# Patent

## Title
1,2-disubstituted heterocyclic compounds

## 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 to, those associated with cognitive deficits or schizophrenic symptoms.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 13/919,320, filed Jun. 17, 2013, which is a continuation of U.S. patent application Ser. No. 13/290,527, filed on Nov. 7, 2011, now U.S. Pat. No. 8,466,148, which is a continuation of U.S. patent application Ser. No. 12/490,808, filed on Jun. 24, 2009, now U.S. Pat. No. 8,071,595, which claims priority to U.S. Provisional Application No. 61/176,413, filed on May 7, 2009, U.S. Provisional Application No. 61/138,866, filed on Dec. 18, 2008, U.S. Provisional Application No. 61/109,162, filed on Oct. 28, 2008 and U.S. Provisional Application No. 61/075,594, filed on Jun. 25, 2008, the disclosures each of which are hereby incorporated by reference in their entirety.


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, PDE10, was reported simultaneously by three groups in 1999 (Soderling et al. “Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A” Proc. Natl. Sci. 1999, 96, 7071-7076; Loughney et al. “Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclic nucleotide phosphodiesterase” Gene 1999, 234, 109-117; Fujishige et al. “Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)” J. Biol. Chem. 1999, 274, 18438-18445). The human PDE10 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.
PDE10 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 PDE10 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.
PDE10 hydrolyzes both cAMP (Km=0.05 uM) and cGMP (Km=3 uM) (Soderling et al. “Isolation and Characterization of a dual-substrate phosphodiesterase gene family: PDE10.” Proc. Natl. USA 1999, 96(12), 7071-7076). In addition, PDE10 has a five-fold greater Vmax for cGMP than for cAMP and these in vitro kinetic data have lead to the speculation that PDE10 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).
PDE10 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 (PDF2, 5, 6, and 11) bind cGMP while recent data points to the tight binding of cAMP to the GAF domain of PDE10 (Handa et al. “Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP” J. Biol. Chem. 2008, May 13th, ePub).
PDE10 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 PDE10 inhibitor, reduces apomorphine induced stereotypies and rat brain dopamine levels and increases haloperidol induced catalepsy. This experiment lends support to the use of a PDE10 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 Psychopharmacology, 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 dystipidemia), 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, 2095, 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 PDE10 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-10A):




Wherein:

HET is a heterocyclic ring selected from Formulas A1-A26 and A29-42 below



















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—, —O—, —SO2—, —CH2O—, —OCH2— and —CH2CH2— with the rightmost radical of the Y group connected to the Z substituent;
Z is optionally substituted heteroaryl;
R1a is selected from alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl and optionally substituted alkoxyalkyl;
R1b 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 C1-C4 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 embodiments, 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 various 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 A1, A2, A7, A8, A14, 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 A1, A2, A7, A8, A14, A15 and A19.
In another embodiment, HET is selected from Formulas A5, A6, A9 A10, A20 and A24.
In an additional embodiment, HET is selected from Formulas A1, 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 arid 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 front 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 A1.
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 A10.
In another embodiment, HET is Formula A11.
In another embodiment, HET is Formula A12.
In another embodiment, HET is Formula A13.
In another embodiment, HET is Formula A14.
In another embodiment, HET is Formula A15.
In another embodiment, HET is Formula A16.
In another embodiment, HET is Formula A17.
In another embodiment, HET is Formula A18.
In another embodiment, HET is Formula A19.
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, alkylaimino 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 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-C5 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:







wherein R6 is selected from hydrogen and C1-C6 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 tetrahydronfuranyl.
In another embodiment X is selected from morpholinyl (having Formula B1) 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 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 1H-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 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 1H-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 C1-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C1-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 C1-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethyl, C1-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 C1-C4 alkyl, cyclopropyl, cyclopropyloxy, cyclopropylmethy, 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][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isoxazolyl, 1H-benzo[d]imidazoyl, benzo[d]thiazoyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl, imidazo[1,2-a]pyridinyl and imidazo[1,5-a]pyridinyl
In another embodiment X is selected from benzo[c][1,2,5]oxadiazyl and benzo[c][1,2,5]thiadiazolyl.
In a further embodiment, X is selected from benzo[d]oxazoyl, 1H-benzo[d]imidazoyl and benzo[d]thiazoyl.
In a further embodiment, X is benzo[d]oxazoyl.
In a further embodiment, X is 1H-benzo[d]imidazoyl.
In a further embodiment, X is benzo[d]thiazoyl.
In another embodiment X is benzo[c][1,2,5]oxadiazoyl.
In a further embodiment X is benzo[c][1,5]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[1,2-a]pyridinyl.
In another embodiment, X is imidazo[1,5-a]pyridinyl.
In an additional embodiment, X is aryl.
In another embodiment, X is selected from phenyl and pryidinyl.
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, CH2CF2 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[1,2-a]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 isoquinolinyl, 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[1,2-a]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 isoquinolinyl 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, cycloalkyl alkoxy, 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, R1a is selected from cycloalkyl and alkyl.
In an additional embodiment, R1a is cycloalkyl.
In another embodiment, R1a 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, R1b 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 C1-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 C1-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 C1-6 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 para-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 C1-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., C1-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—(C1-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(O)— wherein alkyl is as defined above.
Aromatic is heteroaryl or aryl wherein heteroaryl and aryl are as defined below.
Aryl is a phenyl or naplhyl 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, iPr, 1Bu, unsubstituted cyolopropyl, 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 Ra 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-(C1-C4 alkyl)-O— group wherein aryl is as defined above.
Carboxy is a CO2H or CO2Rc group wherein Rc is independently chosen from, alkyl, C1-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.
Cycloalkykoxy is a cycloalkyl-O— group wherein cycloalkyl is as defined above. Examples include cycloptopyloxy, cyclobutyloxy and cyclopentyloxy. C3-C6 cycloalkyloxy is the subset of cycloalkyl-O— where cycloalkyl contains 3-6 carbon atoms.
Cycloalkylalkyl is a cycloalkyl-(C1-C4 alkyl)- group. Examples include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl.
Cycloalkylalkoxy is a cycloalkyl-(C1-C4 alkyl)-O— group wherein cycloalkyl and alkyl are as defined above. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclopentylmethoxy and cyctohexylmethoxy.
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, 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, iPr, 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 Ra and Rb taken together with the atom(s) to which they are attached form a 5-6 membered ring.
Heteroarylalkyl is a heteroaryl-(C1-C4 alkyl)- group wherein heteroaryl and alkyl are as defined above. Examples of heteroarylalkyl groups include 4-pyridinylmethyl and 4-pyridinylethyl.
Heteroaryloxy is a heteroaryl-O group wherein heteroaryl is as defined above.
Heteroarylalkoxy is a heteroaryl-(C1-C4 alkyl)-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, 1,2,3,4-tetrahydro-1,5-naphthyridyl 1,6-naphthyridyl, 1,2,3,4-tetrahydro-1,6-naphthyridyl 1,7-naphthyridyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl 1,8-naplithyridyl, 1,2,3,4-tetrahydro-1,8-naphthyridyl, 2,6-naphthyridyl, 2,7-naphthyridyl, cinnolyl, isoquinolyl, tetrahydroisoquinolinyl, phthalazyl, quinazolyl, 1,2,3,4-tetrahydroquinazolinyl, quinolyl, tetrahydroquinolinyl, quinoxalyl, tetrahydroquinoxalinyl, benzo[d][1,2,3]triazyl, benzo[e][1,2,4]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-d]pyrimidyl, pyrido[3,4-b]pyrazyl, pyrido[3,4-c]pyridazyl, pyrido[3,4-d]pyrimidyl, pyrido[4,3-b]pyrazyl, pyrido[4,3-c]pyridazyl, pyrido[4,3-d]pyrimidyl, quinazolyl, 1H-benzo[d][1,2,3]triazoyl, 1H-benzo[d]imidazoyl, 1H-indazoyl, 1H-indoyl, 2H-benzo[d][1,2,3]triazoyl, 2H-pyrazolo[3,4-b]pyridinyl, 2H-pyrazolo[4,3-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, benzo[b]thienyl, benzo[c][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]isothiazoyl, benzo[d]isoxazoyl, benzo[d]oxazoyl, benzo[d]thiazoyl, benzofuryl, imidazo[1,2-a]pyrazyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidyl, imidazo[1,2-b]pyridazyl, imidazo[1,2-c]pyrimidyl, imidazo[1,5-a]pyrazyl, imidazo[1,5-a]pyridinyl, imidazo[1,5-a]pyrimidyl, imidazo[1,5-b]pyridazyl, imidazo[1,5-c]pyrimidyl, indolizyl, pyrazolo[1,5-a]pyrazyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidyl, pyrazolo[1,5-b]pyridazine, pyrazolo[1,5-c]pyrimidine, pyrrolo[1,2-a]pyrazine, pyrrolo[1,2-a]pyrimidyl, pyrrolo[1,2-b]pyridazyl, pyrrolo[1,2-c]pyrimidyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-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-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridiyl, isothiazolo[4,5-b]pyridinyl, isothiazole[4,5-c]pyridinyl, isothiazolo[5,4-b]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-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl, oxazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridiyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-c]pyridinyl, thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]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[2.1.1]heptanyl, octahydro-1H-pyrido[1,2-a]pyrazine, 3-thia-6-azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]heptanyl
Heterocycloalkylalkyl is a heterocycloalkyl-(C1-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-(C1-C4 alkyl)—O— 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, —OCH2CH2OCH3, —OC(O)Ra, —OC(O)ORa, —C(O)NHRa, —C(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, iPr, 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 Ra 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)Ra, —OC(O)ORa, —OC(O)N(Ra), —N(Ra)(Rb), —NHC(O)Ra, —N(Ra)C(O)Rb, —NHC(O)ORa, —N(Ra)C(O)ORb, —C(O)N(Ra)(Rb), —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, iPr, 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 Ra 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)—)
        AeN Acetonitrile
        BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
        Bn Benzyl
        Celite® Diatomaceous earth
        DBU 1,8-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 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride
        Et3N Triethylamine
        g gram(s)
        h Hour(s)
        hr Hour(s)
        HATU 2-(7-Aza-1H-benzotruazole-1-yl)-1,1,3,3-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 1,3-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
        PEA Polyphosphoric acid
        PPAA 1-Propanephosphonic Acid Cyclic Anhydride
        PTSA p-Toluenesulfonic acid
        PyBOP® Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
        RT (or rt) room temperature (about 20-25° C.)
        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, A14, A15, A16, A18, A19, 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 A1, A2, A4, A6, A10, A11, 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.




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.




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:




Compounds of the disclosure of Formulas (I), (II) or (III) in which X=phenyl, restricted phenyl or heteroaryl are as described previously and thus having general Formula XLIV and XLV may be prepared generally as depicted in Scheme 4:




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:




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:




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:




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:




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:




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:




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:




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.




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.




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.




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.




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.




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.




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:




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-butyl 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




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 (3×50 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 250×4.6 mm, 5 um (SHCL06E001)
Mobile Phase: AcN (A): 0.1% TFA in Water. (B).
Flow rate: 1.5 ml/min (Gradient)
Condition-B:
Column: Zobrax SB-C18 250×4.6 mm, 5 um
Mobile Phase: AcN (A): 0.1% TFA in Water. (B).
Flow rate: 1.5 ml/min (Gradient)
Condition-C:
Column: Targa C-18 250×4.6 mm, 5 um
Mobile Phase: AcN (A): 0.1% TFA in Water. (B).
Flow rate: 1.5 ml/min (Gradient)
Condition-D:
Column: Targa C18 250×4.6 mm, 5 um (SNCL-12)
Mobile Phase: AcN (A): 5 M Ammonium Acetate in Water. (B).
Flow rate: 1.0 ml/min (Gradient
Condition-E:
Column: Higgins-C18 250×4.6 mm, 5 um
Mobile Phase: AcN (A): 0.1% TFA in Water. (B).
Flow rate: 1.5 ml/min (Gradient)
Condition-F:
Column: Chiralpak AD
Mobile Phase: n-Hexane: Ethanol (50:50)
Flow rate: 0.6 ml/min (Gradient)
Condition-G:
Column: Venusil C8, 250×4.6 mm, 5 um.
Mobile Phase: AcN (A): 0.1% TFA in Water. (B).
Flow rate: 1.5 ml/min (Gradient)
Condition-H:
Column: Eclipse XDB-C18, 150×4.6 mm, 5 um.
Mobile Phase: 0.1% TFA in Water. (A).ACN (B)
Flow rate: 1.5 ml/min (Gradient)
Condition-I:
Column: Acquity BEH-C18, (50×2.1 mm, 1.7 um.)
Mobile Phase: AcN (B)
Flow rate: 0.5 ml/min (Gradient)
Condition-J:
Column: Zobrax C18, (150×4.6 mm, 5 um.)
Mobile Phase: AcN (A): 0.1% TFA in Water. (B).
Flow rate: 1.0 ml/min (Gradient)
Synthesis of 1-Methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (Example 11)
Ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate




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 (2×100 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 




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 LiOH.H2O (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 (1N), filtered and dried in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (7.0 g, 95%) as a solid.
2-Bromo-1-(pyridin-4-yl)ethanone hydro bromide




To a stirred solution of 1-(pyridin-4-yl)-ethanone (10 g, 0.08 mol) in CCl4 (150 mL) was added Br2 (3.99 mL, 0.02 mol) dropwise at 0° C. and the mixture was then refluxed for 1 h. The reaction mixture was filtered and dried in vacuo to afford 2-bromo-1-(pridin-4-yl)-ethanone hydrobromide (22 g, 94%) as a solid.
4-(Pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one




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-1-(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° C. and stirring was continued for another 2 h at 0° C. The reaction mixture was quenched with HCl (1 N), aqueous layer was basified with NaHCO3 solution and extracted with DCM (2×50 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 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




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)-1H-pyrrol-2(5H)-one




To a solution of (Z)-4-hrydroxy-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 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-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).
1-Methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (Example 11)




To a stirred solution of 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-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 1N HCl and extracted with EtOAc (2×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford 1-methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-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: M−H: m/z=420.1.
Synthesis of 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)one (Example 33)
4-Hydroxy-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one 




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-methylpropaanoate (1.4 g, 0.012 mol) and t-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 (1N), and extracted with EtOAc (2×200 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




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° C. under an inert atmosphere. The mixture was then stirred for 2 h at 0° C. The reaction mixture was diluted with water and extracted with DCM (2×100 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 (2.50 mg, 37%) as a white solid.
4-(4-Methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 33) 




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 (2×100 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, d6-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-yl)-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)




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, d6-DMSO): δ 8.68 (d, J=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-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 63)
Methyl 2-amino-2-methylpropanoate




To a solution of 2-amino-2-methylpropanoic acid (5.0 g) in MeOH (15 mL) was added SOCl2 (4 mL) at 0° C. 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




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 LiOH.H2O (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 (1N) and extracted with EtOAc (2×300 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)prepanoate




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 (2×200 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-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one




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° C. under an inert atmosphere. The reaction mixture was then stirred for 2 h, diluted with ice water and then extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-hydroxy-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-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-1-pyrrol-3-yl trifluoromethanesulfonate




To a solution of 4-hydroxy-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (500 mg, 1.3 mmol) in DCM (15 mL) were added TEA (422 mg, 4.1 mmol) and triflic anyhdride (785 mg, 2.7 mol) at 0° C. under an inert atmosphere. The mixture as then stirred for 2 h., diluted with water and extracted with DCM (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and then concentrated in vacuo to afford 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (400 mg, 58%) as a white solid.
5,5-Dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 63)




To a solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (2.0 g, 0.004 mol) 1,4-dioxane (50 mL) were added pyridin-4-yl boronic acid (598 mg, 4.8 mol), Na2CO3 (1.0 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° C. for 16 h, diluted with water, and extracted with EtOAc (2×200 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)-1H-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)phenyl)-1H-pyrrol-2(5H)one (Example 823)
4-(4-Methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 823)




To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-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 (2×200 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)-1H-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-methoxyphenyl)-1,5,5-trimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 73)
4-(4-Methoxyphenyl)-1,5,5-trimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (Example 73)




To a solution of 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-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° C. 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)-1,5,5-trimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-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-methoxyphenyl)-2,2-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 262)
Ethyl 2-(4-methoxyphenyl)acetate




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° C. for 2 h and then extracted with EtOAc (2×300 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-Methoxyphenyl)acetic acid




To a solution of ethyl 2-(4-methoxyphenyl)acetate (12 g, 0.06 mol) 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 (1N) and extracted with EtOAc (2×400 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.
1-(4-Hydroxyphenyl)-2-(4-methoxyphenyl)ethanone




To a solution of 2-(4-methoxyphenyl)acetic acid (10 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 (2×300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to obtain the crude product which was purified via silica gel column chromatography to afford 1-(4-hydroxyphenyl)-2-(4-methoxyphenyl)-ethanone (3 g, 20%) as a pale yellow solid
1-(4-(Benzyloxy)phenyl)-2-(4-methoxyphenyl)ethanone 




To a 0° C. solution of 1-(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° C. and stirred for 2 h. The reaction was quenched with cold water, filtered and the filtrate was extracted with DCM (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 1-(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-one




To a pre-cooled 0° C. solution of 1-(4-(benzyloxy)phenyl)-2-(4-methoxyphenyl)-ethanone (2 g, 6.02 mmol) in THF (20 mL) under an inert atmosphere was added t-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 (2×50 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 




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)




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 mg, 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), 7.19-7.11 (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




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 (3×200 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 80° C. to afford trimethyl (2-methylbut-3-yn-2-yloxy)silane (25 g) as an oil.
4-Methyl-1-(pyridin-4-yl)-4-(trimethylsilyoxy)pent-2-yn-1-one




To a pre-cooled −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy)silane (5.0 g, 0.03 mol) in dry THF (150 mL), n-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 −78° C. and then 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° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 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-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (2.2 g, 27%) as oil.
4-Hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one




To a stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-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-1-(pyridin-4-yl)pent-2-yn-1-one (0.35 g, 96%) as an oil.
2,2-Dimethyl-5-(pyridin-4-yl)furan-3(2H)-one




To a stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one (1.49 g, 0.007 mol) in ethanol (15 mL), diethylamine (0.511 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




To a stirred solution of 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.81 g, 4.28 mmol) 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)




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-1,3,2-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 refluxed 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-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water (A), AcN (B), Flow rate: 1.5 ml/min (Gradient)
Synthesis of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 138)
1-(4-Methoxyphenyl)-4-methylpent-2-yne-1,4-diol




Too pre-cooled, −78° C. 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° C., 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° C. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 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-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one




To a room temperature, stirred solution of 1-(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 over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (6 g, 96%) as an oil.
5-(4-Methoxyphenyl)-2,2-dimethylfuran-3(2H)-one




To a stirred solution of 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-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-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one




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)




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-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (2.43 g, 0.0067 mol), and Cs2CO3 (11 g, 0.034 mol) in toluene (25 mL) and water (8 mL) was degassed. Pd(dppf)Cl2 (1.1 g, 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 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-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-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water (A), AcN (B), Flow rate: 1.5 ml/min (Gradient)
Synthesis of 5-(4-hydroxyphenyl)-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-ylmethoxy)phenyl)furan-3(2H)-one (Example 813)




To a stirred 0° C. 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 (2×50 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-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2,4]hept-6-en-5-one (Example 26)
Methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropane carboxylate




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 (2×50 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 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropenecarboxylate (2.0 g,) as a solid.
7-Hydroxy-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2,4]hept-6-en-5-one 




To a 0° C. solution of methyl 1-(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 (2×50 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 etude 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 trifluoromethanesulfonate




To a 0° C. 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 0° C. The reaction mixture was then diluted with water and extracted with DCM (2×50 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)




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), Na2CO3 (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 (2×40 mL). The combined organic layers were washed with water and 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 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 7-(4-methoxyphenyl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]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) 




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, J=7.2 Hz, 2 H), 7.28 (d, J=7.2 Hz, 2 H), 7.22 (d, J=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: m/z=472.1. HPLC: 96%, (Condition-I).
Synthesis of 4-4-methoxyphenyl)-1,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)-1H-imidazol-2(3H)-one (Example 822)
2-Hydroxy-1,2-bis(4-methoxyphenyl)ethanone




To a stirred solution of 4-methoxybenzaldehyde (2g, 14.6 mmol) in EtOH (50 mL) was added a solution 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 (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and then concentrated in vacuo to yield a crude material which was purified via silica gel column chromatography eluting with 40% EtOAc hexanes to afford 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone (1.3 g, 65%) as a solid.
4,5-bis(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one




A mixture of 2-hydroxy-1,2-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 (2×50 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 hexanes to afford 4,5-bis(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.8 g, 67%) as a solid.
4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one




To a stirred −40° C. solution of 4,5-bis(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.6 g, 1.84 mmol) 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)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.38 mg, 66%) as a solid.
4-(4-Methoxyphenyl)-1,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)-1H-imidazol-2(3H)-one (Example 822) 




To a stirred solution of 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.35 h, 1.12 mmol) in AcN (20 mL) was added K2CO3 (0.46 g, 3.3 mmol) at RT. The reaction mixture was heated to 80° C. 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 80° C. 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)-1,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)-1H-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, 1 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-yl)-5-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 249)
1-(4-(Benzyloxy)phenyl)-4-methylpent-2-yne-1,4-diol




To a precooled −78° C. solution of 2-methylbut-3-yn-2-ol (4.71 g, 0.05 mol) in THF (250 mL), n-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 NH4Cl solution and concentrated in vacuo. The residue was acidified with HCl (1 N) and extracted with DCM (3×200 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 1-(4-(benzyloxy)phenyl)-4-methylpent-2-yne-1,4-diol (6 g, 54%) as a solid.
1-(4-(Benzyloxy)phenyl)-4-hydroxy-4-methylpent-2-yn-1-one




To a solution of 1-(4-(benzyloxy)phenyl)-4-methylpent-2-yne-1,4-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 1-(4-(benzyloxy)phenyl)-4-hydroxy-4-methylpent-2-yn-1-one (1.5 g, 51%) as a solid.
5-(4-(Benzyloxy)phenyl)-2,2-dimethylfuran-3(2H)-one




To a RT solution of 1-(4-(benzyloxy)phenyl)-4-hydroxy-4-methylpent-2-yn-1-one (1.5 g, 0.005 mol) in EtOH (10 mL) was added a solution of Et2NH (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 




To a room temperature solution of 5-(4(benzyloxy)phenyl)-2,2-dimethylfuran-3(2H)-one (1.5 g, 0.005 mol) 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 Na2SO4, 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-dimethyl-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 (2×40 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  




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)




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 (2×50 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 (509 MHz, d6-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, 1H), 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-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 138)
Ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate




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° C. for 16 h, diluted with water (50 mL) and extracted with EtOAc (3×100 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




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 (2×100 mL) and acidified to pH  ̃3 with 1 N HCl at 0° C. 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 




A mixture of acid 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (2.0 g, 6.8 mmol) in SOCl2 (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.
1-(4-Methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy)phenyl)ethanone




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° C. 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 1 h, extracted with DCM (2×50 mL). The combined organic layers were washed with water (2×10 mL) and brine, concentrated, and dried under vacuum to afford 1-(4-methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy)phenyl)ethanone (1.85 g, 90%) as a solid.
2-Bromo-2-methylpropanoyl chloride




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 




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)




To a room temperature, stirred solution of 1-(4-methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy)phenyl)ethanone (100 mg, 0.26 mmol) in THF (5 mL), t-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 (2×50 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, 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-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water (A), AcN (B), Flow rate: 1.5 ml/min (Gradient).
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




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 (3×200 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° C. to afford trimethyl(2-methylbut-3-yn-2-yloxy)silane (25 g) as an oil.
4-Methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one




To a stirred −78° C. solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (5.0 g, 0.03 mol) in dry THF (150 mL), n-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° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 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-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (2.2 g, 27%) as an oil.
4-Hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one




To a room temperature, stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-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-1-(pyridin-4-yl)pent-2-yn-1-one (0.35 g, 97%) as an oil.
2,2-Dimethyl-5-(pyridin-4-yl)furan-3(2H)-one




To a room temperature, stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one (1.49 g, 0.007 mol) ethanol (15 mL), a solution of diethylamine (0.511 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 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




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)




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-1,3,2-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-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water (A), AcN (B), Flow rate: 1.5 ml/min (Gradient).
Synthesis of 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (Example 26) 
Ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate




To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 111.10 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° C. 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 (3×100 mL). The combined organic layers were washed with water, a saturated NH4Cl 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




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° C., The aqueous layer was extracted with EtOAc (2×150 mL) and the combined 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 (30.0 g, 95%) as a white solid.
2-(4-(Quinolin-2-ylmethoxy)phenyl)acetyl chloride 




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° C. 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 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropanecarboxylate




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 (2×50 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 1-(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 




To a 0° C. solution of methyl 1-(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 (2×50 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




To a 0° C. 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 0° C., diluted with water and then extracted with DCM (2×50 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)




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)4 (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 (2×40 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 1-methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (Example 812)
3-Bromo-1-methyl-4-morpholino-1H-pyrrole-2,5-dione




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 (2×50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-bromo-1-methyl-4-morpholino-1H-pyrrole-2,5-dione (0.87 g, 85%) as a solid.
1-Methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (Example 812)




To a stirred solution of 3-bromo-1-methyl-4-morpholino-1H-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-1,3,2-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 hexanes to afford 1-methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-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-1-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (Example 820)
3-Bromo-1-methyl-4-(4-oxopiperidin-1-yl)-1H-pyrrole-2,5-dione 




To a stirred solution of 3,4-dibromo-1-methyl-1H-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 (2×20 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 hexanes to afford 3-bromo-1-methyl-4-(4-oxopiperidin-1-yl)-1H-pyrrole-2,5-dione (100 mg, 99%) as a pale yellow solid.
1-Methyl-3-(4-oxopiperidin-1-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (Example 820)




To a room temperature, stirred solution of 3-bromo-1-methyl-4-(4-oxopiperidin-1-yl)-1H-pyrrole-2,5-dione (100 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was added 2-((4-(4,4,5,5-tetramethyl-1,3,2-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 (2×20 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 hexanes to afford 1-methyl-3-(4-oxopiperidin-1-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (80 mg, 52%) as a solid. 1H NMR (500 MHz, d6-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, 1 H), 7.64 (t, J=7.6 Hz, 1 H), 7.18 (d, J=7.2 Hz, 2 H), 7.12 (d, J=7.2 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-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 164)
4-Methyl-1-(4-nitrophenyl)pent-2-yne-1,4-diol




To a stirred −78° C. solution of 2-methylbut-3-yn-2-ol (6.1 mL, 63.5 mmol, 1.2 eq) in dry THF (250 mL), n-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 1 h at −78° C. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×200 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-1-(4-nitrophenyl)pent-2-yne-1,4-diol (8 g, 65%) as a yellow solid.
4-Hydroxy-4-methyl-1-(4-nitrophenyl)pent-2-yn-1-one




To a room temperature solution of 4-methyl-1-(4-nitrophenyl)pent-2-yne-1,4-diol (2 g, 8.51 mmol, 1 eq) in dry DCM (100 mL) was added NaHCO3 (680 mg, 8.51 mmol, 1 eq) followed by Dess Martin Periodinane (9.2 g, 21.27 mmol, 2.5 eq). The reaction mixture was stirred at RT for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was quenched with a saturated sodium bisulfite solution and extracted with DCM (2×100 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 20% EtOAc hexanes to afford 4-hydroxy-4-methyl-1-(4-nitrophenyl)pent-2-yn-1-one (1.7 g, 86%) as an oil.
2,2-Dimethyl-5-(4-nitrophenyl)furan-3(2H)-one




To a stirred solution of 4-hydroxy-4-methyl-1-(4-nitrophenyl)pent-2-yn-1-one (1.74 g, 7.46 mmol, 1 eq) in ethanol (30 mL), a solution of diethylamine (778 mg, 7.46 mmol, 1 eq) 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%) which was used in the next step without further purification.
4-Bromo-2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one




To a 0° C. 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 2 h. 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-(quinolln-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 164)




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-1,3,2-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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 5-(4-chlorophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 147)
1-(4-Chlorophenyl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one 




To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (11.79 g, 75.15 mmol) in dry THF (100 mL), n-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° C., 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° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 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 1-(4-chlorophenyl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (3.8 g, 57%) as a light green oil.
1-(4-Chlorophenyl)-4-hydroxy-4-methylpent-2-yn-1-one




To a stirred solution of 1-(4-chlorophenyl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-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 1-(4-chlorophenyl)-4-hydroxy-4-methylpent-2-yn-1-one (2.40 g) as a pale red oil.
5-(4-Chlorophenyl)-2,2-dimethylfuran-3(2H)-one 




To a stirred solution of 1-(4-chlorophenyl)-4-hydroxy-4-methylpent-2-yn-1-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 over Na2SO4, 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




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 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-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) 




A solution of 4-bromo-5-(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (1.0 g, 3.30 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)benzonitrile (Example 141)
4-Cyano-N-methoxy-N-methylbenzamide




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 (3×100 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




To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (3.3 g, 20.00 mmol) in dry THF (45 mL), n-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° C., 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° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 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 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




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 (2×50 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




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 over Na2SO4, 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




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) 




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-1,3,2-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 Na2SO4, 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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 5-(Benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 166)
4-Bromo-2-nitroaniline




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 0° C. under a N2 atmosphere. The reaction mixture was stirred at 40° C. 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][1,2,5]oxadiazole1-oxide




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° C. for 2 h. The reaction was then cooled to 0° C. 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][1,2,5]oxadiazole1-oxide (7.0 g, 88%) as a light yellow solid.
5-Bromobenzo[c][1,2,5]oxadiazole




To a stirred solution of 5-bromobenzo[c][1,2,5]oxadiazole1-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° C. 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][1,2,5]oxadiazole (4.0 g, 71%) as a light yellow solid.
Benzo[c][1,2,5]oxadiazole-5-carbonitrile 




To a stirred solution of 5-bromobenzo[c][1,2, 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° C. 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][1,2,5]oxadiazole-5-carbonitrile (0.7 g, 48%) as a yellow solid.
Ethyl benzo[c][1,2,5]oxadiazole-5-carboxylate




To a solution of benzo[c][1,2,5]oxadiazole-5-carbonitrile (700 mg, 1.33 mol) EtOH (100 mL) was added H2SO4 (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 (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and then concentrated in vacuo to afford ethyl benzo[c][1,2,5]oxadiazole-5-carboxylate (0.7 g, 75%) as a yellow, sticky solid.
Benzo[c][1,2,5]oxadiazole-5-carboxylic acid




To a room temperature, stirred solution of ethyl benzo[c][1,2,5]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 40° C. for 3 h. The reaction mixture was then acidified to pH  ̃2 with 2 N HCl and the aqueous layer was extracted with DCM (3×150 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][1,2,5]oxadiazole-5-carboxylic acid (0.49 g, 82%) as a solid.
N-Methoxy-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide




To a stirred solution of benzo[c][1,2,5]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 (3×50 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][1,2,5]oxadiazole-5-carboxamide (0.49 g, 79%) as a yellow oil.
1-(Benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one




To a −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.49 g, 2.367 mmol) in dry THF (20 mL), n-BuLi (3.70 mL, 5.917 mmol, 1.6 M 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][1,2,5]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° c. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×20 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 hexanes to afford 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 63%) as a colorless oil.
1-(Benzo[c][1,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one 




To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 1.490 mmol) DCM (15 mL) was added p-TSA (0.341 g, 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][1,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.3 g, 87%) as an oil.
5-(Benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethyfuran-3(2H)-one




To a stirred solution of 1-(benzo[c][1,2,5]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 2 h. 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][1,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 83%) as a black oil.
5-(Benzo[c][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one




To a stirred solution of 5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 1.086 mmol) 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 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][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 60%) as a yellow solid.
5-(Benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 166)




A solution of 5-(Benzo[c][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 0.645 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-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 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-(benzo[c][1,2,5]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, d6-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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 167)
N-Methoxy-N-methylbenzene[c][1,2,5]thiadiazole-5-carboxamide




To a stirred solution of benzo[c][1,2,5]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 (3×50 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-methylbenzone[c][1,2,5]thiadiazole-5-carboxamide (1.14 g, 95%) as a light yellow solid.
1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one




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), n-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° C., and then a solution N-methoxy-N-methylbenzene[c][1,2,5]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° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×40 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][1,2,5]thiadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (1.01 g, 76%) as a yellow oil.
1-(Benzo[c][1,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yl-1-one




To a stirred solution of 1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.80 g, 2.515 mol) 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 NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.6 g, 100%) as a colorless oil.
5-(Benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one




To a stirred solution of 1-(benzo[c][1,2,5]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 Na2SO4, filtered, and concentrated in vacuo to afford 5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.5 g, 83%) as a light yellow solid.
5-(Benzo[c][1,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one 




To a stirred solution of 5-(benzo[c][1,2,5]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][1,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.45 g, 69%) as a yellow oil.
5-(Benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 167)




A solution of 5-(benzo[c][1,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.45 g, 1.465 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-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 Na2SO4, 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][1,2,5]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, 14 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), 7.2 (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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 5-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihrydrofuran-2-yl)-2-methoxybenzonitrile (Example 137)
Methyl 3-bromo-4-hydroxybenzoate




To a stirred solution of methyl 4-hydroxybenzoate (10.0 g, 84.935 mmol) in CCl4 (30 mL) was added AcOH (20 mL, 2 Vol). Br2 (1.80 mL, 71.428 mmol) was then added slowly at 0° C. 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 NaHCO3 solution and extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (2×50 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




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° C. 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




To a stirred solution of methyl 3-cyano-4-hydroxybenzoate (2.0 g, 11.20 mmol) in DMF (20 mL) were added CH3I (2.40 g, 16.01 mmol) and K2CO3 (2.30 g, 16.01 mmol) at 0° c. under a N2 atmosphere. The reaction mixture was stirred at 80° C. for 2 h. After completion of starting material (monitored by TLC), reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (2×50 mL), brine and dried over anhydrous Na2SO4. 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




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 (3×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, 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




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 (3×50 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-ynoyl)benzonitrile




To a −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (1.9 g, 12.501 mmol) in dry THF (25 mL), n-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° C., and then a solution of 3-cyano-N,4-dimethoxy-N-methylbenzamide (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 (2×50 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-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (0.8 g, 56%) as a pale yellow oil.
5-(4-Hydroxy-4-methylpent-2-ynoyl)-2-methoxybenzonitrile




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 over Na2SO4, filtered, and then concentrated in vacuo to afford 5-(4-hydroxy-4-methylpent-2-ynoyl)-2-methoxybenzonitrile (0.9 g, 97%) as a semi-solid.
5-(5,5-Dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile




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 




To a stirred solution of 5-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.9 g, 3.70 mmol) 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 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-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofran-2-yl)-2-methoxybenzonitrile (0.5 g, 42%) as a yellow solid.
5-(5,5-Dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (Example 137)




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-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.17 g, 0.465 mmol), and Cs2CO3 (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, d6-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, 50×2.1 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-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (Example 135)
3-Chloro-4-hydroxybenzaldehyde




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 (2×100 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




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° C. and stirred for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2×50 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.
1-(3-Chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol




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 (16.0 mL, 27.001 mmol, 1.6 M hexane) was added dropwise over 5 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., 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 (2×50 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 hexanes to afford 1-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (0.69 g, 26%) as a yellow syrup.
1-(3-Chloro-4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-1-one 




To a stirred solution of 1-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-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 Na2SO4, filtered, and then concentrated in vacuo to afford 1-(3-chloro4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-1-one (0.45 g, 65%) as a brown oil.
5-(3-Chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one




To a stirred solution of 1-(3-chloro-4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-1-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 Na2SO4, 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




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 mmol was added portionwise at RT. The reaction mixture was then stirred for 1 h. and diluted with DCM (20 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 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)




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-1,3,2-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 Na2SO4, 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, 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, 2H), 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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 810, 4-(4-((6-fluoroquinolin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one
N-methoxy-N-methylisonicotinamide




To a stirred solution of isonicotinic acid (20.0 g, 162 mmol) in DCM (400 mL) were added HATU (92.6 g, 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 (3×500 mL). The combined organic extracts were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SO4, 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-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one




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 n-BuLi (17.9 mL, 28.7 mmol, 1.6 M in hexane) dropwise at −78° C. under an inert atmosphere for a period of 10 min. After being stirred for 30 min at −78° C., 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 (2×100 mL). The combined organic layers were washed with water (80 mL), 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 2-3% EtOAc in Hexane to afford 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (4.8 g, 57%) as an oil.
4-Hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one




To a stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-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-1-(pyridin-4-yl)pent-2-yn-1-one (1.5 g, 69%) as an oil.
2,2-Dimethyl-5-(pyridin-4-yl)furan-3(2H)-one




To a stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one (1.8 g, 9.50 mmol) in ethanol (18 mL) was added diethyl amine (1.04 g, 14.0 mmol) 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-(pyridin-4-yl)furan-3(2H)-one




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-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline




6-Fluoro-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline may be prepared in manner analogous to 2-((4-(4,4,5,5-tetramethyl-1,3,2-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




A mixture of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.085 g, 0.32 mmol), 6-Fluror-2-((4-(4,4,5,5-tetramethyl-1,3,2-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), 7.11 (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-C18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of 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-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine




5-Methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-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)-5-methylpyridine instead of 2-(chloromethyl)quinoline.
Example 808
2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-5-(pryidin-4-yl)furan-3(2H)-one 




A mixture of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.11 g, 0.34 mmol), 5-methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine (0.1 g, 0.37 mmol), and Cs2CO3 (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, J=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), 7.11 (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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 809, 4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one
3,5-Dimethyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine




3,5-Dimethyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-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-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one




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-1,3,2-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, J=7.8 Hz, 1 H), 7.50 (d, J=8.6 Hz, 3 H), 7.23 (d, J=7.4 Hz, 2 H), 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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 824, 2-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1-oxaspiro[4.4]non-2-en-4-one 
1-(Pyridin-4-yl)-3-(1-(trimethylsilyloxy)cyclopentyl)prop-2-yn-1-one




To a stirred solution of (1-ethynylcyclopentyloxy)trimethylsilane (2.0 g, 11.0 mmol) in dry THF (50 mL) was added n-BuLi (20.0 mL, 20.0 mmol, 1.6 M in hexane) drop wise at −78° C. under an inert atmosphere for a period of 10 min. After being stirred for 30 min at −78° C., 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° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×60 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-(1-(trimethylsilyloxy)cyclopentyl)prop-2-yn-1-one (1.0 g, 32%) as an oil.
3-(1-Hydroxycyclopentyl)-1-(pyridin-4-yl)prop-2-yn-1-one




To a stirred solution of 1-(pyridin-4-yl)-3-(1-(trimethylsilyloxy)cyclopentyl)prop-2-yn-1-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-(1-hydroxycyclopentyl)-1-(pyridin-4-yl)prop-2-yn-1-one (0.42 g, 51%) as an oil.
2-(Pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one 




To a stirred solution of 3-(1-hydroxycyclopentyl)-1-(pyridin-4-yl)prop-2-yn-1-one (0.42 g, 1.95 mmol) in ethanol (10 mL) was added diethyl amine (0.21 g, 2.9 mmol) 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 Na2SO4, filtered and concentrated in vacuo to afford 2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.4 g) as an oil.
3-Bromo-2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one




To a stirred solution of afford 2-(pyridin-4-yl)-1-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 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 3-bromo-2-(pyridin-4-yl)-1-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)-1-oxaspiro[4.4]non-2-en-4-one




A mixture of 3-bromo-2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.2 g, 0.68 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-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)-1-oxaspiro[4.4]non-2-en-4-one (20 mg, 5%) as a solid. 1H NMR (500 MHz, d6:-DMSO): δ 8.68 (d, J=8.5 Hz, 2 H), 8.44 (d, J=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 (t, 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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% 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




To a stirred 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° C. 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° C. 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 (2×10 mL), brine and dried over anhydrous Na2SO4. 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)-4,5-dihydrofuran-2-yl)phenyl)acetamide




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) DCM (5 mL) were added Ac2O (0.018 mL, 0.19 mmol) and TEA (0.04 mL, 0.32 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM (2×15 mL). Combined organic layers were washed with water (2×5 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)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, 1H), 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), 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, 50×2.1 mm, 1.7 um. 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-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)acetamide, (30 mg, 18.0%) 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, 1H), 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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 817, N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methane sulfonamide




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 TFA (0.04 mL, 0.27 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 10 min. The reaction mixture diluted with water and extracted with DCM (2×10 mL). The combined organic layers were washed with water (2×5 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, 1H), 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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 815, N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)methane sulfonamide




To a stirred solution of N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)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° C. under N2 atmosphere. The reaction mixture was stirred at 0° C. for 10 min. Upon complete consumption of the starting material (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers were washed with water (2×5 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)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, 1H), 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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 811, 2,2-dimethyl-5-phenyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one




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° C. under N2 atmosphere. The reaction mixture was stirred at 0° C. for 10 min. After being stirred for 5 min then added NaNO2 in water and stirred for 40 min at 0° C. The reaction mixture was stirred at 70° C. for 2h. After completion of starting material (by TLC), reaction mass was diluted with water and extracted with EtOAc (2×25 mL). Combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. 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, J=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, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Synthesis of Example 174, 2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)-5-(thiazol-4-yl)furan-3(2H)-one
4-Methyl-1-(thiazol-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one




To a stirred solution trimethyl (2-methylbut-3-yn-2-yloxy)silane (0.56 g, 3.57 mmol) in dry THF (10 mL) was added n-BuLi (1.3 mL, 2.1 mmol, 1.6 M in hexane) dropwise at −78° C. under an inert atmosphere for a period of 5 min. After being stirred for 30 min at −78° C., a solution of N-methoxy-N-methylthiazole-4-carboxamide (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° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×30 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-1-(thiazol-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (0.15 g, 31.44%) as an oil.
4-Hydroxy-4-methyl-1-(thiazol-4-yl)pent-2-yn-1-one




To a stirred solution of 4-methyl-1-(thiazol-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-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-1-(thiazol-4-yl)pent-2-yn-1-one (0.12 g, crude) as an oil.
2,2-Dimethyl-5-(thiazol-4-yl)furan-3(2H)-one 




To a stirred solution of 4-hydroxy-1-methyl-1-(thiazol-4-yl)pent-2-yn-1-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




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-(thiazol-4-yl)furan-3(2H)-one




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-1,3,2-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 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, d6-DMSO): δ 9.17 (s, 1H), 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, 50×2.1 mm, 1.7 um. 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 “R1a and R1b”, then both R1a and R1b (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 R1a and the second to be R1b. 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











PCT




R1a,






#
HET
X
Y
Z
R1b
R2
R3
R4
R7
























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-tetrahydroiso-
—
—
—
—
Me






quinoline







5
A3
4-pyridinyl
OCH2
2-pyridinyl
—
—
—
—
Me


6
A3
4-pyridinyl
OCH2
2-benzoxazole
—
—
—
—
Me


7
A3
4-pyridinyl
OCH2
2-benzthiazole
—
—
—
—
Me


8
A3
4-pyridinyl
OCH2
2-quinoxaline
—
—
—
—
Me


9
A3
4-pyridinyl
OCH2
2-naphthyridine
—
—
—
—
Me


10
A3
4-pyridinyl
OCH2
2-quinazoline
—
—
—
—
Me


11
A3
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
Me


12
A3
4-pyridinyl
CH2O
2-quinoline
—
—
—
—
Me


13
A4
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
—


15
A4
4-pyridinyl
CH2O
2-quinoline
—
—
—
—
—


17
A5
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
H


18
A5
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
Me


19
A5
4-pyridinyl
CH2O
2-quinoline
—
—
—
—
H


20
A5
4-pyridinyl
CH2O
2-quinoline
—
—
—
—
Me


21
A6
4-pyridinyl
OCH2
2-quinoline
Me, —
—
—
—
H


22
A6
4-pyridinyl
CH2O
2-quinoline
Me, —
—
—
—
H


23
A7
4-pyriclinyl
OCH2
2-quinoline
—
—
Me
Me
—


24
A7
4-pyridinyl
CH2O
2-quinoline
—
—
Me
Me
—


25
A7
4-pyridinyl
OCH2
2-quinoline
—
—
Et
Et
—















26
A7
4-pyridinyl
OCH2
2-quinoline
—
—
cyclopropyl

















27
A7
3-F, 4-OMe
OCH2
2-quinoline
—
—
Me
Me
—




phenyl









28
A7
3-Cl, 4-OMe
OCH2
2-quinoline
—
—
Me
Me
—




phenyl









29
A7
3-CN, 4-OMe
OCH2
2-quinoline
—
—
Me
Me
—




phenyl









30
A7
3-OMe, 4-F
OCH2
2-quinoline
—
—
Me
Me
—




phenyl









31
A7
3-OMe, 4-Cl
OCH2
2-quinoline
—
—
Me
Me
—




phenyl









32
A7
3-OMe, 4-CN
OCH2
2-quinoline
—
—
Me
Me
—




phenyl









 


33
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


34
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


35
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


36
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


37
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


38
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


39
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


40
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


41
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


42
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


43
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


44
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


45
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


46
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


47
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


48
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


49
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


50
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


51
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


52
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


53
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


54
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


55
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


56
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


57
A7




OCH2
2-quinoline
—
—
Me
Me
—


 


58
A7




OCH2
2-quinoline
—
—
Me
Me
—


 















59
A8
4-pyridinyl
OCH2
2-quinoline
—
—
cyclopropyl
H
















60
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Me
Me
cyclo-











propyl


61
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Et
Et
cyclo-











propyl















62
A8
4-pyridinyl
OCH2
2-quinoline
—
—
cyclopropyl
cyclo-

























propyl


63
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Me
Me
H


64
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Me
Me
Me


65
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Et
Et
Me















66
A8
4-pyridinyl
OCH2
2-quinoline
—
—
cyclopropyl
Me
















67
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Me
Me
Et


68
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Et
Et
Et















69
A8
4-pyridinyl
OCH2
2-quinoline
—
—
cyclopropyl
Et
















70
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Me
Me
—CH2CF3


71
A8
4-pyridinyl
OCH2
2-quinoline
—
—
Et
Et
—CH2CF3















72
A8
4-pyridinyl
OCH2
2-quinoline
—
—
cyclopropyl
—CH2CF3


 
















73
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


74
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


75
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


76
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


77
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


78
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


79
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


80
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


81
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


82
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


83
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


84
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


85
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


86
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


87
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


88
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


89
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


90
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


91
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


92
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


93
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


94
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


95
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


96
A8




OCH2
2-quinoline
—
—
Me
Me
Me


 


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, —
—
—
—
—


104
A10
4-pyridinyl
OCH2
2-tetrahydro-
Me, —
—
—
—
—






isoquinoline







105
A10
4-pyridinyl
OCH2
2-pyridinyl
Me, —
—
—
—
—


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
Me, —
—
—
—
—


110
A10
4-pyridinyl
OCH2
2-quinazoline
Me, —
—
—
—
—


111
A10
4-pyridinyl
OCH2
2-quinoline
Me, —
—
—
—
—


113
A11
4-pyridinyl
OCH2
2-quinoline
Me, —
—
—
—
—


114
A11
4-pyridinyl
CH2O
2-quinoline
Me, —
—
—
—
—


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
A15
4-pyridinyl
OCH2
2-quinoline
Me, —
—
—
—
—


122
A15
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
—
-cyclo-
—
—
—








propyl-





 


127
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


128
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


129
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


130
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


131
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


132
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


133
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


134
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


135
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


136
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


137
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


138
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


139
A29




OCH2
2-quinoline
—
Me, Et
—
—
—


 


140
A29




OCH2
2-quinoline
—
Et, Me
—
—
—


 


141
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


142
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


143
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


144
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


145
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


146
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


147
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


148
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


149
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


150
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


151
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


152
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


153
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


154
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


155
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


156
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


157
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


158
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


159
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


160
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


161
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


162
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


163
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


164
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


165
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


166
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


167
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


168
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


169
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


170
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


171
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


172
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


173
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


174
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


175
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


176
A29




OCH2




—
Me, Me
—
—
—


 


177
A29




OCH2




—
Me, Me
—
—
—


 


178
A29




OCH2




—
Me, Me
—
—
—


 


179
A29




OCH2




—
Me, Me
—
—
—


 


180
A29




OCH2




—
Me, Me
—
—
—


 


181
A29




OCH2




—
Me, Me
—
—
—


 


182
A29




OCH2




—
Me, Me
—
—
—


 


183
A29




OCH2




—
Me, Me
—
—
—


 


184
A29




OCH2




—
Me, Me
—
—
—


 


185
A29




OCH2




—
Me, Me
—
—
—


 


186
A29




OCH2




—
Me, Me
—
—
—


 


187
A29




OCH2




—
Me, Me
—
—
—


 


188
A29




OCH2




—
Me, Me
—
—
—


 


189
A29




OCH2




—
Me, Me
—
—
—


 


190
A29




OCH2




—
Me, Me
—
—
—


 


191
A29




OCH2




—
Me, Me
—
—
—


 


192
A29




OCH2




—
Me, Me
—
—
—


 


193
A29




OCH2




—
Me, Me
—
—
—


 


194
A29




OCH2




—
Me, Me
—
—
—


 


195
A29




OCH2




—
Me, Me
—
—
—


196
A29




OCH2




—
Me, Me
—
—
—


 


197
A29




OCH2




—
Me, Me
—
—
—


 


198
A29




OCH2




—
Me, Me
—
—
—


 


199
A29




OCH2




—
Me, Me
—
—
—


 


200
A29




OCH2




—
Me, Me
—
—
—


 


201
A29




OCH2




—
Me, Me
—
—
—


 


202
A29




OCH2




—
Me, Me
—
—
—


 


203
A29




OCH2




—
Me, Me
—
—
—


 


204
A29




OCH2




—
Me, Me
—
—
—


 


205
A29




OCH2




—
Me, Me
—
—
—


 


206
A29




OCH2




—
Me, Me
—
—
—


 


207
429




OCH2




—
Me, Me
—
—
—


 


208
A29




OCH2




—
Me, Me
—
—
—


 


209
A29




OCH2




—
Me, Me
—
—
—


 


210
A29




OCH2




—
Me, Me
—
—
—


 


211
A29




OCH2




—
Me, Me
—
—
—


 


212
A29




OCH2




—
Me, Me
—
—
—


 


213
A29




OCH2




—
Me, Me
—
—
—


 


214
A29




OCH2




—
Me, Me
—
—
—


 


215
A29




OCH2




—
Me, Me
—
—
—


 


216
A29




OCH2




—
Me, Me
—
—
—


 


217
A29




OCH2




—
Me, Me
—
—
—


 


218
A29




OCH2




—
Me, Me
—
—
—


 


219
A29




OCH2




—
Me, Me
—
—
—


 


220
A29




OCH2




—
Me, Me
—
—
—


 


221
A29




OCH2




—
Me, Me
—
—
—


 


222
A30
4-pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—
H


223
A30
4-pyridinyl
OCH2
2-quinoline
—
-cyclo-
—
—
H








propyl-





224
A30
4-pyridinyl
OCH2
2-quinoline
—
Me, Me


Me


 


225
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


226
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


227
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


228
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


229
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


230
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


231
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


232
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


233
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


234
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


235
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


236
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


237
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


238
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


239
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


240
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


241
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


242
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


243
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


244
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


245
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


246
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


247
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


248
A30




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


249
A31
4- pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—
—


250
A31
4-pyridinyl
OCH2
2-quinoline
—
-cyclo-
—
—
—








propyl-





 


251
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


252
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


253
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


254
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


255
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


256
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


257
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


258
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


259
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


260
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


261
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


262
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


263
A31




OCH2
2-quinoline
—
Me, Et
—
—
—


 


264
A31




OCH2
2-quinoline
—
Et, Me
—
—
—


 


265
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


266
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


267
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


268
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


269
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


270
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


271
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


272
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


273
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


274
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


275
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


276
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


277
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


278
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


279
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


280
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


281
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


282
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


283
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


284
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


285
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


286
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


287
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


288
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


289
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


290
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


291
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


292
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


293
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


294
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


295
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


296
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


297
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


298
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


299
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


300
A31




OCH2




—
Me, Me
—
—
—


 


301
A31




OCH2




—
Me, Me
—
—
—


 


302
A31




OCH2




—
Me, Me
—
—
—


 


303
A31




OCH2




—
Me, Me
—
—
—


 


304
A31




OCH2




—
Me, Me
—
—
—


 


305
A31




OCH2




—
Me, Me
—
—
—


 


306
A31




OCH2




—
Me, Me
—
—
—


 


307
A31




OCH2




—
Me, Me
—
—
—


 


308
A31




OCH2




—
Me, Me
—
—
—


 


309
A31




OCH2




—
Me, Me
—
—
—


 


310
A31




OCH2




—
Me, Me
—
—
—


 


311
A31




OCH2




—
Me, Me
—
—
—


 


312
A31




OCH2




—
Me, Me
—
—
—


 


313
A31




OCH2




—
Me, Me
—
—
—


 


314
A31




OCH2




—
Me, Me
—
—
—


 


315
A31




OCH2




—
Me, Me
—
—
—


 


316
A31




OCH2




—
Me, Me
—
—
—


 


317
A31




OCH2




—
Me, Me
—
—
—


 


318
A31




OCH2




—
Me, Me
—
—
—


 


319
A31




OCH2




—
Me, Me
—
—
—


 


320
A31




OCH2




—
Me, Me
—
—
—


 


321
A31




OCH2




—
Me, Me
—
—
—


 


322
A31




OCH2




—
Me, Me
—
—
—


 


323
A31




OCH2




—
Me, Me
—
—
—


 


324
A31




OCH2




—
Me, Me
—
—
—


 


325
A31




OCH2




—
Me, Me
—
—
—


 


326
A31




OCH2




—
Me, Me
—
—
—


 


327
A31




OCH2




—
Me, Me
—
—
—


 


328
A31




OCH2




—
Me, Me
—
—
—


 


329
A31




OCH2




—
Me, Me
—
—
—


 


330
A31




OCH2




—
Me, Me
—
—
—


 


331
A31




OCH2




—
Me, Me
—
—
—


 


332
A31




OCH2




—
Me, Me
—
—
—


 


333
A31




OCH2




—
Me, Me
—
—
—


 


334
A31




OCH2




—
Me, Me
—
—
—


 


335
A31




OCH2




—
Me, Me
—
—
—


 


336
A31




OCH2




—
Me, Me
—
—
—


 


337
A31




OCH2




—
Me, Me
—
—
—


 


338
A31




OCH2




—
Me, Me
—
—
—


 


339
A31




OCH2




—
Me, Me
—
—
—


 


340
A31




OCH2




—
Me, Me
—
—
—


 


341
A31




OCH2




—
Me, Me
—
—
—


 


342
A31




OCH2




—
Me, Me
—
—
—


 


343
A31




OCH2




—
Me, Me
—
—
—


 


344
A31




OCH2




—
Me, Me
—
—
—


 


345
A31




OCH2




—
Me, Me
—
—
—


 


776
A31




OCH2




—
Me, Me
—
—
—


 


777
A31




OCH2




—
Me, Me
—
—
—


 


778
A31




OCH2




—
Me, Me
—
—
—


 


779
A31




OCH2




—
Me, Me
—
—
—


 


780
A31




OCH2




—
Me, Me
—
—
—


 


781
A31




OCH2




—
Me, Me
—
—
—


 


782
A31




OCH2




—
Me, Me
—
—
—


 


783
A31




OCH2




—
Me, Me
—
—
—


 


784
A31




OCH2




—
Me, Me
—
—
—


 


785
A31




OCH2




—
Me, Me
—
—
—


 


786
A31




OCH2




—
Me, Me
—
—
—


 


787
A31




OCH2




—
Me, Me
—
—
—


 


788
A31




OCH2




—
Me, Me
—
—
—


 


789
A31




OCH2




—
Me, Me
—
—
—


 


790
A31




OCH2




—
Me, Me
—
—
—


 


791
A31




OCH2




—
Me, Me
—
—
—


 


792
A31




OCH2




—
Me, Me
—
—
—


 


793
A31




OCH2




—
Me, Me
—
—
—


 


794
A31




OCH2




—
Me, Me
—
—
—


 


795
A31




OCH2




—
Me, Me
—
—
—


 


796
A31




OCH2




—
Me, Me
—
—
—


 


797
A31




OCH2




—
Me, Me
—
—
—


 


798
A31




OCH2




—
Me, Me
—
—
—


 


799
A29




OCH2




—
Me, Me
—
—
—


 


800
A29




OCH2




—
Me, Me
—
—
—


 


801
A29




OCH2




—
Me, Me
—
—
—


 


802
A29




OCH2




—
Me, Me
—
—
—


 


803
A29




OCH2




—
Me, Me
—
—
—


 


804
A29




OCH2




—
Me, Me
—
—
—


 


805
A29




OCH2




—
Me, Me
—
—
—


 


806
A29




OCH2




—
Me, Me
—
—
—


 


807
A29




OCH2




—
Me, Me
—
—
—


 


808
A29




OCH2




—
Me, Me
—
—
—


 


809
A29




OCH2




—
Me, Me
—
—
—


 


810
A29




OCH2




—
Me, Me
—
—
—


 


811
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


812
A3




OCH2
2-quinoline
—
—
—
—
Me


 


813
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


814
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


815
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


817
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


818
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


819
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


820
A3




OCH2
2-quinoline
—
—
—
—
Me


 


821
A29




OCH2
2-quinoline
—
Me, Me
—
—
—


 


822
A14




OCH2
2-quinoline
Me, Me
—
—
—
—


 


823
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


824
A29




OCH2
2-quinoline
—
-cyclo- pentyl-
—
—
—


 


825
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


826
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


827
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


828
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


829
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


830
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


831
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


832
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


833
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


834
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


835
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


836
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


837
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


838
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


839
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


840
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


841
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


842
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


843
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


844
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


845
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


846
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


847
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


848
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


849
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


850
A8




OCH2
2-quinoline
—
—
Me
Me
H


 


851
A29




OCH2




—
Me, Me
—
—
—


 


852
A29




OCH2




—
Me, Me
—
—
—


 


853
A29




OCH2




—
Me, Me
—
—
—


 


854
A29




OCH2




—
Me, Me
—
—
—


 


855
A29




OCH2




—
Me, Me
—
—
—


 


856
A29




OCH2




—
Me, Me
—
—
—


 


857
A29




OCH2




—
Me, Me
—
—
—


 


858
A29




OCH2




—
Me, Me
—
—
—


 


859
A29




OCH2




—
Me, Me
—
—
—


 


860
A29




OCH2




—
Me, Me
—
—
—


 


861
A29




OCH2




—
Me, Me
—
—
—


 


862
A29




OCH2




—
Me, Me
—
—
—


 


863
A29




OCH2




—
Me, Me
—
—
—


 


864
A29




OCH2




—
Me, Me
—
—
—


 


865
A29




OCH2




—
Me, Me
—
—
—


 


866
A29




OCH2




—
Me, Me
—
—
—


 


867
A29




OCH2




—
Me, Me
—
—
—


 


868
A29




OCH2




—
Me, Me
—
—
—


 


869
A29




OCH2




—
Me, Me
—
—
—


 


870
A29




OCH2




—
Me, Me
—
—
—


 


871
A29




OCH2




—
Me, Me
—
—
—


 


872
A29




OCH2




—
Me, Me
—
—
—


 


873
A29




OCH2




—
Me, Me
—
—
—


 


874
A29




OCH2




—
Me, Me
—
—
—


 


875
A29




OCH2




—
Me, Me
—
—
—


 


876
A29




OCH2




—
Me, Me
—
—
—


 


877
A30




OCH2
2-quinoline
—
Me, Me
—
—
—


 


878
A30




OCH2




—
Me, Me
—
—
—


 


879
A30




OCH2




—
Me, Me
—
—
—


 


880
A30




OCH2




—
Me, Me
—
—
—


 


881
A31




OCH2
2-quinoline
—
Me, Me
—
—
—


 


882
A31




OCH2




—
Me, Me
—
—
—


 


883
A31




OCH2




—
Me, Me
—
—
—


 


884
A31




OCH2




—
Me, Me
—
—
—


 















885
A7




OCH2
2-quinoline
—
—
-cyclopropyl-
—


 
















886
A39




OCH2
2-quinoline
—
—
—
—
—


 


887
A39




OCH2
2-quinoline
—
—
—
—
—


 


888
A39




OCH2
2-quinoline
—
—
—
—
—


 


889
A39




OCH2
2-quinoline
—
—
—
—
—


 


890
A40




OCH2
2-quinoline
—
—
—
—
Me


 


891
A40




OCH2
2-quinoline
—
—
—
—
Me


 


892
A40




OCH2
2-quinoline
—
—
—
—
Me


 


893
A40




OCH2
2-quinoline
—
—
—
—
Me


 


894
A29




OCH2
2-quinoline
—
Me, Me
—
—









In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in the table below taken from Formula (II):




















Ex












PCT #
HET
W
X
Y
Z
R1a,R1b
R2
R3
R4
R7







346
A2
Cl
4-pyridinyl
OCH2
2-quinoline
—
—
Me
Me
Me


347
A2
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
—
Me
Me
Me


348
A2
Cl
4-pyrazolyl
OCH2
2-quinoline
—
—
Me
Me
Me


349
A2
Cl
3-(1-methyl-
OCH2
2-quinoline
—
—
Me
Me
Me





1H-pyrazolyl)









350
A2
Cl
4-(1-methyl-
OCH2
2-quinoline
—
—
Me
Me
Me





1H-pyrazolyl)









 


351
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


352
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


353
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


354
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


355
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


356
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


357
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


358
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


359
A5
Cl
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
H


360
A5
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
—
—
—
H


361
A5
Cl
4-pyrazolyl
OCH2
2-quinoline
—
—
—
—
H


362
A5
Cl
3-(1-methyl-
OCH2
2-quinoline
—
—
—
—
H





1H-pyrazolyl)









363
A5
Cl
4-(1-methyl-
OCH2
2-quinoline
—
—
—
—
H





1H-pyrazolyl)









 


364
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


365
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


366
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


367
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


368
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


369
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


370
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


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
—
—



375
A22
Cl
3-(1-methyl-
OCH2
2-quinoline
—
Me
—
—






1H-pyrazolyl)









376
A22
Cl
4-(1-methyl-
OCH2
2-quinoline
—
Me
—
—






1H-pyrazolyl)









 


377
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


378
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


379
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


380
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


381
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


382
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


383
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


384
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


385
A23
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—



386
A23
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—



387
A23
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—



388
A23
Cl
3-(1-methyl-
OCH2
2-quinoline
—
Me
—
—






1H-pyrazolyl)









389
A23
Cl
4-(1-methyl-
OCH2
2-quinoline
—
Me
—
—






1H-pyrazolyl)









 


390
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


391
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


392
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


393
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


394
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


395
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


396
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


397
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


398
A26
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—



399
A26
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—



400
A26
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—



401
A26
Cl
3-(1-methyl-
OCH2
2-quinoline
—
Me
—
—






1H-pyrazolyl)









402
A26
Cl
4-(1-methyl-
OCH2
2-quinoline
—
Me
—
—






1H-pyrazolyl)









 


403
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


404
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


405
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


406
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


407
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


408
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


409
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


410
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


411
A31
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—



412
A31
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me, Me
—
—



413
A31
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me, Me
—
—



414
A31
Cl
3-(1-methyl-
OCH2
2-quinoline
—
Me, Me
—
—






1H-pyrazolyl)









415
A31
Cl
1-(1-methyl-
OCH2
2-quinoline
—
Me, Me
—
—






1H-pyrazolyl)









 


416
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


417
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


418
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


419
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


420
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


421
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


422
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


423
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


424
A32
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


425
A32
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


426
A32
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


427
A32
Cl
3-(1-methyl-
OCH2
2-quinoline
—
Me, Me
—
—
Me





1H-pyrazolyl)









428
A32
Cl
4-(1-methyl-
OCH2
2-quinoline
—
Me, Me
—
—
Me





1H-pyrazolyl)









 


429
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


430
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


431
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


432
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


433
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


434
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


435
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


436
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


437
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


438
A32
Cl




OCH2
2-guinoline
—
Me, Me
—
—
H


 


439
A32
Cl




OCH2
2-guinoline
—
Me, Me
—
—
Me


 


440
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


441
A32
Cl




OCH2
2-guinoline
—
Me, Me
—
—
Me


 


442
A32
Cl




OCH2
2-guinoline
—
Me, Me
—
—
H


 


443
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


444
A35
Cl
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
—


445
A35
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
—
—
—
—


446
A35
Cl
4-pyrazolyl
OCH2
2-quinoline
—
—
—
—
—


447
A35
Cl
3-(1-methyl-
OCH2
2-quinoline
—
—
—
—
—





1H-pyrazolyl)









448
A35
Cl
4-(1-methyl-
OCH2
2-quinoline
—
—
—
—
—





1H-pyrazolyl)









 


449
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


450
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


451
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


452
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


453
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


454
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


455
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


456
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


457
A2
CN
4-pyridinyl
OCH2
2-quinoline
—
—
Me
Me
Me


458
A2
CN
4-OMe-phenyl
OCH2
2-quinoline
—
—
Me
Me
Me


459
A2
CN
4-pyrazolyl
OCH2
2-quinoline
—
—
Me
Me
Me


460
A2
CN
3-(1-methyl-1H-
OCH2
2-quinoline
—
—
Me
Me
Me





pyrazolyl)









461
A2
CN
4-(1-methyl-1H-
OCH2
2-quinoline
—
—
Me
Me
Me





pyrazolyl)









 


462
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


463
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


464
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


465
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


466
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


467
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


468
A2
CN

OCH2
2-quinoline
—
—
Me
Me
Me


 


469
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


470
A5
CN
4-pyridinyl
OCH2
2-quinoilne
—
—
—
—
H


471
A5
CN
4-OMe-phenyl
OCH2
2-quinoline
—
—
—
—
H


472
A5
CN
4-pyrazolyl
OCH2
2-quinoline
—
—
—
—
H


473
A5
CN
3-(1-methyl-1H-
OCH2
2-quinoline
—
—
—
—
H





pyrazolyl)









474
A5
CN
4-(1-methyl-1H-
OCH2
2-quinoline
—
—
—
—
H





pyrazolyl)









 


475
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


476
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


477
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


478
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


479
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


480
A5
CN




OCH2
2-guinoline
—
—
—
—
H


 


481
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


482
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


483
A22
CN
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—
—


484
A22
CN
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—
—


485
A22
CN
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—
—


486
A22
CN
3-(1-methyl-1H-
OCH2
2-quinoline
—
Me
—
—
—





pyrazolyl)









487
A22
CN
4-(1-methyl-1H-
OCH2
2-quinoline
—
Me
—
—
—





pyrazolyl)









 


488
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


489
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


490
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


491
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


492
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


493
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


494
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


495
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


496
A23
CN
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—
—


497
A23
CN
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—
—


498
A23
CN
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—
—


499
A23
CN
3-(1-methyl-1H-
OCH2
2-quinoline
—
Me
—
—
—





pyrazolyl)









500
A23
CN
4-(1-methyl-1H-
OCH2
2-quinoline
—
Me
—
—
—





pyrazolyl)









 


501
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


502
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


503
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


504
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


505
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


506
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


507
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


508
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


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
—
—
—


512
A26
CN
3-(1-methyl-1H-
OCH2
2-quinoline
—
Me
—
—
—





pyrazolyl)









513
A26
CN
4-(1-methyl-1H-
OCH2
2-quinoline
—
Me
—
—
—





pyrazolyl)









 


514
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


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
—
—
—


 


519
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


520
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


521
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


522
A31
CN
4-pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—
—


523
A31
CN
4-OMe-phenyl
OCH2
2-quinoline
—
Me, Me
—
—
—


524
A31
CN
4-pyrazolyl
OCH2
2-quinoline
—
Me, Me
—
—
—


525
A31
CN
3-(1-methyl-1H-
OCH2
2-quinoline
—
Me, Me
—
—
—





pyrazolyl)









526
A31
CN
4-(1-methyl-1H-
OCH2
2-quinoline
—
Me, Me
—
—
—





pyrazolyl)









 


527
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


528
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


529
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


530
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


531
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


532
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


533
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


534
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


535
A32
CN
4-pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


536
A32
CN
4-OMe-phenyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


537
A32
CN
4-pyrazolyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


538
A32
CN
3-(1-methyl-1H-
OCH2
2-quinoline
—
Me, Me
—
—
Me





pyrazolyl)









539
A32
CN
4-(1-methyl-1H-
OCH2
2-quinoline
—
Me, Me
—
—
Me





pyrazolyl)









 


540
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


541
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


542
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


543
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


544
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


545
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


546
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


547
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


548
A35
CN
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
—


549
A35
CN
4-OMe-phenyl
OCH2
2-quinoline
—
—
—
—
—


550
A35
CN
4-pyrazolyl
OCH2
2-quinoline
—
—
—
—
—


551
A35
CN
3-(1-methyl-1H-
OCH2
2-quinoline
—
—
—
—
—





pyrazolyl)









552
A35
CN
4-(1-methyl-1H-
OCH2
2-quinoline
—
—
—
—
—





pyrazolyl)









 


553
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


554
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


555
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


556
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


557
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


558
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


559
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


560
A35
CN




OCH2
2-quinoline
—
—
—
—
—









In a further aspect the compounds of the disclosure are embodied in with distinct examples listed in the table below taken from Formula (III):




















Ex PCT #
HET
W
X
Y
Z
R1a, R1b
R2
R3
R4
R7







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


564
A2
Cl
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
Me
Me
Me


565
A2
Cl
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
Me
Me
Me


 


566
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


567
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


568
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


569
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


570
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


571
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


572
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


573
A2
Cl




OCH2
2-quinoline
—
—
Me
Me
Me


 


574
A5
Cl
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
H


575
A5
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
—
—
—
H


576
A5
Cl
4-pyrazolyl
OCH2
2-quinoline
—
—
—
—
H


577
A5
Cl
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
—
—
H


578
A5
Cl
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
—
—
H


 


579
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


580
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


581
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


582
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


583
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


584
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


585
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


586
A5
Cl




OCH2
2-quinoline
—
—
—
—
H


 


587
A22
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—



588
A22
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—



589
A22
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—



590
A22
Cl
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—



591
A22
Cl
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—



 


592
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


593
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


594
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


595
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


596
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


597
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


598
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


599
A22
Cl




OCH2
2-quinoline
—
Me
—
—



 


600
A23
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—



601
A23
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—



602
A23
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—



603
A23
Cl
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—



604
A23
Cl
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—



 


605
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


606
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


607
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


608
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


609
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


610
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


611
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


612
A23
Cl




OCH2
2-quinoline
—
Me
—
—



 


613
A26
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—



614
A26
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—



615
A26
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—



616
A26
Cl
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—



617
A26
Cl
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—



 


618
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


619
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


620
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


621
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


622
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


623
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


624
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


625
A26
Cl




OCH2
2-quinoline
—
Me
—
—



 


626
A31
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—



627
A31
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me, Me
—
—



628
A31
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me, Me
—
—



629
A31
Cl
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me, Me
—
—



630
A31
Cl
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me, Me
—
—



 


631
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


632
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


633
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


634
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


635
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


636
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


637
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


638
A31
Cl




OCH2
2-quinoline
—
Me, Me
—
—



 


639
A32
Cl
4-pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


640
A32
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


641
A32
Cl
4-pyrazolyl
OCH2
2-quinoline
—
Me, Me
—
—
Me


642
A32
Cl
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me, Me
—
—
Me


643
A32
Cl
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me, Me
—
—
Me


 


644
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


645
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


646
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


647
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


648
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


649
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


650
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


651
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


652
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


653
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


654
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


655
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


656
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


657
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
H


 


658
A32
Cl




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


659
A35
Cl
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
—


660
A35
Cl
4-OMe-phenyl
OCH2
2-quinoline
—
—
—
—
—


661
A35
Cl
4-pyrazolyl
OCH2
2-quinoline
—
—
—
—
—


662
A35
Cl
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
—
—
—


663
A35
Cl
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
—
—
—


 


664
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


665
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


666
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


667
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


668
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


669
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


670
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


671
A35
Cl




OCH2
2-quinoline
—
—
—
—
—


 


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


675
A2
CN
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
Me
Me
Me


676
A2
CN
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
Me
Me
Me


 


677
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


678
A2
CN




OCH2
2-quinoline
—
—
Me
Me
Me


 


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


 


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


688
A5
CN
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
—
—
H


689
A5
CN
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
—
—
H


 


690
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


691
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


692
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


693
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


694
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


695
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


696
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


697
A5
CN




OCH2
2-quinoline
—
—
—
—
H


 


698
A22
CN
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—
—


699
A22
CN
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—
—


700
A22
CN
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—
—


701
A22
CN
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—
—


702
A22
CN
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—
—


 


703
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


704
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


705
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


706
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


707
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


708
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


709
A22
CN




OCH2
2-quinoline
—
Me
—
—
—


 


710
A22
CN




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
—
—
—


714
A23
CN
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—
—


715
A23
CN
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—
—


 


716
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


717
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


718
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


719
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


720
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


721
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


722
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


723
A23
CN




OCH2
2-quinoline
—
Me
—
—
—


 


724
A26
CN
4-pyridinyl
OCH2
2-quinoline
—
Me
—
—
—


725
A26
CN
4-OMe-phenyl
OCH2
2-quinoline
—
Me
—
—
—


726
A26
CN
4-pyrazolyl
OCH2
2-quinoline
—
Me
—
—
—


727
A26
CN
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—
—


728
A26
CN
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me
—
—
—


 


729
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


730
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


731
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


732
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


733
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


734
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


735
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


736
A26
CN




OCH2
2-quinoline
—
Me
—
—
—


 


737
A31
CN
4-pyridinyl
OCH2
2-quinoline
—
Me, Me
—
—
—


738
A31
CN
4-OMe-phenyl
OCH2
2-quinoline
—
Me, Me
—
—
—


739
A31
CN
4-pyrazolyl
OCH2
2-quinoline
—
Me, Me
—
—
—


740
A31
CN
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me, Me
—
—
—


741
A31
CN
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me, Me
—
—
—


 


742
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


743
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


744
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


745
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


746
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


747
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


748
A31
CN




OCH2
2-quinoline
—
Me, Me
—
—
—


 


749
A31
CN




OCH2
2-quinoline
—
Me, 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


753
A32
CN
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me, Me
—
—
Me


754
A32
CN
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
Me, Me
—
—
Me


 


755
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


756
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


757
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


758
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


759
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


760
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


761
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


762
A32
CN




OCH2
2-quinoline
—
Me, Me
—
—
Me


 


763
A35
CN
4-pyridinyl
OCH2
2-quinoline
—
—
—
—
—


764
A35
CN
4-OMe-phenyl
OCH2
2-quinoline
—
—
—
—
—


765
A35
CN
4-pyrazolyl
OCH2
2-quinoline
—
—
—
—
—


766
A35
CN
3-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
—
—
—


767
A35
CN
4-(1-methyl-1H-pyrazolyl)
OCH2
2-quinoline
—
—
—
—
—


 


768
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


769
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


770
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


771
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


772
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


773
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


774
A35
CN




OCH2
2-quinoline
—
—
—
—
—


 


775
A35
CN




OCH2
2-quinoline
—
—
—
—
—









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 incorporated 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 isotomcity. 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 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 Calif.). 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. Thu 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 Calif.). 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 dB for 20 msec followed a 100 msec later by a 120 dB pulse for 40 msec. Each animal received 12 trials for each condition for a total of 60 trials with an average intertidal interval of 15 sec. Percent PPI was calculated according to the following formula: (1-(startle response to prepulse+pulse)/startle response to pulse alone))×100.
MK-801-induced hyperactivity: After a 30 min acclimation 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 (0.3 mg/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
hPDE10A1 Enzyme Activity: 50 μl samples of serially diluted Human PDE10A1 enzyme were incubated with 50 μl of [3H]-cAMP for 20 minutes (at 37° C.). Reactions were carried out in Greiner 96 deep well 1 ml master-block. The enzyme was diluted in 20 mM 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 PDF enzyme (at 70° C.) after which [3H]-5′-AMP was converted to [3H]-adenosine by adding 25 μl snake venom nucleotidase and incubating for 10 minutes (at 37° C.). Adenosine, being neutral, was separated from charged cAMP or AMP by the addition of 200 μl Dowex resin. Samples were shaken for 20 minutes then centrifuged for 3 minutes at 2,500 r.p.m. 50 μl of supernatant was removed and added to 200 μl of MicroScint-20 in white plates (Greiner 96-well Optiplate) and shaken for 30 minutes before reading on Perkin Elmer TopCount Scintillation Counter.
hPDE10A1 Enzyme Inhibition: To check inhibition profile 11 μl of serially diluted inhibitor was added to 50 μl of [3H]-cAMP and 50 ul of diluted Human PDE10A1 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:














hPDE10A1


Ex
Name
IC50 Band

















11
1-methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-
B



2,5-dione



23
5,5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-
A



2(5H)-one



26
7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-
B



en-5-one



33
4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-2(5H)-one



73
4-(4-methoxyphenyl)-1,5,5-trimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)- 
B



1H-pyrrol-2(5H)-one



125
2,2-dimethyl-5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-
A



3(2H)-one



126
7-(4-methoxyphenyl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-
A



oxaspiro[2.4]hept-6-en-5-one



127
2,2-dimethyl-5-(pyrimidin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan- 
B



3(2H)-one 



130
5-(2-hydroxypyridin-4-yl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



131
5-(2-methoxypyridin-4-yl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



132
5-(6-hydroxypyridin-3-yl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



133
5-(6-methoxypyridin-3-yl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



134
5-(3-fluoro-4-rnethoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



135
5-(3-chloro-4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



137
5-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-
A



dihydrofuran-2-yl)-2-methoxybenzonitrile



138
5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



141
4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-
A



dihydrofuran-2-yl)benzonitrile



147
5-(4-chlorophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-
A



3(2H)-one



153
5-(4-fluorophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-
A



3(2H)-one



154
2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)-5-(4-
A



(trifluoromethyl)phenyl)furan-3(2H)-one



155
2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)-5-(4-
A



(trifluoromethoxy)phenyl)furan-3(2H)-one



156
2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)-5-(4-(2,2,2-
A



trifluoroethyl)phenyl)furan-3(2H)-one



157
5-(4-ethoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-
A



3(2H)-one



158
5-(4-isopropoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-
B



ylmethoxy)phenyl)furan-3(2H)-one



159
5-(4-(difluoromethoxy)phenyl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



161
5-(4-(cyclopropylmethoxy)phenyl)-2,2-dimethyl-4-(4-(quinolin-2-
B



ylmethoxy)phenyl)furan-3(2H)-one



162
2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)-5-(4-(2,2,2-
A



trifluoroethoxy)phenyl)furan-3(2H)-one



166
5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



167
5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



169
2-(difluoromethoxy)-5-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-
A



ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)benzonitrile



174
2,2-dimethyl-4-(4-quinolin-2-ylmethoxy)phenyl)-5-(thiazol-4-yl)furan-
A



3(2H)-one



164
2,2-dimethyl-5-(4-nitrophenyl)-4-(4-quinolin-2-ylmethoxy)phenyl)furan-
A



3(2H)-one



170
5-4-(1H-tetrazol-1-yl)phenyl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



249
2,2-dimethyl-4-(pyridin-4-yl)-5-(4-(quinolin-2-ylmethoxy)phenyl)furan-
A



3(2H)-one



262
4-(4-methoxyphenyl)-2,2-dimethyl-5-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



808
2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-5-(pyridin-4-
A



yl)furan-3(2H)-one



809
4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-
A



yl)furan-3(2H)-one



810
4-(4-((6-fluoroquinolin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-
A



yl)furan-3(2H)-one



811
2,2-dimethyl-5-phenyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one
A


812
1-methyl-3-morpholino-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-
B



dione



813
5-(4-hydroxyphenyl)-2,2-dimethyl-4-(4-(quinolin-
A



2-ylmethoxy)phenyl)furan-3(2H)-one



814
N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-
A



dihydrofuran-2-yl)phenyl)acetamide



815
N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-
A



dihydrofuran-2-yl)phenyl)methanesulfonamide



63
5,5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-
A



pyrrol-2(5H)-one



817
N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-
A



dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methanesulfonamide



818
2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)-5-p-tolylfuran-3(2H)-one
A


819
N-acetyl-N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-
A



dihydrofuran-2-yl)phenyl)acetamide



820
1-methyl-3-(4-oxopiperidin-1-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H- 
B



pyrrole-2,5-dione



821
5-(benzo[d]oxazol-5-yl)-2,2-dimethyl-4-(4-(quinolin-2-
A



ylmethoxy)phenyl)furan-3(2H)-one



822
4-(4-methoxyphenyl)-1,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)-1H-
B



imidazol-2(3H)-one



823
4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-
A



pyrrol-2(5H)-one



824
2-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1-oxaspiro[4.4]non-2-
A



en-4-one

## Claims

1. A method for making 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof, the method comprising contacting 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof with a brominating reagent to provide 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one or a salt thereof.

2. The method of claim 1, wherein the brominating reagent is N-bromosuccinimide.

3. A method for making a compound of formula




or a salt thereof, the method comprising contacting 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one with a compound of formula




to provide a compound of formula




or a salt thereof,
wherein,
Y is —OCH2— with the rightmost radical of the Y group connected to the Z substituent; and
Z is imidazo[1,2-b]pyridazine or quinolinyl.

4. The method of claim 3, wherein Z is quinolinyl.

5. The method of claim 3, wherein Z is imidazo[1,2-b]pyridazine.

6. The method of claim 3, conducted in the presence of a catalyst.

7. The method of claim 6, wherein the catalyst is a palladium(0) or palladium(II) catalyst.

8. The method of claim 3 conducted in the presence of a base.

9. The method of claim 8, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate and cesium carbonate.

10. The method of claim 3, further comprising isolating




or a salt thereof.