Heterocyclic aspartyl protease inhibitors

Information

  • Patent Grant
  • 8691831
  • Patent Number
    8,691,831
  • Date Filed
    Friday, March 9, 2012
    12 years ago
  • Date Issued
    Tuesday, April 8, 2014
    10 years ago
Abstract
Disclosed are compounds of the formula I
Description
FIELD OF THE INVENTION

This invention relates to heterocyclic aspartyl protease inhibitors, pharmaceutical compositions comprising said compounds, their use in the treatment of cardiovascular diseases, cognitive and neurodegenerative diseases, and their use as inhibitors of the Human Immunodeficiency Virus, plasmepsins, cathepsin D and protozoal enzymes.


BACKGROUND

Eight human aspartic proteases of the A1 (pepsin-like) family are known to date: pepsin A and C, renin, BACE, BACE 2, Napsin A, cathepsin D in pathological conditions.


The role of renin-angiotensin system (RAS) in regulation of blood pressure and fluid electrolyte has been well established (Oparil, S, et al. N Engl J Med 1974; 291:381-401/446-57). The octapeptide Angiotensin-II, a potent vasoconstrictor and stimulator for release of adrenal aldosterone, was processed from the precursor decapeptide Angiotensin-I, which in turn was processed from angiotensinogen by the renin enzyme. Angiotensin-II was also found to play roles in vascular smooth muscle cell growth, inflammation, reactive oxygen species generation and thrombosis, influence atherogenesis and vascular damage. Clinically, the benefit of interruption of the generation of angiotensin-II through antagonism of conversion of angiotensin-I has been well known and there are a number of ACE inhibitor drugs on the market. The blockade of the earlier conversion of angiotensinogen to angiotensin-I, i.e. the inhibition of renin enzyme, is expected to have similar but not identical effects. Since renin is an aspartyl protease whose only natural substrate is angiotensinogen, it is believed that there would be less frequent adverse effect for controlling high blood pressure and related symptoms regulated by angiotensin-II through its inhibition.


Another protease, Cathepsin-D, is involved in lysosomal biogenesis and protein targeting, and may also be involved in antigen processing and presentation of peptide fragments. It has been linked to numerous diseases including, Alzheimer's, disease, connective tissue disease, muscular dystrophy and breast cancer.


Alzheimer's disease (AD) is a progressive neurodegenerative disease that is ultimately fatal. Disease progression is associated with gradual loss of cognitive function related to memory, reasoning, orientation and judgment. Behavioral changes including confusion, depression and aggression also manifest as the disease progresses. The cognitive and behavioral dysfunction is believed to result from altered neuronal function and neuronal loss in the hippocampus and cerebral cortex. The currently available AD treatments are palliative, and while they ameliorate the cognitive and behavioral disorders, they do not prevent disease progression. Therefore there is an unmet medical need for AD treatments that halt disease progression.


Pathological hallmarks of AD are the deposition of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles comprised of abnormally phosphorylated protein tau. Individuals with AD exhibit characteristic Aβ deposits, in brain regions known to be important for memory and cognition. It is believed that Aβ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioral decline. Amyloid plaques consist predominantly of Aβ peptides comprised of 40-42 amino acid residues, which are derived from processing of amyloid precursor protein (APP). APP is processed by multiple distinct protease activities. Aβ peptides result from the cleavage of APP by β-secretase at the position corresponding to the N-terminus of Aβ, and at the C-terminus by γ-secretase activity. APP is also cleaved by α-secretase activity resulting in the secreted, non-amyloidogenic fragment known as soluble APP.


An aspartyl protease known as BACE-1 has been identified as the β-secretase activity responsible for cleavage of APP at the position corresponding to the N-terminus of Aβ peptides.


Accumulated biochemical and genetic evidence supports a central role of Aβ in the etiology of AD. For example, Aβ has been shown to be toxic to neuronal cells in vitro and when injected into rodent brains. Furthermore inherited forms of early-onset AD are known in which well-defined mutations of APP or the presenilins are present. These mutations enhance the production of Aβ and are considered causative of AD.


Since Aβ peptides are formed as a result β-secretase activity, inhibition of BACE-1 should inhibit formation of Aβ peptides. Thus inhibition of BACE-1 is a therapeutic approach to the treatment of AD and other cognitive and neurodegenerative diseases caused by Aβ plaque deposition.


Human immunodeficiency virus (HIV), is the causative agent of acquired immune deficiency syndrome (AIDS). It has been clinically demonstrated that compounds such as indinavir, ritonavir and saquinavir which are inhibitors of the HIV aspartyl protease result in lowering of viral load. As such, the compounds described herein would be expected to be useful for the treatment of AIDS. Traditionally, a major target for researchers has been HIV-1 protease, an aspartyl protease related to renin.


In addition, Human T-cell leukemia virus type I (HTLV-I) is a human retrovirus that has been clinically associated with adult T-cell leukemia and other chronic diseases. Like other retroviruses, HTLV-I requires an aspartyl protease to process viral precursor proteins, which produce mature virions. This makes the protease an attractive target for inhibitor design. (Moore, et al. Purification of HTLV-I Protease and Synthesis of Inhibitors for the treatment of HTLV-I Infection 55th Southeast Regional Meeting of the American Chemical Society, Atlanta, Ga., US Nov. 16-19, 2003 (2003), 1073. CODEN; 69EUCH Conference, AN 2004:137641 CAPLUS.)


Plasmepsins are essential aspartyl protease enzymes of the malarial parasite. Compounds for the inhibition of aspartyl proteases plasmepsins, particularly I, II, IV and HAP, are in development for the treatment of malaria. (Freire, et al. WO 2002074719. Na Byoung-Kuk, et al. Aspartic proteases of Plasmodium vivax are highly conserved in wild isolates Korean Journal of Prasitology (2004 June), 42(2) 61-6. Journal code: 9435800) Furthermore, compounds used to target aspartyl proteases plasmepsins (e.g. I, II, IV and HAP), have been used to kill malarial parasites, thus treating patients thus afflicted.


SUMMARY OF THE INVENTION

The present invention relates to compounds having the structural formula I




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or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate or ester thereof, wherein


W is a bond, —C(═S)—, —S(O)—, —S(O)2—, —C(═O)—, —O—, —C(R6)(R7)—, —N(R5)— or —C(═N(R5))—;


X is —O—, —N(R5)— or —C(R6)(R7)—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O)2—, —C(═O)— or —C(═NR5)—;


U is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —P(O)(OR15)—, —C(═NR5)—, —(C(R6)(R7))b— or —N(R5)—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, U is not —S(O)—, —S(O)2—, —O—, or —N(R5)—; provided that when X is —N(R5)— and W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, then U is not a bond;


R1, R2 and R5 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —OR15, —CN, —C(O)R8, —C(O)OR9, —S(O)R10, —S(O)2R10, —C(O)N(R11)(R12), —S(O)N(R11)(R12), —S(O)2N(R11)(R12), —NO2, —N═C(R8)2 and —N(R8)2, provided that R1 and R5 are not both selected from —NO2, —N═C(R8)2 and —N(R8)2;


R3, R4, R6 and R7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH2—O—Si(R9)(R10)(R19), —SH, —CN, —OR9, —C(O)R8, —C(O)OR9, —C(O)N(R11)(R12), —SR19, —S(O)N(R11)(R12), —S(O)2N(R11)(R12), —N(R11)(R12), —N(R11)C(O)R8, —N(R11)S(O)R10, —N(R11)C(O)N(R12)(R13), —N(R11)C(O)OR9 and —C(═NOH)R8; provided that when U is —O— or —N(R5)—, then R3, R4, R6 and R7 are not halo, —SH, —OR9, —SR19, —S(O)N(R11)(R12), —S(O)2N(R11)(R12), —N(R11)(R12), —N(R11)C(O)R8, —N(R11)S(O)R10, —N(R11)C(O)N(R12)(R13), or —N(R11)C(O)OR9; provided that when W is —O— or —N(R5)—, then R3 and R4 are not halo, —SH, —OR9, —SR19, —S(O)N(R11)(R12), —S(O)2N(R11)(R12), —N(R11)(R12), —N(R11)C(O)R8, —N(R11)S(O)R10, —N(R11)C(O)N(R12)(R13), or —N(R11)C(O)OR9; and provided that when X is —N(R5)—, W is —C(O)— and U is a bond, R3 and R4 are not halo, —CN, —SH, —OR9, —SR19, —S(O)N(R11)(R12) or —S(O)2N(R11)(R12); or R3, R4, R6 and R7, together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group optionally substituted by R14 or a 3-7 membered cycloalkylether optionally substituted by R14;


or R3 and R4 or R6 and R7 together with the carbon to which they are attached, are combined to form multicyclic groups such as




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wherein M is —CH2—, S, —N(R19)— or O, A and B are independently aryl or heteroaryl and q is 0, 1 or 2 provided that when q is 2, one M must be a carbon atom and when q is 2, M is optionally a double bond; and with the proviso that when R3, R4, R6 and R7 form said multicyclic groups




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then adjacent R3 and R4 or R6 and R7 groups cannot be combined to form said multicyclic groups;


R8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR15, —N(R15)(R16), —N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17) and —N(R15)C(O)OR16;


R9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;


R10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R15)(R16);


R11, R12 and R13 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —C(O)R8, —C(O)OR9, —S(O)R10, —S(O)2R10, —C(O)N(R15)(R16), —S(O)N(R15)(R16), —S(O)2N(R15)(R16) and —CN;


R14 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), —N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17) and —N(R15)C(O)OR16;


R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R18-alkyl, R18-cycloalkyl, R18-cycloalkylalkyl, R18-heterocycloalkyl, R18-heterocycloalkylalkyl, R18-aryl, R18-arylalkyl, R18-heteroaryl and R18-heteroarylalkyl; or


R15, R16 and R17 are




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wherein R23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5;


R18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO2, halo, heteroaryl, HO-alkyoxyalkyl, —CF3, —CN, alkyl-CN, —C(O)R19, —C(O)OH, —C(O)OR19, —C(O)NHR20, —C(O)NH2, —C(O)NH2—C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR19, —S(O)2R20, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR19, —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OCF3, —OH, —OR20, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR20, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R20, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R20, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


or two R18 moieties on adjacent carbons can be linked together to form




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R19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;


R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;


and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are independently unsubstituted or substituted by 1 to 5 R21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —CH(R15)(R16), —S(O)2N(R15)(R16), C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —CH2—N(R15)C(O)N(R16)(R17), —CH2—R15; —CH2N(R15)(R16), —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —S(O)R15, ═NOR15, —N3, —NO2 and —S(O)2R15; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR15, —C(O)R15, —C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —N3, ═NOR15, —NO2, —S(O)R15 and —S(O)2R15;


or two R21 or two R22 moieties on adjacent carbons can be linked together to form




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and when R21 or R22 are selected from the group consisting of —C(═NOR15)R16, —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16 and —CH2—N(R15)C(O)OR16, R15 and R16 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R15 and R16, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R23;


R23 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR24, —C(O)R24, —C(O)OR24, —C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R23 are independently unsubstituted or substituted by 1 to 5 R27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR24, —C(O)R24, —C(O)OR24, alkyl-C(O)OR24, C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;


R24, R25 and R26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R27-alkyl, R27-cycloalkyl, R27-cycloalkylalkyl, R27-heterocycloalkyl, R27-heterocycloalkylalkyl, R27-aryl, R27-arylalkyl, R27-heteroaryl and R27-heteroarylalkyl;


R27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO2, halo, —CF3, —CN, alkyl-CN, —C(O)R28, —C(O)OH, —C(O)OR28, —C(O)NHR29, —C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR28, —S(O)2R29, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR28, —S(O)2NH(aryl), —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OH, —OR29, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR29, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R29, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R29, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


R28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and


R29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;


provided that when W is —C(O)— and U is a bond, R1 is not optionally substituted phenyl, and that when U is —C(O)— and W is a bond, R5 is not optionally substituted phenyl;


provided that neither R1 nor R5 is —C(O)-alkyl-azetidinone or alkyl di-substituted with (—COOR15 or —C(O)N(R15)(R16)) and (—N(R15)(R16), —N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), or —N(R15)C(O)OR16);


provided that when R1 is methyl, X is —N(R5)—, R2 is H, W is —C(O)— and U is a bond, (R3, R4) is not (H, H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl), (i-butyl, H), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH3O-phenyl, NO2-phenyl); and when W is a bond and U is —C(O)—, (R3, R4) is not (H, H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl), (i-butyl, H), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH3O-phenyl, NO2-phenyl);


provided that when X is —N(R5)—, R1 and R5 are each H, W is —C(O)— and U is a bond, (R3, R4) is not (optionally substituted phenyl, optionally substituted benzyl), (optionally substituted phenyl, heteroarylalkyl) or (heteroaryl, heteroarylalkyl);


provided that when U is a bond, W is —C(O)—, and R3 and R4 form a ring with the carbon to which they are attached, R1 is not 2-CF3-3-CN-phenyl;


provided that when X is —N(R5)—, U is —O— and W is a bond or —C(R6)(R7)—, (R3,R4) is not (H, —NHC(O)-alkyl-heteroaryl) or (H, alkyl-NHC(O)-alkyl-heteroaryl); and


provided that when X is —N(R5)—, R1 and R5 are not -alkylaryl-aryl-SO2—N(R15)(R16) wherein R15 is H and R16 is heteroaryl;


provided that when R1 is R21-aryl or R21-arylalkyl, wherein R21 is —OCF3, —S(O)CF3, —S(O)2CF3, —S(O)alkyl, —S(O)2alkyl, —S(O)2CHF2, —S(O)2CF2CF3, —OCF2CHF2, —OCHF2, —OCH2CF3, —SF5 or —S(O)2NR15R16;


wherein R15 and R16 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl, R18-aryl and R18-heteroaryl; U is a bond or —CH2; and X is —N(R5)—; then R5 is H;


provided that when U is a bond,


R3 and R4 are alkyl,




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where R21 is halo, —CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R3 and R4, together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group,


and R1 is




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where a is 0 to 6 and R22 is alkyl, alkoxy, halo, —CN, —OH, —NO2 or haloalkyl;


then R21a is not H, —C(O)2R15, wherein R15 is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkyl-R22, wherein R22 is selected from the group consisting of


phenyl,


phenyl substituted with alkyl,


and




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wherein R22 is selected from the group consisting of H, methoxy, nitro, oxo, —OH, halo and alkyl,




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In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula I and a pharmaceutically acceptable carrier.


In another aspect, the invention comprises the method of inhibiting aspartyl protease comprising administering at least one compound of formula I to a patient in need of such treatment.


More specifically, the invention comprises: the method of treating a cardiovascular disease such as hypertension, renal failure, or a disease modulated by renin inhibition; the method of treating Human Immunodeficiency Virus; the method of treating a cognitive or neurodegenerative disease such as Alzheimer's Disease; the method of inhibiting plasmepins I and II for treatment of malaria; the method of inhibiting Cathepsin D for the treatment of Alzheimer's Disease, breast cancer, and ovarian cancer; and the method of inhibiting protozoal enzymes, for example inhibition of plasmodium falciparnum, for the treatment of fungal infections. Said method of treatment comprise administering at least one compound of formula I to a patient in need of such treatment. In particular, the invention comprises the method of treating Alzheimer's disease comprising administering at least one compound of formula I to a patient in need of such treatment.


In another aspect, the invention comprises the method of treating Alzheimer's disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula I and a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.


In a final aspect, the invention relates to a kit comprising in separate containers in a single package pharmaceutical compositions for use in combination, in which one container comprises a compound of formula I in a pharmaceutically acceptable carrier and a second container comprises a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist in a pharmaceutically acceptable carrier, the combined quantities being an effective amount to treat a cognitive disease or neurodegenerative disease such as Alzheimer's disease.







DETAILED DESCRIPTION

Compounds of formula I wherein X, W and U are as defined above include the following independently preferred structures:




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In compounds of formulas IA to IF, U is preferably a bond or —C(R6)(R7)—. In compounds of formula IG and IH, U is preferably —C(O)—.


It will be understood that since the definition of R1 is the same as the definition of R5, when X is —N(R5)—, compounds of formula I wherein W is a bond and U is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —C(R6)(R7)— or —N(R5)— are equivalent to compounds of formula I wherein U is a bond and W is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —C(R6)(R7)— or —N(R5)—.


More preferred compounds of the invention are those of formula IB wherein U is a bond or those of formula IB wherein U is —C(R6)(R7)—.


Another group of preferred compounds of formula I is that wherein R2 is H.


R3, R4, R6 and R7 are preferably selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH2—O—Si(R9)(R10)(R19), —SH, —CN, —OR9, —C(O)R8, —C(O)OR9, —C(O)N(R11)(R12), —SR19, —S(O)N(R11)(R12), —S(O)2N(R11)(R12), —N(R11)(R12), —N(R11)C(O)R8, —N(R11)S(O)R10, —N(R11)C(O)N(R12)(R13), —N(R11)C(O)OR9 and —C(═NOH)R8.


R3, R4, R6 and R7 are preferably selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl.


In a group of preferred compounds


U is a bond or —C(O)—;


W is a bond or —C(O)—;


X is —N(R5)—;


R1 is H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkylalkyl, R21-cycloalkylalkyl, heterocycloalkyalkyl or R21-heterocycloalkylalkyl,


R2 is H;


R3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkylalkyl, R21-cycloalkyl, R21-aryl or R21-arylalkyl;


R4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkylalkyl, R21-cycloalkyl, R21-aryl or R21-arylalkyl;


R5 is H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkylalkyl, R21-cycloalkylalkyl, heterocycloalkyalkyl or R21-heterocycloalkylalkyl;


R6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkylalkyl, R21-cycloalkyl, R21-aryl or R21-arylalkyl;


R7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkylalkyl, R21-cycloalkyl, R21-aryl or R21-arylalkyl;


R15, R16 and R17 is H, R18-alkyl, alkyl or




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R21 is alkyl, aryl, halo, —OR15, —NO2, —C(O)R15, —CH2—N(R15)C(O)N(R16)(R17) or —CH(R15)(R16);


n is 1;


m is 1;


R18 is —OR20


R20 is aryl;


and


R23 is alkyl.


In a group of preferred compounds


R3, R4, R6 and R7 are




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and


R1 and R5 is H, CH3,




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In an additional group of preferred compounds;


U is a bond or —C(O)—;


W is a bond or —C(O)—;


X is —N(R5)—;


R1 is H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkylalkyl, R21-cycloalkylalkyl, heterocycloalkyalkyl or R21-heterocycloalkylalkyl,


R2 is H;


R3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkylalkyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21-heteroarylalkyl, R21-heteroaryl, R21-heterocycloalkyl or R21-heterocycloalkylalkyl;


R4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkylalkyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21-heteroarylalkyl, R21-heteroaryl, R21-heterocycloalkyl or R21-heterocycloalkylalkyl;


R5 is H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkylalkyl, R21-cycloalkylalkyl, heterocycloalkyalkyl or R21-heterocycloalkylalkyl;


R6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkylalkyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21-heteroarylalkyl, R21-heteroaryl, R21-heterocycloalkyl or R21-heterocycloalkylalkyl;


R7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkylalkyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21-heteroarylalkyl, R21-heteroaryl, R21-heterocycloalkyl or R21-heterocycloalkylalkyl;


R15, R16 and R17 is H, cycloalkyl, cycloalkylalkyl, R18-alkyl, alkyl, aryl, R18-aryl, R18-arylalkyl, arylalkyl,




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n is 1 or 2;


m is 0 or 1;


R18 is —OR20 or halo;


R20 is aryl or halo substituted aryl;


R21 is alkyl, aryl, heteroaryl, R22-alkyl, R22-aryl, R22-heteroaryl, halo, heterocycloalkyl, —N(R15)(R16), —OR15, —NO2, —C(O)R15, —N(R15)C(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17) or —CH(R15)(R16);


R22 is —OR16 or halo


and


R23 is H or alkyl.


It is noted that the carbons of formula I may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.


As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:


“Patient” includes both human and animals.


“Mammal” means humans and other mammalian animals.


“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl and decyl. R21-substituted alkyl groups include fluoromethyl, trifluoromethyl and cyclopropylmethyl.


“Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.


“Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.


“Aryl” means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more substituents (e.g., R18, R21, R22, etc.) which may be the same or different, and are as defined herein or two substituents on adjacent carbons can be linked together to form




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Non-limiting examples of suitable aryl groups include phenyl and naphthyl.


“Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one to eight of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more R21 substituents which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.


“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more R21 substituents which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like. Further non-limiting examples of cycloalkyl include the following




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“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom.


“Cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. The cycloalkenyl ring can be optionally substituted with one or more R21 substituents which may be the same or different, and are as defined above. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.


“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.


“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.


“Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.


“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3, preferably 1 or 2 of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted by one or more R21 substituents which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.


“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.


“Arylcycloalkyl” means a group derived from a fused aryl and cycloalkyl as defined herein. Preferred arylcycloalkyls are those wherein aryl is phenyl and cycloalkyl consists of about 5 to about 6 ring atoms. The arylcycloalkyl can be optionally substituted by 1-5 R21 substituents. Non-limiting examples of suitable arylcycloalkyls include indanyl and 1,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moiety is through a non-aromatic carbon atom.


“Arylheterocycloalkyl” means a group derived from a fused aryl and heterocycloalkyl as defined herein. Preferred arylcycloalkyls are those wherein aryl is phenyl and heterocycloalkyl consists of about 5 to about 6 ring atoms. The arylheterocycloalkyl can be optionally substituted by 1-5 R21 substituents. Non-limiting examples of suitable arylheterocycloalkyls include




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The bond to the parent moiety is through a non-aromatic carbon atom.


Similarly, “heteroarylalkyl” “cycloalkylalkyl” and “heterocycloalkylalkyl” mean a heteroaryl-, cycloalkyl- or heterocycloalkyl-alkyl- group in which the heteroaryl, cycloalkyl, heterocycloalkyl and alkyl are as previously described. Preferred groups contain a lower alkyl group. The bond to the parent moiety is through the alkyl.


“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)— or cycloalkyl-C(O)— group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl.


“Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen.


“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as defined herein. The bond to the parent moiety is through the alkyl.


“Arylalkenyl” means a group derived from an aryl and alkenyl as defined herein. Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of about 3 to about 6 atoms. The arylalkenyl can be optionally substituted by one or more R27 substituents. The bond to the parent moiety is through a non-aromatic carbon atom.


“Arylalkynyl” means a group derived from a aryl and alkynyl as defined herein. Preferred arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of about 3 to about 6 atoms. The arylalkynyl can be optionally substituted by one or more R27 substituents. The bond to the parent moiety is through a non-aromatic carbon atom.


The suffix “ene” on alkyl, aryl, heterocycloalkyl, etc. indicates a divalent moiety, e.g., —CH2CH2— is ethylene, and




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is para-phenylene.


The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties, in available position or positions.


Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl portion of the group.


When a variable appears more than once in a group, e.g., R8 in —N(R8)2, or a variable appears more than once in the structure of formula I, e.g., R15 may appear in both R1 and R3, the variables can be the same or different.


With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases “one or more” and “at least one” mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art. With respect to the compositions and methods comprising the use of “at least one compound of formula I,” one to three compounds of formula I can be administered at the same time, preferably one.


As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.


The wavy line custom character as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example,




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means containing both




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Lines drawn into the ring systems, such as, for example:




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indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.


As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:




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represents




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It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences.


Those skilled in the art will recognize that certain compounds of formula I are tautomeric, and all such tautomeric forms are contemplated herein as part of the present invention. For example, a compound wherein X is —N(R5)— and R1 and R5 are each H can be represented by any of the following structures:




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When R21 and R22, are, for example, —N(R15)C(O)N(R16)(R17) and R15 and R16 form a ring, the moiety formed, is, for example,




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The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.


It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.


When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.


When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.


As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.


Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto. For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.


Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N—(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, —P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.


If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY1 wherein Y1 is H, (C1-C6)alkyl or benzyl, —C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy (C1-C6)alkyl, amino(C1-C4)alkyl or mono-N— or di-N,N—(C1-C6)alkylaminoalkyl, —C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N—(C1-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.


One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.


One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).


“Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting aspartyl protease and/or inhibiting BACE-1 and thus producing the desired therapeutic effect in a suitable patient.


The compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto.


Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates) undecanoates, and the like.


Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.


All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.


Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di(C6-24)acyl glycerol.


Compounds of Formula I, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.


The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.


Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.


It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.


All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention).


Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.


The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.


Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.


Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.


The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be heterocyclic aspartyl protease inhibitors.


The term “pharmaceutical composition” is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said “more than one pharmaceutically active agents”. The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.


Compounds of formula I can be made using procedures known in the art. Preparative methods for preparing starting materials and compounds of formula I are show below as general reaction schemes (Method A, Method B, etc.) followed by specific procedures, but those skilled in the art will recognize that other procedures can also be suitable. In the Schemes and in the Examples below, the following abbreviations are used:


methyl: Me; ethyl: Et; propyl: Pr; butyl: Bu; benzyl: Bn; tertiary butyloxycarbonyl: Boc or BOC


high pressure liquid chromatography: HPLC


liquid chromatography mass spectroscopy: LCMS


room temperature: RT or rt


day: d; hour: h; minute: min


retention time: Rt


microwave: μW


saturated: sat.; anhydrous: anhyd.


1-hydroxybenzotriazole: HOBt


1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: EDCl


ethyl acetate: EtOAc


Benzyloxycarbonyl: CBZ


[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-borate)]: Selectfluor


1,8-diazabicyclo[5,4,0]undec-7-ene: DBU


tetrahydrofuran: THF; N,N-dimethylformamide: DMF; methanol: MeOH; diethyl ether: Et2O; acetic acid: AcOH; acetonitrile: MeCN; trifluoroacetic acid: TFA; dichloromethane: DCM; dimethoxyethane: DME; diphenylphosphinoferrocene (dppf);


n-butyllithium: n-BuLi; lithium diisopropylamide: LDA


1-hydroxy-7-azabenzotriazole: HOAt


4-N,N-dimethylaminopyridine: DMAP; diisopropylethylamine: DIEA; N-methylmorpholine: NMM


Microporous Toluene sulfonic acid resin (MP-TsOH resin)


tris-(2-aminoethyl)aminomethyl polystyrene (PS-trisamine)


methylisocyanate polystyrene (PS-NCO)


Saturated (sat.); anhydrous. (anhyd); room temperature (rt); hour (h); Minutes (Min), Retention Time (Rt); molecular weight (MW); milliliter (mL); gram (g). milligram (mg); equivalent (eq); day (d); microwave (μW); microliter (μL);


All NMR data were collected on 400 MHz NMR spectrometers unless otherwise indicated. LC-Electrospray-Mass spectroscopy with a C-18 column and 5% to 95% MeCN in water as the mobile phase was used to determine the molecular mass and retention time. The tables contain the compounds with retention time/observed MW and/or NMR data.


For internal consistency in the reaction schemes shown in Methods A to DF, the product of each method is shown as structure A4, B4, C3, etc., wherein certain variables are as defined for that method, but it will be apparent that, for example, A4 has the same structure as C3. That is, different methods can be used to prepare similar compounds.


The compounds in the invention may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below. The tables contain the compounds with observed m/e values from mass spectroscopy and/or NMR data. These compounds can be obtained with synthetic methods similar to these listed in the last column using appropriate reagents.


Method A



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Method A, Step 1

To a solution of A1 (R3=CH3 & R4=CH2CH(CH3)2) (10 mmol, 1 eq) in 30 ml of anhyd. CH2Cl2 was added thiocarbonyl dipyridone (1.2 eq). After stirring overnight the solution was diluted with CH2Cl2, washed with 1N HCl, H2O (2×), and a saturated aqueous NaCl solution (2×). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography to afford A2 (R3=CH3 & R4=CH2CH(CH3)2).


Method A, Step 2

A solution of 3,5-difluorobenzyl amine (0.15 mmol, 1.5 eq) in THF (0.15 mL) was added to a solution of A2 (R3=CH3 & R4=CH2CH(CH3)2) (0.1 mmol, 1 eq) in anhydrous CH2Cl2 (1 mL). The reaction mixture was refluxed overnight. The reaction solution was added to MP-TsOH resin (2-3 eq) and diluted with CH3CN. The suspension was agitated overnight. The mixture was filtered and the filtrate was concentrated to afford A3 (R1=3,5-difluorobenzyl, R3=CH3, & R4=CH2CH(CH3)2).


Method A, Step 3

To a solution of A3 (R1=3,5-difluorobenzyl, R3=CH3, & R4=CH2CH(CH3)2) (10 mg) in CH3OH (1 mL) was added NH4OH (0.44 mL) and t-butyl hydrogen peroxide (0.1 mL) and the reaction mixture was agitated for 2 d. The solution was concentrated, the resulting residue was dissolved in CH3OH (1.2 mL) and was treated with sulfonic acid resin. The suspension was agitated overnight and the resin was washed with CH3OH (4×10 min) before it was treated with 2 N NH3 in CH3OH for 1 h. The suspension was filtered and the filtrate was concentrated to give the crude material which was purified by preparative HPLC/LCMS eluting with a CH3CN/H2O gradient to afford A4 (R1=3,5-difluorobenzyl, R2=H, R3=CH3, & R4=CH2CH(CH3)2). NMR (CD3OD): δ6.9, m, 3H; δ4.8-4.9, m; δ1.75, d, 2H; δ1.5, m, 1H; δ1.42, s, 3H; δ0.85, d, 3H; δ0.65, d, 3H. ES_LCMS (m/e) 296.1.


The following compounds were synthesized using similar methods:


















Obs.


#
Structure
MW
m/e







 1


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223
224





 2


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223
224





 3


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225
226





 4


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225
226





 5


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227
228





 6


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237
238





 7


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239
240





 8


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239
240





 9


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239
240





 10


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240
241





 11


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241
242





 12


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241
242





 13


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251
252





 14


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253
254





 15


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254
255





 16


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255
256





 17


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255
256





 18


embedded image


255
256





 19


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260
261





 20


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260
261





 21


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265
266





 22


embedded image


265
266





 23


embedded image


265
266





 24


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267
268





 25


embedded image


268
269





 26


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268
269





 27


embedded image


269
270





 28


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273
274





 29


embedded image


273
274





 30


embedded image


274
275





 31


embedded image


274
275





 32


embedded image


274
275





 33


embedded image


277
278





 34


embedded image


279
280





 35


embedded image


280
281





 36


embedded image


280
281





 37


embedded image


280
281





 38


embedded image


280
281





 39


embedded image


281
282





 40


embedded image


282
283





 41


embedded image


282
283





 42


embedded image


282
283





 43


embedded image


283
284





 44


embedded image


285
286





 45


embedded image


287
288





 46


embedded image


287
288





 47


embedded image


289
290





 48


embedded image


293
294





 49


embedded image


294
295





 50


embedded image


294
295





 51


embedded image


295
296





 52


embedded image


296
297





 53


embedded image


301
302





 54


embedded image


303
304





 55


embedded image


304
305





 56


embedded image


304
305





 57


embedded image


305
306





 58


embedded image


307
308





 59


embedded image


307
308





 60


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308
309





 61


embedded image


310
311





 62


embedded image


317
318





 63


embedded image


319
320





 64


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322
323





 65


embedded image


324
325





 66


embedded image


327
328





 67


embedded image


327
328





 68


embedded image


327
328





 69


embedded image


327
328





 70


embedded image


328
329





 71


embedded image


330
331





 72


embedded image


331
332





 73


embedded image


331
332





 74


embedded image


335
336





 75


embedded image


335
336





 76


embedded image


337
338





 77


embedded image


337
338





 78


embedded image


342
343





 79


embedded image


345
346





 80


embedded image


345
346





 81


embedded image


349
350





 82


embedded image


349
350





 83


embedded image


351
352





 84


embedded image


351
352





 85


embedded image


351
352





 86


embedded image


359
360





 87


embedded image


361
362





 88


embedded image


361
362





 89


embedded image


361
362





 90


embedded image


363
364





 91


embedded image


363
364





 92


embedded image


363
364





 93


embedded image


363
364





 94


embedded image


363
364





 95


embedded image


363
364





 96


embedded image


369
370





 97


embedded image


374
375





 98


embedded image


375
376





 99


embedded image


375
376





100


embedded image


377
378





101


embedded image


377
378





102


embedded image


377
378





103


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381
382





104


embedded image


382
383





105


embedded image


385
386





106


embedded image


385
386





107


embedded image


386
387





108


embedded image


389
390





109


embedded image


391
392





110


embedded image


391
392





111


embedded image


391
392





112


embedded image


391
392





113


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393
394





114


embedded image


393
394





115


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400
401





116


embedded image


401
402





117


embedded image


401
402





118


embedded image


401
402





119


embedded image


401
402





120


embedded image


403
404





121


embedded image


403
404





122


embedded image


403
404





123


embedded image


405
406





124


embedded image


405
406





125


embedded image


409
410





126


embedded image


409
410





127


embedded image


409
410





128


embedded image


409
410





129


embedded image


411
412





130


embedded image


413
414





131


embedded image


413
414





132


embedded image


414
415





133


embedded image


415
416





134


embedded image


415
416





135


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415
416





136


embedded image


417
418





137


embedded image


419
420





138


embedded image


421
422





139


embedded image


423
424





140


embedded image


425
426





141


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425
426





142


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425
426





143


embedded image


427
428





144


embedded image


429
430





145


embedded image


430
431





146


embedded image


430
431





147


embedded image


431
432





148


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433
434





149


embedded image


437
438





150


embedded image


439
440





151


embedded image


440
441





152


embedded image


440
441





153


embedded image


441
442





154


embedded image


441
442





155


embedded image


442
443





156


embedded image


447
448





157


embedded image


449
450





158


embedded image


455
456





159


embedded image


463
464





160


embedded image


463
464





161


embedded image


471
472





162


embedded image


473
474





163


embedded image


481
482





164


embedded image


481
482





165


embedded image


487
488





166


embedded image


488
489





167


embedded image


499
500





168


embedded image


504
505





169


embedded image


523
524





170


embedded image


525
526





171


embedded image


525
526





172


embedded image


527
528





173


embedded image


528
529





174


embedded image


535
536





175


embedded image


535
536





176


embedded image


535
536





177


embedded image


535
536





178


embedded image


550
551





179


embedded image


554
555





180


embedded image


556
557





181


embedded image


569
570





182


embedded image


581
582





183


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374
NA





184


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388
NA





185


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337
NMR





186


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351
NMR









Method B



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A modified literature procedure was used (Ugi, I. Angew. Chem. 1962, 74 9-22).


Method B, Step 1

To a solution of B1 (HCl salt, R1=3-chlorophenethyl) (1.1 g, 5.73 mmol) in anhydrous CH3OH (15 mL) was added potassium thiocyanate (0.56 g, 5.73 mmol). The reaction mixture was heated to 60° C. for 1 h. The suspension was filtered and the filtrate was added to B5 (R3=Me, R4=iBu) (0.72 mL, 5.73 mmol) and benzyl isocyanide (0.77 mL, 6.3 mmol). The mixture was stirred overnight before the solution was concentrated and the residue was purified via flash chromatography eluting with ethyl acetate in hexane to yield 0.28 g of B2 (R3=CH3, R4=CH2CH(CH3)2, and R1=3-Chlorophenethyl).


Method B, Step 2

A solution of 40% concentrated HCl in CH3CH2OH was added to B2 (R3=CH3, R4=CH2CH(CH3)2, and R1=3-Chlorophenethyl) and the solution was heated in a microwave at 160° C. for 30 min. The solution was concentrated and purified via reverse phase preparative HPLC eluting with a CH3CN/H2O (with 0.1% formic acid) gradient to afford B3 (R3=CH3, R4=CH2CH(CH3)2, and R1=3-Chlorophenethyl).


Method B, Step 3

Compound B4 (R2=H, R3=CH3, R4=CH2CH(CH3)2, and R1=3-Chlorophenethyl) was prepared from B3 (R3=CH3, R4=CH2CH(CH3)2, and R1=3-Chlorophenethyl) following a procedure similar to Method A, Step 3. NMR(CD3OD): δ 8.1, br, 1H; δ 7.35, s, 1H; δ 7.25, m, 3H; δ 3.6, m, 1H; δ 3.4, m, 1 H; δ 3.0, m, 1H; δ 2.8, m, 1H; δ 1.75, m, 1H; δ 1.6, m, 1H; δ 1.35, m, 1H; δ 1.2 s, 3H; δ 0.8, m, 6H. ES_LCMS (m/e): 308.1


The following compounds were prepared using similar methods


















Obs.


#
Structure
MW
m/e







545


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251
252





546


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293
294





547


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307
308





548


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357
358





549


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371
372





550


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413






551


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265









Method C



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Method C, Step 1

A solution of C1 (R3=R4=CH2CH2CH2CH3) (50 mg, 0.25 mmol) and C4 (R1=3-chlorophenyl) (38 μL, 0.26 mmol) was refluxed overnight. Trisamine resin (2 eq) and polystyrene isocyanate resin (2 eq) was added and the mixture was agitated. After 3 h, the suspension was filtered and the resin was washed with CH2Cl2 (3×) and CH3OH (3×). The filtrate was concentrated to afford C2 (R1=3-Cl—C6H4, R3=R4=CH2CH2CH2CH3) (60 mg, 68%).


Method C, Step 2

Compound C3 (R1=3-Cl—C6H4, R2=H, R3=R4=CH2CH2CH2CH3) was prepared from C2 (R1=3-Cl—C6H4, R3=R4=CH2CH2CH2CH3) following a procedure similar to Method A, Step 3. NMR (CDCl3): δ 7.4, m, 2H; δ 7.2, m, 2H; δ 5.0, s, 2H; δ 1.7, m, 4H; δ 1.1, m, 8H; δ 0.7; m, 6H. ES_LCMS (m/e): 336.1.


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e







641


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209
210





642


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211
212





643


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215
216





644


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225
226





645


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239
240





646


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245
246





647


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246
247





648


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251
252





649


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267
268





650


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309
310





651


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317
318





652


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319
320





653


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323
324





654


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324
325





655


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329
330





656


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329
330





657


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335
336





658


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335
336





659


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335
336





660


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335
336





661


embedded image


335
336





662


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352
353





663


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352
353





664


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377
378





665


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385
386





666


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391
392





667


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420
421





668


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420
421









Method D



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Method D, Step 1

A mixture of D1 (R3=R4=CH2C6H5) (20 g), potassium cyanide (40 g) and ammonium carbonate (15 g) in ethanol (100 mL) and H2O (200 mL) was heated in a sealed flask at 130° C. overnight to yield 25 g of D2 (R3=R4=CH2C6H5) after filtration followed by washing with water.


Method D, Step 2

A solution of 2 N KOH (3 eq) was added to D2 (R3=R4=CH2C6H5) (1 eq) and irradiated via microwave at 185° C. for 3 h followed by addition of concentrated HCl to the solution until a pH=2-3 was obtained. The solid was filtered and washed with water to afford D3 (R3=R4=CH2C6H5).


Method D, Step 3

A solution of trimethylsilyldiazomethane in hexane (2 N) (2 eq) was added drop wise to a solution of D3 (R3=R4=CH2C6H5) (1 eq) in anhydrous CH3OH (30 mL). After 1 h, an additional 2 eq of trimethylsilyldiazomethane in hexane (2 N) was added and the reaction was stirred for 20 minutes before it was concentrated. The residue was dissolved in a 0.2 N HCl solution (25 mL) and washed with ether (3×). A saturated solution of Na2CO3 was added to the aqueous phase until the pH of the solution was basic. The solution was extracted with ethyl acetate (3×). The organic extracts were combined, dried over Na2SO4, and concentrated to afford D4 (R3=R4=CH2C6H5).


The following amino esters were prepared using a similar method.




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Method E



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Method E, Step 1

Thionyl chloride (0.47, 6.38 mmol) was added drop wise to a solution of E1 (R3=CH2CH2C6H5) (2 g, 6.38 mmol) and benzaldehyde dimethyl acetal (0.96 mL, 6.38 mmol) in anhydrous THF at 0° C. under N2. After 5 min, ZnCl2 (0.87 g, 6.38 mmol) was added and the reaction mixture was stirred at 0° C. After 3 h, an additional amount of ZnCl2 (0.18 g, 1.28 mmol) and thionyl chloride (0.1 mL, 1.28 mmol) were added and stirred for 1 h at 0° C. The reaction mixture was poured into a stirred suspension of ice/H2O. The mixture was stirred occasionally until the ice melted. The aqueous solution was extracted with ether (3×). The combined organic extracts were washed with H2O (3×), a sat. aqueous solution of NaHCO3 (1×), and H2O (2×). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to yield compound E2 (R3=CH2CH2C6H5).


Method E, Step 2

A solution of lithium hexamethyldisilazide in hexane (1.0 M, 1.65 mL, 1.64 mmol) was added drop wise to a solution of E2 (R3=CH2CH2C6H5) (600 mg, 1.49 mmol) and HMPA (0.85 mL) in THF (6.5 mL) cooled at −78° C. under N2. After 15 min, isobutyl iodide (0.52 mL, 4.48 mmol) was added drop wise and the reaction mixture was stirred at −78° C. for 3 h. The reaction was warmed to −65° C., stirred for 2 h and warmed to rt overnight. The reaction solution was poured into a mixture of sat. NaHCO3 (aq)/ether/ice. The aqueous layer was extracted with ether (3×). The organic extracts were combined and washed with brine (2×). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to yield compound E3 (R3=CH2CH2C6H5, R4=CH2CH(CH3)2).


Method E, Step 3

A solution of lithium methoxide (1 N in CH3OH) (0.36 mL, 0.36 mmol) was added to compound E3 (R3=CH2CH2C6H5, R4=CH2CH(CH3)2). The reaction mixture was shaken at rt for 50 min. An additional 0.55 eq of lithium methoxide were added. After 2.5 h, a sat. aqueous solution of NaHSO3 (0.75 mL) and ethyl acetate (3 mL) was added to the reaction mixture and shaken for 15 min. The suspension was filtered. The resulting white solid was washed with a sat. aqueous solution of NaHSO3 (1×) and ethyl acetate (1×). The aqueous phase of the filtrate was separated and extracted with ethyl acetate (2×). The organic extracts were combined and washed with a sat. aqueous solution of NaHSO3 (8×). The organic solution was dried over Na2SO4, filtered and concentrated to afford E4 (R3=CH2CH2C6H5, R4=CH2CH(CH3)2) (109 mg, 87%).


Method E, Step 4

To a solution of E4 (R3=CH2CH2C6H5, R4=CH2CH(CH3)2) (109 mg, 0.28 mmol) in CH3OH (4 mL) was added 1 N HCl (0.28 mL, 0.28 mmol) and 20% palladium hydroxide on carbon (22 mg). The reaction mixture was hydrogenated at 40 psi. After 2.5 h, the reaction was filtered and the catalyst was washed with CH3OH (3×). The filtrate was concentrated to afford E5 (R3=CH2CH2C6H5, R4=CH2CH(CH3)2) (78 mg, 96%).


The following aminoesters were prepared using similar method.




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Method F



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A 500 mL methanol solution of 20 g of D5 (R3=benzyl, n=1) with 1.5 eq of HCl was hydrogenated with 1 g of Rh/C (5% w/w) and 2 g of Pt/C (5% w/w) at 60 psi for 2 days. The solid was filtered and washed with excessive methanol. The combined solution was evaporated to give 20 g of F1 (R3=cyclohexylmethyl, n=1) as HCl salt.


The following amino esters were examples prepared using similar method.




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Method G



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Method G, Step 1

To a solution of G1 (R1=CH2(3-ClC6H4) and R3=CH3) (400 mg, 1.23 mmol, generated following a procedure similar to Method C, Step 1) in ethanol (5 mL) was added lithium hydroxide monohydrate (100 mg, 2.45 mmol) in H2O (0.5 mL). After 2.5 h, another portion of lithium hydroxide monohydrate (100 mg, 2.45 mmol) was added. After 5.5 h, the reaction mixture was diluted with H2O (15 mL) and extracted with ether (2×). A solution of 30% HCl was added to the aqueous phase until its pH=1 to 2. The solution was saturated with NaCl and extracted with ethyl acetate (3×). The organic solution was dried over Na2SO4, filtered and concentrated to afford G2 (R1=CH2(3-ClC6H4) and R3=CH3) (357 mg, 93%).


Method G, Step 2

A solution of benzyl amine (1.2 eq) was added to G2 (R1=CH2(3-ClC6H4) and R3=CH3) (1 eq), HOBT (1.5 eq) and polystyrene EDC resin (94 mg, 1.53 mmol/g, 3 eq) in 1:1 THF:CH3CN (1 mL). The reaction mixture was shaken overnight at rt. Trisamine resin (85 mg, 3.38 mmol/g, 6 eq) and isocyanate resin (100 mg, 1.47 mmol/g, 3 eq) was added. After 6 h, the suspension was filtered and the filtrate was concentrated to afford G3 (R1=CH2(3-ClC6H4), R3=CH3, R15=CH2C6H5 and R16=H).


Method G, Step 3

Compound G4 (R1=CH2(3-ClC6H4), R2=H, R3=CH3, R15=CH2C6H5 and R15=H) was prepared from G3 (R1=CH2(3-ClC6H4), R3=CH3, R15=CH2C6H5 and R16=H) following a procedure similar to Method A, Step 3.


The following compounds were prepared using similar methods.


















Obs.


#
Structure
MW
m/e







669


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322
323





670


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334
335





671


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336
337





672


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348
349





673


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364
365





674


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364
365





675


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376
377





676


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384
385





677


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390
391





678


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393
394





679


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398
399





680


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398
399





681


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406
407





682


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412
413





683


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414
415





684


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414
415





685


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414
415





686


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421
422





687


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428
429





688


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434
435





689


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442
443





690


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449
450





691


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461
462





692


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511
512





693


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511
512









Method H



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Method H, Step 1

To a solution of H1 (R3=CH3) (5 g, 39 mmol) in a 1:1 mixture of 0.5 M NaHCO3:CH3CH2OH was added R1—NCS (R1=3-chlorobenzyl) (11.5 mL, 78 mmol). The reaction mixture was heated at 50° C. overnight. The reaction was cooled and diluted with water. The aqueous phase was extracted with ethyl acetate (5×). The organic extracts were combined, washed with water (2×) and dried over Na2SO4. The solution was filtered and solvent was removed to give a small volume of solution. Hexane was added and the resulting suspension was filtered to yield 6.8 g of a solid H2 (R3=CH3, R1=CH2(3-ClC6H4)) (61%).


Method H, Step 2

Compound H3 (R3=CH3, R1=CH2(3-ClC6H4)) was synthesized from H2 (R3=CH3, R1=CH2(3-ClC6H4)) following a procedure similar to Method A, Step 3.


Method H, Step 3

To a solution of crude H3 (R3=CH3, R1=CH2(3-ClC6H4)) (14 mmol) in a 1:3 mixture of CH3OH:THF was added 0.5 M NaHCO3 in H2O (28 mL, 14 mmol) and di-tert-butyl dicarbonate (3.69 g, 16.9 mmol). The reaction was stirred at rt for 2.5 h and then stored at −10° C. overnight. The reaction was diluted with brine and extracted with ethyl acetate (4×). The organic extracts were combined and washed with brine (1×). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to afford 1.5 g of H4 (R1=CH2(3-ClC6H4) and R3=CH3).


Method H, Step 4

A solution of triflic anhydride (128 μL, 0.76 mmol) in CH2Cl2 (5 mL) was added drop wise to a solution of H4 (R1=CH2(3-ClC6H4) and R3=CH3) (200 mg, 0.55 mmol) and 2,6-lutidine (176 μL, 2.18 mmol) at −30° C. The reaction mixture was stirred for 1.5 h. Water (10 mL) was added at −20° C. and the ice bath was removed. The reaction was stirred until it reached 0° C. The organic layer was separated, dried over Na2SO4, filtered and concentrated to afford 310 mg of H5 (R1=CH2(3-ClC6H4) and R3=CH3).


Method H, Step 5

A solution of crude H5 (R1=CH2(3-ClC6H4) and R3=CH3) (0.11 mmol) and 7N ammonia in Methanol (R21—H═NH2—H) (10 eq) was stirred overnight at rt. The reaction solution was concentrated. The crude material was purified using reverse phase preparative HPLC eluting with a CH3CN/H2O gradient with 0.1% formic acid to yield H6 (R1=CH2(3-ClC6H4), R3=CH3, R21=NH2).


Method H, Step 6

A solution of 50% trifluoroacetic acid in CH2Cl2 (2 mL) was added to H6 (R1=CH2(3-ClC6H4), R3=CH3, R21=NH2). After 40 min the solvent was evaporated and residue purified by preparative HPLC/LCMS eluting with a CH3CN/H2O gradient to afford H7 (R1=CH2(3-ClC6H4), R3=CH3, R21=NH2). NMR (CDCl3), δ 7.45, m, 3H, δ 7.35, m, 1H; δ 4.9, m, 2H; δ 3.5, m, 2H; δ 1.65, s, 3H. ES_LCMS (m/e) 267.07.


The following compounds were prepared using similar methods.


















Obs.


#
Structure
MW
m/e







694


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238
239





695


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248
249





696


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257
258





697


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264
265





698


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266
267





699


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292
293





700


embedded image


308
309





701


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314
315





702


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320
321





703


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328
329





704


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334
335





705


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342
343





706


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354
355





707


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372
373





708


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418
419





709


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483
484









Method I



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Method I, Step 1

Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of the formate salt of I1 (R1=CH2(3-ClC6H4), R3=CH3 and R16=H) in CH2Cl2 and the suspension was agitated. After 15 min, the mixture was filtered and the resin was washed with CH2Cl2 (4×). The filtrate was concentrated to afford the free base I1 (R1=CH2(3-ClC6H4), R3=CH3 and R16=H).


A solution of R15COOH(R15=Phenethyl) (1.3 eq) was added to a mixture of EDC resin (41 mg, 1.53 mmol/g, 3 eq), HOBT (1.5 eq), and the free base of I1 (R1=CH2(3-ClC6H4), R3=CH3 and R16=H) (0.021 mmol) in 1:1 CH3CN:THF. The suspension was agitated overnight. Polystyrene isocyanate resin (45 mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1 mixture of CH3CN:THF (0.5 mL) was added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was concentrated to afford I2 (R1=CH2(3-ClC6H4), R3=CH3, R16=H and R15=CH2CH2C6H5).


Method I, Step 2

I3 (R1=CH2(3-ClC6H4), R3=CH3, R16=H and R15=CH2CH2C6H5) was prepared from I2 (R1=CH2(3-ClC6H4), R3=CH3, R16=H and R15=CH2CH2C6H5) using method similar to method H step 6.


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e


















710


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280
281





711


embedded image


308
309





712


embedded image


308
309





713


embedded image


334
335





714


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342
343





715


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362
363





716


embedded image


372
373





717


embedded image


376
377





718


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398
399





719


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406
407





720


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410
11





721


embedded image


410
11





722


embedded image


414
15





723


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420
21





724


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428
29





725


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511
12









Method J



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Method J, Step 1

Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of J1 (TFA salt, R1=CH2(3-ClC6H4) and R3=CH3) in CH2Cl2 and the suspension was agitated. After 15 min, the mixture was filtered and the resin was washed with CH2Cl2 (4×). The filtrate was concentrated to afford the free base. A solution of R15NCO(R15=butyl) (2 eq) in CH2Cl2 was added to the free base of J1 (R1=CH2(3-ClC6H4) and R3=CH3) (0.021 mmol) in 1:1 CH3CN:THF. The suspension was agitated overnight. Polystyrene isocyanate resin (45 mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1 mixture of CH3CN:THF (0.5 mL) was added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was concentrated to afford J2 (R1=CH2(3-ClC6H4), R3=CH3, and R15=CH2CH2CH2CH3).


Method J, Step 2

Compound J3 (R1=CH2(3-ClC6H4), R3=CH3, and R15=CH2CH2CH2CH3) was prepared from J2 (R1=CH2(3-ClC6H4), R3=CH3, and R15=CH2CH2CH2CH3) following the procedure described in Method H, Step 2.


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e


















726


embedded image


323
324





727


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337
338





728


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1
352





729


embedded image



358





730


embedded image


365
366





731


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377
378





732


embedded image


413
414





733


embedded image


417
418





734


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421
422





735


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425
426









Method K



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Method K, Step 1

A solution of R15SO2Cl (R15=Propyl) (1.5 eq) was added to a suspension of polystyrene diisopropylethylamine resin (18 mg, 3.45 mmol/g, 3 eq) and the free base of K1 prepared using method H (R1=CH2(3-ClC6H4) and R3=CH3) (0.021 mmol) in 1:1 CH3CN:THF. The suspension was agitated overnight. Polystyrene isocyanate resin (45 mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1 mixture of CH3CN:THF (0.5 mL) was added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was concentrated to afford K2 (R1=CH2(3-ClC6H4), R3=CH3, and R15=CH2CH2CH3).


Method K, Step 2

Compound K3 (R1=CH2(3-ClC6H4), R3=CH3, and R15=CH2CH2CH3) was prepared from K2 (R1=CH2(3-ClC6H4), R3=CH3, and R15=CH2CH2CH3) following the procedure described in Method H, Step 6.


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e







736


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316
317





737


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344
345





738


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372
373





739


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378
379





740


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442
443





741


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454
455





742


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492
493









Method L



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(In the scheme, —Z—NH—C(O)R16— is equivalent to R1 substituted by R21, or R1 Substituted by alkyl-R22, wherein R21 and R22 are —N(R15)C(O)R16 and R15 is H, and wherein Z is optionally substituted alkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)


Method L, Step 1

A solution of L1 (R3=CH3 and R4=CH2CH(CH3)2) (1 eq) and Z=-para-methylene-benzyl) (1.05 eq) in CH2Cl2 was stirred at rt. The reaction solution was concentrated and purified via flash chromatography. The material was treated with 50% trifluoroacetic acid in CH2Cl2 for 30 min. The solution was concentrated. The residue was dissolved in 1 N HCl (10 mL) and washed with ether (2×). A saturated solution of Na2CO3 in H2O was added to the aqueous phase until the solution became basic. The solution was extracted with CH2Cl2 (3×). The CH2Cl2 extracts were combined, dried over Na2SO4, filtered and concentrated to yield L2 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—).


Method L, Step 2

Compound L3 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R16=CH2CH2CH2CH3) was prepared from L2 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—) following the procedure described in Method I, Step 1.


Method L, Step 3

Compound L4 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R1=CH2CH2CH2CH3) was prepared from (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R16=CH2CH2CH2CH3) following the procedure described in Method A, Step 3.


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e







743


embedded image


316
317





744


embedded image


316
317





745


embedded image


330
331





746


embedded image


330
331





747


embedded image


344
345





748


embedded image


344
345





749


embedded image


358
359





750


embedded image


358
359





751


embedded image


386
387





752


embedded image


386
387





753


embedded image


386
387





754


embedded image


400
401





755


embedded image


400
401





756


embedded image


420
421





757


embedded image


434
435





758


embedded image


434
435





759


embedded image


436
437





760


embedded image


436
437





761


embedded image


450
451





762


embedded image


450
451





763


embedded image


450
451





764


embedded image


450
451





765


embedded image


464
465





766


embedded image


464
465





767


embedded image


470
471





768


embedded image


478
479





769


embedded image


478
479





770


embedded image


484
485





771


embedded image


484
485





772


embedded image


492
493





773


embedded image


492
493





774


embedded image


519
520





775


embedded image


519
520





776


embedded image


533
534





777


embedded image


533
534









Method M



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(In the scheme, —Z—NH—C(O)—NHR15— is equivalent to R1 substituted by R21, or R1 Substituted by alkyl-R22, wherein R21 and R22 are —N(R16)—C(O)—NHR15 and R16 is H, and wherein Z is optionally substituted alkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)


Method M, Step 1

Compound M2 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R15=3,4-difluorophenyl) was prepared from M1 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—) following the procedure described in Method J, Step 1.


Method M, Step 2

Compound M3 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R15=3,4-difluorophenyl) was prepared from M2 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R15=3,4-difluorophenyl) following the procedure described in Method A, Step 3. NMR (CD3OD) δ 7.45, m, 1H; δ 7.26, m, 4H, 7.24, m, 1H; δ 6.96, m, 1H; δ 4.8, m; δ 4.3, s, 2H; δ 1.69, m, 2H; δ 1.44, m, 1H; δ 1.37, s, 3H; δ 0.8, m, 3H; δ 0.63, m, 3H. ES_LCMS (m/e) 430.27


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e







778


embedded image


331
332





779


embedded image


359
360





780


embedded image


359
360





781


embedded image


373
374





782


embedded image


373
374





783


embedded image


373
374





784


embedded image


373
374





785


embedded image


387
388





786


embedded image


387
388





787


embedded image


387
388





788


embedded image


387
388





789


embedded image


401
402





790


embedded image


401
402





791


embedded image


405
406





792


embedded image


407
408





793


embedded image


407
408





794


embedded image


407
408





795


embedded image


413
414





796


embedded image


413
414





797


embedded image


418
419





798


embedded image


418
419





799


embedded image


421
422





800


embedded image


421
422





801


embedded image


421
422





802


embedded image


421
422





803


embedded image


421
422





804


embedded image


421
422





805


embedded image


421
422





806


embedded image


421
422





807


embedded image


423
424





808


embedded image


423
424





809


embedded image


423
424





810


embedded image


423
424





811


embedded image


425
426





812


embedded image


425
426





813


embedded image


427
428





814


embedded image


429
430





815


embedded image


429
430





816


embedded image


429
430





817


embedded image


432
433





818


embedded image


432
433





819


embedded image


432
433





820


embedded image


433
434





821


embedded image


433
434





822


embedded image


435
436





823


embedded image


435
436





824


embedded image


435
436





825


embedded image


435
436





826


embedded image


435
436





827


embedded image


435
436





828


embedded image


435
436





829


embedded image


437
438





830


embedded image


437
438





831


embedded image


437
438





832


embedded image


437
438





833


embedded image


437
438





834


embedded image


437
438





835


embedded image


437
438





836


embedded image


439
440





837


embedded image


439
440





838


embedded image


439
440





839


embedded image


441
442





840


embedded image


441
442





841


embedded image


441
442





842


embedded image


441
442





843


embedded image


443
444





844


embedded image


443
444





845


embedded image


443
444





846


embedded image


447
448





847


embedded image


447
448





848


embedded image


449
450





849


embedded image


450
451





850


embedded image


450
451





851


embedded image


450
451





852


embedded image


451
452





853


embedded image


451
452





854


embedded image


451
452





855


embedded image


452
453





856


embedded image


453
454





857


embedded image


453
454





858


embedded image


455
456





859


embedded image


455
456





860


embedded image


455
456





861


embedded image


457
458





862


embedded image


457
458





863


embedded image


457
458





864


embedded image


458
459





865


embedded image


458
459





866


embedded image


460
461





867


embedded image


461
462





868


embedded image


461
462





869


embedded image


461
462





870


embedded image


461
462





871


embedded image


461
462





872


embedded image


461
462





873


embedded image


461
462





874


embedded image


463
464





875


embedded image


466
467





876


embedded image


466
467





877


embedded image


467
468





878


embedded image


469
470





879


embedded image


469
470





880


embedded image


471
472





881


embedded image


471
472





882


embedded image


472
473





883


embedded image


472
473





884


embedded image


475
476





885


embedded image


475
476





886


embedded image


475
476





887


embedded image


475
476





888


embedded image


475
476





889


embedded image


475
476





890


embedded image


475
476





891


embedded image


475
476





892


embedded image


475
476





893


embedded image


475
476





894


embedded image


475
476





895


embedded image


475
476





896


embedded image


477
478





897


embedded image


477
478





898


embedded image


479
480





899


embedded image


479
480





900


embedded image


480
481





901


embedded image


483
484





902


embedded image


483
484





903


embedded image


485
486





904


embedded image


485
486





905


embedded image


485
486





906


embedded image


485
486





907


embedded image


485
486





908


embedded image


489
490





909


embedded image


489
490





910


embedded image


489
490





911


embedded image


491
492





912


embedded image


493
494





913


embedded image


493
494





914


embedded image


493
494





915


embedded image


493
494





916


embedded image


496
497





917


embedded image


496
497





918


embedded image


497
498





919


embedded image


497
498





920


embedded image


499
500





921


embedded image


501
502





922


embedded image


501
502





923


embedded image


502
503





924


embedded image


502
503





925


embedded image


502
503





926


embedded image


502
503





927


embedded image


503
504





928


embedded image


505
506





929


embedded image


507
508





930


embedded image


507
508





931


embedded image


507
508





932


embedded image


509
510





933


embedded image


509
510





934


embedded image


509
510





935


embedded image


510
511





936


embedded image


511
512





937


embedded image


511
512





938


embedded image


514
515





939


embedded image


515
516





940


embedded image


515
516





941


embedded image


519
520





942


embedded image


519
520





943


embedded image


522
523





944


embedded image


523
524





945


embedded image


523
524





946


embedded image


525
526





947


embedded image


527
528





948


embedded image


529
530





949


embedded image


533
534





950


embedded image


537
538





951


embedded image


539
540





952


embedded image


543
544





953


embedded image


545
546





954


embedded image


545
546





955


embedded image


547
548





956


embedded image


549
550





957


embedded image


553
554





958


embedded image


555
556





959


embedded image


559
560





960


embedded image


559
560





961


embedded image


387









Method N



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(In the scheme, —Z—NH—S(O)2R16— is equivalent to R1 substituted by R21, or R1 Substituted by alkyl-R22, wherein R21 and R22 are —N(R16)—C(O)—NHR15 and R16 is H, and wherein Z is optionally substituted alkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)


Method N, Step 1

Compound N2 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R16=CH2CH(CH3)2) was prepared from N1 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—) following the procedure described in Method K, Step 1.


Method N, Step 2

Compound N3 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R16=CH2CH(CH3)2) was prepared from N2 (R3=CH3, R4=CH2CH(CH3)2, Z=para-(CH2)C6H4(CH2)—, R16=CH2CH(CH3)2) following the procedure described in Method A, Step 3.


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e







962


embedded image


380
381





963


embedded image


380
381





964


embedded image


394
395





965


embedded image


394
395





966


embedded image


451
452





967


embedded image


484
485





968


embedded image


484
485





969


embedded image


498
499





970


embedded image


498
499









Method O



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Method O, Step 1

A solution of indole-6-methanol (400 mg, 2.72 mmol), tert-butyldimethysilyl chloride (816 mg, 5.41 mmol) and imidazole (740 mg, 10.9 mmol) in CH2Cl2 was stirred at rt. overnight before the solvent was evaporated and residue chromatographed using ethylacetate/hexane to give product O2.


Method O, Step 2

To a solution of O2 (200 mg, 0.77 mmol) in THF (10 mL) at −78° C. was added butyl lithium (1.2 eq). The solution was stirred at −78° C. for 5 min and then warmed to rt. The reaction mixture was cooled to −78° C. and p-toluenesulfonyl chloride was added. The solution was warmed to rt and stirred overnight. The reaction was quenched with a saturated aqueous K2CO3 solution, extracted with ethyl acetate and CH2Cl2. The crude material was purified via flash chromatography using ethylacetate/hexane to afford 360 mg of O3.


Method O, Step 3

A solution butyl lithium (1.2 eq) was added to a solution of O3 (340 mg, 0.829 mmol) in THF (20 mL). The reaction mixture was stirred for 15 min at −78° C. then sulfur dioxide was bubbled through the solution for 15 min. Hexane (100 mL) was added to the reaction mixture. The reaction mixture was evaporated to afford O4 which was used in the next step without further purification.


Method O, Step 4

To a solution of O4 (0.829 mmol) in CH2Cl2 cooled to 0° C. was added N-chlorosuccinimide (220 mg, 1.66 mmol). After 2 h of stirring, the solution was filtered through a Celite plug. The filtrate was concentrated to afford O5.


Method O, Step 5

To a solution of O5 in anhydrous pyridine (3 mL) was added butyl amine (100 μL). The reaction was agitated at rt for 4 d. The reaction mixture was partitioned between 1 N HCl and CH2Cl2. The organic layer was separated and washed with 1 N HCl (3×). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography using ethylacetate/hexane to yield O6.


Method O, Step 6

To a solution of O6 (70 mg) in THF was added TBAF. The reaction was stirred at rt. before the reaction mixture was chromatographed using ethylacetate/hexane to afforded 50 mg of O7 (95%).


Method O, Step 7

To a solution of O7 (50 mg) in CH2Cl2 (5 mL) was added thionyl chloride (1 mL) the reaction was stirred for 5 min and then evaporated to afford O8.


Method O, Step 8

To a solution of O8 in CH3OH (5 mL) was added sodium azide (50 mg). The solution was stirred at rt overnight and solvent evaporated. The residue was chromatographed using ethylacetate/hexane to afforded O9 after purification.


Method O, Step 9

To a suspension of O9 (70 mg) in CH3OH was added 1 eq HCl (aq) and palladium on carbon. The reaction mixture was hydrogenated at 1 atm for 20 min to yield 90 mg of crude product O10.


Method O, Step 10

A solution of lithium hydroxide (30 mg) in H2O was added to a solution of O10 (40 mg) in CH3OH (3 mL). The reaction was stirred at rt for 2 h and an additional portion of LiOH (40 mg) was added and solution was stirred for 2 more hours. The solvent was evaporated and residue chromatographed using ethylacetate/hexane to afforded O11.


Method P



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Method P, Step 1

A 300 mL of THF solution of 100 g of P1 (R23=n-Pr) was added to a suspension of 38 g of LAH in 2 L of anhydrous THF at 0 C. The reaction mixture is stirred at r.t. for 1 h before 30 ml of H2O, 90 ml of 15% NaOH was added at 0° C. The mixture was stirred at r.t. for one hour before Na2SO4 (anh) was added, the mixture was filtered, and the solution evaporated to give a product which was dried under vacuo overnight. This product was dissolved in 600 ml of DCM and the solution was added into a solution of oxalyl chloride (37.3 ml) and DMSO (60.8 ml) in 1.4 L of DCM at −78° C. over 40 min before Diisopropylethylamine (299 ml) was added at −78° C. The reaction was allowed to reach −10° C. The reaction was quenched with 1 L H2O at −10° C. and the mixture was extracted with DCM. After removal of solvent, P2 (R23=Pr, 106 g) was obtained. The crude material was used for next step without purification.


Method P, Step 2

To a 1.5 L DCM solution of P2 (R23=Pr, 106 g) was added p-Boc-aminomethylbenzylamine (1.1 eq) and sodium triacetoxyborohydride (1.1 eq) and the reaction was stirred at r.t. overnight. The reaction was quenched with H2O and content extracted with DCM. After removal of solvents the residue was chromatographed using a silica gel column eluted with 3% MeOH in DCM to give 42.5 g of P3 (R23=Pr).


Method P, Step 3

A 10 ml MeOH solution of P3 (R23=Pr, 110 mg) was hydrogenated using Pd/C (5%, 11 mg) at 1 atm of hydrogen to give product P4 (R23=Pr) after removal of solvent and catalyst.


Method P, Step 4

To a 10 ml DCM solution of P4 at 0° C. (R23=Pr) was added triphosgene (1.2 eq) and triethylamine (2.4 eq) and the solution was stirred at 0 C for 2 h before the reaction was extracted with DCM/H2O. After removal of the solvent, the residue was chromatographed using a silica gel column eluted with EtOAc/Hexane to give a white solid which was treated with 2N HCl in dioxane for 2 h. After removal of the solvent, compound P5 (R23=Pr) as a white solid was obtained (80 mg).


The following compounds were synthesized using similar methods:




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Method Q



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Method Q, Step 1

At room temperature, Q1 (R3=Me; R4=iBu) (1.00 g) and Q8 (n=1, p=2, m=1) (1.24 g) in dichloromethane (30 mL) were stirred for 42 h. This mixture was concentrated in vacuo to give an amber oil which was purified on a column of silica gel (200 mL) eluted with ethylacetate/hexane to give Q2 (n=1, p=2, m=1, R3=Me; R4=iBu), a colorless oil (1.59 g).


Method Q, Step 2

Compound Q3 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu) was prepared from Q2 (n=1, p=2, m=1, R3=Me; R4=iBu) using method similar to method A step 3.


Method Q, Step 3

Compound Q3 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu) (1.37 g) in anhydrous dichloromethane (25 mL) was treated with di-tert-butyl dicarbonate (0.68 g, 1.1 equiv.) and diisopropylethylamine (0.66 mL, 1.1.equiv.). The resulting solution was stirred at room temperature for 20 h before it was diluted with dichloromethane and washed with 1N hydrochloric acid. The dried dichloromethane solution was concentrated in vacuo to give a colorless film (1.32 g) which was purified on a column of silica gel (125 mL) and eluted with hexane:ethyl acetate to give compound Q4 (n=1, p=2, m=1, R2=H, R3=Me; R4=i-Bu) as a white foam (0.74 g).


Method Q, Step 4

Compound Q4 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu) (0.540 g) in absolute EtOH (20 mL) was hydrogenated with 10% Pd/C (0.400 g) at 1 atm for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give Q5 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu) as a colorless oil (0.35 g).


Method Q, Step 5

Compound Q5 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu) (0.012 g) and HOBt (0.005 g) dissolved in acetonitrile (0.8 mL) and tetrahydrofuran (0.25 mL) was treated with EDC resin (0.080 g, 3 eq., 1.53 mmol/g) in a microtiter plate well followed by addition of a 1M dichloroethane solution of R15—COOH (40 uL, 1.25 eq.). After the well was capped and shaken for 18 h, the mixture was filtered and the resin washed with acetonitrile (0.5 mL). The combined solution was treated with Trisamine resin (0.050 g, 6 eq., 4.23 mmol/g) and Isocyanate resin (0.067 g, 3 eq., 1.53 mmol/g) for 18 h before the solution was filtered and the solvent was removed in vacuo to give Q6 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu, R15=Me).


Method Q, Step 6

A dichloromethane solution (1.0 mL) of Q6 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu, R16=Me) was mixed with trifluoroacetic acid (1.0 mL) and the solution was shaken for 2 h before it was concentrated. Diethyl ether (0.5 mL) was added and then concentrated in vacuo to give a residue, which was purified on a Prep LCMS unit to give Q7 (=1, p=2, m=1, R2=H, R3=Me; R4=iBu, R15=Me). NMR (CDCl3): δ 8.38, br, 2H; δ 4.56, m, 1H; δ 3.79, m, 1H; δ 3.57, m, 2H; δ 2.99, m, 1H, δ 2.48, m, 1H; δ 2.04, s, 3H, δ1.95, m, 1H; δ 1.5-1.8, m, 5H; δ 1.5, s, 3H, 1.25, m, 2H; δ 0.95, m, 3H; δ 0.85, m, 3H. ES_LCMS (m/e) 309.17.


The following compounds were prepared using similar methods:


















Obs.


#
Structure
MW
m/e


















971


embedded image


308
309





972


embedded image


308
309





973


embedded image


310
311





974


embedded image


322
323





975


embedded image


324
325





976


embedded image


334
335





977


embedded image


336
337





978


embedded image


348
349





979


embedded image


348
349





980


embedded image


0
351





981


embedded image


350
351





982


embedded image


350
351





983


embedded image


360
361





984


embedded image


360
361





985


embedded image


362
363





986


embedded image


362
363





987


embedded image


364
365





988


embedded image


364
365





989


embedded image


364
365





990


embedded image


370
371





991


embedded image


370
371





992


embedded image


376
377





993


embedded image


376
377





994


embedded image


376
377





995


embedded image


378
379





996


embedded image


378
379





997


embedded image


378
379





998


embedded image


378
379





999


embedded image


379
380





1000


embedded image


384
385





1001


embedded image


384
385





1002


embedded image


384
385





1003


embedded image


386
387





1004


embedded image


388
389





1005


embedded image


389
390





1006


embedded image


390
391





1007


embedded image


390
391





1008


embedded image


390
391





1009


embedded image


390
391





1010


embedded image


390
391





1011


embedded image


390
391





1012


embedded image


390
391





1013


embedded image


390
391





1014


embedded image


390
391





1015


embedded image


392
393





1016


embedded image


392
393





1017


embedded image


392
393





1018


embedded image


394
395





1019


embedded image


398
399





1020


embedded image


398
399





1021


embedded image


398
399





1022


embedded image


398
399





1023


embedded image


398
399





1024


embedded image


400
401





1025


embedded image


400
401





1026


embedded image


400
401





1027


embedded image


400
401





1028


embedded image


400
401





1029


embedded image


400
401





1030


embedded image


400
401





1031


embedded image


400
401





1032


embedded image


402
403





1033


embedded image


402
403





1034


embedded image


404
405





1035


embedded image


404
405





1036


embedded image


404
405





1037


embedded image


404
405





1038


embedded image


404
405





1039


embedded image


404
405





1040


embedded image


404
405





1041


embedded image


404
405





1042


embedded image


409
410





1043


embedded image


410
411





1044


embedded image


0
411





1045


embedded image


410
411





1046


embedded image


412
413





1047


embedded image


412
413





1048


embedded image


412
413





1049


embedded image


414
415





1050


embedded image


414
415





1051


embedded image


414
415





1052


embedded image


414
415





1053


embedded image


414
415





1054


embedded image


414
415





1055


embedded image


414
415





1056


embedded image


416
417





1057


embedded image


416
417





1058


embedded image


417
418





1059


embedded image


418
419





1060


embedded image


418
419





1061


embedded image


418
419





1062


embedded image


418
419





1063


embedded image


418
419





1064


embedded image


420
421





1065


embedded image


423
424





1066


embedded image


424
425





1067


embedded image


424
425





1068


embedded image


426
427





1069


embedded image


426
427





1070


embedded image


426
427





1071


embedded image


426
427





1072


embedded image


426
427





1073


embedded image


427
428





1074


embedded image


428
429





1075


embedded image


428
429





1076


embedded image


428
429





1077


embedded image


428
429





1078


embedded image


428
429





1079


embedded image


430
431





1080


embedded image


430
431





1081


embedded image


430
431





1082


embedded image


432
433





1083


embedded image


432
433





1084


embedded image


432
433





1085


embedded image


432
433





1086


embedded image


432
433





1087


embedded image


432
433





1088


embedded image


438
439





1089


embedded image


438
439





1090


embedded image


438
439





1091


embedded image


438
439





1092


embedded image


438
439





1093


embedded image


440
441





1094


embedded image


440
441





1095


embedded image


440
441





1096


embedded image


440
441





1097


embedded image


442
443





1098


embedded image


442
443





1099


embedded image


442
443





1100


embedded image


442
443





1101


embedded image


442
443





1102


embedded image


444
445





1103


embedded image


444
445





1104


embedded image


444
445





1105


embedded image


446
447





1106


embedded image


446
447





1107


embedded image


446
447





1108


embedded image


449
450





1109


embedded image


451
452





1110


embedded image


452
453





1111


embedded image


452
453





1112


embedded image


452
453





1113


embedded image


456
457





1114


embedded image


456
457





1115


embedded image


456
457





1116


embedded image


458
459





1117


embedded image


460
461





1118


embedded image


460
461





1119


embedded image


460
461





1120


embedded image


460
461





1121


embedded image


462
463





1122


embedded image


462
463





1123


embedded image


462
463





1124


embedded image


462
463





1125


embedded image


462
463





1126


embedded image


464
465





1127


embedded image


466
467





1128


embedded image


466
467





1129


embedded image


470
471





1130


embedded image


472
473





1131


embedded image


474
475





1132


embedded image


474
475





1133


embedded image


476
477





1134


embedded image


476
477





1135


embedded image


478
479





1136


embedded image


482
483





1137


embedded image


482
483





1138


embedded image


482
483





1139


embedded image


488
489





1140


embedded image


490
491





1141


embedded image


500
501





1142


embedded image


502
503





1143


embedded image


502
503





1144


embedded image


504
505





1145


embedded image


504
505





1146


embedded image


504
505





1147


embedded image


511
512





1148


embedded image


512
513





1149


embedded image


512
513





1150


embedded image


520
521





1151


embedded image


520
521





1152


embedded image


520
521





1153


embedded image


520
521





1154


embedded image


522
523





1155


embedded image


522
523





1156


embedded image


536
537





1157


embedded image


536
537





1158


embedded image


536
537





1159


embedded image


538
539





1160


embedded image


538
539





1161


embedded image


540
541





1162


embedded image


541
542





1163


embedded image


542
543





1164


embedded image


546
547





1165


embedded image


546
547





1166


embedded image


550
551





1167


embedded image


550
551





1168


embedded image


569
570





1169


embedded image


582
583





1170


embedded image


582
583





1171


embedded image


584
585





1172


embedded image


584
585





1173


embedded image


594
595





1174


embedded image


596
597





1175


embedded image


596
597









Method R



embedded image


Method R, Step 1

A solution of R1 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu) (0.010 g) in acetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into a microtiter plate well followed by addition of 0.12 ml of 0.5M phenylisocyanate solution in dichloroethane. The well was sealed and the plate shaken for 20 h before the mixture was filtered and the solid washed with acetonitrile (0.5 ml). The combined solution was treated with Trisamine resin (0.050 g, 6 eq., 4.23 mmol/g) and Isocyanate resin (0.067 g, 3 eq., 1.53 mmol/g) and the mixture was shaken for 18 h. The mixture was filtered and the solution was evaporated to give R2 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu and R15=Ph).


Method R, Step 2

Procedure similar to Method Q, step 6 was used for the transformation of R2 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu and R15=Ph) to R3 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu and R15=Ph).


The following compounds were prepared using similar methods:


















Obs.


#
Structure
MW
m/e







1176


embedded image


309
310





1177


embedded image


309
310





1178


embedded image


311
312





1179


embedded image


325
326





1180


embedded image


337
338





1181


embedded image


346
347





1182


embedded image


351
352





1183


embedded image


351
352





1184


embedded image


351
352





1185


embedded image


365
366





1186


embedded image


365
366





1187


embedded image


365
366





1188


embedded image


367
368





1189


embedded image


377
378





1190


embedded image


381
382





1191


embedded image


385
386





1192


embedded image


391
392





1193


embedded image


393
394





1194


embedded image


395
396





1195


embedded image


399
400





1196


embedded image


399
400





1197


embedded image


399
400





1198


embedded image


399
400





1199


embedded image


399
400





1200


embedded image


401
402





1201


embedded image


403
404





1202


embedded image


403
404





1203


embedded image


407
408





1204


embedded image


407
408





1205


embedded image


410
411





1206


embedded image


410
411





1207


embedded image


413
414





1208


embedded image


413
414





1209


embedded image


415
416





1210


embedded image


415
416





1211


embedded image


415
416





1212


embedded image


415
416





1213


embedded image


417
418





1214


embedded image


419
420





1215


embedded image


419
420





1216


embedded image


419
420





1217


embedded image


421
422





1218


embedded image


421
422





1219


embedded image


425
426





1220


embedded image


427
428





1221


embedded image


427
428





1222


embedded image


429
430





1223


embedded image


429
430





1224


embedded image


431
432





1225


embedded image


431
432





1226


embedded image


433
434





1227


embedded image


435
436





1228


embedded image


441
442





1229


embedded image


441
442





1230


embedded image


441
442





1231


embedded image


445
446





1232


embedded image


449
450





1233


embedded image


453
454





1234


embedded image


453
454





1235


embedded image


453
454





1236


embedded image


453
454





1237


embedded image


453
454





1238


embedded image


455
456





1239


embedded image


455
456





1240


embedded image


457
458





1241


embedded image


461
462





1242


embedded image


463
464





1243


embedded image


467
468





1244


embedded image


467
468





1245


embedded image


471
472





1246


embedded image


475
476





1247


embedded image


477
478





1248


embedded image


477
478





1249


embedded image


487
488





1250


embedded image


487
488





1251


embedded image


487
488





1252


embedded image


491
492









Method S



embedded image


Method S, Step 1

A solution of S1 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu) (0.010 g) in acetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into a microtiter plate followed by addition of DIPEA-MP resin (0.030 g, 4 eq) and phenylsulfonyl chloride in dioxane (1M, 45 μL, 0.045 mmol. The well was capped and shaken for 18 h before it was filtered and residue washed with acetonitrile (0.5 mL). The combined solution was treated with Trisamine resin (0.040 g, 6 eq., 4.23 mmol/g) and Isocyanate resin (0.060 g, 3 equiv., 1.53 mmol/g) and shaken for 18 h before the mixture was filtered and the solvent removed to give S2 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu and R15=Ph).


Method S, Step 2

Procedure similar to Method Q, step 6 was used for the transformation of S2 to S3 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu and R15=Ph).


The following compounds were prepared using similar methods:


















Obs.


#
Structure
MW
m/e







1253


embedded image


344
345





1254


embedded image


344
345





1255


embedded image


358
359





1256


embedded image


358
359





1257


embedded image


360
361





1258


embedded image


372
373





1259


embedded image


372
373





1260


embedded image


386
387





1261


embedded image


406
407





1262


embedded image


406
407





1263


embedded image


406
407





1264


embedded image


412
413





1265


embedded image


416
417





1266


embedded image


420
421





1267


embedded image


420
421





1268


embedded image


420
421





1269


embedded image


420
421





1270


embedded image


420
421





1271


embedded image


420
421





1272


embedded image


424
425





1273


embedded image


424
425





1274


embedded image


424
425





1275


embedded image


431
432





1276


embedded image


432
433





1277


embedded image


434
435





1278


embedded image


434
435





1279


embedded image


436
437





1280


embedded image


436
437





1281


embedded image


438
439





1282


embedded image


440
441





1283


embedded image


440
441





1284


embedded image


440
441





1285


embedded image


442
443





1286


embedded image


442
443





1287


embedded image


442
443





1288


embedded image


442
443





1289


embedded image


442
443





1290


embedded image


446
447





1291


embedded image


448
449





1292


embedded image


448
449





1293


embedded image


448
449





1294


embedded image


454
455





1295


embedded image


456
457





1296


embedded image


456
457





1297


embedded image


458
459





1298


embedded image


458
459





1299


embedded image


458
459





1300


embedded image


462
463





1301


embedded image


464
465





1302


embedded image


466
467





1303


embedded image


466
467





1304


embedded image


466
467





1305


embedded image


466
467





1306


embedded image


470
471





1307


embedded image


474
475





1308


embedded image


474
475





1309


embedded image


474
475





1310


embedded image


474
475





1311


embedded image


474
475





1312


embedded image


474
475





1313


embedded image


474
475





1314


embedded image


474
475





1315


embedded image


474
475





1316


embedded image


474
475





1317


embedded image


476
477





1318


embedded image


480
481





1319


embedded image


482
483





1320


embedded image


484
485





1321


embedded image


484
485





1322


embedded image


488
489





1323


embedded image


490
491





1324


embedded image


490
491





1325


embedded image


492
493





1326


embedded image


498
499





1327


embedded image


508
509





1328


embedded image


508
509





1329


embedded image


508
509





1330


embedded image


508
509





1331


embedded image


542
543





1332


embedded image


557
558









Method T



embedded image


Method T, Step 1

To a microtiter plate well containing 1 ml solution of T1 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu) in DCM (0.010 g) and R15C(O)R16 (5 equiv, R15=H, R16=Ph) was added Sodium cyanoborohydride in dichloroethane (14.3 mg/mL, 2 equiv.). The well was capped and shaken for 20 h before MP-TsOH Resin (100 mg, 1.29 mmol/g) was added to the well followed by additional MP-TsOH resin (50 mg) after 2 h. After the mixture was shaken for another 1 h, the mixture was filtered and the resin washed with dichloroethane (1 mL) (3×), then MeOH (1 mL) (2×). The resin was treated with 7N ammonia in MeOH (1 mL) for 30 min (2×) followed by filtration and evaporation of solvent to give T2 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu and R15=Ph and R16=H).


Method T, Step 2

Procedure similar to Method Q, step 6 was used for the transformation of T2 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu and R15=Ph and R16=H) to T3 (n=1, p=2, m=1, R2=H, R3=Me; R4=iBu and R15=Ph and R16=H).


The following compounds were prepared using similar methods:















#
Structure
MW
Obs. m/e







1333


embedded image


348
348





1334


embedded image


350
351





1335


embedded image


350
351





1336


embedded image


356
357





1337


embedded image


362
363





1338


embedded image


370
371





1339


embedded image


384
385





1340


embedded image


384
385





1341


embedded image


400
401





1342


embedded image


446
447





1343


embedded image


448
449









Method U



embedded image



Alternatively, similar synthetic method can be used for the generation of other types of compounds. i.e.




embedded image


In a microwave vial was charged U1 (R2=H; R3=i-Bu, R4=Me) (0.025 g) in toluene (4 mL), potassium carbonate (0.035 g), Pd(dppf)Cl2 (0.020 g). water (0.02 mL) and R21B(OH)2 (R21=m-Methoxyphenyl) (3 eq.) were placed. The vial was placed in a microwave for 10 min. at 150° C. The reaction mixture was diluted with dichloromethane and extracted with 2.5N NaOH. The dried (MgSO4) dichloromethane solution was concentrated in vacuo to give a brown residue which was purified via a RP Prep LCMS system to give product U2 (R2=H; R3=iBu: R4=Me; R21=m-methoxyphenyl).


The following compounds were prepared using similar methods:


















Obs.


#
Structure
MW
m/e







1344


embedded image


279
280





1345


embedded image


285
286





1346


embedded image


293
294





1347


embedded image


299
300





1348


embedded image


299
300





1349


embedded image


304
305





1350


embedded image


309
310





1351


embedded image


313
314





1352


embedded image


318
319





1353


embedded image


323
324





1354


embedded image


323
324





1355


embedded image


323
324





1356


embedded image


329
330





1357


embedded image


335
336





1358


embedded image


335
336





1359


embedded image


337
338





1360


embedded image


343
344





1361


embedded image


347
348





1362


embedded image


347
348





1363


embedded image


347
348





1364


embedded image


347
348





1365


embedded image


347
348





1366


embedded image


349
350





1367


embedded image


349
350





1368


embedded image


350
351





1369


embedded image


351
352





1370


embedded image


352
353





1371


embedded image


357
358





1372


embedded image


359
360





1373


embedded image


360
361





1374


embedded image


360
361





1375


embedded image


360
361





1376


embedded image


360
361





1377


embedded image


360
361





1378


embedded image


360
361





1379


embedded image


365
366





1380


embedded image


365
366





1381


embedded image


365
366





1382


embedded image


365
366





1383


embedded image


366
367





1384


embedded image


371
372





1385


embedded image


371
372





1386


embedded image


371
372





1387


embedded image


372
373





1388


embedded image


372
373





1389


embedded image


375
376





1390


embedded image


377
378





1391


embedded image


377
378





1392


embedded image


377
378





1393


embedded image


377
378





1394


embedded image


379
380





1395


embedded image


379
380





1396


embedded image


380
381





1397


embedded image


381
382





1398


embedded image


383
384





1399


embedded image


384
385





1400


embedded image


385
386





1401


embedded image


385
386





1402


embedded image


386
387





1403


embedded image


387
388





1404


embedded image


389
390





1405


embedded image


389
390





1406


embedded image


392
393





1407


embedded image


395
396





1408


embedded image


403
404





1409


embedded image


403
404





1410


embedded image


405
406





1411


embedded image


406
407





1412


embedded image


413
414





1413


embedded image


419
420





1414


embedded image


497
498





1415


embedded image


398
TBD





1416


embedded image


399
TBD









Method V



embedded image


Method V, Step 1

Compound V1 (R3=R4=Me) (14.76 mmole), EDCI (14.76 mmole), HOAt (14.76 mmole), and DIEA (14.76 mmole) were mixed with 36 ml DCM. This mixture was stirred at RT for 15 min before 3-chlorobenzylamine was added. After the reaction solution was stirred at RT overnight, it was washed with sodium carbonate (3×), water, 1N HCl (4×), and aq sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified on flash column to give the amide product V2 (R1=3-chlorobenzyl; R3=R4=Me).


Method V, Step 2

Compound V2 (R1=3-chlorobenzyl; R3=R4=Me) (8.33 mmole) was dissolved in 35 ml anhydrous DCM, and cooled to 0-5° C. Thiophosgene (9.16 mmole) in 10 ml DCM was added dropwise under N2 followed by addition of DIEA (11.96 mmole). The solution was stirred in ice bath for 0.5 h before the reaction mixture was washed with saturated sodium bicarbonate (3×), brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and residue purified on flash column using ethylacetate/hexane to give the thiohydantoin V3 (R1=3-chlorobenzyl; R3=R4=Me).


Method V, Step 3

The thiohydantoin V3 (R1=3-chlorobenzyl; R3=R4=Me) was treated with t-butyl hydroperoxide and ammonium hydroxide in MeOH at RT for 48 h to give compound V4 (R1=3-chlorobenzyl; R2=H; R3=R4=Me).


The following compounds were prepared using similar method.





















Obs.



#
Structure
MW
m/e









1417


embedded image


251
252







1418


embedded image


265
266







1419


embedded image


293
294







1420


embedded image


307
308







1421


embedded image


357
358







1422


embedded image


371
372










Method W



embedded image


Compound W1 obtained using method A (n=1, R2=m-Cl—Bn, R3=Me) was hydrolyzed to W2 (n=1, R2=m-Cl—Bn, R3=Me) using two equivalent of LiOH in MeOH.


The following compounds were synthesized in similar fashion:















#
Structure
MW
Obs. m/e







1423


embedded image


295
296





1424


embedded image


311
312





1425


embedded image


325
326





1426


embedded image


411
412





1427


embedded image


425
426









Method X



embedded image


(In the scheme, —Z—NH—C(O)—N(R16)(R17)— is equivalent to R1 substituted by R21, or R1 Substituted by alkyl-R22, wherein R21 and R22 are —NH—C(O)—N(R16)(R17) and R15 is H, and wherein Z is optionally substituted alkylene-)arylene, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)


Method X, Step 1

To a mixture of the amine X1 obtained using method L (R3=Me; R4=i-Bu; Z=para-(CH2)C6H4(CH2)—) (10 mg) in DCM and sat. NaHCO3 (1:1 by volume) was added triphosgene (0.33 eq) at r.t. The solution was stirred vigorously for 40 minutes before the organic layer was separated and dried over anhydrous Na2SO4. The organic solution was evaporated to give compound X2 (R3=Me; R4=i-Bu; Z=para-(CH2)C6H4(CH2)—).


Method X, Step 2

Compound X3 (R15=H; R16=cyclopropylmethyl; R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—) was prepared from X2 (R3=Me; R4=i-Bu; Z=para-(CH2)C6H4(CH2)—) using method similar to method M, step 1.


Method X, Step 3

Compound X4 (R16=H; R17=cyclopropylmethyl; R2=H; R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—) was prepared from X3 (R16=H; R17=cyclopropylmethyl; R2=H; R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—) using method similar to method A Step 3. NMR (CD3OD): δ 7.25, s, 4H; δ 4.8, m, 2H; δ 4.25, s, 2H; δ 2.9, m, 2H; δ 1.68, m, 2H; δ 1.44, m, 1H; δ 1.36, s, 3H; δ 0.9, m, 1H; δ 0.82, m, 3H; δ 0.66, m, 3H; δ 0.4, m, 2H; δ 0.12, m, 2H. ES_LCMS (m/e) 386.1.


The following compounds were prepared using a similar method.


















Obs.


#
Structure
MW
m/e







1428


embedded image


385
386





1429


embedded image


401
402





1430


embedded image


401
402





1431


embedded image


415
416





1432


embedded image


427
428





1433


embedded image


435
436





1434


embedded image


435
436





1435


embedded image


443
444





1436


embedded image


449
450





1437


embedded image


463
464





1438


embedded image


471
472





1439


embedded image


485
486





1440


embedded image


496
497





1441


embedded image


504
505





1442


embedded image


513
514





1443


embedded image


518
519





1444


embedded image


518
519





1445


embedded image


524
525





1446


embedded image


524
525





1447


embedded image


526
527





1448


embedded image


532
533





1449


embedded image


533
534





1450


embedded image


537
538





1451


embedded image


537
538





1452


embedded image


545
546





1453


embedded image


559
560





1454


embedded image


570
571





1455


embedded image


572
573





1456


embedded image


598
599









Method Y



embedded image


(In the scheme,




embedded image



is equivalent to R1 substituted by R21, or R1Substituted by alkyl-R22, wherein R21 and R22 are —N(R15)—C(O)—N(R16)(R17) and R15 and R16 form a ring as defined above, and wherein Z is optionally substituted alkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)


Method Y, Step 1

The reaction mixture of compound Y1 obtained from Method L (R3=Me; R4=i-Bu; Z=para-(CH2)C6H4(CH2)—) (0.1639 mmole), Y2 (R23=H; R23=Pr) (0.1967 mmole), PS-EDC resin (0.4917 mmole) and HOBT (0.2459 mmole) in 3.5 ml of mixture of THF, MeCN and DMF (1:1:0.3) was shaken overnight at RT before 6 eq of PS-trisamine resin 3 eq of PS-isocyanate resin were added. After 6 hrs the reaction mixture was filtered and the resin was washed with THF, DCM and MeOH. The combined filtrate was evaporated and the crude was treated with 40% TFA in DCM for 40 min before the solvent was evaporated and residue purified on RP HPLC system to give product Y3 (R3=Me; R4=i-Bu; Z=para-(CH2)C6H4(CH2)—, R23=H; R23=Pr).


Method Y, Step 2

The reaction solution of Y3 (R3=Me; R4=i-Bu; Z=para-(CH2)C6H4(CH2)—, R23=H; R23=Pr) (0.030 mmole), carbonyl diimidazole (0.032 mmole), and DIEA (0.09 mmole) in 0.5 ml DCM was shaken overweekend at RT. The crude was then purified on reverse column to give the thiohydantoin product which was converted into Y4 (R2=H; R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—, R23=H; R23=Pr).


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e







1457


embedded image


413
414





1458


embedded image


413
414





1459


embedded image


427
428









Method Z



embedded image


(In the scheme, —Z—NH—C(O)—N(R16)(R17)— is equivalent to R1 substituted by R21, or R1 Substituted by alkyl-R22, wherein R21 and R22 are —N(R15)—C(O)—N(R16)(R17) and R15 is H, and wherein Z is optionally substituted alkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene; alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene)


Method Z, Step 1

To the solution of the Phoxime™ resin (1.23 mmol/g) in DCM was added the amine Z1 obtained from method L (R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—) (2 eq). The mixture was shaken overnight before the resin was filtered and washed with DCM, MeOH, THF (3 cycles), then DCM (×2), dried in vacuum to get resin Z2 (R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—).


Method Z, Step 2

To the resin Z2 (R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—), swelled in DCM, in toluene was added N-methylbenzylamine (4 eq). The mixture was heated at 80-90° C. overnight before MP-TSOH resin (1.3 mmol/g, 12 eq) was added. The mixture was shaken for 1.5 hours, the solution was filtered and the resin washed with DCM and MeOH. The combined organic solution was concentrated in vacuo to get Z3 (R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—; R16=Me; R17=Bn).


Method Z, Step 3

Compound Z4 (R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—; R16=Me; R17=Bn) was generated from Z3 (R3=Me; R4=iBu; Z=para-(CH2)C6H4(CH2)—; R16=Me; R17=Bn) using method similar to Method A step 3.


The following compounds were prepared using similar method.


















Obs.


#
Structure
MW
m/e







1460


embedded image


457
458





1461


embedded image


469
470





1462


embedded image


471
472





1463


embedded image


471
472





1464


embedded image


483
484





1465


embedded image


485
486





1466


embedded image


485
486





1467


embedded image


495
496





1468


embedded image


499
500





1469


embedded image


501
502





1470


embedded image


507
508





1471


embedded image


509
510





1472


embedded image


517
518





1473


embedded image


517
518





1474


embedded image


531
532





1475


embedded image


533
534





1476


embedded image


533
534





1477


embedded image


538
539





1478


embedded image


545
546





1479


embedded image


547
548





1480


embedded image


547
548





1481


embedded image


547
548





1482


embedded image


551
552





1483


embedded image


568
569





1484


embedded image


571
572





1485


embedded image


593
594





1486


embedded image


596
597





1487


embedded image


607
608





1488


embedded image


364
365





1489


embedded image


377
377





1490


embedded image


513
514









Method AA



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8,11-Dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (AA2) (18 mg) was reacted with AA1, obtained from method Q, and diisopropylethylamine (14 uL) in acetonitrile (2.5 mL). The resulting mixture was heated at 65° C. for 18 h. The reaction mixture was placed on a preparative silica gel plate and eluted with hexane:ethyl acetate 3:1 to give the desired product which was treated with 40% TFA. Evaporation of the solvent followed by purification afforded compound AA3.


The following compounds were prepared by similar methods:


















Obs.


#
Structure
MW
m/e







187


embedded image


491
492





188


embedded image


493
494









Method AB



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Method AB, Step 1

To a solution of (R)-(+)-2-methyl-2-propane sulfinamide (1.0 g, 8.3 mmol, 1 eq) and AB1 (R6=Ph, R7=n-Bu) (3 mL, 9.1 mmol, 1.1 eq) in anhydrous THF (30 mL) at room temperature was added Ti(OEt)4 (7 mL, 17 mmol, 2 eq). The mixture was heated at 70° C. for 24 h. After cooling to room temperature, the mixture was poured into 30 mL of brine under vigorous stirring. The resulting suspension was filtered through a pad of Celite and the solid was washed with EtOAc (2×20 mL). The filtrate was washed with brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica by eluting with hexane/Et2O (5:1) to give 1.9 g (85%) of (R)-2-methyl-N-(1-phenylpentylidene)propane-2-sulfinamide. 1HNMR (CDCl3, 300 MHz): δ 7.91 (m, 2H), 7.52-7.37 (m, 3H), 3.27 (m, 1H), 3.15 (m, 1H), 1.73-1.61 (m, 2H), 1.47-1.38 (m, 2H), 1.31 (s, 9H), 0.95 (m, 3H). MS(ESI): MH+=265.9. HPLC tR=7.24, 7.58 min (E/Z=5.5:1).


To a solution of methyl acetate (0.6 mL, 6.9 mmol, 2 eq) in THF (5 mL), LDA (2M in heptane/THF, 3.4 mL, 6.9 mmol, 2 eq) was added dropwise via a syringe at −78° C. After stirring at −78° C. for 30 min, a solution of ClTi(Oi-Pr)3 (1.8 mL, 7.6 mmol, 2.2 eq) in THF (5 mL) was added dropwise. After stirring for another 30 min, a solution of (R)-2-methyl-N-(1-phenylpentylidene)propane-2-sulfinamide (0.9 g, 3.4 mmol, 1 eq) in THF (2 mL) was added dropwise via a syringe. The mixture was stirred at −78° C. for 3 h and TLC showed no starting material left. A saturated aqueous solution of NH4Cl (10 eq) was added and the suspension was warmed to room temperature. The mixture was diluted with H2O (50 mL) and stirred for 10 min. The mixture was then partitioned between H2O (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give 1.1 g of a brown oil. Chromatography on silica gel using 50% EtOAc/hexanes as eluent gave 0.8 g (76%) of methyl 3-((R)-2-methylpropan-2-ylsulfinamido)-3-phenylheptanoate as a yellow oil. 1HNMR (CDCl3, 300 MHz): custom character 7.15-7.07 (m, 5H), 3.35 (s, 1H), 3.19 (dd, J=16, 5.6 Hz, 1H), 3.01 (dd, J=15.8, 5.5 Hz, 1H), 2.07 (m, 2H), 1.71 (m, 2H), 1.35-1.26 (m, 4H), 1.17 (s, 9H), 0.89 (m, 3H). MS(ESI): MH+=339.9. HPLC tR=7.50, 7.6 min (E/Z=1.5:1)


To a solution of methyl 3-((R)-2-methylpropan-2-ylsulfinamido)-3-phenylheptanoate (0.4 g, 1.1 mmol) in 12 mL of MeOH was added 16 mL of 4N HCl/dioxane. After stirring for 30 min, the volatiles were removed in vacuo. The residue was re-dissolved in MeOH (6 mL), stirred for 5 min, and evaporated again to afford 0.30 g (97%) of AB2 (R6=Ph, R7=n-Bu) as a yellow solid. 1HNMR (CDCl3, 300 MHz): custom character 9.01 (br s, 2H), 7.37-7.12 (m, 5H), 3.64 (m, 1H), 3.54 (s, 3H), 3.31 (m, 1H), 2.09 (m, 2H), 1.8 (m, 2H), 1.1 (m, 4H), 1.07 (s, 9H), 0.7 (m, 3H). MS (ESI): MH+=235.9. HPLC tR=4.72 min.


Method AB, Step 2

Treatment of compound AB2 (R6=Ph, R7=n-butyl) with thiophosgene in CH2Cl2 in the presence of aqueous NaHCO3 at 0° C. generates isothiocyanate AB3 (R6=Ph, R7=n-butyl) which was converted into final product using method similar to Method A Step 2 and Method A Step 3 to give product AB5 (R6=Ph, R7=n-butyl, R1=Me). 1HNMR (CDCl3, 300 MHz): δ 10.4 (br s, 1H), 7.25-7.11 (m, 5H), 3.23 (dd, J=16, 5.6 Hz, 1H), 3.03 (s, 3H), 2.8 (dd, J=15.8, 5.5 Hz, 1H), 2.49 (s, 1H), 1.78 (m, 2H), 1.1-1.0 (m, 4H), 0.99 (m, 3H). MS(ESI): MH+=260.2. HPLC tR=5.09 min.


The following compounds were synthesized using similar methods:


















Obs.


#
Structure
MW
m/e







189


embedded image


239
240





190


embedded image


253
254





191


embedded image


259
260





192


embedded image


333
334





193


embedded image


333
334





194


embedded image


349
350





195


embedded image


443
444





196


embedded image


463
464





197


embedded image


537
538





198


embedded image


537
538





199


embedded image


295
296





200


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295
296









Method AC



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The synthesis was adapted from a procedure by Hull, R. et al, J. Chem. Soc. 1963, 6028-6033. Thus, to a solution of AC2 (R1=Benzyl) (0.72 g, 5.9 mmol) in AC1 (R4=Me, R3=Me) (1.4 mL) was added a 50% aqueous solution of cyanamide (0.31 mL, 8.0 mmol). The reaction was heated with stirring at reflux (˜40° C.) for 0.5 h, then cooled to 25° C. and stirred for an additional 16 h. The volatiles were removed in vacuo and the residue was partitioned between ether and H2O. The organic layer was dried over Na2SO4, filtered and the volatiles were removed in vacuo. The residue was purified by column chromatography using 5-10% CH3OH/CH2Cl2 as eluent followed by reverse phase preparative HPLC to give 0.15 g (8.0%) of AC3 (R1=benzyl, R4=Me and R3=Me) as a white solid. 1H NMR (CH3OH, 300 MHz): δ 7.35-7.33 (m, 5H), 4.71 (s, 2H), 1.46 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 157.8, 135.6, 129.1, 128.5, 127.9, 104.2, 59.6, 28.8. MS (ESI) m/e 206.1 (M+H)+.


















#
Structure
MW
Obs. m/e









201


embedded image


205
206










Method AD



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Method AD, Step 1

AD2 (R3=Ph, R4=tButyl) was prepared from AD1 using method similar to Method AB, step 2.


Method AD, Step 2

The synthesis was adapted from a procedure by Hussein, A. Q. et al, Chem. Ber. 1979, 112, 1948-1955. Thus, to a mixture of AD2 (R3=Ph, R4=tert-Butyl) (0.56 g, 2.7 mmol) and boiling chips in CCl4 (25 mL) was added N-bromosuccinimide (0.49 g, 2.7 mmol). The mixture was irradiated with a 200 watt light source for 1 h. The reaction was cooled, the solid filtered off and the volatiles were removed in vacuo. Chromatography on silica gel by eluting with 5% EtOAc/hexane gave 0.57 g (73%) of 1-(1-bromo-1-isothiocyanato-2,2-dimethylpropyl)benzene as a beige powder. 1H NMR (CDCl3, 300 MHz): δ 7.63-7.61 (m, 2H), 7.37-7.26 (m, 3H), 1.17 (s, 9H); 13C NMR (CDCl3, 75 MHz): δ 139.1, 129.0, 128.9, 128.6, 127.5, 91.2, 45.6, 26.6. MS (ESI) m/e 284.9 (M+H)+.


To a solution of 1-(1-bromo-1-isothiocyanato-2,2-dimethylpropyl)benzene (0.13 g, 0.47 mmol) and the hydrochloride salt of N-methylhydroxylamine (0.047 g, 0.57 mmol) in THF (3 mL) was added triethylamine (0.18 mL, 1.32 mmol). The mixture was stirred at 25° C. for 16 h, filtered and the volatiles were removed in vacuo. The residue was purified by column chromatography using CH3OH/CH2Cl2 as eluent to give 0.050 g (42%) of AD3 (R3=Ph, R4=tert-Butyl) as a glassy solid. 1H NMR (CDCl3, 300 MHz): δ 7.35-7.26 (m, 5H), 3.38 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 251.1 (M+H)+.


Method AD, Step 3

To a solution of AD3 (R3=Ph, R4=tert-Butyl) (0.065 g, 0.26 mmol) in CH3OH (5 mL) at 0° C. was added a solution of aqueous ammonia (2 mL) followed by a 70% aqueous solution of t-butylhydroperoxide (2 mL). The reaction was allowed to warm to 25° C. and stirred for 16 h, The volatiles were removed and the residue was purified by reverse phase HPLC to give 2.0 mg (2.2%) of AD4 (R3=Ph, R4=tert-Butyl) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.47-7.43 (m, 2H), 7.39-7.35 (m, 3H), 3.23 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 234.2 (M+H)+.


The following compounds were synthesized using similar methods:





















Obs.



#
Structure
MW
m/e









202


embedded image


213
214







203


embedded image


233
234







204


embedded image


309
310










Method AE



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Method AE, Step 1

TBDMS-Cl (5.3 g, 35.19 mmole) and imidazole (2.4 g, 35.19 mmole) were added to a suspension of H2 (R1=Me, R3=cyclohexylmethyl) (8.2 g, 31.99 mmole) in 220 ml DCM. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was diluted with 1200 ml EtOAc. The organic phase was washed with saturated NaHCO3 3× and brine 3×, and dried over anhydrous Na2SO4 to give 12 g of AE2 (R1=Me, R3=cyclohexylmethyl), which was used for next step without further purification.


Method AE, Step 2

AE2 (R1=Me, R3=cyclohexylmethyl; 12 grams crude) was converted to iminohydantoin using conditions similar to Method A Step 3, which was subsequently treated with 75% TFA in DCM at room temperature for 24 hrs. The solvent was evaporated in vacuo to give 13.6 g of a product that was reacted with Boc anhydride to give 5.8 g AE3 (R1=Me, R3=cyclohexylmethyl) after column purification.


Method AE, Step 3

AE4 (R1=Me, R3=cyclohexylmethyl)(8.2 g) was obtained from AE3 (5.8 g) according to the step 4 of the method H.


Method AE, Step 4

To a solution of AE4 (R1=Me, R3=cyclohexylmethyl) ((3.95 g, 8.38 mmol) in anhydrous THF (98 mL) was added diisopropylethylamine (7 mL, 40 mmol). The reaction was stirred under N2 (gas) at room temperature. After 5.5 h, the reaction was concentrated and the crude material was purified via flash chromatography eluting with a gradient of 0 to 75% ethyl acetate in hexane to afford AE5 (R1=Me, R3=cyclohexylmethyl) (2.48 g, 92%).


Method AE, Step 4

To a solution of R15OH (R15=cyclobutyl) (10 μl) and HBF4 (1 equiv) in anhydrous methylene chloride (0.5 mL) was added a solution of AE5 (R1=Me, R3=cyclohexylmethyl) (20 mg, 0.062 mmol) in methylene chloride (0.5 mL). The reaction was agitated overnight at rt. Trifluoroacetic acid (1 mL) was added to the reaction mixture and the solution was agitated for 1 h at rt. The reaction was concentrated and the crude material was purified via reverse phase preparative HPLC/MS eluting with a 7 min gradient of 5 to 95% CH3CN in H2O with 0.1% formic acid to afford AE5 (R1=Me, R3=cyclohexylmethyl, R15=cyclobutyl).


The following compounds were synthesized using similar method:


















Obs.


#
Structure
MW
m/e







205


embedded image


267
268





206


embedded image


293
294





207


embedded image


295
296





208


embedded image


295
296





209


embedded image


295
296





210


embedded image


295
296





211


embedded image


305
306





212


embedded image


307
308





213


embedded image


307
308





214


embedded image


309
310





215


embedded image


309
310





216


embedded image


309
310





217


embedded image


309
310





218


embedded image


321
322





219


embedded image


321
322





220


embedded image


321
322





221


embedded image


322
323





222


embedded image


329
330





223


embedded image


333
334





224


embedded image


335
336





225


embedded image


335
336





226


embedded image


335
336





227


embedded image


335
336





228


embedded image


335
336





229


embedded image


335
336





230


embedded image


335
336





231


embedded image


335
336





232


embedded image


335
336





233


embedded image


337
338





234


embedded image


337
338





235


embedded image


349
350





236


embedded image


349
350





237


embedded image


349
350





238


embedded image


349
350





239


embedded image


353
354





240


embedded image


361
362





241


embedded image


363
364





242


embedded image


363
364





243


embedded image


363
364





244


embedded image


389
390





245


embedded image


321
NA









Method AF



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To a solution of tBuOK (9.5 mg, 0.0848 mmole) in 0.5 ml anhydrous THF was added ArOH (Ar=m-Chlorophenyl)(13 μl, 0.1273 mmole) in 0.5 ml anhydrous THF followed by addition of AE4 (R1=Me, R3=cyclohexylmethyl) (20 mg, 0.0424 mmole) in 0.5 ml anhydrous THF. The reaction mixture was stirred at room temperature for 2 days before it was diluted with 1 ml MeCN, treated with 100 mg MP-TsOH resin and 100 mg Amberlyst A26 resin. The resin was removed by filtration and the filtrate was evaporated down to give a product that was treated with 50% TFA for 1 hr. After evaporation of TFA in vacuo, the residue was dissolved in 2 ml MeCN, and treated with 100 mg MP-TsOH resin. The resin was washed thoroughly with THF, MeCN and MeOH, and then treated with 2M NH3 in MeoH to give AF2 (R1=Me, R3=cyclohexylmethyl and R15=3-chlorophenyl).


The following compounds were synthesized using similar method:


















Obs.


#
Structure
MW
m/e







246


embedded image


316
317





247


embedded image


316
317





248


embedded image


316
317





249


embedded image


329
330





250


embedded image


329
330





251


embedded image


329
330





252


embedded image


330
331





253


embedded image


331
332





254


embedded image


331
332





255


embedded image


333
334





256


embedded image


333
334





257


embedded image


333
334





258


embedded image


333
334





259


embedded image


333
334





260


embedded image


340
341





261


embedded image


340
341





262


embedded image


340
341





263


embedded image


343
344





264


embedded image


343
344





265


embedded image


343
344





266


embedded image


343
344





267


embedded image


344
345





268


embedded image


344
345





269


embedded image


345
346





270


embedded image


345
346





271


embedded image


345
346





272


embedded image


345
346





273


embedded image


347
348





274


embedded image


347
348





275


embedded image


349
350





276


embedded image


349
350





277


embedded image


349
350





278


embedded image


349
350





279


embedded image


351
352





280


embedded image


351
352





281


embedded image


351
352





282


embedded image


351
352





283


embedded image


351
352





284


embedded image


351
352





285


embedded image


351
352





286


embedded image


351
352





287


embedded image


355
356





288


embedded image


355
356





289


embedded image


357
358





290


embedded image


357
358





291


embedded image


357
358





292


embedded image


357
358





293


embedded image


358
359





294


embedded image


358
359





295


embedded image


358
359





296


embedded image


358
359





297


embedded image


359
360





298


embedded image


359
360





299


embedded image


359
360





300


embedded image


359
360





301


embedded image


359
360





302


embedded image


360
361





303


embedded image


360
361





304


embedded image


360
361





305


embedded image


363
364





306


embedded image


363
364





307


embedded image


363
364





308


embedded image


363
364





309


embedded image


365
366





310


embedded image


365
366





311


embedded image


366
367





312


embedded image


366
367





313


embedded image


366
367





314


embedded image


366
367





315


embedded image


366
367





316


embedded image


366
367





317


embedded image


366
367





318


embedded image


367
368





319


embedded image


367
368





320


embedded image


367
368





321


embedded image


369
370





322


embedded image


371
372





323


embedded image


371
372





324


embedded image


371
372





325


embedded image


372
373





326


embedded image


372
373





327


embedded image


372
373





328


embedded image


372
373





329


embedded image


373
374





330


embedded image


373
374





331


embedded image


375
376





332


embedded image


375
376





333


embedded image


375
376





334


embedded image


377
378





335


embedded image


377
378





336


embedded image


377
378





337


embedded image


383
384





338


embedded image


383
384





339


embedded image


383
384





340


embedded image


383
384





341


embedded image


383
384





342


embedded image


383
384





343


embedded image


383
384





344


embedded image


383
384





345


embedded image


383
384





346


embedded image


383
384





347


embedded image


385
386





348


embedded image


385
386





349


embedded image


386
387





350


embedded image


387
388





351


embedded image


387
388





352


embedded image


393
394





353


embedded image


393
394





354


embedded image


393
394





355


embedded image


393
394





356


embedded image


399
400





357


embedded image


399
400





358


embedded image


400
401





359


embedded image


400
401





360


embedded image


400
401





361


embedded image


401
402





362


embedded image


401
402





363


embedded image


401
402





364


embedded image


405
406





365


embedded image


411
412





366


embedded image


414
415





367


embedded image


417
418





368


embedded image


417
418





369


embedded image


421
422





370


embedded image


434
435





371


embedded image


451
452









Method AG



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Method AG, Step 1

R21—H (R21=PhS—) (33 μl, 0.318 mmole) was treated with NaH (10.2 mg, 60% in mineral oil) in 0.5 ml anhydrous THF. A solution of AE4 (R1=Me, R3=Cyclohexylmethyl) (20 mg, 0.0424 mmol) in 0.5 ml anhydrous THF was added. The reaction mixture was stirred at room temperature overnight before it was partitioned between ether and saturated NaHCO3 water solution. The aqueous phase was extracted with ether 2 times. The combined organic phase was washed with brine 2 times, and dried over anhydrous NaSO4. The crude was purified on flash column with EtOAc/hexane to give 9 mg of AG1 (R21=PhS—, R1=Me, R3=cyclohexylmethyl) (49.2% yield).


Method AG, Step 2

AG1 (R21=PhS—, R1=Me, R3=cyclohexylmethyl) was treated with 50% TFA according to the Step 6 of the method H to give AG2 (R21=PhS—, R1=Me, R3=cyclohexylmethyl).


The following compounds were synthesized using similar method:





















Obs.



#
Structure
MW
m/e









372


embedded image


315
316







373


embedded image


331
332







374


embedded image


337
338










Method AH



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Method AH, Step 1

Benzophenone imine (3.27 g, 18.04 mmole) was added to a suspension of AH1 (R3=cyclohexylmethyl) (4 g, 18.04 mmole) in 65 ml DCM. The reaction mixture was stirred at room temperature overnight under N2 before the solid was filtered, and the solvent was evaporated. The residue was dissolved in 100 ml ether, washed with water 2× and dried over anhydrous MgSO4. The crude was purified on flash column to give 5.08 g (80.57% yield) of AH2 (R3=cyclohexylmethyl).


Method AH, Step 2

A solution of AH2 (R3=cyclohexylmethyl) (1 g, 2.86 mmole) in 12 ml anhydrous THF was added to a suspension of 18-crown-6 (0.76 g, 2.86 mmole) and 30% KH in mineral oil (1.16 g, 8.58 mmole) in 4 ml anhydrous THF under N2. The mixture was cooled in ice-bath and R4Br (R4=3-pyridylmethyl, as a hydrobromide salt) was then added. The reaction mixture was stirred in ice-bath for 30 min and at room temperature for 2 more hrs before the reaction was quenched with 2 ml of HOAc/THF/H2O (0.25:0.75:1). The mixture was diluted with 40 ml EtOAc/H2O (1:1). The aqueous phase was extracted with EtOAc 3 times. The combined organic phase was washed with brine 3 times and dried over anhydrous MgSO4. The crude was purified on flash column to give 0.44 g (35.14% yield) of product which was treated with 1N HCl (2.2 ml, 2.22 mmole) in 3 ml ether in ice-bath followed by stirred at r.t. overnight. The aqueous phase was evaporated and purified on C-18 reverse phase column to give 0.22 g (66% yield) of AH3 (R4=3-pyridylmethyl; R3=cyclohexylmethyl).


Method AI



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To a solution of compound AI1 (R1=Me, R3=n-Bu) (34 mg, 0.105 mmol) in methanol (1 ml) was added 10% Pd/C (5 mg). The mixture was kept under an H2 balloon for 1 hr. After filtration of the catalyst, the filtrate was concentrated to get crude product. This residue was purified by RP HPLC to get compound AI2 (R1=Me, R3=n-Bu) (25 mg, 100%). Observed MW (M+H) 246.1; exact mass 245.15. 1H NMR (400 MHz, CD3OD): δ=7.59 (m, 2H), 7.36 (m, 3H), 3.17 (s, 3H), 2.17 (m, 2H), 1.27 (m, 4H), 0.86 (t, 3H, J=7.2 Hz).


The following compounds were synthesized using similar method:


















Obs.


#
Structure
MW
m/e







375


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283
284





376


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285
286





377


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299
300





378


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450
451





379


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462
463





380


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463
464





381


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487
488





382


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489
490





383


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503
504





384


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516
517









Method AJ



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To a mixture of compound AJ1 (R1=Me, R3=n-Bu) (70 mg, 0.165 mmol) and butylzincbromide (1.32 ml, 0.6 mmol) was added Pd(dppf)Cl2. The mixture was degassed, sealed and heated at 55° C. for 1 day. The mixture was diluted with CH2Cl2 and NH3/H2O. The organic layer was separated, dried, concentrated, and purified by RP HPLC to get product which was then treated with 4N HCl/dioxane for 30 min to give compound AJ2 (R1=Me, R3=n-Bu) (12 mg, 25%). Observed MW (M+H) 302.1; 1H NMR (400 MHz, CD3OD): δ=7.32 (m, 3H), 7.22 (m, 1H), 3.19 (s, 3H), 2.65 (m, 2H), 2.20 (m, 2H), 1.60 (m, 2H), 1.38 (m, 4H), 1.24 (m, 2H), 0.92 (m, 6H).


The following compound was synthesized in a similar fashion:


















Obs.


#
Structure
MW
m/e







386


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518
519





385


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301
302









Method AK



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To a solution of AK1 (R1=Me, R3=n-Butyl, R21=n-Bu) (9 mg, 0.03 mmol) in methanol (1 ml) was added 5% Pt/C (5 mg), Rh/C (5 mg) and conc. HCl (0.05 ml). The mixture was kept under H2 (50 psi) for 2 days. After the filtration of the catalyst, the filtrate was concentrated to get compound AK2 (R1=Me, R3=n-butyl, R21=n-Bu) Observed MW (M+H) 308.1. 1H NMR (CD3OD): δ=3.16 (s, 3H), 1.80 (m, 6H), 1.26 (m, 16H), 0.88 (m, 6H).


The following compounds were synthesized using similar method:


















Obs.


#
Structure
MW
m/e







387


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277
278





388


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291
292





389


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305
306





390


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307
308





391


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391
392





392


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391
392









Method AL



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Method AL, Step 1

To a solution of compound AL1 (R3=n-Bu) (418 mg, 1.39 mmol) in methanol (8 ml) was added PtO2 (40 mg) and conc. HCl (0.4 ml). The mixture was hydrogenated (50 psi) for 1 day. After filtration of the catalyst, the filtrate was concentrated. The crude residue was basified to pH=11-12 by 1N NaOH. This mixture was extracted with ethyl acetate. The organic layer was separated, dried and concentrated to get compound AL2 (R3=n-Bu) (316 mg, 100%).


Method AL, Step 2

To a solution of compound AL2 (R3=n-Bu) (300 mg, 1.32 mmol) in dichloromethane (6 ml) was added (BOC)2O (316 mg, 1.45 mmol). The mixture was stirred at RT for 1.5 hr. It was diluted with water and dichloromethane. The organic layer was separated, dried and concentrated to get compound AL3 (R3=n-Bu) (464 mg, 100%).


Method AM



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Method AM, Step 1

Compound AM1 (R1=Me, R3=n-Butyl) was treated with 4N HCl in dioxane for 2 hr. The mixture was concentrated to get compound AM2 as an HCl salt (R1=Me, R3=n-Butyl). Observed MW (M+H) 470.1; 1H NMR (CD3OD): δ=7.28 (m, 2H), 6.96 (m, 3H), 4.80 (m, 2H), 4.56 (m, 1H), 4.00 (m, 1H), 3.64 (m, 4H), 3.37 (m, 2H), 3.12 (m, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.72 (m, 1H), 2.38 (m, 1H), 2.12-1.62 (m, 8H), 1.35 (m, 6H), 1.12 (m, 1H), 0.91 (m, 3H).


Method AM, Step 2

To a solution of compound AM2 (R1=Me, R3=n-Butyl) (32 mg, 0.068 mmol) in dichloromethane (1 ml) was added acetyl chloride (5 ul, 0.072 mmol). The mixture was stirred for 2 hr. It was then diluted with CH2Cl2 and water. The organic layer was separated, dried, concentrated and purified by RP HPLC to get compound AM3 (R1=Me, R3=n-Butyl and R15=Me) Observed MW (M+H) 512.3; 1H NMR (400 MHz, CDCl3): δ=7.27 (m, 2H), 6.98 (m, 1H), 6.92 (m, 2H), 4.65 (s, 2H), 4.50 (m, 2H), 3.98 (m, 1H), 3.70 (m, 1H), 3.41 (m, 2H), 2.98 (m, 2H), 2.62 (m, 1H), 2.50 (m, 1H), 2.47 (m, 1H), 2.02 (m, 5H), 1.75 (m, 6H), 1.26 (m, 7H), 0.84 (m, 3H).


The following compounds were synthesized using similar method:


















Obs.


#
Structure
MW
m/e







394


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252
253





395


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252
253





396


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456
457





397


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469
470





398


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498
499





399


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511
512









Method AN



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To a solution of compound AN2 (R1=4-N-(α-phenoxyacetyl)piperidinylmethyl, R3=n-Butyl) (28 mg, 0.06 mmol) in dichloroethane (2 ml) was added butyraldehyde (5.3 ul, 0.06 mmol), triethylamine (8.4 ul, 0.06 mmol) and NaBH(OAc)3 (18 mg, 0.084 mmol). The mixture was stirred overnight. It was then diluted with dichloromethane and water. The organic layer was separated, dried, concentrated and purified by RP HPLC to get AN2 (R1=4-N-(a-phenoxyacetyl)piperidinylmethyl, R3=n-Butyl, R15=propyl and R16=H) (5.4 mg, 17%). Observed MW (M+H) 526.1; exact mass 525.37. 1H NMR (CD3OD): δ=7.28 (m, 2H), 6.96 (m, 3H), 4.76 (m, 2H), 4.55 (m, 1H), 4.05 (m, 1H), 3.77 (m, 1H), 3.61 (m, 3H), 3.50 (m, 1H), 3.11 (m, 4H), 2.85 (m, 1H), 2.68 (m, 1H), 2.38 (m, 1H), 2.05 (m, 2H), 1.95 (m, 2H), 1.73 (m, 5H), 1.39 (m, 8H), 1.10 (m, 1H), 0.99 (m, 3H), 0.92 (m, 3H).


The following compound was synthesized using similar method:















#
Structure
MW
Obs. m/e







400


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308
309





401


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308
309





402


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525
526









Method AO



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A mixture of copper chloride (2.06 g, 20.8 mmol) and lithium chloride (1.76 g, 41.6 mmol) in 100 ml of THF was cooled down to −78° C. To this mixture, a 2.0M solution of AO1 (R3=n-butyl) (10 ml, 20 mmol) was added gradually. The reaction was warmed up to −60° C., and AO2 (R4=m-Br-Ph) (2.9 ml, 22 mmol) was injected. The mixture was stirred at −60° C. for 15 minutes and then quickly warmed up to RT by removing the dry-ice bath. The reaction was quenched with water and sat. NaHCO3. After addition of diethyl ether, a lot of precipitate formed and was filtered. From the biphasic filtrate, the organic layer was separated, dried, concentrated and purified by silica gel chromatography (10% EtOAc/hexane) to get ketone AO3 (R4=m-BrPh, R3=n-Bu) (3.93 g, 82%). Observed MW (M+H) 241.1; exact mass 240.01. 1H NMR (400 MHz, CDCl3): δ=8.07 (m, 1H), 7.88 (m, 1H), 7.64 (m, 1H), 7.34 (m, 1H), 2.94 (t, 3H, J=7.2 Hz), 1.71 (m, 2H), 1.40 (m, 2H), 0.95 (t, 3H, J=7.6 Hz).


The following ketones were made according to Method 9:


















Observed MW
Exact



Structure
(M + H)
mass











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242.1
241.01










Method AP



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Method AP, Step 1

To a solution of AP1 (R4=3-Bromophenyl) (5 g, 25 mmol) in dichloromethane (10 ml) were added N,O-dimethylhydroxylamine hydrochloride (2.56 g, 26.25 mmol) and 4-methylmorpholine (2.95 ml, 26.25 mmol). EDCI (5.04 g, 26.25 mmol) was then added portionwise. The reaction mixture was stirred at RT overnight and was then quenched with 1N HCl (60 ml). The mixture was extracted with dichloromethane. The organic layer was washed with 1N HCl and brine, dried over Na2SO4, and concentrated to give the Weinreb amide AP2 (R4=m-Bromophenyl) (5.96 g, 98%). Observed MW (M+H) 244.1; exact mass 243.99. 1H NMR (CDCl3): δ=7.78 (m, 1H), 7.58 (m, 2H), 7.24 (m, 1H), 3.51 (s, 3H), 3.32 (s, 3H). This material was used in the next step without purification.


Method AP, Step 2

To a suspension of magnesium turnings (1.19 g, 48.8 mmol) in 30 ml of THF was added dropwise a solution of R3Br (R3=cyclohexylethyl) (5.73 ml, 36.6 mmol) in 24 ml of THF. After addition of half of the solution of bromide, several crystals of iodine were added to initiate the reaction. The mixture became cloudy and heat evolved. The rest of the solution of bromide was added dropwise. The mixture was stirred at RT for 30 minutes and then was cooled to 0° C., and the AP2 (R4=m-Bromophenyl) (5.96 g, 24.4 mmol) was added. The mixture was stirred at RT for 3 hr and then quenched with 1N HCl until no residual Mg(0) was left. The phases was separated, and the water layer was extracted with ether. The combined organic layers were washed with brine, dried, and concentrated. The crude was purified by silica chromatography (15% EtOAc/hexane) to get ketone AP3 (R4=m-Bromophenyl, R3=Cyclohexylethyl) (8.06 g, 100%). Observed MW (M+H) 295.2; exact mass 294.06. 1H NMR (400 MHz, CDCl3): δ=8.18 (m, 1H), 7.85 (m, 1H), 7.64 (m, 1H), 7.33 (m, 1H), 2.94 (t, 3H, J=7.2 Hz), 1.70 (m, 9H), 1.63 (m, 4H).


Method AQ



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To a −78° C. solution of AQ1 (R4=cyclopropyl) (2.55 g, 38.0 mmol) in diethyl ether (100 ml) was added AQ3 (R3=n-Bu) (38 ml, 1.5 M in hexanes, 57 mmol). After 45 min, the cooling bath was removed. After 3 h at RT, the reaction was quenched by dropwise addition of water and then diluted further with EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The organic portions were combined, washed with brine, dried over MgSO4, and concentrated. This crude residue was subjected to column chromatography (silica gel, 0%→100% CH2Cl2/hexanes) to provide the desired ketone AQ4 (R4=cyclopropyl, R3=n-Butyl) (2.57 g, 20.4 mmol, 54%). 1H NMR (CDCl3) δ 2.52 (t, J=7.2 Hz, 2 H), 1.90 (m, 1 H), 1.57 (m, 2 H), 1.30 (m, 2 H), 0.98 (m, 2 H), 0.89 (t, J=7.6 Hz, 3 H), 0.83 (m, 2 H).


Method AR



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Method AR

Compound B2 (R1=m-Cl-Phenethyl, R3=Me, R4=i-butyl and R5=benzyl) was converted into AR2 (R1=m-Cl-Phenethyl, R3=Me, R4=i-butyl and R5=benzyl) using method A step 3.


The following compounds were synthesized using similar methods:


















Obs.


#
Structure
MW
m/e







403


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396
397





404


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354
NA





405


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477
NA





406


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460
NA





407


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340
NA





408


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382
NA





409


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446
NA









Method AS



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Method AS, Step 1

To a mixture of AS1 (R3=Ph) (3.94 g) in toluene (10 ml) was added thionyl chloride (1.61 ml) and the resulting mixture as heated under reflux for 6 h (until HCl evolution ceased). The reaction mixture was kept overnight at it before it was concentrated in vacuo. Toluene (10 ml) was added and the mixture was concentrated in vacuo again. The reaction mixture was dissolved in CH2Cl2, solid sodium bicarbonate added, filtered and then the CH2Cl2 solution was concentrated in vacuo to give AS2 (R3=Ph).


Method AS, Step 2

To AS2 (R3=Ph) (0.645 g) and AS5 (R4=4-chlorophenyl) (0.464 g), and 1,3-dimethylimidazolium iodide (0.225 g) in anhydrous THF (20 ml) was added 60% sodium hydride in oil (0.132 g). The resulting mixture was stirred at rt for 18 h. The reaction mixture was concentrated and partitioned between H2O and Et2O. The dried Et2O solution was concentrated in vacuo to give a yellow residue which was placed on preparative silica gel plates and eluted with CH2Cl2 to give AS3 (R3=Ph, R4=p-ClPh). (Miyashita, A., Matsuda, H., Hiagaskino, T., Chem. Pharm. Bull., 1992, 40 (10), 2627-2631).


Method AS, Step 3

Hydrochloric acid (1N, 1.5 ml) was added to AS3 (R3=Ph, R4=p-ClPh) in THF (10 ml) and the resulting solution was stirred at it for 20 h. The reaction mixture was concentrated in vacuo and then partitioned between CH2Cl2 and H2O. The dried CH2Cl2 was concentrated in vacuo to give a residue which was placed on preparative silica gel plates and eluted with CH2Cl2:hexane 1:1 to afford AS4 (R3=Ph, R4=p-ClPh).


Method AS, Step 4

AS4 (R3=Ph, R4=p-ClPh) (0.12 g) and methylguanidine, HCl (AS6, R1=Me) (0.055 g) were mixed in absolute EtOH (5 ml) with triethylamine (0.2 ml) and then heated under reflux for 20 h. The resulting mixture was concentrated and then partitioned between CH2Cl2 and H2O. The dried CH2Cl2 was concentrated in vacuo to give a residue which was placed on preparative silica gel plates and eluted with CH2Cl2:MeOH 9:1 to afford AS5 (R3=Ph, R4=p-ClPh and R1=Me).


The following compounds were synthesized using similar methods:


















Obs.


#
Structure
MW
m/e







411


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265
266





412


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265
266





413


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271
272





414


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271
272





415


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279
280





416


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295
296





417


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295
296





418


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299
300





419


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299
300





420


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309
310





421


embedded image


325
326





422


embedded image


343
344





423


embedded image


343
344





424


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421
422





425


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482
483





426


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512
513





427


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560
561









Method AT



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Method AT, Step 1

AT1, prepared using a method similar to Method H, Step 1, 2 and 3, (n=4, R3=R4=n-Bu) (0.146 g) in MeOH (3 ml) and 1N NaOH (0.727 ml) were stirred overnight at rt. The mixture was concentrated and then partitioned in water (pH ˜3, adjusted using conc. HCl) and EtOAc. The dried EtOAc layer was concentrated in vacuo to afford AT2 (n=4, R3=R4=n-Bu).


Method AT, Step 2

Compound AT2 (n=4, R3=R4=n-Bu) (0.012 g) in MeCN (1 ml) was treated with EDC resin (0.12 g, 1.44 mmol/g), HOBT (0.004 g) in THF (1 ml), and n-butylamine (R15=H, R16=n-butyl) (0.007 ml). The reaction was carried out overnight at rt. before Argonaut PS—NCO resin (0.150 g), PS-polyamine resin (0.120 g) and THF (2 ml) were added and the mixture shaken for 4 h. The reaction mixture was filtered and resin washed with THF (2 ml). The combined organic phase was concentrated in vacuo before the residue was treated with 1N HCl in MeOH (1 ml) for 4 h followed by evaporation of solvent to give AT3 (n=4, R3=R4=n-Bu, R15=H and R16=n-Butyl).


The following compounds were synthesized using similar method:


















Obs.


#
Structure
MW
m/e







428


embedded image


324
325





429


embedded image


325
326





430


embedded image


338
339





431


embedded image


339
340





432


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366
367





433


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368
369





434


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380
381





435


embedded image


382
383





436


embedded image


400
401





437


embedded image


406
407





438


embedded image


414
415





439


embedded image


414
415





440


embedded image


420
421





441


embedded image


428
429





442


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444
445





443


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458
459









Method AU



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A published procedure was adapted (Varga, I.; Nagy, T.; Kovesdi, I.; Benet-Buchholz, J.; Dormab, G.; Urge, L.; Darvas, F. Tetrahedron, 2003, (59) 655-662).


AU1 (R15=H, R16=H) (0.300 g), prepared according to procedure described by Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R., (Vogel's Textbook of Practical Organic Chemistry. 5th ed. Longman: new York, 1989; pp 1034-1035), AU2 (HCl salt, R1=Me) (0.237 g), 50% KOH (0.305 ml), 30% H2O2 (0.115 ml) and EtOH (4.6 ml) were heated in a sealed tube for 2 h. Reaction mixture was concentrated and extracted with CH2Cl2. The dried organic solution was concentrated in vacuo to give a residue which was placed on preparative silica gel plates eluting with CH2Cl2:MeOH 9:1 to afford AU3 (R15=H, R16=H, R1=Me).


The following compounds were synthesized using similar method:





















Obs.



#
Structure
MW
m/e









444


embedded image


265
266







446


embedded image


280
281







447


embedded image


285
286







448


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285
286







449


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309
310







450


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309
310










Method AV



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Method AV, Step 1

In a microwave tube, AV1 (R3=Me, R4=Bu-i) (0.0012 g) and AV2 (R22=OPh) (0.0059 ml) in isopropanol (2 ml) was placed in a microwave at 125° C. for 5 min. The reaction mixture was concentrated in vacuo to give AV3 (R3=Me, R4=i-Bu, R22=OPh).


Method AV, Step 2

AV3 (R3=Me, R4=i-Bu, R22=OPh) in CH2Cl2 (1 ml) and TFA (1 ml) was shaken for 2 h and the concentrated in vacuo and purified on Prep LCMS to afford AV4 (R3=Me, R4=i-Bu, R22=OPh).


The following compounds were synthesized in a similar fashion.















#
Structure
Mw
Obs. m/e







451


embedded image


378
379





452


embedded image


396
397





453


embedded image


416
417









Method AW



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Method similar to Method U was used for this transformation. The following compounds were generated using similar methods.


The following compounds were synthesized in a similar fashion:


















Obs.


#
Structure
MW
m/e







454


embedded image


341
342





455


embedded image


341
342





456


embedded image


342
343





457


embedded image


342
343





458


embedded image


347
348





459


embedded image


359
360





460


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323
324





461


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294
295









Method AX



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Method AX, Step 1

A literature procedure was adapted. (J-Q Yu and E. J. Corey, Organic Letters, 2002, 4, 2727-2730).


To a 400 ml DCM solution of AX1 (n=1, R4=phenethyl) (52 grams) in a ice bath was added 5 g of Pd/C (5% w/w), 50 g of potassium carbonate and 100 ml of anhydrous t-BuOOH. The mixture was stirred in air for overnight before it was diluted with DCM and washed with water. The residue after removal of organic solvent and drying was chromatographed using ethylacetate/hexane to give 25 g of AX2 (n=1, R4=phenethyl).


Method AX, Step 2

A solution of AX2 (4.5 g, n=1, R4=phenethyl) in MeOH (50 ml) was treated with 0.4 g of Sodium borohydride and the reaction was stirred for 30 min before the solvent was removed and residue chromatographed to give a mixture of AX3 (n=1, R4=phenethyl) and AX4 (n=1, R4=phenethyl) which was separated using an AS chiralpak column eluted with 8% IPA in Hexane (0.05% DEA) to give 2.1 g of AX3 (n=1, R4=phenethyl) as the first fraction and 2.2 g of AX4 (n=1, R4=phenethyl) as the second fraction.


Method AX, Step 3

A 100 ml methanolic solution of AX4 (n=1, R4=phenethyl) (2.2 g) and 1,1′-bis(di-1-propylphosphino)ferrocene (1,5-cyclooctadiene)rhodium (I) tetrafluoroborate (0.4 g, 0.57 mmol) was hydrogenated at 55 psi overnight. The reaction was concentrated, and the brown oil was purified by silica gel chromatography to yield AX6 (n=1, R4=phenethyl) (1.7 g).


The following compounds were generated using similar method.




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Method AY



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A solution of AY1 (n=1; 1.5 g, 3.4 mmol), 5% Rh/C (1.5 g), 5% Pd/C (0.5 g) in AcOH (30 mL) was shaken in a Parr apparatus at 55 psi for 18 hours. The vessel was flushed with N2, and the reaction was filtered through a pad of celite. After concentration AY2 was obtained which was carried on without purification. MS m/e: 312.0 (M+H).


AY3 was generated using similar method.




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Method AZ



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Method AZ, Step 1

To a solution of AZ1 (n=1, R1=Me, R3=2-cyclohexylethyl) (0.441 g, 1.01 mmol), generated from AY2 using Method C and Method H Step 3, in DCM was added Dess-Martin Periodinane (0.880 g, 2.07 mmol). The reaction was stirred for 3 hours at room temperature. The reaction was quenched with H2O and diluted with EtOAc. After removal of the organic phase, the aqueous layer was extracted with EtOAc (3×). The combined organics were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield AZ2 (n=1, R1=Me, R3=2-cyclohexylethyl) (0.408 g, 0.94 mmol, 93% yield). MS m/e: 434.1 (M+H).


Method AZ Step 2

To a solution of AZ2 (n=1, R1=Me, R3=2-cyclohexylethyl) (0.011 g, 0.025 mmol) and AZ5 (R15=H and R16=m-pyridylmethyl) (0.0067 mL, 0.066 mmol) in DCE (1.8 mL) and MeOH (0.2 mL) was added AcOH (4 drops) and MP-cycanoborohydride resin (0.095 g, 2.42 mmol/g). The reaction was agitated for 40 hours at room temperature. The reaction was treated with 7N NH3/MeOH, and solution was filtered. After concentration, the residue was purified by silica gel HPLC (0-4% [(5% 7N NH3/MeOH)/MeOH]/(50% DCM/hexanes) to furnish fraction 1 and fraction 2 which, after removal of solvent, were treated with 20% TFA in DCM for 3 h at r.t. to give AZ4 (n=1, R1=Me, R3=2-cyclohexylethyl, R15=H and R16=m-pyridylmethyl) (0.005 g, 0.009 mmol) and the AZ3 (n=1, R1=Me, R3=2-cyclohexylethyl, R15=H and R16=m-pyridylmethyl) (0.012 g, 0.022 mmol) respectively.


The following compounds were generated using similar methods:


















Obs.


#
Structure
MW
m/e







462


embedded image


333
334





463


embedded image


348
349





464


embedded image


374
375





465


embedded image


374
375





466


embedded image


374
375





467


embedded image


374
375





468


embedded image


376
377





469


embedded image


376
377





470


embedded image


376
377





471


embedded image


376
377





472


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377
378





473


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377
378





474


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378
379





475


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378
379





476


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388
389





477


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388
389





478


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388
389





479


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388
389





480


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388
389





481


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388
389





482


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388
389





483


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388
389





484


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390
391





485


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390
391





486


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390
391





487


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390
391





488


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391
392





489


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391
392





490


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391
392





491


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391
392





492


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392
393





493


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392
393





494


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392
393





495


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392
393





496


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402
403





497


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402
403





498


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402
403





499


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405
406





500


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406
407





501


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406
407





502


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406
407





503


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406
407





504


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406
407





505


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410
411





506


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410
411





507


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410
411





508


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411
412





509


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411
412





510


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411
412





511


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416
417





512


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416
417





513


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416
417





514


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416
417





515


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417
418





516


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417
418





517


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424
425





518


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424
425





519


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424
425





520


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424
425





521


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425
426





522


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425
426





523


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425
426





524


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425
426





525


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425
426





526


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425
426





527


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425
426





528


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425
426





529


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425
426





530


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425
426





531


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425
426





532


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425
426





533


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428
429





534


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428
429





535


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439
440





536


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439
440





537


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442
443





538


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442
443





539


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442
443





540


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442
443





541


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444
445





542


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445
446





543


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459
460





544


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459
460









Method BA



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Method BA, Step 1

BA1, prepared according to a literature procedure (Terao, Y; Kotaki, H; Imai, N and Achiwa K. Chemical and Pharmaceutical Bulletin, 33 (7), 1985, 2762-2766) was converted to BA2 using a procedure described by Coldham, I; Crapnell, K. M; Fernandez, J-C; Moseley J. D. and Rabot, R. (Journal of Organic Chemistry, 67 (17), 2002, 6185-6187).



1H NMR (CDCl3) for BA2: 1.42 (s, 9H), 4.06 (d, 4H), 4.09 (s, 1H), 4.18 (s, 2H), 5.62 (d, 1H).


Method BA, Step 2

BA3 was generated from BA2 using a literature procedure described by Winkler J. D.; Axten J.; Hammach A. H.; Kwak, Y-S; Lengweiler, U.; Lucero, M. J.; Houk, K. N. (Tetrahedron, 54 1998, 7045-7056). Analytical data for compound BA3: MS m/e: 262.1, 264.1 (M+H). 1H NMR (CDCl3) 1.43 (s, 9H), 3.98 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1H).


Method BB



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Method BB, Step 1

Compound BB1 (n=1, R1=Me, R3=cyclohexylethyl) was converted to BB2 (n=1, R1=Me, R3=cyclohexylethyl) and BB3 (n=1, R1=Me, R3=cyclohexylethyl) which were separated via a silica gel column eluted with EtOAc in Hexane (0-15%).


Method BB, Step 2

Compound BB4 (n=1, R1=Me, R3=cyclohexylethyl) was generated from BB2 (n=1, R1=Me, R3=cyclohexylethyl) using 20% TFA in DCM.


The following compounds were generated using similar method:




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Method BC



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Method BC, Step 1

Compound BC2 (n=1, R1=Me, R3=cyclohexylethyl and R15=m-Pyridyl) was obtained from BC1 (n=1, R2=Me, R3=cyclohexylethyl) using method L step 2.


Method BC, Step 2

Compound BC3 (n=1, R1=Me, R3=cyclohexylethyl and R15=m-Pyridyl) was obtained from BC2 (n=1, R1=Me, R3=cyclohexylethyl and R15=m-Pyridyl) using method L step 3.


The following compounds were generated using a similar method:















#
Structure
MW
Obs. m/e







552


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374
375





553


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388
389





554


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388
389





555


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388
389





556


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388
389





557


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390
391





558


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390
391





559


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402
403





560


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402
403





561


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402
403





562


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402
403





563


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404
405





564


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404
405





565


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404
405





566


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404
405





567


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410
411





568


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410
411





569


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411
412





570


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411
412





571


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411
412





572


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411
412





573


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411
412





574


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411
412





575


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416
417





576


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416
417





577


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416
417





578


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416
417





579


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424
425





580


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424
425





581


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424
425





582


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424
425





583


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425
426





584


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425
426





585


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425
426





586


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425
426





587


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425
426





588


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425
426





589


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425
426





590


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430
431





591


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430
431





592


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438
439





593


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438
439





594


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439
440









Method BD



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Method BD, Step 1

Compound BD2 (n=1, R1=Me, R3=cyclohexylethyl and R15=Ph) was obtained from BD1 (n=1, R2=Me, R3=cyclohexylethyl) using Method N, Step 1.


Method BD, Step 2

Compound BD3 (n=1, R1=Me, R3=cyclohexylethyl and R15=Ph) was obtained from BD2 (n=1, R1=Me, R3=cyclohexylethyl and R15=m-Pyridyl) using Method N, Step 2.


The following compounds were generated using a similar method:


















Obs.


#
Structure
MW
m/e







595


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440
441





596


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460
461









Method BE



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Method similar to Method M was adapted for these transformations. The following compounds were generated similar methods.


















Obs.


#
Structure
MW
m/e







597


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405
406





598


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439
440









Method BF



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Method BF, Step 1

Method similar to Method T, Step 1 was used for the synthesis of BF2 (n=1, R1=Me and R3=phenethyl, R15=H and R16=n-propyl).


Method BF, Step 2

Method similar to method L Step 3 was adapted for this transformation.


The following compounds were generated using similar methods.















#
Structure
MW
Obs. m/e







599


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376
377





600


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390
391





601


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390
391





602


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390
391





603


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397
398





604


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397
398





605


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397
398





606


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397
398





607


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411
412









Method BG



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Method BG

To a solution of BG1 (n=1, R3=cyclohexylethyl) (0.136 g, 0.31 mmol) in CH2Cl2 was added 2,6-lutidine, AgOTf, and butyl iodide. The reaction was stirred at room temperature for 96 hours. The reaction was filtered through a pad of Celite, and the solution was concentrated. The residue was purified by silica chromatography (0-100% EtOAc/hexanes) to furnish BG2 (n=1, R3=cyclohexylethyl, R15=n-butyl) (0.124 g, 0.25 mmol, 80% yield). MS m/e: 426.1 (M-OBu).


The following compound was prepared using similar method:




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Method BH



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Method BH, Step 1

Compound BH1 (n=1, R3=cyclohexylethyl and R15=n-butyl) (0.060 g, 0.12 mmol) and 5% Pd(OH)2/C (0.040 g) in EtOAc (1 mL)/MeOH (0.2 mL) was stirred under an atmosphere of H2 for 20 hours at room temperature. The reaction was filtered through a pad of Celite, and the solution was concentrated. The crude product mixture BH2 (n=1, R3=cyclohexylethyl and R15=n-butyl) was carried on to the next step without purification.


Method BH, Step 2

A solution of BH2 (n=1, R3=cyclohexylethyl and R15=n-butyl) was converted to a product mixture of BH4 and BH3 using a method similar to Method C Step 1. The mixture was purified by silica gel chromatography using EtOAc/hexanes to yield BH4 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl) (0.032 g, 0.078 mmol, 56% yield) and BH3 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl) (0.008 g, 0.020 mmol, 14% yield). For BH4 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl), MS m/e: 409.1M+H). For BH3 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl), MS m/e: 409.1 (M+H).


Method BH, Step 3

Compound BH4 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl) (0.032 g, 0.078 mmol) was converted to BH5 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl) (0.016 g, 0.043 mmol, 57% yield) using a method similar to Method A, step 3. MS m/e: 392.1 (M+H).


The following compound was generated using a similar method:





















Obs.



#
Structure
MW
m/e









608


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391
392







609


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391
392







610


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391
392










Method BI



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A solution of BI1 (0.020 g, 0.040 mmol) in DCM (1 mL) was degassed using freeze/pump/thaw (4×) method. At the end of the fourth cycle Crabtree's catalyst was added and the system was evacuated. While thawing, the system was charged with hydrogen gas, and the reaction was stirred at room temperature for 16 hours under an H2 atmosphere. The reaction was concentrated, and the brown oil was purified by reverse phase HPLC to furnish BI2 (0.011 g, 0.022 mmol, 55% yield). MS m/e: 368.2 (M+H).


Method BJ



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Method BJ, Step 1

A mixture of 2 ml dioxane solution of BJ1 (R1=Me, R3=Me) (140 mg, 0.5 mmol) generated using Method BK Steps 1 & 2, indole (1.2 eq), potassium t-Butoxide (1.4 eq), Pd2(dba)3 (0.02 eq) and 2-di-t-butylphospinobiphenyl (0.04 eq) in a sealed tube was irradiated in a microwave oven at 120° C. for 10 min and the mixture was separated via a silica gel column to give BJ2 (R1=Me, R3=Me) (0.73 mg).


Method BJ, Step 2

BJ2 (R1=Me, R3=Me) was converted to BJ3 (R1=Me, R3=Me) using Method BK, Steps 3 & 4. Obs. Mass for BJ3 (R1=Me, R3=Me): 319.2.





















Obs.



#
Structure
MW
m/e









614


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318
319










Method BK



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Method BK, Step 1

Hydantoin BK2 (R3=N-benzyl-3-piperidyl, R4=n-Bu) was prepared according to Method D, Step 1 from the corresponding ketone BK1 (R3=N-benzyl-3-piperidyl, R4=n-Bu). Analytical data for BK2 (R3=N-benzyl-3-piperidyl, R4=n-Bu): (M+H)=330.1.


Method BK, Step 2

To a suspension of hydantoin BK2 (R3=N-benzyl-3-piperidyl, R4=n-Bu) (138 mg, 0.419 mmol) in DMF (1.5 ml) was added dimethylformamide dimethylacetal (0.11 ml, 0.84 mmol). The resulting mixture was heated in a 100° C. oil bath for 16 h and then cooled to RT and concentrated under vacuum. This crude residue was purified by column chromatography (MeOH/DCM) to give product BK3 (R3=N-benzyl-3-piperidyl, R4=n-Bu) (140 mg, 0.408 mmol, 97%), (M+H)=344.1.


Method BK, Step 3

To a solution of a portion of BK3 (R3=N-benzyl-3-piperidyl, R4=n-Bu) (70 mg, 0.20 mmol) in toluene (1 ml) was added Lawesson's reagent (107 mg, 0.26 mmol). The resulting mixture was placed in an oil bath at 60° C. for 16 h and then at 100° C. for 24 h. After cooling to RT, the reaction was quenched by addition of several drops of 1 N HCl and then diluted with EtOAc and 1 N KOH. The phases were separated and the aqueous layer extracted with EtOAc (2×). The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. This crude residue was purified by preparative TLC (1000 μm silica, 15% EtOAc/DCM) to give two separated diastereomers BK4 (R3=N-benzyl-3-piperidyl, R4=n-Bu) (24 mg, 0.067 mmol, 33%, MS: (M+H)=360.2) and BK5 (R3=N-benzyl-m-piperidyl, R4=n-Bu) (22 mg, 0.062 mmol, 31%, MS: (M+H)=360.2).


Method BK, Step 4

Diastereomer BK5 (R3=N-benzyl-3-piperidyl, R4=n-Bu) was treated with NH4OH (2 ml) and t-butyl hydrogen peroxide (70% aqueous, 2 ml) in MeOH (4 ml) for 24 h. After concentration, the crude sample was purified by preparative TLC (1000 mm silica, 7.5% 7N NH3/MeOH in DCM). The resulting sample was dissolved in DCM (1 ml), treated with 4N HCl in dioxane for 5 min, and finally concentrated to give diastereomeric products BK7 (R3=N-benzyl-3-piperidyl, R4=n-Bu) (12 mg, 0.029 mmol, 43%). 1H NMR (CD3OD) δ 7.60 (m, 2 H), 7.49 (m, 3 H), 4.39 (ABq, JAB=12.8 Hz, ΔνAB=42.1 Hz, 2 H), 3.69 (m, 1 H), 3.39 (br d, J=13.6 Hz, 1 H), 3.20 (s, 3 H), 2.96 (m, 2 H), 2.45 (m, 1 H), 1.99 (m, 1 H), 1.92-1.78 (m, 3 H), 1.68 (br d, J=12.4 Hz, 1 H), 1.50 (dq, Jd=3.6 Hz, Jq=12.8 Hz, 1 H), 1.36-1.22 (m, 4 H), 1.03 (m, 1 H), 0.90 (t, J=7.2 Hz, 3 H). LCMS: tR (doubly protonated)=0.52 min, (singly protonated)=2.79 min; (M+H) for both peaks=343.2.


The following compounds were synthesized using similar methods:





















Obs.



#
Structure
MW
m/e









615


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281
282










Method BL



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To a 2 ml Methanolic solution of BL1 (n=1, R3=cyclohexylethyl, R1=Me) (10 mg) was added BL3 (HCl salt, R15=H, 2 eq) and NaOAc (2 eq) and the mixture was heated to 60 C for 16 h. After removal of solvent, the residue was treated with 20% TFA in DCM for 30 min before the solvent was evaporated and residue purified using a reverse phase HPLC to give BL2 (n=1, R3=cyclohexylethyl, R1=Me and R15=H).


The following compounds were synthesized using similar methods.


















Obs.


#
Structure
MW
m/e







616


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348
349





617


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388
389









Method BM



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Method BM, Step 1

To a toluene solution (3 ml) of BM1 (n=1, R3=cyclohexylethyl, R2=Me) (0.050 mg) was added 1.5 eq of diphenylphosphorylazide and 1.5 eq of DBU and the solution was stirred at r.t. overnight. The reaction mixture was diluted with EtOAc and washed with 1% aq HOAc before the organic layer was dried and solvent evaporated. The residue was chromatographed using EtOAc/Hex to give a product that was treated with triphenylphosphine (2 eq) in THF (1% water) overnight to give BM2 (n=1, R3=cyclohexylethyl, R2=Me) after reverse phase purification.


Method BM Step 2

To a DCM solution of BM2 (n=1, R3=cyclohexylethyl, R2=Me) was added 1 eq of benzyloxycarbonyl-OSu and the reaction was stirred overnight before the solvent was evaporated and residue chromatographed to give BM3 (n=1, R3=cyclohexylethyl, R2=Me).


Compound BM4 (n=1, R3=cyclohexylethyl, R2=Me) and BM5 (n=1, R3=cyclohexylethyl, R2=Me) were generated from BM2 (n=1, R3=cyclohexylethyl, R2=Me) and BM3 (n=1, R3=cyclohexylethyl, R2=Me) through Boc-deprotection.


The following compounds were synthesized using similar method:


















Obs.


#
Structure
MW
m/e







618


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332
333





619


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468
469









Method BN



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A mixture of Pd(OAc)2 (9 mg), triethylamine (17 microliter), triethylsilane (11 microliter) and BN1 (20 mg) in DCM was hydrogenated at 1 atm at rt for 1.5 h before the reaction was filtered through a Celite pad to give BN2 after removal of solvent.


Method BO

The following compounds were generated through boc-deprotection of the corresponding starting material using 50% TFA in DCM, rt 30 min.





















Obs.



#
Structure
MW
m/e









620


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266
267







621


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266
267







622


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274
275







623


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274
275







624


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288
289







625


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320
321







626


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320
321










Method BP



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Method BP, Step 1

To a solution of BP1 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.012 g, 0.028 mmol) in CH2Cl2 (0.5 mL) was added 2,6-lutidine (0.010 mL, 0.086 mmol), AgOTf (0.024 g, 0.093 mmol), and benzyl bromide (0.010 mL, 0.084 mmol). The reaction was stirred at room temperature for 16 hours. The solid was filtered, and after concentration the residue was purified by reverse phase HPLC to yield BP2 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.010 g, 0.019 mmol). MS m/e: 526.1 (M+H).


Method BP, Step 2

BP3 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) was prepared from BP2 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) using 30% TFA/DCM. MS m/e: 426.1 (M+H).

















M
Obs.


#
Structure
W
m/e







627


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425
426









Method BQ



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Method BQ Step 1

BQ1 was prepared according to Method AZ.


To a solution of BQ1 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.004 g, 0.007 mmol) in CH2Cl2 (0.3 mL) was added DIEA (0.007 mL, 0.040 mmol), acetic acid (0.001 mL, 0.017 mmol), HOBt (0.003 g, 0.019 mmol), and EDCI (0.003 g, 0.016 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse phase HPLC to provide BQ2 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.003 g, 0.005 mmol). MS m/e: 627.1 (M+H).


Method BQ Step 2

BQ2 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.003 g, 0.005 mmol) was treated with 20% TFA/CH2Cl2 (1 mL) in the presence of PS-thiophenol resin (0.030 g, 1.42 mmol/g) for 3 hours. The solution was filtered and concentrated to produce BQ3 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.002 g, 0.005 mmol). MS m/e: 377.2 (M+H).















#
Structure
MW
Obs. m/e







628


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376
377









Method BR



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Method BR, Step 1

To a solution of BR1(n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.004 g, 0.007 mmol) in pyridine (0.2 ml) was added DMAP (a few crystals) and methylsulfonyl chloride (3 drops). The reaction was stirred at room temperature for 6 days. The reaction was quenched with water and diluted with CH2Cl2. The organic layer was removed, and the aqueous phase was extracted with CH2Cl2 (3×). After concentration, the brown residue was purified by reverse phase HPLC to yield BR2(n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.003 g, 0.004 mmol). MS m/e: 663.2 (M+H).


Method BR, Step 2

BR3 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) was prepared from BR2(n=1, R1=Me, R2=H, R3=cyclohexylethyl) following a procedure similar to Method BQ Step 2. MS m/e: 413.1 (M+H).


















Obs.


#
Structure
MW
m/e







629


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412
413









Method BS



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Method BS Step 1

To a solution of BS1(n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.003 g, 0.006 mmol) in CH2Cl2 (0.3 mL) was added phenyl isocyanate (2 drops). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse phase HPLC to provide BS2 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.002 g, 0.002 mmol). MS m/e: 823.5 (M+H).


Method BS Step 2

Compound BS2 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) was subjected to the same conditions in Method BQ Step 2. The crude mixture prepared above was treated with LiOH (0.006 g, 0.25 mmol) in MeOH (0.3 mL) for 2 hours. The reaction was concentrated, and the residue was purified by reverse phase HPLC to furnish BS3 (n=1, R1=Me, R2=H, R3=cyclohexylethyl) (0.0012 g, 0.002 mmol). MS m/e: 454.1 (M+H).


















Obs.


#
Structure
MW
m/e







630


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453
454









Method BT



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Method BT

To a round bottom flask were added compound BT1 (R1=Me, R3=Me) (100 mg, 0.29 mmol), anhydrous toluene (2 ml), 3-aminopyridine (55 mg, 0.58 mmol) and 2-(di-tert-butyl phosphino) biphenyl (17 mg, 0.058). The solution was then degassed by N2 for 2 minutes before NaO-t-Bu (61 mg, 0.638 mmol) and Pd2(dba)3 (27 mg, 0.029 mmol) were added. The reaction was stirred at 80° C. for 22 hours. After cooling down to room temperature, the reaction was poured to cold water and extracted by CH2Cl2. The combined organic layer was then dried over Na2SO4. After the filtration, the concentrated residue was separated by TLC(CH3OH:CH2Cl2=1:10) and reverse phase HPLC (10%-100% acetonitrile in water w/0.1% formic acid) to produce the desired compound BT2 (R1=Me, R3=Me and R21=m-pyridyl) as a formate salt (23.6 mg, white solid, 20%). 1HNMR (CDCl3) δ 7.50-6.90 (m, 13 H), 3.14 (s, 3H) MS m/e 358 (M+H).


















Obs.


#
Structure
MW
m/e







631


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347
348





632


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356
357





633


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357
358





634


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357
358





635


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357
358





636


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358
359









Method BU



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Method BU, Step 1

To a round bottomed flask containing BU1 (m=1, n=1, R1=Me, R3=Cyclohexylethyl) (99 mg, 0.307 mmol) of the trifluoroacetic acid salt of pyrollidine derivative in 5 ml of DCM was added (86 μL, 0.614 mmol) of triethylamine followed by addition of (76 mg, 0.307 mmol) N-(benzyloxycarbonyloxy)succinimide. Stir at room temperature for 18 h. Dilute the mixture with DCM and extract with sat'd NaHCO3 soln, then water. Collect the organic portion and dry over Na2SO4, filter and concentrate in vacuo. Purify by silica gel chromatography (eluting with 0 to 60% EtOAc/hexanes) to yield BU2 (m=1, n=1, R1=Me, R3=Cyclohexylethyl) (130 mg, 0.284 mmol, 93% yield). MS m/e: 458.1 (M+H).


Method BU, Step 2

To a solution of BU2 (m=1, n=1, R1=Me, R3=Cyclohexylethyl) (130 mg) in 1 ml of MeOH in a reaction vial was added 0.5 ml of a solution of 70% tBuOOH in water and 0.5 ml of NH4OH. Seal the vial and shake at room temperature for 72 h. The mixture was concentrated in vacuo. The mixture was diluted with 1 ml of MeOH and a mixture 30 mg of NaHCO3 and Boc2O (87 mg, 0.398 mmol) were added. The solution mixture was stirred at room temperature for 18 h before it was concentrated and the residue purified by silica gel chromatography using EtOAc/hexanes to yield the BU3 (m=1, n=1, R1=Me, R3=Cyclohexylethyl) (90 mg, 0.167 mmol, 58% yield). MS m/e: 541.1, 441.1 (M+H).


Method BU, Step 3

A solution of BU3 (m=1, n=1, R1=Me, R3=Cyclohexylethyl) (90 mg, 0.167 mmol) in 5 ml of MeOH was hydrogenated using 100 mg of Pd(OH)2—C (20% w/w) at 1 atm for 1 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with MeOH. Concentration of the collected organic portions in vacuo yielded BU4 (m=1, n=1, R1=Me, R3=Cyclohexylethyl) (47 mg 0.116 mmol, 70% yield). MS m/e: 407.1 (M+H).


Method BU, Step 4

To a vial containing 10 mg of powdered 4 4 molecular sieves was added 3-methoxyphenyl boronic acid (60 mg, 0.395 mmol) then 3 ml of anhydrous MeOH. To this mixture was added pyridine (100 ml, 0.650 mmol), Cu(OAc)2 (7 mg, 0.038 mmol), and BU4 (m=1, n=1, R1=Me, R3=Cyclohexylethyl) (7.83 mg, 0.019 mmol) and the mixture was stirred at room temperature for 96 h before it was quenched with 0.25 ml of 7N ammonia in methanol solution. The reaction mixture was extracted with water and DCM and the organic layers were dried and concentrate in vacuo. The residue was purified via a reverse-phase HPLC to give a product which was treated with 5 ml of 40% of TFA in DCM for 5 h. After removal of the volatiles, the residue was purified using a reverse phase HPLC system to furnish BU5 (m=1, n=1, R1=Me, R3=Cyclohexylethyl and R21=m-MeOPh) as the formic acid salt (0.7 mg, 0.0015 mmol, 30.1% yield). MS m/e: 413.1 (M+H).


















Obs.


#
Structure
MW
m/e







637


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358
359





638


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412
413









Method BV



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Method BV Step 1

The method was adapted from a literature procedure (Page et al., Tetrahedron 1992, 35, 7265-7274)


A hexane solution of nBuLi (4.4 mL, 11 mmol) was added to a −78 C solution of BV2 (R4=phenyl) (2.0 g, 10 mmol) in THF (47 mL). After 60 minutes at −78 C, a solution of BV1 (R3=3-bromo-4-fluorophenyl) (2.24 g, 11 mmol) was added and the reaction slowly warmed to RT over 18 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with CH2Cl2 (2×), dried over MgSO4 and concentrated under vacuum. The resulting oil was subjected to silica gel chromatography using 4-10% EtOAc/Hexanes to give a white solid BV3 (R3=3-bromo-4-fluorophenyl and R4=phenyl) (1.69 g, 4.23 mmol, 42%). 1H NMR (CDCl3) δ 7.61 (m, 2 H), 7.27 (m, 3 H), 6.94 (m, 1 H), 6.92 (m, 1 H), 6.68 (m, 1 H), 3.15 (bs, 1H), 2.57-2.73 (m, 4 H), 1.89 (m, 2 H).


Method BV Step 2

A solution of BV3 (R3=3-bromo-4-fluorophenyl and R4=phenyl) (1.69 g, 4.23 mmol) in acetone (40 mL) was slowly added via addition funnel to a 0° C. solution of N-bromosuccinimide (NBS, 11.3 g, 63.3 mmol) in acetone (200 mL) and water (7.5 mL). The mixture was slowly warmed to RT, and quenched after 60 minutes with 10% aqueous Na2SO3. After diluting with CH2Cl2, the layers were separated, and the organic layer washed with water (2×), brine (1×) and dried over MgSO4. Concentration under vacuum afforded an oil which was subjected to silica gel chromatography using 5% EtOAc/Hexanes to give a solid BV4 (R3=3-bromo-4-fluorophenyl and R4=phenyl) (690 mg, 2.24 mmol, 53%). 1H NMR (CDCl3) custom character 8.19 (m, 1 H), 7.93 (m, 3 H), 7.66 (m, 1 H), 7.50 (m, 2 H), 7.20 (m, 1 H).


Method BV Step 3

BV5 (R3=3-bromo-4-fluorophenyl and R4=phenyl and R1=Me and R2=H) was prepared from BV4 (R3=3-bromo-4-fluorophenyl and R4=phenyl) using Method AS, Step 4.




















Obs.



#
Structure
MW
m/e








639


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361
362






640


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361
NA









Method BW



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To an oven-dried vial was added Pd2(dba)3 (15.4 mg, 0.0168 mmol) and 2-(Di-t-butylphosphino)biphenyl (10.0 mg, 0.0336 mmol) followed by addition of a solution of BW1 (R4=Me; R1=Me and n=1) (56.8 mg, 0.168 mmol) in 2 mL of anhydrous THF. 2-Bromopyridine (17.0 mL, 0.178 mmol) was added followed by addition of 0.80 mL of 1.0 N LHMDS solution in THF. The reaction mixtures was stirred at 35° C. for 90 min followed by addition of MeOH and filteration through a silica gel pad. Purification by silica gel chromatography (0 to 100% EtOAc in hexanes) yielded the product which was treated with 5 mL of a 30% TFA in DCM solution to give BW2 after concentration and purification via a reverse phase column (R4=Me; Me; R22=2-pyridyl and n=1) (69.3 mg, 99%). ES_LCMS (m/e): 416.2


Method BX



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Method BX, Step 1

To a solution of BX1 (R4=Me and n=1) (0.78 g, 3.63 mmol) in 10 mL of anhydrous DMF, was added N-Boc-N′-methyl thiourea (0.70 g, 3.70 mmol), EDCI.HCl (0.90 g, 4.71 mmol), and diisopropylethylamine (2.5 mL). The mixture was stirred at RT for 16 h before it was quenched with water and extracted with EtOAc (3×50 mL). The organic solution was dried, concentrated and the residue chromatographed via a silica gel column to yield BX2 (R1=R4=Me and n=1) (1.23 g, 100%). ES_LCMS (m/e): 340.1


Method BX, Step 2

To a solution of BX2 (R1=R4=Me and n=1) (1.23 g, 3.63 mmol) in 40 mL of anhydrous THF was added triphenylphosphine (1.43 g, 5.44 mmol) and the mixture was cooled to 0° C. followed by slow addition of diisopropylcarbodiimide (1.07 mL, 5.44 mmol). After the mixture was stirred for 15 min at 0° C., nicotinoyl azide (Synthesis, 2004 (17), 2886) (0.66 g, 4.71 mmol) was added in one portion and the reaction was allowed to warm to RT and stir for 3 h. The reaction was diluted with EtOAc (200 mL) and washed with water (3×100 mL). The residue from the organic layer was purified through a silica gel column to yield the product azide which was hydrogenation using 20% Pd(OH)2/C (0.64 mg) in MeOH to give BX3 (R1=R4=Me and n=1). ES_LCMS (m/e): 339.1.


Method BY

The following compounds were synthesized using methods similar to Methods AO or AP.




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Method BZ

The following aminoacids were generated using methods similar to Method D




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Method CA



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Compound CA2 (R3=R4=Ph; Z=m-phenylene, R15=H and R16=cyclopentyl) was obtained from CA1 (R3=R4=Ph; Z=m-phenylene, R15=H and R16=cyclopentyl) using a method similar to Method G.


Method CB

The following compounds were synthesized using methods similar to Method E and/or AX.




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Method CC



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Method CC, Step 1

To a methanol solution (20 mL) of CC1 (5 g) cooled to 0° C. was added sodium borohydride (1 eq) and the reaction was stirred for 30 min before the reaction mixture was evaporated to dryness then extracted with DCM/water. The DCM fractions were pooled, dried (MgSO4), filtered and concentrated to dryness. The crude product was dissolved in 20 mL. of anhydrous DCM. To this solution was added t-butyldimethylchlorosilane (2 eq.) and imidazole (2 eq.). The reaction was stirred overnight at RT before it was quenched DCM and saturated NaHCO3. The organic phase was dried (MgSO4), filtered and evaporated to dryness to give crude product CC2.


Method CC, Step 2

A literature procedure was adapted (Aust. J. Chem. 1990, 43(7), 1195). Compound CC2 (50 g) in 80 mL. THF was added to mercuric oxide (1.5 eq.) and borontrifluoride etherate (1.6 eq.) in 540 mL. of THF/H2O (5:1) and the mixture was stirred under nitrogen for 2 h before the reaction was quenched with saturated NaHCO3 (aq.) and ether. The ether phase was dried over anhyd. Na2SO4, filtered through a silica pad and concentrated to give'crude CC3.


Method CC, Step 3

To CC3 (10.4 grams) in 200 mL MeOH was added 1.1 eq. of sodium borohydride and the mixture was stirred for 30 min before the reaction mixture was concentrated and the residue partitioned in DCM/H2O. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was chromatographed to give product CC4.


Method CC, Step 4

Compound CC4 (2.5) in 5 mL. anhydrous DCM was added Bis(1,2-diphenylphosphino)ethane (DPPE; 1.2 eq.) followed by carbon tetrabromide (1.1 eq.) at 0° C. and the reaction was stirred for 30 min. The reaction was quenched with hexane and poured over a silica pad. The organic solution was evaporated to give product CC5 as an oil. 1H-NMR (CDCl3) δ 5.72, br s, 1H, 4.18, t, 1H, 3.83, q, 2H, 2.00-2.10, m, 2H, 1.76-1.81, m, 2H, 1.43-1.56, m, 2H, 0.84, s, 9H, 0.03, s, 6H.


Method CC, Step 5

Compound CC6 was generated from CC5 using a similar procedure in Method E. Crude compound CC6 was purified by flash chromatography (gradient 0-10% EtOAc in hexane). Two isomers were isolated during purification isomer A which eluted first followed by isomer B.


ISOMER A: 1H-NMR (CDCl3) δ 7.26-7.37, m, 5H, 5.57, s, 1H, 5.38, s, 1H, 5.02, q, 2H, 4.08, br s, 1H, 3.67, s, 3H, 3.08, d, 1H, 2.58, d, 1H, 1.80-1.92, m, 1H, 1.60-1.75, m, 3H, 1.32-1.44, m, 3H, 0.83, s, 9H, 0.35-0.45, m, 4H, 0.01, s, 6H.


ISOMER B: 1H-NMR (CDCl3) δ 7.286-7.36, m, 5H, 5.56, s, 1H, 5.39, s, 1H, 5.06, q, 2H, 4.15, br s, 1H, 3.71, s, 3H, 3.06, d, 1H, 2.70, d, 1H, 1.60-1.90, m, 4H, 1.33-1.48, m, 3H, 0.87, s, 9H, 0.37-0.51, m, 4H, 0.03, s, 6H. Yield 26% isomer A and 22% isomer B.


Method CC, Step 6

Compound CC7 was obtained from CC6 (isomer B) through treatment with 1 N TBAF in THF for 30 min followed by extraction with ether/water. The organic phase was separated and washed four times with water. The aqueous phase was pooled and washed once with Et2O (pH ˜6 to 7). The organic phase was dried over Na2SO4, filtered and evaporated to give product CC7 in 94% yield. 1H-NMR (CDCl3) δ 7.28-7.39, m, 5H, 5.58, br s, 1H, 5.49, br s, 1H, 5.10, d, 1H, 5.02, d, 1H, 4.09, br s, 1H; 3.72, s, 3H, 3.14, d, 1H, 2.70, s, 1H, 1.79-1.87, m, 2H, 1.67-1.79, m, 1H, 1.53-1.67, m, 2H, 1.44-1.53, m, 2H, 1.31-1.39, m, 1H, 0.35-0.54, m, 4H


Method CD



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Step 1: tert-Butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate

To a solution of tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (CD1; R4=Me) (1.5 g, 4.6 mmol) in EtOAc (150 mL) at reflux was added IBX (3.82 g, 13.6 mmol, 3 eq). Reflux was continued for another 2 h and then the mixture was cooled to RT. The white precipitate was filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel by eluting with EtOAc/hexanes to give 1.0 g (66%) of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 9.42 (s, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.55-7.40 (m, 2H), 5.85 (bs, 1H), 1.96 (s, 3H), 1.56 (s, 9H).


Step 2: tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate

To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R4=Me) (1.0 g, 3 mmol) in dichloroethane (50 mL) was added methylamine (0.48 g, 6.1 mmol, 2 eq) in water (40%) and 1 mL of AcOH. The solution was allowed to stir at RT for 1 h followed by the addition of sodium triacetoxyborohydride (1.8 g, 8.5 mmol, 2.8 eq). The resulting mixture was stirred at RT for 16 h and quenched with MeOH. After stirring for 30 min the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel by eluting with EtOAc/MeOH to give 0.62 g (60%) of tert-butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R1=Me, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.47(bs, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 7.23 (m, 1H), 5.97 (bs, 1H), 3.18-2.82 (m, 2H), 2.45 (s, 3H), 1.74 (s, 3H), 1.40 (s, 9H). MS (ESI) m/e 342.9 (M+H)+.


Step 3: 4-(3-Bromophenyl)-1,4-dimethylimidazolidin-2-imine

tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R1=Me, R4=Me) (0.62 g, 1.8 mmol) was dissolved in 25% TFA in DCM (25 mL) and the mixture was left stirring at RT for 1 h. The mixture was concentrated in vacuo and the residue was redissolved in CHCl3 (20 mL). The solution was washed with 15% NaOH (10 mL) and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 0.33 g (76%) of crude 2-(3-bromophenyl)-N1-methylpropan-1,2-diamine as a colorless oil. 1H NMR (CDCl3) δ 7.65(t, J=1.7 Hz, 1H), 7.41-7.34 (m, 2H), 7.21 (t, J=7.8 Hz, 1H), 2.86 (dd, J=11.7, 0.6 Hz, 1H), 2.64 (dd, J=11.7, 0.6 Hz, 1H), 2.38 (s, 3H), 1.54 (bs, 3H), 1.43 (s, 9H). MS (ESI) m/e 242.9 (M+H)+. The compound was used in the next step without further purification.


To a solution of 2-(3-bromophenyl)-N1-methylpropan-1,2-diamine (0.12 g, 0.50 mmol) in EtOH (10 mL) was added BrCN (0.073 g, 0.70 mmol, 1.4 eq). The mixture was stirred at RT for 16 h and then concentrated in vacuo. The residue was redissolved in CHCl3 (20 mL) and the solution was washed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl3 (3×10 mL) and the combined organic layer was dried (MgSO4), and concentrated to give 0.14 g (100%) of 4-(3-bromophenyl)-1,4-dimethylimidazolidin-2-imine (CD4; R1=Me, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.42 (t, J=1.7 Hz, 1H), 7.35 (dd, J=8.1, 1.7 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 3.62 (d, J=9.3 Hz, 1H), 3.53 (d, J=9.0 Hz, 1H), 3.08 (s, 3H), 1.56 (bs, 3H). MS (ESI) m/e 268.1, 270.1 (M+H)+.


Step 4: 4-(3-(3,4-Difluorophenyl)phenyl)-1,4-dimethylimidazolidin-2-imine

A mixture of 4-(3-bromophenyl)-4-methyloxazolidin-2-imine (0.027 g, 0.1 mmol, 1 eq), 3,4-difluorophenyl boronic acid (0.020 g, 0.13 mmol, 1.3 eq), FibreCat (20 mg), anhydrous ethanol (2 mL), and a 1N K2CO3 aqueous solution (0.12 mL, 0.12 mmol, 1.2 eq) was heated in a microwave reactor (Emrys Optimizer) at 110° C. for 15 min. The mixture was transferred to a prepacked column of Si-carbonate (2 g, 0.79 mmol/g), which had been conditioned with MeOH/DCM (1:1). The column was eluted with 1:1 MeOH/DCM (3×3 mL) and the eluants were collected and concentrated to give 0.019 g (63%) of 4-(3-(3,4-difluorophenyl)phenyl)-1,4-dimethylimidazolidin-2-imine (CD5; R1=Me, R4=Me, R21=3,4-difluorophenyl) as a white solid. 1H NMR (CDCl3) δ 7.60 (s, 1H), 7.50-7.20 (m, 6H), 3.48 (m, 2H), 2.79 (s, 3H), 1.66 (s, 3H). MS (ESI) m/e 302.2 (M+H)+, HPLC (A) Rt=5.48 min.


Alternative for Method CD for Compound: R1=OR15
Alternative Method CD, Step 2: tert-Butyl 2-(3-bromophenyl)-1-(methoxyamino)propan-2-ylcarbamate

To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R4=Me) (2.7 g, 8.2 mmol) in dichloroethane (40 mL) was added methoxylamine hydrochloride (0.89 g, 10.7 mmol, 1.3 eq) and 1 mL of AcOH. The solution was allowed to stir at RT for 16 h. The reaction mixture was concentrated to give the oxime intermediate. The oxime was dissolved in EtOH (20 mL) and borane-pyridine complex (0.74 g, 7.9 mmol) was added dropwise. After stirring at r.t for 20 min, the reaction mixture was concentrated in vacuo. The residue was redissolved in DCM (50 mL) and washed with water (3×20 mL). The organic layer was dried (Na2SO4) and concentrated to give 1.6 g (54%) of tert-butyl 2-(3-bromophenyl)-1-(methoxyamino)propan-2-ylcarbamate (CD3; R1=OMe, R4=Me). 1H NMR (CDCl3) δ 7.60-7.10 (m, 4H), 5.82 (s, 1H), 3.90 (s, 3H), 3.70 (m, 2H), 1.80 (s, 3H), 1.40 (s, 9H). The crude compound was used in the next step without further purification.


Alternative Method CD, Step 3: 4-(3-Bromophenyl)-1-methoxy-4-methylimidazolidin-2-imine

tert-Butyl 2-(3-bromophenyl)-1-(methoxyamino)propan-2-yl carbamate (CD3; R1=OMe, R4=Me) (1.6 g, 4.4 mmol) was dissolved in 25% TFA in DCM (25 mL) and the mixture was left stirring at RT for 1 h. The mixture was concentrated in vacuo. The residue was redissolved in CHCl3 (20 mL) and washed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in EtOH (10 mL) and BrCN (0.096 g, 0.91 mmol) was added. After stirring at RT for 16 h, the mixture was concentrated in vacuo. The residue was redissolved in CHCl3 (20 mL) and washed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic layer was dried over MgSO4 and concentrated to give 0.2 g (16%) of 4-(3-bromophenyl)-1-methoxy-4-methylimidazolidin-2-imine (CD4; R1=OMe, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.65-7.35 (m, 4H), 4.02 (s, 3H), 3.98 (d, 1H), 3.91 (d, 1H), 1.94 (s, 3H).


Alternative Method CD, Step 4: 4-(3-(3-Chlorophenyl)phenyl)-1-methoxy-4-methylimidazolidin-2-imine

A mixture of 4-(3-bromophenyl)-4-methyloxazolidin-2-imine (CD4; R1=OMe, R4=Me) (0.027 g, 0.1 mmol, 1 eq), 3-chloro phenylboronic acid (0.023 g, 0.13 mmol, 1.3 eq), FibreCat (0.020 g), anhydrous ethanol (2 mL), and 1N K2CO3 aqueous solution (0.12 mL, 0.12 mmol, 1.2 eq) was heated in a microwave reactor (Emrys Optimizer) at 110° C. for 15 min. The mixture was transferred to a prepacked column of Si-carbonate (2 g, 0.79 mmol/g), which had been conditioned with MeOH/DCM (1:1). The column was eluted with 1:1 MeOH/DCM (3×3 mL) and the eluants were collected and concentrated to give 0.008 g (25%) of 4-(3-(3-chlorophenyl)phenyl)-1-methoxy-4-methylimidazolidin-2-imine (CD5; R1=OMe, R4=Me, R21=3-ClC6H4) as a white solid. 1H NMR (CDCl3) δ 7.75-7.60 (m, 5H), 7.58-7.42 (m, 3H), 4.00 (m, 2H), 3.97 (s, 3H), 1.97 (s, 3H). MS (ESI) m/e 316.0, 318.0 (M+H)+, HPLC (A) Rt=5.64 min.


Method CE



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Method CE, Step 1

The synthesis of CE2 (R1=R4=Me, R21=Br and R4=Me) was adapted from the procedure of Spanu, P. et. al., Tet. Lett., 2003, 44, 671-675. Thus, to a solution of (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CE1; R1=R6=Me, R21=Br) (0.24 g, 0.6 mmol, 1 eq) in THF (4 mL), LDA (2M in heptane/THF, 0.6 mL, 0.12 mmol, 2 eq) was added dropwise via a syringe at −78° C. After stirring at −78° C. for 30 min, a solution of iodomethane (0.080 mL, 0.12 mmol, 2 eq) in THF (4 mL) was added dropwise to form an orange-colored enolate solution. The mixture was stirred at −78° C. for 3 h. Water was added to quench the reaction and the suspension was warmed to RT. The mixture was then partitioned between H2O and Et2O. The organic layer was separated and the aqueous layer was extracted with Et2O (3×25 mL).


The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give 0.38 g of a brown oil. Chromatography on silica gel using 50% EtOAc/hexanes as eluent gave 0.14 g (54%) of tert-butyl (4S,5R)-4-(3-bromophenyl)-1,4,5-trimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CE2; R1=R4=Me, R21=Br and R6=Me) as a white solid. 1HNMR (CDCl3, 300 MHz): custom character 10.16 (s, 1H), 7.46 (m, 2H), 7.26 (m, 2H), 3.21 (s, 1H), 3.01 (m, 3H), 3.02 (m, 1H), 1.51(s, 12H), 1.17 (d, J=7.1 Hz, 3H). MS(ESI): MH+=441.7 HPLC (A) Rt=7.20 min.


Method CE, Step 2

A mixture of (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidene carbamate (CE2; R1=R4=Me, R6=Me, R21=Br) (0.25 g, 0.6 mmol), 5-cyanothien-1-ylboronic acid (0.2 g, 1.3 mmol, 2 eq), Fibrecat (4.26% Pd, 0.7 g), and 1N aq. K2CO3 (0.5 mL) was heated at 110° C. in a 20 mL Smith process vial using the Emrys microwave synthesizer. After cooling, the reaction mixture was transferred to a pre-packed column of Si-Carbonate column and eluted with MeOH/CH2Cl2 (1:1). The eluent was concentrated to give 0.32 g of a yellow oil, which was purified by silica gel chromatography (20-50% EtOAc/hexanes to give 0.13 g (0.3 mmol, 48% yield, syn:anti ratio: 5:1) of (S)-tert-butyl 4-(3-(5-cyanothien-1-yl)phenyl)-1,4-dimethyl-6-oxotetrahydro-pyrimidin-2(1H)-ylidenecarbamate as a white solid. 1HNMR (CDCl3, 300 MHz): δ 10.15 (s, 1H), 7.58-7.53 (m, 3H), 7.53-7.38 (m, 2H), 7.23 (m, 1H), 3.32 (s, 3H), 3.16(m, 1H), 1.57 (s, 9H), 1.23 (d, J=6.9 Hz, 3H). MS (ESI): MH+=438.7; M+−56=383.1. HPLC Rt=7.28 min (syn isomer).


(S)-tert-Butyl 4-(3-(5-cyanothien-1-yl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH2Cl2 at RT for 30 min. The volatiles were removed in vacuo and the residue was re-dissolved in acetonitrile (5 mL) and evaporated again to afford 17 mg of crude iminopyrimidinone as a yellow solid. The crude product was purified by reverse phase HPLC (B) to provide 10 mg (60%) of (S)-6-(3-(5-cyanothien-1-yl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1H)-one (CE3; R1=R4=Me, R6=Me, R21=5-cyanothien-1-yl) as a white solid. 1HNMR (CDCl3, 300 MHz): custom character 11.1 (br s, 1H), 10.0 (s, 1H), 7.58-7.53 (m, 3H), 7.44 (m, 1H), 7.40-7.26 (m, 2H), 3.30 (m, 1H), 3.16(s, 3H), 1.60 (s, 3H), 1.27 (d, J=7.2 Hz, 3H). MS (ESI): MH+=438.7; M+−56=339.1. HPLC Rt=7.24 min (syn isomer).


Method CF



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Method CF, Step 1

To a solution of t-butylcarbamate (0.5 g, 4.3 mmol, 1 eq) in anhydrous THF (5.0 mL) at RT was added NaH (0.17 g, 4.3 mmol, 1 eq). The mixture was stirred at RT for 15 min. Then a solution of methyl isocyanate (0.3 g, 4.2 mmol, 1 eq.) in anhydrous THF (5.0 mL) was added dropwise. The reaction mixture was allowed to stir at 25° C. for 15 min. The mixture was then poured into 30 mL of ice-water under vigorous stirring. The reaction solution was extracted with Et2O (2×25 mL). The organic layers were combined and washed with brine (30 mL), dried (Na2SO4), and concentrated in vacuo to give 0.42 g (50% yield) of tert-butyl methylcarbamothioylcarbamate CF1 (R1=Me) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 8.3 (br s, 1H), 3.19 (d, 3H, J=4.8 Hz), 1.8 (br s, 1H), 1.5 (s, 9H).


Method CF, Step 2

To a solution of an HCl salt of AB2 (R6=3-bromophenyl and R7=Me) (0.2 g, 0.7 mmol) and CF1 (R1=Me) in DMF (2 mL) at RT was added DIEA (0.5 mL, 2.8 mmol, 4 eq) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (EDCI, 0.2 g, 1.0 mmol, 1.4 eq). After stirring at RT for 16 h, the mixture was diluted with EtOAc (10 mL), washed with brine, dried (MgSO4), and filtered. The filtrate was evaporated under reduced pressure to afford 0.34 g of crude product as a yellow oil which was purified using silica gel chromatography by eluting with 20% EtOAc/hexanes to give 0.17 g (0.4 mmol, 60%) of (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF2; R1=R6=Me) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 10.63 (s, 1H), 7.42 (m, 2H), 7.24 (m, 2H), 3.21 (s, 3H), 3.2 (d, 1H, J=16.3 Hz), 2.87 (d, 1H, J=16.1 Hz), 1.65 (s, 3H), 1.55 (s, 9H). MS(ESI): MH+=395.7, 398.7. HPLC Rt=7.11 min.


Method CF, Step 3

A mixture of (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF2; R1=R6=Me) (0.25 g, 0.6 mmol), 5-chloro-2-hydroxyphenylboronic acid (R21=5-chloro-2-hydroxyphenyl; 0.2 g, 1.2 mmol, 2 eq), Fibrecat (4.26% of Pd, 0.7 g) and 1N aq. K2CO3 (0.5 mL) in dimethoxyethane (DME, 10 mL) or tert-butanol (10 mL) in a 20 mL Smith process vial equipped with stir a bar was sealed and heated in an Emrys optimizer at 110° C. for 15 min. After cooling, the reaction mixture was transferred to a pre-packed Si-Carbonate column and eluted with MeOH/CH2Cl2 (1:1). The eluant was collected and concentrated under reduced pressure to give 0.32 g of the crude product as an oil. The crude product was purified by silica gel chromatography (20-50% EtOAc/hexanes gradient) to yield 0.13 g (0.3 mmol, 48%) of (S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)-phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 7.48-4.32 (m, 2H), 7.20 (m, 3H), 6.84 (m, 2H), 5.68 (br s, 1H), 3.28 (d, J=15.7 Hz, 1H), 3.21 (s, 3H), 2.96(d, J=15.3 Hz, 1H), 1.68 (s, 3H), 1.53 (s, 9H). MS (ESI): MH+=443.7, 445.7; M+−56=388.0. HPLC Rt (A)=6.99 min.


Method CF, Step 4

(S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH2Cl2 at RT for 30 min. The volatiles were removed in vacuo. The residue was redissolved in acetonitrile (5 mL) and evaporated again to afford 17 mg of the crude product as a yellow solid. The crude product was purified via reverse phase HPLC to provide 10 mg (60%) of (S)-6-(3-(3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1H)-one (CF4; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): custom character11.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m, 3H), 3.68 (br s, 1H), 5.18 (br s, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s, 3H), 2.95(d, J=15.8 Hz, 1H),1.74 (s, 3H). MS(ESI): MH+=344.1. HPLC (A) Rt=5.07 min.


Method CG



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Method CG, Step 1

A solution of CG1 (R21=Br, 12.29 g, 45 mmol) and NaOH (1.93 g, 49 mmol) in MeOH (70 mL) and water (10 mL) was refluxed for 3 h. After removal of MeOH under vacuum, the aqueous residue was adjusted to pH 3 and the resulting solid filtered off, dried under vacuum to give CG2 (R21=Br, 11.41 g, 98%). 1H NMR (400 MHz, CD3OD) δ 8.49 (m, 1 H), 8.27 (m, 1 H), 3.90 (s, 3 H).


Method CG, Step 2

A mixture of CG2 (R21=Br, 11.41 g, 44 mmol), EDCI (8.6 g, 45 mmol), dipropylamine (6.2 mL, 44.8 mmol), HOBt (6.0 g, 44.4 mmol) and NEt3 (10 mL, 72 mmol) in CH2Cl2 (100 mL) was stirred at RT for 48 h. The reaction was washed with sat. NaHCO3, water (1×), NH4Cl (1×), water (1×), brine (1×), dried over MgSO4, filtered and concentrated under vacuum. The resulting material was subjected to silica gel chromatography (0%→40% EtOAc/hexanes) to give CG3 (R21=Br, R15=R16=Pr, 3.62 g, 24%).


Method CG, Step 3

A mixture of CG3 (R21=Br, R15=R16=Pr, 3.6 g, 10.5 mmol), HN(Me)SO2Me (1.4 mL, 16.3 mmol), Pd(OAc)2 (355 mg, 1.58 mmol), Xantphos (1.41 g, 2.44 mmol), Cs2CO3 (5.17 g, 15.8 mmol) in toluene (40 mL) was degassed under a stream of N2 for 10 min, then heated at 95° C. for 18 h. The reaction was cooled to RT, filtered through celite, and the filtrate partitioned between EtOAc and water. The organic layer was washed with water (1×), brine (1×), dried over MgSO4, filtered, and evaporated under vacuum. The resulting residue was subjected twice to silica gel chromatography (0%→3% MeOH/CH2Cl2) to give CG4 (R21=N(Me)SO2Me, R15=R16=Pr, 2.65 g, 68%).


Method CG, Step 4

LiBH4 (2 M THF, 8 mL, 16 mmol) was added to a solution of CG4 (R21=N(Me)SO2Me, R15=R16=Pr, 2.65 g, 7.15 mmol) in THF (40 mL) at 0° C. After 18 h at RT, the reaction was quenched with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine (1×), dried over MgSO4, filtered, and evaporated under vacuum. The resulting residue was subjected to silica gel chromatography (0%→5% MeOH/CH2Cl2) to give CG5 (R21=N(Me)SO2Me, R15=R16=Pr, 1.77 g, 72%).


Method CG, Step 5

A mixture of CG5 (R21=N(Me)SO2Me, R15=R16=Pr, 1.77 g, 5.17 mmol), sodium azide (404 mg, 6.21 mmol), and PPh3 (2.85 g, 10.87 mmol) in CCl4 (5 mL) and DMF (20 mL) was stirred at 90° C. for 5 h, then at RT for 18 h. The reaction was stirred with water (10 mL) for 10 min, then diluted with Et2O. The organic layer was triturated with water, filtered, dried over MgSO4, and evaporated under vacuum. The resulting material was directly used in the next step (azide reduction).


Method CG, Step 6

The product from method CG, step 5 was dissolved in EtOH (5 mL) and stirred in the presence of 10% Pd/carbon under an atmosphere of hydrogen (50 psi) for 18 h at RT. The reaction mixture was passed through a PTFE-filter, and the filtrate evaporated under reduced pressure. The resulting material was subjected to preparative thin layer chromatography (5% MeOH/CH2Cl2) to give CG6 (R21=N(Me)SO2Me, R15=R16=Pr, 130 mg, 7.5% from CG5).


Method CG, Step 7

A mixture of CG6 (R21=N(Me)SO2Me, R15=R16=Pr, 130 mg, 0.38 mmol), 1,3-di(tert-butoxycarbonyl)-2-methylisothiourea (110 mg, 0.38 mmol), NEt3 (55 μL, 0.38 mmol) in DMF (1.5 mL) was stirred at RT for 48 h. After removal of the volatiles in vacuo, the resulting material was subjected to preparative thin layer chromatography (5% MeOH/CH2Cl2 as eluent). The resulting intermediate (140 mg, 0.24 mmol) was treated with 50% TFA/CH2Cl2 at RT for 3 h, followed by removal of all volatiles under vacuum to give CG7 (R21=N(Me)SO2Me, R15=R16=Pr, 140 mg, 74% from CG6).


Method CG, Step 8

A mixture of CG7 (R21=N(Me)SO2Me, R15=R16=Pr, 120 mg, 0.24 mmol), benzil (50 mg, 0.24 mmol) and NEt3 (134 μL, 0.96 mmol) in EtOH (5 mL) was heated at 100° C. for 18 h. After evaporating all volatiles, the residue was partitioned between water and CH2Cl2. The organic layer was washed with brine (1×), dried over MgSO4, filtered and evaporated. The resulting material was subjected to preparative thin layer chromatography (10% MeOH/CH2Cl2 as eluent) to give CG8 (R21=N(Me)SO2Me, R15=R16=Pr, R3=R4=Ph, 69 mg, 50%) as the formate salt. 1H NMR (400 MHz, CDCl3) δ 7.10-7.40 (m, 13 H), 4.72 (m, 2 H), 3.34 (m, 2 H), 3.08 (s, 3 H), 3.00 (m, 2H), 2.60 (s, 3 H), 1.59 (m, 2H), 1.39 (m, 2 H), 0.92 (m, 3 H), 0.64 (m, 3 H); LCMS: 576.3 (M+H).


Method CH



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A solution of 0.35 mL of 1 M BBr3 in DCM (0.35 mmole) was added dropwise to a solution of CH1 (52 mg, 0.11 mole) in 1.5 mL anhydrous DCM in ice bath. The reaction solution was stirred in ice bath for 10 min. and 2 hrs at RT. The reaction was quenched with 5 mL MeOH in ice bath. After concentration the crude was purified on C18 reverse phase column to give CH2 (37.3 mg, 67. % yield) as a formate.


Method CI



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A solution of CI1 (20 mg as a formate; 0.042 mmole) in 4 mL of DCM was treated with mCPBA (0.42 mmole) at RT for 2 hrs. The crude mixture was purified on C18 reverse phase column to give compound CI2.


Method CJ



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To a solution of CJ1 (R1=R6=Me; 324 mg, 0.87 mmole) in 2.5 mL CHCl3 and 2.5 mL HOAc in ice bath was added NBS (312 mg, 1.75 mmole) and the reaction mixture was stirred at RT. Upon reaction completion, the crude mixture was diluted with DCM, and washed with saturated aqueous Na2S2O3, aqueous NaHCO3 and brine. The crude was purified on flash column to give a product which was treated with 50% TFA in DCM to give CJ2 (R1=R6=Me 220 mg, 56. % yield) after evaporation.


Method CK



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Method CK, Step 1

Similar to a literature procedure (Moloney et al., J. Med. Chem. 1997, 2347-2362), methyl bromomethylbenzoate (7.00 g, 30.5 mmol) was added to a suspension of CK1 (R3=R4=Ph, 7.00 g, 27.8 mmol) and K2CO3 (3.85 g, 27.8 mmol) in DMF (50 mL) at RT. After 18 h, the reaction mixture was diluted with water and extracted with CH2Cl2 (3×). The combined organic layers were washed with NaHCO3 (1×), water (3×), dried over MgSO4, filtered and concentrated under vacuum to give compound CK2 (12.7 g, 100%)


Method CK, Step 2

Compound CK3 was obtained from CK2 using method BK, step 3.


Method CK, Step 3

CK3 (1.18 g, 2.83 mmol) in THF (15 mL) and 2 N LiOH (4 mL, 8 mmol) was stirred overnight at RT. The mixture was quenched with 6 N HCl (2 mL, 12 mmol) and then partitioned between water and EtOAc. The dried EtOAc layer was concentrated in vacuo and the residue subjected to reverse-phase HPLC (gradient from 10%→95% CH3CN/H2O with 0.1% HCO2H, 30 mL/min flow rate on a preparative C18 reverse-phase column) to afford CK4.


Method CK, Step 4

Compounds CK5 were obtained from CK4 using method G, step 2.


Method CK, Step 5

Compounds CK6 were obtained from CK5 using method A, step 3.


Method CL



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Method CL, Step 1

CL2 was obtained from CL1 (3-chlorophenyl boronic acid) following method AW.


Method CL, Step 2

Trimethylsilyldiazomethane (2 M hexanes, 2.5 mL, 5.0 mmol) was added to a solution of LDA (freshly prepared from DIPA and nBuLi) in THF at −78° C. After 30 min at −78° C., a solution of aldehyde CL2 (900 mg, 4.13 mmol) in THF (5 mL) was added and the reaction slowly warmed to RT over 3 h. The reaction was quenched with water, then extracted with Et2O (2×100 mL). The combined organic layers were washed with brine (1×), dried over MgSO4, filtered, and evaporated under vacuum. The resulting material was subjected to silica gel chromatography (100% hexanes) to give CL3 (752 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.21-7.65 (m, 8 H), 3.08 (s, 1 H).


Method CL, Step 3

A mixture of CL3 (202 mg, 0.95 mmol), aryl bromide (Ar=3,5-pyrimidinyl, 181 mg, 1.14 mmol), Pd(dba)2 (27 mg. 47.5 μmol), PPh3 (25 mg, 95 μmol), CuI (18 mg, 95 μmol) and DIPA (400 μL, 285 μmol) in DMF (2 mL) was degassed for 10 min under a stream of N2, then heated at 100° C. for 30 min in a Smith Synthesizer microwave. The reaction was cooled to RT, filtered and diluted with EtOAc. The organic layer was washed with water (1×), brine (1×), dried over MgSO4, filtered, and evaporated under vacuum. The resulting material was subjected to silica gel chromatography (0→20% EtOAc/hexanes) to give CL4 (R3=3,5-pyrimidinyl, 220 mg, 80%).


Method CL, Step 4

A mixture of CL4 (R3=3,5-pyrimidinyl, 210 mg, 0.72 mmol), KMnO4 (297 mg, 1.88 mmol), tetrabutylammonium bromide (TBAB, 55 mg, 0.17 mmol) in AcOH (263 μL) and CH2Cl2 (5 mL) was stirred for 3 h at RT. The reaction mixture was filtered through a plug of silica gel, eluting with MeOH, and the filtrate was concentrated under vacuum. The residue was subjected to preparative thin layer chromatography (5% MeOH/DCM) to give CL5 (R3=3,5-pyrimidinyl, 154 mg, 66%).


Method CL, Step 5

Diketone CL5 was converted into CL6 as described in Method CG, step 8. LCMS (CL6, R3=3,5-pyrimidinyl): 378.2 (M+H).


Method CM



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Method CM, Step 1

To a round bottom flask were added CM1 (R1=Me, R3=Ph; 500 mg, 1.22 mmol), methanol (20 mL) and 10% Pd/C (200 mg). The mixture was hydrogenated by a hydrogen balloon for 3 hour 40 min at stirring. After filtration, the concentrated residue was purified by Analogix flash column chromatography (EtOAc/Hexane=0%-50%) to produce CM2 (R1=Me, R3=Ph; 443 mg, 92%) as white solid. Observed MW (M+H) 381.2. (400 MHz, CD3OD): δ=9.13 (s, br, 1H), 7.36-7.26 (m, 5H), 7.09 (m, 1H), 6.68-6.57 (m, 3H), 3.13 (s, 3H), 1.49 (s, 9H).


Method CN



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To an Ace pressure tube were added CN1 (R3=phenyl; R1=Me; 100 mg, 0.290 mmol), bis(pinacolato)diboron (81.0 mg, 0.319 mmol), KOAc (85.0 mg, 0.87 mmol), PdCl2(dppf)2.CH2Cl2 (24 mg, 0.029 mmol) and anhydrous DMSO (1.0 mL). The reaction was then heated to 120° C. (oil bath temperature) at stirring for 2 hour 15 min. After cooling down to RT, the reaction were added 3,5-dibromo pyridine (206 mg, 0.87 mmol), anhydrous DMSO (1.0 mL) and 1M aq. K2CO3 (1.45 mL, 1.45 mmol). The reaction was then heated to 120° C. at stirring for 45 min. After cooling down to RT, the reaction was poured to cold water. The aqueous layer was extracted by DCM (3×50 mL) and the combined organic layer was dried over Na2SO4. The concentrated residue was purified first by preparative TLC (7M NH3/MeOH:DCM=1:10) and then preparative HPLC (reverse phase, C-18 column, 0.1% HCOOH/CH3CN: 0.1% HCOOH/H2O=10%-100%) to afford the desired product CN2 (formic acid salt; R3=phenyl; R1=Me; R21=3′-(5-bromopyridyl; 53.5 mg, 40%) as a white solid. Observed MW (M+H) 421.1. (400 MHz, CD3OD): δ=8.83-8.50 (m, br. 2H), 8.21 (s, 1H), 7.65 (m, 2H), 7.50 (m, 2H), 7.37 (m, 5H), 3.22 (s, 3H).


Method CO



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A microwave tube was charged with CO1 (R1=Me, R2=H; R3=cyclopropyl, n=0) (30 mg, 0.097 mmol), PS-Ph3P—Pd (49 mg, 0.12 mmol), and R21SnBu3 (R21=2-pyrazinyl) (43 mg, 0.12 mmol) as a solution in 1 mL of PhCF3. The tube was sealed, and evacuated and back-filled with N2 (5×). The mixture was then exposed to microwave irradiation (110° C., 30 min). The resulting mixture was filtered with copious MeOH washes. Concentration of the filtrate gave a crude product that was subjected to RP-HPLC to give CO2 (R1=Me, R2=H; R3=c-Pr, n=0, R21=2-pyrazinyl) as a formate salt (12 mg, 0.063 mmol, 35%). LCMS Rt=3.58 min, m/e=308.2 (M+H).


Method CP



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Method CP; Step 1: 1,4,2-Diazaphospholidin-5-one, 2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP3)

Using methods similar to those described by I. V. Konovalova et al. (Zhurnal Obshchei Khimii, 50(7), 1653-1654), 1.0 equivalent of phosphorisocyanatidous acid dimethyl ester (CP2), is added to a solution of benzophenone imine (CP1) in toluene and the mixture is warmed to reflux for 4 h. Removal of solvent and purification by flash chromatography provides the title compound (CP3).


Method CP, Step 2: 1,4,2-Diazaphospholidin-5-thione, 2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP4)

To a solution of CP3 in toluene (or xylene) is added Lawesson's reagent (1.2 equivalents), and the mixture is stirred at reflux for 2 h. The mixture is cooled and poured into cold water. The organic phase is dried (MgSO4) and filtered, and solvent is removed. The crude product is purified by flash chromatography to provide the title compound (CP4).


Method P1, Step 3: 1,4,2-Diazaphospholidin-5-imine, 2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP5)

Using a route similar to that described in Method A, step 3, CP4 is used to prepare the title compound (CP5).


As a variant of Method CP, benzophenone imine (CP1) is treated with 1.0 equivalent of phosphorisocyanatidous acid dimethyl ester [(CH3O)2P—N═C═S], giving directly CP4, which is coverted to CP5 as described in Method CP, Step 3.


Method CQ



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Method CQ, Step 1: 1,4,2-Diazaphospholidin-5-thione, 2-methoxy-1-methyl-3-methyl-3-(4-chloro)phenyl-2-oxide (CQ2)

Using an approach similar to that described by R. Merten et al. [(Chem. Ber., 102, 2143 (1969)], methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl [1-amino-1-(4-chloro)phenyl]ethylphosphonate (CQ1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provides the title compound.


Method CQ, Step 2: 1,4,2-Diazaphospholidin-5-imine, 2-methoxy-1-methyl-3-methyl-3-(4-chloro)phenyl-2-oxide (CQ3)

Using a route similar to that described in Method A, step 3, CQ2 is used to prepare the title compound.


Method CR



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Method CR, Step 1: 1,4,2-Diazaphospholidin-5-one, 2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR2)

Using an approach similar to that described by R. Merten et al. [(Chem. Ber., 102, 2143 (1969)), methylisocyanate (1.2 equivalents) is added to a solution of dimethyl [1-amino-1-(4-bromo)phenyl]ethylphosphonate (CR1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provides the title compound (CR2).


Method CR, Step 2: 1,4,2-Diazaphospholidin-5-thione, 2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR3)

To a solution of CR2 in toluene or xylene is added Lawesson's reagent (1.2 equivalents), and the mixture is stirred at reflux for 2 h. The mixture is cooled and poured into cold water. The organic phase is dried (MgSO4) and filtered, and solvent is removed. The crude product is purified by flash chromatography to provide the title compound.


Method CR, Step 3: 1,4,2-Diazaphospholidin-5-imine, 2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR4)

Using a route similar to that described in Method A, step 3, CR3 is used to prepare the title compound.


Method CS



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Method CS, Step 1: 1,4,2-Diazaphospholidin-5-thione, 2-methoxy-4-(4-methoxy)phenylmethyl)-1-methyl-3-phenylmethyl-2-oxide (CS2)

Using an approach similar to that described by R. Merten et al. [(Chem. Ber., 102, 2143 (1969)), methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl [1-(4-methoxy)phenylmethylamino-2-(4-bromo)phenyl]ethylphosphonate (CS1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provide the title compound.


Method CS, Step 2: 1,4,2-Diazaphospholidin-5-imine, 2-methoxy-4-(4-methoxy)phenylmethyl)-1-methyl-3-phenylmethyl-2-oxide (CS3)

Using a route similar to that described in Method A, step 3, CS2 is used to prepare the title compound.


Method CS, Step 3: 1,4,2-Diazaphospholidin-5-imine, 2-methoxy-1-methyl-3-phenylmethyl-2-oxide (CS4)

A solution of CS3 in methanol is hydrogenated at 1 atm in the presence of 5 mol % Pd/C, yielding the title compound after filtration and purification by flash chromatography.


Method CT



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Method CT, Step 1: Dimethyl-[(4-bromophenyl)-1-isothiocyanato]ethylphosphonate

To a mixture of CT1 in DCM and 0.1 N aqueous sodium bicarbonate (1.0 equivalent) is added thiophosgene (1.5 equivalents), and the mixture is stirred for 4 h at RT. Water is added, and the organic phase is dried (MgSO4), filtered and concentrated to give the product CT2 which is used without purification.


Method CT, Step 2: 1,4,2-Diazaphospholidin-5-thione, 2-methoxy-1-ethyl-3-(4-bromo)phenyl-2-oxide (CT3)

To a solution of CT2 in acetonitrile is added ethylamine (2 equivalents) and diisopropylethylamine (2 equivalents) and the solution is slowly warmed to reflux for 2 h. After removal of solvent, the product is purified by flash chromatography to give the title product.


Method CT Step 3: 1,4,2-Diazaphospholidin-5-imine, 2-methoxy-1-ethyl-3-(4-bromo)phenyl-2-oxide (CT4)

Using a route similar to that described in Method A, step 3, CT3 is used to prepare the title compound.


Method CU



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Method CU, Step 1: 1,5,2-Diazaphosphorine-6(1H)-thione, 1-methyl-2-methoxy-3-phenyl-2-oxide (CU2)

Using an approach similar to that described by R. Merten et al. [(Chem. Ber., 102, 2143 (1969)), methylisothiocyanate (1.2 equivalents) is added to a solution of dimethyl (2-amino-1-phenyl)ethylphosphonate (CU1) in chloroform and the mixture is gradually warmed to reflux. After 2 h at reflux, the mixture is cooled and solvent is removed by evaporation. Purification of the crude product by flash chromatography provides the title compound.


Method CU, Step 2: 1,5,2-Diazaphosphorine-6(1H)-imine, 1-methyl-2-methoxy-3-phenyl-2-oxide (CU3)

Using a route similar to that described in Method A, step 3, CU2 is used to prepare the title compound.


Method CV



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Method CV, Step 1: Dimethyl (2-isothiocyanato-1-phenyl)ethylphosphonate (CV2)

To a mixture of CV1 in methylene chloride and 0.1 N aqueous sodium bicarbonate (1.0 equivalent) is added thiophosgene (1.5 equivalents), and the mixture is stirred for 4 h at RT. Water is added, and the organic phase is dried (MgSO4), filtered and concentrated to give the product which is used without purification.


Method CV, Step 2: 1,5,2-Diazaphosphorine-6(1H)-thione, 1-cyclopropyl-2-methoxy-3-phenyl-2-oxide (CV3)

To a solution of CV2 in acetonitrile is added cyclopropylamine (2 equivalents) and diisopropylethylamine (2 equivalents) and the solution is heated at reflux for 2 h. After removal of solvent, the product is purified by flash chromatography to give the title product.


Method CV Step 3: 1,4,2-Diazaphospholidin-5-imine, 2-methoxy-1-cyclopropyl-3-(4-bromo)phenyl-2-oxide (CV4)

Using a route similar to that described in Method A, step 3, CV3 is used to prepare the title compound.


Method CW



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Method CW; Step 1: Boc-1,5,2-diazaphosphorine-5-imine, 2-methoxy-1-methyl-4-(3-aryl phenyl)-2-oxides (CW2)

Reaction of tert-butyl methylcarbamothioylcarbamate with CW1 (R6=Me) using EDCI and DIEA in DMF affords CW2 (R6=Me) after purification.


Method CW; Step 2: 1,5,2-Diazaphosphorine-5-imine, 2-methoxy-1-methyl-4-(3-(m-cyanophenyl)phenyl)-2-oxides (CW3)

Following the procedure of Sauer, D. R. et al, Org. Lett., 2004, 6, 2793-2796, Suzuki reaction of CW2 (R6=Me) with aryl boronic acids using polymer-support Pd catalysts such as Fibre Cat or PS—PPh3-Pd under microwave heating conditions provides CW3 (R6=Me and R21=m-CN-Ph) of the invention after subsequent Boc-deprotection.


Method CX



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Method CX, Step 1, (S)-2-(tert-Butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylic acid

To a solution of (S)-tert-butyl 4-(furan-2-yl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate CX1 (R6=Me) (1.12 g, 3.64 mmol, prepared using Method CF) in DCM (7 mL) was added MeCN (7 mL) and H2O (10.5 mL), followed by RuCl3.H2O (7.6 mg, 0.036 mmol, 1 mol %), and NaIO4 (11.6 g, 54.2 mmol, 15 eq). The mixture was stirred at RT for 2 h. The mixture was diluted with DCM (100 mL) and the organic layer was separated, dried (Na2SO4), and concentrated to give 0.90 g (86%) of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylic acid CX2 (R6=Me) as a brown solid. 1H NMR (CD3OD): custom character 3.17 (s, 3H), 3.02 (m, 2H), 1.63 (s, 9H), 1.57 (s, 3H).


Method CX, Step 2, (6S)-2-Imino-3,6-dimethyl-6-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-tetrahydropyrimidin-4(1H)-one (CX3)

To a solution of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylic acid (CX2, R6=Me, 0.035 g, 0.12 mmol) in DMF (0.24 mL) was added TBTU (0.040 mg, 0.12 mmol, 1 eq), HOBt (0.0035 mg, 0.024 mmol, 0.2 eq), and DIEA (0.107 mL, 0.60 mmol, 5 eq). The mixture was stirred at RT for 10 min and then N′-hydroxy-3-(trifluoromethyl)benzamidine (0.028 mg, 0.13 mmol, 1.1 eq) was added. After stirring for another 2 h, the reaction mixture was diluted with EtOAc (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The crude residue was dissolved in THF (0.4 mL) and then TBAF (1M in THF, 0.099 mL, 0.9 eq) was added. The mixture was stirred at RT for 2 h. EtOAc (20 mL) was added to the reaction mixture, which was washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was treated with 30% TFA/DCM (1 mL) at RT for 1. The reaction mixture was concentrated in vacuo and the crude product was purified on reverse phase HPLC (B) to give 0.015 g (26%) of (6S)-2-imino-3,6-dimethyl-6-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-tetrahydropyrimidin-4(1H)-one (CX3; R6=Me, R7=3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)) as a white solid. 1H NMR (CD3OD): custom character 8.40 (m, 2H), 8.04 (d, 1H, J=6.9 Hz), 7.90 (t, 1H, J=8.1 Hz), 3.81 (m, 2H), 3.39 (s, 3H), 1.82 (s, 3H). MS (ESI): MH+=354.2, HPLC (A) Rt=6.234 min.


Method CY



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(S)-2-(tert-Butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide

To a solution of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylic acid CX2 (R6=Me) (0.357 g, 1.25 mmol) in 1:5 MeOH/toluene (3 mL) was added TMSCHN2 (2M in hexane, 1.9 mL, 3.8 mmol, 3 eq). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo to give 0.37 g (100%) of (S)-methyl 2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylate as a brown solid. 1H NMR (CDCl3): custom character 8.80 (s, 1H), 3.70 (s, 3H), 3.14 (s, 1H), 2.79 (s, 2H), 1.53 (s, 9H), 1.50 (s, 3H).


To a solution of (S)-methyl 2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylate (0.074 g, 0.25 mmol) in EtOH (0.5 mL) was added NH2NH2 (0.023 mL, 0.75 mmol, 3 eq) and the mixture was stirred at RT for 4 h. The mixture was concentrated in vacuo to give 0.074 g (100%) of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide (CY1, R6=Me) as a yellow solid. 1H NMR (CDCl3) custom character 8.95 (s, 1H), 3.11 (s, 3H), 2.28 (m, 2H), 1.50 (s, 9H), 1.47 (s, 3H).


Method CZ



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3-(5-((S)-2-Imino-1,4-dimethyl-6-oxo-hexahydropyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)benzonitrile

To a solution of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide (CY1; R6=Me, 0.037 g, 0.12 mmol) in DCM (0.3 mL) at 0° C. was added Et3N (0.035 mL, 0.24 mmol, 2 eq) followed by 3-cyanobenzoyl chloride (0.027 g, 0.16 mmol, 1.3 eq). The mixture was stirred at RT for 6 h. The mixture was diluted with DCM (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was then treated with TsCl (0.035 g, 0.18 mmol, 1.5 eq), Et3N (0.046 mL, 0.31 mmol, 2.6 eq), and DMAP (0.002 g, 0.016 mmol, 0.13 eq) in DCM (0.25 mL) at RT for 16 h. The mixture was diluted with DCM (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was treated with 30% TFA/DCM (1 mL) at RT for 1 h. The mixture was concentrated in vacuo and the residue was purified on reverse phase HPLC (B) to give 0.006 g (12%) of 3-(5-((S)-2-imino-1,4-dimethyl-6-oxo-hexahydropyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)benzonitrile as a white solid (CZ1; R6=Me). 1HNMR (CD3OD, 300 MHz): custom character 8.49 (m, 2H), 8.12 (d, 1H), 7.92 (t, 1H), 3.75 (m, 2H), 3.36 (s, 3H), 1.82 (s, 3H). MS (ESI): MH+=311.2, HPLC (A) Rt=4.175 min.


Method DA



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(S)-6-(5-(3-Chlorophenylamino)-1,3,4-oxadiazol-2-yl)-2-imino-3,6-dimethyl-tetrahydropyrimidin-4(1H)-one

To a solution of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide (CY1, R6=Me, 0.030 g, 0.10 mmol) in DCM (0.25 mL) was added 3-chlorophenylisocyanate (0.015 mL, 0.20 mmol, 2 eq). The mixture was stirred at RT for 3 h and volatiles were then removed in vacuo. The residue was treated with TsCl (0.020 g, 0.10 mmol, 1 eq), Et3N (0.083 mL, 0.60 mmol, 6 eq), and DMAP (0.002 g, 0.016 mmol, 0.16 eq) in DCM (0.25 mL) at RT for 16 h. The mixture was diluted with DCM (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was treated with 30% TFA/DCM (1 mL) at RT for 1 h. The mixture was concentrated in vacuo and the residue was purified on reverse phase HPLC (B) to give 0.006 g (10%) of (S)-6-(5-(3-chlorophenylamino)-1,3,4-oxadiazol-2-yl)-2-imino-3,6-dimethyl-tetrahydropyrimidin-4(1H)-one (DA1; R6=Me). 1HNMR (CD3OD, 300 MHz): custom character 7.78 (t, 1H), 7.47 (m, 2H), 7.17 (dt, 1H), 3.53 (m, 2H), 3.36 (s, 3H), 1.78 (s, 3H). MS (ESI): MH+=335.3, HPLC (A) Rt=5.710 min.


Method DB



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Method DB, Step 1; (1-(3-Bromophenyl)ethylidene)cyanamide (DB1, R4=Me)

Following the procedure of Cuccia, S. J.; Fleming, L. B.; France, D. J. Synth. Comm. 2002, 32 (19), 3011-3018: 3-Bromoacetophenone (2.0 g, 10 mmol, 1 eq), was dissolved in 20 mL DCM. A 1.0 N solution of titanium tetrachloride in DCM (20 mL, 20 mmol, 2 eq) was added dropwise over 15 min and the resulting mixture was stirred at 25° C. for 1 h. Bis-trimethylsilylcarbodiimide (5.0 mL, 22 mmol, 2.2 eq) in 5 mL of DCM was added over 15 min and the reaction was stirred for 16 h under argon. The reaction was poured onto 200 mL of an ice/water mixture and extracted with 3×200 mL of DCM. The combined organic phase was dried over MgSO4, filtered, and concentrated to give 2.3 g (100%) of (1-(3-bromophenyl)ethylidene)cyanamide (DB1, R4=Me) as a white solid: 1H NMR (CDCl3) custom character 8.16 (t, J=1.8 Hz, 1H), 7.94 (dd, J=1.7, 1.1 Hz, 1H), 7.76 (dd, J=1.7, 1.1 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 2.82 (s, 3H).


Method DB, Step 2; 5-(3-Bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (DB2, R4=Me)

To a solution of the HCl salt of methylhydroxylamine (0.19 g, 2.2 mmol, 1 eq) in ethanol (25 mL) at 25° C. was added a 21% solution of NaOEt in ethanol (0.75 mL, 2.0 mmol, 0.9 eq) followed by (1-(3-bromophenyl)ethylidene) cyanamide (0.50 g, 2.2 mmol, 1 eq). After stirring at 25° C. for 10 min, the solvent was removed in vacuo. The residue was redissolved in CH2Cl2 (25 mL), the mixture was filtered, and the solvent was removed in vacuo to give 0.5 g (83%) of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (DB2, R1=Me, R4=Me) as a colorless oil: 1H NMR (CDCl3) custom character 7.63 (t, J=1.8 Hz, 1H), 7.52 (dd, J=2.0, 1.1 Hz, 1H), 7.38 (dd, J=2.0, 1.1 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H), 3.28 (s, 3H), 1.88 (s, 3H). MS (ESI) m/e 270.0, 272.0 (M+H)+.


Method DB, Step 3; 5-(3-(3-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

To a solution of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (25 mg, 0.093 mmol) and 3-chlorophenyl boronic acid (17 mg, 0.11 mmol) in ethanol (1 mL) was added a 1 M aqueous solution of K2CO3 (0.22 mL, 0.22 mmol) and PS—PPh3—Pd (46 mg, 0.0046 mmol). The sample was heated in an Emrys Optimizer Microwave at 110° C. for 10 min. The resin was filtered off and rinsed alternately three times with CH2Cl2 (5 mL) and CH3OH (5 mL). The combined filtrates were concentrated and the residue was purified by reverse phase prep-HPLC to give 12.3 mg (44%) of 5-(3-(3′-chlorophenyl)-phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (DB3; R1=Me, R4=Me, R21=3-chlorophenyl) as a colorless oil: 1H NMR (CDCl3) custom character 7.69 (s, 1H), 7.58 (m, 2H), 7.49 (m, 3H), 7.37 (m, 2H), 3.29 (s, 3H), 1.94 (s, 3H). MS (ESI) m/e 302.0, 304.0 (M+H)+.


Using a similar procedure, the following compounds were also prepared.


5-(3-(3-Methoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine



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1H NMR (CDCl3) custom character 7.72 (s, 1H), 7.62 (dt, 1H), 7.49 (m, 2H), 7.38 (t, J=8.2 Hz, 1H), 7.20 (m, 1H), 7.14 (t, 1H), 6.93 (m, 1H), 3.88 (s, 3H), 3.27 (s, 3H), 1.95 (s, 3H). MS m/e 298.1 (M+H)


5-(3-(2,5-Dimethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine



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1H NMR (CDCl3) custom character 7.67 (s, 1H), 7.57 (m, 1H), 7.45 (m, 2H), 6.92 (m, 3H), 3.82 (s, 3H), 3.77 (s, 3H), 3.27 (s, 3H), 1.95 (s, 3H). MS m/e 328.1 (M+H)


5-(3-(3-Fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine



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1H NMR (CDCl3) custom character 7.71 (s, 1H), 7.60 (m, 1H), 7.50 (m, 2H), 7.41 (m, 2H), 7.31 (m, 1H), 7.08 (m, 1H), 3.29 (s, 3H), 1.94 (s, 3H). MS m/e 286.0 (M+H)


5-(3-(3-Trifluoromethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine



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1H NMR (CDCl3) custom character 7.70 (s, 1H), 7.59 (m, 1H), 7.55 (m, 1H), 7.50 (m, 2H), 7.46-7.48 (m, 2H), 7.26 (m, 1H), 3.29 (s, 3H), 1.95 (s, 3H). MS m/e 352.1 (M+H)


5-(3-(3-Pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine



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1H NMR (CD3OD) custom character 9.17 (s, 1H), 8.84 (m, 2H), 8.08 (m, 1H), 7.99 (s, 1H), 7.88 (m, 1H), 7.72 (m, 2H), 3.37 (s, 3H), 2.00 (s, 3H). MS m/e 269.1 (M+H)


5-(3-(3,5-Dichlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine



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1H NMR (CDCl3) custom character 7.66 (s, 1H), 7.54 (m, 1H), 7.52 (m, 2H), 7.47 (m, 2H), 7.38 (m, 1H), 3.30 (s, 3H), 1.94 (s, 3H). MS m/e 336.1 (M+H)


5-(3-(2-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine



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1H NMR (CDCl3) custom character 7.59 (m, 1H), 7.50 (m, 4H), 7.34 (m, 3H), 3.28 (s, 3H), 1.95 (s, 3H). MS m/e 302.1 (M+H)


5-(3-(3-Chloro-4-fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine



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1H NMR (CDCl3) custom character 7.65 (m, 2H), 7.48-7.54 (m, 4H), 7.22 (m, 1H), 3.30 (s, 3H), 1.94 (s, 3H). MS m/e 320.1 (M+H)


Method DC



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Method DC, Step 1, 5-(3-Bromophenyl)-5-methylimidazolidine-2,4-dione

A mixture of 3-bromoacetophenone (10 g, 50 mmol), KCN (8.16 g, 130 mmol, 2.5 eq) and (NH4)2CO3 (21.7 g, 225 mmol, 4.5 eq) in EtOH/H2O (1:1, 110 mL) was heated at 60° C. for 16 h. The reaction mixture was cooled to 0° C. The resulting precipitate was filtered, washed with water, hexane, and then dried to give 12.6 g (93%) of 5-(3-bromophenyl)-5-methylimidazolidine-2,4-dione as an off-white solid (DC1; R6=Me). 1H NMR (CD3OD) custom character 7.64 (s, 1H), 7.45 (t, J=9.7 Hz, 2H), 7.26 (t, J=7.6 Hz, 1H), 1.68 (s, 3H).


Method DC, Step 2, 2-Amino-2-(3-bromophenyl)propanoic acid

5-(3-Bromophenyl)-5-methylimidazolidine-2,4-dione (DC1; R6=Me) (1.5 g, 5.6 mmol) was dissolved in 15 mL of 1N KOH, heated to 185° C. in a microwave reactor (Emrys Optimizer) for 2 h. Afterward, the mixture was carefully acidified using conc. HCl to pH ˜2. The mixture was extracted once with Et2O (20 mL). The aqueous layer was concentrated in vacuo to give 1.6 g (100%) of 2-amino-2-(3-bromophenyl)-2-propanoic acid (DC2; R6=Me) as an off white solid. 1H NMR (CD3OD) custom character 7.75 (t, J=2.0, 1H), 7.66 (m, 1H), 7.56 (m, 1H), 7.45 (t, J=8.1 Hz, 1H), 1.99 (s, 3H).


Method DC, Step 3, 2-(3-Bromophenyl)-2-(tert-butoxycarbonyl)propanoic acid

To a solution of 2-amino-2-(3-bromophenyl)-propanoic acid (DC2; R6=Me) (10.5 g, 43 mmol) in 1N KOH (105 mL) and dioxane (70 mL) at 0° C. was added (Boc)2O (20.6 g, 95 mmol, 2.2 eq). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated to 100 mL. EtOAc (100 mL) was added and the mixture was cooled to 0° C. After acidifying with 2N KHSO4 to pH 2-3, the aqueous layer was extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with H2O (2×50 mL), dried (Na2SO4), and concentrated to give 11.7 g (79%) of 2-(3-bromophenyl)-2-(tert-butoxycarbonyl) propanoic acid as a white solid. 1H NMR (CDCl3) custom character 7.61 (s, 1H), 7.41 (m, 2H), 7.24 (m, 1H), 1.98 (s, 3H), 1.44 (s, 9H).


To a solution of 2-(3-bromophenyl)-2-(tert-butoxycarbonyl) propanoic acid (11.3 g, 32.8 mmol) in MeOH (35 mL) was added toluene (175 mL) followed by TMSCHN2 (2M in hexane, 44 mL, 98 mmol, 3 eq). The mixture was stirred at RT for 16 h. Solvents were evaporated and the residue was chromatographed on silica by eluting with EtOAc/hexanes to give 11.8 g (100%) of methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoate as a yellow oil. 1H NMR (CDCl3) custom character 7.59 (t, J=1.8 Hz, 1H), 7.36-7.44 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 5.92 (s, 1H), 3.70 (s, 3H), 1.97 (s, 3H), 1.36 (br s, 9H).


To a solution of methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonyl) propanoate (11.8 g, 33 mmol) in THF (150 mL) at −78° C. was added LAH powder (3.1 g, 82.0 mmol, 2.5 eq). The mixture was stirred at −78° C. and allowed to warm to RT over 16 h. The mixture was cooled to 0° C. and the reaction was quenched by slowly adding 3 mL of H2O. The mixture was diluted with DCM (500 mL) followed by the addition of 1N NaOH (6 mL) and H2O (9 mL). After stirring at 0° C. for 30 min, the mixture was filtered and the filtrate was concentrated to give 10 g (95%) of tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R6=Me) as a colorless oil. 1H NMR (CDCl3) custom character 7.49 (t, J=1.8 Hz, 1H), 7.35-7.39 (m, 1H), 7.27-7.30 (m, 1H), 7.21 (t, J=7.8 Hz, 1H), 3.72 (m, 2H), 1.57 (s, 3H), 1.41 (br s, 9H).


Method DC, Step 4; 3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide

To a solution of SOCl2 (5.7 mL, 2.5 eq) in dry CH3CN (37 mL) under argon was cooled to −40° C. was added tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R4=Me) (10.3 g, 31 mmol) in dry CH3CN (27 mL) was added dropwise, followed by the addition of dry pyridine (12.4 mL, 160 mmol, 5 eq). The mixture was then allowed to warm to RT in 1 h. The mixture was concentrated to about 30 mL. EtOAc (30 mL) was added and the precipitate was filtered off. The filtrate was concentrated in vacuo to give 10.4 g (89%) of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide as a colorless oil. 1H NMR (CDCl3) custom character 7.64 (t, J=2.0 Hz, 1H), 7.36-7.53 (m, 2H), 7.24 (m, 1H), 4.52 (q, J=9.5 Hz, 2H), 1.86 (s, 3H), 1.42 (br s, 9H).


To a solution of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide (10.4 g, 28 mmol) in CH3CN (50 mL) at 0° C. was added RuO4 (0.5% in stabilized aq., 50 mg, 0.1% by weight) in H2O (10 mL) and NaIO4 (8.9 g, 41.5 mmol, 1.5 eq) in H2O (35 mL). The mixture was stirred at RT for 2 h. The mixture was partitioned between Et2O (200 mL) and H2O (50 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3×50 mL). The combined organic layer was dried (Na2SO4), and concentrated to give 10.8 g (100%) of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC4; R6=Me) as a white solid (˜10.8 g, yield: 100%). 1H NMR (CDCl3) custom character 7.56 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.38-7.44 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 4.41 (dd, J1=9.3 Hz, J2=20.4 Hz, 2H), 2.01 (s, 3H), 1.39 (s, 9H).


Method DC, Step 5; 3-Allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide

3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC4; R6=Me) (10.8 g, 28 mmol) was dissolved in 25% TFA in DCM (40 mL, 5 eq) and the mixture was left standing at RT for 3 h. The mixture was concentrated in vacuo to give 7.3 g (91%) of 4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide as a yellow oil. 1H NMR (CDCl3) custom character 7.59 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.39-7.42 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 4.59 (m, 2H), 1.82 (s, 3H).


To a solution of 4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (7.3 g, 25 mmol) in DCM (77 mL) was added allyl iodide (9.1 mL, 100 mmol, 4 eq), followed by BnBu3NCl (0.39 g, 1.3 mmol) and 40% NaOH (28 mL). The mixture was stirred at RT for 16 h. The organic layer was separated and the solvent was evaporated. Silica gel chromatography using 5-20% EtOAc/hexanes gave 8.3 g (100%) of 3-allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC5; R6=Me) as a colorless oil. 1H NMR (CDCl3) custom character 7.64 (t, J=1.8 Hz, 1H), 7.46-7.54 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 5.77-5.89 (m, 1H), 5.19-5.33 (m, 2H), 4.38 (dd, J1=8.7 Hz, J2=23.7 Hz, 2H), 3.46-3.68 (m, 2H), 1.83 (s, 3H).


Method DC, Step 6; N-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine

To a suspension of NaH (60%, 0.14 g, 1.5 eq) in 0.5 mL of anhydrous DMF was added tert-butyl hydroxy(methyl)carbamate (0.52 g, 1.5 eq) in 1.5 mL of DMF. After stirring at RT for 15 min, a solution of 3-allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC5; R6=Me) (0.78 g, 2.3 mmol) in 6 mL of anhydrous DMF was added dropwise. The mixture was stirred at RT for 16 h. The mixture was partitioned between EtOAc (10 mL) and 1N HCl (3 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layer was dried over Na2SO4 and concentrated to give 0.45 g (41%) of a product which was used without purification.


To a solution of the above product (3.86 g, 8.1 mmol) in THF (30 mL) was added a pre-stirred (15 min) mixture of Pd2(dba)3 (0.51 g, 0.41 mmol) and 1,4-bis(diphenylphosphio)butane (0.25 g, 0.41 mmol) in THF (5 mL), followed by thiosalicyliacid (2.2 g, 1.2 eq). The mixture was stirred at RT for 16 h. Solvent was evaporated and the residue was chromatographed on silica by eluting with 50% EtOAc/hexanes to give 1.3 g (37%) product as a oil which was dissolved in 4M HCl/dioxane (11 mL) and the mixture was stirred at RT for 2 h. Solvent was evaporated in vacuo and the residue was diluted with CHCl3 (10 mL) followed by treatment with 1N NaOH tol pH˜12. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic layer was dried (Na2SO4) and concentrated to give 0.56 g (76%) of N-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine (DC6; R6=Me, R1=Me) as a colorless oil. 1H NMR (CDCl3) custom character 7.74 (t, J=1.8 Hz, 1H), 7.41-7.50 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 3.85 (dd, J1=9.6 Hz, J2=28.8 Hz, 2H), 2.72 (s, 3H), 1.48 (s, 3H).


Method DC, Step 7; 5-(3-Bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

To a solution of N-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine (DC6; R6=Me, R1=Me) (0.76 g, 2.9 mmol) in EtOH (10 mL) was added BrCN (0.46 g, 4.4 mmol, 1.5 eq). After stirring at RT for 16 h, the mixture was concentrated. The residue was redissolved in CHCl3 (20 mL) and washed with 2N NaOH (10 mL). The aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic layer was dried over Na2SO4 and concentrated to give 0.82 g (100%) of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC7; R6=Me, R1=Me) as a light yellow oil. 1H NMR (CDCl3) δ 10.59 (s, 1H), 8.12 (br s, 1H), 7.46 (m, 2H), 7.29 (m, 2H), 4.14 (dd, J1=11.5 Hz, J2=57.7 Hz, 2H), 3.39 (s, 3H), 1.69 (s, 3H).


Method DC, Step 8; 5-(3-(3-Cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

A mixture of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC7; R6=Me, R1=Me) (0.025 g, 0.088 mmol, 1 eq), 3-cyanophenylboronic acid (0.019 g, 0.13 mmol, 1.5 eq), FibreCat (40 mg), anhydrous ethanol (1.5 mL), and a 1N K2CO3 aqueous solution (0.12 mL, 0.12 mmol, 1.4 eq) in a microwave vial was heated in a microwave reactor (Emrys Optimizer) at 110° C. for 15 min. The mixture was filtered, concentrated and purified by prep HPLC (B) to give 0.012 g (44%) of 5-(3-(3-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC8; R6=Me, R1=Me, R21=3-cyanophenyl) as a white solid. 1H NMR (CDCl3) custom character 10.67 (s, 1H), 8.05 (br s, 1H), 7.85 (m, 2H), 7.50-7.66 (m, 5H), 7.35 (m, 1H), 4.22 (dd, J1=11.8 Hz, J2=48.6 Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 307.3 (M+H)


Using a similar procedure, the following compounds were also prepared:


5-(3-(3-Pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.85 (s, 1H), 9.13 (s, 1H), 8.76 (m, 1H), 8.65 (m, 1H), 7.92 (m, 2H), 7.81 (s, 1H), 7.60 (m, 2H), 7.44 (m, 1H), 4.26 (dd, J1=11.8 Hz, J2=37.4 Hz, 2H), 3.41 (s, 3H), 1.77 (s, 3H). MS m/e 283.2 (M+H)


5-(3-(5-Pyrimidyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.77 (br s, 1H), 10.42 (s, 1H), 9.26 (s, 1H), 9.07 (s, 1H), 7.84 (br s, 1H), 7.57-7.63 (m, 3H), 7.46 (m, 1H), 4.23 (dd, J1=11.5 Hz, J2=45.9 Hz, 2H), 3.41 (s, 3H), 1.77 (s, 3H). MS m/e 284.2 (M+H)


5-(3-(3-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.63 (s, 1H), 8.00 (br s, 1H), 7.46-7.55 (m, 5H), 7.31-7.7.40 (m, 3H), 4.20 (dd, J1=11.5 Hz, J2=54.4 Hz, 2H), 3.39 (s, 3H), 1.76 (s, 3H). MS m/e 316.2 (M+H)


5-(3-(3-Trifluoromethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.72 (s, 1H), 8.03 (br s, 1H), 7.55 (m, 1H), 7.51 (m, 2H), 7.46 (m, 2H), 7.41 (m, 1H), 7.32-7.34 (dt, J1=1.6 Hz, J2=7.2 Hz, 1H), 7.21-7.23 (m, 1H), 4.21 (dd, J1=11.8 Hz, J2=53.0 Hz, 2H), 3.39 (s, 3H), 1.76 (s, 3H). MS m/e 366.2 (M+H)


5-(3-(3-Toluyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.61 (s, 1H), 8.07 (br s, 1H), 7.53 (m, 2H), 7.45 (m, 1H), 7.33-7.37 (m, 3H), 7.28-7.32 (m, 1H), 7.17-7.19 (m, 1H), 4.20 (dd, J1=11.8 Hz, J2=58.2 Hz, 2H), 3.38 (s, 3H), 2.42 (s, 3H), 1.76 (s, 3H). MS m/e 296.4 (M+H)


5-(3-(3,5-Dichlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.71 (s, 1H), 8.06 (br s, 1H), 7.47 (m, 3H), 7.43 (m, 2H), 7.35 (m, 2H), 4.20 (dd, J1=11.7 Hz, J2=54.9 Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 350.2 (M+H)


5-(3-(2-Fluoro-5-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.50 (s, 1H), 7.86 (br s, 1H), 7.77 (dd, J1=2.1 Hz, J2=6.9 Hz, 1H), 7.65 (m, 1H), 7.50 (m, 2H), 7.42 (m, 1H), 7.27 (t, J=5.0 Hz, 2H), 4.20 (dd, J1=12.0 Hz, J2=50.4 Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 325.1 (M+H)


5-(3-(2-Fluoro-5-methoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.53 (s, 1H), 7.94 (br s, 1H), 7.47 (m, 3H), 7.37 (m, 1H), 7.07 (t, J=9.5 Hz, 1H), 6.93 (m, 1H), 6.86 (m, 1H), 4.19 (dd, J1=11.7 Hz, J2=58.5 Hz, 2H), 3.82 (s, 3H), 3.38 (s, 3H), 1.75 (s, 3H). MS m/e 330.1 (M+H)


5-(3-(3-Dimethylaminocarbonylphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.58 (s, 1H), 7.95 (br s, 1H), 7.26-7.65 (m, 8H), 4.20 (dd, J1=11.5 Hz, J2=54.7 Hz, 2H), 3.38 (s, 3H), 3.14 (s, 3H), 3.02 (s, 3H), 1.75 (s, 3H). MS m/e 353.2 (M+H)


5-(3-(2,5-Dimethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.50 (s, 1H), 7.99 (br s, 1H), 7.40-7.50 (m, 3H), 7.29-7.33 (m, 1H), 6.84-6.94 (m, 3H), 4.18 (dd, J1=11.5 Hz, J2=65.4 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.37 (s, 3H), 1.74 (s, 3H). MS m/e 342.2 (M+H)


5-(3-(3-Hydroxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 9.75 (s, 1H), 7.39-7.54 (m, 3H), 7.21-7.30 (m, 2H), 7.10-7.12 (m, 2H), 6.82-6.84 (m, 1H), 5.83 (br s, 2H), 4.15 (dd, J1=11.5 Hz, J2=35.7 Hz, 2H), 3.36 (s, 3H), 1.74 (s, 3H). MS m/e 298.3 (M+H)


5-(3-(3-Fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.77 (s, 1H), 8.15 (s, 1H), 7.25-7.56 (m, 7H), 7.01-7.08 (m, 1H), 4.20 (dd, J1=11.5 Hz, J2=53.0 Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 300.2 (M+H)


5-(3-(4-Cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.67 (s, 1H), 8.01 (br s, 1H), 7.74 (s, 4H), 7.63 (s, 1H), 7.48-7.56 (m, 2H), 7.33-7.35 (m, 1H), 4.23 (dd, J1=11.5 Hz, J2=47.2 Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 307.2 (M+H)


5-(3-(4-Methoxy-3-pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine



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1H NMR (CDCl3) custom character 10.55 (s, 1H), 8.74 (d, J=6.0 Hz, 1H), 8.64 (s, 1H), 7.83 (br s, 1H), 7.49-7.53 (m, 3H), 7.37-7.42 (m, 2H), 4.20 (dd, J1=11.5 Hz, J2=49.4 Hz, 2H), 4.11 (s, 3H), 3.39 (s, 3H), 1.76 (s, 3H). MS m/e 313.2 (M+H)


Method DD



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Method DD, Step 1

To a 10 mL MeOH solution of DD1 (R3=R6=H, R7=Me, 1 g) was added p-methoxybenzaldehyde (1 eq) and 4 A molecular sieves (4 g). The solution was stirred overnight before sodium borohydride (1 eq) was added and reaction stirred for 1 h. The reaction mixture was filted and solvent evaporated. The residue was chromatographed using MeOH/DCM to afford compound DD2 (R3=R6=H, R7=Me).


Method DD, Step 2

Procedure similar to Method CF, step 2 was used for generation of DD3 (R1=Me, R3=R6=H, R7=Me).


Method DD, Step 3

Procedure similar to Method CF, step 3 was used for generation of DD4 (R1=Me, R3=R6=H, R7=Me) from DD3


Method DD, Step 4

Compound DD4 was hydrogenated using Pd(OH)2/C in Methanol. After removal of the catalyst and solvent the crude product was treated with 20% TFA in DCM to give product DD5 (R1=Me, R3=R6=H, R7=Me) after purification.


Method DE



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Method DE, Step 1: 5-(4-Chlorophenyl)-3-methylsulfanyl-5,6-dihydro-4H-[1,2,4]thiadiazine 1,1-dioxide

2-(4-Chlorophenyl)ethenesulfonyl chloride DE1 is treated with 1.2 equivalents of S-methyl isothiourea hemisulfate and a slight excess of 1N NaOH in acetone. After 12 h at RT the mixture is concentrated in vacuo and the precipitate collected to give the title compound.


Method DE, Step 2: N-(2-(4-Chlorophenyl)ethene-1-sulfonyl)-S-methylisothiourea

Using a method similar to that described by K. Hasegawa and S. Hirooka (Bull. Chem. Soc. Jap., 1972, 45, 1893), N-(2-(4-chlorophenyl)ethylene-1-sulfonyl)thiourea DE2 in DMF is treated with 1N NaOH (2.4 equivalents) and dimethyl sulfate (1.2 equivalents) at 0-10° C. After 3 h at RT, the reaction mixture is poured into ice water. The precipitate is collected, washed with water and dried to give the title compound DE3.


Method DE, Step 2: 5-(4-Chlorophenyl)-1,1-dioxo-[1,2,4]thiadiazinan-3-one

Using a method similar to that described by K. Hasegawa and S. Hirooka (Bull. Chem. Soc. Jap., 1972, 45, 1893), 5-(4-chlorophenyl)-3-methylsulfanyl-5,6-dihydro-4H-[1,2,4]thiadiazine 1,1-dioxide DE2 in acetone is treated with 1N NaOH and the mixture is refluxed for 2 h. The acetone is evaporated and the mixture is acidified with conc. HCl to afford the title compound DE3.


Method DE, Step 3: 5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-one

Using a method similar to that described by A. Etienne et al. (Bull. Soc. Chim. Fr., 1974, 1395) 5-(4-chlorophenyl)-1,1-dioxo-[1,2,4]thiadiazinan-3-one DE3 is treated with sodium methoxide (1 equivalent) in methanol. Add methyl iodide (1.2 equivalent) in DMF and allow to stir for 12 h. Pour the mixture into ice water and collect the precipitate of the title compound DE4.


Method DE, Step 4: 5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-thione

To a solution of DE4 in toluene (or xylene) is added Lawesson's reagent (1.2 equivalents), and the mixture is stirred at reflux for 2 h. The mixture is cooled and poured into cold water. The organic phase is dried (MgSO4) and filtered, and solvent is removed. The crude product is purified by flash chromatography to provide the title compound (DE5).


Method DE, Step 5: 5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-ylideneamine

Using a route similar to that described in Method A, step 3, DE5 is used to prepare the title compound (DE6).


As a variant of this method, DE2 is treated with ammonia and the resultant product is treated with sodium hydride and methyl iodide in DMF to give the product DE6


Method DF



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Method DF, Step 1: 2-Hydrazinocarbonylpropane-2-sulfonic acid cyclohexylamide

Using a method similar to that described by S. Paik and E. H. White (Tetrahedron, 1996, 52, 5303), 2-cyclohexylsulfamoyl-2-methylpropionic acid ethyl ester DF1 (which is prepared by the method of A. De Blic et al. (Synthesis, 1982, 281)) in ethanol is treated with 1.2 equivalent of 95% hydrazine under N2 and the mixture is allowed to stand at RT for 12 h. The reaction mixture is concentrated to give the title compound DF2 which is used directly in Step 2.


Method DF, Step 2: 2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-one-1,1-dioxide

A solution of DF2 in CH2Cl2 is refluxed under a N2 for 10 h. The solvent is removed in vacuo and the crude product is purified by flash chromatography to provide the title compound DF3.


Method DF, Step 3: 2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-thione-1,1-dioxide

To a solution of DF3 in toluene (or xylene) is added Lawesson's reagent (1.2 equivalents), and the mixture is stirred at reflux for 2 h. The mixture is cooled and poured into cold water. The organic phase is dried (MgSO4) and filtered, and solvent is removed. The crude product is purified by flash chromatography to provide the title compound (DF4).


Method DF, Step 4: 2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-imine-1,1-dioxide

Using a route similar to that described in Method A, step 3, DF4 is used to prepare the title compound (DF5).


Method DG



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Method DG, Step 1

To a stirred solution of the iminopyrimidinone DG1 (R1=Me, W=—(CO)—, R7=Me, R6=4-(m-cyanophenyl)thien-2-yl; 200 mg, 0.47 mmol, 1 equiv) in 1 mL THF at −20° C. in a reaction vial protected with nitrogen was slowly added 1M LiHMDS in THF (1 mL, 1.04 mmol, 2.2 equiv). After 20 min at −20° C., a solution of zinc chloride (142 mg, 1.04 mmol, 2.2 equiv) in THF (0.71 mL) was added. After 30 min at −20° C., the solution was transferred to a mixture of 2-(Dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl (DavePhos) (14 mg, 35.3 μmol, 7.5 mol %), Pd2 (dba)3 (22 mg, 23.6 μmol, 5.0 mol %) and Br—R3 (R3=Ph, 50 μL, 0.47 mmol, 1 equiv) in THF (0.5 mL). The reaction mixture was heated to 65° C. overnight, cooled to rt, quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with aqueous NaHCO3, brine and dried over anhydrous Na2SO4. The crude was purified on a flash column with EtOAc/hexane from 0 to 50% in 25 min.


The purified material was treated with 25% TFA in DCM for 30 min. After evaporation of TFA in vacuum, the residue was dissolved in DCM and neutralized with aqueous NaHCO3. The organic phase was washed with brine and dried over anhydrous Na2SO4. Solvent was evaporated in vacuum to give 78 mg (41.3%) of DG2 (R1=Me, W=—(CO)—, R7=Me, R6=4-(m-cyanophenyl)thien-2-yl, R3=Ph) as free base. 1H NMR (CDCl3) δ: 7.74 (m, 1H), 7.70-7.67 (m, 1H), 7.57-7.52 (m, 1H), 7.50-7.44 (m, 1H), 7.37-7.30 (m, 4H), 7.18-7.16 (m, 2H), 6.93 (m, 1H), 4.10 (s, 1H), 3.30 (s, 3H), 1.45 (s, 3H). MS (LCMS): Calcd for C23H21N4OS (M+H+): 401.14. Found: 401.2.


The following table contains example compounds which were synthesized with procedure(s) similar to methods listed in the corresponding column and whose LCMS data (obs. mass) (M+1) are also listed.


















Obs.


#
Compounds
Method
Mass


















1491


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CF
297





1492


embedded image


CF
333.9





1493


embedded image


CF
329.9





1494


embedded image


CF
367.9





1495


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AW
281





1496


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CF
306





1497


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AB
307





1498


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CF
314





1499


embedded image


CF
318





1500


embedded image


CF
325





1501


embedded image


CF
325





1502


embedded image


CF
330





1503


embedded image


CF
336





1504


embedded image


CF
336





1505


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AB
340





1506


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CE
342





1507


embedded image


CF
343





1508


embedded image


CF
344





1509


embedded image


CF
344





1510


embedded image


CF
344





1511


embedded image


AB
354





1512


embedded image


A
354





1513


embedded image


CF
358





1514


embedded image


CF
358





1515


embedded image


BS
358





1516


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A
364





1517


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A
366





1518


embedded image


A
366





1519


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A
368





1520


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A
370





1521


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AB
374





1522


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A
380





1523


embedded image


A
382





1524


embedded image


A
382





1525


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BS
383





1526


embedded image


CF
384





1527


embedded image


A
384





1528


embedded image


A
384





1529


embedded image


A
384





1530


embedded image


A
384





1531


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A
396





1532


embedded image


A
396





1533


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A
397





1534


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A
398





1535


embedded image


A
398





1536


embedded image


A
398





1537


embedded image


A
398





1538


embedded image


A
398





1539


embedded image


A
400





1540


embedded image


A
402





1541


embedded image


AB
404





1542


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A
406





1543


embedded image


A
406





1544


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BS
408





1545


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A
410





1546


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A
410





1547


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A
411





1548


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A
412





1549


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A
412





1550


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A
414





1551


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CE
415





1552


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A
416





1553


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A
417





1554


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A
417





1555


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A
419





1556


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A
420





1557


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A
421





1558


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A
422





1559


embedded image


A
422





1560


embedded image


A
422





1561


embedded image


A
423





1562


embedded image


A
423





1563


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CE
424





1564


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A
425





1565


embedded image


A
426





1566


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A
426





1567


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A
426





1568


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A
431





1569


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A
431





1570


embedded image


A
431





1571


embedded image


A
433





1572


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A
434





1573


embedded image


A
437





1574


embedded image


A
439





1575


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A
465





1576


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CG
470





1577


embedded image


CG
470





1578


embedded image


CG
470





1579


embedded image


CG
470





1580


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CE
474





1581


embedded image


CG
484





1582


embedded image


CG
484





1583


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BR
489





1584


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CF
274.1





1585


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AW
311.1





1586


embedded image


AB
312.1





1587


embedded image


AB
319.1





1588


embedded image


CF
320.1





1589


embedded image


CF
325.1





1590


embedded image


AB
328.1





1591


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AW
332.1





1592


embedded image


CE
333.1





1593


embedded image


CF
336.1





1594


embedded image


AW
337.1





1595


embedded image


CF
337.1





1596


embedded image


CF
337.1





1597


embedded image


CF
337.1





1598


embedded image


AB
338.1





1599


embedded image


AB
338.1





1600


embedded image


CE
338.1





1601


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CF
339.1





1602


embedded image


CE
339.1





1603


embedded image


AB
342.1





1604


embedded image


AW
343.1





1605


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AB
345.1





1606


embedded image


AB
346.1





1607


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AB
350.1





1608


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CF
350.1





1609


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AW
356.1





1610


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AW
357.1





1611


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AW
359.1





1612


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AB
362.1





1613


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CE
364.1





1614


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CE
365.1





1615


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AW
367.1





1616


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AW
368.1





1617


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AW
372.1





1618


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CF
373.1





1619


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AB
378.1





1620


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AW
378.1





1621


embedded image


CF
379.1





1622


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CF
384.1





1623


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BQ
386.1





1624


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BQ
387.1





1625


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AB
388.1





1626


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CO
399.1





1627


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BW
412.1





1628


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BW
412.1





1629


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CE
414.1





1630


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BQ
419.1





1631


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AW
421.1





1632


embedded image


AM
425.1





1633


embedded image


AW
425.1





1634


embedded image


BW
426.1





1635


embedded image


AW
436.1





1636


embedded image


BQ
439.1





1637


embedded image


BQ
440.1





1638


embedded image


BQ
453.1





1639


embedded image


CH
455.1





1640


embedded image


BW
463.1





1641


embedded image


Q
468.1





1642


embedded image


BS
478.1





1643


embedded image


BS
478.1





1644


embedded image


BS
484.1





1645


embedded image


BS
484.1





1646


embedded image


BQ
492.1





1647


embedded image


BW
492.1





1648


embedded image


BW
495.1





1649


embedded image


BW
496.1





1650


embedded image


Q
560.1





1651


embedded image


AW
569.1





1652


embedded image


BW
573.1





1653


embedded image


AW
470.1





1654


embedded image


AW
307.2





1655


embedded image


AW
308.2





1656


embedded image


CP
308.2





1657


embedded image


AW
315.2





1658


embedded image


AW
321.2





1659


embedded image


CO
321.2





1660


embedded image


AW
325.2





1661


embedded image


AW
326.2





1662


embedded image


AW
328.2





1663


embedded image


AW
331.2





1664


embedded image


CE
335.2





1665


embedded image


AW
336.2





1666


embedded image


AW
337.2





1667


embedded image


CF
339.2





1668


embedded image


AW
340.2





1669


embedded image


CO
341.2





1670


embedded image


AW
342.2





1671


embedded image


AW
346.2





1672


embedded image


AW
350.2





1673


embedded image


CJ
352.2





1674


embedded image


AW
354.2





1675


embedded image


AW
355.2





1676


embedded image


CE
359.2





1677


embedded image


AW
361.2





1678


embedded image


AW
361.2





1679


embedded image


AW
361.2





1680


embedded image


AW
362.2





1681


embedded image


AW
368.2





1682


embedded image


AW
372.2





1683


embedded image


AW
374.2





1684


embedded image


BQ
375.2





1685


embedded image


CL
377.2





1686


embedded image


BK
377.2





1687


embedded image


AW
377.2





1688


embedded image


CG
378.2





1689


embedded image


AW
383.2





1690


embedded image


CO
385.2





1691


embedded image


BQ
386.2





1692


embedded image


AW
406.2





1693


embedded image


CL
408.2





1694


embedded image


BS
409.2





1695


embedded image


BW
412.2





1696


embedded image


BW
413.2





1697


embedded image


BW
413.2





1698


embedded image


BS
420.2





1699


embedded image


R
425.2





1700


embedded image


R
425.2





1701


embedded image


BQ
429.2





1702


embedded image


BQ
430.2





1703


embedded image


R
434.2





1704


embedded image


R
434.2





1705


embedded image


BW
437.2





1706


embedded image


AW
439.2





1707


embedded image


BQ
440.2





1708


embedded image


BQ
441.2





1709


embedded image


BQ
441.2





1710


embedded image


BW
442.2





1711


embedded image


BQ
445.2





1712


embedded image


BQ
446.2





1713


embedded image


R
446.2





1714


embedded image


R
446.2





1715


embedded image


BS
448.2





1716


embedded image


R
448.2





1717


embedded image


BQ
450.2





1718


embedded image


BQ
450.2





1719


embedded image


BW
451.2





1720


embedded image


CI
452.2





1721


embedded image


BQ
454.2





1722


embedded image


BQ
454.2





1723


embedded image


AW
419.2





1724


embedded image


AW
423.2





1725


embedded image


AW
430.2





1726


embedded image


AW
431.2





1727


embedded image


AW
435.2





1728


embedded image


CK
439.2





1729


embedded image


AW
441.2





1730


embedded image


AW
450.3





1731


embedded image


CK
453.3





1732


embedded image


CK
453.3





1733


embedded image


AW
453.3





1734


embedded image


CK
455.3





1735


embedded image


L
467.3





1736


embedded image


L
467.3





1737


embedded image


CK
469.3





1738


embedded image


CK
481.3





1739


embedded image


CK
483.3





1740


embedded image


CK
497.3





1741


embedded image


CK
525.3





1742


embedded image


BQ
515.3





1743


embedded image


BQ
516.3





1744


embedded image


BQ
519.3





1745


embedded image


BS
522.3





1746


embedded image


BQ
525.3





1747


embedded image


BQ
532.3





1748


embedded image


CG
576.3





1749


embedded image


BQ
455.3





1750


embedded image


BW
456.3





1751


embedded image


BQ
456.3





1752


embedded image


BQ
456.3





1753


embedded image


BS
456.3





1754


embedded image


BQ
456.3





1755


embedded image


AW
456.3





1756


embedded image


BQ
458.3





1757


embedded image


BQ
458.3





1758


embedded image


BQ
458.3





1759


embedded image


BQ
458.3





1760


embedded image


BS
460.3





1761


embedded image


R
460.3





1762


embedded image


BW
462.3





1763


embedded image


BW
462.3





1764


embedded image


BW
463.3





1765


embedded image


BQ
464.3





1766


embedded image


BQ
464.3





1767


embedded image


BW
465.3





1768


embedded image


BQ
467.3





1769


embedded image


Q
467.3





1770


embedded image


BS
468.3





1771


embedded image


BW
468.3





1772


embedded image


Q
468.3





1773


embedded image


BQ
469.3





1774


embedded image


BQ
469.3





1775


embedded image


CG
469.3





1776


embedded image


BQ
470.3





1777


embedded image


BQ
470.3





1778


embedded image


BS
472.3





1779


embedded image


BQ
473.3





1780


embedded image


BQ
473.3





1781


embedded image


BS
473.3





1782


embedded image


Q
473.3





1783


embedded image


AW
473.3





1784


embedded image


BQ
474.3





1785


embedded image


BQ
478.3





1786


embedded image


AZ
478.3





1787


embedded image


AZ
478.3





1788


embedded image


BS
479.3





1789


embedded image


Q
481.3





1790


embedded image


BS
482.3





1791


embedded image


Q
482.3





1792


embedded image


R
482.3





1793


embedded image


R
482.3





1794


embedded image


R
482.3





1795


embedded image


R
482.3





1796


embedded image


BS
484.3





1797


embedded image


R
486.3





1798


embedded image


R
486.3





1799


embedded image


CK
487.3





1800


embedded image


BS
488.3





1801


embedded image


BS
488.3





1802


embedded image


BS
488.3





1803


embedded image


BQ
488.3





1804


embedded image


BW
488.3





1805


embedded image


R
488.3





1806


embedded image


BQ
489.3





1807


embedded image


BQ
489.3





1808


embedded image


AW
489.3





1809


embedded image


BQ
492.3





1810


embedded image


Q
493.3





1811


embedded image


BS
497.3





1812


embedded image


CG
497.3





1813


embedded image


BS
498.3





1814


embedded image


R
498.3





1815


embedded image



498.3





1816


embedded image



498.3





1817


embedded image


R
500.3





1818


embedded image


R
502.3





1819


embedded image


R
502.3





1820


embedded image


BS
504.3





1821


embedded image


BS
504.3





1822


embedded image


BQ
504.3





1823


embedded image


BQ
508.3





1824


embedded image


CF
329.1, 331.1





1825


embedded image


CF
334.0, 336.0





1826


embedded image


CF
342.1, 344.1





1827


embedded image


CF
352.0, 353.9





1828


embedded image


CF
358.1, 360.1





1829


embedded image


CF
363.1, 365.1





1830


embedded image


CF
367.9, 369.9





1831


embedded image


A
501.1 499





1832


embedded image


CE
309









The following compounds with their observed molecular masses (M+1) are listed in the table below.














#
Structure
Obs. Mass







1890


embedded image


376.2





1891


embedded image


340.2





1892


embedded image


380.2





1893


embedded image


456.3





1894


embedded image


405.1





1895


embedded image


498.3





1896


embedded image


350.2





1897


embedded image


484.3





1898


embedded image


388.2





1899


embedded image


416.1





1900


embedded image








1901


embedded image


457.4





1902


embedded image


541.3





1903


embedded image


500.3





1904


embedded image


397.1





1905


embedded image


336.8





1906


embedded image


364.4





1907


embedded image


399.2





1908


embedded image


321.1





1909


embedded image


461.3





1910


embedded image








1911


embedded image


476.3





1912


embedded image


561.3





1913


embedded image


332.2





1914


embedded image


385.2





1915


embedded image


308.0





1916


embedded image


460.3





1917


embedded image


468.3





1918


embedded image


493.3





1919


embedded image


399.2





1920


embedded image


466.3





1921


embedded image


358.1





1922


embedded image


428.3





1923


embedded image








1924


embedded image


308.2





1925


embedded image


360.2





1926


embedded image


341.2





1927


embedded image


338.3





1928


embedded image








1929


embedded image


448.3





1930


embedded image


262.1





1931


embedded image


489.3





1932


embedded image


459.9





1933


embedded image








1934


embedded image


446.0





1935


embedded image


435.2





1936


embedded image


400.2





1937


embedded image


479.3





1938


embedded image


480.3





1939


embedded image


392.0





1940


embedded image


374.2





1941


embedded image


380.0





1942


embedded image


314.2





1943


embedded image


476.3





1944


embedded image


358.2





1945


embedded image


373.2





1946


embedded image


312.2





1947


embedded image


393.2





1948


embedded image


468.3





1949


embedded image


319.0





1950


embedded image


503.3





1951


embedded image


362.0





1952


embedded image








1953


embedded image


314.2





1954


embedded image


392.2





1955


embedded image


451.3





1956


embedded image


533.3





1957


embedded image


373.3





1958


embedded image


350.2





1959


embedded image


472.3





1960


embedded image


340.4





1961


embedded image


455.3





1962


embedded image


332.2





1963


embedded image


505.3





1964


embedded image


409.2





1965


embedded image


300.2





1966


embedded image


340.1





1967


embedded image


410.2





1968


embedded image


363.2





1969


embedded image


441.2





1970


embedded image


375.2





1971


embedded image


412.2





1972


embedded image


418.2





1973


embedded image


434.1





1974


embedded image


329.2





1975


embedded image


441.2





1976


embedded image


568.3





1977


embedded image


267.2





1978


embedded image


455.3





1979


embedded image


327.9





1980


embedded image








1981


embedded image


344.1





1982


embedded image


396.1





1983


embedded image


358.0





1984


embedded image


443.2





1985


embedded image


404.2





1986


embedded image


314.2





1987


embedded image


303.2





1988


embedded image


375.2





1989


embedded image


410.4





1990


embedded image


384.2





1991


embedded image


314.2





1992


embedded image


349.0





1993


embedded image


379.9





1994


embedded image


408.2





1995


embedded image


470.3





1996


embedded image


379.3





1997


embedded image


449.3





1998


embedded image


285.2





1999


embedded image


254.1





2000


embedded image


321.3





2001


embedded image


337.1





2002


embedded image


338.1





2003


embedded image


420.2





2004


embedded image


427.2





2005


embedded image


490.9





2006


embedded image


457.4





2007


embedded image


461.3





2008


embedded image








2009


embedded image


336.2





2010


embedded image


506.3





2011


embedded image


484.3





2012


embedded image


352.0





2013


embedded image


387.0





2014


embedded image


384.2





2015


embedded image


523.3





2016


embedded image


353.2





2017


embedded image


419.1





2018


embedded image


343.2





2019


embedded image


475.3





2020


embedded image


364.1





2021


embedded image


413.2





2022


embedded image


472.3





2023


embedded image








2024


embedded image


479.3





2025


embedded image


357.2





2026


embedded image


434.2





2027


embedded image


432.2





2028


embedded image


400.1





2029


embedded image


384.2





2030


embedded image


448.3





2031


embedded image


401.2





2032


embedded image


295.1





2033


embedded image


392.2





2034


embedded image


456.3





2035


embedded image


421.0





2036


embedded image


343.2





2037


embedded image


343.0





2038


embedded image


344.2





2039


embedded image


303.0





2040


embedded image


250.0





2041


embedded image


469.3





2042


embedded image








2043


embedded image


373.2





2044


embedded image


381.2





2045


embedded image


471.3





2046


embedded image


356.2





2047


embedded image


299.2





2048


embedded image


333.0





2049


embedded image


475.3





2050


embedded image


352.2





2051


embedded image








2052


embedded image


531.3





2053


embedded image


382.0





2054


embedded image


372.2





2055


embedded image


377.2





2056


embedded image


402.2





2057


embedded image


434.2





2058


embedded image


448.3





2059


embedded image


477.3





2060


embedded image


366.2





2061


embedded image


462.3





2062


embedded image


435.2





2063


embedded image


341.2





2064


embedded image


489.3





2065


embedded image


365.2





2066


embedded image


357.2





2067


embedded image


519.3





2068


embedded image


338.2





2069


embedded image


362.2





2070


embedded image


442.2





2071


embedded image


282.0





2072


embedded image


443.2





2073


embedded image


486.3





2074


embedded image


413.2





2075


embedded image


444.2





2076


embedded image


503.3





2077


embedded image


430.2





2078


embedded image


429.2





2079


embedded image


357.2





2080


embedded image


326.0





2081


embedded image


339.2





2082


embedded image


335.2





2083


embedded image


354.2





2084


embedded image


442.2





2085


embedded image


343.2





2086


embedded image


434.0





2087


embedded image








2088


embedded image


460.3





2089


embedded image


398.2





2090


embedded image








2091


embedded image


476.3





2092


embedded image


376.2





2093


embedded image


413.2





2094


embedded image


432.2





2095


embedded image


579.3





2096


embedded image


388.2





2097


embedded image


471.3





2098


embedded image


435.2





2099


embedded image


317.2





2100


embedded image


357.2





2101


embedded image








2102


embedded image


416.2





2103


embedded image


468.3





2104


embedded image








2105


embedded image


434.2





2106


embedded image


398.2





2107


embedded image


349.2





2108


embedded image


381.2





2109


embedded image


423.2





2110


embedded image


486.3





2111


embedded image


320.0





2112


embedded image


350.2





2113


embedded image


232.1





2114


embedded image


360.2





2115


embedded image


356.2





2116


embedded image


366.2





2117


embedded image


346.2





2118


embedded image


375.2





2119


embedded image


336.2





2120


embedded image


393.0





2121


embedded image


310.2





2122


embedded image


339.2





2123


embedded image


408.2





2124


embedded image


479.3





2125


embedded image


355.2





2126


embedded image


397.2





2127


embedded image


432.3





2128


embedded image


337.2





2129


embedded image


402.2





2130


embedded image


359.2





2131


embedded image


380.2





2132


embedded image


352.1





2133


embedded image


370.2





2134


embedded image


314.2





2135


embedded image


397.9





2136


embedded image


408.2





2137


embedded image


504.3





2138


embedded image


347.1





2139


embedded image


362.2





2140


embedded image


326.3





2141


embedded image


381.2





2142


embedded image


320.1





2143


embedded image


329.2





2144


embedded image


471.3





2145


embedded image


445.2





2146


embedded image


321.2





2147


embedded image


560.3





2148


embedded image


255.0





2149


embedded image


338.2





2150


embedded image


474.3





2151


embedded image


360.2





2152


embedded image


371.2





2153


embedded image


342.9





2154


embedded image


560.3





2155


embedded image








2156


embedded image


374.8





2157


embedded image


296.0





2158


embedded image


391.2





2159


embedded image








2160


embedded image


441.9





2161


embedded image


387.2





2162


embedded image


330.2





2163


embedded image


407.2





2164


embedded image


408.2





2165


embedded image


483.1





2166


embedded image


386.2





2167


embedded image


441.2





2168


embedded image


519.3





2169


embedded image


388.2





2170


embedded image


298.2





2171


embedded image


471.0





2172


embedded image


409.2





2173


embedded image


339.1





2174


embedded image


368.2





2175


embedded image


501.3





2176


embedded image


388.2





2177


embedded image








2178


embedded image








2179


embedded image


405.1





2180


embedded image


331.2





2181


embedded image


454.3





2182


embedded image


479.3





2183


embedded image


392.2





2184


embedded image


379.1





2185


embedded image


351.2





2186


embedded image


482.3





2187


embedded image








2188


embedded image


319.0





2189


embedded image


352.2





2190


embedded image








2191


embedded image


372.1





2192


embedded image


449.3





2193


embedded image


353.2





2194


embedded image


379.3





2195


embedded image


447.3





2196


embedded image








2197


embedded image


377.3





2198


embedded image


372.2





2199


embedded image


385.2





2200


embedded image


433.2





2201


embedded image


420.2





2202


embedded image


350.2





2203


embedded image


459.3





2204


embedded image


363.0





2205


embedded image


383.2





2206


embedded image


431.9





2207


embedded image


287.2





2208


embedded image


402.9





2209


embedded image


429.2





2210


embedded image


365.2





2211


embedded image


325.1





2212


embedded image


461.3





2213


embedded image


449.2





2214


embedded image


310.2





2215


embedded image


431.2





2216


embedded image


336.2





2217


embedded image


372.2





2218


embedded image








2219


embedded image


395.2





2220


embedded image


484.3





2221


embedded image


479.3





2222


embedded image


360.2





2223


embedded image


543.3





2224


embedded image


411.2





2225


embedded image


358.2





2226


embedded image


286.2





2227


embedded image


290.0





2228


embedded image


386.1





2229


embedded image


386.1





2230


embedded image








2231


embedded image


415.2





2232


embedded image


456.3





2233


embedded image


377.2





2234


embedded image


447.3





2235


embedded image


366.2





2236


embedded image


340.2





2237


embedded image


388.1





2238


embedded image


417.2





2239


embedded image


398.2





2240


embedded image


471.3





2241


embedded image


427.3





2242


embedded image


312.2





2243


embedded image


466.3





2244


embedded image


218.1





2245


embedded image


470.3





2246


embedded image


373.2





2247


embedded image


415.2





2248


embedded image


400.0





2249


embedded image


275.2





2250


embedded image


466.0





2251


embedded image


435.2





2252


embedded image


371.2





2253


embedded image


394.2





2254


embedded image


449.3





2255


embedded image


483.3





2256


embedded image


495.3





2257


embedded image


340.0





2258


embedded image


413.2





2259


embedded image


302.2





2260


embedded image


350.2





2261


embedded image


321.1





2262


embedded image


455.3





2263


embedded image


526.3





2264


embedded image


477.3





2265


embedded image


341.1





2266


embedded image


316.2





2267


embedded image


392.2





2268


embedded image


301.0





2269


embedded image


483.3





2270


embedded image








2271


embedded image


321.2





2272


embedded image


448.3





2273


embedded image


481.3





2274


embedded image


257.1





2275


embedded image


325.0





2276


embedded image


250.3





2277


embedded image


450.3





2278


embedded image


316.2





2279


embedded image


486.3





2280


embedded image


464.3





2281


embedded image








2282


embedded image


369.2





2283


embedded image


302.0





2284


embedded image


362.2





2285


embedded image


300.0





2286


embedded image


462.3





2287


embedded image


331.0





2288


embedded image


535.3





2289


embedded image


364.2





2290


embedded image


305.1





2291


embedded image


337.0





2292


embedded image


376.2





2293


embedded image


418.2





2294


embedded image


345.3





2295


embedded image


353.1





2296


embedded image


375.2





2297


embedded image


411.1





2298


embedded image








2299


embedded image


409.2





2300


embedded image


310.2





2301


embedded image


339.2





2302


embedded image


394.2





2303


embedded image


383.2





2304


embedded image


356.2





2305


embedded image


479.3





2306


embedded image


269.2





2307


embedded image


341.2





2308


embedded image


439.2





2309


embedded image


439.1





2310


embedded image


410.2





2311


embedded image


322.1





2312


embedded image


401.0





2313


embedded image


351.2





2314


embedded image


439.2





2315


embedded image








2316


embedded image


420.2





2317


embedded image


438.2





2318


embedded image








2319


embedded image


509.3





2320


embedded image


425.2





2321


embedded image


434.2





2322


embedded image


390.2





2323


embedded image


357.2





2324


embedded image


467.3





2325


embedded image


296.1





2326


embedded image


310.2





2327


embedded image


342.2





2328


embedded image


331.3





2329


embedded image


343.0





2330


embedded image








2331


embedded image


489.3





2332


embedded image


332.2





2333


embedded image


487.3





2334


embedded image


411.0





2335


embedded image


442.2





2336


embedded image


356.2





2337


embedded image


441.2





2338


embedded image


496.3





2339


embedded image


472.3





2340


embedded image


425.2





2341


embedded image


359.2





2342


embedded image


379.0





2343


embedded image


459.3





2344


embedded image


435.2





2345


embedded image


436.2





2346


embedded image


390.2





2347


embedded image


383.2





2348


embedded image


281.1





2349


embedded image


363.2





2350


embedded image


359.2





2351


embedded image


363.2





2352


embedded image


418.2





2353


embedded image


427.2





2354


embedded image


450.9





2355


embedded image


483.3





2356


embedded image


415.2





2357


embedded image


395.2





2358


embedded image


466.3





2359


embedded image


390.2





2360


embedded image


460.3





2361


embedded image


388.0





2362


embedded image


486.3





2363


embedded image


375.2





2364


embedded image


445.2





2365


embedded image


444.2





2366


embedded image


392.2





2367


embedded image


417.2





2368


embedded image


326.2





2369


embedded image


337.8





2370


embedded image


418.2





2371


embedded image


487.3





2372


embedded image








2373


embedded image


329.3





2374


embedded image


493.3





2375


embedded image


354.2





2376


embedded image


368.2





2377


embedded image


288.2





2378


embedded image


429.2





2379


embedded image


519.3





2380


embedded image


354.2





2381


embedded image


376.2





2382


embedded image


274.2





2383


embedded image


314.1





2384


embedded image


388.2





2385


embedded image


412.2





2386


embedded image


351.2





2387


embedded image


395.1





2388


embedded image


372.2





2389


embedded image


375.2





2390


embedded image


411.9





2391


embedded image


249.1





2392


embedded image


442.2





2393


embedded image


397.0





2394


embedded image


327.3





2395


embedded image


433.2





2396


embedded image


420.2





2397


embedded image


383.2





2398


embedded image


378.2





2399


embedded image


258.1





2400


embedded image


460.3





2401


embedded image








2402


embedded image


491.3





2403


embedded image


416.1





2404


embedded image


465.3





2405


embedded image


350.4





2406


embedded image


457.3





2407


embedded image


389.2





2408


embedded image


386.2





2409


embedded image


407.2





2410


embedded image








2411


embedded image


337.1





2412


embedded image


329.1





2413


embedded image


478.3





2414


embedded image


413.0





2415


embedded image


327.2





2416


embedded image








2417


embedded image


450.3





2418


embedded image








2419


embedded image


314.2





2420


embedded image


405.2





2421


embedded image


450.3





2422


embedded image


396.1





2423


embedded image


449.3





2424


embedded image








2425


embedded image


317.2





2426


embedded image


472.3





2427


embedded image


448.3





2428


embedded image


342.2





2429


embedded image


370.2





2430


embedded image








2431


embedded image


491.3





2432


embedded image








2433


embedded image





2434


embedded image


344.2





2435


embedded image


508.3





2436


embedded image


390.2





2437


embedded image


368.2





2438


embedded image


370.2





2439


embedded image


331.2





2440


embedded image


427.2





2441


embedded image


365.2





2442


embedded image


419.2





2443


embedded image


447.3





2444


embedded image


436.2





2445


embedded image


389.2





2446


embedded image


341.2





2447


embedded image


428.2





2448


embedded image


377.2





2449


embedded image


456.3





2450


embedded image


387.4





2451


embedded image


431.2





2452


embedded image


307.2





2453


embedded image


392.0





2454


embedded image


467.3





2455


embedded image


428.2





2456


embedded image


407.4





2457


embedded image


324.2





2458


embedded image


451.3





2459


embedded image


377.2





2460


embedded image


318.2





2461


embedded image


304.2





2462


embedded image








2463


embedded image


432.2





2464


embedded image


515.3





2465


embedded image


343.2





2466


embedded image


427.0





2467


embedded image


414.2





2468


embedded image


501.3





2469


embedded image


475.3





2470


embedded image


401.2





2471


embedded image


366.2





2472


embedded image


312.1





2473


embedded image


461.9





2474


embedded image


335.2





2475


embedded image


481.3





2476


embedded image


304.2





2477


embedded image


344.3





2478


embedded image


393.2





2479


embedded image


383.2





2480


embedded image


508.9





2481


embedded image


363.2





2482


embedded image


405.2





2483


embedded image


435.2





2484


embedded image


319.0





2485


embedded image


356.2





2486


embedded image


395.1





2487


embedded image


461.3





2488


embedded image


406.2





2489


embedded image


434.2





2490


embedded image


467.3





2491


embedded image








2492


embedded image


469.4





2493


embedded image


408.1





2494


embedded image


446.2





2495


embedded image


384.0





2496


embedded image


380.2





2497


embedded image


392.2





2498


embedded image








2499


embedded image


510.3





2500


embedded image


469.3





2501


embedded image


363.0





2502


embedded image


375.1





2503


embedded image


372.2





2504


embedded image


236.0





2505


embedded image


260.1





2506


embedded image


417.2





2507


embedded image


322.2





2508


embedded image


512.3





2509


embedded image


465.3





2510


embedded image


454.3





2511


embedded image


427.2





2512


embedded image


250.1





2513


embedded image








2514


embedded image


405.2





2515


embedded image


334.2





2516


embedded image


358.2





2517


embedded image


340.2





2518


embedded image


334.1





2519


embedded image


369.2





2520


embedded image








2521


embedded image


356.2





2522


embedded image


393.2





2523


embedded image


379.2





2524


embedded image


406.0





2525


embedded image


454.1





2526


embedded image


413.2





2527


embedded image


337.1





2528


embedded image


461.3





2529


embedded image


312.2





2530


embedded image


371.2





2531


embedded image


255.1





2532


embedded image


359.2





2533


embedded image


399.2





2534


embedded image


420.2





2535


embedded image


420.2





2536


embedded image


455.3





2537


embedded image


357.0





2538


embedded image


367.2





2539


embedded image


467.3





2540


embedded image


441.2





2541


embedded image


456.3





2542


embedded image


395.1





2543


embedded image


461.1





2544


embedded image


319.2





2545


embedded image


468.3





2546


embedded image


511.1





2547


embedded image


344.0





2548


embedded image


484.3





2549


embedded image


495.3





2550


embedded image


486.3





2551


embedded image


426.2





2552


embedded image


283.0





2553


embedded image


479.3





2554


embedded image


351.2





2555


embedded image


372.2





2556


embedded image


340.1





2557


embedded image


410.2





2558


embedded image


359.2





2559


embedded image


352.2





2560


embedded image


432.2





2561


embedded image


434.2





2562


embedded image


390.2





2563


embedded image


398.3





2564


embedded image


563.0





2565


embedded image


356.2





2566


embedded image


394.0





2567


embedded image


326.2





2568


embedded image


335.2





2569


embedded image


380.2





2570


embedded image


498.3





2571


embedded image


331.2





2572


embedded image


434.2





2573


embedded image


501.3





2574


embedded image


418.2





2575


embedded image


324.0





2576


embedded image


455.3





2577


embedded image


361.0





2578


embedded image


489.3





2579


embedded image


388.2





2580


embedded image


389.2





2581


embedded image


338.0





2582


embedded image


338.1





2583


embedded image


309.5





2584


embedded image








2585


embedded image


330.2





2586


embedded image


430.0





2587


embedded image


459.3





2588


embedded image


403.2





2589


embedded image


339.0





2590


embedded image








2591


embedded image


347.2





2592


embedded image


344.1





2593


embedded image


381.2





2594


embedded image


391.2





2595


embedded image


339.0





2596


embedded image


383.2





2597


embedded image


540.3





2598


embedded image


359.2





2599


embedded image


461.3





2600


embedded image


453.3





2601


embedded image








2602


embedded image


433.2





2603


embedded image


408.3





2604


embedded image


311.2





2605


embedded image


302.2





2606


embedded image


340.2





2607


embedded image








2608


embedded image


466.3





2609


embedded image


406.1





2610


embedded image


386.2





2611


embedded image








2612


embedded image


402.2





2613


embedded image


467.3





2614


embedded image


410.0





2615


embedded image


326.2





2616


embedded image


445.2





2617


embedded image


441.2





2618


embedded image


458.3





2619


embedded image


461.3





2620


embedded image


443.2





2621


embedded image


498.3





2622


embedded image


299.1





2623


embedded image


349.2





2624


embedded image


387.4





2625


embedded image


420.9





2626


embedded image


403.8





2627


embedded image


434.2





2628


embedded image


419.2





2629


embedded image


377.1





2630


embedded image


456.3





2631


embedded image


387.1





2632


embedded image








2633


embedded image








2634


embedded image


384.2





2635


embedded image


290.2





2636


embedded image


310.0





2637


embedded image


399.2





2638


embedded image


431.2





2639


embedded image


354.1





2640


embedded image


313.2





2641


embedded image


393.3





2642


embedded image


424.2





2643


embedded image


495.3





2644


embedded image


326.1





2645


embedded image


418.9





2646


embedded image


302.9





2647


embedded image








2648


embedded image








2649


embedded image


305.1





2650


embedded image


485.1





2651


embedded image


375.2





2652


embedded image


351.2





2653


embedded image


315.9





2654


embedded image








2655


embedded image


503.3





2656


embedded image








2657


embedded image


283.0





2658


embedded image








2659


embedded image


386.2





2660


embedded image


351.2





2661


embedded image


560.3





2662


embedded image


502.3





2663


embedded image


481.3





2664


embedded image


428.2





2665


embedded image


311.2





2666


embedded image


403.8





2667


embedded image


402.2





2668


embedded image








2669


embedded image


444.2





2670


embedded image


366.2





2671


embedded image


385.2





2672


embedded image


497.3





2673


embedded image


497.3





2674


embedded image


381.2





2675


embedded image


279.2





2676


embedded image


444.2





2677


embedded image


413.2





2678


embedded image


323.2





2679


embedded image


430.2





2680


embedded image


325.1





2681


embedded image








2682


embedded image


457.3





2683


embedded image


357.2





2684


embedded image


479.1





2685


embedded image


363.9





2686


embedded image


485.3





2687


embedded image


515.3





2688


embedded image


341.0





2689


embedded image


427.2





2690


embedded image


364.2





2691


embedded image


442.2





2692


embedded image


390.2





2693


embedded image


467.3





2694


embedded image


452.3





2695


embedded image


372.2





2696


embedded image


356.2





2697


embedded image


380.2





2698


embedded image


271.2





2699


embedded image


335.0





2700


embedded image


279.2





2701


embedded image


502.3





2702


embedded image


170.0





2703


embedded image








2704


embedded image


356.2





2705


embedded image


368.2





2706


embedded image


435.2





2707


embedded image


468.3





2708


embedded image


438.2





2709


embedded image


405.1





2710


embedded image


339.2





2711


embedded image


310.3





2712


embedded image


336.2





2713


embedded image


479.3





2714


embedded image


330.2





2715


embedded image


372.2





2716


embedded image


322.2





2717


embedded image


363.1





2718


embedded image


368.2





2719


embedded image


516.3





2720


embedded image


468.3





2721


embedded image


365.0





2722


embedded image


298.1





2723


embedded image


394.2





2724


embedded image


254.0





2725


embedded image


272.2





2726


embedded image


257.1





2727


embedded image


505.3





2728


embedded image


463.3





2729


embedded image


311.0





2730


embedded image


456.3





2731


embedded image


343.2





2732


embedded image


483.3





2733


embedded image








2734


embedded image








2735


embedded image


258.1





2736


embedded image


466.3





2737


embedded image


370.0





2738


embedded image


225.1





2739


embedded image


411.2





2740


embedded image


505.3





2741


embedded image


378.2





2742


embedded image








2743


embedded image


352.2





2744


embedded image


420.2





2745


embedded image


498.3





2746


embedded image


490.3





2747


embedded image


372.2





2748


embedded image


447.3





2749


embedded image


359.3





2750


embedded image


486.3





2751


embedded image


426.2





2752


embedded image


323.2





2753


embedded image


370.2





2754


embedded image








2755


embedded image








2756


embedded image


408.2





2757


embedded image


421.2





2758


embedded image


421.0





2759


embedded image


417.2





2760


embedded image


311.2





2761


embedded image


449.3





2762


embedded image


326.2





2763


embedded image


340.2





2764


embedded image


345.2





2765


embedded image


450.3





2766


embedded image


380.2





2767


embedded image


340.3





2768


embedded image


375.2





2769


embedded image


301.2





2770


embedded image


336.2





2771


embedded image


422.2





2772


embedded image


348.2





2773


embedded image


331.2





2774


embedded image


429.2





2775


embedded image


496.3





2776


embedded image


380.2





2777


embedded image


342.2





2778


embedded image


343.2





2779


embedded image


348.2





2780


embedded image


427.2





2781


embedded image


272.2





2782


embedded image


376.2





2783


embedded image


399.0





2784


embedded image


403.9





2785


embedded image


467.3





2786


embedded image


328.1





2787


embedded image


457.3





2788


embedded image


451.3





2789


embedded image


514.3





2790


embedded image


462.3





2791


embedded image


295.2





2792


embedded image


445.2





2793


embedded image


501.3





2794


embedded image


378.2





2795


embedded image


373.2





2796


embedded image


369.2





2797


embedded image


342.1





2798


embedded image


339.2





2799


embedded image


477.3





2800


embedded image


375.2





2801


embedded image








2802


embedded image


378.0





2803


embedded image


394.2





2804


embedded image


400.2





2805


embedded image


349.2





2806


embedded image


446.3





2807


embedded image


499.3





2808


embedded image


491.3





2809


embedded image


449.1





2810


embedded image


468.3





2811


embedded image


359.2





2812


embedded image


311.0





2813


embedded image


472.3





2814


embedded image


481.3





2815


embedded image


410.2





2816


embedded image


394.2





2817


embedded image


238.2





2818


embedded image


326.2





2819


embedded image


380.2





2820


embedded image


438.2





2821


embedded image


254.1





2822


embedded image


458.8





2823


embedded image


424.2





2824


embedded image


349.2





2825


embedded image


429.2





2826


embedded image








2827


embedded image


395.2





2828


embedded image


392.2





2829


embedded image


350.2





2830


embedded image


363.2





2831


embedded image


388.2





2832


embedded image


531.3





2833


embedded image


397.2





2834


embedded image


379.1





2835


embedded image


435.2





2836


embedded image


327.3





2837


embedded image








2838


embedded image


418.2





2839


embedded image


426.0





2840


embedded image


462.3





2841


embedded image


258.1





2842


embedded image


343.0





2843


embedded image


390.2





2844


embedded image


345.1





2845


embedded image


415.2





2846


embedded image


372.2





2847


embedded image


380.0





2848


embedded image


480.3





2849


embedded image


283.2





2850


embedded image


370.2





2851


embedded image


356.2





2852


embedded image








2853


embedded image


342.2





2854


embedded image


456.3





2855


embedded image


401.1





2856


embedded image


452.3





2857


embedded image


367.2





2858


embedded image


364.2





2859


embedded image


356.2





2860


embedded image


435.2





2861


embedded image


485.3





2862


embedded image


451.3





2863


embedded image


364.1





2864


embedded image


341.2





2865


embedded image


316.0





2866


embedded image


250.3





2867


embedded image








2868


embedded image


340.2





2869


embedded image


367.0





2870


embedded image








2871


embedded image


343.2





2872


embedded image


421.2





2873


embedded image


425.2





2874


embedded image


438.2





2875


embedded image


450.3





2876


embedded image


461.3





2877


embedded image


342.2





2878


embedded image


497.3





2879


embedded image


457.3





2880


embedded image


428.2





2881


embedded image


497.3





2882


embedded image








2883


embedded image


405.1





2884


embedded image


475.3





2885


embedded image


344.0





2886


embedded image


483.3





2887


embedded image


375.2





2888


embedded image


467.3





2889


embedded image


350.2





2890


embedded image








2891


embedded image


335.2





2892


embedded image


342.2





2893


embedded image


434.2





2894


embedded image


384.2





2895


embedded image


317.2





2896


embedded image


393.2





2897


embedded image


443.2





2898


embedded image


444.0





2899


embedded image


316.0





2900


embedded image


379.2





2901


embedded image


386.1





2902


embedded image


258.0





2903


embedded image


379.2





2904


embedded image


394.2





2905


embedded image


449.3





2906


embedded image


427.2





2907


embedded image


219.1





2908


embedded image


410.2





2909


embedded image








2910


embedded image








2911


embedded image


395.0





2912


embedded image


490.3





2913


embedded image


261.1





2914


embedded image


394.2





2915


embedded image


242.1





2916


embedded image


377.2





2917


embedded image


343.7





2918


embedded image


468.3





2919


embedded image


307.2





2920


embedded image


390.2





2921


embedded image


330.0





2922


embedded image


555.3





2923


embedded image


483.3





2924


embedded image


394.2





2925


embedded image


443.2





2926


embedded image


340.2





2927


embedded image


369.2





2928


embedded image


443.2





2929


embedded image


433.2





2930


embedded image


454.3





2931


embedded image


444.1





2932


embedded image


436.2





2933


embedded image


435.2





2934


embedded image


471.3





2935


embedded image


385.2





2936


embedded image


358.2





2937


embedded image








2938


embedded image


451.3





2939


embedded image








2940


embedded image


355.1





2941


embedded image


324.1





2942


embedded image


372.2





2943


embedded image


382.1





2944


embedded image


372.1





2945


embedded image


478.3





2946


embedded image


515.3





2947


embedded image


455.3





2948


embedded image


407.1





2949


embedded image


490.3





2950


embedded image


423.0





2951


embedded image


333.2





2952


embedded image


258.1





2953


embedded image


404.2





2954


embedded image


449.3





2955


embedded image


453.3





2956


embedded image


489.3





2957


embedded image


470.3





2958


embedded image


376.2





2959


embedded image


377.0





2960


embedded image


392.0





2961


embedded image


373.2





2962


embedded image


309.0





2963


embedded image


331.1





2964


embedded image


400.2





2965


embedded image


346.2





2966


embedded image


364.1





2967


embedded image


351.1





2968


embedded image


339.3





2969


embedded image








2970


embedded image


355.0





2971


embedded image


383.1





2972


embedded image


429.2





2973


embedded image


441.2





2974


embedded image


442.2





2975


embedded image


351.0





2976


embedded image


349.2





2977


embedded image


456.3





2978


embedded image








2979


embedded image


443.2





2980


embedded image


333.1





2981


embedded image


450.1





2982


embedded image


359.0





2983


embedded image


368.2





2984


embedded image


352.2





2985


embedded image


253.1





2986


embedded image


453.3





2987


embedded image


350.4





2988


embedded image


392.2





2989


embedded image


355.2





2990


embedded image


432.1





2991


embedded image


462.3





2992


embedded image


399.2





2993


embedded image


402.2





2994


embedded image


305.1





2995


embedded image


429.4





2996


embedded image


337.2





2997


embedded image


418.2





2998


embedded image


460.3





2999


embedded image


359.2





3000


embedded image


296.1





3001


embedded image


452.3





3002


embedded image


405.1





3003


embedded image


441.2





3004


embedded image


349.2





3005


embedded image


423.2





3006


embedded image








3007


embedded image


398.0





3008


embedded image








3009


embedded image


355.1





3010


embedded image


458.3





3011


embedded image


286.2





3012


embedded image


493.3





3013


embedded image


340.2





3014


embedded image


343.0





3015


embedded image


322.0





3016


embedded image


441.2





3017


embedded image








3018


embedded image


428.2





3019


embedded image


329.2





3020


embedded image


340.2





3021


embedded image


294.1





3022


embedded image


479.3





3023


embedded image


404.1





3024


embedded image


489.3





3025


embedded image


308.0





3026


embedded image


447.3





3027


embedded image


365.2





3028


embedded image


407.2





3029


embedded image


460.3





3030


embedded image


449.3





3031


embedded image


312.2





3032


embedded image


406.2





3033


embedded image


272.2





3034


embedded image


601.3





3035


embedded image


321.2





3036


embedded image


404.9





3037


embedded image


357.0





3038


embedded image


311.2





3039


embedded image








3040


embedded image


292.2





3041


embedded image


300.1





3042


embedded image


344.2





3043


embedded image


340.2





3044


embedded image


387.2





3045


embedded image


491.3





3046


embedded image


322.2





3047


embedded image


344.3





3048


embedded image


476.3





3049


embedded image


399.2





3050


embedded image


438.1





3051


embedded image


433.1





3052


embedded image








3053


embedded image


284.2





3054


embedded image


388.2





3055


embedded image


340.2





3056


embedded image


289.0





3057


embedded image


357.2





3058


embedded image


441.2





3059


embedded image


383.2





3060


embedded image


285.2





3061


embedded image


399.2





3062


embedded image


459.3





3063


embedded image


437.2





3064


embedded image


378.2





3065


embedded image


390.2





3066


embedded image


376.2





3067


embedded image


412.2





3068


embedded image


360.2





3069


embedded image


363.2





3070


embedded image


448.3





3071


embedded image








3072


embedded image


434.1





3073


embedded image








3074


embedded image


374.8





3075


embedded image


416.1





3076


embedded image


496.3





3077


embedded image


462.3





3078


embedded image








3079


embedded image


439.1





3080


embedded image


340.2





3081


embedded image


372.1





3082


embedded image


368.2





3083


embedded image


450.3





3084


embedded image


401.9





3085


embedded image


391.0





3086


embedded image


515.3





3087


embedded image


362.2





3088


embedded image


346.1





3089


embedded image


326.3





3090


embedded image


341.2





3091


embedded image


417.2





3092


embedded image


375.1





3093


embedded image


456.3





3094


embedded image


460.3





3095


embedded image


438.2





3096


embedded image


447.3





3097


embedded image


375.2





3098


embedded image


252.0





3099


embedded image


463.3





3100


embedded image


469.3





3101


embedded image


359.0





3102


embedded image


387.2





3103


embedded image


435.2





3104


embedded image


470.3





3105


embedded image


390.2





3106


embedded image


354.2





3107


embedded image


413.2





3108


embedded image


376.2





3109


embedded image


449.3





3110


embedded image


451.1





3111


embedded image


466.3





3112


embedded image


372.2





3113


embedded image


589.3





3114


embedded image


368.0





3115


embedded image


320.0





3116


embedded image








3117


embedded image


381.0





3118


embedded image








3119


embedded image


301.0





3120


embedded image


368.2





3121


embedded image


509.3





3122


embedded image


364.2





3123


embedded image


383.2





3124


embedded image


425.2





3125


embedded image


467.3





3126


embedded image


363.2





3127


embedded image








3128


embedded image


306.2





3129


embedded image


505.8





3130


embedded image


351.2





3131


embedded image


391.2





3132


embedded image


336.2





3133


embedded image


300.1





3134


embedded image


418.2





3135


embedded image


476.9





3136


embedded image


514.3





3137


embedded image


451.3





3138


embedded image


461.3





3139


embedded image


330.2





3140


embedded image


467.3





3141


embedded image


447.3





3142


embedded image








3143


embedded image


344.0





3144


embedded image


371.2





3145


embedded image


391.2





3146


embedded image


341.2





3147


embedded image


452.3





3148


embedded image


314.2





3149


embedded image








3150


embedded image


484.3





3151


embedded image


460.3





3152


embedded image


434.2





3153


embedded image


482.3





3154


embedded image


408.2





3155


embedded image


310.0





3156


embedded image


340.2





3157


embedded image


407.3





3158


embedded image


373.2





3159


embedded image


335.2





3160


embedded image


487.3





3161


embedded image


387.2





3162


embedded image


449.3





3163


embedded image


303.2





3164


embedded image








3165


embedded image


453.3





3166


embedded image


385.3





3167


embedded image


369.0





3168


embedded image


476.3





3169


embedded image








3170


embedded image


350.2





3171


embedded image


371.2





3172


embedded image








3173


embedded image


490.3





3174


embedded image


457.4





3175


embedded image


326.2





3176


embedded image


441.2





3177


embedded image


451.3





3178


embedded image


403.2





3179


embedded image


309.5





3180


embedded image


483.3





3181


embedded image


420.2





3182


embedded image








3183


embedded image


457.3





3184


embedded image


315.2





3185


embedded image


315.0





3186


embedded image


307.0





3187


embedded image


469.3





3188


embedded image








3189


embedded image


362.2





3190


embedded image








3191


embedded image


317.0





3192


embedded image


391.2





3193


embedded image


355.2





3194


embedded image


328.3





3195


embedded image


343.3





3196


embedded image


345.1





3197


embedded image


357.2





3198


embedded image


456.3





3199


embedded image


304.0





3200


embedded image


417.2





3201


embedded image


607.3





3202


embedded image


348.2





3203


embedded image


391.1





3204


embedded image


368.2





3205


embedded image


243.1





3206


embedded image


428.2





3207


embedded image


437.2





3208


embedded image


457.3





3209


embedded image








3210


embedded image


459.3





3211


embedded image


430.2





3212


embedded image


371.2





3213


embedded image


318.2





3214


embedded image


358.2





3215


embedded image


434.1





3216


embedded image


334.2





3217


embedded image


477.3





3218


embedded image


384.1





3219


embedded image


350.2





3220


embedded image


477.3





3221


embedded image








3222


embedded image


326.2





3223


embedded image


432.2





3224


embedded image


439.0





3225


embedded image


333.1





3226


embedded image


457.2





3227


embedded image


512.3





3228


embedded image


479.3





3229


embedded image


372.1





3230


embedded image


376.2





3231


embedded image


455.3





3232


embedded image


428.2





3233


embedded image


467.3





3234


embedded image


348.2





3235


embedded image


370.2





3236


embedded image


459.3





3237


embedded image








3238


embedded image


399.2





3239


embedded image


410.2





3240


embedded image


378.2





3241


embedded image








3242


embedded image


349.2





3243


embedded image


412.2





3244


embedded image


312.2





3245


embedded image


479.3





3246


embedded image


469.3





3247


embedded image


365.2





3248


embedded image


375.3





3249


embedded image


542.3





3250


embedded image


448.3





3251


embedded image


370.2





3252


embedded image


329.0





3253


embedded image


441.2





3254


embedded image


342.2





3255


embedded image


358.0





3256


embedded image


391.2





3257


embedded image


257.1





3258


embedded image


443.2





3259


embedded image


458.3





3260


embedded image


204.1





3261


embedded image


326.2





3262


embedded image


365.2





3263


embedded image


475.3





3264


embedded image


299.1





3265


embedded image


431.2





3266


embedded image


309.2





3267


embedded image


387.4





3268


embedded image


431.2





3269


embedded image


357.2





3270


embedded image


486.3





3271


embedded image








3272


embedded image


380.2





3273


embedded image


404.2





3274


embedded image


432.2





3275


embedded image


432.2





3276


embedded image


379.1





3277


embedded image


400.0





3278


embedded image


409.2





3279


embedded image


306.2





3280


embedded image


347.0





3281


embedded image


593.3





3282


embedded image








3283


embedded image


378.1





3284


embedded image


409.2





3285


embedded image


383.2





3286


embedded image


396.2





3287


embedded image


323.2





3288


embedded image


309.4





3289


embedded image


483.3





3290


embedded image


372.0





3291


embedded image


348.3





3292


embedded image


328.1





3293


embedded image


403.2





3294


embedded image


460.0





3295


embedded image


418.2





3296


embedded image


481.3





3297


embedded image


382.2





3298


embedded image


432.2





3299


embedded image


342.0





3300


embedded image


415.2





3301


embedded image


503.3





3302


embedded image


347.2





3303


embedded image


332.0





3304


embedded image


325.2





3305


embedded image


298.2





3306


embedded image


358.2





3307


embedded image


314.2





3308


embedded image


435.2





3309


embedded image


412.3





3310


embedded image


360.2





3311


embedded image


352.2





3312


embedded image


308.2





3313


embedded image


224.1





3314


embedded image


390.1





3315


embedded image


351.2





3316


embedded image


335.2





3317


embedded image


373.2





3318


embedded image


457.3





3319


embedded image


387.2





3320


embedded image


465.3





3321


embedded image


325.1





3322


embedded image


354.2





3323


embedded image


326.2





3324


embedded image


342.1





3325


embedded image


370.2





3326


embedded image


475.3





3327


embedded image


459.3





3328


embedded image


450.3





3329


embedded image


418.2





3330


embedded image


463.3





3331


embedded image


475.3





3332


embedded image


515.3





3333


embedded image


411.2





3334


embedded image


384.1





3335


embedded image


459.3





3336


embedded image


421.2





3337


embedded image


380.2





3338


embedded image


378.2





3339


embedded image


451.3





3340


embedded image


597.3





3341


embedded image


448.3





3342


embedded image


315.3





3343


embedded image


353.1





3344


embedded image








3345


embedded image


335.2





3346


embedded image


448.3





3347


embedded image


363.2





3348


embedded image


483.3





3349


embedded image


407.2





3350


embedded image


453.3





3351


embedded image


348.2





3352


embedded image


411.2





3353


embedded image


464.3





3354


embedded image


463.3





3355


embedded image


427.2





3356


embedded image


463.3





3357


embedded image


493.7





3358


embedded image








3359


embedded image


236.1





3360


embedded image


441.2





3361


embedded image


420.2





3362


embedded image


343.0





3363


embedded image


306.2





3364


embedded image


324.2





3365


embedded image


554.3





3366


embedded image


424.2





3367


embedded image


302.2





3368


embedded image


392.2





3369


embedded image


392.2





3370


embedded image


421.0





3371


embedded image








3372


embedded image


391.1





3373


embedded image


306.2





3374


embedded image








3375


embedded image


300.2





3376


embedded image


521.3





3377


embedded image


404.9





3378


embedded image


374.0





3379


embedded image


379.2





3380


embedded image


422.2





3381


embedded image


445.2





3382


embedded image


434.3





3383


embedded image


386.2





3384


embedded image


461.3





3385


embedded image


302.0





3386


embedded image


404.4





3387


embedded image


296.2





3388


embedded image


442.2





3389


embedded image


318.0





3390


embedded image


340.2





3391


embedded image


447.3





3392


embedded image


310.1





3393


embedded image


376.2





3394


embedded image


335.9





3395


embedded image








3396


embedded image


344.2





3397


embedded image


336.2





3398


embedded image


456.3





3399


embedded image


424.2





3400


embedded image


413.2





3401


embedded image


412.2





3402


embedded image


364.2





3403


embedded image


389.2





3404


embedded image


356.0





3405


embedded image


385.1





3406


embedded image


462.3





3407


embedded image


311.0





3408


embedded image


418.2





3409


embedded image


444.2





3410


embedded image


365.0





3411


embedded image


386.2





3412


embedded image


390.2





3413


embedded image


437.2





3414


embedded image


337.2





3415


embedded image


312.2





3416


embedded image


367.2





3417


embedded image


466.3





3418


embedded image


349.2





3419


embedded image


343.2





3420


embedded image


285.9





3421


embedded image


327.0





3422


embedded image


427.2





3423


embedded image


305.9





3424


embedded image








3425


embedded image


455.3





3426


embedded image


368.2





3427


embedded image


425.0





3428


embedded image


390.2





3429


embedded image


356.2





3430


embedded image


410.2





3431


embedded image


441.4





3432


embedded image


326.3





3433


embedded image


503.3





3434


embedded image


385.2





3435


embedded image


423.2





3436


embedded image


465.3





3437


embedded image


275.2





3438


embedded image


278.0





3439


embedded image


310.2





3440


embedded image








3441


embedded image


399.2





3442


embedded image


498.3





3443


embedded image


447.0





3444


embedded image


394.2





3445


embedded image


369.0





3446


embedded image


313.2





3447


embedded image


443.2





3448


embedded image


309.4





3449


embedded image


418.2





3450


embedded image


439.2





3451


embedded image


461.3





3452


embedded image


281.1





3453


embedded image


392.0





3454


embedded image


275.1





3455


embedded image


485.1





3456


embedded image








3457


embedded image


460.3





3458


embedded image


434.1





3459


embedded image


342.2





3460


embedded image


555.3





3461


embedded image


329.1





3462


embedded image


354.0





3463


embedded image


457.3





3464


embedded image


455.3





3465


embedded image


395.2





3466


embedded image








3467


embedded image


335.2





3468


embedded image


412.3





3469


embedded image


345.1





3470


embedded image








3471


embedded image


399.0





3472


embedded image


456.3





3473


embedded image


170.1





3474


embedded image


463.3





3475


embedded image


320.0





3476


embedded image


336.2





3477


embedded image


467.0





3478


embedded image


353.2





3479


embedded image


340.0





3480


embedded image


446.0





3481


embedded image


463.1





3482


embedded image


486.3





3483


embedded image


393.2





3484


embedded image


315.4





3485


embedded image








3486


embedded image


317.2





3487


embedded image








3488


embedded image


367.2





3489


embedded image


455.3





3490


embedded image


268.3





3491


embedded image


373.2





3492


embedded image


518.3





3493


embedded image


444.2





3494


embedded image








3495


embedded image


471.3





3496


embedded image


321.1





3497


embedded image


297.3





3498


embedded image


326.2





3499


embedded image


348.2





3500


embedded image








3501


embedded image


379.2





3502


embedded image


470.3





3503


embedded image


362.1





3504


embedded image


372.1





3505


embedded image


406.1





3506


embedded image


377.2





3507


embedded image


365.0





3508


embedded image


368.2





3509


embedded image


379.0





3510


embedded image


224.0





3511


embedded image


463.3





3512


embedded image


449.1





3513


embedded image


546.3





3514


embedded image


382.2





3515


embedded image


446.3





3516


embedded image


463.3





3517


embedded image


408.2





3518


embedded image


448.3





3519


embedded image








3520


embedded image


470.3





3521


embedded image


365.2





3522


embedded image


468.3





3523


embedded image


354.2





3524


embedded image


318.2





3525


embedded image


380.2





3526


embedded image


352.2





3527


embedded image


402.1





3528


embedded image


452.2





3529


embedded image


388.2





3530


embedded image


373.2





3531


embedded image


326.1





3532


embedded image


509.3





3533


embedded image


414.0





3534


embedded image


476.3





3535


embedded image


283.2





3536


embedded image


323.2





3537


embedded image


324.2





3538


embedded image


502.3





3539


embedded image


324.2





3540


embedded image








3541


embedded image








3542


embedded image


393.3





3543


embedded image


516.1





3544


embedded image


491.3





3545


embedded image


353.2





3546


embedded image


324.0





3547


embedded image


371.2





3548


embedded image


374.2





3549


embedded image


418.2





3550


embedded image


415.2





3551


embedded image


346.9





3552


embedded image


360.2





3553


embedded image


365.4





3554


embedded image


364.2





3555


embedded image


441.2





3556


embedded image


436.0





3557


embedded image


507.3





3558


embedded image


337.2





3559


embedded image


341.2





3560


embedded image








3561


embedded image


311.2





3562


embedded image


410.0





3563


embedded image


316.2





3564


embedded image








3565


embedded image








3566


embedded image








3567


embedded image


453.3





3568


embedded image


449.3





3569


embedded image


467.3





3570


embedded image


325.0





3571


embedded image


452.3





3572


embedded image


254.1





3573


embedded image


243.1





3574


embedded image


388.2





3575


embedded image


434.2





3576


embedded image


378.0





3577


embedded image


324.2





3578


embedded image


313.1





3579


embedded image


316.2





3580


embedded image


224.1





3581


embedded image








3582


embedded image


495.3





3583


embedded image








3584


embedded image


373.2





3585


embedded image


439.2





3586


embedded image


365.2





3587


embedded image


455.3





3588


embedded image


356.1





3589


embedded image


475.3





3590


embedded image


380.2





3591


embedded image


417.1





3592


embedded image


427.2





3593


embedded image


299.1





3594


embedded image


366.2





3595


embedded image


435.2





3596


embedded image


348.2





3597


embedded image


196.1





3598


embedded image


378.2





3599


embedded image








3600


embedded image


401.2





3601


embedded image


363.1





3602


embedded image


426.2





3603


embedded image


453.3





3604


embedded image


353.4





3605


embedded image


505.3





3606


embedded image


484.3





3607


embedded image


518.3





3608


embedded image


446.0





3609


embedded image








3610


embedded image


393.2





3611


embedded image


423.2





3612


embedded image


379.2





3613


embedded image


436.2





3614


embedded image


401.2





3615


embedded image


421.2





3616


embedded image


418.2





3617


embedded image


343.2





3618


embedded image


388.2





3619


embedded image


385.0





3620


embedded image


362.1





3621


embedded image


344.0





3622


embedded image


294.1





3623


embedded image


480.4





3624


embedded image


366.1





3625


embedded image


432.2





3626


embedded image


365.2





3627


embedded image


478.3





3628


embedded image


417.2





3629


embedded image


324.1





3630


embedded image








3631


embedded image


326.2





3632


embedded image


351.0





3633


embedded image


434.2





3634


embedded image


443.2





3635


embedded image


392.2





3636


embedded image


457.4





3637


embedded image


328.2





3638


embedded image


466.3





3639


embedded image


447.3





3640


embedded image


396.2





3641


embedded image


485.0





3642


embedded image








3643


embedded image


345.0





3644


embedded image


302.0





3645


embedded image


349.0





3646


embedded image


413.2





3647


embedded image


389.2





3648


embedded image


425.2





3649


embedded image


356.2





3650


embedded image


398.2





3651


embedded image


405.1





3652


embedded image


373.2





3653


embedded image


408.2





3654


embedded image


442.2





3655


embedded image


388.2





3656


embedded image


333.2





3657


embedded image


481.3





3658


embedded image


331.2





3659


embedded image








3660


embedded image


331.0





3661


embedded image


441.2





3662


embedded image


326.2





3663


embedded image


492.3





3664


embedded image


509.3





3665


embedded image


418.1





3666


embedded image


208.2





3667


embedded image


438.2





3668


embedded image


415.2





3669


embedded image


356.2





3670


embedded image


443.2





3671


embedded image


310.1





3672


embedded image


297.0





3673


embedded image


498.3





3674


embedded image


442.2





3675


embedded image


461.3





3676


embedded image


455.3





3677


embedded image


359.2





3678


embedded image


476.3





3679


embedded image


499.3





3680


embedded image


395.2





3681


embedded image


493.3





3682


embedded image


425.2





3683


embedded image


366.0





3684


embedded image


378.2





3685


embedded image


356.2





3686


embedded image


496.3





3687


embedded image


379.2





3688


embedded image


436.2





3689


embedded image


499.3





3690


embedded image


415.9





3691


embedded image


358.0





3692


embedded image


354.2





3693


embedded image


343.0





3694


embedded image


301.2





3695


embedded image


448.3





3696


embedded image


496.3





3697


embedded image


490.3





3698


embedded image


379.2





3699


embedded image








3700


embedded image








3701


embedded image


375.2





3702


embedded image


482.3





3703


embedded image


378.2





3704


embedded image


342.2





3705


embedded image


354.4





3706


embedded image


422.2





3707


embedded image


252.1





3708


embedded image


525.3





3709


embedded image


444.2





3710


embedded image


356.2





3711


embedded image


261.0





3712


embedded image


351.3





3713


embedded image








3714


embedded image


401.2





3715


embedded image


441.2





3716


embedded image


406.9





3717


embedded image


457.3





3718


embedded image


313.1





3719


embedded image








3720


embedded image








3721


embedded image


421.1





3722


embedded image


478.3





3723


embedded image


316.2





3724


embedded image


307.3





3725


embedded image


461.8





3726


embedded image


390.2





3727


embedded image


470.4





3728


embedded image


371.0





3729


embedded image


502.3





3730


embedded image


342.2





3731


embedded image


372.0





3732


embedded image


494.3





3733


embedded image


476.1





3734


embedded image


362.2





3735


embedded image


454.3





3736


embedded image


272.2





3737


embedded image


399.2





3738


embedded image


471.4





3739


embedded image


424.2





3740


embedded image


369.2





3741


embedded image


453.1





3742


embedded image


460.3





3743


embedded image


445.2





3744


embedded image


392.2





3745


embedded image








3746


embedded image


359.2





3747


embedded image


442.2





3748


embedded image


258.1





3749


embedded image


303.2





3750


embedded image


444.2





3751


embedded image


282.3





3752


embedded image


456.3





3753


embedded image


413.2





3754


embedded image


409.0





3755


embedded image


371.0





3756


embedded image


476.3





3757


embedded image


346.0





3758


embedded image


502.3





3759


embedded image


480.3





3760


embedded image


476.3





3761


embedded image


343.1





3762


embedded image


414.2





3763


embedded image


386.2





3764


embedded image


367.1





3765


embedded image


362.2





3766


embedded image


275.0





3767


embedded image


351.2





3768


embedded image


536.3





3769


embedded image


333.2





3770


embedded image








3771


embedded image


376.2





3772


embedded image


436.2





3773


embedded image


471.3





3774


embedded image


297.3





3775


embedded image


385.2





3776


embedded image


448.3





3777


embedded image


462.3





3778


embedded image


273.2





3779


embedded image


308.2





3780


embedded image


328.2





3781


embedded image


381.0





3782


embedded image








3783


embedded image








3784


embedded image


354.1





3785


embedded image


449.2





3786


embedded image


445.2





3787


embedded image


475.3





3788


embedded image


484.0





3789


embedded image


343.0





3790


embedded image


430.2





3791


embedded image


391.3





3792


embedded image


355.4





3793


embedded image


335.9





3794


embedded image


457.3





3795


embedded image








3796


embedded image


470.3





3797


embedded image


344.2





3798


embedded image


396.2





3799


embedded image


439.2





3800


embedded image


332.2





3801


embedded image


555.3





3802


embedded image


264.2





3803


embedded image


407.2





3804


embedded image


399.2





3805


embedded image


404.2





3806


embedded image








3807


embedded image


443.2





3808


embedded image


339.2





3809


embedded image








3810


embedded image


421.2





3811


embedded image


369.2





3812


embedded image


496.3





3813


embedded image








3814


embedded image


384.2





3815


embedded image


436.2





3816


embedded image


394.2





3817


embedded image


354.1





3818


embedded image


543.3





3819


embedded image


352.2





3820


embedded image


402.2





3821


embedded image


460.3





3822


embedded image


453.3





3823


embedded image


470.3





3824


embedded image


502.3





3825


embedded image


508.3





3826


embedded image


337.0





3827


embedded image


258.1





3828


embedded image


410.2





3829


embedded image


267.3





3830


embedded image


390.1





3831


embedded image


300.2





3832


embedded image


351.1





3833


embedded image


352.2





3834


embedded image


373.2





3835


embedded image








3836


embedded image


384.2





3837


embedded image


484.3





3838


embedded image


348.2





3839


embedded image


388.0





3840


embedded image


396.2





3841


embedded image


326.1





3842


embedded image


302.2





3843


embedded image


461.3





3844


embedded image


345.2





3845


embedded image


448.3





3846


embedded image


357.1





3847


embedded image








3848


embedded image


250.1





3849


embedded image


445.9





3850


embedded image


417.2





3851


embedded image


336.0





3852


embedded image


254.1





3853


embedded image


369.1





3854


embedded image


541.1





3855


embedded image


420.2





3856


embedded image


503.1





3857


embedded image


382.2





3858


embedded image


340.2





3859


embedded image


358.1





3860


embedded image


453.3





3861


embedded image


362.2





3862


embedded image


421.1





3863


embedded image


353.1





3864


embedded image


384.2





3865


embedded image


371.2





3866


embedded image


328.0





3867


embedded image


249.0





3868


embedded image


309.2





3869


embedded image


485.3





3870


embedded image


431.2





3871


embedded image








3872


embedded image








3873


embedded image


384.2





3874


embedded image


314.2





3875


embedded image


459.3





3876


embedded image


382.2





3877


embedded image


336.1





3878


embedded image


260.1





3879


embedded image


438.2





3880


embedded image


325.1





3881


embedded image


296.2





3882


embedded image


456.3





3883


embedded image


337.1





3884


embedded image


376.2





3885


embedded image


459.3





3886


embedded image


379.4





3887


embedded image


446.2





3888


embedded image


384.2





3889


embedded image


357.2





3890


embedded image


456.3





3891


embedded image


375.2





3892


embedded image


378.2





3893


embedded image


354.1





3894


embedded image


399.2





3895


embedded image


467.3





3896


embedded image


351.2





3897


embedded image


327.3





3898


embedded image


301.2





3899


embedded image


348.2





3900


embedded image


507.3





3901


embedded image


321.1





3902


embedded image


451.3





3903


embedded image








3904


embedded image


331.1





3905


embedded image


379.0





3906


embedded image


331.0





3907


embedded image


460.3





3908


embedded image


282.1





3909


embedded image








3910


embedded image


594.7





3911


embedded image


387.2





3912


embedded image








3913


embedded image


299.2





3914


embedded image


423.0





3915


embedded image


400.1





3916


embedded image


400.0





3917


embedded image


351.2





3918


embedded image


312.2





3919


embedded image


427.2





3920


embedded image


297.0





3921


embedded image


483.3





3922


embedded image


252.1





3923


embedded image


308.1





3924


embedded image


376.2





3925


embedded image


354.2





3926


embedded image








3927


embedded image


442.2





3928


embedded image


430.2





3929


embedded image


324.2





3930


embedded image


399.2





3931


embedded image


330.2





3932


embedded image


349.2





3933


embedded image


314.2





3934


embedded image


339.0





3935


embedded image








3936


embedded image


478.3





3937


embedded image


430.2





3938


embedded image


281.0





3939


embedded image


385.2





3940


embedded image


490.3





3941


embedded image


501.3





3942


embedded image


515.3





3943


embedded image


483.3





3944


embedded image


345.3





3945


embedded image


492.3





3946


embedded image


481.3





3947


embedded image








3948


embedded image


385.2





3949


embedded image


358.2





3950


embedded image


507.3





3951


embedded image


335.2





3952


embedded image


314.2





3953


embedded image


415.1





3954


embedded image








3955


embedded image


452.3





3956


embedded image


431.2





3957


embedded image


321.2





3958


embedded image


390.2





3959


embedded image


433.2





3960


embedded image


325.2





3961


embedded image


354.2





3962


embedded image


443.2





3963


embedded image


408.2





3964


embedded image


351.2





3965


embedded image


357.2





3966


embedded image


397.2





3967


embedded image


559.3





3968


embedded image


465.3





3969


embedded image


455.3





3970


embedded image


459.3





3971


embedded image


341.2





3972


embedded image


504.3





3973


embedded image


490.1





3974


embedded image


429.2





3975


embedded image


459.3





3976


embedded image


386.2





3977


embedded image


440.2





3978


embedded image


409.2





3979


embedded image


402.2





3980


embedded image


354.2





3981


embedded image


490.3





3982


embedded image


457.3





3983


embedded image


330.3





3984


embedded image


419.2





3985


embedded image


369.2





3986


embedded image


412.2





3987


embedded image


447.3





3988


embedded image


460.3





3989


embedded image


436.2





3990


embedded image


461.3





3991


embedded image


466.1





3992


embedded image


468.0





3993


embedded image


359.2





3994


embedded image


299.2





3995


embedded image


432.2





3996


embedded image


293.2





3997


embedded image


422.2





3998


embedded image


329.1





3999


embedded image


389.4





4000


embedded image








4001


embedded image


515.3





4002


embedded image


370.0





4003


embedded image


463.3





4004


embedded image


314.3





4005


embedded image


489.3





4006


embedded image


399.2





4007


embedded image


431.4





4008


embedded image


472.3





4009


embedded image








4010


embedded image


427.2





4011


embedded image








4012


embedded image


359.9





4013


embedded image


385.2





4014


embedded image


372.0





4015


embedded image


300.2





4016


embedded image


657.1





4017


embedded image


345.1





4018


embedded image


387.2





4019


embedded image


358.2





4020


embedded image


401.2





4021


embedded image


350.2





4022


embedded image


415.0





4023


embedded image


392.0





4024


embedded image








4025


embedded image


497.3





4026


embedded image


442.2





4027


embedded image


286.2





4028


embedded image


516.3





4029


embedded image


336.2





4030


embedded image


396.2





4031


embedded image


408.2





4032


embedded image


330.0





4033


embedded image


383.2





4034


embedded image


287.0





4035


embedded image








4036


embedded image


354.1





4037


embedded image


493.3





4038


embedded image


481.3





4039


embedded image


389.2





4040


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501.3





4041


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476.3





4042


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416.2





4043


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344.2





4044


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423.8





4045


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483.3





4046


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452.3





4047


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537.7





4048


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469.0





4049


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501.3





4050


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326.0





4051


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361.0





4052


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495.3





4053


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470.3





4054


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459.0





4055


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393.2





4056


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337.2





4057


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342.2





4058


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422.2





4059


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367.2





4060


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452.3





4061


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357.2





4062


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186.2





4063


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477.3





4064


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351.2





4065


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409.2





4066


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340.2





4067


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408.1





4068


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447.0





4069


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372.2





4070


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405.2





4071


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359.2





4072


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4073


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351.2





4074


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311.2





4075


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515.3





4076


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4077


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444.1





4078


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417.2





4079


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323.2





4080


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4081


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389.1





4082


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539.3





4083


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363.0





4084


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395.2





4085


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408.2





4086


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4087


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309.2





4088


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395.2





4089


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455.3





4090


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386.2





4091


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447.3





4092


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463.3





4093


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436.2





4094


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340.2





4095


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505.3





4096


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433.2





4097


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347.1





4098


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376.2





4099


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299.1





4100


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411.1





4101


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426.1





4102


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375.1





4103


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496.3





4104


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352.2





4105


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394.2





4106


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369.2





4107


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311.2





4108


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377.2





4109


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372.2





4110


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341.2





4111


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459.3





4112


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423.0





4113


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351.1





4114


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481.3





4115


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350.2





4116


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420.2





4117


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330.1





4118


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407.2





4119


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426.1





4120


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393.2





4121


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446.3





4122


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338.2





4123


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336.2





4124


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405.1





4125


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408.2





4126


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449.3





4127


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396.2





4128


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461.3





4129


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365.2





4130


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404.2





4131


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470.3





4132


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428.2





4133


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425.2





4134


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382.2





4135


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445.2





4136


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509.3





4137


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426.2





4138


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313.1





4139


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385.2





4140


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483.3





4141


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326.1





4142


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500.3





4143


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427.2





4144


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489.3





4145


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334.2





4146


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359.0





4147


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315.3





4148


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373.2





4149


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462.3





4150


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453.3





4151


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371.2





4152


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410.2





4153


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450.3





4154


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380.2





4155


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407.2





4156


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297.1





4157


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350.2





4158


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390.2





4159


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326.0





4160


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4161


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397.2





4162


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340.3





4163


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419.2





4164


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377.2





4165


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397.2





4166


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399.2





4167


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330.2





4168


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392.0





4169


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469.3





4170


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472.3





4171


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416.2





4172


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481.3





4173


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325.1





4174


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4175


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528.3





4176


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322.1





4177


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398.2





4178


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374.2





4179


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421.2





4180


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392.2





4181


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409.5





4182


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364.2





4183


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386.1





4184


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339.2





4185


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286.2





4186


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547.3





4187


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359.2





4188


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354.2





4189


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301.2





4190


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436.0





4191


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472.3





4192


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380.2





4193


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315.2





4194


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4195


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316.2





4196


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390.1





4197


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393.1





4198


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516.3





4199


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404.2





4200


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452.3





4201


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337.8





4202


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397.1





4203


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350.1





4204


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496.3





4205


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417.1





4206


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458.3





4207


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4208


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343.0





4209


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434.3





4210


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357.2





4211


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476.3





4212


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4213


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511.3





4214


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342.2





4215


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254.1





4216


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360.2





4217


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344.2





4218


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4219


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469.3





4220


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325.3





4221


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322.2





4222


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344.2





4223


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364.2





4224


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285.9





4225


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465.3





4226


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386.2





4227


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427.2





4228


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4229


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337.2





4230


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426.2





4231


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343.2





4232


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501.3





4233


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404.9





4234


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210.1





4235


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507.3





4236


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467.3





4237


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336.2





4238


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249.1





4239


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368.2





4240


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426.2





4241


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399.2





4242


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480.3





4243


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360.2





4244


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403.2





4245


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375.2





4246


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340.2





4247


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4248


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357.0





4249


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286.2





4250


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341.2





4251


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444.2





4252


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361.2





4253


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432.1





4254


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499.3





4255


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356.0





4256


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310.0





4257


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426.2





4258


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388.1





4259


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428.0





4260


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313.9





4261


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410.2





4262


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443.2





4263


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359.0





4264


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335.2





4265


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411.2





4266


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250.0





4267


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391.2





4268


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490.3





4269


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309.2





4270


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475.9





4271


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449.3





4272


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316.0





4273


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482.3





4274


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497.1





4275


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331.2





4276


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320.1





4277


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509.3





4278


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444.2





4279


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373.2





4280


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541.3





4281


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493.3





4282


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359.0





4283


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300.2





4284


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359.2





4285


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338.0





4286


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446.3





4287


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396.2





4288


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4289


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419.2





4290


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444.2





4291


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337.3





4292


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568.3





4293


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375.2





4294


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297.0





4295


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4296


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340.2





4297


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4298


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482.3





4299


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397.2





4300


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383.2





4301


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382.2





4302


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406.2





4303


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434.1





4304


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359.2





4305


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274.2





4306


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320.2





4307


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308.2





4308


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394.2





4309


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323.1





4310


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356.2





4311


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354.2





4312


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500.3





4313


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4314


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384.2





4315


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463.3





4316


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441.2





4317


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346.2





4318


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403.2





4319


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449.3





4320


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476.3





4321


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4322


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389.2





4323


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312.2





4324


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439.1





4325


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335.2





4326


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323.1





4327


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380.2





4328


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409.2





4329


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378.2





4330


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340.2





4331


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394.2





4332


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378.2





4333


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434.1





4334


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465.3





4335


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356.2





4336


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443.2





4337


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403.2





4338


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4339


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329.2





4340


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423.0





4341


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368.2





4342


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369.0





4343


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326.3





4344


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332.0





4345


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4346


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4347


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486.3





4348


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433.2





4349


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469.3





4350


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260.1





4351


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393.2





4352


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4353


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4354


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459.3





4355


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335.1





4356


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351.0





4357


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486.3





4358


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250.3





4359


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379.2





4360


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332.2





4361


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342.1





4362


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4363


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562.3





4364


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370.2





4365


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360.0





4366


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402.7





4367


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487.1





4368


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427.2





4369


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421.0





4370


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272.2





4371


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316.2





4372


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4373


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409.0





4374


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301.9





4375


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358.2





4376


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326.2





4377


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429.2





4378


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357.0





4379


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363.2





4380


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4381


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380.2





4382


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357.2





4383


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4384


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369.2





4385


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310.0





4386


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332.2





4387


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375.2





4388


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283.3





4389


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384.0





4390


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302.0





4391


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4392


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469.3





4393


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354.2









Human Cathepsin D FRET Assay

This assay can be run in either continuous or endpoint format. The substrate used below has been described (Y. Yasuda et al., J. Biochem., 125, 1137 (1999)). Substrate and enzyme are commercially available.


The assay is run in a 30 ul final volume using a 384 well Nunc black plate. 8 concentrations of compound are pre-incubated with enzyme for 30 mins at 37 C followed by addition of substrate with continued incubation at 37 C for 45 mins. The rate of increase in fluorescence is linear for over 1 h and is measured at the end of the incubation period using a Molecular Devices FLEX station plate reader. K is are interpolated from the IC50s using a Km value of 4 uM and the substrate concentration of 2.5 uM.


Reagents




  • Na-Acetate pH 5

  • 1% Brij-35 from 10% stock (Calbiochem)

  • DMSO

  • Purified (>95%) human liver Cathepsin D (Athens Research & Technology Cat#16-12-030104)

  • Peptide substrate (Km=4 uM) Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH2 Bachem Cat # M-2455

  • Pepstatin is used as a control inhibitor (Ki˜0.5 nM) and is available from Sigma.

  • Nunc 384 well black plates


    Final Assay Buffer Conditions

  • 100 mM Na Acetate pH 5.0

  • 0.02% Brij-35

  • 1% DMSO



Compound is diluted to 3× final concentration in assay buffer containing 3% DMSO. 10 ul of compound is added to 10 ul of 2.25 nM enzyme (3×) diluted in assay buffer without DMSO, mixed briefly, spun, and incubated at 37 C for 30 mins. 3× substrate (7.5 uM) is prepared in 1× assay buffer without DMSO. 10 ul of substrate is added to each well mixed and spun briefly to initiate the reaction. Assay plates are incubated at 37 C for 45 mins and read on 384 compatible fluorescence plate reader using a 328 nm Ex and 393 nm Em.


Compounds of the present invention exhibit hCathD Ki data ranges from about 0.1 to about 500 nM, preferably about 0.1 to about 100 nM more preferably about 0.1 to about 75 nM.


The following are examples of compounds that exhibit hCathD Ki data under 75 nM.












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The following compound




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has a hCath D Ki value of 0.45 nM.


BACE-1 Cloning, Protein Expression and Purification

A predicted soluble form of human BACE1 (sBACE1, corresponding to amino acids 1-454) was generated from the full length BACE1 cDNA (full length human BACE1 cDNA in pcDNA4/mycHisA construct; University of Toronto) by PCR using the advantage-GC cDNA PCR kit (Clontech, Palo Alto, Calif.). A HindIII/PmeI fragment from pcDNA4-sBACE1myc/His was blunt ended using Klenow and subcloned into the Stu I site of pFASTBACI(A) (Invitrogen). A sBACE1mycHis recombinant bacmid was generated by transposition in DH10Bac cells (GIBCO/BRL). Subsequently, the sBACE1mycHis bacmid construct was transfected into sf9 cells using CellFectin (Invitrogen, San Diego, Calif.) in order to generate recombinant baculovirus. Sf9 cells were grown in SF 900-II medium (Invitrogen) supplemented with 3% heat inactivated FBS and 0.5× penicillin/streptomycin solution (Invitrogen). Five milliliters of high titer plaque purified sBACEmyc/His virus was used to infect 1 L of logarithmically growing sf9 cells using CellFectin (Invitrogen, San Diego, Calif.) in order to generate recombinant baculovirus. Sf9 cells were grown in SF 900-II medium (Invitrogen) supplemented with 3% heat inactivated FBS and 0.5× penicillin/streptomycin solution (Invitrogen). Five milliliters of high titer plaque purified sBACEmyc/His virus was used to infect 1 L of logarithmically growing sf9 cells for 72 hours. Intact cells were pelleted by centrifugation at 3000×g for 15 minutes. The supernatant, containing secreted sBACE1, was collected and diluted 50% v/v with 100 mM HEPES, pH 8.0. The diluted medium was loaded onto a Q-sepharose column. The Q-sepharose column was washed with Buffer A (20 mM HEPES, pH 8.0, 50 mM NaCl).


Proteins, were eluted from the Q-sepharose column with Buffer B (20 mM HEPES, pH 8.0, 500 mM NaCl). The protein peaks from the Q-sepharose column were pooled and loaded onto a Ni-NTA agarose column. The Ni-NTA column was then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mM NaCl). Bound proteins were then eluted with Buffer D (Buffer C+250 mM imidazole). Peak protein fractions as determined by the Bradford Assay (Biorad, CA) were concentrated using a Centricon 30 concentrator (Millipore). sBACE1 purity was estimated to be ˜90% as assessed by SDS-PAGE and Commassie Blue staining. N-terminal sequencing indicated that greater than 90% of the purified sBACE1 contained the prodomain; hence this protein is referred to as sproBACE1.


Peptide Hydrolysis Assay

The inhibitor, 25 nM EuK-biotin labeled APPsw substrate (EuK-KTEEISEVNLDAEFRHDKC-biotin (SEQ ID NO: 1); CIS-Bio International, France), 5 μM unlabeled APPsw peptide (KTEEISEVNLDAEFRHDK (SEQ ID NO: 2); American Peptide Company, Sunnyvale, Calif.), 7 nM sproBACE1, 20 mM PIPES pH 5.0, 0.1% Brij-35 (protein grade, Calbiochem, San Diego, Calif.), and 10% glycerol were preincubated for 30 min at 30° C. Reactions were initiated by addition of substrate in a 5 μl aliquot resulting in a total volume of 25 μl. After 3 hr at 30° C. reactions were terminated by addition of an equal volume of 2× stop buffer containing 50 mM Tris-HCl pH 8.0, 0.5 M KF, 0.001% Brij-35, 20 μg/ml SA-XL665 (cross-linked allophycocyanin protein coupled to streptavidin; CIS-Bio International, France) (0.5 μg/well). Plates were shaken briefly and spun at 1200×g for 10 seconds to pellet all liquid to the bottom of the plate before the incubation. HTRF measurements were made on a Packard Discovery® HTRF


and a fixed concentration of enzyme and substrate. Nonlinear regression analysis of this data was performed using GraphPad Prism 3.0 software selecting four parameter logistic equation, that allows for a variable slope. Y=Bottom+(Top−Bottom)/(1+10^((LogEC50−X)*Hill Slope)); X is the logarithm of concentration of I, Y is the percent change in ratio and Y starts at bottom and goes to top with a sigmoid shape.


Compounds of the present invention have an IC50 range from about 0.001 to about 500 μM, preferably about 0.001 to about 100 μM, more preferably about 0.001 to about 20 μM.


Examples of compounds with human BACE 1 IC50<1 μM are listed below:




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The following compounds below were named with the CAS name generating program: ACD/Labs Version 6.0; (Advanced Chemistry Development, Inc./110 Yonge Street/14th floor/Toronto, Ontario, Canada M5C 1T4). Examples of compounds with a BACE-1Ki less than 5 micromolar (uM) are listed below:

  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-2-imino-3-(2,2,2-trifluoroethyl)-
  • 3-[5-[5-[(E)-3-(4-FLUOROPHENYL)-2-PROPENYL]HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 3′-(4(R)-CYCLOPROPYL-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL)-4-FLUORO[1,1′-BIPHENYL]-3-CARBONITRILE
  • 3-CYANO-N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]BENZENESULFONAMIDE (RACEMIC)
  • N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]CYCLOPROPANEACETAMIDE (RACEMIC)
  • 5-[4-(3-CHLOROPHENYL)-2-THIENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE
  • PIPERIDINE, 1-(3-AMINO-1-OXOPROPYL)-4-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-
  • 2-IMINO-5-METHYL-5-[3-(3-PYRIDINYL)PHENYL]-3-[[3-(TETRAHYDRO-1,1-DIOXIDO-2H-1,2-THIAZIN-2-YL)PHENYL]METHYL]-4-IMIDAZOLIDINONE (RACEMIC)
  • 5(R)-[3-(5-CHLORO-3-PYRIDINYL)PHENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]METHANESULFONAMIDE
  • 5-[5[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]BENZO[b]THIEN-3-YL]-2-THIOPHENECARBONITRILE
  • 2-IMINO-5-[3-(5-METHOXY-3-PYRIDINYL)PHENYL]-5-METHYL-3-[[5-OXO-1-(PHENYLMETHYL)-3-PYRROLIDINYL]METHYL]-4-IMIDAZOLIDINONE
  • urea, N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]-N′-(4-chlorophenyl)-
  • 5-(3-BROMOPHENYL)-2-IMINO-3-METHYL-5-(1-METHYLCYCLOPROPYL)-4-IMIDAZOLIDINONE
  • 5(R)-ETHYLTETRAHYDRO-2-IMINO-6(S)-[3′-METHOXY[1,1′-BIPHENYL]-3-YL]-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 3-[2-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-4-THIAZOLYL]BENZONITRILE
  • 2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S),5(R)-TRIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(1-METHYL-1H-INDOL-5-YL)-4(1H)-PYRIMIDINONE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(2-METHYL-2H-INDAZOL-5-YL)-4(1H)-PYRIMIDINONE (ISOMER 2)
  • 1-piperidinecarboxamide, N-(3-fluorophenyl)-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-
  • 3-[5-(TETRAHYDRO-3-IMINO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-5-YL)-3-THIENYL]BENZONITRILE
  • 3-[2-ETHYL-5-(5(R)-ETHYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • 3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(METHYLSULFONYL)PYRROLIDINE
  • 1-[3-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)PHENYL]-3-PYRROLIDINECARBONITRILE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[3-(1-PIPERIDINYL)PHENYL]-4(1H)-PYRIMIDINONE
  • 5(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-5-[[3(R)-[(2-OXO-3(S)-PYRROLIDINYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • 5(R)-[3-(5-BROMO-3-PYRIDINYL)PHENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
    • 6(S)-[3-(5-BENZOTHIAZOLYL)PHENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 2-IMINO-5-OXO-4,4-DIPHENYL-N,N-DIPROPYL-1-IMIDAZOLIDINEPENTANAMIDE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-METHYL-5-[3-(TRIFLUOROMETHOXY)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE
  • 6(S)-[7-(6-FLUORO-3-PYRIDINYL)BENZO[b]THIEN-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5-[′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-(1-METHYL-1H-IMIDAZOL-2-YL)-4-IMIDAZOLIDINONE
  • 6(S)-[7-(3-FLUOROPHENYL)BENZO[b]THIEN-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • piperidine, 4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-(2-naphthalenylsulfonyl)-
  • piperidine, 1-(ethylsulfonyl)-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-
  • 5(R)-[3-(4-BROMO-2-PYRIDINYL)PHENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-2-METHYLBENZONITRILE
  • 5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-1-METHYL-1H-PYRAZOL-3-YL]-1,3-BENZENEDICARBONITRILE
  • 6(S)-[4-BROMO-5-(5-BROMO-3-PYRIDINYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 2-FLUORO-5-[4-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]BENZONITRILE
  • 6(S)-(2,4-DIFLUOROPHENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5-[3-[(1-ETHYL-1H-PYRAZOL-5-YL)AMINO]PHENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE
  • 1-ACETYL-4-[[2-IMINO-4-[5′-METHOXY-2′-[(PHENYLAMINO)METHYL][1,1′-BIPHENYL]-3-YL]-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[7-(4-PYRIDINYL)BENZO[b]THIEN-5-YL]-4(1H)-PYRIMIDINONE
  • PIPERIDINE, 3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-(1-OXOBUTYL)-, (3S)-
  • 6(S)-[3-(2-CYCLOPROPYLETHYL)BENZO[b]THIEN-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • PIPERIDINE, 1-ACETYL-3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-, (3S)-
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-4-PYRIDAZINECARBOXAMIDE
  • 2-IMINO-3-METHYL-5-PHENYL-5-[4-(3-PYRIDINYL)-2-THIENYL]-4-IMIDAZOLIDINONE
  • N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]-2-THIOPHENESULFONAMIDE (RACEMIC)
  • 6(S)-[3-(3-BROMOPHENYL)-1-METHYL-1H-PYRAZOL-5-YL]TETRAHYDRO-2-IMINO-3,5,5,6-TETRAMETHYL-4(1H)-PYRIMIDINONE
  • 6(S)-(1,3-DIMETHYL-1H-THIENO[2,3-c]PYRAZOL-5-YL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 6(S)-[4-(3-CHLOROPHENYL)-2-PYRIDINYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 2-IMINO-3-[(1-METHYL-1H-PYRAZOL-5-YL)METHYL]-5,5-DIPHENYL-4-IMIDAZOLIDINONE
  • 6(S)-[4-(3-ETHOXY-5-FLUOROPHENYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-5-METHOXY-1,4-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE (ENANTIOMER C)
  • 5(R)-[[3(R)-(CYCLOHEXYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-5-(2-PHENYLETHYL)-4-IMIDAZOLIDINONE
  • 2-IMINO-3-METHYL-5-PHENYL-5-[4-(5-PYRIMIDINYL)-2-THIENYL]-4-IMIDAZOLIDINONE
  • 6(S)-[3-(3-BROMOPHENYL)-5-ISOTHIAZOLYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-(3-PYRIDINYL)-2-THIAZOLYL]-4(1H)-PYRIMIDINONE
  • 4-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]BENZOYL]MORPHOLINE
  • 5-[5-FLUORO-3′-METHOXY[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE (RACEMIC)
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-[3-(TRIFLUOROMETHOXY)PHENYL]-2-PYRIDINYL]-4(1H)-PYRIMIDINONE
  • 1-ACETYL-4-[[4-(3′-HYDROXY[1,1′-BIPHENYL]-3-YL)-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE
  • 3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(PHENYLSULFONYL)PYRROLIDINE
  • 2-IMINO-3-METHYL-5(R)-(2-PHENYLETHYL)-5-[[3(S)-(3-PYRIDINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • 5-[5-(HEXAHYDRO-2-IMINO-1,4(S),5(R)-TRIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-1,3-BENZENEDICARBONITRILE
  • CYCLOPENTANECARBOXAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-
  • piperidine, 4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-(methylsulfonyl)-
  • 3-CHLORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]-3-FURANCARBOXAMIDE (RACEMIC)
  • 3-[4-(4-CYCLOPROPYL-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL)-2-THIENYL]BENZONITRILE
  • 6-(5-BROMO-2-THIENYL)-6-CYCLOPROPYLTETRAHYDRO-2-IMINO-3-METHYL-4(1H)-PYRIMIDINONE
  • 5-[5-[5(R)-CYCLOPROPYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-2-FLUORO-3-THIENYL]-2-FLUOROBENZONITRILE
  • 3-FLUORO-5-[2-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-5-THIAZOLYL]BENZONITRILE
  • 2-IMINO-5,5-DIPHENYL-3-(3-PYRIDINYLMETHYL)-4-IMIDAZOLIDINONE
  • 3-[[4-(3-BROMOPHENYL)-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-N,N-DIPROPYLBENZAMIDE (RACEMIC)
  • 1-[[5-[[4-(3-BROMOPHENYL)-4-CYCLOPROPYL-2-IMINO-5-OXO-1-IMIDAZOLIDINYL]METHYL]-3-PYRIDINYL]CARBONYL]-2(R)-(METHOXYMETHYL)PYRROLIDINE
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]BENZENESULFONAMIDE
  • 5-[4-FLUORO-3-(3-PYRIDINYL)PHENYL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE (RACEMIC)
  • 5(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-5-[[3(R)-[(2-PHENYLETHYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-(S)-CYCLOHEXYL]-N′-PHENYLUREA
  • piperidine, 4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-[[4-(trifluoromethoxy)phenyl]sulfonyl]-
  • 4-FLUORO-5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIOPHENECARBONITRILE
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-METHYL-2-THIENYL]BENZONITRILE
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-5(R)-[1-(4-METHYLPHENYL)-4-PIPERIDINYL]-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 5(S)-CYCLOPROPYL-2-IMINO-3-METHYL-5-[[3(R)-(2-QUINOLINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • N-ETHYL-N-[2-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]ETHYL]ACETAMIDE (RACEMIC)
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-4-METHYL-3-THIENYL]BENZONITRILE
  • 1-BUTANESULFONAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-(3-PYRIDINYL)-2-THIENYL]-4(1H)-PYRIMIDINONE
  • PIPERIDINE, 1-(CYCLOPROPYLSULFONYL)-3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-, (3R)-
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S),5(R)-TRIMETHYL-6-OXO-4-PYRIMIDINYL)-2-METHYL-3-THIENYL]-5-METHOXYBENZONITRILE
  • 6(S)-(3-BROMO-1H-INDAZOL-6-YL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5-[4-(5-CHLORO-3-PYRIDINYL)-2-THIENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-3-[1-(hydroxymethyl)propyl]-2-imino-
  • N-[3(S)-[[2-IMINO-1-METHYL-5-OXO-4(R)-(2-PHENYLETHYL)-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-4-PYRIDINECARBOXAMIDE
  • 2-IMINO-3,5-DIMETHYL-5-[3-(5-METHYL-3-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE (RACEMIC)
  • 6(S)-(2,4-DIFLUOROPHENYL)-5(R)-[1-(4-FLUOROPHENYL)-4-PIPERIDINYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 2-propanesulfonamide, N-[4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]phenyl]-
  • 2-IMINO-3-METHYL-5(R)-(2-PHENYLETHYL)-5-[[3(R)-(3-PYRIDINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • benzeneacetamide, N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]-
  • 4(S)-[4-(3-CYANOPHENYL)-2-THIENYL]HEXAHYDRO-2-IMINO-1,4-DIMETHYL-6-OXO-5(R/S)-PYRIMIDINEACETONITRILE
  • PIPERIDINE, 1-(CYCLOPROPYLCARBONYL)-3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-, (3S)-
  • 2-IMINO-5-[3-(5-METHOXY-3-PYRIDINYL)PHENYL]-5-METHYL-3-[(5-OXO-1-PHENYL-3-PYRROLIDINYL)METHYL]-4-IMIDAZOLIDINONE
  • 3(R)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]N-PHENYL-1-PYRROLIDINECARBOXAMIDE
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-5(R)-[1-(1-METHYLETHYL)-1H-PYRAZOL-4-YL]-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 3-[5-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)-3-THIENYL]BENZONITRILE
  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-2-imino-3-(1-methylethyl)-
  • 5(R)-CYCLOPROPYL-6(S)-[4-(2-FLUORO-3-PYRIDINYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 6(S)-[1-(3-ETHYLPHENYL)-1H-PYRAZOL-4-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 2-IMINO-5-[3′-METHOXY[1,1′-BIPHENYL]-3-YL]-5-METHYL-3-[[3-(TETRAHYDRO-1,1-DIOXIDO-2H-1,2-THIAZIN-2-YL)PHENYL]METHYL]-4-IMIDAZOLIDINONE (RACEMIC)
  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-3-cyclopentyl-5-cyclopropyl-2-imino-
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-[3-(METHYLTHIO)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE
  • 1-ACETYL-4-[[4-[2′-FORMYL-5′-METHOXY[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE
  • N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-N-METHYLMETHANESULFONAMIDE
  • 5-[3-(3-CHLOROPYRAZINYL)PHENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE (RACEMIC)
  • CYCLOHEXANECARBOXAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-
  • 2,6-DICHLORO-N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-4-PYRIDINECARBOXAMIDE
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)CYCLOHEXYL]-2-PYRIDINECARBOXAMIDE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-[3-(1-METHYLETHOXY)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE
  • urea, N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]-N′-phenyl-
  • 6(S)-(7-BROMOBENZO[b]THIEN-2-YL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 3-[5-(1-ETHYLHEXAHYDRO-2-IMINO-4(S)-METHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • 1-[3-[(2-IMINO-4-METHYL-5-OXO-4-PHENYL-1-IMIDAZOLIDINYL)METHYL]BENZOYL]-2(R)-(METHOXYMETHYL)PYRROLIDINE
  • 6(S)-(BENZO[b]THIEN-2-YL)TETRAHYDRO-2-IMINO-3,5(R),6-TRIMETHYL-4(1H)-PYRIMIDINONE
  • 5-CYCLOPROPYL-5-[4-[3-(HYDROXYMETHYL)PHENYL]-2-THIENYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 5-CYCLOPROPYL-5-[3-(1H-IMIDAZOL-1-YL)PHENYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-(1H-PYRAZOL-1-YL)-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE (ISOMER 2)
  • 2-FLUORO-5-[5-(TETRAHYDRO-3-IMINO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-5-YL)-3-THIENYL]BENZONITRILE
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-[(E)-3-PHENYL-2-PROPENYL]-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • N-[3(S)-[[2-IMINO-1-METHYL-5-OXO-4(R)-(2-PHENYLETHYL)-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-3-PYRIDINECARBOXAMIDE
  • 5(R)-CYCLOPROPYL-5-(4′-HYDROXY-3′-METHOXY[1,1′-BIPHENYL]-3-YL)-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 3-[5-(4(S)-ETHYLHEXAHYDRO-2-IMINO-1-METHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]BENZONITRILE
  • 2-IMINO-3,5(R)-DIMETHYL-5-[[3(R)-(PYRAZINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • 5-[2-(3,5-DICHLOROPHENYL)-4-PYRIDINYL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE
  • 5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-5-CYCLOHEXYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]CYCLOPENTANECARBOXAMIDE
  • 5-[4-(1,3-BENZODIOXOL-5-YL)-2-THIENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-4-HYDROXYBENZONITRILE
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-1-METHYL-1H-PYRAZOL-3-YL]BENZONITRILE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[7-(3-THIENYL)BENZO[b]THIEN-3-YL]-4(1H)-PYRIMIDINONE
  • PIPERIDINE, 4-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-(3-PYRIDINYLACETYL)-
  • N-[[[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]AMINO]CARBONYL]BENZAMIDE
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-2-NAPHTHALENEACETAMIDE
  • 5-[5-(3,4-DICHLOROPHENYL)HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-2-THIOPHENECARBONITRILE
  • N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]ETHANESULFONAMIDE
  • N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-1-PROPANESULFONAMIDE
  • 5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-DIHYDRO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-3(4H)-IMINE
  • 6(S)-ETHYLTETRAHYDRO-2-IMINO-3-METHYL-6-[4-(3-PYRIDINYL)-2-THIENYL]-4(1H)-PYRIMIDINONE
  • 6(S)-[3-(2-FLUORO-3-PYRIDINYL)PHENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 4-CHLORO-3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)BENZO[b]THIEN-7-YL]BENZONITRILE
  • 1-piperidinecarboxamide, N-(3-chlorophenyl)-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-
  • 3′-(TETRAHYDRO-3-IMINO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-5-YL)[1,1-BIPHENYL]-3-CARBONITRILE
  • 6(S)-[5-(3-ETHYLPHENYL)-1-METHYL-1H-PYRAZOL-3-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • PIPERIDINE, 3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-(1-OXOBUTYL)-, (3R)-
  • 1-ACETYL-4-[[2-IMINO-4-[3-(1H-INDOL-4-YL)PHENYL]-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE
  • 1-ACETYL-4-[[4(R)-[3-(5-BROMO-3-PYRIDINYL)PHENYL]-4-CYCLOPROPYL-2-IMINO-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE
  • 5-(3-BROMOPHENYL)-5-CYCLOHEXYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 6(S)-[5-(3-BROMOPHENYL)-2-THIAZOLYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5(R)-[4-(1,1-DIFLUOROETHYL)PHENYL]TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(2,4,6-TRIFLUOROPHENYL)-4(1H)-PYRIMIDINONE
  • piperidine, 1-[(3-chloro-4-fluorophenyl)sulfonyl]-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-
  • 5-[4-CHLORO-5-(HEXAHYDRO-2-IMINO-1,4(R)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-METHYL-2-THIENYL]-2-FLUOROBENZONITRILE
  • 6(S)-[4-(6-CHLOROPYRAZINYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-5-METHOXYBENZONITRILE
  • 3-CHLORO-5-[5-(5(R)-CYCLOPROPYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]BENZONITRILE
  • 3-[2-(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)ETHYL]-1-(METHYLSULFONYL)PIPERIDINE (RACEMIC)
  • 3(S)[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(CYCLOHEXYLCARBONYL)PYRROLIDINE
  • 1-ACETYL-4-[[2-IMINO-4-METHYL-4-[3-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL]-5-OXO-1-IMIDAZOLIDINYL]ETHYL]PIPERIDINE
  • 2-THIOPHENEACETAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-
  • 5(R)-(2-CYCLOHEXYLETHYL)-5-[[3(S)-(3(S)-HYDROXY-1-PYRROLIDINYL)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • PIPERIDINE, 3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-(PROPYLSULFONYL)-, (3R)-
  • 3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(CYCLOHEXYLACETYL)PYRROLIDINE
  • 5-[3′,5′-DICHLORO[1,1′-BIPHENYL]-3-YL]DIHYDRO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-3(4H)-IMINE
  • 6(S)-[1-(CYCLOPENTYLMETHYL)-1H-INDAZOL-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 1-BENZOYL-3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PYRROLIDINE
  • CYCLOPROPANESULFONAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-
  • 5-(3-BROMOPHENYL)-5-CYCLOBUTYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 5-CYCLOPROPYL-2-IMINO-3-METHYL-5-[3-(2-METHYL-4-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE
  • 2-IMINO-3,5(R)-DIMETHYL-5-[[3(R)-(2-QUINOXALINYLAMINO)-1 (S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]BENZAMIDE (RACEMIC)
  • BUTANAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-3,3-DIMETHYL-
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[1-METHYL-3-(2-THIENYL)-1H-INDOL-5-YL]-4(1H)-PYRIMIDINONE
  • 3-[3-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)BENZO[b]THIEN-7-YL]BENZONITRILE
  • 3-[5-[(1′2,3,3′,4′,6′-HEXAHYDRO-2′-IMINO-5-METHOXY-1′,4′(S)-DIMETHYL-6′-OXOSPIRO[1H-INDENE-1,5′(2′H)-PYRIMIDIN]-4′-YL]-3-THIENYL]BENZONITRILE
  • BENZAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-
  • TETRAHYDRO-2-IMINO-6(S)-[5-(3-METHOXYPHENYL)-4-METHYL-2-THIENYL]-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5(R)-[3-(5-CHLORO-2-FLUORO-3-PYRIDINYL)PHENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • N-[[5-CHLORO-3′-(2-IMINO-1,4-DIMETHYL-5-OXO-4-IMIDAZOLIDINYL)[1,1′-BIPHENYL]-2-YL]METHYL]-3-PYRIDINECARBOXAMIDE
  • 5-[3′-(HYDROXYMETHYL)[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE
  • 5-[3-(2-IMINO-1,4-DIMETHYL-5-OXO-4-IMIDAZOLIDINYL)PHENYL]-3-PYRIDINECARBONITRILE (RACEMIC)
  • 6(S)-[5-CHLORO[2,3′-BITHIOPHEN]-5′-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 3-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-1-METHYL-1H-PYRAZOL-3-YL]BENZONITRILE
  • 1-ACETYL-4-[[4-[3-(3-FURANYL)PHENYL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE
  • 6(S)-(2,6-DIFLUOROPHENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-5(R)-[4-(TRIFLUOROMETHYL)PHENYL]-4(1H)-PYRIMIDINONE
  • 5-[5(R)-(4-CYCLOPROPYLPHENYL)HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIOPHENECARBONITRILE
  • 5-(3-BROMOPHENYL)-2-IMINO-3-METHYL-5-(1-METHYLETHYL)-4-IMIDAZOLIDINONE
  • 6(S)-[4-[3-CHLORO-5-(1-METHYLETHOXY)PHENYL]-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-[2-(1-PIPERIDINYL)ETHYL]-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 5-[5-(5(S)-CYCLOBUTYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-3-PYRIDINECARBONITRILE
  • 5-[5-(5-BROMOHEXAHYDRO-2-IMINO-1,4(R)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-2-FLUOROBENZONITRILE
  • N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]METHANESULFONAMIDE (RACEMIC)
  • 2-IMINO-3-[(4-METHYLPHENYL)METHYL]-5,5-DIPHENYL-4-IMIDAZOLIDINONE
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5(R)-PROPYL-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • 5(R)-CYCLOPROPYLTETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[5-[3-(TRIFLUOROMETHYL)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE
  • 2-IMINO-5,5-DIPHENYL-3-[(TETRAHYDRO-2H-PYRAN-4-YL)METHYL]-4-IMIDAZOLIDINONE
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-THIAZOLYL]BENZONITRILE
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]ETHYL]-1(R)-CYCLOHEXYL]-2-QUINOLINECARBOXAMIDE
  • N-[3(S)-[[2-IMINO-1-METHYL-5-OXO-4(R)-(2-PHENYLETHYL)-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]ACETAMIDE
  • N-ETHYL-N-[2-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]ETHYL]METHANESULFONAMIDE (RACEMIC)
  • 2-IMINO-3-METHYL-5-PHENYL-5-[3-(2-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE (RACEMIC)
  • 6(S)-(3-CHLORO-2-THIENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 3′-(HEXAHYDRO-2-IMINO-1,4(R)-DIMETHYL-5-METHYLENE-6-OXO-4-PYRIMIDINYL)[1,1′-BIPHENYL]-3-CARBONITRILE
  • 4-imidazolidinone, 5-(3′-chloro[1,1-biphenyl]-3-yl)-5-cyclopropyl-2-imino-3-(1-methylpropyl)-2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-4-METHYL-3-THIENYL]BENZONITRILE
  • 2-IMINO-3-METHYL-5(R)-(2-PHENYLETHYL)-5-[[3-(2-PYRIDINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • 6(S)-[5-(3-CHLOROPHENYL)-2-THIAZOLYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-(2-THIAZOLYL)-4-IMIDAZOLIDINONE
  • 2-IMINO-3-METHYL-5-PHENYL-5-[3-[(PHENYLMETHYL)AMINO]PHENYL]-4-IMIDAZOLIDINONE (RACEMIC)
  • 6(S)-[7-(2-CHLORO-5-METHOXYPHENYL)BENZO[b]THIEN-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5(R)-CYCLOPROPYL-5-[3-(2-FLUORO-3-PYRIDINYL)PHENYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 6(S)-(3-BROMO-1-METHYL-1H-INDOL-5-YL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • benzenesulfonamide, N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]-
  • 2-IMINO-3,5(R)-DIMETHYL-5-[[3(R)-(2-QUINOLINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • 1-ACETYL-4-[[4-[3-[(1-ETHYL-1H-PYRAZOL-5-YL)AMINO]PHENYL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE (RACEMIC)
  • 6(S)-[2-(CYCLOHEXYLMETHYL)-2H-INDAZOL-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 6(S)-(BENZO[b]THIEN-5-YL)TETRAHYDRO-2-IMINO-3-(2-METHOXYETHYL)-6-METHYL-4(1H)-PYRIMIDINONE
  • 5(S)-[[3(R)-[(8-CHLORO-2-QUINOLINYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-5-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 6(S)-BENZO[b]THIEN-5-YLTETRAHYDRO-3-(2-HYDROXYETHYL)-2-IMINO-6-METHYL-4(1H)-PYRIMIDINONE
  • piperidine, 4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-(phenylsulfonyl)-
  • 5(R)-(2-CYCLOHEXYLETHYL)-5-[[3(R)-(3(R)-HYDROXY-1-PYRROLIDINYL)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 3-BROMO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • 3-[2-BROMO-5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • 6(S)-(2,4-DIFLUOROPHENYL)-5(R)-[4-(1,1-DIOXIDO-2-ISOTHIAZOLIDINYL)PHENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 2-IMINO-3-METHYL-5(R)-[[3(R)-(PHENYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-5-(2-PHENYLETHYL)-4-IMIDAZOLIDINONE
  • 1-ACETYL-4-[[2-IMINO-4-METHYL-5-OXO-4-[3-(1H-PYRAZOL-4-YL)PHENYL]-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE
  • TETRAHYDRO-2-IMINO-3,6-DIMETHYL-6(S)-[3-(1-PYRROLIDINYL)PHENYL]-4(1H)-PYRIMIDINONE
  • CYCLOPENTANEACETAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-
  • 2-IMINO-5,5-DIPHENYL-3-(3-THIENYLMETHYL)-4-IMIDAZOLIDINONE
  • DIHYDRO-5-[3′-METHOXY[1,1′-BIPHENYL]-3-YL]-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-3(4H)-IMINE
  • 5(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-5-[[3(S)-[(2-PHENYLETHYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • 5-[5-(5(S)-CYCLOBUTYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-2-FLUOROBENZONITRILE
  • benzamide, N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]-2-methoxy-
  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-3-cyclobutyl-5-cyclopropyl-2-imino-
  • 3-CHLORO-5-[5-(5(S)-CYCLOPROPYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-(3-PHENYLPROPYL)-5-(1H-PYRAZOL-1-YL)-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-2-METHOXYBENZAMIDE
  • 5-[3-(5-BROMO-3-PYRIDINYL)PHENYL]-2-IMINO-3-METHYL-5-(1-METHYLCYCLOPROPYL)-4-IMIDAZOLIDINONE
  • 5(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-5-[[3(S)-[(2-OXO-3(S)-PYRROLIDINYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE
  • 3-[5-[5-[(E)-3-(3-FLUOROPHENYL)-2-PROPENYL]HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 5-[3-BROMO-5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]-3-PYRIDINECARBONITRILE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[7-(3-PYRIDINYL)BENZO[b]THIEN-5-YL]-4(1H)-PYRIMIDINONE
  • 5-[5′-CHLORO-2′-(2-HYDROXYETHYL)[1,1′-BIPHENYL]-3-YL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE
  • 5-[5′-CHLORO-2′-[2-(FORMYLOXY)ETHYL][1,1′-BIPHENYL]-3-YL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE
  • BUTANAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-3-METHYL-5-CYCLOPROPYL-2-IMINO-5-[4-(5-METHOXY-3-PYRIDINYL)-2-THIENYL]-3-METHYL-4-IMIDAZOLIDINONE
  • 5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-(2-PYRIMIDINYL)-4-IMIDAZOLIDINONE
  • ethanesulfonamide, N-[4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]phenyl]-
  • 5-[3′-BROMO-5′-(TRIFLUOROMETHOXY)[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE (RACEMIC)
  • N-[[5-CHLORO-3′-(2-IMINO-1,4-DIMETHYL-5-OXO-4-IMIDAZOLIDINYL)[1,1′-BIPHENYL]-2-YL]METHYL]-4-PYRIDAZINECARBOXAMIDE
  • 6(S)-(4-ETHYL-2-THIENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 4-CHLORO-5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIOPHENECARBONITRILE
  • 5-[5-(4-CYCLOPROPYLHEXAHYDRO-2-IMINO-1-METHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]-2-FLUOROBENZONITRILE
  • TETRAHYDRO-2-IMINO-6(S)-[1-(3-IODOPHENYL)-1H-PYRAZOL-4-YL]-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 3′-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5(R)-PROPYL-4-PYRIMIDINYL)[1,1′-BIPHENYL]-3-CARBONITRILE
  • 5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-1,3-BENZENEDICARBONITRILE
  • 1-[3-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]BENZOYL]-2(R)-(METHOXYMETHYL)PYRROLIDINE
  • TETRAHYDRO-2-IMINO-5(R)-(4-METHOXYPHENYL)-3,6(S)-DIMETHYL-6-(5-THIAZOLYL)-4(1H)-PYRIMIDINONE
  • 1-[[5-[(4-CYCLOPROPYL-2-IMINO-5-OXO-4-PHENYL-1-IMIDAZOLIDINYL)METHYL]-3-PYRIDINYL]CARBONYL]-2(R)-(METHOXYMETHYL)PYRROLIDINE
  • 5-(3-BROMOPHENYL)-5-CYCLOPENTYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-3-[3-(diethylamino)propyl]-2-imino-
  • 5(R)-(4-CYCLOPROPYLPHENYL)-6(S)-[2′-FLUORO[2,3′-BIPYRIDIN]-4-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5-CYCLOPROPYL-2-IMINO-3-METHYL-5-[3-(6-METHYL-2-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE
  • N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]ETHYL]-1(R)-CYCLOHEXYL][1,1′-BIPHENYL]-2-CARBOXAMIDE
  • 3-[5-[HEXAHYDRO-2-IMINO-4(S)-METHYL-6-OXO-1-(4-PYRIDINYLMETHYL)-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 5(R)-CYCLOPROPYL-5-[3′(HYDROXYMETHYL)[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • TETRAHYDRO-2-IMINO-6(S)-(3-IODOPHENYL)-3,6-DIMETHYL-5(R)-PROPYL-4(1H)-PYRIMIDINONE
  • 2-IMINO-5-PHENYL-3-(4-PIPERIDINYLMETHYL)-5-[3-(3-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE
  • 5-[5-[5(R)-CYCLOPROPYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIENYL]-2-FLUOROBENZONITRILE
  • 5(R)-[[3(R)-(CYCLOPENTYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-5-(2-PHENYLETHYL)-4-IMIDAZOLIDINONE
  • 6(S)-[4-(2,6-DIFLUORO-3-PYRIDINYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 5(R)-(2-CYCLOHEXYLETHYL)-5-[[3(S)-(3(R)-HYDROXY-1-PYRROLIDINYL)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(1-PROPYL-1H-INDAZOL-6-YL)-4(1H)-PYRIMIDINONE
  • 6(S)-(4-FLUORO-2-METHYLPHENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(7-PHENYLBENZO[b]THIEN-3-YL)-4(1H)-PYRIMIDINONE
  • piperidine, 4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-(propylsulfonyl)-
  • 5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-5-(CYCLOPROPYLMETHYL)-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • piperidine, 4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-[(4-methoxyphenyl)sulfonyl]-
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-(5-PYRIMIDINYL)-2-THIENYL]-4(1H)-PYRIMIDINONE
  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-3-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-2-imino-
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-[3-(4-PYRIDINYL)PROPYL]-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-(1-METHYLCYCLOPROPYL)-4-IMIDAZOLIDINONE
  • 5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-5-METHYL-3-[(1-METHYL-3(S)-PYRROLIDINYL)METHYL]-4-IMIDAZOLIDINONE
  • 6(S)-(4-BROMO-2-FURANYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(PHENYLACETYL)PYRROLIDINE
  • 3-(3-FURANYLMETHYL)-2-IMINO-5,5-DIPHENYL-4-IMIDAZOLIDINONE
  • 5(R)-(2-CYCLOHEXYLETHYL)-5-[[3(R)-(DIMETHYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-5(R)-[3-(1-METHYLETHOXY)PHENYL]-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • PIPERIDINE, □4-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-[(1-PHENYLCYCLOPROPYL)CARBONYL]-
  • BUTANAMIDE, N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-
  • 3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-(3-PHENYLPROPYL)-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 5-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-N,N-DIPROPYL-1H-IMIDAZOLE-2-CARBOXAMIDE
  • N-[[5-CHLORO-3′-(2-IMINO-1,4-DIMETHYL-5-OXO-4-IMIDAZOLIDINYL)[1,1′-BIPHENYL]-2-YL]METHYL]-4-PYRIDINECARBOXAMIDE
  • 6(S)-[2′-FLUORO[2,3′-BIPYRIDIN]-4-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE
  • 2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-1-METHYL-1H-PYRAZOL-3-YL]BENZONITRILE
  • 3-CHLORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S),5(R)-TRIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE
  • N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]BENZENESULFONAMIDE (RACEMIC)
  • 2-FLUORO-5-[(4S)-2′,3′,5′,6,6′,7-HEXAHYDRO-2′-IMINO-1′-METHYL-6′-OXOSPIRO[BENZO[b]THIOPHENE-4(5H), 4′(1′H)-PYRIMIDIN]-2-YL]BENZONITRILE
  • 5-[3-(5-FLUORO-3-PYRIDINYL)PHENYL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE
  • 5-[2′-FLUORO-5′-METHOXY[1,1′-BIPHENYL]-3-YL]DIHYDRO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-3(4H)-IMINE
  • 5-[3-(3-FURANYL)PHENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE (RACEMIC)
  • piperidine, 1-(butylsulfonyl)-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-
  • 2-IMINO-3-METHYL-5-PHENYL-5-[3-(3-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE (ENANTIOMER B)
  • 5(S)-[[3(R)-[(6-CHLORO-2-QUINOXALINYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-5-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE
  • 3-[5-[5(R)-BENZO[b]THIEN-3-YLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE
  • 5-[5(R)[3-(1,1-DIFLUOROETHYL)PHENYL]HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-1H-IMIDAZOLE
  • 5-CYCLOPROPYL-2-IMINO-3-METHYL-5-[4-METHYL[2,3′-BITHIOPHEN]-5′-YL]-4-IMIDAZOLIDINONE
  • 1-butanesulfonamide, N-[4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]phenyl]-
  • 5-[4-(3-FLUOROPHENYL)-2-THIENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE
  • 2-IMINO-5,5-DIPHENYL-[[3-1-(2-QUINOLINYL)-4-PIPERIDINYL]METHYL]-4-IMIDAZOLIDINONE
  • PIPERIDINE, 1-(AMINOACETYL)-4-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-
  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-2-imino-3-(tetrahydro-2H-pyran-4-yl)-
  • 3′-[1-[(1-ACETYL-4-PIPERIDINYL)METHYL]-2-IMINO-4-METHYL-5-OXO-4-IMIDAZOLIDINYL]-N-(2-FURANYLMETHYL)[1,1′-BIPHENYL]-3-CARBOXAMIDE
  • 5(R)-CYCLOPROPYL-2-IMINO-3-METHYL-5-[3′-(METHYLTHIO)[1,1′-BIPHENYL]-3-YL]-4-IMIDAZOLIDINONE
  • 4-imidazolidinone, 5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-3-[2-hydroxy-1-(hydroxymethyl)ethyl]-2-imino-
  • 2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-5-METHOXY-1,4-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE (ENANTIOMER B)
  • 5-[5(R)-[4-(1,1-DIFLUOROETHYL)PHENYL]HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-2-THIOPHENECARBONITRILE
  • 4-[4(S)-[4-(3-CYANOPHENYL)-2-THIENYL]HEXAHYDRO-2-IMINO-1,4-DIMETHYL-6-OXO-5(R)-PYRIMIDINYL]-N,N-DIMETHYL-1-PIPERIDINECARBOXAMIDE
  • TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[3-METHYL-4-[3-(TRIFLUOROMETHOXY)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE
  • 3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-(1,2,3,6-TETRAHYDRO-1-PHENYL-4-PYRIDINYL)-3-THIENYL]BENZONITRILE


    Human Mature Renin Enzyme Assay:


Human Renin was cloned from a human kidney cDNA library and C-terminally epitope-tagged with the V5-6His sequence into pcDNA3.1. pCNDA3.1-Renin-V5-6His was stably expressed in HEK293 cells and purified to >80% using standard Ni-Affinity chromatography. The prodomain of the recombinant human renin-V5-6His was removed by limited proteolysis using immobilized TPCK-trypsin to give mature-human renin. Renin enzymatic activity was monitored using a commercially available fluorescence resonance energy transfer (FRET) peptide substrate, RS-1 (Molecular Probes, Eugene, Oreg.) in 50 mM Tris-HCl pH 8.0, 100 mM NaCl, 0.1% Brij-35 and 5% DMSO buffer for 40 mins at 30 degrees celsius in the presence or absence of different concentrations of test compounds. Mature human Renin was present at approximately 200 nM. Inhibitory activity was defined as the percent decrease in renin induced fluorescence at the end of the 40 min incubation compared to vehicle controls and samples lacking enzyme.














1% of hRenin


Compound
at 100 μM









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68.8







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75.3







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76.9









In another embodiment of a compound of formula I having the structural formula




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or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate or ester thereof, wherein


W is —C(═O)—;


X is —N(R5)—;


U is a bond;


R1, R2 and R5 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;


R3 and R4 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;


R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R18-alkyl, R18-cycloalkyl, R18-cycloalkylalkyl, R18-heterocycloalkyl, R18-heterocycloalkylalkyl, R18-aryl, R18-arylalkyl, R18-heteroaryl and R18-heteroarylalkyl; or


R18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO2, halo, heteroaryl, HO-alkyoxyalkyl, —CF3, —CN, alkyl-CN, —C(O)R19, —C(O)OH, —C(O)OR19, —C(O)NHR20, —C(O)NH2, —C(O)NH2—C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR19, —S(O)2R20, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR19, —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OCF3, —OH, —OR20, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR20, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R20, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R20, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


or two R18 moieties on adjacent carbons can be linked together to form




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R19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;


R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;


and wherein each of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl groups in R1, R2, R3, R4, and R5 are independently unsubstituted or substituted by 1 to 5 R21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —CH(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —CH2—N(R15)C(O)N(R16)(R17), —CH2—R15; —CH2N(R15)(R16), —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —S(O)R15, ═NOR15, —N3, —NO2 and —S(O)2R15; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR15, —C(O)R15, —C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —N3, ═NOR15, —NO2, —S(O)R15 and —S(O)2R15;


or two R21 or two R22 moieties on adjacent carbons can be linked together to form




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and when R21 or R22 are selected from the group consisting of —C(═NOR15)R16, —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16 and —CH2—N(R15)C(O)OR16, R15 and R16 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R15 and R16, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R23;


R23 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR24, —C(O)R24, —C(O)OR24, —C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R23 are independently unsubstituted or substituted by 1 to 5 R27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR24, —C(O)R24, —C(O)OR24, alkyl-C(O)OR24, C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;


R24, R25 and R26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R27-alkyl, R27-cycloalkyl, R27-cycloalkylalkyl, R27-heterocycloalkyl, R27-heterocycloalkylalkyl, R27-aryl, R27-arylalkyl, R27-heteroaryl and R27-heteroarylalkyl;


R27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO2, halo, —CF3, —CN, alkyl-CN, —C(O)R28, —C(O)OH, —C(O)OR28, —C(O)NHR29, —C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR28, —S(O)2R29, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR28, —S(O)2NH(aryl), —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OH, —OR29, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR29, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R29, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R29, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


R28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and


R29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;


provided that when R1 is methyl, X is —N(R5)—, R2 is H, W is —C(O)— and U is a bond, (R3, R4) is not (H, H), (benzyl, H) or (i-butyl, H).


In another embodiment of a compound of formula I having the structural formula




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or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or ester thereof, wherein


W is —C(═O)—;


X is —N(R5)—;


U is a bond;


R1, R2 and R5 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;


R3 is independently selected from the group consisting of aryl and heteroaryl;


R4 is independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;


R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R18-alkyl, R18-cycloalkyl, R18-cycloalkylalkyl, R18-heterocycloalkyl, R18-heterocycloalkylalkyl, R18-aryl, R18-arylalkyl, R18-heteroaryl and R18-heteroarylalkyl; or


R18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO2, halo, heteroaryl, HO-alkyoxyalkyl, —CF3, —CN, alkyl-CN, —C(O)R19, —C(O)OH, —C(O)OR19, —C(O)NHR20, —C(O)NH2, —C(O)NH2—C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR19, —S(O)2R20, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR19, —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OCF3, —OH, —OR20, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR20, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R20, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R20, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


or two R18 moieties on adjacent carbons can be linked together to form




embedded image


R19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;


R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;


and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl and heteroaryl groups in R1, R2, R3, R4 and R5 are independently unsubstituted or substituted by 1 to 5 R21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —CH(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —(P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —CH2—N(R15)C(O)N(R16)(R17), —CH2—R15; —CH2N(R15)(R16), —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —S(O)R15, ═NOR15, —N3, —NO2 and —S(O)2R15; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR15, —C(O)R15, —C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —N3, ═NOR15, —NO2, —S(O)R15 and —S(O)2R15;


or two R21 or two R22 moieties on adjacent carbons can be linked together to form




embedded image


and when R21 or R22 are selected from the group consisting of —C(═NOR15)R16, —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16 and —CH2—N(R15)C(O)OR16, R15 and R16 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R15 and R16, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R23;


R23 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR24, —C(O)R24, —C(O)OR24, —C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R23 are independently unsubstituted or substituted by 1 to 5 R27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR24, —C(O)R24, —C(O)OR24, alkyl-C(O)OR24, C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;


R24, R25 and R26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R27-alkyl, R27-cycloalkyl, R27-cycloalkylalkyl, R27-heterocycloalkyl, R27-heterocycloalkylalkyl, R27-aryl, R27-arylalkyl, R27-heteroaryl and R27-heteroarylalkyl;


R27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO2, halo, —CF3, —CN, alkyl-CN, —C(O)R28, —C(O)OH, —C(O)OR28, —C(O)NHR29, —C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —S(O)2R29, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR28, —S(O)2NH(aryl), —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OH, —OR29, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR29, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R29, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R29, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


R28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and


R29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;


provided that when R1 is methyl, X is —N(R5)—, R2 is H, W is —C(O)— and U is a bond, (R3, R4) is not (phenyl, phenyl), (H, phenyl), (benzyl, phenyl), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH3O-phenyl, NO2-phenyl);


provided that when X is —N(R5)—, R1 and R5 are each H, W is —C(O)— and U is a bond, (R3, R4) is not (optionally substituted phenyl, optionally substituted benzyl), (optionally substituted phenyl, heteroarylalkyl) or (heteroaryl, heteroarylalkyl).


In another embodiment of a compound of formula I having the structural formula




embedded image



or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or ester thereof, wherein


W is —C(═O)—;


X is —N(R5)—;


U is a —(C(R6)(R7))—;


R1, R2 and R5 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;


R3 and R4 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, —SH, —SR19, —CN, —OR9, —N(R11)(R12) and halo;


R6 and R7 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;


R8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR15, —N(R15)(R16), —N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17) and —N(R15)C(O)OR16;


R9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;


R10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R15)(R16);


R11 and R12 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —C(O)R8, —C(O)OR9, —S(O)R10, —S(O)2R10, —C(O)N(R15)(R16), —S(O)N(R15)(R16), —S(O)2N(R15)(R16) and —CN;


R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R18-alkyl, R18-cycloalkyl, R18-cycloalkylalkyl, R18-heterocycloalkyl, R18-heterocycloalkylalkyl, R18-aryl, R18-arylalkyl, R18-heteroaryl and R18-heteroarylalkyl; or


R18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO2, halo, heteroaryl, HO-alkyoxyalkyl, —CF3, —CN, alkyl-CN, —C(O)R19, —C(O)OH, —C(O)OR19, —C(O)NHR20, —C(O)NH2, —C(O)NH2—C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR19, —S(O)2R20, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR19, —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OCF3, —OH, —OR20, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR20, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R20, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R20, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


or two R18 moieties on adjacent carbons can be linked together to form




embedded image


R19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;


R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;


and wherein each of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl groups in R1, R2, R3, R4, R5, R6 and R7 are independently unsubstituted or substituted by 1 to 5 R21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —CH(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —CH2—N(R15)C(O)N(R16)(R17), —CH2—R15; —CH2N(R15)(R16), —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —S(O)R15, ═NOR15, —N3, —NO2 and —S(O)2R15; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR15, —C(O)R15, —C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —N3, ═NOR15, —NO2, —S(O)R15 and —S(O)2R15;


or two R21 or two R22 moieties on adjacent carbons can be linked together to form




embedded image


and when R21 or R22 are selected from the group consisting of —C(═NOR15)R16, —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16 and —CH2—N(R15)C(O)OR16, R15 and R16 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R15 and R16, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R23;


R23 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR24, —C(O)R24, —C(O)OR24, —C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R23 are independently unsubstituted or substituted by 1 to 5 R27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR24, —C(O)R24, —C(O)OR24, alkyl-C(O)OR24, C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;


R24, R25 and R26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R27-alkyl, R27-cycloalkyl, R27-cycloalkylalkyl, R27-heterocycloalkyl, R27-heterocycloalkylalkyl, R27-aryl, R27-arylalkyl, R27-heteroaryl and R27-heteroarylalkyl;


R27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO2, halo, —CF3, —CN, alkyl-CN, —C(O)R28, —C(O)OH, —C(O)OR28, —C(O)NHR29, —C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR28, —S(O)2R29, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR28, —S(O)2NH(aryl), —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OH, —OR29, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR29, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R29, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R29, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


R28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and


R29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.


In another embodiment of a compound of formula I having the structural formula




embedded image



or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or ester thereof, wherein


W is —O—;


X is —N(R5)—;


U is a —(C(R6)(R7))—;


R1, R2 and R5 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;


R3 and R4 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl and —CN;


R6 and R7 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryalkyl and arylalkyl;


R8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR15, —N(R15)(R16); —N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17) and —N(R15)C(O)OR16;


R10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R15)(R16);


R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R18-alkyl, R18-cycloalkyl, R18-cycloalkylalkyl, R18-heterocycloalkyl, R18-heterocycloalkylalkyl, R18-aryl, R18-arylalkyl, R18-heteroaryl and R18-heteroarylalkyl; or


R18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO2, halo, heteroaryl, HO-alkyoxyalkyl, —CF3, —CN, alkyl-CN, —C(O)R19, —C(O)OH, —C(O)OR19, —C(O)NHR20, —C(O)NH2, —C(O)NH2—C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR19, —S(O)2R20, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR19, —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OCF3, —OH, —OR20, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR20, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R20, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R20, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


or two R18 moieties on adjacent carbons can be linked together to form




embedded image


R19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;


R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;


and wherein each of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl groups in R1, R2, R3, R4, R5, R6 and R7 are independently unsubstituted or substituted by 1 to 5 R21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —CH(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —CH2—N(R15)C(O)N(R16)(R17), —CH2—R15; —CH2N(R15)(R16), —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —S(O)R15, ═NOR15, —N3, —NO2 and —S(O)2R15; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR15, —C(O)R15, —C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —N3, ═NOR15, —NO2, —S(O)R15 and —S(O)2R15;


or two R21 or two R22 moieties on adjacent carbons can be linked together to form




embedded image


and when R21 or R22 are selected from the group consisting of —C(═NOR15)R16, —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16 and —CH2—N(R15)C(O)OR16, R15 and R16 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R15 and R16, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R23;


R23 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR24, —C(O)R24, —C(O)OR24, —C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R23 are independently unsubstituted or substituted by 1 to 5 R27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR24, —C(O)R24, —C(O)OR24, alkyl-C(O)OR24, C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;


R24, R25 and R26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R27-alkyl, R27-cycloalkyl, R27-cycloalkylalkyl, R27-heterocycloalkyl, R27-heterocycloalkylalkyl, R27-aryl, R27-arylalkyl, R27-heteroaryl and R27-heteroarylalkyl;


R27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO2, halo, —CF3, —CN, alkyl-CN, —C(O)R28, —C(O)OH, —C(O)OR28, —C(O)NHR29, —C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR28, —S(O)2R29, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR28, —S(O)2NH(aryl), —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OH, —OR29, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR29, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R29, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R29, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);


R28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and


R29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.


Another embodiment of the invention is a process for preparing a compound of Formula B:




embedded image



the process comprising the steps of:


(a) reacting the compound of Formula A:




embedded image



with R3—X in a solvent in the presence of a base, optionally with ZnCl2, and a palladium/phosphine catalyst at about −78 to 0° C., wherein X is Cl, Br, I, or OTf;


(b) raising the temperature of the reaction mixture to about 50-100° C.; and


(c) treating with an acid, to provide the compound of Formula B, wherein


W is —C(O)— or —S(O)2—;


R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl and heteroaryl;


R3 is selected from the group consisting of aryl, heteroaryl and alkenyl; and


R6 and R7 are selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl.


In another embodiment of the process to prepare the compound of Formula B the solvent is an ether (e.g. THF, diethyl ether), hydrocarbon (e.g. toluene), amide (e.g. DMF) or sulfoxide (e.g. DMSO).


In another embodiment of the process to prepare the compound of Formula B, the palladium/phosphine catalyst is Pd2(dba)3, PdCl2, PdOAc2/Davephos, 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (Q-phos), Bis(2-diphenylphosphinophenyl)ether, 9,9-Dimethyl-4,5-bis(diphenylphoshino)xanthene, 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl, 1,1′-Bis(diphenylphosphino)ferrocene, 1,4-Bis(diphenylphosphino)butane, 1-dicyclohexylphosphino-2-di-tert-butylphosphinoethylferrocene (CyPF-tBu), Bis(2-diphenylphosphinophenyl)ether (DPEphos), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) or 1,1′-Bis(diphenylphosphino)ferrocene (DPPF), triphenylphosphine, 1,3-bis(diphenylphospino)propane, 1,2-bis(diphenylphosphino)ethane, 1,4-bis(diphenylphosphino)butane, tri-tertbutylphosphine, tricyclohexylphosphine, 1,1′-bis(di-tert-butylphosphino)ferrocene, 1,1′-bis(di-isopropylphosphino)ferrocene, tri-o-tolylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, di-tert-butylphenylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, FibreCat (e.g. Fibrecat Anchored Homogenous Catalysts, FibreCat 1001, 1007, 1026, 1032 from Johnson Matthey Catalysts) or 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos).


In another embodiment of the process to prepare the compound of Formula B, the acid is selected from the group consisting of trifluoroacetic acid, hydrochloric acid and hydrobromic acid.


In another embodiment of the process to prepare the compound of Formula B, X is bromide.


In another embodiment of the process to prepare the compound of Formula B, the base is selected from the group consisting of LIHMDS, LDA, BuLi, s-BuLi and tert-Butyllithium.


In the aspect of the invention relating to a combination of at least one compound of formula I with at least one cholinesterase inhibitor, acetyl- and/or butyrylchlolinesterase inhibitors can be used. Examples of cholinesterase inhibitors are tacrine, donepezil, rivastigmine, galantamine, pyridostigmine and neostigmine, with tacrine, donepezil, rivastigmine and galantamine being preferred. Preferably, these combinations are directed to the treatment of Alzheimer's disease.


In the aspect of the invention relating to a combination of at least one compound of formula I with at least one muscarinic m1 agonist or m2 antagonist can be used. Examples of m1 agonists are known in the art. Examples of m2 antagonists are also known in the art; in particular, m2 antagonists are disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006; 6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138; 6,294,554; 6,043,255; and 6,458,812; and in WO 03/031412, all of which are incorporated herein by reference.


In other aspects of the invention relating to a combination of at least one compound of formula I and at least one other agent, for example a beta secretase inhibitor; a gamma secretase inhibitor; an HMG-CoA reductase inhibitor such as atorvastatin, lovastatin, simvistatin, pravastatin, fluvastatin and rosuvastatin; cholesterol absorption inhibitors such as ezetimibe; non-steroidal anti-inflammatory agents such as, but not necessarily limited to ibuprofen, relafen or naproxen; N-methyl-D-aspartate receptor antagonists such as memantine; anti-amyloid antibodies including humanized monoclonal antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; antibiotics such as doxycycline; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity. Preferably, these combinations are directed to the treatment of Alzheimer's disease.


For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.


Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.


Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.


Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.


The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.


Preferably the compound is administered orally.


Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.


The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.


The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.


The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two to four divided doses.


When a compound of formula I is used in combination with a cholinesterase inhibitor to treat cognitive disorders, these two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising a compound of formula I and a cholinesterase inhibitor in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional oral or parenteral dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc. The dosage of the cholinesterase inhibitor can be determined from published material, and may range from 0.001 to 100 mg/kg body weight.


When separate pharmaceutical compositions of a compound of formula I and a cholinesterase inhibitor are to be administered, they can be provided in a kit comprising in a single package, one container comprising a compound of formula I in a pharmaceutically acceptable carrier, and a separate container comprising a cholinesterase inhibitor in a pharmaceutically acceptable carrier, with the compound of formula I and the cholinesterase inhibitor being present in amounts such that the combination is therapeutically effective. A kit is advantageous for administering a combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms.


While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims
  • 1. A method of treating or ameliorating a disease or disorder for which the inhibition of an aspartyl protease is therapeutic, said method comprising administering to a patient in need thereof with an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is selected from the group consisting of:
  • 2. The method of claim 1, wherein said disease or disorder is cardiovascular disease, cognitive or neurodegenerative disease, a fungal infection, or a protozoal infection.
  • 3. The method of claim 1, wherein said disease or disorder is cognitive or neurodegenerative disease.
  • 4. The method of claim 1, wherein said disease or disorder is Alzheimer's disease.
  • 5. The method of claim 4, further comprising administering to said patient, simultaneously or sequentially, at least one additional active agent selected from: a cholinesterase inhibitor; a muscarinic m1, agonist; a muscarinic m2 antagonist; a N-methyl-D-aspartate receptor antagonist; a beta secretase inhibitor other than a compound of claim 1; a gamma secretase inhibitor; an HMG-CoA reductase inhibitor; a cholesterol absorption inhibitor; a non-steroidal anti-inflammatory agent; an anti-amyloid antibody; vitamin E; a nicotinic acetylcholine receptor agonist; a CB1 receptor inverse agonist; a CB1 receptor antagonist; an antibiotic; a growth hormone secretagogue; a histamine H3 antagonist; an AMPA agonist; a PDE4 inhibitor; a GABAA inverse agonist; an inhibitor of amyloid aggregation; a glycogen synthase kinase beta inhibitor; and a promoter of alpha secretase activity.
  • 6. The method of either of claim 4 or 5, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is selected from the group consisting of:
  • 7. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 8. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 9. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 10. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 11. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 12. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 13. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 14. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 15. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 16. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 17. The method of claim 4, comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
  • 18. The method according to any one of claims 7 to 17, further comprising administering, simultaneously or sequentially, at least one additional active agent selected from: a cholinesterase inhibitor; a muscarinic m1 agonist; a muscarinic m2 antagonist; a N-methyl-D-aspartate receptor antagonist; a beta secretase inhibitor other than a compound of claim 1; a gamma secretase inhibitor; an HMG-CoA reductase inhibitor; a cholesterol absorption inhibitor; a non-steroidal anti-inflammatory agent; an anti-amyloid antibody; vitamin E; a nicotinic acetylcholine receptor agonist; a CB1 receptor inverse agonist; a CB1 receptor antagonist; an antibiotic; a growth hormone secretagogue; a histamine H3 antagonist; an AMPA agonist; a PDE4 inhibitor; a GABAA inverse agonist; an inhibitor of amyloid aggregation; a glycogen synthase kinase beta inhibitor; and a promoter of alpha secretase activity; and a pharmaceutically acceptable carrier.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional application of U.S. patent application Ser. No. 12/693,874, filed Jan. 26, 2010, pending, which is a Divisional application of U.S. patent application Ser. No. 11/710,582, filed Feb. 23, 2007, U.S. Pat. No. 7,763,609, incorporated herein by reference.

US Referenced Citations (140)
Number Name Date Kind
3197476 Erner Jul 1965 A
3200123 Richardson et al. Aug 1965 A
3632814 Richter et al. Jan 1972 A
5338740 Carpino et al. Aug 1994 A
5391560 Fuchs et al. Feb 1995 A
5534520 Fisher et al. Jul 1996 A
5731431 Nakagawa et al. Mar 1998 A
5883096 Lowe et al. Mar 1999 A
5889006 Lowe et al. Mar 1999 A
5935958 Kazlowski et al. Aug 1999 A
5952349 Asberom et al. Sep 1999 A
5977138 Wang et al. Nov 1999 A
6037352 Lowe et al. Mar 2000 A
6043255 Lowe et al. Mar 2000 A
6066636 Kazlowski et al. May 2000 A
6087509 Claussner et al. Jul 2000 A
6294554 Clader et al. Sep 2001 B1
6344473 Hansen, Jr. et al. Feb 2002 B1
6458812 McKittrick et al. Oct 2002 B1
6713276 Cordell Mar 2004 B2
7183070 Cordell Feb 2007 B2
7223774 Aquino et al. May 2007 B2
7238774 Peters et al. Jul 2007 B2
7241786 Chen Jul 2007 B2
7244606 Chou et al. Jul 2007 B2
7244708 Tang et al. Jul 2007 B2
7244725 John et al. Jul 2007 B2
7244755 Fisher et al. Jul 2007 B2
7244757 Chen et al. Jul 2007 B2
7253195 Chen Aug 2007 B2
7253198 Demont et al. Aug 2007 B2
7273882 Gerritz et al. Sep 2007 B2
7276484 John et al. Oct 2007 B2
7285682 Hu Oct 2007 B2
7291620 Coburn et al. Nov 2007 B2
7300936 Parker et al. Nov 2007 B2
7312188 Kiso Dec 2007 B2
7312360 TenBrink et al. Dec 2007 B2
7335632 Ghosh et al. Feb 2008 B2
7338965 Moon et al. Mar 2008 B2
7338974 Marcin et al. Mar 2008 B2
7354933 Patek et al. Apr 2008 B2
7388007 Thompson, III et al. Jun 2008 B2
7390802 Han et al. Jun 2008 B2
7390896 Olson et al. Jun 2008 B2
7390925 Wu et al. Jun 2008 B2
7408071 Boy et al. Aug 2008 B2
7417047 Malamas et al. Aug 2008 B2
7423158 Malamas et al. Sep 2008 B2
7488832 Cole et al. Feb 2009 B2
7560451 Zhu et al. Jul 2009 B2
7592348 Zhu et al. Sep 2009 B2
7598250 Cumming et al. Oct 2009 B2
7652003 Stamford et al. Jan 2010 B2
7662816 Cumming et al. Feb 2010 B2
7700603 Zhu et al. Apr 2010 B2
7759353 Zhu et al. Jul 2010 B2
7759354 Zhu et al. Jul 2010 B2
7763606 Zhu et al. Jul 2010 B2
7763709 Zhu et al. Jul 2010 B2
7803802 Huang et al. Sep 2010 B2
7812013 Iserloh et al. Oct 2010 B2
7868000 Zhu et al. Jan 2011 B2
7910590 Cumming et al. Mar 2011 B2
7973067 Zhu et al. Jul 2011 B2
8012953 Stamford et al. Sep 2011 B2
8012960 Zhu et al. Sep 2011 B2
20050171112 Schulz et al. Aug 2005 A1
20050282825 Malamas et al. Dec 2005 A1
20050282826 Malamas et al. Dec 2005 A1
20060034848 Kinoshita et al. Feb 2006 A1
20060046984 Thompson, III et al. Mar 2006 A1
20060111370 Zhu et al. May 2006 A1
20060173049 Malamas et al. Aug 2006 A1
20060183790 Cole et al. Aug 2006 A1
20060183792 Fobare et al. Aug 2006 A1
20060183943 Hu Aug 2006 A1
20060287287 Gerritz et al. Dec 2006 A1
20070004730 Zhou et al. Jan 2007 A1
20070004786 Malamas et al. Jan 2007 A1
20070027199 Malamas et al. Feb 2007 A1
20070037868 Marcin et al. Feb 2007 A1
20070049589 Thompson, III et al. Mar 2007 A1
20070072925 Malamas et al. Mar 2007 A1
20070117793 Ghosh et al. May 2007 A1
20070142634 Barrow et al. Jun 2007 A1
20070149584 John et al. Jun 2007 A9
20070167433 Herold et al. Jul 2007 A1
20070173521 Xue et al. Jul 2007 A1
20070185133 Zhong et al. Aug 2007 A1
20070185273 Albrecht et al. Aug 2007 A1
20070203116 Quagliato et al. Aug 2007 A1
20070203147 Coburn et al. Aug 2007 A1
20070213316 John et al. Sep 2007 A1
20070213331 Dally et al. Sep 2007 A1
20070213407 John et al. Sep 2007 A1
20070225267 Broughton et al. Sep 2007 A1
20070225372 Bueno Melendo et al. Sep 2007 A1
20070225374 Tucker et al. Sep 2007 A1
20070232581 Wu et al. Oct 2007 A1
20070232630 Richter et al. Oct 2007 A1
20070232642 Baxter et al. Oct 2007 A1
20070232679 Boy et al. Oct 2007 A1
20070259898 Baxter et al. Nov 2007 A1
20070270426 Chen Nov 2007 A1
20070270474 Chen et al. Nov 2007 A1
20070299087 Berg et al. Dec 2007 A1
20070299093 Rosini et al. Dec 2007 A1
20070299117 Fisher et al. Dec 2007 A1
20070299263 Freskos et al. Dec 2007 A1
20080015213 Nantermet et al. Jan 2008 A1
20080015233 Barrow et al. Jan 2008 A1
20080021196 Tang et al. Jan 2008 A1
20080036196 Steenblik et al. Feb 2008 A1
20080051390 Malamas et al. Feb 2008 A1
20080051420 Berg et al. Feb 2008 A1
20080058336 Ham et al. Mar 2008 A1
20080058349 Berg et al. Mar 2008 A1
20080076801 Yan et al. Mar 2008 A1
20080153846 Coburn et al. Jun 2008 A1
20080153868 Thompson et al. Jun 2008 A1
20080161269 Berg et al. Jul 2008 A1
20080161325 Fabian et al. Jul 2008 A1
20080161363 Coburn et al. Jul 2008 A1
20080166332 Pulley et al. Jul 2008 A1
20080200445 Zhu et al. Aug 2008 A1
20080214526 Lerchner et al. Sep 2008 A1
20080214577 Berg et al. Sep 2008 A1
20080215249 Benson et al. Sep 2008 A1
20080255172 Su et al. Oct 2008 A1
20090023762 Berg et al. Jan 2009 A1
20090029960 Betschart et al. Jan 2009 A1
20090042867 Fuchs et al. Feb 2009 A1
20090042908 Zhou et al. Feb 2009 A1
20090042912 Malamas et al. Feb 2009 A1
20090042961 John et al. Feb 2009 A1
20090042964 Malamas et al. Feb 2009 A1
20090062282 Albert et al. Mar 2009 A1
20110009395 Audia et al. Jan 2011 A1
20110046122 Andreini et al. Feb 2011 A1
Foreign Referenced Citations (139)
Number Date Country
0231919 Mar 1987 EP
0361341 Apr 1990 EP
0 512 817 Nov 1992 EP
0763054 Mar 1997 EP
0 969 011 Jan 2000 EP
1942105 Jul 2008 EP
20081942101 Jul 2008 EP
8903842 May 1989 WO
9004917 May 1990 WO
9705137 Feb 1997 WO
0107440 Feb 2001 WO
0202505 Jan 2002 WO
0202506 Jan 2002 WO
0202512 Jan 2002 WO
0202518 Jan 2002 WO
0202520 Jan 2002 WO
0207419 Jan 2002 WO
0288101 Jan 2002 WO
0212243 Feb 2002 WO
02062803 Aug 2002 WO
02074719 Sep 2002 WO
03031412 Apr 2003 WO
03035613 May 2003 WO
03106405 Dec 2003 WO
03106405 Dec 2003 WO
2005014540 Feb 2005 WO
2005016876 Feb 2005 WO
2005013020 Feb 2005 WO
2005058311 Jun 2005 WO
2005097767 Oct 2005 WO
2005103020 Nov 2005 WO
2005108391 Nov 2005 WO
2005103043 Nov 2005 WO
2005113484 Dec 2005 WO
2005113582 Dec 2005 WO
2006002051 Jan 2006 WO
2006009655 Jan 2006 WO
2006002004 Jan 2006 WO
2006009653 Jan 2006 WO
2006014762 Feb 2006 WO
2006014944 Feb 2006 WO
2006017836 Feb 2006 WO
2006017844 Feb 2006 WO
2006024932 Mar 2006 WO
2006081072 Mar 2006 WO
2006041404 Apr 2006 WO
2006041405 Apr 2006 WO
2006044497 Apr 2006 WO
2006041404 Apr 2006 WO
2006065277 Jun 2006 WO
2006076284 Jul 2006 WO
2006058724 Aug 2006 WO
2006080043 Aug 2006 WO
2006099352 Sep 2006 WO
2006138192 Dec 2006 WO
2006138195 Dec 2006 WO
2006138217 Dec 2006 WO
2006138230 Dec 2006 WO
2006138264 Dec 2006 WO
2006138265 Dec 2006 WO
2006138266 Dec 2006 WO
2007005366 Jan 2007 WO
2007005404 Jan 2007 WO
2007002214 Jan 2007 WO
2007016012 Feb 2007 WO
2007017507 Feb 2007 WO
2007017509 Feb 2007 WO
2007017510 Feb 2007 WO
2007017511 Feb 2007 WO
2007038271 Apr 2007 WO
2007050721 May 2007 WO
2007053506 May 2007 WO
2007058580 May 2007 WO
2007058582 May 2007 WO
2007058583 May 2007 WO
2007058601 May 2007 WO
2007058602 May 2007 WO
2007002007 May 2007 WO
2007058580 May 2007 WO
2007058581 May 2007 WO
2007058582 May 2007 WO
2007058583 May 2007 WO
2007058601 May 2007 WO
2007061670 May 2007 WO
2007061930 May 2007 WO
2007073284 Jun 2007 WO
2007058602 Jun 2007 WO
2007078813 Jul 2007 WO
2007100536 Sep 2007 WO
2007114771 Oct 2007 WO
2007073284 Oct 2007 WO
2007114771 Oct 2007 WO
2007145568 Dec 2007 WO
2007145569 Dec 2007 WO
2007145570 Dec 2007 WO
2007145571 Dec 2007 WO
2007146225 Dec 2007 WO
2007149033 Dec 2007 WO
2007120096 Dec 2007 WO
2007145568 Dec 2007 WO
2007145569 Dec 2007 WO
2007145570 Dec 2007 WO
2007146225 Dec 2007 WO
2007149033 Dec 2007 WO
2008022024 Feb 2008 WO
2008063114 May 2008 WO
2008063114 May 2008 WO
2008076043 May 2008 WO
2008076044 May 2008 WO
2008073365 Jun 2008 WO
2008073370 Jun 2008 WO
2008076043 Jun 2008 WO
2008076044 Jun 2008 WO
2008076045 Jun 2008 WO
2008076046 Jun 2008 WO
2008076045 Jun 2008 WO
2008076046 Jun 2008 WO
2008092785 Aug 2008 WO
2008103351 Aug 2008 WO
2008115552 Sep 2008 WO
2008118379 Oct 2008 WO
2009005470 Jan 2009 WO
2009007300 Jan 2009 WO
2009022961 Feb 2009 WO
2009091016 Jul 2009 WO
2009092566 Jul 2009 WO
2010030954 Mar 2010 WO
2010042892 Apr 2010 WO
2011009897 Jan 2011 WO
2011009898 Jan 2011 WO
2011044057 Apr 2011 WO
2011044181 Apr 2011 WO
2011044184 Apr 2011 WO
2011044185 Apr 2011 WO
2011044187 Apr 2011 WO
2011063233 May 2011 WO
2011063272 May 2011 WO
2011115928 Sep 2011 WO
2011115938 Sep 2011 WO
Non-Patent Literature Citations (115)
Entry
Salome Younes, et al., Synthesis and Structure-activity Relationship of Novel Arylalkyl 4-benzyl Piperazine Derivatives as O Site Selective Ligands, Eur. J. Med. Chem., 35, 107-121, table II (2000).
Blennow Kaj, et al., “CSF markers for incipient Alzheimer's disease”, The Lancet Neurology, 2003, pp. 605-613, vol. 2, No. 10.
J.M.G. Fernández, et al., “Syntheses and Spectral Properties of β-Iodoureas and 2-Amino-4,4-diphenyl-2-oxazolines”, J. Heterocyclic Chem., 1991, pp. 777-780, vol. 28.
J.M.G. Fernandez, et al., “Syntheses of β-iodourea derivatives of carbohydrates and glycosylamino-oxazolines”, Carbohydrate Research, 1991, pp. 21-32, vol. 216.
Lin, Peishan, et al., “Synthesis of Novel Guanidinoglycoside: 2-Glycosylamino 4,5-dihydro-6-pyrimidinone”, J. Org. Chem., 2001, pp. 8243-8247, vol. 66, No. 24.
Mota, José Fuentes, et al., “Synthesis of N-Hetarylthiourea Derivatives of Carbohydrates”, J. Carbohydrate Chemistry, 1990, pp. 837-851, vol. 9, No. 6.
Talaty, Erach R., et al., “Preparation of Substituted Imidazolidinones and Hydantoins by Ring-Expansion of Aziridinones”, Synlett, 1997, pp. 683-684. vol. 6.
Yusoff, Mashitah M., et al., “Ring-Expansion of an Aziridinone to a Hexahydrotriazine through the Agency of a Novel Rearrangement”, Tetrahedron Letters, 1996, pp. 8695-8698, vol. 37, No. 48.
ROC (Taiwan) Patent Application No. 093138776 Search Report—1 page Translation, (Sep. 20, 2007).
Mari, Yotsu-Yamashita, et al., “The structure of zetekitoxin from the Panamanian frog Atelopus zeteki”, Tennen Yuki Kagobutsu Toronkai Koen Yoshishu (2000), 42nd, 415-420; 2001:101914 (English Abstract).
Mitsumi, Minoru, et al., “Three-dimensional H-bonded networks based on mono- and tetranuclear metal-pteridine complexes”, Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals (1996), 276, 229-235; 1996:295932 (Abstract).
Nagamatsu, Kentaro, et al., “Reactions of 8-(triphenylphosphoimino)quinoline with aryl aldehydes and aryl isocyanates: formation of 2-aryl-4H-imidazo[4,5,1-ij]quinolines and related systems”, Heterocycles (2006), 69, 167-178; 2007:16172 (Abstract).
Poludnenko, V.G., et al., “Derivatives of 5,6-dihydro-4H-imidazo[4,5,1-i,j]quinoline. I. Synthesis and reactions of 2-amino derivatives”, Khimiya Geterotsiklicheskikh Soedinenii (1970), (10), 1410-13; 1971:53657 (English Abstract).
Pozharskii, A.F., et al., “Heterocyclic analogs of pleiadiene. 53. Properties of 1,9-trimethyleneperimidine”, Khimiya Geterotsiklicheskikh Soedinenii (1981), (7), 980-2; 1981:603864 (English Abstract).
Price, Clayton, et al., “Macrochelation, cyclometallation and G-quartet formation: N3- and C8-bound PdII complexes of adenine and guanine”, Chemistry—A European Journal (2001), 7(6), 1194-1201; 2001:240418 (Abstract).
Richardson, Alfred, Jr., “The synthesis and chemistry of certain 2-substituted 5,6-dihydroimidazo-,-oxazolo-, and -thiazolo[ij]quinolines”, Journal of Organic Chemistry (1963), 28(10), 2581-7; 1963:462271 (Abstract).
Roseen, Jill S., et al., “Comparison of the effects of atelopidtoxin with those of tetrodotoxin, saxitoxin, and batrachotoxin on beating of cultured chick heart cells”, Toxicon (1971), 9(4), 411-15; 1972:21760 (Abstract).
Shindelman, Jeffrey, et al., “Atelopidtoxin from the Panamanian frog, Atelopus zeteki”, Toxicon (1969), 7(4), 315-19; 1970:98699 (Abstract).
Simonov, A.M., et al., “Amination of 5,6-dihydro-4H-imidazo[4,5,1-i,j]quinoline”, Khimiya Geterotsiklicheskikh Soedinenii (1969), (3), 567; 1969:524323 (English Abstract).
Simonov, A.M., et al., “Derivatives of 5,6-dihydro-4H-imidazo[4,5,1-i,j]quinoline. III. Substitution reactions in a 5,6-dihydro-4H-imidazo[4,5,1-i-j]quinoline series”, Khimiya Geterotsiklicheskikh Soedinenii (1972), (2), 242-6; 1972:140645 (English Abstract).
International Search Report for PCT/US2006/022701, mailed Nov. 22, 2006 (3 pages) for CN06361.
Vilar, Santiago, et al., “Probabilistic Neural Network Model for the In Silico Evaluation of Anti-HIV Activity and Mechanism of Action”, Journal of Medicinal Chemistry (2006), 49(3), 1118-1124; 2006:44967 (Abstract).
Werbel, Leslie M., et al., “Synthesis of 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1,˜ij] quinolines and some related ring systems”, Journal of Heterocyclic Chemistry (1968), 5(3), 371-8; 1968:436031 (Abstract).
Byoung-Kuk, Na, et. al., “Aspartic proteases of Plasmodium vivax are highly conserved in wild isolates”, The Korean Journal of Parasitology, 2004, pp. 61-66, vol. 42, No. 2.
Oparil, Suzanne, et. al., The Renin-Angiotensin System (Second of Two Parts), the New England Journal of Medicine, 1974, pp. 446-457, vol. 291, No. 9.
Yasuda, Yoshiyuki, et. a., “Characterization of New Fluorogenic Substrates for the Rapid and Sensitive Assay of Cathepsin E and Cathepsin D”, J. Biochem. , 1999, pp. 1137-1143, vol. 125, No. 6.
Vippagunta, et. al., “Advanced Drug Delivery Reviews”, vol. 48, pp. 3-26, (2001).
US 5,853,029, 12/1999, Fisher, et al. (withdrawn).
PCT International Search Report dated Apr. 26, 2012 for related International Application No. PCT/US2011/053194; 1 page.
Written Opinion of the PCT International Search Report dated Apr. 26, 2012 for related International Application No. PCT/US2011/053194; 2 pages.
Bhave et al., “Peripheral group I metabotropic glutamate receptors modulate nociception in mice”, Nature Neuroscience, (2001) vol. 4, pp. 417-423.
Bousquet E. et al., Synthesis and Pharmacological Activity of 3-Substituted Pyrido(3′, 2′:4,5)Thieno(3,2-d) Pyrimidin-4(3H)-Ones, Farmaco, Edizione Scientifica, Societa Chimica Italiana, Pavia, IT, (1984) vol. 39, No. 2, pp. 110-119.
Dolan et al., “Behavioral evidence supporting a differential role for spinal group I and II metabotropic glutamate receptors in inflammatory hyperalgesia in sheep”, Neuropharmacology, (2002) vol. 43, pp. 319-326.
Dolan et al., “Up-regulation of metabotropic glutamate receptor subtypes 3 and 5 in spinal cord in a clinical model of persistent inflammation and hyperalgesia”, Pain, (2003), vol. 106, pp. 501-512.
Fisher et al., “Hyperalgesia and allodynia induced by intrathecal (RS)-dihydroxyphenylglycine in rats”, NeuroReport, (1998) vol. 9, pp. 1169-1172.
Fundytus et al., “Antisense oligonucleotide knockdown of mGluR1 alleviates hyperalgesia and allodynia associated with chronic inflammation”, Pharmacology, Biochemistry and Behavior, (2002) vol. 73, pp. 401-140.
Fundytus et al., “In vivo antinociceptive activity of anti-rate mGluR1 and mGluR5 antibodies in rats”, NeuroReport, (1998) vol. 9, pp. 731-735.
Fundytus et al., “Knockdown of spinal metabotropic glutamate receptor 1 (mGluR1) alleviates pain and restores opioid efficacy after nerve injury in rats”, British Journal of Pharmacology, (2001) vol. 132, pp. 354-367.
Mills and Hulsebosch, “Increased expression of metabotropic glutamate receptor subtype 1 on spinothalamic tract neurons following spinal cord injury in the rat”, Neuroscience Letters (2002) vol. 319, pp. 59-62.
Neugebauer et al., “Peripheral metabotropic glutamate receptors: fight the pain where it hurts”, Trends in Neurosciences, (2001) vol. 24, pp. 550-552.
Neugebauer et al., “Role of Metabotropic Glutamate Receptor Subtype mGluR1 in Brief Nociception and Central Sensitization of Primate STT Cells”, Journal of Neurophysiology, (1999) vol. 82, pp. 272-282.
Tacconi G et al., “Indolizzazione di 3-piridilidrazoni della 2,3-dichetopiperidina”, Annali Di Chimica, Societa Chimica Italiana, Rome, IT, (1965) vol. 55, No. 12, pp. 1223-1232.
Young et al., “Antisense Ablation of Type I Metabotropic Glutamate Receptor mGluR1 Inhibits Spinal Nociceptive Transmission”, The Journal of Neuroscience, (1998) vol. 18, pp. 10180-10188.
Young et al., “Behavioural and electrophysiological evidence supporting a role for group I metabotropic glutamate receptors in the mediation of nociceptive inputs to the rat spinal cord”, (1997) vol. 777, pp. 161-169.
Young et al., “Evidence for a Role of Metabotropic Glutamate Receptors in Sustained Nociceptive Inputs to Rat Dorsal Horn Neurons”, Neuropharmacology, (1994), vol. 33, pp. 141-144.
Zheng G.Z. et al., “Structure-Activity Relationship of Triazafluorenone Derivatives as Potent and Selective mGluR1 Antagonists”, Journal of Medicinal Chemistry, American Chemical Society, Washington, US, (2005) vol. 48, No. 48, pp. 7374-7388.
Chemical Abstracts Service, Columbus, Ohio; Mar. 2, 2005—XP002428679; Database accession No. 840457-75-2; abstract; compounds 840457-75-2.
Chemical Abstracts Service, Columbus, Ohio; Feb. 24, 2005—XP002428680; Database accession No. 836632-30-5; abstract; compounds 836632-30-5.
Chemical Abstracts Service, Columbus, Ohio; Dec. 20, 2004—XP002428681; Database accession No. 799818-75-0; abstract; compounds 799818-75-0.
Chemical Abstracts Service, Columbus, Ohio; Dec. 20, 2004—XP002428682; Database accession No. 799809-04-4; abstract; compounds 799809-04-4.
Chemical Abstracts Service, Columbus, Ohio; Dec. 20, 2004—XP002428683; Database accession No. 799778-39-5; abstract; compounds 799778-39-5.
Chemical Abstracts Service, Columbus, Ohio; Jun. 21, 2004—XP002428684; Database accession No. 696658-55-6; abstract; compounds 696658-55-6.
Chemical Abstracts Service, Columbus, Ohio; Apr. 12, 2004—XP002428685; Database accession No. 674332-81-1; abstract; compounds 674332-81-1.
Chemical Abstracts Service, Columbus, Ohio; Apr. 9, 2004—XP002428686; Database accession No. 673495-74-4; abstract; compounds 673495-74-4.
Chemical Abstracts Service, Columbus, Ohio; Apr. 9, 2004—XP002428687; Database accession No. 673493-15-7; abstract; compounds 673493-15-7.
Chemical Abstracts Service, Columbus, Ohio; Apr. 9, 2004—XP002428688; Database accession No. 673489-94-6; abstract; compounds 673489-94-6.
Chemical Abstracts Service, Columbus, Ohio; Apr. 8, 2004—XP002428689; Database accession No. 672920-18-2; abstract; compounds 672920-18-2.
Chemical Abstracts Service, Columbus, Ohio; Apr. 7, 2004—XP002428690; Database accession No. 672281-18-4; abstract; compounds 672281-18-4.
Chemical Abstracts Service, Columbus, Ohio; Apr. 7, 2004—XP002428691; Database accession No. 672264-77-6; abstract; compounds 672264-77-6.
Chemical Abstracts Service, Columbus, Ohio; Mar. 23, 2003—XP002428692; Database accession No. 500276-33-5; abstract; compounds 500276-33-5.
Chemical Abstracts Service, Columbus, Ohio; Mar. 3, 2003—XP002428693; Database accession No. 496771-54-1; abstract; compounds 496771-54-1.
Chemical Abstracts Service, Columbus, Ohio; Feb. 12, 2003—XP002428694; Database accession No. 488801-73-6; abstract; compounds 488801-73-6.
Chemical Abstracts Service, Columbus, Ohio; Feb. 11, 2003—XP002428695; Database accession No. 488723-48-4; abstract; compounds 488723-48-4.
Chemical Abstracts Service, Columbus, Ohio; Nov. 20, 2001—XP002428696; Database accession No. 371134-99-5; abstract; compounds 371134-99-5.
International Search Report for International Application No. PCT/US2005/020972, mailed Oct. 26, 2005 (5 pages) for CN06202.
International Search Report for International Application No. PCT/US2006/046943, mailed Aug. 30, 2007 (5 pages) for CN06202-01.
International Search Report for International Application No. PCT/US2006/031972, mailed Jan. 16, 2007 (4 pages) for CN06342.
International Search Report for International Application No. PCT/US2006/031944, mailed Feb. 13, 2007 (5 pages) for CN06343.
International Search Report for International Application No. PCT/US2006/036858, mailed Apr. 24, 2007 (6 pages) for CN06344.
Attachment “A” Forms PTO/SB/08a (08-03) and PTO/SB/08b (08-03) for U.S. Appl. No. 11/152,535, filed Jun. 14, 2005 (Julius J. Matasi), 2 pages, for CN06202US01.
Attachment “B” Form PTO-892 (Rev.01-2001) for U.S. Appl. No. 11/152,535, 1 page, p. 1 of 1, for CN06202US01.
Attachment “C” Form PTO/SB/08a (08-03) and PTO/SB/08B (08-03) for U.S. Appl. No. 11/301,672, filed Dec. 13, 2005 (Julius J. Matasi et al.), 2 pages, for CN06202-01US02.
Attachment “D” Forms PTO/SB/08a (08-03) and PTO/SB/08b (08-03) for U.S. Appl. No. 11/505,140, filed Aug. 16, 2006 (Chad E. Bennett, et al.), 3 pages, for CN06343US01.
Barton, H.J, et al., “On the Structure of some Substituted 4,6-Pyrimidinediones”, Polish J. Chem., 1995, pp. 235-245, vol. 69.
Berge, Stephen M, et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, pp. 1-19, vol. 66, No. 1.
Bingham, Ann L, et al., “Over one hundred solvates of sulfathiazole†”, Chem. Commun., 2001, pp. 603-604.
Caira, Mino R, et al., “Preparation and Crystal Characterization of a Polymorph, a Monohydrate, and an Ethyl Acetate Solvate of the Antifungal Fluconazole”, Journal of Pharmaceutical Sciences, 2004, pp. 601-611, vol. 93, No. 3.
Coldham, Iain, et al., “Synthesis of the ABC Ring System of Manzamine A”, J. Org. Chem., 2002, pp. 6181-6187, vol. 67 No. 17.
Garratt, Peter J, et al., “A Novel Synthesis of Dihydropyrimidines”, J. Chem. Soc., Chem. Commun., 1987, pp. 568-569.
Gould, Philip L, “Salt selection for basic drugs”, International Journal of Pharmaceutics, 1986, pp. 201-217, vol. 33.
Hasegawa, Kiyoshi, et al., “The Synthesis of the 1,2,4-Thiadiazine-1,1-dioxides1)”, Bulletin of The Chemical Society of Japan, 1972, pp. 1893-1896, vol. 45, No. 6.
Hussein, Ahmad Q, et al., “Synthesen von α-Bromisothiocyanaten” Chem. Ber. 1979, pp. 1948-1955, vol. 112, (abstract included).
Kwon, Chul-Hoon, et al., “Facile Synthesis of Substituted 2-Iminohydantoins”, Synthetic Communications, 1987, pp. 1677-1682, vol. 17, No. 14.
Merten, Rudolf, et al., “Notiz über eine neue Synthese von Derivaten des 1.4.2-Diazaphospholidins”, Chem. Ber. 1969, pp. 2143-2145, vol. 102, (abstract not included).
Moloney, Gerard P, et al., “A Novel Series of 2,5-Substituted Tryptamine Derivatives as Vascular 5HT1B/1D Receptor Antagonists”, J. Med. Chem., 1997, pp. 2347-2362, vol. 40, No. 15.
Na, Byoung-Kuk, et al., “Aspartic proteases of Plasmodium vivax are highly conserved in wild isolates”, The Korean Journal of Parasitology, 2004, pp. 61-66, vol. 42, No. 2.
Oparil, Suzanne, et al., “The Renin-Angiotensin System (Second of Two Parts)”, The New England Journal of Medicine, 1974, pp. 446-457, vol. 291, No. 9.
Page, Philip C. Bulman, et al., “A Convenient Preparation of Symmetrical and Unsymmetrical 1,2-Diketones: Application to Fluorinated Phenytoin Synthesis”, Tetrahedron,1992, pp. 7265-7274, vol. 48, No. 35.
Paik, Seunguk, et al., “α-Aminosulfonopeptides as Possible Functional Analogs of Penicillin; Evidence for their Extreme Instablility”, Tetrahedron, 1996, pp. 5303-5318, vol. 52, No. 15.
Ugi, Ivar, Novel Methods of Preparative Organic Chemistry IV, “The α-Addition of Immonium Ions and Anions to Isonitriles Accompanied by Secondary Reactions”, Angew. Chem. Internat. Edit., 1962, pp. 8-21, vol. 1, No. 1.
Van Tonder, Elsa C, et al., “Preparation and Physicochemical Characterization of 5 Niclosamide Solvates and 1 Hemisolvate”, AAPS PharmSciTech, 2004, pp. 1-10, vol. 5, No. 1, Article 12.
Varga, László, et al., “Solution-phase parallel synthesis of 4,6-diaryl-pyrimidine-2-ylamines and 2-amino-5,5-disubstituted-3,5-dihydro-imidazol-4-ones via a rearrangement”, Tetrahedron, 2003, pp. 655-662, vol. 59.
Wang, Ying, et al., “Use of Polymer-Supported Pd Reagents for Rapid and Efficient Suzuki Reactions Using Microwave Heating”, American Chemical Society, Organic Letters, 2004, pp. 2793-2796, vol. 6, No. 16.
Weber, W. et al., “First synthesis of the main metabolite of secobarbital”, Pharmazie, 1998, pp. 771-775, vol. 53, No. 11.
Winkler, Jeffrey D, et al., Stereoselective Synthesis of the Tetracyclic Core of Manzamine via the Vinylogous Amide Photocycloaddition Cascade§, Tetrahedron, 1998, pp. 7045-7056, vol. 54.
Yu, Jin-Quan, et al., “Diverse Pathways for the Palladium(II)-Mediated Oxidation of Olefins by tert-Butylhydroperoxide”, American Chemical Society, Organic Letters, 2002, pp. 2727-2730, vol. 4, No. 16.
Intellectual Search Report for PCT/US 2004/041700, mailed Jun. 1, 2005 (6 pages) for CN06136.
Intellectual Search Report for PCT/US 2005/020446, mailed Jul. 26, 2006 (6 pages) for CN06136-01.
PCT Invitation to Pay Additional Fees Form for PCT/US2008/002182. Annex to Form PCT/ISA/206 Communication Relating to the Results of the Partial International Search for CN06136-02, International filing date—Feb. 20, 2008 (6 pages).
Balaban, Teodor Silviu, et al., “2-Aminopyrimidine Directed Self-Assembly of Zinc Porphyrins Containing Bulky 3,5-Di-tert-butylphenyl Groups”, Journal of the American Chemical Society (2003), 125(14), 4233-4239; 2003:215204 (Abstract).
Brown, George Barremore, “Atelopidtoxin. Purification and Chemistry”, University Microfilms, Ann Arbor, Order No. 73-4474 (1972) 186 pp.; 1973:401115 (Abstract).
Brownlee, T.C., et al., “Infrared absorption of substituents in heterocyclic systems. X. Amine-imine tautomerism by infrared spectroscopy: Further examples”, Journal of the Chemical Society [Section] B: Physical Organic (1966), (8), 726-7; 1966:465084 (Abstract).
Coppola, Gary M., “Novel heterocycles. I. Synthesis and reactions of 6,7-dihydro-1H, 3H,5H-pyrido[3,2,1-ij][3,1] benzoxazine-1,3-dione”, Journal of Heterocyclic Chemistry (1978), 15 (4), 645-7; 1979:22931 (Abstract).
Drusvyatskaya, S.K., et al., “Synthesis and anthelmintic properties of pyrimidinoperimidines”, Khimiko-Farmatsevticheskii Zhurnal (1983), 17(2), 158-60; 1983:198150 (English Abstract).
Fuhrman, Frederick A., et al., “Toxin from skin of frogs of the genus Atelopus; differentiation from dendrobatid toxins”, Science (Washington, DC, United States) (1969), 165(3900), 1376-7; 1969:521925 (Abstract).
Golubushina, G.M., et al., “Condensation of 2-amino-3,4,5,6-tetrahydroimidazo [4,5,1-ij]quinoline and 2-amino-2-pyrrline with β-diketones”, Khimiya Geterotsiklicheskikh Soedinenii (1972), (3), 419-21; 1972:488425 (English Abstract).
Henderson, R., et al., “Binding of labeled saxitoxin to the sodium channels in nerve membranes”, Journal of Physiology (Cambridge, United Kingdom) (1973), 235(3), 783-804; 1974:116904 (Abstract).
Huang, Minta, et al., “Accumulation of cyclic adenosine monophosphate in incubated slices of brain tissue. 2. Effects of depolarizing agents, membrane stabilizers, phosphodiesterase inhibitors, and adenosine analogs”, Journal of Medicinal Chemistry (1972), 15(5), 462-6; 1972:443058 (Abstract).
Iwamoto, Osamu, et al., “Total synthesis of (−)-decarbamoyloxysaxitoxin”, Angewandte Chemie, International Edition (2007), 46(45), 8625-8628; 2007:1398087 (Abstract).
Kim, Yong Hae, et al., “Potent Neurotoxins: Tetrodotoxin, Chiriquitoxin, and Zetekitoxin from Atelopus Frogs in Central America”, Journal of Toxicology, Toxin Reviews (2003), 22(4), 521-532; 2003:985614 (Abstract).
Kukla, Michael J., et al., “Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk] [1,4] benzodiazepin-2(1H)-one (TIBO) derivatives”, Journal of Medicinal Chemistry (1991), 34(11), 3187-97; 1991:632195 (Abstract).
Price, Clayton, et al., “Macrochelation, cyclometallation and G-quartet formation: N3- and C8-bound PdII complexes of adenine and quanine”, Chemistry—A European Journal (2001), 7(6), 1194-1201; 2001:240418 (Abstract).
Richardson, Alfred, Jr., “The synthesis and chemistry of certain 2-substituted 5,6-dihydroimidazo-,-oxazolo-, and-thiazolo[ij]quinolines”, Journal of Organic Chemistry (1963), 28(10), 2581-7; 1963:462271 (Abstract).
Werbel, Leslie M., et al., “Synthesis of 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1,-ij] quinolines and some related ring systems”, Journal of Heterocyclic Chemistry (1968), 5(3), 371-8; 1968:436031 (Abstract).
Iwamoto, Osamu, et al., “Total synthesis of (−)-decarbamoyloxysaxitoxin”, Angewandte Chemie, International Edition (2007), 46(45), 8625-8628; 2007;1398087 (Abstract).
Related Publications (1)
Number Date Country
20120231018 A1 Sep 2012 US
Divisions (2)
Number Date Country
Parent 12693874 Jan 2010 US
Child 13416140 US
Parent 11710582 Feb 2007 US
Child 12693874 US