under an inert atmosphere. The reaction was concentrated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy) phenyl) acetyl chloride (2.0 g, 95%) as a light yellow solid.
l-(4-Methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy) phenyl) ethanone
Figure imgf000081_0002
To a stirred solution of PPA (2.0 g, 20 mmol) were added 2-(4-(quinolin-2-ylmethoxy) phenyl) acetyl chloride (2.0 g, 5.0 mmol) and anisole (1.0 g, 10 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 80 0C for 3 h, quenched with ice cold water and stirred for another 10 minutes. The precipitated solid was filtered, and then the solid was stirred in 10% NaOH solution for Ih, extracted with DCM (2 X 50 mL). The combined organic layers were washed with water (2 x 10 mL) and brine, concentrated, and dried under vacuum to afford l-(4-methoxyphenyl)-2-(4-(quinolin-2- ylmethoxy) phenyl) ethanone (1.85 g, 90 %) as a solid.
2-Bromo-2-methyIpropanoyl chloride
Figure imgf000081_0003
A stirred solution of 2-bromo-2-methylpropanoic acid (3.0 g, 17.9 mmol) in SOCl2 (20 mL) was refluxed for 3 h. The reaction was concentrated in vacuo to afford 2-bromo-2- methylpropanoyl chloride (2.5 g, 76%) as a colorless oil.
2-Bromo-2-methylpropanoyl cyanide
Figure imgf000082_0001
A stirred solution of 2-bromo-2-methylpropanoyl chloride (2.5 g, 13.5 mmol) in trimethylsilanecarbonitrile (3.0 mL) was stirred at RT for 3 h under an inert atmosphere. The reaction mixture was concentrated in vacuo to afford 2-bromo-2-methylpropanoyl cyanide (1.8 g, 76 %) as a black oil.
5-(4-Methoxyphenyl)-2, 2-dimethyl-4-(4-(quinolin-2-ylmethoxy) phenyl) furan- 3(2H)-one (Example 138)
Figure imgf000082_0002
To a room temperature, stirred solution of l-(4-methoxyphenyl)-2-(4-(quinolin-2- ylmethoxy) phenyl) ethanone (100 mg, 0.26 mmol) in THF (5 mL), f-BuOK (1.0 mL, 1.0 N solution in THF) was added under an inert atmosphere and the resulting mixture was stirred for 30 min. 2-Bromo-2-methylpropanoyl cyanide (90 mg, 0.5 mmol) was then added to the reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (10-15% ethyl acetate in hexanes) to afford 5-(4-methoxyphenyl)-2, 2-dimethyl-4-(4- (quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (10 mg ) as a solid. 1H NMR (500 MHz, (I6-DMSO): δ 8.42 (d, J= 7.6 Hz, 1 H), 8.06-7.99 (m, 2 H), 7.95 (t, J= 7.2 Hz, 1 H), 7.72 (t, J= 7.2 Hz, 1 H), 7.63 (t, J= 7.8 Hz, 1 H), 7.56 (d, J= 7.2 Hz, 2 H); 7.18 (d, J= 7.4 Hz, 2 H), 7.12 (d, J= 7.2 Hz, 2 H), 6.89 (d, J= 7.2 Hz, 2 H), 5.38 (s, 2 H), 3.79 (s, 3 H).1.42 (s, 6 H). MS: M+H: m/z = 452.1 ; M+Na: m/z= 474.2. HPLC: 96%, Column: Eclipse XDB- C18, 150 X 4.6 mm, 5um. Mobile Phase: 0.1 % TFA in Water (A), AcN (B), Flow rate: 1.5ml/min (Gradient). Synthesis of 2, 2-Dimethyl-5-(pyridin-4-v0-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 125)
Trimethyl (2-methylbut-3-yn-2-yloxy) silane
Figure imgf000083_0001
To a room temperature, stirred solution of 2-methylbut-3-yn-2-ol (20 g, 0.23 mol) in HMDS (42.3 g, 0.261 mol), LiClO4 (38.03 g, 0.35 mol) was added and the mixture was stirred for additional 30 min. The reaction mixture was then diluted with water (100 mL) and extracted with ether (3 x 200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and filtered. The ether was distilled off at 80 0C to afford trimethyl (2-methylbut-3-yn-2-yloxy) silane (25 g) as an oil.
4-Methyl-l-(pyridin-4-yl)-4-(trimethylsily-oxy) pent-2-yn-l-one
Figure imgf000083_0002
To a stirred -780C solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (5.0 g, 0.03 mol) in dry THF (150 mL), w-BuLi (23.82 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. After stirring for 30 min at -78 °C, a solution of N-methoxy-N-methylisonicotinamide (6.34 g, 0.03 mol) in dry THF (30 mL) was added to the reaction mixture and stirring was continued for an additional 40 min at -78 0C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5 % EtOAc in hexanes to afford 4-methyl-l-(pyridin-4-yl)- 4-(trimethylsilyloxy) pent-2-yn-l-one (2.2 g, 27 %) as an oil. 4-Hydroxy-4-methyl-l-(pyridin-4-yl) pent-2-yn-l-one
Figure imgf000084_0001
To a room temperature, stirred solution of 4-methyl-l-(pyridin-4-yl)-4- (trimethylsilyloxy) pent-2-yn-l-one (0.5 g, 1.915 mmol) in DCM (10 mL) was added PTSA (0.47 g, 2.49 mmol). The reaction mixture was stirred for 2 h and then diluted with DCM (50 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 4-hydroxy-4-methyl-l-(pyridin-4-yl) pent-2-yn-l-one (0.35 g, 97%) as an oil.
2, 2-Dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
Figure imgf000084_0002
To a room temperature, stirred solution of 4-hydroxy-4-methyl-l-(pyridin-4-yl) pent-2- yn-l-one (1.49 g, 0.007 mol) in ethanol (15 mL), a solution of diethylamine (0.51 1 g, 0.007 mol) in EtOH (15 mL) was added dropwise and the reaction mixture was stirred for additional 40 min. The ethanol was removed, and the mixture was then diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2, 2- dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.4 g).
4-Bromo-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
Figure imgf000084_0003
To a room temperature, stirred solution of 2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
(0.81 g, 4.28 mmol) in CHCl3 (20 mL), NBS (1.3 g, 7.28 mmol) was added portionwise. The reaction mixture was then stirred for 2 h and diluted with DCM (100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2, 2- dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.25 g, 22 %) as a solid.
2, 2-Dimethyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 125)
Figure imgf000085_0001
A solution of 4-bromo-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.25 g, 0.93 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.37 g, 1.026 mmol), and Cs2CO3 (1.52 g, 4.664 mmol) in 5:1 toluene/water (12 mL) was degassed. Then, Pd(dppf)Cl2 (152.2 mg, 0.18 mmol) was added under an inert atmosphere and the solution was degassed again. The reaction mixture was then refluxed for 3 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2, 2-dimethyl-5- (pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (0.29 g, 74 %) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.78 (d, J= 7.2 Hz, 1 H), 8.56-8.50 (m, 2 H), 8.15- 8.05 (m, 2 H), 7.78-7.72 (m, 1 H), 7.63-7.59 (m, 1 H), 7.56-7.47 (m, 2 H); 7.18-7.09 (m, 2 H), 7.02-6.96 (m, 3 H), 5.40 (s, 2 H), 1.50 (s, 6 H). MS: M+H: m/z = 423.1. LC-MS: 98%, Column: Eclipse XDB- C 18, 150 X 4.6 mm, 5um. Mobile Phase: 0.1 % TFA in Water (A), AcN (B), Flow rate: 1.5ml/min (Gradient).
Synthesis of 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenvD-4- oxaspirof2.41hept-6-en-5-one (Example 26) Ethyl 2-(4-(quinolin-2-ylmethoxy) phenyl) acetate
Figure imgf000086_0001
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 11 1.10 mmol) in AcN (200 mL) were added K2CO3 (145.9 g, 333.30 mmol) and 2-(chloromethyl) quinoline (28.50 g, 133.32 mmol) at RT. The reaction mixture was heated at 90 0C for 12 h and then cooled to RT and filtered. The filtrate was concentrated in vacuo. The residue was then diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water, a saturated NH4C 1 solution, and then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2- ylmethoxy) phenyl) acetate (38.0 g, 89 %) as a solid.
2-(4-(Quinolin-2-ylmethoxy) phenyl) acetic acid
Figure imgf000086_0002
To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy) phenyl) acetate (38.0 g, 106.741 mmol) in ethanol (200 mL) and water (100 mL) was added KOH (23.9 g, 426.964 mmol) at room temperature. The mixture was stirred at RT for 4 h and after complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (50 mL) and acidified using 1 N HCl at 0 0C. The aqueous layer was extracted with EtOAc (2 x 150 mL) and thecombined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and evaporated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy) phenyl) acetic acid (30.Og, 95%) as a white solid. 2-(4-(Quinolin-2-ylmethoxy) phenyl) acetyl chloride
Figure imgf000087_0001
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy) phenyl) acetic acid (2.0 g, 6.825 mmol) in CHCl3 (6 mL) was added SOCl2 (10 mL) at 0 0C and the reaction mixture was stirred at RT for 2 h. The reaction was concentrated in vacuo and the residue was re- dissolved in ether (50 mL). The mixture was concentrated in vacuo again to afford 2-(4- (quinolin-2-ylmethoxy) phenyl) acetyl chloride (2.0 g, 95 %) as a light yellow oil.
Methyl l-(2-(4-(quinolin-2-ylmethoxy) phenyl) acetoxy) cyclopropanecarboxylate
Figure imgf000087_0002
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy) phenyl) acetyl chloride (2.0 g, 6.557 mmol) in DCM (50 mL) was added DMAP (1.4 g, 13.11 mmol) followed by methyl 1- hydroxycyclopropanecarboxylate (1.1 g, 9.836 mmol) under a nitrogen atmosphere at RT. The reaction mixture was stirred for 14 h and after complete consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were washed with a saturated NaHCCh solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude methyl l-(2-(4- (quinolin-2-ylmethoxy) phenyl) acetoxy) cyclopropanecarboxylate (2.0 g) as a solid.
7-Hydroxy-6-(4-(quinolin-2-ylmethoxy) phenyl)-4-oxaspiro [2.4] hept-6-en-5-one
Figure imgf000088_0001
To a O0C solution of methyl l-(2-(4-(quinolin-2-ylmethoxy) phenyl) acetoxy) cyclopropanecarboxylate (2.0 g, 6.825 mmol) in DMF (20 mL), NaH (49 mg, 20.477 mol) was added nd the mixture was stirred at RT for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice water (3 mL) and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layes were washed with water (30 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude 7-hydroxy-6-(4- (quinolin-2-ylmethoxy) phenyl)-4-oxaspiro [2.4] hept-6-en-5-one (2.0 g, 83 %) as a light yellow solid.
5-Oxo-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-7-yl trifluoromethanesulfonate
Figure imgf000088_0002
To a 00C solution of 7-hydroxy-6-(4-(quinolin-2-ylmethoxy) phenyl)-4-oxaspiro [2.4] hept-6-en-5-one (400 mg, 1.1 mmol) in DCM (15 mL) were added TEA (226 mg, 3.36 mmol) and triflic anhydride (631 mg, 2.2 mol) under an inert atmosphere. The reaction mixture was stirred for 2 h at O0C, diluted with water and then extracted with DCM (2 x 50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 5-oxo-6-(4-(quinolin-2-ylmethoxy)phenyl)-4- oxaspiro[2.4]hept-6-en-7-yl trifluoromethanesulfonate (400 mg, 73 %) as an ash-colored solid. 7-(Pyridin-4-yl)-6-(4-(quinolin-2-yliτiethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (Example 26)
Figure imgf000089_0001
To a room temperature, stirred solution of 5-oxo-6-(4-(quinolin-2-ylmethoxy)phenyl)-4- oxaspiro[2.4]hept-6-en-7-yl trifluoromethanesulfonate (200 mg, 0.4 mmol) in 1, 4- dioxane (10 mL) were added pyridin-4-ylboronic acid (74 mg, 0.6 mmol), Na2CO3 (102 mg, 1.2 mmol) and water (4 mL) under an inert atmosphere. The mixture was stirred for 30 minutes and then Pd(PPh3^ (46 mg, 0.04 mmol) was added and the mixture refluxed for 16. h. The reaction mixture was then diluted with water and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)- 4-oxaspiro[2.4]hept-6-en-5-one (30 mg, 18 %) as a white solid. 1H NMR (500 MHz, d6- DMSO): δ 8.64-8.61 (m, 2 H), 8.40 (d, J= 7.2 Hz, 1 H), 8.02 - 7.99 (m, 2 H), 7.81-7.77 (m, 1 H), 7.67- 7.51 (m, 3 H), 7.38-7.24 (m, 5 H), 5.36 (s, 2 H), 1.88-1.85 (m, 2 H), 1.24- 1.21 (m, 2 H). MS: M+H: m/z = 421.2; M+Na: m/z = 443.2. HPLC: 92%, (Condition-I).
Synthesis of l-methyl-3-tnorpholino-4-(4-(quinolin-2-ylmethoxy) phenvO-lH- pyrrole-2, 5-dione (Example 812);
3-Bromo-l-methyl-4-morpholino-lH-pyrrole-2, 5-dione
Figure imgf000089_0002
To a room temperature, stirred solution of 2,3-dibromo-N-methylmaleimide (1 g, 0.004 mol) in DMF (10 mL) was added Cs2CO3 (1.34 g, 0.004 mol) followed by morpholine (360 mg, 0.004 mol) under N2 atmosphere. The reaction mixture was then stirred for 30 minutes, quenched with ice water, and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-bromo-l-rnethyl-4-morpholino-lH-pyrrole-2, 5-dione (0.87 g, 85 %) as a solid.
l-Methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy) phenyl)-lH-pyrrole-2, S-dione (Example 812)
Figure imgf000090_0001
To a stirred solution of 3-bromo-l-methyl-4-moφholino-lH-pyrrole-2,5-dione (100 mg, 0.36 mol) in DMF (40 mL) were added Cs2CO3 (415 mg, 1.27 mmol), water (5 mL), and Pd(Ph3P)4 (84 mg, 0.072 mmol). 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline (138 mg, 0.38 mmol) was then added and the reaction mixture was heated at 80 °C for 3 h, filtered through a pad of Celite® and the filtrate was then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 60% EtOAc in hexanes to afford 1- methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy) phenyl)- lH-pyrrole-2, 5-dione (70 mg, 45 %). 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J = 7.2 Hz, 1 H), 8.1 (t, J= 7.2 Hz, 2 H) 7.78 (t, J= 7.8 Hz, 1 H), 7.70 (d, J= 7.2 Hz, 1 H), 7.64 (t, J= 7.2 Hz, 1 H), 7.28 (d, J= 7.4 Hz, 2 H), 7.12 (d, J= 7.4 Hz, 2 H), 5.38 (s, 2 H), 3.62-3.58 (m, 4 H), 3.45- 3.39 (m, 4 H), 2.96 (s, 3 H); MS: M+H: m/z = 430.2 HPLC: 96%, (Condition-C).
Synthesis of 1-methyl- 3-(4-oxopiperidin-l-yO-4-(4-(quinolin-2-ylmethoxy)phenyD- lH-pyrrole-2,5-dione (Example 820)
3-Bromo-l-methyl-4-(4-oxopiperidin-l-yl)-lH-pyrrole-2,5-dione
Figure imgf000091_0001
To a stirred solution of 3,4-dibromo-l-methyl-lH-pyrrole-2,5-dione (100 mg, 0.373 mmol) in AcN (20 mL) was added piperidin-4-one hydrochloride (101 mg, 0.746 mmol) at room temperature followed by K2CO3 (102 mg, 7.46 mol). The reaction mixture was then refluxed for 2 h, diluted with water, extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 30% EtOAc in hexanes to afford 3-bromo-l-methyl-4-(4- oxopiperidin-l-yl)-lH-pyrrole-2,5-dione (100 mg, 99 %) as a pale yellow solid.
l-Methyl- 3-(4-oxopiperidin-l-yl)-4-(4-(quinoHn-2-ylmethoxy)phenyl)-lH-pyrrole- 2,5-dione (Example 820)
Figure imgf000091_0002
To a room temperature, stirred solution of 3-bromo-l-methyl-4-(4-oxopiperidin-l-yl)- lH-pyrrole-2,5-dione (100 mg, 0.34 mmol) in 1, 4-dioxane (10 mL) was added 2-((4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (151 mg, 0.41 mol) under a N2 atmosphere. The reaction mixture was stirred for 30 minutes and then Na2CO3 (87 mg, 1.04 mmol), water (4 mL) and Pd(PPh3)4 (40 mg, 0.03 mmol) were added also under a N2 atmosphere. The resulting mixture was then refluxed for 16 h, diluted with water and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 60% EtOAc in hexanes to afford 1 -methyl- 3-(4-oxopiperidin-l-yl)-4-(4-(quinolin- 2-ylmethoxy)phenyl)-lH-pyrrole-2,5-dione (80 mg, 52 %) as a solid. 1H NMR (500 MHz, (J6-DMSO): δ 8.45 (d, J = 7.4 Hz, 1 H), 8.12 (t, J = 7.2 Hz, 2 H) 7.79 (t, J= 7.2 Hz, 1 H), 7.72 (d, J= 7.8 Hz,l H), 7.64 (t, J= 7.6 Hz, 1 H), 7.18 (d, J= 7.2 Hz, 2 H), 7.12 (d, J= 12 Hz, 2 H), 5.38 (s, 2 H), 3.62-3.58 (m, 4 H), 2.96-2.85 (m, 4 H), 2.56 (s,4 H). MS: M+: m/z = 441.6; M+H: m/z = 442.7. HPLC: 97%, (Condition-B).
Synthesis of 2, 2-dimethyl-5-(4-nitiOphenyl)-4-(4-(quinol-n-2-ylinethoxy) phenyl) furan-3(2H)-one (Example 164):
4-Methyl-l-(4-nitrophenyl) pent-2-yne-l, 4-diol
Figure imgf000092_0001
To a stirred -780C solution of 2-methylbut-3-yn-2-ol (6.1 mL, 63.5 mmol, 1.2 eq) in dry THF (250 mL), «-BuLi (62 mL, 2.3 M in hexane, 142 mmol, 2.7 eq) was added dropwise over 10 minutes under an inert atmosphere. After being stirred for 40 min at -78 °C, a solution of 4-nitrobenzaldehyde (8 g, 52.9 mmol, 1 eq) in dry THF (50 mL) was added to the reaction mixture and stirring was continued for an additional Ih at -78 0C. The reaction mixture was then quenched with a saturated NH4CI solution and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (30% ethyl acetate in hexanes) to afford 4-methyl-l -(4-nitrophenyl) pent-2-yne-l, 4-diol (8 g, 65 %) as a yellow solid.
4-Hydroxy-4-methyl-l-(4-nitrophenyl) pent-2-yn-l-one
Figure imgf000092_0002
To a room temperature solution of 4-methyl-l-(4-nitrophenyl) pent-2-yne-l, 4-diol (2g, 8.51 mmol, leq) in dry DCM (100 mL) was added NaHCO3 (680 mg, 8.51 mmol, 1 eq) followed by Dess Martin Periodinane (9.2g, 21.27 mmol, 2.5 eq). The reaction mixture was stirred at RT for 16h. After completion of the reaction (as monitored by TLC), the reaction mixture was quenched with a saturated sodium bisulfite solution and extracted with DCM (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried overNa2Sθ4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 20% EtOAc in hexanes to afford 4-hydroxy-4-methyl-l-(4-nitrophenyl) pent-2-yn-l-one (1.7 g, 86 %) as an oil.
2, 2-Dimethyl-5-(4-nitrophenyl) furan-3(2H)-one
Figure imgf000093_0001
To a stirred solution of 4-hydroxy-4-methyl-l-(4-nitrophenyl) pent-2-yn-l-one (1.74 g, 7.46 mmol, leq) in ethanol (30 mL), a solution of diethylamine (778 mg, 7.46 mmol, leq) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 90 min. The ethanol was removed, and the mixture was then diluted with EtOAc (100 mL). The combined organic layers were washed with water (50 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 2, 2- dimethyl-5-(4-nitrophenyl) furan-3(2H)-one (1.6 g, 92%) whichw as used in the next step without further purification.
4-Bromo-2, 2-dimethyl-5-(4-nitrophenyl) furan-3(2H)-one
Figure imgf000093_0002
To a O0C stirred solution of crude 2, 2-dimethyl-5-(4-nitrophenyl) furan-3(2H)-one (170 mg, 0.73 mmol, 1 eq) in CHCl3 (10 mL) was added NBS (259 mg, 1.45 mmol, 2 eq), and the reaction mixture was then stirred at RT for 2h. The chloroform was removed and the crude material was then purified via silica gel column chromatography eluting with 10 % EtOAc in hexanes to afford 4-bromo-2, 2-dimethyl-5-(4-nitrophenyl) furan-3(2H)-one (100 mg, 44 %) as a yellow solid.
2, 2-Dimethyl-5-(4-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy) phenyl) furaπ-3(2H)- one (Example 164)
Figure imgf000094_0001
A solution of 4-bromo-2, 2-dimethyl-5-(4-nitrophenyl) furan-3(2H)-one (100 mg, 0.32 mmol, 1 eq), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline (115 mg, 0.32 mmol, 1 eq), and Cs2CO3 (521 mg, 1.6 mmol, 5 eq) in toluene (7 mL) and water (2.5 mL) was degassed. Then Pd (dppf)Cl2 (52 mg, 0.06 mmol, 0.2 eq) was added under an inert atmosphere and the solution was again degassed. The reaction mixture was then refluxed for 3 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography (10% ethyl acetate in hexanes) to afford 2, 2-dimethyl- 5-(4-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (80 mg, 54 %) as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.42 (d, J= 8.5 Hz, 1 H), 8.27 (d, J= 8.5 Hz, 2 H), 8.00 (t, J= 7.9 Hz, 2 H), 7.82 - 7. 76 (m, 3 H), 7.68 (d, J= 8.5 Hz, 1 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.18 (d, J= 8.7 Hz, 2 H), 7.10 (d, J= 8.7 Hz, 2 H), 5.38 (s, 2 H), 1.48 (s, 6 H).MS: [M + H]: m/z = 467.1. HPLC: 89%, Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient). Synthesis of 5-(4-chlorophenvO-2, 2-dimethyl-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 147): l-(4-Chlorophenyl)-4-methyl-4-(trimethylsilyloxy) pent-2-yn-l-one
Figure imgf000095_0001
To a -780C stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (1 1.79 g, 75.15 mmol) in dry THF (100 mL), H-BuLi (14.08 mL, 22.54 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. After being stirred for 30 min at -78 0C, a solution of 4-chloro-N-methoxy-N-methylbenzamide (5.0 g, 25.0 mmol) in dry THF ( 10 mL) was added to reaction mixture and stirring was continued for an additional 1 h at -78 0C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5-7 % EtOAc in hexanes to afford l-(4- chlorophenyl)-4-methyl-4-(trimethylsilyloxy) pent-2-yn-l-one (3.8 g, 57 %) as a light green oil.
l-(4-Chlorophenyl)-4-hydroxy-4-methylpent-2-yn-l-one
Figure imgf000095_0002
To a stirred solution of l-(4-chlorophenyl)-4-methyl-4-(trimethylsilyloxy) pent-2-yn-l- one (3.7 g, 12.50 mmol) in DCM (20 mL) was added PTSA (2.87 g, 15.01 mmol) at RT. The reaction mixture was stirred for 1 h and diluted with water (10 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford l-(4-chlorophenyl)-4-hydroxy- 4-methylpent-2-yn-l-one (2.40 g) as a pale red oil.
5-(4-Chlorophenyl)-2, 2-dimethylfuran-3(2H)-one
Figure imgf000096_0001
To a stirred solution of l-(4-chlorophenyl)-4-hydroxy-4-methylpent-2-yn-l-one (2.4 g, 10.70 mmol) in ethanol (20 mL), a solution of diethyl amine (1.34 mL, 12.90 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 30 min. The ethanol was then removed and the mixture was diluted with EtOAc (50 mL). The combined organic layers were then washed with water (10 mL), and brine (10 mL), dried OVCrNa2SO4, filtered, and concentrated in vacuo to afford 5-(4- chlorophenyl)-2, 2-dimethylfuran-3(2H)-one (2.1 g) as a light green gummy oil.
4-Bromo-5-(4-chlorophenyl)-2, 2-dimethylfuran-3(2H)-one
Figure imgf000096_0002
To stirred solution of crude 5-(4-chlorophenyl)-2, 2-dimethylfuran-3(2H)-one (2.1 g, 13.0 mmol) in CHCl3 (15 mL), NBS (3.93 g, 22.10 mmol) was added portionwise at RT. The reaction mixture was stirred for 1 h and then diluted with DCM (100 mL). The combined organic layers were washed with water (50 mL) and brine (30 mL), dried OVCrNa2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-5-(4- chlorophenyl)-2, 2-dimethylfuran-3(2H)-one (2.0 g, 51 % over three steps) as an off- white solid.
5-(4-Chlorophenyl)-2, 2-dimethyl-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)- one (Example 147)
Figure imgf000097_0001
A solution of 4-bromo-5-(4-chlorophenyl)-2, 2-dimethylfuran-3(2H)-one (1.0 g,'3.3O mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (1.30 g, 3.60 mmol), and Cs2CO3 (5.37 g, 16.50 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)Cl2 (0.54 g, 0.601 mmol) was added under an inert atmosphere and the solution was degassed again. The reaction mixture was then refluxed for 2 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4- chlorophenyl)-2, 2-dimethyl-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (520 mg, 35 %) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J= 8.5 Hz,
1 H), 8.02 (t, J = 7.9 Hz, 2 H), 7.81 (t, J= 8.4 Hz, 1 H), 7.70 (d, J= 8.2 Hz, 1 H), 7.63 (t, J= 8.2 Hz, 1 H), 7.58 (d, J= 8.5 Hz, 2 H), 7.52 (d, J= 8.5 Hz, 2 H), 7.18 (d, J= 7.4 Hz,
2 H), 7.11 (d, J= 7.5 Hz, 2 H), 5.39 (s, 2 H), 1.44 (s, 6 H). MS: [M + Na]: m/z= 478.1, [M + H]: m/z = 456.1. HPLC: 97%, Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 4-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyQ-4, 5- dihvdrofuran-2-vD benzonitrile (Example 141):
4-Cyano-N-methoxy-N-methyIbenzamide
Figure imgf000097_0002
To a stirred solution of 4-cyanobenzoic acid (5.0 g, 34.0 mmol) in DCM (75 mL) were added HATU (19.40 g, 51.0 mmol), N-methoxy, N-methylamine (4.90 g, 51.0 mmol) and TEA (14.30 mL, 102.0 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic extracts were washed with water (60 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure- to afford 4-cyano-N-methoxy-N-methylbenzamide (6.2 g, 96 %) as a yellow color oil.
4-(4-Methyl-4-(trimethylsilyloxy) pent-2-ynoyl) benzonitrile
Figure imgf000098_0001
To a -780C stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (3.3 g, 20.00 mmol) in dry THF (45 mL), «-BuLi (4.1 mL, 9.00 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at -78 0C, and then a solution of 4-cyano-N-methoxy-N-methylbenzamide (2.0 g, 10.00 mmol) in dry THF (15 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at -78 0C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried OVCr Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 15 % EtOAc in hexanes to afford 4-(4- methyl-4-(trimethylsilyloxy) pent-2-ynoyl) benzonitrile (3.8 g, 68 %) as a yellow oil.
4-(4-Hydroxy-4-methylpent-2-ynoyl) benzonitrile
Figure imgf000098_0002
To a stirred solution of 4-(4-methyl-4-(trimethylsilyloxy) pent-2-ynoyl) benzonitrile (1.7 g, 5.00 mmol) in DCM (15 mL) was added PTSA (1.70 g, 8.90 mmol) at RT and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 4-(4-hydroxy-4-methylpent-2-ynoyl) benzonitrile (1.20 g) as a yellow oil.
4-(5, 5-Dimethyl-4-oxo-4, 5-dihydrofuran-2-yl) benzonitrile
Figure imgf000099_0001
To a stirred solution of crude 4-(4-hydroxy-4-methylpent-2-ynoyl) benzonitrile (1.2 g, 5.60 mmol) in ethanol (12 mL), a solution of diethyl amine (0.58 mL, 5.60 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 1 h. The ethanol was removed and the mixture then diluted with EtOAc (50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried OVCrNa2SO4, filtered, and concentrated in vacuo to afford crude 4-(5, 5-dimethyl-4- oxo-4, 5-dihydrofuran-2-yl) benzonitrile (1.2 g) as a light green semi solid which was taken on to the next step without further purification.
4-(3-Bromo-5, 5-dimethyl-4-oxo-4, 5-dihydrofuran-2-yl) benzonitrile
Figure imgf000099_0002
To a stirred solution of 4-(5, 5-dimethyl-4-oxo-4, 5-dihydrofuran-2-yl) benzonitrile (1.2 g, 5.60 mmol) in CHCl3 (12 mL), NBS (1.1 g, 6.00 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (100 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(3-bromo-5, 5- dimethyl-4-oxo-4, 5-dihydrofuran-2-yl) benzonitrile (0.50 g, 31 %) as an off white solid.
4-(5, 5-Dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, 5-dihydrofuran-2-yl) benzonitrile (Example 141)
Figure imgf000100_0001
A solution of 4-(3-bromo-5, 5-dimethyl-4-oxo-4, 5-dihydrofuran-2-yl) benzonitrile (0.3 g, 1.03 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline (0.374 g, 1.03 mmol), and Cs2CO3 (1.70 g, 5.14 mmol) in toluene (7 mL) and water (2.5 mL) was degassed. Then, Pd(dppf)Cl2 (0.17 g, 0.20 mmol) was added under an inert atmosphere and the solution was again degassed. Then the reaction was refluxed for 2 h. The reaction mixture was then filtered through a pad of Celite® and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2Sθ4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2- ylmethoxy) phenyl)-4, 5-dihydrofuran-2-yl) benzonitrile (280 mg, 61 %) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO): δ 8.42 (d, J = 8.5 Hz, 1 H), 8.01 (t, J= 7.9 Hz, 2 H), 7.90 (d, J= 8.4 Hz, 2 H), 7.78 (t, J= 8.3 Hz, 1 H), 7.72 - 7.67 (m, 3 H), 7.62 (t, J= 8.3 Hz, 1 H), 7.16 (d, J= 8.8 Hz, 2 H), 7.10 (d, J= 8.8 Hz, 2 H), 5.38 (s, 2 H), 1.46 (s, 6 H). MS: [M + H]: m/z = 447.5. HPLC: 98%, Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 5-(Benzofclϊl,2,51oxadiazol-5-v0-2,2-dimethyl-4-(4-(quinolin-2- ylmethoxy)phenyl)furan-3(2HVone (Example 166):
4-Bromo-2-nitroaniline
Figure imgf000100_0002
To a stirred solution of 2-nitroaniline (10.0 g, 72.462 mmol) in AcOH (50 mL) was added NBS (12.0 g, 72.463 mmol) .at 00C under a N2 atmosphere. The reaction mixture was stirred at 400C for 30 min. After completion of starting material (monitored by TLC), reaction mixture was diluted with water and a white precipitate was formed. After filtration, the crude solid was recrystalised from n-hexanes to afford 4-bromo-2- nitroaniline (12 g, 76%), as a brown solid.
5-Bromobenzo[c][l,2,5]oxadiazoIe 1 -oxide
Figure imgf000101_0001
To a room temperature, stirred solution of 4-bromo-2-nitroaniline (8.0 g, 37.037 mmol) in EtOH (80 mL) was added KOH (6.20 g, 111.111 mmol) and the reaction mixture was stirred at 60 °Cfor 2 h. The reaction was then cooled to O0C and NaOCl (80 mL) was added. The reaction mixture was then stirred at RT for another 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered, washed with water, and dried in vacuo to afford 5-bromobenzo[c][l,2,5]oxadiazole 1 -oxide (7.0 g, 88 %) as a light yellow solid.
5-Bromobenzo[c][l, 2, 5] oxadiazole
Figure imgf000101_0002
To a stirred solution of 5-bromobenzo[c][l,2,5]oxadiazole 1-oxide (6.0 g, 28.436 mmol) in ethanol (60 mL) was added triethyl phosphite (6.2 mL, 34.123 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 60 0C for 1 h., cooled to RT, diluted with hexane (100 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5- , bromobenzo[c][l,2,5] oxadiazole (4.0 g, 71%) as a light yellow solid.
Benzo[c] [l,2,5]oxadiazoIe-S-carbonitrile
Figure imgf000102_0001
To a stirred solution of 5-bromobenzo[c][l, 2, and 5] oxadiazole (2.0 g, 10.050 mmol) in DMF (50 mL) was added CuCN (1.79 g, 230.10 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 140 0C for 24 h., cooled to RT, diluted with water (10 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford benzo[c][l,2,5]oxadiazole-5- carbonitrile (0.7 g, 48 %) as a yellow solid.
Ethyl benzo[c][l,2,5]oxadiazole-5-carboxylate
Figure imgf000102_0002
To a solution of benzo[c][l,2,5]oxadiazole-5-carbonitrile (700 mg, 1.33 mol) in EtOH (100 mL) was added H2SC^ (20 mL) and the reaction mixture was refluxed for 14 h. The reaction was concentrated in vacuo and the residue was diluted with water (50 mL), and extracted with DCM (2 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and then concentrated in vacuo to afford ethyl benzo[c][l,2,5]oxadiazole-5-carboxylate (0.7 g, 75%) as a yellow, sticky solid.
Benzo[c] [1, 2,5] oxadiazole-5-carboxylic acid
Figure imgf000102_0003
To a room temperature, stirred solution of ethyl benzo[c][l,2,5]oxadiazole-5-carboxylate (0.7 g, 3.626 mmol) in MeOH (30 mL) was added 10% NaOH solution (6 mL) and the reaction mixture was then stirred at 400C for 3 h. The reaction mixture was then acidified to pH ~ 2 with 2 N HCl and the aqueous layer was extracted with DCM (3 x 150 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford benzo[c][l,2,5]oxadiazole-5-carboxylic acid (0.49 g, 82%) as a solid. N-Methoxy-N-methylbenzo[c][l,2,5]oxadiazole-5-carboxami(le
Figure imgf000103_0001
To a stirred solution of benzo[c][l,2,5]oxadiazole-5-carboxylic acid (0.49 g, 2.987 mmol) in DCM (50 mL) were added HATU (1.7 g , 4.481 mmol), N-methoxy, N-methylamine (0.44 g, 4.481 mmol) and TEA (914 mg, 8.963 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford N-methoxy-N- methylbenzo[c][l,2,5]oxadiazole-5-carboxamide (0.49 g, 79 %) as a yellow oil.
l-(Benzo[c][l,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-l-one
Figure imgf000103_0002
To a -780C stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.49 g, 2.367 mmol) in dry THF (20 mL), M-BuLi (3.70 mL, 5.917 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at -78 °C, and then a solution of N-methoxy -N- methylbenzo[c][l,2,5]oxadiazole-5-carboxamide (0.557 g, 3.550 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at -78 0C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5 % EtOAc in hexanes to afford l-(benzo[c][l,2,5]oxadiazol-5-yl)-4-methyl- 4-(trimethylsilyloxy)pent-2-yn-l-one (0.45 g, 63 %) as a colorless oil.
l-(Benzo[c][l,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-l-one
Figure imgf000104_0001
To a stirred solution of l-(benzo[c][l,2,5]oxadiazol-5-yl)-4-methyl-4- (trimethylsilyloxy)pent-2-yn-l-one (0.45 g, 1.490 mmol) in DCM (15 rtiL) was added p- TSA (0.34 Ig, 1.790 mmol) at RT and the reaction mixture was stirred for 3 h. The reaction mixture was then diluted with water (5 mL) and the layers were separated. The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1- (benzo[c][l,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-l-one (0.3 g, 87 %) as an oil.
5-(Benzo[c][l,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one
Figure imgf000104_0002
To a stirred solution of l-(benzo[c][l,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn- 1-one (0.3 g, 1.304 mmol) in ethanol (15 mL), a solution of diethyl amine (0.095 g, 1.304 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for 2h. The ethanol was then removed, and the mixture was diluted with EtOAc (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(benzo[c][l,2,5]oxadiazol-5- yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 83 %) as a black oil.
5-(Benzo[c][l,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one
Figure imgf000104_0003
To a stirred solution of 5-(benzo[c][l,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 1.086 mmoi) in CHCl3 (15 mL), NBS (0.29 g, 1.630 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (10 mL). The organic layer was then washed with water (5 mL) and brine (10 mL), dried over Na2SO1I5 filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5- (benzo[c][l,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 60 %) as a yellow solid.
5-(Benzo[c][l,2,5]oxadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2- ylmethoxy)phenyl)furan-3(2H)-one (Example 166)
Figure imgf000105_0001
A solution of 5-(Benzo[c][l,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 0.645 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline (0.256 g, 0.709 mmol), and Cs2CO3 (1.0 g, 3.220 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)Cl2 (0.105 g, 0.129 mmol) was added under an inert atmosphere and the solution was again degassed. Then the reaction mixture was refluxed for 12 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried OVCrNa2SO,), filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][l,2,5]oxadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin- 2-ylmethoxy)phenyl)furan-3(2H)-one (170 mg, 57 %) as a yellow color solid. 1H NMR (500 MHz, de-DMSO): δ 8.44 (d, J= 8.5 Hz, 1 H), 8.39 (s, 1 H), 8.07 - 8.00 (m, 3 H), 7.81 (t, J= 8.4 Hz, 1 H), 7.70 (d, J= 8.2 Hz, 1 H), 7.64 (t, J= 8.2 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 2 H), 7.25 (d, J= 8.3 Hz, 2 H), 7.12 (d, J= 8.4 Hz, 2 H), 5.39 (s, 2 H), 1.49 (s, 6 H). MS: [M + H]: m/z = 464.2. HPLC: 93%, Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient). Synthesis of 5-(benzo[cl[l, 2, 51 thiadiazol-5-v0-2,2-dimethyl-4-(4-(quinolin-2- ylmethoxy)phenvDfuran-3(2ID-one (Example 167):
N-Methoxy-N-methylbenzene[c][l,2,5]thiadiazole-5-carboxamide
Figure imgf000106_0001
To a stirred solution of benzo[c][l,2,5]thiadiazole-5-carboxylic acid (1.0 g, 5.556 mmol) in DCM (20 mL) were added HATU (3.1 g mg, 8.334 mmol), N-methoxy methylamine (0.58 g, 8.334 mmol) and TEA (1.7 g, 16.666 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SCU, filtered, and evaporated under reduced pressure to afford N-methoxy -N- methylbenzene[c][l,2,5]thiadiazole-5-carboxamide (1.14 g, 95 %) as a light yellow solid.
l-(benzo[c][l,2,5]thiadiazol-5-yl)-4-methyl-4-(trimethyIsilyloxy)pent-2-yn-l-one
Figure imgf000106_0002
To a -78°C stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.557 g, 3.636 mmol) in dry THF (50 mL), H-BuLi (5.0 mL, 4.484 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at -78 0C, and then a solution N-methoxy-N- methylbenzene[c][l,2,5]thiadiazole-5-carboxamide (1.0 g, 2.242 mmol) in dry THF (10 mL) was added to the reaction mixture and stirring was continued for an additional 3 h at -78 0C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 1-
(benzo[c][l,2,5]thiadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-l-one (1.0 g, 76 %) as a yellow oil.
l-(Benzo[c][l,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-l-one
Figure imgf000107_0001
To a stirred solution of l-(benzo[c][l,2,5]thiadiazol-5-yl)-4-methyl-4- (trimethylsilyloxy)pent-2-yn-l-one (0.80 g, 2.515 mmol) in DCM (15 mL) was added p- TSA (0.574 g, 3.018 mmol) at RT. The reaction mixture was stirred for 2 h and diluted with water (5 mL). The combined organic layers were washed with a saturated NaHCCh solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford l-(benzo[c][l,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-l-one (0.6 g, 100 %) as a colorless oil.
5-(Benzo[c][l,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one
Figure imgf000107_0002
To a stirred solution of l-(benzo[c][l,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn- 1-one (0.6 g, 2.597 mmol) in ethanol (10 mL), a solution of diethyl amine (0.189 g, 2.597 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 3 h. The ethanol was then removed, and the mixture further diluted with EtOAc (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2Sθ4, filtered, and concentrated in vacuo to afford 5- (benzo[c][l,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.5 g, 83 %) as a light yellow solid.
5-(Benzo[c][l,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one
To a stirred solution of 5-(benzo[c][l,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.5 g, 2.164 mmol) in CHCl3 (15 mL), NBS (0.462 g, 2.590 mmol) was added portionwise at RT, The reaction mixture was then stirred for 2 h and diluted with DCM (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][l,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.45 g, 69 %) as a yellow oil.
5-(Benzo[c][l, 2, 5] thiadiazol-5-yl)-2,2-dimethyI-4-(4-(quinolin-2- ylmethoxy)phenyl)furan-3(2H)-one (Example 167)
Figure imgf000108_0002
A solution of 5-(benzo[c][l,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.45 g, 1.465 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline (0.634 g, 1.759 mmol), and Cs2CO3 (2.3 g, 7.329 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)Cl2 (0.24 g, 0.293 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 12 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SU4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][l,2,5]thiadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2- ylmethoxy)phenyl)furan-3(2H)-one (65 mg) as a yellow solid. 1H NMR (500 MHz, d6- DMSO): δ 8.44 (d, J = 8.5 Hz, 1 H), 8.35 (s, 1 H), 8.12 (d, J= 8.2 Hz, 1 H), 8.02 (t, J= 7.4 Hz, 2 H), 7.79 (t, J= 8.4 Hz, 1 H), 7.73 - 7.69 (m, 2 H), 7.63 (t, J= 8.2 Hz, 1 H), 7.24 (d, J= 8.3 Hz, 2 H), 7.12 (d, J= 8.4 Hz, 2 H), 5.39 (s, '2 H), 1.49 (s, 6 H). MS: [M + Na]: m/z= 502.2, [M + H]: m/z = 480.1. HPLC: 98%, Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 5-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenvD-4, 5- dihvdrofuran-2-vO-2-methoxybenzonitrile (Example 137):
Methyl 3-bromo-4-hydroxybenzoate
Figure imgf000109_0001
To a stirred solution of methyl 4-hydroxybenzoate (10.0 g, 84.935 mmol) in CCU (30 mL) was added AcOH (20 mL, 2 VoI). Br2 (1.80 mL, 71.428 mmol) was then added slowly at 0 0C. After the addition was completed, the reaction mixture was brought to RT and stirred for 8 h. Reaction mixture was quenched with water (50 mL), neutralized with saturated NaHCC^ solution and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc- 95% hexanes to afford methyl 3-bromo-4-hydroxybenzoate (10.0 g, 66 %) as a brown solid.
Methyl 3-cyano-4-hydroxybenzoate
Figure imgf000109_0002
To a stirred solution of methyl 3-bromo-4-hydroxybenzoate (2.50 g, 10.775 mmol) in NMP (7.5 mL) was added CuCN (1.05 g, 11.853 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 200 0C for 4 h., cooled to RT, diluted with water (10 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford methyl 3-cyano-4-hydroxybenzoate (1 .50 g, 78%) as a yellow solid.
Methyl 3-cyano-4-methoxybenzoate
Figure imgf000110_0001
To a stirred solution of methyl 3-cyano-4-hydroxybenzoate (2.0 g, 1 1.20 mmol) in DMF (20 mL) were added CH3I (2.40 g, 16.01 mmol) and K2CO3 (2.30 g, 16.01 mmol) at 0 0C under a N2 atmosphere. The reaction mixture was stirred at 80 0C for 2 h. After completion of starting material (monitored by TLC), reaction mixture was diluted with water and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (2 x 50 mL), brine and dried over anhydrous Na2Sθ4. After filtration and evaporation in vacuo, the crude material was purified by silica gel column chromatography to afford methyl 3-cyano-4-methoxybenzoate (1.1 g, 52%), as a pale yellow solid.
3-Cyano-4-methoxybenzoic acid
Figure imgf000110_0002
To a stirred solution of methyl 3-cyano-4-methoxybenzoate (1.1 g, 5.70 mmol) in a mixture of THF (70 mL), MeOH (70 mL) and water (5 mL) was added LiOH (0.97 g, 23.01 mmol) at RT and the reaction mixture was then stirred at RT for 1 h. The reaction mixture was acidified to pH ~ 2 with 2 N HCl and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SC^, filtered and evaporated under reduced pressure to afford 3-cyano-4-methoxybenzoic acid (1.0 g, 100 %) as a solid.
3-Cyano-N,4-dimethoxy-N-methylbenzamide
Figure imgf000111_0001
To a stirred solution of 3-cyano-4-methoxybenzoic acid (1.0 g, 5.60 mmol) in DCM (30 mL) were added HATU (3.20 g, 8.01 mmol), N-methoxy,N-methylamine (0.82 g, 8.01 mmol) and TEA (2.3 mL, 17.01 mmol) at RT under a nitrogen atomosphere. The reaction mixture was then stirred at RT for 2 h, diluted with water and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 3-cyano-N,4-dimethoxy-N-methylbenzamide (1.3 g, 100 %) as a white solid.
2-Methoxy-5-(4-methyl-4-(trimethylsilyloxy) pent-2-ynoyI) benzonitrile
Figure imgf000111_0002
To a -780C stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (1.9 g, 12.501 mmol) in dry THF (25 mL), M-BuLi (2.80 mL, 4.50 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction was stirred for 30 min at -78 0C, and then a solution of 3-cyano-N,4-dimethoxy-N-methylbenzarnide (1 .10 g, 5.01 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at -78 °C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5 % EtOAc in hexanes to afford 2- methoxy-5-(4-methyl-4-(trirnethylsilyloxy) pent-2-ynoyl) benzonitrile (0.8 g, 56%) as a pale yellow oil.
5-(4-Hydrpxy-4-methylpent-2-ynoyl)-2-methoxy benzonitrile
Figure imgf000112_0001
To a stirred solution of 2-methoxy-5-(4-methyl-4-(trimethylsilyloxy) pent-2-ynoyl) benzonitrile (1.2 g, 3.01 mmol) in DCM (20 mL) was added PTSA (1.08 g, 5.60 mmol) at RT. The reaction mixture was stirred for 30 minutes and diluted with water (5 mL). The combined organic layers were then washed with a saturated NaHCO3 solution and water, dried OVCr Na2SO4, filtered, and then concentrated in vacuo to afford 5-(4-hydroxy-4- methylpent-2-ynoyl)-2-methoxybenzonitrile (0.9^, 97%) as a semi-solid.
5-(5, 5-Dimethyl-4-oxo-4, 5-dihydrofuran-2-yl)-2-methoxy benzonitrile
Figure imgf000112_0002
To a stirred solution of 5-(4-hydroxy-4-methylpent-2-ynoyl)-2-methoxybenzonitrile (0.9 g, 3.70 mmol) in ethanol (10 mL), a solution of diethyl amine (0.38 mL, 3.70 mmol) in EtOH (2.0 mL) was added dropwise at RT and the reaction mixture was stirred for additional 1 h. The ethanol was then was removed, and the mixture diluted with EtOAc (40 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(5, 5-dimethyl-4- oxo-4, 5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.9 g, 100 %) as a yellow semi solid.
5-(3-Bromo-5, 5-dimethyl-4-oxo-4, 5-dihydrofuran-2-yl)-2-methoxybenzonitrile
Figure imgf000113_0001
To a stirred solution of 5-(5, 5-dimethyl-4-oxo-4, 5-dihydrofuran-2-yl)-2- methoxybenzonitrile (0.9 g, 3.70 mmol) in CHCl3 (10 mL), NBS (1.1 g, 6.29 mmol) was added portionwise at RT. The reaction mixture was then stirred for 1 h and diluted with DCM (50 mL). the combined organic layers were washed with water (20 mL) and brine (15 mL), dried over Na2SCu, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(3-bromo-5, 5-dimethyl-4-oxo-4, 5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.5 g, 42 %) as a yellow solid.
5-(5, 5-DimethyI-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, 5-dihydrofuran-2-yl)-
2-methoxybenzonitrile (Example 137)
Figure imgf000113_0002
A solution of 5-(3-bromo-5, 5-dimethyl-4-oxo-4, 5-dihydrofuran-2-yl)-2- methoxybenzonitrile (0.15 g, 0.465 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.17 g, 0.465 mmol), and Cs2CC^ (0.75 g, 2.32 mmol) in toluene (6 mL) and water (3 mL) was degassed. Then, Pd(dppf)Cl2 (0.76 g, 0.090 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 2 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, 5-dihydrofuran-2-yl)-2-methoxybenzonitrile (125 mg, 58 %) as a pale yellow solid. 1H NMR (500 MHz, (J6-DMSO): δ 8.43 (d, J= 8.5 Hz, 1 H), 8.02 (t, J= 7.9 Hz, 2 H), 7.90 (s, 1 H), 7.81 - 7.77 (m, 2 H), 7.70 (d, J= 8.2 Hz, 1 H), 7.62 (t, J= 8.2 Hz, 1 H), 7.32 (d, J= 8.1 Hz, 1 H), 7.19 (d, J= 7.4 Hz, 2 H), 7.12 (d, J= 7.5 Hz, 2 H), 5.40 (s, 2 H), 3.95 (s, 3H), 1.46 (s, 6 H). MS: [M + Na]: m/z= 499.3, [M ■+ H]: m/z = 477.2. HPLC: 98%, Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 um. Mobile Phase: 0.025 % TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 5-(3-chloro-4-methoxyphenyl)-2, 2-dimethvI-4-(4-(quinolin-2- ylmethoxy) phenyl) furan-3(2H)-one (Example 135):
3-Chloro-4-hydroxybenzaldehyde
Figure imgf000114_0001
To a stirred solution of 4-hydroxybenzaldehyde (5.0 g, 40.0 mmol) in DCM (50 mL) SOCl2 (3.30 mL, 40.0 mmol) was added slowly at 0 °C. After the addition was completed, the reaction mixture was brought to RT and stirred for 14 h. The reaction mixture was then quenched with water (50 mL), neutralized with a saturated NaHCO3 solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography to afford 3-chloro-4-hydroxybenzaldehyde (5.0 g, 77 %) as a brown solid.
3-Chloro-4-methoxybenzaldehyde
Figure imgf000114_0002
13 To a stirred solution of 3-chloro-4-hydroxybenzaldehyde (2.9 g, 18.412 mmol) in DMF (30 mL) was added K2CO3 (7.6 g, 55.238 mmol). CH3I (7.80 g, 55.238 mmol) was then added slowly at RT under an inert atmosphere. After addition was completed, the reaction mixture was brought to 80 0C and stirred for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography to afford 3-chloro-4-methoxybenzaldehyde (2.78 g, 93%) as a yellow solid.
l-(3-Chloro-4-methoxyphenyl)-4-methylpent-2-yne-l, 4-diol
Figure imgf000115_0001
To a -78°C stirred solution of 2-methylbut-3-yn-2-ol (0.89 g, 10.710 mmol) in dry THF (50 mL), n-BuLi (16.OmL, 27.001 mmol, 1.6 M in hexane) was added dropwise over 5 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at -78 0C, and then a solution of 3-chloro-4-methoxybenzaldehyde (1.8 g, 10.710 mmol) in dry THF (10 mL) was added and stirring was continued for an additional 3 h at RT. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-4 % EtOAc in hexanes to afford l-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-l, 4-diol (0.69 g, 26%) as a yellow syrup.
l-(3-Chloro-4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-l-one
14
Figure imgf000116_0001
To a stirred solution of l-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-l, 4-diol (0.69 g, 2.716 mmol) in DCM (20 mL) was added DMP (2.36 g, 5.430 mmol) at RT. The reaction mixture was stirred for 1 h and diluted with water (10 mL). The combined organic -layers were washed with a saturated NaHCO3 solution and water, dried over Na2SC>4, filtered, and then concentrated in vacuo to afford l-(3-chloro-4- methoxyphenyl)-4-hydroxy-4-'rnethylpent-2-yn-l-one (0.45g, 65 %) as a brown oil.
5-(3-Chloro-4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one
Figure imgf000116_0002
To a stirred solution of l-(3-chloro-4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-l- one (0.7 g, 2.75 mmol) in ethanol (5 mL), a solution of diethyl amine (0.20 g, 2.75 mmol) in EtOH (7 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 30 min. The ethanol was removed, and the reaction mixture diluted with EtOAc (10 mL). The combined organic layers were then washed with water (5 mL) and brine (5 mL), dried over Na2Sθ4, filtered, and concentrated in vacuo to afford 5-(3- chloro-4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one (0.7 g, 100 %) as a semi solid.
4-Bromo-5-(3-chloro-4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one
Figure imgf000116_0003
To a stirred solution of afford 5-(3-chloro-4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)- one (0.7 g, 2.77 mmol) in CHCl3 (10 mL), NBS (0.84 g, 4.72 mmolwas added portionwise at RT. The reaction mixture was then stirred for 1 h. and diluted with DCM
15 (20 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SC^, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-5-(3-chloro-4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one (340 mg, 37%) as a thick syrup.
5-(3-Chloro-4-methoxyphenyl)-2, 2-dimethyl-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (Example 135)
Figure imgf000117_0001
A solution of 4-bromo-5-(3-chloro-4-methoxyphenyl)-2, 2-dimethylfuran-3(2H)-one 0.34 g, 1.021 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline (0.37 g, 1.021 mmol), and CS2CO3 (1.67 g, 5.130 mmol) in toluene (6 mL) and water (3 mL) was degassed. Then, Pd(dppf)Cl2 (0.167 g, 0.204 mmol) was added under an inert atmosphere and the solution was again degassed. Then the reaction mixture was refluxed for 1 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (20 mL). The combined organic layers were washed with water (5 mL ) and brine (5 mL), dried over Na2SU4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(3-chloro-4-methoxyphenyl)-2, 2-dimethyl-4-(4-(quinolin-2- ylmethoxy) phenyl) furan-3(2H)-one (122 mg, 23 %) as a solid. 1H NMR (500 MHz, d6- DMSO): δ 8.42 (d, J = 8.5 Hz, 1 H), 8.02 (t, J= 7.9 Hz, 2 H), 7.79 (t, J= 7.4 Hz, 1 H), 7.70 (d, J= 8.2 Hz, 1 H), 7.65 - 7.59 (m, 2H), 7.51 (d, J= 8.1 Hz, 1 H), 7.22 - 7.18 (m, 3 H), 7.12 (d, J= 7.5 Hz, 2 H), 5.40 (s, 2 H), 3.91 (s, 3H), 1.46 (s, 6 H). MS: [M + Na]: m/z= 508.2, [M + H]: m/z = 486.2. HPLC: 96%, Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 um. Mobile Phase: 0.025 % TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
16 Synthesis of Example 810, 4-(4-((6-fluorόquinolin-2-yl)methoxy)phenyl)-2,2- dimethyl-5-(pyridin-4-yl)furan-3(2H)-one
N-methoxy-N-methylisonicotinamide
Figure imgf000118_0001
To a stirred solution of isonicotinic acid (20.0 g, 162 mmol) in DCM (400 mL) were added HATU (92.6g , 243 mmol), N-methoxy methylamine (17.24 g, 178 mmol) and TEA (68.7 mL, 487 mmol) at RT under nitrogen atmosphere. The reaction mixture was then stirred at RT for 12 h. The reaction mixture was diluted with water and the aqueous layer was extracted with DCM (3 x 500 mL). The combined organic extracts were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 30-40 % EtOAc in Hexane to afford to afford N-methoxy-N-methylisonicotinamide (15.0 g, 55 %) as an oil.
4-Methyl-l-(pyridin-4-y.)-4-(trimethylsilyloxy) pent-2-yn-l-one
Figure imgf000118_0002
To a stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (4.22 g, 25.4 mmol) in dry THF (100 mL) was added M-BuLi (17.9 mL, 28.7 mmol, 1.6 M in hexane) dropwise at -78 0C under an inert atmosphere for a period of 10 min. After being stirred for 30 min at -78 0C, a solution of N-methoxy-N-methylisonicotinamide (5.0 g, 31.8 mmol) in dry THF (15 mL) was added to reaction mixture and stirring was continued for an additional 2 h at -78 °C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (80 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated
17 in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-3 % EtOAc in Hexane to afford 4-methyl-l- (pyridin-4-yl)-4-(trirnethylsilyloxy) pent-2-yn-l-one (4.8 g, 57%) as an oil.
4-Hydroxy-4-methyl-l-(pyridin-4-yI) pent-2-yn-l-one
Figure imgf000119_0001
To a stirred solution of 4-methyl-l-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-l-one (3.0 g, 11.0 mmol) in DCM (60 mL) was added PTSA (2.62 g, 13.0 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-l- (pyridin-4-yl) pent-2-yn-l-one (1.5 g, 69 %) as an oil.
2, 2-Dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
Figure imgf000119_0002
To a stirred solution of 4-hydroxy-4-methyl-l-(pyridin-4-yl) pent-2-yn-l-one (1.8 g, 9.50 mmol) in ethanol (18 mL) was added diethyl amine (1.04 g, 14.0 mmol) in EtOH (1 mL) dropwise at RT and the reaction mixture was stirred for additional 1 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford crude 2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.3 g) as an oil.
4-Bromo-2, 2-dimethyl-5-(pyπdin-4-yl) furan-3(2H)-one
Figure imgf000119_0003
To a stirred solution of 2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.3 g, 6.80 mmol) in CHCl3 (13 mL) was added NBS (2.08 g, 11.6 mmol) portionwise at RT and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with DCM (30 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (1.2 g) as an oil.
6-Fluoro-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline
Figure imgf000120_0001
6-Fluoro-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline may be prepared in manner analogous to 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline using 2-(chloromethyl)-6-fluoroquinoline instead of 2- (chloromethyl)quinoline.
Example 810
4-(4-((6-Fluoroquinolin-2-yl) methoxy) phenyl)-2, 2-dimethyl-5-(pyridin-4-yl) furan-
3(2H)-one
Figure imgf000120_0002
A mixture of 4-bromo-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.085 g, 0.32 mmol), 6-Fluoro-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)quinoline (0.12 g, 0.32 mmol), and Cs2CO3 (0.52 g, 1.58 mmol) in toluene (5 mL) and water (2 mL) was degassed, added Pd(dppf)Cl2 (0.052 g, 0.06 mmol) under an inert atmosphere and degassed again. Then the reaction was refluxed for 2 h. The reaction mixture was filtered through a pad of Celite®, the filtrate was diluted with EtOAc (30 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(4-((6-fluoroquinolin-2-yl) methoxy) phenyl)-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (35 mg, 25%) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.71 (d, J = 8.5 Hz, 2 H), 8.42 (t, J= 7.9 Hz, 1 H), 8.1 (t, J= 8.4 Hz, 1 H), 7.70 - 7.61 (m, 3H), 7.44 (d, J= 8.5 Hz, 2 H), 7.18 (d, J = 7.4 Hz, 2 H), 7.1 1 (d, J= 7.5 Hz, 2 H), 5.40 (s, 2 H), 1.44 (s, 6 H). MS: [M + H]: m/z = 441.1. HPLC: 90.1% (RT-2.39 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 808, 2, 2-dimethyl-4-(4-((5-methylpyridin-2-yl) methoxy) phenyl)- 5-(pyridin-4-yl) furan-3(2H)-one
5-Methyl-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)pyridine
Figure imgf000121_0001
5-Methyl-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine may be prepared in a manner analogous to 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-
2-yl)phenoxy)methyl)quinoline using 2-(chloromethyl)-5-methylpyridine instead of 2-
(chloromethyl)quinoline.
Example 808
2, 2-dimethyl-4-(4-((5-methylpyridin-2-yl) methoxy) phenyl)-5-(pyridin-4-yl) furan-
3(2H)-one
Figure imgf000122_0001
A mixture of 4-bromo-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.1 1 g, 0.34 mmol), 5-methyl-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenoxy)methyl)pyridine (0.1 g, 0.37 mmol), and Cs2Cθ3 (0.55 g, 1.86 mmol) in toluene (7 mL) and water (3 mL) was degassed, Pd(dppf)Cl2 (0.058 g, 0.07 mmol) was added under an inert atmosphere and the mixture was degassed again. Then the reaction was refluxed for 2 h and was filtered through a pad of Celite®. The filtrate was diluted with EtOAc (50 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2, 2-dimethyl-4-(4-((5-methylpyridin-2- yl) methoxy) phenyl)-5-(pyridin-4-yl) furan-3(2H)-one (70 mg, 48%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.72 (d, J= 8.5 Hz, 2 H), 8.42 (t, J= 7.9 Hz, 1 H), 7.70 (d, /= 8.2 Hz, 2 H), 7.63 (t, J= 8.2 Hz, 1 H), 7.52 - 7.43 (m, 3 H), 7.18 (d, J= 7.4 Hz, 2 H), 7.1 1 (d, J= 7.5 Hz, 2 H), 5.18 (s, 2 H), 2.35 (s,3H) , 1.54 (s, 6 H). MS: [M + H]: m/z = 387.0. HPLC: 91.4% (RT- 1.73 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 809, 4-(4-((3, 5-dimethylpyridin-2-yI) methoxy) phenyl)-2, 2- dimethyl-5-(pyridin-4-yl) furan-3(2H)-one
3,5-Dimethyl-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)pyridine
Figure imgf000122_0002
3,5-Dimethyl-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy) methyl)pyridine may be prepared in a manner analogous to 2-((4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline using 2-(chloromethyl)-3,5- dimethylpyridine instead of 2-(chloromethyl)quinoline.
Example 809
4-(4-((3, 5-Dimethylpyridin-2-yI) methoxy) phenyI)-2, 2-dimethyI-5-(pyridin-4-yl) furan-3(2H)-one
Figure imgf000123_0001
A mixture of 4-bromo-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.28 g, 1.04 mmol), 3,5-dimethyl-2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)methyl)pyridine (0.32 g, 0.94 mmol), and Cs2CO3 (1.3 g, 4.0 mmol) in toluene (10 mL) and water (3 mL) was degassed, Pd(dppf)Cl2 (0.14 g, 0.16 mmol) was added under an inert atmosphere and again degassed. Then the reaction was refluxed for 2 h and was filtered through a pad of Celite®. The filtrate was diluted with EtOAc (50 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(4-((3, 5-dimethylpyridin-2-yl) methoxy) phenyl)-2, 2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (90 mg, 24%) as an oil. 1H NMR (500 MHz, d6-DMSO): δ 8.72 (d, J= 7.5 Hz, 2 H), 8.24 (d, /= 7.8 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 3 H), 7.23 (d, J= IA Hz, 2 H)5 7.08 (d, J= 7.5 Hz, 2 H), 5.18 (s, 2 H), 2.35 (s, 3H), 2.25 (s,3H), 1.52 (s, 6 H). MS: [M + H]: m/z = 401.1. HPLC: 95.2% (RT-1.78 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 824, 2-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-l- oxaspiro[4.4] non-2-en-4-one l-(Pyridin-4-yl)-3-(l-(trimethylsilyloxy) cyclopentyI) prop-2-yn-l-one
Figure imgf000124_0001
To a stirred solution of (l-ethynylcyclopentyloxy)trimethylsilane (2.0 g, 11.0 mmol) in dry THF (50 mL) was added w-BuLi (20.0 mL, 20.0 mmol, 1.6 M in hexane) drop wise at -78 0C under an inert atmosphere for a period of 10 min. After being stirred for 30 min at -78 0C, a solution of compound N-methoxy-N-methylisonicotinamide (2.1 g, 13.2 mmol) in dry THF (10 mL) was added to the reaction mixture and stirring was continued for an additional 2 h at -78 0C. The reaction mixture was quenched with a saturated NH4CI solution and extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5 % EtOAc in Hexane to afford 1- (pyridin-4-yl)-3-(l-(trimethylsilyloxy) cyclopentyl) prop-2-yn-l -one (1.0 g, 32%) as an oil.
3-(l-Hydroxycyclopentyl)-l-(pyridin-4-yl) prop-2-yn-l-one
Figure imgf000124_0002
To a stirred solution of l-(pyridin-4-yl)-3-(l-(trimethylsilyloxy) cyclopentyl) prop-2-yn-l-one (1.1 g, 3.8 mmol) in DCM (15 mL) was added PTSA (0.87 g, 4.6 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (2 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 3-(l- hydroxycyclopentyl)-l-(pyridin-4-yl) prop-2-yn-l-one (0.42 g, 51%) as an oil.
2-(Pyridin-4-yl)-l-oxaspiro [4.4] non-2-en-4-one
Figure imgf000125_0001
To a stirred solution of 3-(l-hydroxycyclopentyl)-l-(pyridin-4-yl) prop-2-yn-l-one (0.42 g, 1.95 mmol) in ethanol (10 mL) was added diethyl amine (0.21 g, 2.9 mmol) in EtOH (1 mL) dropwise at RT and the reaction mixture was stirred for additional 1 h. Then the EtOH was removed, diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over Na2Sθ4, filtered and concentrated in vacuo to afford 2-(pyridin-4-yl)-l- ox.aspiro[4.4] non-2-en-4-one (0.4 g) as an oil.
3-Bromo-2-(pyridin-4-yl)-l-oxaspiro [4.4] non-2-en-4-one
Figure imgf000125_0002
To a stirred solution of afford 2-(pyridin-4-yl)-l-oxaspiro [4.4] non-2-en-4-one (0.18 g, 0.84 mmol) in CHCl3 (10 mL) was added NBS (0.22 g, 1.25 mmol) portionwise at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with water (10 mL), brine (10 mL), dried OVCrNa2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-bromo-2-(pyridin-4-yl)-l-oxaspiro [4.4] non-2-en-4-one (0.18 g, 40%) as an oil. Example 824 2-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl)-l-oxaspiro [4.4] non-2-en-4-one
Figure imgf000125_0003
A mixture of 3-bromo-2-(pyridin-4-yl)-l-oxaspiro [4.4] non-2-en-4-one (0.2 g, 0.68 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl) quinoline (0.25 g, 0.82 mmol), and Cs2CO3 (1.25 g, 6.68 mmol) in toluene (10 mL) and water (2 mL) was degassed, Pd(dppf)Cl2 (0.05 g, 0.014 mmol) was added under an inert atmosphere and again degassed. Then the reaction was refluxed for 3 h. and was filtered through a pad of Celite®, the filtrate was diluted with EtOAc (50 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy) phenyl)-l- oxaspiro [4.4] non-2-en-4-one (20 mg, 5%) as a solid. 1H NMR (500 MHz, (J6-DMSO): δ 8.68 (d, J= 8.5 Hz, 2 H), 8.44 (d, /= 7.9 Hz, 1 H), 8.02 (t, J= 8.4 Hz, 2 H), 7.80 (t, J = 8.2 Hz, 1 H), 7.68 (d, J= 8.2 Hz, 1 H), 7.63 (X, J= 8.5 Hz, 1 H), 7.48 (d, J= 8.5 Hz, 2 H), 7.18 (d, J= 7.4 Hz, 2 H), 7.12 (d, J = 7.5 Hz, 2 H), 5.42 (s, 2 H), 2.08-1.82 (m, 8 H). MS: [M + H]: m/z = 449.2. HPLC: 96.9% (RT-2.24 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 894, 5-(4-aminophenyl)-2, 2-dimethyl-4-(4-(quinolin-2- ylmethoxy) phenyl) furan-3(2H)-one
Figure imgf000126_0001
To a stirred solution of 2,2-dimethyl-5-(4-nitrophenyl)-4-(4-(quinolin-2- ylmethoxy)phenyl)furan-3(2H)-one (0.6 g, 1.28 mmol) in ethanol (10 mL) was added AcOH ( 1.28 mL) at RT under N2 atmosphere. After being stirred for 10 min at RT, the reaction mixture was heated to 70 0C and Fe (0.524 g, 9.04 mmol) and FeCl3 (0.062 g, 0.38 mmol) were added under N2 atmosphere. The reaction mixture was stirred at 70 0C for 2 h. After completion of starting material (by TLC), reaction mixture was cooled to RT, and the volatiles were evaporated in vacuo to obtain the crude product. The crude product was extracted in EtOAc (25 mL), washed with water (2 x 10 mL), brine and dried over anhydrous Na2SO,). After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford 5-(4-aminophenyl)-2, 2-dimethyl-4-(4- (quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (400 mg, 71%), as a yellow solid.
Synthesis of Example 817, N-(4-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, S-dihydrofuran-2-yl) phenyl) acetamide
Figure imgf000127_0001
To a stirred solution of 5-(4-aminophenyl)-2, 2-dimethyl-4-(4-(quinolin-2- ylmethoxy) phenyl) furan-3(2H)-one (0.07 g, 0.16 mmol) in DCM (5 mL) were added Ac2O (0.018 mL, 0.19 mmol) and TEA (0.04 mL, 0.32 mmol) at 0 0C under N2 atmosphere. The reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM (2 x 15 mL). Combined organic layers were washed with water (2 x 5 mL), brine and dried over anhydrous Na2Sθ4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, 5- dihydrofuran-2-yl) phenyl) acetamide (20 mg, 26%), as an off white solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J= 8.5 Hz, 1 H), 8.08 (d, J= 7.9 Hz, IH), 7.84 (d, J= 8.4 Hz, 1 H), 7.74 (t, J= 8.2 Hz, 1 H), 7.68 (d, J= 8.2 Hz, 1 H), 7.64 (d, J= 8.2 Hz, 2 H), 7.56 (t, J= 8.5 Hz, 1 H), 7.48 (d, J= 7.4 Hz, 2 H), 7.22 (d, J= 7.5 Hz, 2 H)5 7.08 (d, J = 8.9 Hz, 2H), 5.42 (s, 2 H), 2.22 (s, 3 H), 1.58 (s, 6 H). MS: [M + Na]: m/z = 501.3, [M + H]: m/z = 479.3. HPLC: 95.9 % (RT-2.32 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient). Also isolated was Example 819, N-acetyl-N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2- }imethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)acetamide, (30 mg, 18 .0%) as an off white solid
Figure imgf000128_0001
(d, J = 8.5 Hz, 1 H), 8.08 (d, J= 7.9 Hz, IH), 7.78
7.68 (m, 5 H), 7.64 (t, J= 8.2 Hz, 1 H), 7.28 (d, J= 7.4 Hz, 2 H), 7.12 (d, J= 7.5 Hz, 2 H), 7.06 (d, J= 8.9 Hz, 2H), 5.42 (s, 2 H), 2.32 (s, 6 H), 1.44 (s, 6 H). MS: [M + Na]: m/z = 543.2, [M + H]: m/z = 521.3. HPLC: 92.7 % (RT-2.53 min), Column: Acquity BEH- C- 18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 817, N-(4-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, S-dihydrofuran-2-yl) phenyl)-N-(methylsulfonyl) methane sulfonamide
Figure imgf000128_0002
To a stirred solution of 5-(4-aminophenyl)-2, 2-dimethyl-4-(4-(quinolin-2- ylmethoxy) phenyl) furan-3(2H)-one (60 mg, 0.13 mmol) in DCM (5 mL) were added methane sulfonyl chloride (0.012 g, 0.15 mmol) and TEA (0.04 mL, 0.27 mmol) at 0 0C under N2 atmosphere. The reaction mixture was stirred at RT for 10 min. The reaction mixture diluted with water and extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (2 x 5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, 5-dihydrofuran-2-yl) phenyl)-N-(methylsulfonyl) methane sulfonamide (25 mg, 30 %), as a white color solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J = 8.5 Hz, 1 H), 8.10 (d, J = 7.9 Hz, IH), 7.76 (d, J= 8.4 Hz, 1 H), 7.80 (d, J= 8.2 Hz, 2 H), 7.74 (t, J = 8.2 Hz, 1 H), 7.70 (d, J= 8.5 Hz, 1 H), 7.56 (d, J= 7.5 Hz, 1 H), 7.28 (d, J= 7.4 Hz, 2 H), 7.12 (d, J= 7.5 Hz, 2 H), 7.08 (d, J= 7.6 Hz, 2H), 5.42 (s, 2 H), 3.42 (s, 6 H), 1.58 (s, 6H-). MS: [M + Na]: m/z = 615.1, [M + H]: m/z = 593.1. HPLC: 98.9 % (RT-2.52 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 815, N-(4-(5, 5-dimethyI-4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, 5-dihydrofuran-2-yl) phenyl) methane sulfonamide
Figure imgf000129_0001
To a stirred solution of N-(4-(5, 5-dimethyl-4-oxo-3-(4-(quinolin-2-ylrnethoxy) phenyl)- 4, 5-dihydrofuran-2-yl) phenyl)-N-(methylsulfonyl) methane sulfonamide (40 mg, 0.06 mmol) in THF: H2O (6 mL) was added 2N NaOH (1.0 mL) at 0 0C under N2 atmosphere. The reaction mixture was stirred at 00C for 10 min. Upon complete consumption of the starting material (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with water (2 x 5 mL), brine and dried over anhydrous Na2SO^ After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5, 5-dimethyl- 4-oxo-3-(4-(quinolin-2-ylmethoxy) phenyl)-4, 5-dihydrofuran-2-yl) phenyl) methane sulfonamide (20 mg, 26 %), as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.45 (d, J= 8.5 Hz, 1 H), 8.12 (t, J= 7.9 Hz, IH), 7.78 (t, J= 8.4 Hz, 1 H), 7.70 (d, J= 8.2 Hz, 1 H), 7.64 (t, J = 8.2 Hz, 1 H), 7.44 (d, J= 8.5 Hz, 2 H), 7.18 (d, J= 7.5 Hz, 2 H), 7.10 (d, J= 7.5 Hz, 2 H), 6.98 (d, J= 8.2 Hz, 2H), 5.42 (s, 2 H), 2.85 (s, 3 H), 1.44 (s, 6H). MS: [M + Na]: m/z = 537.3, [M + H]: m/z = 515.2 HPLC: 95.7 % (RT-2.37 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 811, 2, 2-dimethyl-5-phenyl-4-(4-(quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one
Figure imgf000130_0001
To a stirred solution of 5-(4-aminophenyl)-2, 2-dimethyl-4-(4-(quinolin-2- ylmethoxy) phenyl) furan-3(2H)-one (80 mg, 0.18 mmol) in ACN: H2O (6 mL, 1 :1) was added cone HCl (0.2 mL) at 0 0C under N2 atmosphere. The reaction mixture was stirred at 0 0C for 10 min. After being stirred for 5 min then added NaNO2 in water and stirred for 40 min at 00C. The reaction mixture was stirred at 70 0C for 2h. After completion of starting material (by TLC)5 reaction mass was diluted with water and extracted with EtOAc (2 x 25 mL). Combined organic layers were washed with water (2 x 5 mL), brine and dried over anhydrous Na2SO^ After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford 2, 2-dimethyl-5-phenyl-4-(4- (quinolin-2-ylmethoxy) phenyl) furan-3(2H)-one (18 mg, 23 %), as an off white solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (d, J= 8.5 Hz, 1 H), 8.10 (d, J= 7.9 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.75-7.62 (m, 3H), 7.52 (t, J= 8.2 Hz, 1 H), 7.45 (d, J= 8.5 Hz, 1 H), 7.32 (d, J= 7.5 Hz, 2 H), 7.21 (d, /= 7.4 Hz, 2 H), 7.03 (d, J= 7.5 Hz, 2 H),5.42 (s, 2 H), 1.51 (s, 6 H). MS: [M + Na]: m/z = 444.1, [M + H]: m/z = 422.1. HPLC: 98.72 % (RT- 2.83 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient). Synthesis of Example 174, 2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)-5- (thiazol-4-yl)furan-3(2H)-one
4-Methyl-l-(thiazol-4-yl)-4-(trimethylsilyloxy) pent-2-yn-l-one
Figure imgf000131_0001
To a stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (0.56 g, 3.57 mmol) in dry THF (10 mL) was added rc-BuLi (1.3 mL, 2.1 mmol, 1.6 M in hexane) dropwise at -78 0C under an inert atmosphere for a period of 5 min. After being stirred for 30 min at - 78 0C, a solution of N-methoxy-N-methylthiazole-4-carboxarnide (0.25 g, 1.78 mmol) in dry THF (5 mL) was added to reaction mixture and stirring was continued for an additional 1 h at -78 0C. The reaction mixture was quenched with a saturated NH4CI solution and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-4 % EtOAc in Hexane to afford 4-methyl-l- (thiazol-4-yl)-4-(trimethylsilyloxy) pent-2-yn-l-one (0.15 g, 31.44 %) as an oil.
4-Hyd roxy-4-m ethyl-1 -(thiazol-4-yl) pent-2-yn- 1 -one
Figure imgf000131_0002
To a stirred solution of 4-methyl-l-(thiazol-4-yl)-4-(trimethylsilyloxy) pent-2-yn-l-one (0.15 g, 0.56 mmol) in DCM (3 mL) was added PTSA (0.16 g, 0.84 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-l -(thiazol- 4-yl) pent-2-yn-l-one (0.12 g, crude) as an oil.
2, 2-Dimethyl-5-(thiazol-4-yl) furan-3(2H)-one
Figure imgf000132_0001
To a stirred solution of 4-hydroxy-4-methyl-l-(thiazol-4-yl) pent-2-yn-l-one (0.1 g, 0.53 mmol) in ethanol (1 mL) was added diethyl amine (0.057 mL, 0.59 mmol) in EtOH (0.5 mL) dropwise at RT and the reaction mixture was stirred for additional 45 min. Then the EtOH was removed, diluted with EtOAc (10 mL), washed with water (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2, 2- dimethyl-5-(thiazol-4-yl) furan-3(2H)-one (0.1 g) as an oil.
4-Bromo-2, 2-dimethyl-5-(thiazol-4-yl) furan-3(2H)-one
Figure imgf000132_0002
To a stirred solution of 2, 2-dimethyl-5-(thiazol-4-yl) furan-3(2H)-one (90 mg, 0.46 mmol) in CHCl3 (1.8 mL) was added NBS (0.12 g, 0.69 mmol) portionwise at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with water (5 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2, 2-dimethyl-5-(thiazol-4-yl) furan- 3(2H)-one (40 mg, 71 %) as an off white solid. Example 174 2, 2-dimethyl-4-(4-(quinolin-2-ylmethoxy) phenyl)-5-(thiazoI-4-yl) furan-3(2H)-one
Figure imgf000132_0003
A mixture of 4-bromo-2, 2-dimethyl-5-(thiazol-4-yl) furan-3(2H)-one (0.1 g, 0.37 mmol), 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.164 g, 0.454 mmol), and Cs2CO3 (0.673 g, 2.06 mmol) in toluene (1 mL) and water (1 mL) was degassed and Pd(dppf)Cl2 (0.067 g, 0.082 mmol) was added under an inert atmosphere, and degassed once more. Then the reaction was refluxed for 2 h and was filtered through a pad of Celite® , the filtrate was diluted with EtOAc (10 mL), washed with water (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2, 2-dimethyl-4-(4-(quinolin-2-ylmethoxy) phenyl)-5-(thiazol-4-yl) furan-3(2H)- one (30 mg, 18 %) as a solid. 1H NMR (500 MHz, (J6-DMSO): δ 9.17 (s, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.30 (s, 1 H), 8.02-7.98 (m, 2 H), 7.80 (t, J= 8.2 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.62 (t, J= 8.5 Hz, 1 H), 7.24 (d, J= 7.5 Hz, 2 H), 7.08 (d, J= 7.4 Hz, 2 H), 5.38 (s, 2 H), 1.42 (s, 6 H). MS: [M + H]: m/z = 429.1. HPLC: 97.9 % (RT-2.36 min), Column: Acquity BEH- C-18, 50 X 2.1 mm, 1.7 urn. Mobile Phase: 0.025 % TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Tables
In the following tables, if a specific example contains a single value in the column "Ri a and Rib", then both Ri3 and Rn, (if present) are taken to be this value. If this column contains multiple values separated by a comma, the first value is taken to be Ria and the second to be Rib. In the following tables, if a specific example contains multiple instances of R2, they will be separated by commas in the table (e.g. Me, Me or Et, Me). If the R2 column contains a value "-group--" e.g. "--cyclopropyl--", then both R2 values are taken together to be a spiro ring.
In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in the table below taken from Formula (I):
Ex Ru1
HET X Y Z R2 Ro R4 RT PCT # Rib
1 A1 4-pyridinyl OCH2 2-quinoline ... ... Me Me —
2 A1 4-pyridinyl CH2O 2-quinoline ... ... Me Me —
3 A3 4-pyridinyl OCH2 2-benzimidazole ... ... ... ... Me
4 A3 4-pyridinyl OCH2 2- ... — ... ... Me tetrahydroisoquinoli ne
A3 4-pyridinyl OCH2 2-pyridinyl ... — Me
A3 4-pyridinyl OCH2 2-benzoxazole — — Me
A3 4-pyridinyl OCH2 2-benzthiazole — — Me
A3 4-pyridinyl OCH2 2-quinoxaline ... ... Me
A3 4-pyridinyl OCH2 2-naphthyridine ... ... Me
A3 4-pyridinyl OCH2 2-quinazoline ... ... Me
A3 4-pyridinyl OCH2 2-quinoline ... ... Me
A3 4-pyridinyl CH2O 2-quinoline ... ... Me
A4 4-pyridinyl OCH2 2-quinoline ... ... —
A4 4-pyridinyl CH2O 2-quinoline ... ... —
A5 4-pyridinyl OCH2 2-quinoline ... ... H
A5 4-pyridinyl OCH2 2-quinoline ... ... Me
A5 4-pyridinyl CH2O 2-quinoline ... ... H
A5 4-pyridinyl CH2O 2-quinoline ... ... Me
A6 4-pyridinyl OCH2 2-quinoline Me, ... ... H
A6 4-pyridinyl CH2O 2-quinoline Me, ... ... H
A7 4-pyridinyl OCH2 2-quinoline Me Me —
A7 4-pyridinyl CH2O 2-quinoline Me Me —
A7 4-pyridinyl OCH2 2-quinoline — --- Et Et —
A7 4-pyridinyl OCH2 2-quinoline cyclopropyl
3-F,4-OMe
A7 OCH2 2-quinoline Me Me phenyl
3-CI,4-OMe
A7 OCH2 2-quinoline Me Me phenyl
3-CN,4-OMe
A7 OCH2 2-quinoline Me Me phenyl
3-OMe,4-F
A7 OCH2 2-quinoline Me Me phenyl
3-OMe,4-CI
A7 OCH2 2-quinoline Me Me phenyl
3-OMe,4-CN
A7 OCH2 2-quinoline Me Me phenyl
A7 OCH2 2-quinoline Me Me
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
97 A8 OCH2 2-quinoline Me Me Me
98 A8 OCH2 2-quinoline Me Me Me
99 A9 4-pyridinyl OCH2 2-quinoline ...
100 A9 4-pyridinyl OCH2 2-quinoline ...
101 A9 4-pyridinyl CH2O 2-quinoline ...
102 A9 4-pyridinyl CH2O 2-quinoline ...
103 A10 4-pyridinyl OCH2 2-benzimidazole Me,
2-
104 A10 4-pyridinyl OCH2 tetrahydroisoquinoli Me1 ne
105 A10 4-pyridinyl OCH2 2-pyridinyl Mo ...
106 A10 4-pyridinyl OCH2 2-benzoxazole Me,
107 A10 4-pyridinyl OCH2 2-benzthiazole Me,
108 A10 4-pyridinyl OCH2 2-quinoxaline Me,
109 A10 4-pyridinyl OCH2 2-naphthyridine Mo
110 A10 4-pyridinyl OCH2 2-quinazoline Me,
111 A10 4-pyridinyl OCH2 2-quinoline IVI β, ™ ""• ■■■
113 A11 4-pyridinyl OCH2 2-quinoline Me,
114 A11 4-pyridinyl CH2O 2-quinoline
115 A12 4-pyridinyl OCH2 2-quinoline Me,
116 A12 4-pyridinyl CH2O 2-quinoline Me,
117 A13 4-pyridinyl OCH2 2-quinoline Me, Me —
118 A13 4-pyridinyl CH2O 2-quinoline Me, Me —
119 A14 4-pyridinyl OCH2 2-quinoline Me, Me
120 A14 4-pyridinyl CH2O 2-quinoline Me, Me —
121 A1S 4-pyridinyl OCH2 2-quinoline Me,
122 A1S 4-pyridinyl CH2O 2-quinoline Me,
123 A25 4- pyridinyl OCH2 2-quinoline Me
124 A25 4- pyridinyl OCH2 2-quinoline CH2CF3 ---
125 A29 4- pyridinyl OCH2 2-quinoline Me, Me —
126 A29 4- pyridinyl OCH2 2-quinoline cyclopro pyi-
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
243 A30 OCH2 2-quinoline Me, Me Me
244 A30 OCH2 2-quinoline Me1 Me Me
245 A30 OCH2 2-quinoline Me, Me — Me
246 A30 OCH2 2-quinoline Me1 Me Me
247 A30 OCH2 2-quinoline Me1 Me Me
248 A30 OCH2 2-quinoline Me1 Me Me
Figure imgf000148_0002
249 A31 4- pyridinyl OCH2 2-quinoline Me1 Me
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
369 A5 Cl OCH2 2-quinoline ... H
Figure imgf000167_0001
371 A5 Cl OCH2 2-quinoline ... H
372 A22 Cl 4-pyridinyl OCH2 2-quinoline Me ...
373 A22 Cl 4-OMe-phenyl OCH2 2-quinoline Me ...
374 A22 Cl 4-pyrazolyl OCH2 2-quinoline Me ...
3-(1 -methyl-
375 A22 Cl OCH2 2-quinoline Me ... 1 H-pyrazolyl)
4-(1 -methyl-
376 A22 Cl OCH2 2-quinoline Me ... 1 H-pyrazolyl)
377 A22 Cl OCH2 2-quinoline Me ...
Figure imgf000167_0002
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
509 A26 CN 4-pyridinyl OCH2 2-quinoline — Me
510 A26 CN 4-OMe-phenyl OCH2 2-quinoline Me
511 A26 CN 4-pyrazolyl OCH2 2-quinoline Me
3-(1 -methyl-1 H-
512 A26 CN OCH2 2-quinoline Me pyrazolyl)
4-(1 -methyl-1 H-
513 A26 CN OCH2 2-quinoline Me pyrazolyl)
Figure imgf000177_0001
515 A26 CN OCH2 2-quinoline Me
516 A26 CN OCH2 2-quinoline Me
517 A26 CN OCH2 2-quinoline Me
518 A26 CN OCH2 2-quinoline Me —
Figure imgf000177_0002
Figure imgf000178_0001
Figure imgf000179_0001
545 A32 CN OCH2 2-quinoline --- Me1 Me Me
Figure imgf000180_0001
Figure imgf000180_0002
547 A32 CN OCH2 2-quinoline Me, Me Me
548 A35 CN 4-pyrJdinyl OCH2 2-quinoline ...
549 A3S CN 4-OMe-phenyl OCH2 2-quinoline ...
550 A35 CN 4-pyrazolyl OCH2 2-quinoline ...
3-(1 -methyl-1 H-
551 A35 CN OCH2 2-quinoline ... pyrazolyl)
4-(1-methyl-1H-
552 A35 CN OCH2 2-quinoline ... pyrazolyl)
Figure imgf000180_0003
554 A35 CN XX OCH2 2-quinoline ...
555 A36 CN OCH2 2-quinoline ...
556 A35 CN OCH2 2-quinoline — 557 A35 CN OCH2 2-quinoline
Figure imgf000181_0001
Figure imgf000181_0002
In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in the table below taken from Formula (III):
Figure imgf000181_0003
561 A2 Cl 4-pyridinyl OCH2 2-quinoline ... Me Me Me
562 A2 Cl 4-OMe-phenyl OCH2 2-quinoline ... Me Me Me
563 A2 Cl 4-pyrazolyl OCH2 2-quinoline ... Me Me Me
3-(1-methyl-
564 A2 Cl OCH2 2-quinoline ... Me Me Me 1H-pyrazolyl)
4-(1-methyl-
565 A2 Cl OCH2 2-quinoline ... Me Me Me 1H-pyrazolyl)
Figure imgf000181_0004
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
-
667 A35 Cl OCH2 2-quinoline
Figure imgf000188_0002
669 A35 Cl OCH2 2-quinoline
Figure imgf000188_0003
672 A2 CN 4-pyridinyl OCH2 2-quinoline — — Me Me Me
673 A2 CN 4-OMe-phenyl OCH2 2-quinoline Me Me Me
674 A2 CN 4-pyrazolyl OCH2 2-quinoline Me Me Me
3-(1 -methyl-
675 A2 CN OCH2 2-quinoline Me Me Me 1H-pyrazolyl)
4-(1-methyl-
676 A2 CN OCH2 2-quinoline Me Me Me 1H-pyrazolyl)
Figure imgf000188_0004
678 A2 CN OCH2 2-quinoline -- -- Me Me Me
Figure imgf000189_0001
679 A2 CN OCH2 2-quinoline Me Me Me
680 A2 CN OCH2 2-quinoline Me Me Me
681 A2 CN OCH2 2-quinoline Me Me Me
682 A2 CN OCH2 2-quinoline Me Me Me
683 A2 CN OCH2 2-quinoline Me Me Me
684 A2 CN OCH2 2-quinoline Me Me Me
Figure imgf000189_0002
685 A5 CN 4-pyridinyl OCH2 2-quinoline ... ... H
686 A5 CN 4-OMe-phenyl OCH2 2-quinoline ... ... H
687 A5 CN 4-pyrazolyl OCH2 2-quinoline ... ... H
3-(1 -methyl-
688 A5 CN OCH2 2-quinoline ... ... H 1H-pyrazolyl)
4-(1-methyl-
689 AS CN OCH2 2-quinoline ... ... H 1H-pyrazolyl)
Figure imgf000190_0001
_ 4-(1 -methyl-
702 A22 CN OCH2 2-quinoline — Me
1 H-pyrazolyl)
703 A22 CN OCH2 2-quinoline Me
704 A22 CN OCH2 2-quinoline Me
705 Il
A22 CN OCH2 2-quinoline Me
\\
706 A22 CN OCH2 2-quinoline Me
Figure imgf000191_0001
709 A22 CN OCH2 2-quinoline — Me
Figure imgf000191_0002
710 A22 CN XX OCH2 2-quinoline Me
711 A23 CN 4-pyridinyl OCH2 2-quinoline Me
712 A23 CN 4-OMe-phenyl OCH2 2-quinoline Me 713 A23 CN 4-pyrazolyl OCH2 2-quinoline — Me
3-(1 -methyl-
714 A23 CN OCH2 2-quinoline Me — 1 H-pyrazolyl)
4-(1 -methyl-
715 A23 CN OCH2 2-quinoline Me 1 H-pyrazolyl)
Figure imgf000192_0001
717 A23 CN OCH2 2-quinoline Me —
718 A23 CN OCH2 2-quinoline Me
719 A23 CN OCH2 2-quinoline
720 A23 CN OCH2 2-quinoline Me
Figure imgf000192_0002
723 A23 CN OCH2 2-quinoline — Me
Figure imgf000192_0003
724 A26 CN 4-pyridinyl OCH2 2-quinoline — Me
Figure imgf000193_0001
Figure imgf000194_0001
749 A31 CN OCH2 2-quinoline Me1 Me
750 A32 CN 4-pyridinyl OCH2 2-quinoline Me, Me Me
751 A32 CN 4-OMe-phenyl OCH2 2-quinoline Me, Me Me
752 A32 CN 4-pyrazolyl OCH2 2-quinoline — Me, Me — — Me
3-(1-methyl-
753 A32 CN OCH2 2-quinoline — Me1 Me — — Me
1 H-pyrazolyl)
4-(1-methyl-
754 A32 CN OCH2 2-quinoline Me, Me — Me 1 H-pyrazolyl)
Figure imgf000195_0001
756 A32 CN -A OCH2 2-quinoline Me, Me — Me
757 A32 CN OCH2 2-quinoline Me, Me — Me
Figure imgf000195_0002
760 A32 CN OCH2 2-quinoline Me1 Me Me
Figure imgf000196_0001
Figure imgf000196_0002
763 A3S CN 4-pyridinyl OCH2 2-quinoline — — —
764 A35 CN 4-OMe-phenyl OCH2 2-quinoline — — ---
765 A35 CN 4-pyrazolyl OCH2 2-quinoline — — ---
3-(1-methyl-
766 A35 CN OCH2 2-quinoline — — — 1H-pyrazolyl)
4-(1-methyl-
767 A35 CN OCH2 2-quinoline — — — 1 H-pyrazolyl)
768 A35 CN OCH2 2-quinoline — --- —
769 A35 CN OCH2 2-quinoline — ■-- —
Figure imgf000196_0003
771 A35 CN OCH2 2-quinoline — — — 772 A35 CN OCH2 2-quinoline
Figure imgf000197_0001
N ^N
773 A35 CN OCH2 2-quinoline
N *
774 A35 CN OCH2 2-quinoline
Figure imgf000197_0002
Figure imgf000197_0003
Dosage and Administration
The present disclosure includes pharmaceutical composition for treating a subject having a neurological disorder comprising a therapeutically effective amount of a compound of Formulas (I), (II) and (III), a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent. The pharmaceutical compositions can be administered in a variety of dosage forms including, but not limited to, a solid dosage form or in a liquid dosage form, an oral dosage form, a parenteral dosage form, an intranasal dosage form, a suppository, a lozenge, a troche, buccal, a controlled release dosage form, a pulsed release dosage form, an immediate release dosage form, an intravenous solution, a suspension or combinations thereof. The dosage can be an oral dosage form that is a controlled release dosage form. The oral dosage form can be a tablet or a caplet. The compounds can be administered, for example, by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration. In one embodiment, the compounds or pharmaceutical compositions comprising the compounds are delivered to a desired site, such as the brain, by continuous injection via a shunt. In another embodiment, the compound can be administered parenterally, such as intravenous (IV) administration. The formulations for administration will commonly comprise a solution of the compound of the Formulas (I), (II) and (III) dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of compound of Formulas (I), (II) and (III) in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
In one embodiment, a compound of Formulas (I), (II) and (III) can be administered by introduction into the central nervous system of the subject, e.g., into the cerbrospinal fluid of the subject. The formulations for administration will commonly comprise a solution of the compound of Formulas (I), (II) and (III) dissolved in a pharmaceutically acceptable carrier. In certain aspects, the compound of Formulas (I), (II) and (III) is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna. In another aspect, the compound of Formulas (I), (II) and (III) is introduced intraocularly, to thereby contact retinal ganglion cells. The pharmaceutically acceptable formulations can easily be suspended in aqueous vehicles and introduced through conventional hypodermic needles or using infusion pumps. Prior to introduction, the formulations can be sterilized with, preferably, gamma radiation or electron beam sterilization.
In one embodiment, the pharmaceutical composition comprising a compound of Formulas (I), (II) and (III) is administered into a subject intrathecally. As used herein, the term "intrathecal administration" is intended to include delivering a pharmaceutical composition comprising a compound of Formulas (I), (II) and (III) directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebroventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1 : 169-179, the contents of which are incoφorated herein by reference). The term "lumbar region" is intended to include the area between the third and fourth lumbar (lower back) vertebrae. The term "cisterna magna" is intended to include the area where the skull ends and the spinal cord begins at the back of the head. The term "cerebral ventricle" is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord. Administration of a compound of Formulas (I), (II) and (III) to any of the above mentioned sites can be achieved by direct injection of the pharmaceutical composition comprising the compound of Formulas (I), (II) and (III) or by the use of infusion pumps. For injection, the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the pharmaceutical compositions may be formulated in solid form and re- dissolved or suspended immediately prior to use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.
In one embodiment, the pharmaceutical composition comprising a compound of Formulas (I), (II) and (III) is administered by lateral cerebro ventricular injection into the brain of a subject. The injection can be made, for example, through a burr hole made in the subject's skull. In another embodiment, the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject. For example, the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.
In yet another embodiment, the pharmaceutical composition is administered by injection into the cisterna magna, or lumbar area of a subject.
For oral administration, the compounds will generally be provided in unit dosage forms of a tablet, pill, dragee, lozenge or capsule; as a powder or granules; or as an aqueous solution, suspension, liquid, gels, syrup, slurry, etc. suitable for ingestion by the patient. Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
Pharmaceutical preparations for oral use can be obtained through combination of a compound of Formulas (I), (II) and (III) with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
For transmucosal administration (e.g., buccal, rectal, nasal, ocular, etc.), penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.
The suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The compounds can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.
The compounds may also be presented as aqueous or liposome formulations. Aqueous suspensions can contain a compound of Formulas (I), (II) and (III) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.
Oil suspensions can be formulated by suspending a compound of Formulas (I), (II) and (III) in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an-injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations can also be in the form of oil- in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
For administration by inhalation, the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
In general a suitable dose will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 10 mg per kilogram body weight per day. The desired dose is preferably presented once daily, but may be dosed as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
The compounds can be administered as the sole active agent, or in combination with other known therapeutics to be beneficial in the treatment of neurological disorders. In any event, the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of drug administration on the basis of observations of one or more symptoms (e.g., motor or cognitive function as measured by standard clinical scales or assessments) of the disorder being treated. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. After a pharmaceutical composition has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of Formulas (I), (II) and (III), such labeling would include, e.g., instructions concerning the amount, frequency and method of administration.
Biological Examples
In Vivo METHODS
Subjects: Male C57BL/6J mice (Charles River; 20-25 g) were used for all assays except prepulse inhibition (PPI) which used male DBA/2N mice (Charles River, 20-25g). For all studies, animals were housed five/cage on a 12-h light/dark cycle with food and water available ad libitum.
Conditioned avoidance responding: Testing was performed in commercially available avoidance boxes (Kinder Scientific, Poway CA). The boxes were divided into two compartments separated by an archway. Each side of the chamber has electronic grid flooring that is equipped to administer footshocks and an overhead light. Training consisted of repeated pairings of the light (conditioned stimulus) followed by a shock (unconditioned stimulus). For each trial the light was presented for 5 sec followed by a 0.5 mA shock that would terminate if the mouse crossed to the other chamber or after 10 seconds. The intertrial interval was set to 20 seconds. Each training and test session consisted a four min habituation period followed by 30 trials. The number of avoidances (mouse crossed to other side during presentation of the light,), escapes (mouse crossed to the other side during presentation of the shock) and failures (mouse did not cross during the entire trial period) were recorded by a computer. For study inclusion an animal had to reach a criterion of at least 80% avoidances for two consecutive test sessions. PPI: Mice were individually placed into the test chambers (StartleMonitor, Kinder Scientific, Poway CA). The animals were given a five min acclimation period to the test chambers with the background noise level set to 65 decibel (dB) which remained for the entire test session. Following acclimation, four successive trials 120 dB pulse for 40 msec were presented, however these trials were not included in data analysis. The mice were then subjected to five different types of trials in random order: pulse alone (120 dB for 40 msec), no stimulus and three different prepulse + pulse trials with the prepulse set at 67, 69 or 74 dBibr 20 msec followed a 100 msec later by al20 dB pulse for 40 msec. Each animal received 12 trials for each condition" for a total of 60 trials with an average intertrial interval of 15 sec. Percent PPI was calculated according to the following formula: (1 -(startle response to prepulse + pulse) / startle response to pulse alone)) x 100.
MK-801 -induced hyperactivity: After a 30 min acclimatation to the test room mice were individually placed into test cages for a 30 min habituation period. Following habituation to test cages, baseline activity was recorded for 60 min. Mice were then briefly removed and administered test compound and placed immediately back into the test cage. At 5 min prior to test time mice were again briefly removed from test cages and administered MK-801 (0.3mg/kg, i.p. in 0.9% saline) and then immediately placed back into test cages and activity level recorded 1 hour. Activity level was measured as distance travelled in centimeters (Ethovision tracking software, Noldus Inc. Wageningen, Netherlands).
Catalepsy: Mice were placed on a wire mesh screen set at a 60 degree angle with their heads facing upwards and the latency to move or break stance was recorded. Animals were given three trials per time point with a 30 sec cut-off per trial.
Data analysis: A one-way or two-way ANOVA was used to evaluate overall differences between treatments and a Tukey's post-hoc test or Student's t-test was used to evaluate differences between treatment groups for the one-way ANOVA and a Bonferroni test was used for the two-way ANOVA. The criterion for statistical significance was set to p<0.05. In Vitro METHODS
hPDElOAl Enzyme Activity: 50μl samples of serially diluted Human PDElOAl enzyme were incubated with 50μl of [3H]-CAMP for 20 minutes (at 370C). Reactions were carried out in Greiner 96 deep well ImI master-block. The enzyme was diluted in 2OmM Tris HCl pH7.4 and [3H]-CAMP was diluted in 10 mM MgCl2, 40 mM Tris.HCl pH 7.4. The reaction was terminated by denaturing the PDE enzyme (at 700C) after which [3H]-5'- AMP was converted to [3H]-adenosine by adding 25μl snake venom nucleotidase and incubating for 10 minutes (at 370C). Adenosine, being neutral, was separated from charged cAMP or AMP by the addition of 200μl Dowex resin. Samples were shaken for 20 minutes then centrifuged for 3 minutes at 2,500 r.p.m. 50μl of supernatant was removed and added to 200μl of MicroScint-20 in white plates (Greiner 96-well Optiplate) and shaken for 30 minutes before reading on Perkin Elmer TopCount Scintillation Counter.
hPDElOAl Enzyme Inhibition: To check inhibition profile 1 lμl of serially diluted inhibitor was added to 50μl of [3H]-CAMP and 50ul of diluted Human PDElOAl and assay was carried out as in the enzyme activity assay. Data was analysed using Prism software (GraphPad Inc). Representative compounds of this disclosure are shown in the table below. A compound with the value "A" had an IC50 value less than or equal to 50 nM. A compound with the value "B" had an IC50 value greater than 50 nM:
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001

Claims

ClaimsWhat is claimed is:
1. A compound of Formula (I) or (II) or (III) or pharmaceutically acceptable salt thereof
Figure imgf000211_0001
(I) (II) (III)
Wherein: HET is a heterocyclic ring selected from Formulas A1-A26 and A29-42 below
Figure imgf000211_0002
A1 A2 A3 A4 A5 A6
Figure imgf000211_0003
A7 A8 A9 A10 A11 A12
Figure imgf000211_0004
A13 A14 A15 A16 A17 A18
Figure imgf000212_0001
A19 A20 A21 A22 A23 A24
Figure imgf000212_0002
A25 A26
Figure imgf000212_0003
A31 A32 A33 A34 A35 A36
Figure imgf000212_0004
A37 A38 A39 A40 A41 A42
and the left most radical is connected to the X group;
W is selected from halogen, cyano, nitro, alkoxy, amino, alkylamino, dialkylamino, carboxy, amido, alkylamido, and dialkylamido;
X is selected from C3-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C7 cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; Y is a bond or a divalent linker group selected from -CH2-, -O-, -SO2-, -CH2O-, -OCH2- and -CH2CH2- with the rightmost radical of the Y group connected to the Z substituent;
Z is optionally substituted heteroaryl;
Ria is selected from C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C7 cycloalkylalkyl and optionally substituted C4-C7 alkoxyalkyl; Rib is selected from C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C7 cycloalkylalkyl and optionally substituted C4-C7 alkoxyalkyl;
Each R2 is independently selected from Ci -C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C7 cycloalkylalkyl and optionally substituted C4-C7 alkoxyalkyl, or two R2 groups taken together form a 3-6 membered cycloalkyl ring;
R3 and R4 are independently selected from C1-C4 alkyl, CF3, optionally substituted C3-C6 cycloalkyl, or R3 and R4 taken together form a 3-6 membered cycloalkyl ring;
R5 is selected from Ci-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C7 cycloalkylalkyl and optionally substituted C4-C7 alkoxyalkyl;
R6 is selected from hydrogen, Ci-C6 alkyl, optionally substituted C3-C6 cycloalkyl and optionally substituted C3-C6 cycloalkylalkyl;
R7 is selected from hydrogen, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C7 cycloalkylalkyl and optionally substituted C4-C7 alkoxyalkyl;
n is independently selected from 1 and 2.
2. The compound of Claim 1 having Formula (II).
3. The compound of Claim 1 having Formula (III).
4. The compound of Claim 1 having Formula (I).
5. The compound of any of Claims 1-4 where Y is -CH2CH2- with the rightmost radical connected to the Z substituent.
6. The compound of any of Claims 1-4 where Y is selected from -CH2O- or -OCH2- with the rightmost radical connected to the Z substituent.
7. The compound of any of Claims 1-4 where Y is -CH2O- with the rightmost radical connected to the Z substituent.
8. The compound of any of Claims 1-4 where Y is -OCH2- with the rightmost radical connected to the Z substituent.
9. The compound of any of Claims 1-8 where Z is selected from an optionally substituted heteroaryl having only 6 ring atoms and an optionally substituted heterobicyclic ring system.
10. The compound of any of Claims 1-8 where Z is an optionally substituted heterobicyclic ring system.
11. The compound of any of Claims 1-8 where Z is an optionally substituted heterobicyclic ring system where one ring is aromatic.
12. The compound of any of Claims 1-8 where Z is an optionally substituted heterobicyclic ring system where both rings are aromatic.
13. The compound of any of Claims 1-8 where Z is an optionally substituted heterobicyclic ring system containing exactly 9 ring atoms.
14. The compound of any of Claims 1-8 where Z is an optionally substituted heterobicyclic ring system containing exactly 10 ring atoms.
15. The compound of any of Claims 1-8 where Z is an optionally substituted heteroaryl having only 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two; said ring is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, Ci-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
16. The compound of any of Claims 1-8 where Z is an optionally substituted heteroaryl having only 6 ring atoms selected from C and N provided the total number of ring nitrogens is less than or equal to two.
17. The compound of any of Claims 1-8 where Z is selected from benzimidazolyl, quinolinyl, tetrahydroquinolyl, imidazo[l,2-α]pyridin-2-yl, tetrahydroisoquinolyl, 5- methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl, 6-fluoroquinolyl and isoquinolinyl substituted with up to 3 substituents independently selected from Ci-C4 alkyl, Ci-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
18. The compound of any of Claims 1-8 where Z is selected from benzimidazolyl, quinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and isoquinolinyl substituted with up to 3 substituents independently selected from Ci-C4 alkyl, Ci-C4 alkoxy, C3-C6 cycloalkyl, C3- C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl, cyano and nitro.
19. The compound of any of Claims 1-8 where Z is selected from quinolinyl, imidazo[l,2- α]pyridin-2-yl, 5-methylpyridin-2-yl, 3,5-dimethylpyridin-2-yl and 6-fluoroquinolin-2-yl substituted with up to 3 substituents independently selected from Ci-C4 alkyl, Ci-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
20. The compound of any of Claims 1-8 where Z is 2-pyridinyl optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
21. The compound of any of Claims 1-8 where Z is 6-fluoroquinolin-2-yl substituted with up to 3 substituents independently selected from Ci-C4 alkyl, Ci-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
22. The compound of any of Claims 1-8 where Z is 2-quinolinyl substituted with up to 3 substituents independently selected from Ci-C4 alkyl, Ci-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C4-C7 cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano and nitro.
23. The compound of any of Claims 1-8 where Z is selected from 2-quinolinyl and 6- fluoroquinolin-2-yl.
24. The compound of any of Claims 1-8 where Z is 2-quinolinyl.
25. The compound of any of Claims 1-8 where any Z is substituent may be unsubstituted.
26. The compound of any of Claims 1-25 where HET is selected from Formulas Al, A2, A7, A8, A14, A15, A19, A25, A29, A30, A31, A32, A35, A37, A38, A39, A40.
27. The compound of any of Claims 1-25 where HET is selected from Formulas Al, A2, A7, A8, A25, A29, A30, A31, A32, A35, A37, A38, A39, A40.
28. The compound of any of Claims 1-25 where HET is selected from Formulas Al, A2, A7, A8, A14, A15 and A19.
29. The compound of any of Claims 1-25 where HET is selected from Formulas A7, A8, A25, A29, A30, A31, A32, A35, A37 and A38.
30. The compound of any of Claims 1-25 where HET is selected from Formulas Al, A2, A7 and A8.
31. The compound of any of Claims 1-25 where HET is selected from Formulas A29, A30, A31 and A32.
32. The compound of any of Claims 1-25 where HET is selected from Formulas A7, A8, A29 and A31.
33. The compound of any of Claims 1-25 where HET is selected from Formulas A29, A31, A37 and A38.
34. The compound of any of Claims 1-25 where HET is selected from Formulas A25, A29, A30 and A35.
35. The compound of any of Claims 1-25 where HET is selected from Formulas A7 and
A8.
36. The compound of any of Claims 1-25 where HET is selected from Formulas A29 and A30.
37. The compound of any of Claims 1-25 where HET is selected from Formulas A35 and A36.
38. The compound of any of Claims 1-25 where HET is selected from Formulas A29 and A31.
39. The compound of any of Claims 1-25 where HET is selected from Formulas A37 and
A38.
40. The compound of any of Claims 1-25 where HET is Formula A7.
41. The compound of any of Claims 1-25 where HET is Formula A8.
42. The compound of any of Claims 1-25 where HET is Formula A29.
43. The compound of any of Claims 1-25 where HET is Formula A30.
44. The compound of any of Claims 1 -25 where HET is Formula A31.
45. The compound of any of Claims 1-44 where X is a heterocycloalkyl group selected from Formulas Bl -B 16 depicted below:
Figure imgf000219_0001
B1 B2 B3 B4
Figure imgf000219_0002
Figure imgf000219_0003
B9 B10 B11 B12
-!-N£)) -!-NQ)) -!-NQVR6
Figure imgf000219_0004
B13 B14 B15 B16
wherein R6 is selected from hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl and C4-C7 cycloalkylalkyl.
46. The compound of any of Claims 1-44 where X is an optionally substituted heterocycloalkyl having only 6 ring atoms.
47. The compound of any of Claims 1-44 where X is an optionally substituted heterocycloalkyl having only 5 ring atoms.
48. The compound of any of Claims 1-44 where X is an optionally substituted heteroaryl.
49. The compound of any of Claims 1-44 where X is selected from an optionally substituted monocyclic aromatic ring having 5 ring atoms selected from C, O, S and N provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms may be oxygen or sulfur, and a monocyclic aromatic ring having 6 atoms selected from C and N provided that not more than 3 ring atoms are N and where said ring may be optionally and independently substituted with up to two groups selected from C1-C4 alkyl, cycloalkyl, cycloalkyloxy, C1-C4 alkoxy, CF3, carboxy, alkoxyalkyl, C1-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro.
50. The compound of any of Claims 1-44 where X is an optionally substituted monocyclic aromatic ring having 6 ring atoms selected from C and N provided that not more than 3 ring atoms are N and where said ring may be optionally and independently substituted with up to two groups selected from Ci-C4 alkyl, cycloalkyl, cycloalkyloxy, Ci-C4 alkoxy, CF3, carboxy, alkoxyalkyl, Ci-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro.
51. The compound of any of Claims 1 -44 where X is an optionally substituted monocyclic aromatic ring having 5 ring atoms selected from C, O, S, and N, provided the total number of ring heteroatoms is less than or equal to four and where no more than one of the total number of heteroatoms may be oxygen or sulfur and where said ring may be optionally and independently substituted with up to two groups selected from Ci-C4 alkyl, cycloalkyl, cycloalkyloxy, Ci-C4 alkoxy, CF3, carboxy, alkoxyalkyl, Ci-C4 cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano, and nitro.
52. The compound of any of Claims 1-44 where X is an optionally substituted heterobicyclic ring system.
53. The compound of any of Claims 1-44 where X is an optionally substituted heterobicyclic ring system where one ring is aromatic.
54. The compound of any of Claims 1-44 where X is an optionally substituted heterobicyclic ring system where both rings are aromatic.
55. The compound of any of Claims 1-44 where X is an optionally substituted heterobicyclic ring system containing exactly 9 ring atoms.
56. The compound of any of Claims 1-44 where X is an optionally substituted heterobicyclic ring system containing exactly 10 ring atoms.
57. The compound of any of Claims 1-44 where X is selected from phenyl and pyridinyl.
58. The compound of any of Claims 1-44 where X is restricted phenyl.
59. The compound of any of Claims 1-44 where X is phenyl optionally substituted with one or more substituents selected from F, Cl, CN, NO2, CF3, OCF3, OCHF2, CH2CF3 and OMe.
60. The compound of any of Claims 1-44 where X is selected from a 3,4-disubstituted phenyl, 3-substituted phenyl and 4-substituted phenyl.
61. The compound of any of Claims 1-44 where X is selected from 3,4-disubstituted phenyl and 4-substituted phenyl.
62. The compound of any of Claims 1-44 where X is 4-substituted phenyl.
63. The compound of any of Claims 1-44 where X is selected from benzo[<i]oxazoyl, benzo[c][l,2,5]oxadiazyl, benzo[c][l,2,5]thiadiazolyl, benzo[<i]isoxazolyl, IH- benzo[<i]imidazoyl, benzo[<i]thiazoyl, benzo[c]isothiazolyl, benzo[<i]isothiazolyl, benzo[c]isoxazolyl, imidazo[l,2-α]pyridinyl and imidazo[l,5-α]pyridinyl
64. The compound of any of Claims 1-44 where X is selected from benzo[c][l,2,5]oxadiazyl and benzo[c][l,2,5]thiadiazolyl.
65. The compound of any of Claims 1-44 where X is selected from benzo[<i]oxazoyl, IH- benzo[<i]imidazoyl and benzo[<i]thiazoyl.
66. The compound of any of Claims 1-44 where X is selected from morpholinyl, pyranyl and tetrahydrofuranyl.
67. The compound of any of Claims 1-44 where X is 4-pyridinyl optionally substituted with one group selected from C1-C4 alky 1, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C1- C4 alkoxy, CF3, amino, alkylamino, dialkylamino, thioalkyl, halogen and cyano.
68. The compound of any of Claims 1-44 where X is selected from morpholinyl (having Formula Bl) and 4-pyranyl (having Formula B2).
69. The compound of any of Claims 1-44 where X is 4-pyridinyl.
70. The compound of any of Claims 1-44 where X is benzo[c][l,2,5]oxadiazoyl.
71. The compound of any of Claims 1-44 where X is benzo[c][l,2,5]thiadiazolyl
72. The compound of any of Claims 1-44 where X is 3-chloro-4-methoxyphenyl
73. The compound of any of Claims 1-44 where X is 3-cyano-4-methoxyphenyl
74. The compound of any of Claims 1-44 where X is 3-chloro-4-difluoromethoxyphenyl
75. The compound of any of Claims 1-44 where X is 3-cyano-4-difluoromethoxyphenyl
76. The compound of any of Claims 1-44 where X is 4-nitrophenyl.
77. The compound of any of Claims 1-44 where X is 4-methoxyphenyl.
78. The compound of any of Claims 1-44 where X is 4-chlorophenyl.
79. The compound of any of Claims 1-44 where X is 4-cyanophenyl.
80. The compound of any of Claims 1-44 where X is 4-trifluoromethoxyphenyl.
81. The compound of any of Claims 1-80 where W is selected from nitro, carboxy, amido, alkylamido, and dialkylamido.
82. The compound of any of Claims 1-80 where W is is selected from halogen, cyano and Ci -C4 alkoxy.
83. The compound of any of Claims 1-80 where W is selected from halogen and cyano.
84. The compound of any of Claims 1-83 where Ria is selected from C3-C6 cycloalkyl and Ci-C4 alkyl.
85. The compound of any of Claims 1-83 where Ria is C3-C6 cycloalkyl.
86. The compound of any of Claims 1-83 where Ria is Ci-C4 alkyl.
87. The compound of any of Claims 1-86 where Rib is selected from an optionally substituted C3-C6 cycloalkyl and Ci-C4 alkyl.
88. The compound of any of Claims 1-86 where Rib is an optionally substituted C3-C6 cycloalkyl.
89. The compound of any of Claims 1-86 where R^ is Ci-C4 alkyl.
90. The compound of any of Claims 1-89 where each R2 is independently selected from an optionally substituted C3-C6 cycloalkyl, Ci-C4 alkyl or two R2 groups taken together form a 3-6 membered cycloalkyl ring.
91. The compound of any of Claims 1-89 where each R2 is independently selected from an optionally substituted C3-C6 cycloalkyl and C1-C4 alkyl.
92. The compound of any of Claims 1-89 where each R2 is independently selected from an optionally substituted C3-C6 cycloalkyl.
93. The compound of any of Claims 1-89 where each R2 is independently selected from Ci-C4 alkyl.
94. The compound of any of Claims 1-89 where two R2 groups taken together form a 3-6 membered cycloalkyl ring.
95. The compound of any of Claims 1-89 where two R2 groups taken together form a three membered ring.
96. The compound of any of Claims 1-95 where R3 and R4 are independently selected from Ci-C4 alkyl or R3 and R4 taken together form a C3-C6 cycloalkyl ring.
97. The compound of any of Claims 1-95 where R3 and R4 are independently selected from Ci-C4 alkyl and an optionally substituted C3-C6 cycloalkyl.
98. The compound of any of Claims 1-95 where R3 and R4 are taken together form a C3- C6 cycloalkyl ring.
99. The compound of any of Claims 1-95 where R3 and R4 are taken together form a C3 cycloalkyl ring.
100. The compound of any of Claims 1-95 where R3 and R4 are Ci-C4 alkyl.
101. The compound of any of Claims 1-95 where R3 and R4 are methyl.
102. The compound of any of Claims 1-101 where R5 is selected from an optionally substituted C3-C6 cycloalkyl and C1-C4 alkyl.
103. The compound of any of Claims 1-101 where R5 is an optionally substituted C3-C6 cycloalkyl.
104. The compound of any of Claims 1-101 where R5 is C1-C4 alkyl.
105. The compound of any of Claims 1-104 where R7 is selected from hydrogen, Ci-C4 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C4-C7 cycloalkylalkyl and an optionally substituted C4-C7 alkoxyalkyl.
106. The compound of any of Claims 1-104 where R7 is selected from hydrogen, Ci-C4 alkyl, an optionally substituted C3-C6 cycloalkyl and an optionally substituted C4-C7 cycloalkylalkyl.
107. The compound of any of Claims 1-104 where R7 is selected from Ci-C4 alkyl, an optionally substituted C3-C6 cycloalkyl and an optionally substituted C4-C7 cycloalkylalkyl.
108. The compound of any of Claims 1-104 where R7 is selected from Ci-C4 alkyl and an optionally substituted C3-C6 cycloalkyl.
109. The compound of any of Claims 1-104 where R7 is Ci-C4 alkyl.
110. The compound of any of Claims 1-104 where R7 is an optionally substituted C3-C6 cycloalkyl.
111. The compound of any of Claims 1 - 104 where R7 is hydrogen.
112. The compound or pharmaceutically acceptable salt thereof selected from any of Examples 1-13, 15, 17-111, 113-815, and 817-894.
113. A pharmaceutical composition comprising the compound of any of claims 1-112 and a pharmaceutically acceptable carrier or excipient.
114. A method for treating a CNS disorder comprising administering to a human a therapeutically effective amount of the pharmaceutical composition of claim 113.
115. A method for treating eating disorders, obesity, compulsive gambling, sexual disorders, narcolepsy, sleep disorders, diabetes, metabolic syndrome or for use in smoking cessation treatment comprising administering to a human thereof a therapeutically effective amount of the pharmaceutical composition of claim 113.
116. A method for treating obesity, schizophrenia, schizo-affective conditions, Huntington's disease, dystonic conditions and tardive dyskinesia comprising administering to a human thereof a therapeutically effective amount of the pharmaceutical composition of claim 113.
117. A method for treating schizophrenia and schizo-affective conditions comprising comprising administering to a human thereof a therapeutically effective amount of the pharmaceutical composition of claim 113.
118. A method for treating Huntington's disease comprising administering to a human thereof a therapeutically effective amount of the pharmaceutical composition of claim 113.
119. A method for treating obesity and metabolic syndrome comprising administering to a human thereof a therapeutically effective amount of the pharmaceutical composition of claim 113.
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010128995A1 (en) * 2009-05-07 2010-11-11 Envivo Pharmaceuticals, Inc. Phenoxymethyl heterocyclic compounds
WO2012018058A1 (en) * 2010-08-04 2012-02-09 武田薬品工業株式会社 Fused heterocyclic ring compound
WO2012112946A1 (en) 2011-02-18 2012-08-23 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (pde10a)
US8466148B2 (en) 2008-06-25 2013-06-18 Envivo Pharmaceuticals, Inc. 1,2-disubstituted heterocyclic compounds
WO2014071044A1 (en) 2012-11-01 2014-05-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a)
US8765760B2 (en) 2011-01-11 2014-07-01 Sunovion Pharmaceuticals, Inc. [1,2,4] triazol [1,5-a] pyrazines useful as inhibitors of phosphodiesterases
WO2014142322A1 (en) 2013-03-15 2014-09-18 第一三共株式会社 Benzothiophene derivative
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
WO2023059224A1 (en) 2021-10-09 2023-04-13 Joint Stock Company "Pharmasyntez" A new class of antiviral drugs
US11890275B2 (en) 2017-04-18 2024-02-06 Celgene Quanticel Research, Inc. Therapeutic compounds
RU2827993C2 (en) * 2021-10-09 2024-10-04 Акционерное общество «Фармасинтез» New class of antiviral agents

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA105794C2 (en) 2009-06-26 2014-06-25 Новартіс Аг 1,3-DISUBSTITUTED IMIDAZOLIDIN-2-ONE DERIVATIVES AS Cyp17 INHIBITORS
WO2012018909A1 (en) * 2010-08-04 2012-02-09 Takeda Pharmaceutical Company Limited Fused heterocyclic compounds
WO2012040230A1 (en) 2010-09-20 2012-03-29 Envivo Pharmaceuticals, Inc. Imidazotriazinone compounds
EA023064B1 (en) 2011-04-28 2016-04-29 Новартис Аг 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
WO2013047411A1 (en) * 2011-09-29 2013-04-04 富士フイルム株式会社 Novel triazine derivative and ultraviolet absorbent
EP2828262A4 (en) * 2012-03-19 2015-09-23 Forum Pharmaceuticals Inc Imidazotriazinone compounds
MX2014015156A (en) 2012-06-12 2015-08-06 Abbvie Inc Pyridinone and pyridazinone derivatives.
TW201512201A (en) * 2013-03-14 2015-04-01 Forum Pharmaceuticals Inc Polymorphs and salts of a compound
TWI634114B (en) * 2013-05-08 2018-09-01 永恒生物科技公司 Furanone compound as a kinase inhibitor
CA2916653C (en) 2013-06-27 2017-07-18 Pfizer Inc. Heteroaromatic compounds and their use as dopamine d1 ligands
US10039764B2 (en) 2013-07-12 2018-08-07 University Of South Alabama Treatment and diagnosis of cancer and precancerous conditions using PDE10A inhibitors and methods to measure PDE10A expression
CN104211638A (en) * 2014-08-13 2014-12-17 李增 Fatty amino substituted graveoline derivative, its preparation and its application as anti-Alzheimer's disease medicine
CN104610134B (en) * 2015-01-29 2017-01-25 安徽星宇化工有限公司 Preparation method of 6-methyl-2-pyridyl methanol
US10738035B2 (en) 2015-05-13 2020-08-11 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
WO2017011552A1 (en) * 2015-07-13 2017-01-19 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
MX384836B (en) 2016-03-07 2025-03-14 Enanta Pharm Inc ANTIVIRAL AGENTS AGAINST HEPATITIS B
WO2019005241A1 (en) * 2017-03-23 2019-01-03 Clavius Pharmaceuticals, Llc Tri-substituted imidazoles for the inhibition of tgf beta and methods of treatment
NZ762994A (en) 2017-08-28 2025-11-28 Enanta Pharm Inc Hepatitis b antiviral agents
US11058678B2 (en) 2018-01-22 2021-07-13 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
WO2019191166A1 (en) 2018-03-29 2019-10-03 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
US12077548B2 (en) 2018-08-22 2024-09-03 Clavius Pharmaceuticals, LLC. Substituted imidazoles for the inhibition of TGF-β and methods of treatment
AR116474A1 (en) 2018-09-21 2021-05-12 Enanta Pharm Inc 6,7-DIHYDRO-2H-BENZOFUR [2,3-a] QUINOLIZIN-3-CARBOXYL ACID DERIVATIVES AS ANTIVIRAL AGENTS FOR THE TREATMENT OR PREVENTION OF HBV INFECTION
SG11202105007TA (en) 2018-11-21 2021-06-29 Enanta Pharm Inc Functionalized heterocycles as antiviral agents
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11236111B2 (en) 2019-06-03 2022-02-01 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US11760755B2 (en) 2019-06-04 2023-09-19 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
WO2020247575A1 (en) 2019-06-04 2020-12-10 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
WO2021007488A1 (en) 2019-07-11 2021-01-14 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
WO2021055425A2 (en) 2019-09-17 2021-03-25 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
KR102811543B1 (en) 2019-10-16 2025-05-23 삼성디스플레이 주식회사 Organic electroluminescence device and polycyclic compound for organic electroluminescence device
WO2021188414A1 (en) 2020-03-16 2021-09-23 Enanta Pharmaceuticals, Inc. Functionalized heterocyclic compounds as antiviral agents
EP4626878A1 (en) 2022-12-02 2025-10-08 Neumora Therapeutics, Inc. Methods of treating neurological disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006072828A2 (en) * 2005-01-07 2006-07-13 Pfizer Products Inc. Heteroaromatic quinoline compounds and their use as pde10 inhibitors
WO2007077490A2 (en) * 2006-01-05 2007-07-12 Pfizer Products Inc. Bicyclic heteroaryl compounds as pde10 inhibitors
WO2007129183A2 (en) * 2006-05-02 2007-11-15 Pfizer Products Inc. Bicyclic heteroaryl compounds as pde10 inhibitors

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2417277A1 (en) * 2000-07-27 2002-02-07 F. Hoffmann-La Roche Ag 3-indolyl-4-phenyl-1h-pyrrole-2,5-dione derivatives as inhibitors of glycogen synthase kinase-3.beta.
US20030032579A1 (en) 2001-04-20 2003-02-13 Pfizer Inc. Therapeutic use of selective PDE10 inhibitors
WO2004002484A1 (en) 2002-06-26 2004-01-08 Kyowa Hakko Kogyo Co., Ltd. Phosphodiesterase inhibitor
JP2007145819A (en) * 2005-10-28 2007-06-14 Tanabe Seiyaku Co Ltd Pharmaceutical composition
EP1845098A1 (en) 2006-03-29 2007-10-17 Ferrer Internacional, S.A. Imidazo[1,2-b]pyridazines, their processes of preparation and their use as GABA receptor ligands
WO2008033455A2 (en) 2006-09-13 2008-03-20 The Institutes For Pharmaceutical Discovery, Llc Biphenyl and heteroaryl phenyl derivatives as protein tyrosine phosphatases inhibitors
CA2666489C (en) * 2006-10-19 2012-10-02 F. Hoffmann-La Roche Ag Imidazolone and imidazolidinone derivatives as 11b-hsd1 inhibitors for diabetes
FR2928924B1 (en) 2008-03-21 2010-04-23 Sanofi Aventis POLYSUBSTITUTED DERIVATIVES OF 6-HETEROARYL-IMIDAZO-1,2-A! PYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
WO2009158393A1 (en) 2008-06-25 2009-12-30 Envivo Pharmaceuticals, Inc. 1, 2 disubstituted heterocyclic compounds
WO2010128995A1 (en) 2009-05-07 2010-11-11 Envivo Pharmaceuticals, Inc. Phenoxymethyl heterocyclic compounds
IN2012DN02493A (en) 2009-09-03 2015-08-28 Allergan Inc
PL2605652T3 (en) 2010-08-18 2018-04-30 Samumed, Llc Diketones and hydroxyketones as catenin signaling pathway activators

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006072828A2 (en) * 2005-01-07 2006-07-13 Pfizer Products Inc. Heteroaromatic quinoline compounds and their use as pde10 inhibitors
WO2007077490A2 (en) * 2006-01-05 2007-07-12 Pfizer Products Inc. Bicyclic heteroaryl compounds as pde10 inhibitors
WO2007129183A2 (en) * 2006-05-02 2007-11-15 Pfizer Products Inc. Bicyclic heteroaryl compounds as pde10 inhibitors

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9290450B2 (en) 2008-06-03 2016-03-22 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9265767B2 (en) 2008-06-25 2016-02-23 Forum Pharmaceuticals Inc. 1,2-disubstituted heterocyclic compounds
US8481534B2 (en) 2008-06-25 2013-07-09 Envivo Pharmaceuticals, Inc. 5- and 6-membered heterocyclic compounds
US8466148B2 (en) 2008-06-25 2013-06-18 Envivo Pharmaceuticals, Inc. 1,2-disubstituted heterocyclic compounds
US8933074B2 (en) 2008-06-25 2015-01-13 Forum Pharmaceuticals Inc. 1,2-disubstituted heterocyclic compounds
WO2010128995A1 (en) * 2009-05-07 2010-11-11 Envivo Pharmaceuticals, Inc. Phenoxymethyl heterocyclic compounds
US8946222B2 (en) 2009-05-07 2015-02-03 Forum Pharmaceuticals Inc. Phenoxymethyl heterocyclic compounds
US8343973B2 (en) 2009-05-07 2013-01-01 Envivo Pharmaceuticals, Inc. Phenoxymethyl heterocyclic compounds
WO2012018058A1 (en) * 2010-08-04 2012-02-09 武田薬品工業株式会社 Fused heterocyclic ring compound
US8883788B2 (en) 2010-08-04 2014-11-11 Takeda Pharmaceutical Company Limited Fused heterocyclic ring compound
US9856274B2 (en) 2011-01-11 2018-01-02 Sunovion Pharmaceuticals Inc. Substituted pyrazolo[1,5-a]pyridines as PDE-10 inhibitors
US8765760B2 (en) 2011-01-11 2014-07-01 Sunovion Pharmaceuticals, Inc. [1,2,4] triazol [1,5-a] pyrazines useful as inhibitors of phosphodiesterases
US10570156B2 (en) 2011-01-11 2020-02-25 Sunovion Pharmaceuticals Inc. Substituted imidazo[1,2-a]pyridines as PDE-10 inhibitors
US9249162B2 (en) 2011-01-11 2016-02-02 Sunovion Pharmaceuticals Inc. Substituted [1,2,4]triazolo[1,5-a]pyridines as PDE-10 inhibitors
WO2012112946A1 (en) 2011-02-18 2012-08-23 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (pde10a)
US8772316B2 (en) 2011-02-18 2014-07-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A)
US9670181B2 (en) 2011-02-18 2017-06-06 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
WO2014071044A1 (en) 2012-11-01 2014-05-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a)
US9464076B2 (en) 2013-03-15 2016-10-11 Daiichi Sankyo Company, Limited Benzothiophene derivative
WO2014142322A1 (en) 2013-03-15 2014-09-18 第一三共株式会社 Benzothiophene derivative
US9902710B2 (en) 2013-12-05 2018-02-27 Exonhit Therapeutics, Sa Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones
US11890275B2 (en) 2017-04-18 2024-02-06 Celgene Quanticel Research, Inc. Therapeutic compounds
WO2023059224A1 (en) 2021-10-09 2023-04-13 Joint Stock Company "Pharmasyntez" A new class of antiviral drugs
RU2827993C2 (en) * 2021-10-09 2024-10-04 Акционерное общество «Фармасинтез» New class of antiviral agents

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