Heterocyclic aspartyl protease inhibitors

This application is a Continuation 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.

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.

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 55 th 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.

The present invention relates to compounds having the structural formula I

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(R 6 )(R 7 )—, —N(R 5 )— or —C(═N(R 5 ))—;

X is —O—, —N(R 5 )— or —C(R 6 )(R 7 )—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O) 2 —, —C(═O)— or —C(═NR 5 )—;

U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —P(O)(OR 15 )—, —C(═NR 5 )—, —(C(R 6 )(R 7 )) b — or —N(R 5 )—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, U is not —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—; provided that when X is —N(R 5 )— and W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, then U is not a bond;

R 1 , R 2 and R 5 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —OR 15 , —CN, —C(O)R 8 , —C(O)OR 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 11 )(R 12 ), —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —NO 2 , —N═C(R 8 ) 2 and —N(R 8 ) 2 , provided that R 1 and R 5 are not both selected from —NO 2 , —N═C(R 8 ) 2 and —N(R 8 ) 2 ;

R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH 2 —O—Si(R 9 )(R 10 )(R 19 ), —SH, —CN, —OR 9 , —C(O)R 8 , —C(O)OR 9 , —C(O)N(R 11 )(R 12 ), —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), —N(R 11 )C(O)OR 9 and —C(═NOH)R 8 ; provided that when U is —O— or —N(R 5 )—, then R 3 , R 4 , R 6 and R 7 are not halo, —SH, —OR 9 , —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), or —N(R 11 )C(O)OR 9 ; provided that when W is —O— or —N(R 5 )—, then R 3 and R 4 are not halo, —SH, —OR 9 , —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), or —N(R 11 )C(O)OR 9 ; and provided that when X is —N(R 5 )—, W is —C(O)— and U is a bond, R 3 and R 4 are not halo, —CN, —SH, —OR 9 , —SR 19 , —S(O)N(R 11 )(R 12 ) or —S(O) 2 N(R 11 )(R 12 ); or R 3 , R 4 , R 6 and R 7 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group optionally substituted by R 14 or a 3-7 membered cycloalkylether optionally substituted by R 14 ;

or R 3 and R 4 or R 6 and R 7 together with the carbon to which they are attached, are combined to form multicyclic groups such as

wherein M is —CH 2 —, S, —N(R 19 )— 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 R 3 , R 4 , R 6 and R 7 form said multicyclic groups

then adjacent R 3 and R 4 or R 6 and R 7 groups cannot be combined to form said multicyclic groups;

R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR 15 , —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ;

R 9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;

R 10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R 15 )(R 16 );

R 11 , R 12 and R 13 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —C(O)R 8 , —C(O)OR 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 15 )(R 16 ), —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ) and —CN;

R 14 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, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ;

R 15 , R 16 and R 17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -cycloalkylalkyl, R 18 -heterocycloalkyl, R 18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 18 -heteroarylalkyl; or

R 15 , R 16 and R 17 are

wherein R 23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5;

R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO 2 , halo, heteroaryl, HO-alkyoxyalkyl, —CF 3 , —CN, alkyl-CN, —C(O)R 19 , —C(O)OH, —C(O)OR 19 , —C(O)NHR 20 , —C(O)NH 2 , —C(O)NH 2 —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 19 , —S(O) 2 R 20 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OCF 3 , —OH, —OR 20 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 20 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 20 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 20 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

or two R 18 moieties on adjacent carbons can be linked together to form

R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R 20 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 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —CH(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(R 16 ), —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —S(O)R 15 , ═NOR 15 , —N 3 , —NO 2 and —S(O) 2 R 15 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 21 are independently unsubstituted or substituted by 1 to 5 R 22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , -alkyl-C(O)OR 15 , C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —N 3 , ═NOR 15 , —NO 2 , —S(O)R 15 and —S(O) 2 R 15 ;

or two R 21 or two R 22 moieties on adjacent carbons can be linked together to form

and when R 21 or R 22 are selected from the group consisting of —C(═NOR 15 )R 16 , —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 and —CH 2 —N(R 15 )C(O)OR 16 , R 15 and R 16 together can be a C 2 to C 4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R 15 and R 16 , together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R 23 ;

R 23 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, —OR 24 , —C(O)R 24 , —C(O)OR 24 , —C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 23 are independently unsubstituted or substituted by 1 to 5 R 27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 24 , —C(O)R 24 , —C(O)OR 24 , alkyl-C(O)OR 24 , C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ;

R 24 , R 25 and R 26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R 27 -alkyl, R 27 -cycloalkyl, R 27 -cycloalkylalkyl, R 27 -heterocycloalkyl, R 27 -heterocycloalkylalkyl, R 27 -aryl, R 27 -arylalkyl, R 27 -heteroaryl and R 27 -heteroarylalkyl;

R 27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO 2 , halo, —CF 3 , —CN, alkyl-CN, —C(O)R 28 , —C(O)OH, —C(O)OR 28 , —C(O)NHR 29 , —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 28 , —S(O) 2 R 29 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 28 , —S(O) 2 NH(aryl), —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OH, —OR 29 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 29 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)(heteroarylalkyl), —NHC(O)R 29 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 29 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R 29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

provided that when W is —C(O)— and U is a bond, R 1 is not optionally substituted phenyl, and that when U is —C(O)— and W is a bond, R 5 is not optionally substituted phenyl;

provided that neither R 1 nor R 5 is —C(O)-alkyl-azetidinone or alkyl di-substituted with (—COOR 15 or —C(O)N(R 15 )(R 16 )) and (—N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), or —N(R 15 )C(O)OR 16 );

provided that when R 1 is methyl, X is —N(R 5 )—, R 2 is H, W is —C(O)— and U is a bond, (R 3 , R 4 ) 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 (CH 3 O-phenyl, NO 2 -phenyl); and when W is a bond and U is —C(O)—, (R 3 , R 4 ) 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 (CH 3 O-phenyl, NO 2 -phenyl);

provided that when X is —N(R 5 )—, R 1 and R 5 are each H, W is —C(O)— and U is a bond, (R 3 , R 4 ) 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 R 3 and R 4 form a ring with the carbon to which they are attached, R 1 is not 2-CF 3 -3-CN-phenyl;

provided that when X is —N(R 5 )—, U is —O— and W is a bond or —C(R 6 )(R 7 )—, (R 3 ,R 4 ) is not (H, —NHC(O)-alkyl-heteroaryl) or (H, alkyl-NHC(O)-alkyl-heteroaryl); and

provided that when X is —N(R 5 )—, R 1 and R 5 are not -alkylaryl-aryl-SO 2 —N(R 15 )(R 16 ) wherein R 15 is H and R 16 is heteroaryl;

provided that when R 1 is R 21 -aryl or R 21 -arylalkyl, wherein R 21 is —OCF 3 , —S(O)CF 3 , —S(O) 2 CF 3 , —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 CHF 2 , —S(O) 2 CF 2 CF 3 , —OCF 2 CHF 2 , —OCHF 2 , —OCH 2 CF 3 , —SF 5 or —S(O) 2 NR 15 R 16 ;

wherein R 15 and R 16 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -heterocycloalkyl, R 18 -aryl and R 18 -heteroaryl; U is a bond or —CH 2 ; and X is —N(R 5 )—; then R 5 is H;

provided that when U is a bond,

R 3 and R 4 are alkyl,

where R 21 is halo, —CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R 3 and R 4 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group,

and R 1 is

where a is 0 to 6 and R 22 is alkyl, alkoxy, halo, —CN, —OH, —NO 2 or haloalkyl;

then R 21a is not H, —C(O) 2 R 15 , wherein R 15 is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkyl-R 22 , wherein R 22 is selected from the group consisting of

phenyl,

phenyl substituted with alkyl,

and

wherein R 22 is selected from the group consisting of H, methoxy, nitro, oxo, —OH, halo and alkyl,

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 m 1 agonist or m 2 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 m 1 agonist or m 2 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.

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

In compounds of formulas IA to IF, U is preferably a bond or —C(R 6 )(R 7 )—. In compounds of formula IG and IH, U is preferably —C(O)—.

It will be understood that since the definition of R 1 is the same as the definition of R 5 , when X is —N(R 5 )—, compounds of formula I wherein W is a bond and U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —C(R 6 )(R 7 )— or —N(R 5 )— 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(R 6 )(R 7 )— or —N(R 5 )—.

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(R 6 )(R 7 )—.

Another group of preferred compounds of formula I is that wherein R 2 is H.

R 3 , R 4 , R 6 and R 7 are preferably selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH 2 —O—Si(R 9 )(R 10 )(R 19 ), —SH, —CN, —OR 9 , —C(O)R 8 , —C(O)OR 9 , —C(O)N(R 11 )(R 12 ), —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), —N(R 11 )C(O)OR 9 and —C(═NOH)R 8 .

R 3 , R 4 , R 6 and R 7 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(R 5 )—;

R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl,

R 2 is H;

R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;

R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;

R 5 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl;

R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;

R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;

R 15 , R 16 and R 17 is H, R 18 -alkyl, alkyl or

R 21 is alkyl, aryl, halo, —OR 15 , —NO 2 , —C(O)R 15 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ) or —CH(R 15 )(R 16 );

n is 1;

m is 1;

R 18 is —OR 20

R 20 is aryl;

and

R 23 is alkyl.

In a group of preferred compounds

R 3 , R 4 , R 6 and R 7 are

and

R 1 and R 5 is H, CH 3 ,

In an additional group of preferred compounds;

U is a bond or —C(O)—:

W is a bond or —C(O)—;

X is —N(R 5 )—;

R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl,

R 2 is H;

R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;

R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21- cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;

R 5 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl;

R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;

R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;

R 15 , R 16 and R 17 is H, cycloalkyl, cycloalkylalkyl, R 18 -alkyl, alkyl, aryl, R 18 -aryl, R 18 -arylalkyl, arylalkyl,

n is 1 or 2;

m is 0 or 1;

R 18 is —OR 20 or halo;

R 20 is aryl or halo substituted aryl;

R 21 is alkyl, aryl, heteroaryl, R 22 -alkyl, R 22 -aryl, R 22 -heteroaryl, halo, heterocycloalkyl, —N(R 15 )(R 16 ), —OR 15 , —NO 2 , —C(O)R 15 , —N(R 15 )C(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) or —CH(R 15 )(R 16 );

R 22 is —OR 16 or halo

and

R 23 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. R 21 -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., R 18 , R 21 , R 22 , 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

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 R 21 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 R 21 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

“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 R 21 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 R 21 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 R 21 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 R 21 substituents. Non-limiting examples of suitable arylheterocycloalkyls include

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 R 27 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 R 27 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., —CH 2 CH 2 — is ethylene, and

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., R 8 in —N(R 8 ) 2 , or a variable appears more than once in the structure of formula I, e.g., R 15 may appear in both R 1 and R 3 , 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 as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example,

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

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:

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(R 5 )— and R 1 and R 5 are each H can be represented by any of the following structures:

When R 21 and R 22 , are, for example, —N(R 15 )C(O)N(R 16 )(R 17 ) and R 15 and R 16 form a ring, the moiety formed, is, for example,

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, R 2 , 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, (C 1 -C 8 )alkyl, (C 2 -C 12 )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—(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1 -C 2 )alkyl, N,N-di(C 1 -C 2 )alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C 2 -C 3 )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, (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N—(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, α-amino(C 1 -C 4 )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(C 1 -C 6 )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 (C 1 -C 10 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY 1 wherein Y 1 is H, (C 1 -C 6 )alkyl or benzyl, —C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C 1 -C 6 )alkyl, carboxy (C 1 -C 6 )alkyl, amino(C 1 -C 4 )alkyl or mono-N— or di-N,N—(C 1 -C 6 )alkylaminoalkyl, —C(Y 4 )Y 5 wherein Y 4 is H or methyl and Y 5 is mono-N— or di-N,N—(C 1 -C 6 )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 H 2 O.

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) Intl. 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, C 1-4 alkyl, or C 1-4 alkoxy 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 C 1-20 alcohol or reactive derivative thereof, or by a 2,3-di(C 6-24 )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 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with 3 H and 14 C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) 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 beheterocyclic 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: R t

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: Et 2 O; 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 (R t ); 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

Method A, Step 1

To a solution of A1 (R 3 ═CH 3 & R 4 ═CH 2 CH(CH 3 ) 2 ) (10 mmol, 1 eq) in 30 ml of anhyd. CH 2 Cl 2 was added thiocarbonyl dipyridone (1.2 eq). After stirring overnight the solution was diluted with CH 2 Cl 2 , washed with 1N HCl, H 2 O (2×), and a saturated aqueous NaCl solution (2×). The organic solution was dried over Na 2 SO 4 , filtered and concentrated. The crude material was purified via flash chromatography to afford A2 (R 3 ═CH 3 & R 4 ═CH 2 CH(CH 3 ) 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 (R 3 ═CH 3 & R 4 ═CH 2 CH(CH 3 ) 2 ) (0.1 mmol, 1 eq) in anhydrous CH 2 Cl 2 (1 mL). The reaction mixture was refluxed overnight. The reaction solution was added to MP-TsOH resin (2-3 eq) and diluted with CH 3 CN. The suspension was agitated overnight. The mixture was filtered and the filtrate was concentrated to afford A3 (R 1 =3,5-difluorobenzyl, R 3 ═CH 3 , & R 4 ═CH 2 CH(CH 3 ) 2 ).

Method A, Step 3

To a solution of A3 (R 1 =3,5-difluorobenzyl, R 3 ═CH 3 , & R 4 ═CH 2 CH(CH 3 ) 2 ) (10 mg) in CH 3 OH (1 mL) was added NH 4 OH (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 CH 3 OH (1.2 mL) and was treated with sulfonic acid resin. The suspension was agitated overnight and the resin was washed with CH 3 OH (4×10 min) before it was treated with 2 N NH 3 in CH 3 OH 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 CH 3 CN/H 2 O gradient to afford A4 (R 1 =3,5-difluorobenzyl, R 2 ═H, R 3 ═CH 3 , & R 4 ═CH 2 CH(CH 3 ) 2 ). NMR (CD 3 OD): 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:

Method B

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, R 1 =3-chlorophenethyl) (1.1 g, 5.73 mmol) in anhydrous CH 3 OH (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 (R 3 =Me, R 4 = i Bu) (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 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , and R 1 =3-Chlorophenethyl).

Method B, Step 2

A solution of 40% concentrated HCl in CH 3 CH 2 OH was added to B2 (R 3 =

CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , and R 1 =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 CH 3 CN/H 2 O (with 0.1% formic acid) gradient to afford B3 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , and R 1 =3-Chlorophenethyl).

Method B, Step 3

Compound B4 (R 2 ═H, R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , and R 1 =3-Chlorophenethyl) was prepared from B3 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , and R 1 =3-Chlorophenethyl) following a procedure similar to Method A, Step 3. NMR (CD 3 OD): δ 8.1, br, 1H, 87.35, s, 1H, 87.25, m, 3H; δ 3.6, m, 1H; δ 3.4, m, 1H; δ 3.0, m, 1H; δ 2.8, m, 1H; δ 1.75, m, 1H; δ 1.6, m, 1H, 81.35, 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

Method C

Method C, Step 1

A solution of C1 (R 3 ═R 4 ═CH 2 CH 2 CH 2 CH 3 ) (50 mg, 0.25 mmol) and C4 (R 1 =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 CH 2 Cl 2 (3×) and CH 3 OH (3×). The filtrate was concentrated to afford C2 (R 1 =3-Cl—C 6 H 4 , R 3 ═R 4 ═CH 2 CH 2 CH 2 CH 3 ) (60 mg, 68%).

Method C, Step 2

Compound C3 (R 1 =3-Cl—C 6 H 4 , R 2 ═H, R 3 ═R 4 ═CH 2 CH 2 CH 2 CH 3 ) was prepared from C2 (R 1 =3-Cl—C 6 H 4 , R 3 ═R 4 ═CH 2 CH 2 CH 2 CH 3 ) 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.

Method D

Method D, Step 1

A mixture of D1 (R 3 ═R 4 ═CH 2 C 6 H 5 ) (20 g), potassium cyanide (40 g) and ammonium carbonate (15 g) in ethanol (100 mL) and H 2 O (200 mL) was heated in a sealed flask at 130° C. overnight to yield 25 g of D2 (R 3 ═R 4 ═CH 2 C 6 H 5 ) after filtration followed by washing with water.

Method D, Step 2

A solution of 2 N KOH (3 eq) was added to D2 (R 3 ═R 4 ═CH 2 C 6 H 5 ) (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 (R 3 ═R 4 ═CH 2 C 6 H 5 ).

Method D, Step 3

A solution of trimethylsilyldiazomethane in hexane (2 N) (2 eq) was added drop wise to a solution of D3 (R 3 ═R 4 ═CH 2 C 6 H 5 ) (1 eq) in anhydrous CH 3 OH (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 Na 2 CO 3 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 Na 2 SO 4 , and concentrated to afford D4 (R 3 ═R 4 ═CH 2 C 6 H 5 ).

The following amino esters were prepared using a similar method.

Method E

Method E, Step 1

Thionyl chloride (0.47, 6.38 mmol) was added drop wise to a solution of E1 (R 3 ═CH 2 CH 2 C 6 H 5 ) (2 g, 6.38 mmol) and benzaldehyde dimethyl acetal (0.96 mL, 6.38 mmol) in anhydrous THF at 0° C. under N 2 . After 5 min, ZnCl 2 (0.87 g, 6.38 mmol) was added and the reaction mixture was stirred at 0° C. After 3 h, an additional amount of ZnCl 2 (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/H 2 O. The mixture was stirred occasionally until the ice melted. The aqueous solution was extracted with ether (3×). The combined organic extracts were washed with H 2 O (3×), a sat. aqueous solution of NaHCO 3 (1×), and H 2 O (2×). The organic solution was dried over Na 2 SO 4 , filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to yield compound E2 (R 3 ═CH 2 CH 2 C 6 H 5 ).

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 (R 3 ═CH 2 CH 2 C 6 H 5 ) (600 mg, 1.49 mmol) and HMPA (0.85 mL) in THF (6.5 mL) cooled at −78° C. under N 2 . 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. NaHCO 3 (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 Na 2 SO 4 , filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to yield compound E3 (R 3 ═CH 2 CH 2 C 6 H 5 , R 4 ═CH 2 CH(CH 3 ) 2 ).

Method E, Step 3

A solution of lithium methoxide (1 N in CH 3 OH) (0.36 mL, 0.36 mmol) was added to compound E3 (R 3 ═CH 2 CH 2 C 6 H 5 , R 4 ═CH 2 CH(CH 3 ) 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 NaHSO 3 (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 NaHSO 3 (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 NaHSO 3 (8×). The organic solution was dried over Na 2 SO 4 , filtered and concentrated to afford E4 (R 3 ═CH 2 CH 2 C 6 H 5 , R 4 ═CH 2 CH(CH 3 ) 2 ) (109 mg, 87%).

Method E, Step 4

To a solution of E4 (R 3 ═CH 2 CH 2 C 6 H 5 , R 4 ═CH 2 CH(CH 3 ) 2 ) (109 mg, 0.28 mmol) in CH 3 OH (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 CH 3 OH (3×). The filtrate was concentrated to afford E5 (R 3 ═CH 2 CH 2 C 6 H 5 , R 4 ═CH 2 CH(CH 3 ) 2 ) (78 mg, 96%).

The following aminoesters were prepared using similar method.

Method F

A 500 mL methanol solution of 20 g of D5 (R 3 =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 (R 3 =cyclohexylmethyl, n=1) as HCl salt.

The following amino esters were examples prepared using similar method.

Method G

Method G, Step 1

To a solution of G1 (R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ) (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 H 2 O (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 H 2 O (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 Na 2 SO 4 , filtered and concentrated to afford G2 (R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ) (357 mg, 93%).

Method G, Step 2

A solution of benzyl amine (1.2 eq) was added to G2 (R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ) (1 eq), HOBT (1.5 eq) and polystyrene EDC resin (94 mg, 1.53 mmol/g, 3 eq) in 1:1 THF:CH 3 CN (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 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , R 15 ═CH 2 C 6 H 5 and R 16 ═H).

Method G, Step 3

Compound G4 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 2 ═H, R 3 ═CH 3 , R 15 ═CH 2 C 6 H 5 and R 15 ═H) was prepared from G3 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , R 15 ═CH 2 C 6 H 5 and R 16 ═H) following a procedure similar to Method A, Step 3.

The following compounds were prepared using similar methods.

Method H

Method H, Step 1

To a solution of H1 (R 3 ═CH 3 ) (5 g, 39 mmol) in a 1:1 mixture of 0.5 M NaHCO 3 :CH 3 CH 2 OH was added R 1 —NCS(R 1 =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 Na 2 SO 4 . 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 (R 3 ═CH 3 , R 1 ═CH 2 (3-ClC 6 H 4 )) (61%).

Method H, Step 2

Compound H3 (R 3 ═CH 3 , R 1 ═CH 2 (3-ClC 6 H 4 )) was synthesized from H2 (R 3 ═CH 3 , R 1 ═CH 2 (3-ClC 6 H 4 )) following a procedure similar to Method A, Step 3.

Method H, Step 3

To a solution of crude H3 (R 3 ═CH 3 , R 1 ═CH 2 (3-ClC 6 H 4 )) (14 mmol) in a 1:3 mixture of CH 3 OH:THF was added 0.5 M NaHCO 3 in H 2 O (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 Na 2 SO 4 , filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to afford 1.5 g of H4 (R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ).

Method H, Step 4

A solution of triflic anhydride (128 μL, 0.76 mmol) in CH 2 Cl 2 (5 mL) was added drop wise to a solution of H4 (R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ) (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 Na 2 SO 4 , filtered and concentrated to afford 310 mg of H5 (R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ).

Method H, Step 5

A solution of crude H5 (R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ) (0.11 mmol) and 7N ammonia in Methanol (R 21 —H═NH 2 —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 CH 3 CN/H 2 O gradient with 0.1% formic acid to yield H6 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , R 21 ═NH 2 ).

Method H, Step 6

A solution of 50% trifluoroacetic acid in CH 2 Cl 2 (2 mL) was added to H6 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , R 21 ═NH 2 ). After 40 min the solvent was evaporated and residue purified by preparative HPLC/LCMS eluting with a CH 3 CN/H 2 O gradient to afford H7 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , R 21 ═NH 2 ). NMR (CDCl 3 ), 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.

Method I

Method I, Step 1

Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of the formate salt of I1 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 and R 16 ═H) in CH 2 Cl 2 and the suspension was agitated. After 15 min, the mixture was filtered and the resin was washed with CH 2 Cl 2 (4×). The filtrate was concentrated to afford the free base I1(R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 and R 16 ═H).

A solution of R 15 COOH(R 15 =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 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 and R 16 ═H) (0.021 mmol) in 1:1 CH 3 CN: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 CH 3 CN: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 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , R 16 ═H and R 15 ═CH 2 CH 2 C 6 H 5 ).

Method I, Step 2

I3 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , R 16 ═H and R 15 ═CH 2 CH 2 C 6 H 5 ) was prepared from I2 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , R 16 ═H and R 15 ═CH 2 CH 2 C 6 H 5 ) using method similar to method H step 6.

The following compounds were prepared using similar method.

Method J

Method J, Step 1

Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of J1 (TFA salt, R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ) in CH 2 Cl 2 and the suspension was agitated. After 15 min, the mixture was filtered and the resin was washed with CH 2 Cl 2 (4×). The filtrate was concentrated to afford the free base. A solution of R 15 NCO(R 15 =butyl) (2 eq) in CH 2 Cl 2 was added to the free base of J1 (R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ) (0.021 mmol) in 1:1 CH 3 CN: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 CH 3 CN: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 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , and R 15 ═CH 2 CH 2 CH 2 CH 3 ).

Method J, Step 2

Compound J3 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , and R 15 ═CH 2 CH 2 CH 2 CH 3 ) was prepared from J2 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , and R 15 ═CH 2 CH 2 CH 2 CH 3 ) following the procedure described in Method H, Step 2.

The following compounds were prepared using similar method.

Method K

Method K, Step 1

A solution of R 15 SO 2 Cl(R 15 =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(R 1 ═CH 2 (3-ClC 6 H 4 ) and R 3 ═CH 3 ) (0.021 mmol) in 1:1 CH 3 CN: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 CH 3 CN: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 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , and R 15 ═CH 2 CH 2 CH 3 ).

Method K, Step 2

Compound K3 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , and R 15 ═CH 2 CH 2 CH 3 ) was prepared from K2 (R 1 ═CH 2 (3-ClC 6 H 4 ), R 3 ═CH 3 , and R 15 ═CH 2 CH 2 CH 3 ) following the procedure described in Method H, Step 6.

The following compounds were prepared using similar method.

Method L

(In the scheme, —Z—NH—C(O)R 16 — is equivalent to R 1 substituted by R 21 , or R 1 Substituted by alkyl-R 22 , wherein R 21 and R 22 are —N(R 15 )C(O)R 16 and R 15 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 (R 3 ═CH 3 and R 4 ═CH 2 CH(CH 3 ) 2 ) (1 eq) and Z=-para-methylene-benzyl) (1.05 eq) in CH 2 Cl 2 was stirred at rt. The reaction solution was concentrated and purified via flash chromatography. The material was treated with 50% trifluoroacetic acid in CH 2 Cl 2 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 Na 2 CO 3 in H 2 O was added to the aqueous phase until the solution became basic. The solution was extracted with CH 2 Cl 2 (3×). The CH 2 Cl 2 extracts were combined, dried over Na 2 SO 4 , filtered and concentrated to yield L2 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—).

Method L, Step 2

Compound L3 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 16 ═CH 2 CH 2 CH 2 CH 3 ) was prepared from L2 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—) following the procedure described in Method I, Step 1.

Method L, Step 3

Compound L4 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 1 ═CH 2 CH 2 CH 2 CH 3 ) was prepared from (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 16 ═CH 2 CH 2 CH 2 CH 3 ) following the procedure described in Method A, Step 3.

The following compounds were prepared using similar method.

Method M

(In the scheme, —Z—NH—C(O)—NHR 15 — is equivalent to R 1 substituted by R 21 , or R 1 Substituted by alkyl-R 22 , wherein R 21 and R 22 are —N(R 16 )—C(O)—NHR 15 and R 16 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 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—R 15 =3,4-difluorophenyl) was prepared from M1 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—) following the procedure described in Method J, Step 1.

Method M, Step 2

Compound M3 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 15 =3,4-difluorophenyl) was prepared from M2 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 15 =3,4-difluorophenyl) following the procedure described in Method A, Step 3. NMR (CD 3 OD) 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.

Method N

(In the scheme, —Z—NH—S(O) 2 R 16 — is equivalent to R 1 substituted by R 21 , or R 1 Substituted by alkyl-R 22 , wherein R 21 and R 22 are —N(R 16 )—C(O)—NHR 15 and R 16 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 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 16 ═CH 2 CH(CH 3 ) 2 ) was prepared from N1 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—) following the procedure described in Method K, Step 1.

Method N, Step 2

Compound N3 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 16 ═CH 2 CH(CH 3 ) 2 ) was prepared from N2 (R 3 ═CH 3 , R 4 ═CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 16 ═CH 2 CH(CH 3 ) 2 ) following the procedure described in Method A, Step 3.

The following compounds were prepared using similar method.

Method O

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 CH 2 Cl 2 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 K 2 CO 3 solution, extracted with ethyl acetate and CH 2 Cl 2 . 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 CH 2 Cl 2 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 CH 2 Cl 2 . The organic layer was separated and washed with 1 N HCl (3×). The organic solution was dried over Na 2 SO 4 , 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 CH 2 Cl 2 (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 CH 3 OH (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 CH 3 OH 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 H 2 O was added to a solution of O10 (40 mg) in CH 3 OH (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

Method P, Step 1

A 300 mL of THF solution of 100 g of P1 (R 23 =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 H 2 O, 90 ml of 15% NaOH was added at 0° C. The mixture was stirred at r.t. for one hour before Na 2 SO 4 (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 H 2 O at −10° C. and the mixture was extracted with DCM. After removal of solvent, P2 (R 23 =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 (R 23 =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 H 2 O 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 (R 23 =Pr).

Method P, Step 3

A 10 ml MeOH solution of P3 (R 23 =Pr, 110 mg) was hydrogenated using Pd/C (5%, 11 mg) at 1 atm of hydrogen to give product P4 (R 23 =Pr) after removal of solvent and catalyst.

Method P, Step 4

To a 10 ml DCM solution of P4 at 0° C. (R 23 =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 (R 23 =Pr) as a white solid was obtained (80 mg).

The following compounds were synthesized using similar methods:

Method Q

Method Q, Step 1

At room temperature, Q1 (R 3 =Me; R 4 =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, R 3 =Me; R 4 =iBu), a colorless oil (1.59 g).

Method Q, Step 2

Compound Q3 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 =iBu) was prepared from Q2 (n=1, p=2, m=1, R 3 =Me; R 4 =iBu) using method similar to method A step 3.

Method Q, Step 3

Compound Q3 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 =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, R 2 ═H, R 3 =Me; R 4 =i-Bu) as a white foam (0.74 g).

Method Q, Step 4

Compound Q4 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 = i Bu) (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, R 2 ═H, R 3 =Me; R 4 = i Bu) as a colorless oil (0.35 g).

Method Q, Step 5

Compound Q5 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 =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 R 15 —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, R 2 ═H, R 3 =Me; R 4 = i Bu, R 15 =Me).

Method Q, Step 6

A dichloromethane solution (1.0 mL) of Q6 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 = i Bu, R 16 =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, R 3 =Me; R 4 =iBu, R 15 =Me). NMR (CDCl 3 ): 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, δ 1.95, 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:

Method R

Method R, Step 1

A solution of R 1 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 = i Bu) (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 R 2 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 = i Bu and R 15 =Ph).

Method R, Step 2

Procedure similar to Method Q, step 6 was used for the transformation of R 2 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 = i Bu and R 15 =Ph) to R 3 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 = i Bu and R 15 =Ph).

The following compounds were prepared using similar methods:

Method S

Method S, Step 1

A solution of S1 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 =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, R 2 ═H, R 3 =Me; R 4 =iBu and R 15 =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, R 2 ═H, R 3 =Me; R 4 = i Bu and R 15 =Ph).

The following compounds were prepared using similar methods:

Method T

Method T, Step 1

To a microtiter plate well containing 1 ml solution of T1 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 =iBu) in DCM (0.010 g) and R 15 C(O)R 16 (5 equiv, R 15 ═H, R 16 =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, R 2 ═H, R 3 =Me; R 4 = i Bu and R 15 =Ph and R 16 ═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, R 2 ═H, R 3 =Me; R 4 =iBu and R 15 =Ph and R 16 ═H) to T3 (n=1, p=2, m=1, R 2 ═H, R 3 =Me; R 4 = i Bu and R 15 =Ph and R 16 ═H).

The following compounds were prepared using similar methods:

Method U

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

In a microwave vial was charged U1 (R 2 ═H; R 3 =i-Bu, R 4 =Me) (0.025 g) in toluene (4 mL), potassium carbonate (0.035 g), Pd(dppf)Cl 2 (0.020 g). water (0.02 mL) and R 21 B(OH) 2 (R 21 =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 (MgSO 4 ) dichloromethane solution was concentrated in vacuo to give a brown residue which was purified via a RP Prep LCMS system to give product U2 (R 2 ═H; R 3 = i Bu: R 4 =Me; R 21 =m-methoxyphenyl).

The following compounds were prepared using similar methods:

Method V

Method V, Step 1

Compound V1 (R 3 ═R 4 =Me) (14.76 mmole), EDCl (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 (R 1 =3-chlorobenzyl; R 3 ═R 4 =Me).

Method V, step 2

Compound V2 (R 1 =3-chlorobenzyl; R 3 ═R 4 =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 N 2 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 (R 1 =3-chlorobenzyl; R 3 ═R 4 =Me).

Method V, step 3

The thiohydantoin V3 (R 1 =3-chlorobenzyl; R 3 ═R 4 =Me) was treated with t-butyl hydroperoxide and ammonium hydroxide in MeOH at RT for 48 h to give compound V4 (R 1 =3-chlorobenzyl; R 2 ═H; R 3 ═R 4 =Me).

The following compounds were prepared using similar method.

Method W

Compound W1 obtained using method A (n=1, R 2 =m-Cl-Bn, R 3 =Me) was hydrolyzed to W2 (n=1, R 2 =m-Cl-Bn, R 3 =Me) using two equivalent of LiOH in MeOH.

The following compounds were synthesized in similar fashion:

Method X

(In the scheme, —Z—NH—C(O)—N(R 16 )(R 17 )— is equivalent to R 1 substituted by R 21 , or R 1 Substituted by alkyl-R 22 , wherein R 21 and R 22 are —NH—C(O)—N(R 16 )(R 17 ) and R 15 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 (R 3 =Me; R 4 = i -Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) (10 mg) in DCM and sat. NaHCO 3 (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 Na 2 SO 4 . The organic solution was evaporated to give compound X2 (R 3 =Me; R 4 =i-Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—).

Method X, Step 2

Compound X3 (R 15 ═H; R 16 =cyclopropylmethyl; R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) was prepared from X2 (R 3 =Me; R 4 =i-Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) using method similar to method M, step 1.

Method X, Step 3

Compound X4 (R 16 ═H; R 17 =cyclopropylmethyl; R 2 ═H; R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) was prepared from X3 (R 16 ═H; R 17 =cyclopropylmethyl; R 2 ═H; R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) using method similar to method A Step 3. NMR (CD 3 OD): 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.

Method Y

(In the scheme,

is equivalent to R 1 substituted by R 21 , or R 1 Substituted by alkyl-R 22 , wherein R 21 and R 22 are —N(R 15 )—C(O)—N(R 16 )(R 17 ) and R 15 and R 16 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 (R 3 =Me; R 4 =i-Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) (0.1639 mmole), Y 2 (R 23 ═H; R 23 =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 (R 3 =Me; R 4 =i-Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 23 ═H; R 23 =Pr).

Method Y, Step 2

The reaction solution of Y3 (R 3 =Me; R 4 =i-Bu; Z=para-CH 2 )C 6 H 4 (CH 2 )—, R 23 ═H; R 23 =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 (R 2 ═H; R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 23 ═H; R 23 =Pr).

The following compounds were prepared using similar method.

Method Z

(In the scheme, —Z—NH—C(O)—N(R 16 )(R 17 )— is equivalent to R 1 substituted by R 21 , or R 1 Substituted by alkyl-R 22 , wherein R 21 and R 22 are —N(R 15 )—C(O)—N(R 16 )(R 17 ) and R 15 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 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) (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 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—).

Method Z, Step 2

To the resin Z2 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—), 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 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—; R 16 =Me; R 17 =Bn).

Method Z, Step 3

Compound Z4 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—; R 16 =Me; R 17 =Bn) was generated from Z3 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—; R 16 =Me; R 17 =Bn) using method similar to Method A step 3.

The following compounds were prepared using similar method.

Method AA

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:

Method AB

Method AB, Step 1

To a solution of (R)-(+)-2-methyl-2-propane sulfinamide (1.0 g, 8.3 mmol, 1 eq) and ABI (R 6 =Ph, R 7 =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 (Na 2 SO 4 ), and concentrated in vacuo. The residue was chromatographed on silica by eluting with hexane/Et 2 O (5:1) to give 1.9 g (85%) of (R)-2-methyl-N-(1-phenylpentylidene)propane-2-sulfinamide. 1 HNMR (CDCl 3 , 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 t R =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 NH 4 Cl (10 eq) was added and the suspension was warmed to room temperature. The mixture was diluted with H 2 O (50 mL) and stirred for 10 min. The mixture was then partitioned between H 2 O (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 (MgSO 4 ) 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. 1 HNMR (CDCl 3 , 300 MHz): 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 t R =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 (R 6 =Ph, R 7 =n-Bu) as a yellow solid. 1 HNMR (CDCl 3 , 300 MHz): 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 t R =4.72 min.

Method AB, Step 2

Treatment of compound AB2 (R 6 =Ph, R 7 =n-butyl) with thiophosgene in CH 2 Cl 2 in the presence of aqueous NaHCO 3 at 0° C. generates isothiocyanate AB3 (R 6 =Ph, R 7 =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 (R 6 =Ph, R 7 =n-butyl, R 1 =Me). 1 HNMR (CDCl 3 , 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 t R =5.09 min.

The following compounds were synthesized using similar methods:

Method AC

The synthesis was adapted from a procedure by Hull, R. et al, J. Chem. Soc. 1963, 6028-6033. Thus, to a solution of AC2 (R 1 =Benzyl) (0.72 g, 5.9 mmol) in AC1 (R 4 =Me, R 3 =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 H 2 O. The organic layer was dried over Na 2 SO 4 , filtered and the volatiles were removed in vacuo. The residue was purified by column chromatography using 5-10% CH 3 OH/CH 2 Cl 2 as eluent followed by reverse phase preparative HPLC to give 0.15 g (8.0%) of AC3 (R 1 =benzyl, R 4 =Me and R 3 =Me) as a white solid. 1 H NMR (CH 3 OH, 300 MHz): δ 7.35-7.33 (m, 5H), 4.71 (s, 2H), 1.46 (s, 6H); 13 C NMR (CDCl 3 , 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) + .

Method AD

Method AD, Step 1

AD2 (R 3 =Ph, R 4 = t Butyl) 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 (R 3 =Ph, R 4 =tert-Butyl) (0.56 g, 2.7 mmol) and boiling chips in CCl 4 (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. 1 H NMR (CDCl 3 , 300 MHz): δ 7.63-7.61 (m, 2H), 7.37-7.26 (m, 3H), 1.17 (s, 9H); 13 C NMR (CDCl 3 , 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 CH 3 OH/CH 2 Cl 2 as eluent to give 0.050 g (42%) of AD3 (R 3 =Ph, R 4 =tert-Butyl) as a glassy solid. 1 H NMR (CDCl 3 , 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 (R 3 =Ph, R 4 =tert-Butyl) (0.065 g, 0.26 mmol) in CH 3 OH (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 (R 3 =Ph, R 4 =tert-Butyl) as a colorless oil. 1 H NMR (CDCl 3 , 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:

Method AE

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 (R 1 =Me, R 3 =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 NaHCO 3 3× and brine 3×, and dried over anhydrous Na 2 SO 4 to give 12 g of AE2 (R 1 =Me, R 3 =cyclohexylmethyl), which was used for next step without further purification.

Method AE, Step 2

AE2 (R 1 =Me, R 3 =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 (R 1 =Me, R 3 =cyclohexylmethyl) after column purification.

Method AE, Step 3

AE4 (R 1 =Me, R 3 =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 (R 1 =Me, R 3 =cyclohexylmethyl) ((3.95 g, 8.38 mmol) in anhydrous THF (98 mL) was added diisopropylethylamine (7 mL, 40 mmol). The reaction was stirred under N 2 (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 (R 1 =Me, R 3 =cyclohexylmethyl) (2.48 g, 92%).

Method AE, Step 4

To a solution of R 15 OH(R 15 =cyclobutyl) (10 μl) and HBF 4 (1 equiv) in anhydrous methylene chloride (0.5 mL) was added a solution of AE5 (R 1 =Me, R 3 =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% CH 3 CN in H 2 O with 0.1% formic acid to afford AE5 (R 1 =Me, R 3 =cyclohexylmethyl, R 15 =cyclobutyl).

The following compounds were synthesized using similar method:

Method AF

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 (R 1 =Me, R 3 =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 NH 3 in MeoH to give AF2 (R 1 =Me, R 3 =cyclohexylmethyl and R 15 =3-chlorophenyl).

The following compounds were synthesized using similar method:

Method AG

Method AG, Step 1

R 21 —H(R 21 =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 (R 1 =Me, R 3 =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 NaHCO 3 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 NaSO 4 . The crude was purified on flash column with EtOAc/hexane to give 9 mg of AG1 (R 21 =PhS—, R 1 =Me, R 3 =cyclohexylmethyl) (49.2% yield).

Method AG, Step 2

AG1 (R 21 =PhS—, R 1 =Me, R 3 =cyclohexylmethyl) was treated with 50% TFA according to the Step 6 of the method H to give AG2 (R 21 =PhS—, R 1 =Me, R 3 =cyclohexylmethyl).

The following compounds were synthesized using similar method:

Method AH

Method AH, Step 1

Benzophenone imine (3.27 g, 18.04 mmole) was added to a suspension of AH1 (R 3 =cyclohexylmethyl) (4 g, 18.04 mmole) in 65 ml DCM. The reaction mixture was stirred at room temperature overnight under N 2 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 MgSO 4 . The crude was purified on flash column to give 5.08 g (80.57% yield) of AH2 (R 3 =cyclohexylmethyl).

Method AH, Step 2

A solution of AH2 (R 3 =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 R 4 Br (R 4 =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/H 2 O (0.25:0.75:1). The mixture was diluted with 40 ml EtOAc/H 2 O (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 (R 4 =3-pyridylmethyl; R 3 =cyclohexylmethyl).

Method AI

To a solution of compound AI1 (R 1 =Me, R 3 =n-Bu) (34 mg, 0.105 mmol) in methanol (1 ml) was added 10% Pd/C (5 mg). The mixture was kept under an H 2 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 (R 1 =Me, R 3 =n-Bu) (25 mg, 100%). Observed MW (M+H) 246.1; exact mass 245.15. 1 H NMR (400 MHz, CD 3 OD): 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:

Method AJ

To a mixture of compound AJ1 (R 1 =Me, R 3 =n-Bu) (70 mg, 0.165 mmol) and butylzincbromide (1.32 ml, 0.6 mmol) was added Pd(dppf)Cl 2 . The mixture was degassed, sealed and heated at 55° C. for 1 day. The mixture was diluted with CH 2 Cl 2 and NH 3 /H 2 O. 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 (R 1 =Me, R 3 =n-Bu) (12 mg, 25%). Observed MW (M+H) 302.1; 1 H NMR (400 MHz, CD 3 OD): 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:

Method AK

To a solution of AK1 (R 1 =Me, R 3 =n-Butyl, R 21 =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 H 2 (50 psi) for 2 days. After the filtration of the catalyst, the filtrate was concentrated to get compound AK2 (R 1 =Me, R 3 =n-butyl, R 21 =n-Bu) Observed MW (M+H) 308.1. 1 H NMR (CD 3 OD): 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:

Method AL

Method AL, Step 1

To a solution of compound AL1 (R 3 =n-Bu) (418 mg, 1.39 mmol) in methanol (8 ml) was added PtO 2 (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 (R 3 =n-Bu) (316 mg, 100%).

Method AL, Step 2

To a solution of compound AL2 (R 3 =n-Bu) (300 mg, 1.32 mmol) in dichloromethane (6 ml) was added (BOC) 2 O (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 (R 3 =n-Bu) (464 mg, 100%).

Method AM

Method AM, Step 1

Compound AM1 (R 1 =Me, R 3 =n-Butyl) was treated with 4N HCl in dioxane for 2 hr. The mixture was concentrated to get compound AM2 as an HCl salt (R 1 =Me, R 3 =n-Butyl). Observed MW (M+H) 470.1; 1 H NMR (CD 3 OD): 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 (R 1 =Me, R 3 =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 CH 2 Cl 2 and water. The organic layer was separated, dried, concentrated and purified by RP HPLC to get compound AM3 (R 1 =Me, R 3 =n-Butyl and R 15 =Me) Observed MW (M+H) 512.3; 1 H NMR (400 MHz, CDCl 3 ): 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:

Method AN

To a solution of compound AN2 (R 1 =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 (R 1 =4-N-(a-phenoxyacetyl)piperidinylmethyl, R 3 =n-Butyl, R 15 =propyl and R 16 ═H) (5.4 mg, 17%). Observed MW (M+H) 526.1; exact mass 525.37. 1 H NMR (CD 3 OD): 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:

Method AO

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 (R 3 =n-butyl) (10 ml, 20 mmol) was added gradually. The reaction was warmed up to −60° C., and AO2 (R 4 =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. NaHCO 3 . 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 (R 4 =m-BrPh, R 3 =n-Bu) (3.93 g, 82%). Observed MW (M+H) 241.1; exact mass 240.01. 1 H NMR (400 MHz, CDCl 3 ): 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:

Method AP

Method AP, Step 1

To a solution of AP1 (R 4 =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). EDCl (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 Na 2 SO 4 , and concentrated to give the Weinreb amide AP2 (R 4 =m-Bromophenyl) (5.96 g, 98%). Observed MW (M+H) 244.1; exact mass 243.99. 1 H NMR (CDCl 3 ): 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 R 3 Br (R 3 =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 (R 4 =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 (R 4 =m-Bromophenyl, R 3 =Cyclohexylethyl) (8.06 g, 100%). Observed MW (M+H) 295.2; exact mass 294.06. 1 H NMR (400 MHz, CDCl 3 ): 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

To a −78° C. solution of AQ1 (R 4 =cyclopropyl) (2.55 g, 38.0 mmol) in diethyl ether (100 ml) was added AQ3 (R 3 =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 MgSO 4 , and concentrated. This crude residue was subjected to column chromatography (silica gel, 0%→100% CH 2 Cl 2 /hexanes) to provide the desired ketone AQ4 (R 4 =cyclopropyl, R 3 =n-Butyl) (2.57 g, 20.4 mmol, 54%). 1 H NMR (CDCl 3 ) δ 2.52 (t, J=7.2 Hz, 2H), 1.90 (m, 1H), 1.57 (m, 2H), 1.30 (m, 2H), 0.98 (m, 2H), 0.89 (t, J=7.6 Hz, 3H), 0.83 (m, 2H).

Method AR

Method AR

Compound B2 (R 1 =m-Cl-Phenethyl, R 3 =Me, R 4 =i-butyl and R 5 =benzyl) was converted into AR 2 (R 1 =m-Cl-Phenethyl, R 3 =Me, R 4 =i-butyl and R 5 =benzyl) using method A step 3.

The following compounds were synthesized using similar methods:

Method AS

Method AS, Step 1

To a mixture of AS1 (R 3 =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 rt 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 CH 2 Cl 2 , solid sodium bicarbonate added, filtered and then the CH 2 Cl 2 solution was concentrated in vacuo to give AS2 (R 3 =Ph).

Method AS, Step 2

To AS2 (R 3 =Ph) (0.645 g) and AS5 (R 4 =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 H 2 O and Et 2 O. The dried Et 2 O solution was concentrated in vacuo to give a yellow residue which was placed on preparative silica gel plates and eluted with CH 2 Cl 2 to give AS3 (R 3 =Ph, R 4 =p-ClPh). (Miyashita, A., Matsuda, H., Hiagaskino, T., Chem. Pharm. Bull., 1992, 40 (10), 2627-2631).

Method AS, Step 3

Hydrochloric acid (1 N, 1.5 ml) was added to AS3 (R 3 =Ph, R 4 =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 CH 2 Cl 2 and H 2 O. The dried CH 2 Cl 2 was concentrated in vacuo to give a residue which was placed on preparative silica gel plates and eluted with CH 2 Cl 2 :hexane 1:1 to afford AS4 (R 3 =Ph, R 4 =p-ClPh).

Method AS, Step 4

AS4 (R 3 =Ph, R 4 =p-ClPh) (0.12 g) and methylguanidine, HCl (AS6, R 1 =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 CH 2 Cl 2 and H2O. The dried CH 2 Cl 2 was concentrated in vacuo to give a residue which was placed on preparative silica gel plates and eluted with CH 2 Cl 2 :MeOH 9:1 to afford AS5 (R 3 =Ph, R 4 =p-ClPh and R 1 =Me).

The following compounds were synthesized using similar methods:

Method AT

Method AT, Step 1

AT1, prepared using a method similar to Method H, Step 1, 2 and 3, (n=4, R 3 ═R 4 =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, R 3 ═R 4 =n-Bu).

Method AT, Step 2

Compound AT2 (n=4, R 3 ═R 4 =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 (R 15 ═H, R 16 =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, R 3 ═R 4 =n-Bu, R 15 ═H and R 16 =n-Butyl).

The following compounds were synthesized using similar method:

Method AU

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 (R 15 ═H, R 16 ═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. 5 th ed. Longman: new York, 1989; pp 1034-1035), AU2 (HCl salt, R 1 =Me) (0.237 g), 50% KOH (0.305 ml), 30% H 2 O 2 (0.115 ml) and EtOH (4.6 ml) were heated in a sealed tube for 2 h. Reaction mixture was concentrated and extracted with CH 2 Cl 2 . The dried organic solution was concentrated in vacuo to give a residue which was placed on preparative silica gel plates eluting with CH 2 Cl 2 :MeOH 9:1 to afford AU3 (R 15 ═H, R 16 ═H, R 1 =Me).

The following compounds were synthesized using similar method:

Method AV

Method AV, Step 1

In a microwave tube, AV1 (R 3 =Me, R 4 =Bu-i) (0.0012 g) and AV2 (R 22 ═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 (R 3 =Me, R 4 =i-Bu, R 22 ═OPh).

Method AV, Step 2

AV3 (R 3 =Me, R 4 =i-Bu, R 22 ═OPh) in CH 2 Cl 2 (1 ml) and TFA (1 ml) was shaken for 2 h and the concentrated in vacuo and purified on Prep LCMS to afford AV4 (R 3 =Me, R 4 =i-Bu, R 22 ═OPh).

The following compounds were synthesized in a similar fashion.

Method AW

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:

Method AX

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, R 4 =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, R 4 =phenethyl).

Method AX, Step 2

A solution of AX2 (4.5 g, n=1, R 4 =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, R 4 =phenethyl) and AX4 (n=1, R 4 =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, R 4 =phenethyl) as the first fraction and 2.2 g of AX4 (n=1, R 4 =phenethyl) as the second fraction.

Method AX, Step 3

A 100 ml methanolic solution of AX4 (n=1, R 4 =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, R 4 =phenethyl) (1.7 g).

The following compounds were generated using similar method.

Method AY

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 N 2 , 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.

Method AZ

Method AZ, Step 1

To a solution of AZ1 (n=1, R 1 =Me, R 3 =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 H 2 O and diluted with EtOAc. After removal of the organic phase, the aqueous layer was extracted with EtOAc (3×). The combined organics were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield AZ2 (n=1, R 1 =Me, R 3 =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, R 1 =Me, R 3 =2-cyclohexylethyl) (0.011 g, 0.025 mmol) and AZ5 (R 15 ═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 NH 3 /MeOH, and solution was filtered. After concentration, the residue was purified by silica gel HPLC (0-4% [(5% 7N NH 3 /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, R 1 =Me, R 3 =2-cyclohexylethyl, R 15 ═H and R 16 =m-pyridylmethyl) (0.005 g, 0.009 mmol) and the AZ3 (n=1, R 1 =Me, R 3 =2-cyclohexylethyl, R 15 ═H and R 16 =m-pyridylmethyl) (0.012 g, 0.022 mmol) respectively.

The following compounds were generated using similar methods:

Method BA

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).

1 H NMR (CDCl 3 ) 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). 1 H NMR (CDCl 3 ) 1.43 (s, 9H), 3.98 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1H).

Method BB

Method BB, Step 1

Compound BB1 (n=1, R 1 =Me, R 3 =cyclohexylethyl) was converted to BB2 (n=1, R 1 =Me, R 3 =cyclohexylethyl) and BB3 (n=1, R 1 =Me, R 3 =cyclohexylethyl) which were separated via a silica gel column eluted with EtOAc in Hexane (0-15%).

Method BB, Step 2

Compound BB4 (n=1, R 1 =Me, R 3 =cyclohexylethyl) was generated from BB2 (n=1, R 1 =Me, R 3 =cyclohexylethyl) using 20% TFA in DCM.

The following compounds were generated using similar method:

Method BC

Method BC, Step 1

Compound BC2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =m-Pyridyl) was obtained from BC1 (n=1, R 2 =Me, R 3 =cyclohexylethyl) using method L step 2.

Method BC, Step 2

Compound BC3 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =m-Pyridyl) was obtained from BC2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =m-Pyridyl) using method L step 3.

The following compounds were generated using a similar method:

Method BD

Method BD, Step 1

Compound BD2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =Ph) was obtained from BD1 (n=1, R 2 =Me, R 3 =cyclohexylethyl) using Method N, Step 1.

Method BD, Step 2

Compound BD3 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =Ph) was obtained from BD2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =m-Pyridyl) using Method N, Step 2.

The following compounds were generated using a similar method:

Method BE

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

Method BF

Method BF, Step 1

Method similar to Method T, Step 1 was used for the synthesis of BF2 (n=1, R 1 =Me and R 3 =phenethyl, R 15 ═H and R 16 =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.

Method BG

Method BG

To a solution of BG1 (n=1, R 3 =cyclohexylethyl) (0.136 g, 0.31 mmol) in CH 2 Cl 2 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, R 3 =cyclohexylethyl, R 15 =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:

Method BH

Method BH, Step 1

Compound BH1 (n=1, R 3 =cyclohexylethyl and R 15 =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 H 2 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, R 3 =cyclohexylethyl and R 15 =n-butyl) was carried on to the next step without purification.

Method BH, Step 2

A solution of BH2 (n=1, R 3 =cyclohexylethyl and R 15 =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, R 2 =Me, R 3 =cyclohexylethyl and R 15 =n-butyl) (0.032 g, 0.078 mmol, 56% yield) and BH3 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =n-butyl) (0.008 g, 0.020 mmol, 14% yield). For BH4 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =n-butyl), MS m/e: 409.1M+H). For BH3 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =n-butyl), MS m/e: 409.1 (M+H).

Method BH, Step 3

Compound BH4 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =n-butyl) (0.032 g, 0.078 mmol) was converted to BH5 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =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:

Method BI

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 H 2 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

Method BJ, Step 1

A mixture of 2 ml dioxane solution of BJ1 (R 1 =Me, R 3 =Me) (140 mg, 0.5 mmol) generated using Method BK Steps 1 & 2, indole (1.2 eq), potassium t-Butoxide (1.4 eq), Pd 2 (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 (R 1 =Me, R 3 =Me) (0.73 mg).

Method BJ, Step 2

BJ2 (R 1 =Me, R 3 =Me) was converted to BJ3 (R 1 =Me, R 3 =Me) using Method BK, Steps 3 & 4. Obs. Mass for BJ3 (R 1 =Me, R 3 =Me): 319.2.

Method BK

Method BK, Step 1

Hydantoin BK2 (R 3 ═N-benzyl-3-piperidyl, R 4 =n-Bu) was prepared according to Method D, Step 1 from the corresponding ketone BK1 (R 3 ═N-benzyl-3-piperidyl, R 4 =n-Bu). Analytical data for BK2 (R 3 ═N-benzyl-3-piperidyl, R 4 =n-Bu): (M+H)=330.1.

Method BK, Step 2

To a suspension of hydantoin BK2 (R 3 ═N-benzyl-3-piperidyl, R 4 =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 (R 3 ═N-benzyl-3-piperidyl, R 4 =n-Bu) (140 mg, 0.408 mmol, 97%), (M+H)=344.1.

Method BK, Step 3

To a solution of a portion of BK3 (R 3 ═N-benzyl-3-piperidyl, R 4 =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 MgSO 4 , filtered, and concentrated. This crude residue was purified by preparative TLC (1000 μm silica, 15% EtOAc/DCM) to give two separated diastereomers BK4 (R 3 ═N-benzyl-3-piperidyl, R 4 =n-Bu) (24 mg, 0.067 mmol, 33%, MS: (M+H)=360.2) and BK5 (R 3 ═N-benzyl-m-piperidyl, R 4 =n-Bu) (22 mg, 0.062 mmol, 31%, MS: (M+H)=360.2).

Method BK, Step 4

Diastereomer BK5 (R 3 ═N-benzyl-3-piperidyl, R 4 =n-Bu) was treated with NH 4 OH (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 NH 3 /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 (R 3 ═N-benzyl-3-piperidyl, R 4 =n-Bu) (12 mg, 0.029 mmol, 43%). 1 H NMR (CD 3 OD) δ 7.60 (m, 2H), 7.49 (m, 3H), 4.39 (ABq, J AB =12.8 Hz, Δν AB =42.1 Hz, 2H), 3.69 (m, 1H), 3.39 (br d, J=13.6 Hz, 1H), 3.20 (s, 3H), 2.96 (m, 2H), 2.45 (m, 1H), 1.99 (m, 1H), 1.92-1.78 (m, 3H), 1.68 (br d, J=12.4 Hz, 1H), 1.50 (dq, J d =3.6 Hz, J q =12.8 Hz, 1H), 1.36-1.22 (m, 4H), 1.03 (m, 1H), 0.90 (t, J=7.2 Hz, 3H). LCMS: t R (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:

Method BL

To a 2 ml Methanolic solution of BL1 (n=1, R 3 =cyclohexylethyl, R 1 =Me) (10 mg) was added BL3 (HCl salt, R 15 ═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, R 3 =cyclohexylethyl, R 1 =Me and R 15 ═H).

The following compounds were synthesized using similar methods.

Method BM

Method BM, Step 1

To a toulene solution (3 ml) of BM1 (n=1, R 3 =cyclohexylethyl, R 2 =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, R 3 =cyclohexylethyl, R 2 =Me) after reverse phase purification.

Method BM Step 2

To a DCM solution of BM2 (n=1, R 3 =cyclohexylethyl, R 2 =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, R 3 =cyclohexylethyl, R 2 =Me).

Compound BM4 (n=1, R 3 =cyclohexylethyl, R 2 =Me) and BM5 (n=1, R 3 =cyclohexylethyl, R 2 =Me) were generated from BM2 (n=1, R 3 =cyclohexylethyl, R 2 =Me) and BM3 (n=1, R 3 =cyclohexylethyl, R 2 =Me) through Boc-deprotection.

The following compounds were synthesized using similar method:

Method BN

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.

Method BP

Method BP, Step 1

To a solution of BP1 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.012 g, 0.028 mmol) in CH 2 Cl 2 (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, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.010 g, 0.019 mmol). MS m/e: 526.1 (M+H).

Method BP, Step 2

BP3 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) was prepared from BP2 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) using 30% TFA/DCM. MS m/e: 426.1 (M+H).

Method BQ

Method BQ Step 1

BQ1 was prepared according to Method AZ.

To a solution of BQ1 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.004 g, 0.007 mmol) in CH 2 Cl 2 (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 EDCl (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, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.003 g, 0.005 mmol). MS m/e: 627.1 (M+H).

Method BQ Step 2

BQ2 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.003 g, 0.005 mmol) was treated with 20% TFA/CH 2 Cl 2 (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, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.002 g, 0.005 mmol). MS m/e: 377.2 (M+H).

Method BR

Method BR, Step 1

To a solution of BR1 (n=1, R 1 =Me, R 2 ═H, R 3 =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 CH 2 Cl 2 . The organic layer was removed, and the aqueous phase was extracted with CH 2 Cl 2 (3×). After concentration, the brown residue was purified by reverse phase HPLC to yield BR2 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.003 g, 0.004 mmol). MS m/e: 663.2 (M+H).

Method BR, Step 2

BR3 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) was prepared from BR2 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) following a procedure similar to Method BQ Step 2. MS m/e: 413.1 (M+H).

Method BS

Method BS Step 1

To a solution of BS1 (n=1, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.003 g, 0.006 mmol) in CH 2 Cl 2 (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, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.002 g, 0.002 mmol). MS m/e: 823.5 (M+H).

Method BS Step 2

Compound BS2 (n=1, R 1 =Me, R 2 ═H, R 3 =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, R 1 =Me, R 2 ═H, R 3 =cyclohexylethyl) (0.0012 g, 0.002 mmol). MS m/e: 454.1 (M+H).

Method BT

Method BT

To a round bottom flask were added compound BTI (R 1 =Me, R 3 =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 N 2 for 2 minutes before NaO-t-Bu (61 mg, 0.638 mmol) and Pd 2 (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 CH 2 Cl 2 . The combined organic layer was then dried over Na 2 SO 4 . After the filtration, the concentrated residue was separated by TLC (CH 3 OH:CH 2 Cl 2 =1:10) and reverse phase HPLC (10%-100% acetonitrile in water w/0.1% formic acid) to produce the desired compound BT2 (R 1 =Me, R 3 =Me and R 21 =m-pyridyl) as a formate salt (23.6 mg, white solid, 20%). 1 HNMR (CDCl 3 ) δ 7.50-6.90 (m, 13H), 3.14 (s, 3H) MS m/e 358 (M+H).

Method BU

Method BU, Step 1

To a round bottomed flask containing BU1 (m=1, n=1, R 1 =Me, R 3 =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-(benzyyloxycarbonyloxy)succinimide. Stir at room temperature for 18 h. Dilute the mixture with DCM and extract with sat'd NaHCO 3 soln, then water. Collect the organic portion and dry over Na 2 SO 4 , filter and concentrate in vacuo. Purify by silica gel chromatography (eluting with 0 to 60% EtOAc/hexanes) to yield BU2 (m=1, n=1, R 1 =Me, R 3 =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, R 1 =Me, R 3 =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 NH 4 OH. 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 NaHCO 3 and Boc 2 O (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, R 1 =Me, R 3 =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, R 1 =Me, R 3 =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, R 1 =Me, R 3 =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, R 1 =Me, R 3 =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, R 1 =Me, R 3 =Cyclohexylethyl and R 21 =m-MeOPh) as the formic acid salt (0.7 mg, 0.0015 mmol, 30.1% yield). MS m/e: 413.1 (M+H).

Method BV

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 (R 4 =phenyl) (2.0 g, 10 mmol) in THF (47 mL). After 60 minutes at −78 C, a solution of BV1 (R 3 =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 CH 2 Cl 2 (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 (R 3 =3-bromo-4-fluorophenyl and R 4 =phenyl) (1.69 g, 4.23 mmol, 42%). 1 H NMR (CDCl 3 ) δ 7.61 (m, 2H), 7.27 (m, 3H), 6.94 (m, 1H), 6.92 (m, 1H), 6.68 (m, 1H), 3.15 (bs, 1H), 2.57-2.73 (m, 4H), 1.89 (m, 2H).

Method BV Step 2

A solution of BV3 (R 3 =3-bromo-4-fluorophenyl and R 4 =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 Na 2 SO 3 . After diluting with CH 2 Cl 2 , the layers were separated, and the organic layer washed with water (2×), brine (1×) and dried over MgSO 4 . Concentration under vacuum afforded an oil which was subjected to silica gel chromatography using 5% EtOAc/Hexanes to give a solid BV4 (R 3 =3-bromo-4-fluorophenyl and R 4 =phenyl) (690 mg, 2.24 mmol, 53%). 1 H NMR (CDCl 3 ) 8.19 (m, 1H), 7.93 (m, 3H), 7.66 (m, 1H), 7.50 (m, 2H), 7.20 (m, 1H).

Method BV Step 3

BV5 (R 3 =3-bromo-4-fluorophenyl and R 4 =phenyl and R 1 =Me and R 2 ═H) was prepared from BV4 (R 3 =3-bromo-4-fluorophenyl and R 4 =phenyl) using Method AS, Step 4.

Method BW

To an oven-dried vial was added Pd 2 (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 (R 4 =Me; R 1 =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 filtration 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 (R 4 =Me; Me; R 22 =2-pyridyl and n=1) (69.3 mg, 99%). ES_LCMS (m/e): 416.2

Method BX

Method BX, Step 1

To a solution of BX1 (R 4 =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), EDCl.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 (R 1 ═R4=Me and n=1) (1.23 g, 100%). ES_LCMS (m/e): 340.1

Method BX, Step 2

To a solution of BX2 (R 1 ═R 4 =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 (R 1 ═R 4 =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.

Method BZ

The following aminoacids were generated using methods similar to Method D

Method CA

Compound CA2 (R 3 ═R 4 =Ph; Z=m-phenylene, R 15 ═H and R 16 =cyclopentyl) was obtained from CA1 (R 3 ═R 4 =Ph; Z=m-phenylene, R 15 ═H and R 16 =cyclopentyl) using a method similar to Method G.

Method CB

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

Method CC

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 (MgSO 4 ), 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 NaHCO 3 . The organic phase was dried (MgSO 4 ), 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/H 2 O (5:1) and the mixture was stirred under nitrogen for 2 h before the reaction was quenched with saturated NaHCO 3 (aq.) and ether. The ether phase was dried over anhyd. Na 2 SO 4 , 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/H 2 O. The organic phase was dried over Na 2 SO 4 , 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. 1 H-NMR (CDCl 3 ) 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: 1 H-NMR (CDCl 3 ) 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: 1 H-NMR (CDCl 3 ) 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 Et 2 O (pH ˜6 to 7). The organic phase was dried over Na 2 SO 4 , filtered and evaporated to give product CC7 in 94% yield. 1 H-NMR (CDCl 3 ) 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

To a solution of tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (CD1; R 4 =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; R 4 =Me) as a colorless oil. 1 H NMR (CDCl 3 ) 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).

To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate (CD2; R 4 =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; R 1 =Me, R 4 =Me) as a colorless oil. 1 H NMR (CDCl 3 ) 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) + .

tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R 1 =Me, R 4 =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 CHCl 3 (20 mL). The solution was washed with 15% NaOH (10 mL) and the aqueous layer was extracted with CHCl 3 (3×10 mL). The combined organic layer was dried over MgSO 4 and concentrated in vacuo to give 0.33 g (76%) of crude 2-(3-bromophenyl)-N 1 -methylpropan-1,2-diamine as a colorless oil. 1 H NMR (CDCl 3 ) 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)-N 1 -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 CHCl 3 (20 mL) and the solution was washed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl 3 (3×10 mL) and the combined organic layer was dried (MgSO 4 ), and concentrated to give 0.14 g (100%) of 4-(3-bromophenyl)-1,4-dimethylimidazolidin-2-imine (CD4; R 1 =Me, R 4 =Me) as a colorless oil. 1 H NMR (CDCl 3 ) 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) + .

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 K 2 CO 3 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; R 1 =Me, R 4 =Me, R 21 =3,4-difluorophenyl) as a white solid. 1 H NMR (CDCl 3 ) 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) R t =5.48 min.

Alternative for Method CD for Compound: R 1 ═OR 15

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; R 4 =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 (Na 2 SO 4 ) and concentrated to give 1.6 g (54%) of tert-butyl 2-(3-bromophenyl)-1-(methoxyamino)propan-2-ylcarbamate (CD3; R 1 =OMe, R 4 =Me). 1 H NMR (CDCl 3 ) 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; R 1 =OMe, R 4 =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 CHCl 3 (20 mL) and washed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl 3 (3×10 mL). The combined organic layer was dried over MgSO 4 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 CHCl 3 (20 mL) and washed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl 3 (3×10 mL). The combined organic layer was dried over MgSO 4 and concentrated to give 0.2 g (16%) of 4-(3-bromophenyl)-1-methoxy-4-methylimidazolidin-2-imine (CD4; R 1 =OMe, R 4 =Me) as a colorless oil. 1 H NMR (CDCl 3 ) 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; R 1 =OMe, R 4 =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 K 2 CO 3 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; R 1 =OMe, R 4 =Me, R 21 =3-ClC 6 H 4 ) as a white solid. 1 H NMR (CDCl 3 ) 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) R t =5.64 min.

Method CE

Method CE, Step 1

The synthesis of CE2 (R 1 ═R 4 =Me, R 21 =Br and R 4 =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; R 1 ═R 6 =Me, R 21 =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 H 2 O and Et 2 O. The organic layer was separated and the aqueous layer was extracted with Et 2 O (3×25 mL).

The combined organic layers were washed with brine, dried (MgSO 4 ) 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; R 1 ═R 4 =Me, R 21 =Br and R 6 =Me) as a white solid. 1 HNMR (CDCl 3 , 300 MHz): 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) R t =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; R 1 ═R 4 =Me, R 6 =Me, R 21 =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. K 2 CO 3 (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/CH 2 Cl 2 (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. 1 HNMR (CDCl 3 , 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 R t =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/CH 2 Cl 2 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; R 1 ═R 4 =Me, R 6 =Me, R 21 =5-cyanothien-1-yl) as a white solid. 1 HNMR (CDCl 3 , 300 MHz): 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 R t =7.24 min (syn isomer).

Method CF

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 Et 2 O (2×25 mL). The organic layers were combined and washed with brine (30 mL), dried (Na 2 SO 4 ), and concentrated in vacuo to give 0.42 g (50% yield) of tert-butyl methylcarbamothioylcarbamate CF1 (R 1 =Me) as a white solid. 1 HNMR (CDCl 3 , 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 (R 6 =3-bromophenyl and R 7 =Me) (0.2 g, 0.7 mmol) and CF1 (R 1 =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 (EDCl, 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 (MgSO 4 ), 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; R 1 ═R 6 =Me) as a white solid. 1 HNMR (CDCl 3 , 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 R t =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; R 1 ═R 6 =Me) (0.25 g, 0.6 mmol), 5-chloro-2-hydroxyphenylboronic acid (R 21 =5-chloro-2-hydroxyphenyl; 0.2 g, 1.2 mmol, 2 eq), Fibrecat (4.26% of Pd, 0.7 g) and 1N aq. K 2 CO 3 (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/CH 2 Cl 2 (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; R 1 ═R 6 =Me, R 21 =3-chloro-6-hydroxyphenyl) as a white solid. 1 HNMR (CDCl 3 , 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 R t (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; R 1 ═R 6 =Me, R 21 =3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH 2 Cl 2 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; R 1 ═R 6 =Me, R 21 =3-chloro-6-hydroxyphenyl) as a white solid. 1 HNMR (CDCl 3 , 300 MHz): 11.4 (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) R t =5.07 min.

Method CG

Method CG, Step 1

A solution of CG1 (R 21 =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 (R 21 =Br, 11.41 g, 98%). 1 H NMR (400 MHz, CD 3 OD) δ 8.49 (m, 1H), 8.27 (m, 1H), 3.90 (s, 3H).

Method CG, Step 2

A mixture of CG2 (R 21 =Br, 11.41 g, 44 mmol), EDCl (8.6 g, 45 mmol), dipropylamine (6.2 mL, 44.8 mmol), HOBt (6.0 g, 44.4 mmol) and NEt 3 (10 mL, 72 mmol) in CH 2 Cl 2 (100 mL) was stirred at RT for 48 h. The reaction was washed with sat. NaHCO 3 , water (1×), NH 4 Cl (1×), water (1×), brine (1×), dried over MgSO 4 , filtered and concentrated under vacuum. The resulting material was subjected to silica gel chromatography (0%→40% EtOAc/hexanes) to give CG3 (R 21 =Br, R 15 ═R 16 =Pr, 3.62 g, 24%).

Method CG, Step 3

A mixture of CG3 (R 21 =Br, R 15 ═R 16 =Pr, 3.6 g, 10.5 mmol), HN(Me)SO 2 Me (1.4 mL, 16.3 mmol), Pd(OAc) 2 (355 mg, 1.58 mmol), Xantphos (1.41 g, 2.44 mmol), Cs 2 CO 3 (5.17 g, 15.8 mmol) in toluene (40 mL) was degassed under a stream of N 2 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 MgSO 4 , filtered, and evaporated under vacuum. The resulting residue was subjected twice to silica gel chromatography (0%→3% MeOH/CH 2 Cl 2 ) to give CG4 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =Pr, 2.65 g, 68%).

Method CG, Step 4

LiBH 4 (2 M THF, 8 mL, 16 mmol) was added to a solution of CG4 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =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 MgSO 4 , filtered, and evaporated under vacuum. The resulting residue was subjected to silica gel chromatography (0%→>5% MeOH/CH 2 Cl 2 ) to give CG5 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =Pr, 1.77 g, 72%).

Method CG, Step 5

A mixture of CG5 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =Pr, 1.77 g, 5.17 mmol), sodium azide (404 mg, 6.21 mmol), and PPh 3 (2.85 g, 10.87 mmol) in CCl 4 (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 Et 2 O. The organic layer was triturated with water, filtered, dried over MgSO 4 , 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/CH 2 Cl 2 ) to give CG6 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =Pr, 130 mg, 7.5% from CG5).

Method CG, Step 7

A mixture of CG6 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =Pr, 130 mg, 0.38 mmol), 1,3-di(tert-butoxycarbonyl)-2-methylisothiourea (110 mg, 0.38 mmol), NEt 3 (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/CH 2 Cl 2 as eluent). The resulting intermediate (140 mg, 0.24 mmol) was treated with 50% TFA/CH 2 Cl 2 at RT for 3 h, followed by removal of all volatiles under vacuum to give CG7 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =Pr, 140 mg, 74% from CG6).

Method CG, Step 8

A mixture of CG7 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =Pr, 120 mg, 0.24 mmol), benzil (50 mg, 0.24 mmol) and NEt 3 (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 CH 2 Cl 2 . The organic layer was washed with brine (1×), dried over MgSO 4 , filtered and evaporated. The resulting material was subjected to preparative thin layer chromatography (10% MeOH/CH 2 Cl 2 as eluent) to give CG8 (R 21 ═N(Me)SO 2 Me, R 15 ═R 16 =Pr, R 3 ═R 4 =Ph, 69 mg, 50%) as the formate salt. 1 H NMR (400 MHz, CDCl 3 ) δ7.10-7.40 (m, 13H), 4.72 (m, 2H), 3.34 (m, 2H), 3.08 (s, 3H), 3.00 (m, 2H), 2.60 (s, 3H), 1.59 (m, 2H), 1.39 (m, 2H), 0.92 (m, 3H), 0.64 (m, 3H); LCMS: 576.3 (M+H).

Method CH

A solution of 0.35 mL of 1 M BBr 3 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

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 CI18 reverse phase column to give compound CI2.

Method CJ

To a solution of CJ1 (R 1 ═R 6 =Me; 324 mg, 0.87 mmole) in 2.5 mL CHCl 3 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 Na 2 S 2 O 3 , aqueous NaHCO 3 and brine. The crude was purified on flash column to give a product which was treated with 50% TFA in DCM to give CJ2 (R 1 ═R 6 =Me 220 mg, 56. % yield) after evaporation.

Method CK

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 (R 3 ═R 4 =Ph, 7.00 g, 27.8 mmol) and K 2 CO 3 (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 CH 2 Cl 2 (3×). The combined organic layers were washed with NaHCO 3 (1×), water (3×), dried over MgSO 4 , 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% CH 3 CN/H 2 O with 0.1% HCO 2 H, 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

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 n BuLi) 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 Et 2 O (2×100 mL). The combined organic layers were washed with brine (1×), dried over MgSO 4 , filtered, and evaporated under vacuum. The resulting material was subjected to silica gel chromatography (100% hexanes) to give CL3 (752 mg, 86%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.21-7.65 (m, 8H), 3.08 (s, 1H).

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), PPh 3 (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 N 2 , 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 MgSO 4 , filtered, and evaporated under vacuum. The resulting material was subjected to silica gel chromatography (0→20% EtOAc/hexanes) to give CL4 (R 3 =3,5-pyrimidinyl, 220 mg, 80%).

Method CL, Step 4

A mixture of CL4 (R 3 =3,5-pyrimidinyl, 210 mg, 0.72 mmol), KMnO 4 (297 mg, 1.88 mmol), tetrabutylammonium bromide (TBAB, 55 mg, 0.17 mmol) in AcOH (263 μL) and CH 2 Cl 2 (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 (R 3 =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, R 3 =3,5-pyrimidinyl): 378.2 (M+H).

Method CM

Method CM, Step 1

To a round bottom flask were added CM1 (R 1 =Me, R 3 =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 (R 1 =Me, R 3 =Ph; 443 mg, 92%) as white solid. Observed MW (M+H) 381.2. (400 MHz, CD 3 OD): 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

To an Ace pressure tube were added CN1 (R 3 =phenyl; R 1 =Me; 100 mg, 0.290 mmol), bis(pinacolato)diboron (81.0 mg, 0.319 mmol), KOAc (85.0 mg, 0.87 mmol), PdCl 2 (dppf) 2 -CH 2 Cl 2 (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. K 2 CO 3 (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 Na 2 SO 4 . The concentrated residue was purified first by preparative TLC (7M NH 3 /MeOH:DCM=1:10) and then preparative HPLC (reverse phase, C-18 column, 0.1% HCOOH/CH 3 CN: 0.1% HCOOH/H 2 O=10%-100%) to afford the desired product CN2 (formic acid salt; R 3 =phenyl; R 1 =Me; R 21 =3′-(5-bromopyridyl; 53.5 mg, 40%) as a white solid. Observed MW (M+H) 421.1. (400 MHz, CD 3 OD): 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

A microwave tube was charged with CO1 (R 1 =Me, R 2 ═H; R 3 =cyclopropyl, n=0) (30 mg, 0.097 mmol), PS-Ph 3 P—Pd (49 mg, 0.12 mmol), and R 21 SnBu 3 (R 21 =2-pyrazinyl) (43 mg, 0.12 mmol) as a solution in 1 mL of PhCF 3 . The tube was sealed, and evacuated and back-filled with N 2 (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 (R 1 =Me, R 2 ═H; R 3 =c-Pr, n=0, R 21 =2-pyrazinyl) as a formate salt (12 mg, 0.063 mmol, 35%). LCMS R t =3.58 min, m/e=308.2 (M+H).

Method CP

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 (MgSO 4 ) 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 [(CH 3 O) 2 P—N═C═S], giving directly CP4, which is coverted to CP5 as described in Method CP, Step 3.

Method CQ

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

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 (MgSO 4 ) 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

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

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 (MgSO 4 ), 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

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

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 (MgSO 4 ), 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

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 (R 6 =Me) using EDCl and DIEA in DMF affords CW2 (R 6 =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 (R 6 =Me) with aryl boronic acids using polymer-support Pd catalysts such as Fibre Cat or PS—PPh3-Pd under microwave heating conditions provides CW3 (R 6 =Me and R 21 =m-CN-Ph) of the invention after subsequent Boc-deprotection.

Method CX

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 (R 6 =Me) (1.12 g, 3.64 mmol, prepared using Method CF) in DCM (7 mL) was added MeCN (7 mL) and H 2 O (10.5 mL), followed by RuCl 3 .H 2 O (7.6 mg, 0.036 mmol, 1 mol %), and NaIO 4 (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 (Na 2 SO 4 ), and concentrated to give 0.90 g (86%) of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylic acid CX2 (R 6 =Me) as a brown solid. 1 H NMR (CD 3 OD): 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, R 6 =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 H 2 O (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 H 2 O (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; R 6 =Me, R 7 =3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)) as a white solid. 1 H NMR (CD 3 OD): 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) R t =6.234 min.

Method CY

(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 (R 6 =Me) (0.357 g, 1.25 mmol) in 1:5 MeOH/toluene (3 mL) was added TMSCHN 2 (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. 1 H NMR (CDCl 3 ): 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 NH 2 NH 2 (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, R 6 =Me) as a yellow solid. 1 H NMR (CDCl 3 ) 8.95 (s, 1H), 3.11 (s, 3H), 2.28 (m, 2H), 1.50 (s, 9H), 1.47 (s, 3H).

Method CZ

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; R 6 =Me, 0.037 g, 0.12 mmol) in DCM (0.3 mL) at 0° C. was added Et 3 N (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 H 2 O (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), Et 3 N (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 H 2 O (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; R 6 =Me). 1 HNMR (CD 3 OD, 300 MHz): 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) R t =4.175 min.

Method DA

(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, R 6 =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), Et 3 N (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 H 2 O (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; R 6 =Me). 1 HNMR (CD 3 OD, 300 MHz): 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) R t =5.710 min.

Method DB

Method DB, Step 1; (1-(3-Bromophenyl)ethylidene)cyanamide (DB1, R 4 =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 MgSO 4 , filtered, and concentrated to give 2.3 g (100%) of (1-(3-bromophenyl)ethylidene)cyanamide (DB1, R 4 =Me) as a white solid: 1 H NMR (CDCl 3 ) 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, R 4 =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 CH 2 Cl 2 (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, R 1 =Me, R 4 =Me) as a colorless oil: 1 H NMR (CDCl 3 ) 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 K 2 CO 3 (0.22 mL, 0.22 mmol) and PS—PPh 3 -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 CH 2 Cl 2 (5 mL) and CH 3 OH (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; R 1 =Me, R 4 =Me, R 21 =3-chlorophenyl) as a colorless oil: 1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CD 3 OD) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

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 (NH 4 ) 2 CO 3 (21.7 g, 225 mmol, 4.5 eq) in EtOH/H 2 O (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; R 6 =Me). 1 H NMR (CD 3 OD) 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; R 6 =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 Et 2 O (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; R 6 =Me) as an off white solid. 1 H NMR (CD 3 OD) 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; R 6 =Me) (10.5 g, 43 mmol) in 1N KOH (105 mL) and dioxane (70 mL) at 0° C. was added (Boc) 2 O (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 KHSO 4 to pH 2-3, the aqueous layer was extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with H 2 O (2×50 mL), dried (Na 2 SO 4 ), and concentrated to give 11.7 g (79%) of 2-(3-bromophenyl)-2-(tert-butoxycarbonyl) propanoic acid as a white solid. 1 H NMR (CDCl 3 ) 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 TMSCHN 2 (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. 1 H NMR (CDCl 3 ) 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 H 2 O. The mixture was diluted with DCM (500 mL) followed by the addition of 1N NaOH (6 mL) and H 2 O (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; R 6 =Me) as a colorless oil. 1 H NMR (CDCl 3 ) 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 SOCl 2 (5.7 mL, 2.5 eq) in dry CH 3 CN (37 mL) under argon was cooled to −40° C. was added tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R 4 =Me) (10.3 g, 31 mmol) in dry CH 3 CN (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. 1 H NMR (CDCl 3 ) 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 CH 3 CN (50 mL) at 0° C. was added RuO 4 (0.5% in stabilized aq., 50 mg, 0.1% by weight) in H 2 O (10 mL) amd NaIO 4 (8.9 g, 41.5 mmol, 1.5 eq) in H 2 O (35 mL). The mixture was stirred at RT for 2 h. The mixture was partitioned between Et 2 O (200 mL) and H 2 O (50 mL). The organic layer was separated and the aqueous layer was extracted with Et 2 O (3×50 mL). The combined organic layer was dried (Na 2 SO 4 ), 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; R 6 =Me) as a white solid (˜10.8 g, yield: 100%). 1 H NMR (CDCl 3 ) 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; R 6 =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. 1 H NMR (CDCl 3 ) 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 BnBu 3 NCl (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; R 6 =Me) as a colorless oil. 1 H NMR (CDCl 3 ) 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; R 6 =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 Na 2 SO 4 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 Pd 2 (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 CHCl 3 (10 mL) followed by treatment with 1N NaOH tol pH ˜12. The organic layer was separated and the aqueous layer was extracted with CHCl 3 (3×10 mL). The combined organic layer was dried (Na 2 SO 4 ) and concentrated to give 0.56 g (76%) of N-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine (DC6; R 6 =Me, R 1 =Me) as a colorless oil. 1 H NMR (CDCl 3 ) 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; R 6 =Me, R 1 =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 CHCl 3 (20 mL) and washed with 2N NaOH (10 mL). The aqueous layer was extracted with CHCl 3 (3×10 mL). The combined organic layer was dried over Na 2 SO 4 and concentrated to give 0.82 g (100%) of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC7; R 6 =Me, R 1 =Me) as a light yellow oil. 1 H NMR (CDCl 3 ) 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; R 6 =Me, R 1 =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 K 2 CO 3 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; R 6 =Me, R 1 =Me, R 21 =3-cyanophenyl) as a white solid. 1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) 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

1 H NMR (CDCl 3 ) δ 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

1 H NMR (CDCl 3 ) 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

Method DD, Step 1

To a 10 mL MeOH solution of DD1 (R 3 ═R 6 ═H, R 7 =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 (R 3 ═R 6 ═H, R 7 =Me).

Method DD, Step 2

Procedure similar to Method CF, step 2 was used for generation of DD3 (R 1 =Me, R 3 ═R 6 ═H, R 7 =Me,).

Method DD, Step 3

Procedure similar to Method CF, step 3 was used for generation of DD4 (R 1 =Me, R 3 ═R 6 ═H, R 7 =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 (R 1 =Me, R 3 ═R 6 ═H, R 7 =Me) after purification.

Method DE

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-clorophenyl)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 (MgSO 4 ) 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

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 N 2 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 CH 2 Cl 2 is refluxed under a N 2 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 (MgSO 4 ) 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

Method DG, Step 1

To a stirred solution of the iminopyrimidinone DG1 (R 1 =Me, W=—(CO)—, R 7 =Me, R 6 =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 %), Pd 2 (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 NH 4 Cl and extracted with EtOAc. The organic phase was washed with aqueous NaHCO 3 , brine and dried over anhydrous Na 2 SO 4 . 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 NaHCO 3 . The organic phase was washed with brine and dried over anhydrous Na 2 SO 4 . Solvent was evaporated in vacuum to give 78 mg (41.3%) of DG2 (R 1 =Me, W=—(CO)—, R 7 =Me, R 6 =4-(m-cyanophenyl)thien-2-yl, R 3 =Ph) as free base. 1 H NMR (CDCl 3 ) 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 C 23 H 21 N 4 OS (M4-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.

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

#

Structure

Obs.Mass

1890

376.2

1891

340.2

1892

380.2

1893

456.3

1894

405.1

1895

498.3

1896

350.2

1897

484.3

1898

388.2

1899

416.1

1900

1901

457.4

1902

541.3

1903

500.3

1904

397.1

1905

336.8

1906

364.4

1907

399.2

1908

321.1

1909

461.3

1910

1911

476.3

1912

561.3

1913

332.2

1914

385.2

1915

308.0

1916

460.3

1917

468.3

1918

493.3

1919

399.2

1920

466.3

1921

358.1

1922

428.3

1923

1924

308.2

1925

360.2

1926

341.2

1927

338.3

1928

1929

448.3

1930

262.1

1931

489.3

1932

459.9

1933

1934

446.0

1935

435.2

1936

400.2

1937

479.3

1938

480.3

1939

392.0

1940

374.2

1941

380.0

1942

314.2

1943

476.3

1944

358.2

1945

373.2

1946

312.2

1947

393.2

1948

468.3

1949

319.0

1950

503.3

1951

362.0

1952

1953

314.2

1954

392.2

1955

451.3

1956

533.3

1957

373.3

1958

350.2

1959

472.3

1960

340.4

1961

455.3

1962

332.2

1963

505.3

1964

409.2

1965

300.2

1966

340.1

1967

410.2

1968

363.2

1969

441.2

1970

375.2

1971

412.2

1972

418.2

1973

434.1

1974

329.2

1975

441.2

1976

568.3

1977

267.2

1978

455.3

1979

327.9

1980

1981

344.1

1982

396.1

1983

358.0

1984

443.2

1985

404.2

1986

314.2

1987

303.2

1988

375.2

1989

410.4

1990

384.2

1991

314.2

1992

349.0

1993

379.9

1994

408.2

1995

470.3

1996

379.3

1997

449.3

1998

285.2

1999

254.1

2000

321.3

2001

337.1

2002

338.1

2003

420.2

2004

427.2

2005

490.9

2006

457.4

2007

461.3

2008

2009

336.2

2010

506.3

2011

484.3

2012

352.0

2013

387.0

2014

384.2

2015

523.3

2016

353.2

2017

419.1

2018

343.2

2019

475.3

2020

364.1

2021

413.2

2022

472.3

2023

2024

479.3

2025

357.2

2026

434.2

2027

432.2

2028

400.1

2029

384.2

2030

448.3

2031

401.2

2032

295.1

2033

392.2

2034

456.3

2035

421.0

2036

343.2

2037

343.0

2038

344.2

2039

303.0

2040

250.0

2041

469.3

2042

2043

373.2

2044

381.2

2045

471.3

2046

356.2

2047

299.2

2048

333.0

2049

475.3

2050

352.2

2051

2052

531.3

2053

382.0

2054

372.2

2055

377.2

2056

402.2

2057

434.2

2058

448.3

2059

477.3

2060

366.2

2061

462.3

2062

435.2

2063

341.2

2064

489.3

2065

365.2

2066

357.2

2067

519.3

2068

338.2

2069

362.2

2070

442.2

2071

282.0

2072

443.2

2073

486.3

2074

413.2

2075

444.2

2076

503.3

2077

430.2

2078

429.2

2079

357.2

2080

326.0

2081

339.2

2082

335.2

2083

354.2

2084

442.2

2085

343.2

2086

434.0

2087

2088

460.3

2089

398.2

2090

2091

476.3

2092

376.2

2093

413.2

2094

432.2

2095

579.3

2096

388.2

2097

471.3

2098

435.2

2099

317.2

2100

357.2

2101

2102

416.2

2103

468.3

2104

2105

434.2

2106

398.2

2107

349.2

2108

381.2

2109

423.2

2110

486.3

2111

320.0

2112

350.2

2113

232.1

2114

360.2

2115

356.2

2116

366.2

2117

346.2

2118

375.2

2119

336.2

2120

393.0

2121

310.2

2122

339.2

2123

408.2

2124

479.3

2125

355.2

2126

397.2

2127

432.3

2128

337.2

2129

402.2

2130

359.2

2131

380.2

2132

352.1

2133

370.2

2134

314.2

2135

397.9

2136

408.2

2137

504.3

2138

347.1

2139

362.2

2140

326.3

2141

381.2

2142

320.1

2143

329.2

2144

471.3

2145

445.2

2146

321.2

2147

560.3

2148

255.0

2149

338.2

2150

474.3

2151

360.2

2152

371.2

2153

342.9

2154

560.3

2155

2156

374.8

2157

296.0

2158

391.2

2159

2160

441.9

2161

387.2

2162

330.2

2163

407.2

2164

408.2

2165

483.1

2166

386.2

2167

441.2

2168

519.3

2169

388.2

2170

298.2

2171

471.0

2172

409.2

2173

339.1

2174

368.2

2175

501.3

2176

388.2

2177

2178

2179

405.1

2180

331.2

2181

454.3

2182

479.3

2183

392.2

2184

379.1

2185

351.2

2186

482.3

2187

2188

319.0

2189

352.2

2190

2191

372.1

2192

449.3

2193

353.2

2194

379.3

2195

447.3

2196

2197

377.3

2198

372.2

2199

385.2

2200

433.2

2201

420.2

2202

350.2

2203

459.3

2204

363.0

2205

383.2

2206

431.9

2207

287.2

2208

402.9

2209

429.2

2210

365.2

2211

325.1

2212

461.3

2213

449.2

2214

310.2

2215

431.2

2216

336.2

2217

372.2

2218

2219

395.2

2220

484.3

2221

479.3

2222

360.2

2223

543.3

2224

411.2

2225

358.2

2226

286.2

2227

290.0

2228

386.1

2229

386.1

2230

2231

415.2

2232

456.3

2233

377.2

2234

447.3

2235

366.2

2236

340.2

2237

388.1

2238

417.2

2239

398.2

2240

471.3

2241

427.3

2242

312.2

2243

466.3

2244

218.1

2245

470.3

2246

373.2

2247

415.2

2248

400.0

2249

275.2

2250

466.0

2251

435.2

2252

371.2

2253

394.2

2254

449.3

2255

483.3

2256

495.3

2257

340.0

2258

413.2

2259

302.2

2260

350.2

2261

321.1

2262

455.3

2263

526.3

2264

477.3

2265

341.1

2266

316.2

2267

392.2

2268

301.0

2269

483.3

2270

2271

321.2

2272

448.3

2273

481.3

2274

257.1

2275

325.0

2276

250.3

2277

450.3

2278

316.2

2279

486.3

2280

464.3

2281

2282

369.2

2283

302.0

2284

362.2

2285

300.0

2286

462.3

2287

331.0

2288

535.3

2289

364.2

2290

305.1

2291

337.0

2292

376.2

2293

418.2

2294

345.3

2295

353.1

2296

375.2

2297

411.1

2298

2299

409.2

2300

310.2

2301

339.2

2302

394.2

2303

383.2

2304

356.2

2305

479.3

2306

269.2

2307

341.2

2308

439.2

2309

439.1

2310

410.2

2311

322.1

2312

401.0

2313

351.2

2314

439.2

2315

2316

420.2

2317

438.2

2318

2319

509.3

2320

425.2

2321

434.2

2322

390.2

2323

357.2

2324

467.3

2325

296.1

2326

310.2

2327

342.2

2328

331.3

2329

343.0

2330

2331

489.3

2332

332.2

2333

487.3

2334

411.0

2335

442.2

2336

356.2

2337

441.2

2338

496.3

2339

472.3

2340

425.2

2341

359.2

2342

379.0

2343

459.3

2344

435.2

2345

436.2

2346

390.2

2347

383.2

2348

281.1

2349

363.2

2350

359.2

2351

363.2

2352

418.2

2353

427.2

2354

450.9

2355

483.3

2356

415.2

2357

395.2

2358

466.3

2359

390.2

2360

460.3

2361

388.0

2362

486.3

2363

375.2

2364

445.2

2365

444.2

2366

392.2

2367

417.2

2368

326.2

2369

337.8

2370

418.2

2371

487.3

2372

2373

329.3

2374

493.3

2375

354.2

2376

368.2

2377

288.2

2378

429.2

2379

519.3

2380

354.2

2381

376.2

2382

274.2

2383

314.1

2384

388.2

2385

412.2

2386

351.2

2387

395.1

2388

372.2

2389

375.2

2390

411.9

2391

249.1

2392

442.2

2393

397.0

2394

327.3

2395

433.2

2396

420.2

2397

383.2

2398

378.2

2399

258.1

2400

460.3

2401

2402

491.3

2403

416.1

2404

465.3

2405

350.4

2406

457.3

2407

389.2

2408

386.2

2409

407.2

2410

2411

337.1

2412

329.1

2413

478.3

2414

413.0

2415

327.2

2416

2417

450.3

2418

2419

314.2

2420

405.2

2421

450.3

2422

396.1

2423

449.3

2424

2425

317.2

2426

472.3

2427

448.3

2428

342.2

2429

370.2

2430

2431

491.3

2432

2433

2434

344.2

2435

508.3

2436

390.2

2437

368.2

2438

370.2

2439

331.2

2440

427.2

2441

365.2

2442

419.2

2443

447.3

2444

436.2

2445

389.2

2446

341.2

2447

428.2

2448

377.2

2449

456.3

2450

387.4

2451

431.2

2452

307.2

2453

392.0

2454

467.3

2455

428.2

2456

407.4

2457

324.2

2458

451.3

2459

377.2

2460

318.2

2461

304.2

2462

2463

432.2

2464

515.3

2465

343.2

2466

427.0

2467

414.2

2468

501.3

2469

475.3

2470

401.2

2471

366.2

2472

312.1

2473

461.9

2474

335.2

2475

481.3

2476

304.2

2477

344.3

2478

393.2

2479

383.2

2480

508.9

2481

363.2

2482

405.2

2483

435.2

2484

319.0

2485

356.2

2486

395.1

2487

461.3

2488

406.2

2489

434.2

2490

467.3

2491

2492

469.4

2493

408.1

2494

446.2

2495

384.0

2496

380.2

2497

392.2

2498

2499

510.3

2500

469.3

2501

363.0

2502

375.1

2503

372.2

2504

236.0

2505

260.1

2506

417.2

2507

322.2

2508

512.3

2509

465.3

2510

454.3

2511

427.2

2512

250.1

2513

2514

405.2

2515

334.2

2516

358.2

2517

340.2

2518

334.1

2519

369.2

2520

2521

356.2

2522

393.2

2523

379.2

2524

406.0

2525

454.1

2526

413.2

2527

337.1

2528

461.3

2529

312.2

2530

371.2

2531

255.1

2532

359.2

2533

399.2

2534

420.2

2535

420.2

2536

455.3

2537

357.0

2538

367.2

2539

467.3

2540

441.2

2541

456.3

2542

395.1

2543

461.1

2544

319.2

2545

468.3

2546

511.1

2547

344.0

2548

484.3

2549

495.3

2550

486.3

2551

426.2

2552

283.0

2553

479.3

2554

351.2

2555

372.2

2556

340.1

2557

410.2

2558

359.2

2559

352.2

2560

432.2

2561

434.2

2562

390.2

2563

398.3

2564

563.0

2565

356.2

2566

394.0

2567

326.2

2568

335.2

2569

380.2

2570

498.3

2571

331.2

2572

434.2

2573

501.3

2574

418.2

2575

324.0

2576

455.3

2577

361.0

2578

489.3

2579

388.2

2580

389.2

2581

338.0

2582

338.1

2583

309.5

2584

2585

330.2

2586

430.0

2587

459.3

2588

403.2

2589

339.0

2590

2591

347.2

2592

344.1

2593

381.2

2594

391.2

2595

339.0

2596

383.2

2597

540.3

2598

359.2

2599

461.3

2600

453.3

2601

2602

433.2

2603

408.3

2604

311.2

2605

302.2

2606

340.2

2607

2608

466.3

2609

406.1

2610

386.2

2611

2612

402.2

2613

467.3

2614

410.0

2615

326.2

2616

445.2

2617

441.2

2618

458.3

2619

461.3

2620

443.2

2621

498.3

2622

299.1

2623

349.2

2624

387.4

2625

420.9

2626

403.8

2627

434.2

2628

419.2

2629

377.1

2630

456.3

2631

387.1

2632

2633

2634

384.2

2635

290.2

2636

310.0

2637

399.2

2638

431.2

2639

354.1

2640

313.2

2641

393.3

2642

424.2

2643

495.3

2644

326.1

2645

418.9

2646

302.9

2647

2648

2649

305.1

2650

485.1

2651

375.2

2652

351.2

2653

315.9

2654

2655

503.3

2656

2657

283.0

2658

2659

386.2

2660

351.2

2661

560.3

2662

502.3

2663

481.3

2664

428.2

2665

311.2

2666

403.8

2667

402.2

2668

2669

444.2

2670

366.2

2671

385.2

2672

497.3

2673

497.3

2674

381.2

2675

279.2

2676

444.2

2677

413.2

2678

323.2

2679

430.2

2680

325.1

2681

2682

457.3

2683

357.2

2684

479.1

2685

363.9

2686

485.3

2687

515.3

2688

341.0

2689

427.2

2690

364.2

2691

442.2

2692

390.2

2693

467.3

2694

452.3

2695

372.2

2696

356.2

2697

380.2

2698

271.2

2699

335.0

2700

279.2

2701

502.3

2702

170.0

2703

2704

356.2

2705

368.2

2706

435.2

2707

468.3

2708

438.2

2709

405.1

2710

339.2

2711

310.3

2712

336.2

2713

479.3

2714

330.2

2715

372.2

2716

322.2

2717

363.1

2718

368.2

2719

516.3

2720

468.3

2721

365.0

2722

298.1

2723

394.2

2724

254.0

2725

272.2

2726

257.1

2727

505.3

2728

463.3

2729

311.0

2730

456.3

2731

343.2

2732

483.3

2733

2734

2735

258.1

2736

466.3

2737

370.0

2738

225.1

2739

411.2

2740

505.3

2741

378.2

2742

2743

352.2

2744

420.2

2745

498.3

2746

490.3

2747

372.2

2748

447.3

2749

359.3

2750

486.3

2751

426.2

2752

323.2

2753

370.2

2754

2755

2756

408.2

2757

421.2

2758

421.0

2759

417.2

2760

311.2

2761

449.3

2762

326.2

2763

340.2

2764

345.2

2765

450.3

2766

380.2

2767

340.3

2768

375.2

2769

301.2

2770

336.2

2771

422.2

2772

348.2

2773

331.2

2774

429.2

2775

496.3

2776

380.2

2777

342.2

2778

343.2

2779

348.2

2780

427.2

2781

272.2

2782

376.2

2783

399.0

2784

403.9

2785

467.3

2786

328.1

2787

457.3

2788

451.3

2789

514.3

2790

462.3

2791

295.2

2792

445.2

2793

501.3

2794

378.2

2795

373.2

2796

369.2

2797

342.1

2798

339.2

2799

477.3

2800

375.2

2801

2802

378.0

2803

394.2

2804

400.2

2805

349.2

2806

446.3

2807

499.3

2808

491.3

2809

449.1

2810

468.3

2811

359.2

2812

311.0

2813

472.3

2814

481.3

2815

410.2

2816

394.2

2817

238.2

2818

326.2

2819

380.2

2820

438.2

2821

254.1

2822

458.8

2823

424.2

2824

349.2

2825

429.2

2826

2827

395.2

2828

392.2

2829

350.2

2830

363.2

2831

388.2

2832

531.3

2833

397.2

2834

379.1

2835

435.2

2836

327.3

2837

2838

418.2

2839

426.0

2840

462.3

2841

258.1

2842

343.0

2843

390.2

2844

345.1

2845

415.2

2846

372.2

2847

380.0

2848

480.3

2849

283.2

2850

370.2

2851

356.2

2852

2853

342.2

2854

456.3

2855

401.1

2856

452.3

2857

367.2

2858

364.2

2859

356.2

2860

435.2

2861

485.3

2862

451.3

2863

364.1

2864

341.2

2865

316.0

2866

250.3

2867

2868

340.2

2869

367.0

2870

2871

343.2

2872

421.2

2873

425.2

2874

438.2

2875

450.3

2876

461.3

2877

342.2

2878

497.3

2879

457.3

2880

428.2

2881

497.3

2882

2883

405.1

2884

475.3

2885

344.0

2886

483.3

2887

375.2

2888

467.3

2889

350.2

2890

2891

335.2

2892

342.2

2893

434.2

2894

384.2

2895

317.2

2896

393.2

2897

443.2

2898

444.0

2899

316.0

2900

379.2

2901

386.1

2902

258.0

2903

379.2

2904

394.2

2905

499.3

2906

427.2

2907

219.1

2908

410.2

2909

2910

2911

395.0

2912

490.3

2913

261.1

2914

394.2

2915

242.1

2916

377.2

2917

343.7

2918

468.3

2919

307.2

2920

390.2

2921

330.0

2922

555.3

2923

483.3

2924

394.2

2925

443.2

2926

340.2

2927

369.2

2928

443.2

2929

433.2

2930

454.3

2931

444.1

2932

436.2

2933

435.2

2934

471.3

2935

385.2

2936

358.2

2937

2938

451.3

2939

2940

355.1

2941

324.1

2942

372.2

2943

382.1

2944

372.1

2945

478.3

2946

515.3

2947

455.3

2948

407.1

2949

490.3

2950

423.0

2951

333.2

2952

258.1

2953

404.2

2954

449.3

2955

453.3

2956

489.3

2957

470.3

2958

376.2

2959

377.0

2960

392.0

2961

373.2

2962

309.0

2963

331.1

2964

400.2

2965

346.2

2966

364.1

2967

351.1

2968

339.3

2969

2970

355.0

2971

383.1

2972

429.2

2973

441.2

2974

442.2

2975

351.0

2976

349.2

2977

456.3

2978

2979

443.2

2980

333.1

2981

450.1

2982

359.0

2983

368.2

2984

352.2

2985

253.1

2986

453.3

2987

350.4

2988

392.2

2989

355.2

2990

432.1

2991

462.3

2992

399.2

2993

402.2

2994

305.1

2995

429.4

2996

337.2

2997

418.2

2998

460.3

2999

359.2

3000

296.1

3001

452.3

3002

405.1

3003

441.2

3004

349.2

3005

423.2

3006

3007

398.0

3008

3009

355.1

3010

458.3

3011

286.2

3012

493.3

3013

340.2

3014

343.0

3015

322.0

3016

441.2

3017

3018

428.2

3019

329.2

3020

340.2

3021

294.1

3022

479.3

3023

404.1

3024

489.3

3025

308.0

3026

447.3

3027

365.2

3028

407.2

3029

460.3

3030

449.3

3031

312.2

3032

406.2

3033

272.2

3034

601.3

3035

321.2

3036

404.9

3037

357.0

3038

311.2

3039

3040

292.2

3041

300.1

3042

344.2

3043

340.2

3044

387.2

3045

491.3

3046

322.2

3047

344.3

3048

476.3

3049

399.2

3050

438.1

3051

433.1

3052

3053

284.2

3054

388.2

3055

340.2

3056

289.0

3057

357.2

3058

441.2

3059

383.2

3060

285.2

3061

399.2

3062

459.3

3063

437.2

3064

378.2

3065

390.2

3066

376.2

3067

412.2

3068

360.2

3069

363.2

3070

448.3

3071

3072

434.1

3073

3074

374.8

3075

416.1

3076

496.3

3077

462.3

3078

3079

439.1

3080

340.2

3081

372.1

3082

368.2

3083

450.3

3084

401.9

3085

391.0

3086

515.3

3087

362.2

3088

346.1

3089

326.3

3090

341.2

3091

417.2

3092

375.1

3093

456.3

3094

460.3

3095

438.2

3096

447.3

3097

375.2

3098

252.0

3099

463.3

3100

469.3

3101

359.0

3102

387.2

3103

435.2

3104

470.3

3105

390.2

3106

354.2

3107

413.2

3108

376.2

3109

449.3

3110

451.1

3111

466.3

3112

372.2

3113

589.3

3114

368.0

3115

320.0

3116

3117

381.0

3118

3119

301.0

3120

368.2

3121

509.3

3122

364.2

3123

383.2

3124

425.2

3125

467.3

3126

363.2

3127

3128

306.2

3129

505.8

3130

351.2

3131

391.2

3132

336.2

3133

300.1

3134

418.2

3135

476.9

3136

514.3

3137

451.3

3138

461.3

3139

330.2

3140

467.3

3141

447.3

3142

3143

344.0

3144

371.2

3145

391.2

3146

341.2

3147

452.3

3148

314.2

3149

3150

484.3

3151

460.3

3152

434.2

3153

482.3

3154

408.2

3155

310.0

3156

340.2

3157

407.3

3158

373.2

3159

335.2

3160

487.3

3161

387.2

3162

449.3

3163

303.2

3164

3165

453.3

3166

385.3

3167

369.0

3168

476.3

3169

3170

350.2

3171

371.2

3172

3173

490.3

3174

457.4

3175

326.2

3176

441.2

3177

451.3

3178

403.2

3179

309.5

3180

483.3

3181

420.2

3182

3183

457.3

3184

315.2

3185

315.0

3186

307.0

3187

469.3

3188

3189

362.2

3190

3191

317.0

3192

391.2

3193

355.2

3194

328.3

3195

343.3

3196

345.1

3197

357.2

3198

456.3

3199

304.0

3200

417.2

3201

607.3

3202

348.2

3203

391.1

3204

368.2

3205

243.1

3206

428.2

3207

437.2

3208

457.3

3209

3210

459.3

3211

430.2

3212

371.2

3213

318.2

3214

358.2

3215

434.1

3216

334.2

3217

477.3

3218

384.1

3219

350.2

3220

477.3

3221

3222

326.2

3223

432.2

3224

439.0

3225

333.1

3226

457.2

3227

512.3

3228

479.3

3229

372.1

3230

376.2

3231

455.3

3232

428.2

3233

467.3

3234

348.2

3235

370.2

3236

459.3

3237

3238

399.2

3239

410.2

3240

378.2

3241

3242

349.2

3243

412.2

3244

312.2

3245

479.3

3246

469.3

3247

365.2

3248

375.3

3249

542.3

3250

448.3

3251

370.2

3252

329.0

3253

441.2

3254

342.2

3255

358.0

3256

391.2

3257

257.1

3258

443.2

3259

458.3

3260

204.1

3261

326.2

3262

365.2

3263

475.3

3264

299.1

3265

431.2

3266

309.2

3267

387.4

3268

431.2

3269

357.2

3270

486.3

3271

3272

380.2

3273

404.2

3274

432.2

3275

432.2

3276

379.1

3277

400.0

3278

409.2

3279

306.2

3280

347.0

3281

593.3

3282

3283

378.1

3284

409.2

3285

383.2

3286

396.2

3287

323.2

3288

309.4

3289

483.3

3290

372.0

3291

348.3

3292

328.1

3293

403.2

3294

460.0

3295

418.2

3296

481.3

3297

382.2

3298

432.2

3299

432.0

3300

415.2

3301

503.3

3302

347.2

3303

332.0

3304

325.2

3305

298.2

3306

358.2

3307

314.2

3308

435.2

3309

412.3

3310

360.2

3311

352.2

3312

308.2

3313

224.1

3314

390.1

3315

351.2

3316

335.2

3317

373.2

3318

457.3

3319

387.2

3320

465.3

3321

325.1

3322

354.2

3323

326.2

3324

342.1

3325

370.2

3326

475.3

3327

459.3

3328

450.3

3329

418.2

3330

463.3

3331

475.3

3332

515.3

3333

411.2

3334

384.1

3335

459.3

3336

421.2

3337

380.2

3338

378.2

3339

451.3

3340

597.3

3341

448.3

3342

315.3

3343

353.1

3344

3345

335.2

3346

448.3

3347

363.2

3348

483.3

3349

407.2

3350

453.3

3351

348.2

3352

411.2

3353

464.3

3354

463.3

3355

427.2

3356

463.3

3357

493.7

3358

3359

236.1

3360

441.2

3361

420.2

3362

343.0

3363

306.2

3364

324.2

3365

554.3

3366

424.2

3367

302.2

3368

392.2

3369

392.2

3370

421.0

3371

3372

391.1

3373

306.2

3374

3375

300.2

3376

521.3

3377

404.9

3378

374.0

3379

379.2

3380

422.2

3381

445.2

3382

434.3

3383

386.2

3384

461.3

3385

302.0

3386

404.4

3387

296.2

3388

442.2

3389

318.0

3390

340.2

3391

447.3

3392

310.1

3393

376.2

3394

335.9

3395

3396

344.2

3397

336.2

3398

456.3

3399

424.2

3400

413.2

3401

412.2

3402

364.2

3403

389.2

3404

356.0

3405

385.1

3406

462.3

3407

311.0

3408

418.2

3409

444.2

3410

365.0

3411

386.2

3412

390.2

3413

437.2

3414

337.2

3415

312.2

3416

367.2

3417

466.3

3418

349.2

3419

343.2

3420

285.9

3421

327.0

3422

427.2

3423

305.9

3424

3425

455.3

3426

368.2

3427

425.0

3428

390.2

3429

356.2

3430

410.2

3431

441.4

3432

326.3

3433

503.3

3434

385.2

3435

423.2

3436

465.3

3437

275.2

3438

278.0

3439

310.2

3440

3441

399.2

3442

498.3

3443

447.0

3444

394.2

3445

369.0

3446

313.2

3447

443.2

3448

309.4

3449

418.2

3450

439.2

3451

461.3

3452

281.1

3453

392.0

3454

275.1

3455

485.1

3456

3457

460.3

3458

434.1

3459

342.2

3460

555.3

3461

329.1

3462

354.0

3463

457.3

3464

455.3

3465

395.2

3466

3467

335.2

3468

412.3

3469

345.1

3470

3471

399.0

3472

456.3

3473

170.1

3474

463.3

3475

320.0

3476

336.2

3477

467.0

3478

353.2

3479

340.0

3480

446.0

3481

463.1

3482

486.3

3483

393.2

3484

315.4

3485

3486

317.2

3487

3488

367.2

3489

455.3

3490

268.3

3491

373.2

3492

518.3

3493

444.2

3494

3495

471.3

3496

321.1

3497

297.3

3498

326.2

3499

348.2

3500

3501

379.2

3502

470.3

3503

362.1

3504

372.1

3505

406.1

3506

377.2

3507

365.0

3508

368.2

3509

379.0

3510

224.0

3511

463.3

3512

449.1

3513

546.3

3514

382.2

3515

446.3

3516

463.3

3517

408.2

3518

448.3

3519

3520

470.3

3521

365.2

3522

468.3

3523

354.2

3524

318.2

3525

380.2

3526

352.2

3527

402.1

3528

452.2

3529

388.2

3530

373.2

3531

326.1

3532

509.3

3533

414.0

3534

476.3

3535

283.2

3536

323.2

3537

324.2

3538

502.3

3539

324.2

3540

3541

3542

393.3

3543

516.1

3544

491.3

3545

353.2

3546

324.0

3547

371.2

3548

374.2

3549

418.2

3550

415.2

3551

346.9

3552

360.2

3553

365.4

3554

364.2

3555

441.2

3556

436.0

3557

507.3

3558

337.2

3559

341.2

3560

3561

311.2

3562

410.0

3563

316.2

3564

3565

3566

3567

453.3

3568

449.3

3569

467.3

3570

325.0

3571

452.3

3572

254.1

3573

243.1

3574

388.2

3575

434.2

3576

378.0

3577

324.2

3578

313.1

3579

316.2

3580

224.1

3581

3582

495.3

3583

3584

373.2

3585

439.2

3586

365.2

3587

455.3

3588

356.1

3589

475.3

3590

380.2

3591

417.1

3592

427.2

3593

299.1

3594

366.2

3595

435.2

3596

348.2

3597

196.1

3598

378.2

3599

3600

401.2

3601

363.1

3602

426.2

3603

453.3

3604

353.4

3605

505.3

3606

484.3

3607

518.3

3608

446.0

3609

3610

393.2

3611

423.2

3612

379.2

3613

436.2

3614

401.2

3615

421.2

3616

418.2

3617

343.2

3618

388.2

3619

385.0

3620

362.1

3621

344.0

3622

294.1

3623

480.4

3624

366.1

3625

432.2

3626

365.2

3627

478.3

3628

417.2

3629

324.1

3630

3631

326.2

3632

351.0

3633

434.2

3634

443.2

3635

392.2

3636

457.4

3637

328.2

3638

466.3

3639

447.3

3640

396.2

3641

485.0

3642

3643

345.0

3644

302.0

3645

349.0

3646

413.2

3647

389.2

3648

425.2

3649

356.2

3650

398.2

3651

405.1

3652

373.2

3653

408.2

3654

442.2

3655

388.2

3656

333.2

3657

481.3

3658

331.2

3659

3660

331.0

3661

441.2

3662

326.2

3663

492.3

3664

509.3

3665

418.1

3666

208.2

3667

438.2

3668

415.2

3669

356.2

3670

443.2

3671

310.1

3672

297.0

3673

498.3

3674

442.2

3675

461.3

3676

455.3

3677

359.2

3678

476.3

3679

499.3

3680

395.2

3681

493.3

3682

425.2

3683

366.0

3684

378.2

3685

356.2

3686

496.3

3687

379.2

3688

436.2

3689

499.3

3690

415.9

3691

358.0

3692

354.2

3693

343.0

3694

301.2

3695

448.3

3696

496.3

3697

490.3

3698

379.2

3699

3700

3701

375.2

3702

482.3

3703

378.2

3704

342.2

3705

354.4

3706

422.2

3707

252.1

3708

525.3

3709

444.2

3710

356.2

3711

261.0

3712

351.3

3713

3714

401.2

3715

441.2

3716

406.9

3717

457.3

3718

313.1

3719

3720

3721

421.1

3722

478.3

3723

316.2

3724

307.3

3725

461.8

3726

390.2

3727

470.4

3728

371.0

3729

502.3

3730

342.2

3731

372.0

3732

494.3

3733

476.1

3734

362.2

3735

454.3

3736

272.2

3737

399.2

3738

471.4

3739

424.2

3740

369.2

3741

453.1

3742

460.3

3743

445.2

3744

392.2

3745

3746

359.2

3747

442.2

3748

258.1

3749

303.2

3750

444.2

3751

282.3

3752

456.3

3753

413.2

3754

409.0

3755

371.0

3756

476.3

3757

346.0

3758

502.3

3759

480.3

3760

476.3

3761

343.1

3762

414.2

3763

386.2

3764

367.1

3765

362.2

3766

275.0

3767

351.2

3768

536.3

3769

333.2

3770

3771

376.2

3772

436.2

3773

471.3

3774

297.3

3775

385.2

3776

448.3

3777

462.3

3778

273.2

3779

308.2

3780

328.2

3781

381.0

3782

3783

3784

354.1

3785

449.2

3786

445.2

3787

475.3

3788

484.0

3789

343.0

3790

430.2

3791

391.3

3792

355.4

3793

335.9

3794

457.3

3795

3796

470.3

3797

344.2

3798

396.2

3799

439.2

3800

332.2

3801

555.3

3802

264.2

3803

407.2

3804

399.2

3805

404.2

3806

3807

443.2

3808

339.2

3809

3810

421.2

3811

369.2

3812

496.3

3813

3814

384.2

3815

436.2

3816

394.2

3817

354.1

3818

543.3

3819

352.2

3820

402.2

3821

460.3

3822

453.3

3823

470.3

3824

502.3

3825

508.3

3826

337.0

3827

258.1

3828

410.2

3829

267.3

3830

390.1

3831

300.2

3832

351.1

3833

352.2

3834

373.2

3835

3836

384.2

3837

484.3

3838

348.2

3839

388.0

3840

396.2

3841

326.1

3842

302.2

3843

461.3

3844

345.2

3845

448.3

3846

357.1

3847

3848

250.1

3849

445.9

3850

417.2

3851

336.0

3852

254.1

3853

369.1

3854

541.1

3855

420.2

3856

503.1

3857

382.2

3858

340.2

3859

358.1

3860

453.3

3861

362.2

3862

421.1

3863

353.1

3864

384.2

3865

371.2

3866

328.0

3867

249.0

3868

309.2

3869

485.3

3870

431.2

3871

3872

3873

384.2

3874

314.2

3875

459.3

3876

382.2

3877

336.1

3878

260.1

3879

438.2

3880

325.1

3881

296.2

3882

456.3

3883

337.1

3884

376.2

3885

459.3

3886

379.4

3887

446.2

3888

384.2

3889

357.2

3890

456.3

3891

375.2

3892

378.2

3893

354.1

3894

399.2

3895

467.3

3896

351.2

3897

327.3

3898

301.2

3899

348.2

3900

507.3

3901

321.1

3902

451.3

3903

3904

331.1

3905

379.0

3906

331.0

3907

460.3

3908

282.1

3909

3910

594.7

3911

387.2

3912

3913

299.2

3914

423.0

3915

400.1

3916

400.0

3917

351.2

3918

312.2

3919

427.2

3920

297.0

3921

483.3

3922

252.1

3923

308.1

3924

376.2

3925

354.2

3926

3927

442.2

3928

430.2

3929

324.2

3930

399.2

3931

330.2

3932

349.2

3933

314.2

3934

339.0

3935

3936

478.3

3937

430.2

3938

281.0

3939

385.2

3940

490.3

3941

501.3

3942

515.3

3943

483.3

3944

345.3

3945

492.3

3946

481.3

3947

3948

385.2

3949

358.2

3950

507.3

3951

335.2

3952

314.2

3953

415.1

3954

3955

452.3

3956

431.2

3957

321.2

3958

390.2

3959

433.2

3960

325.2

3961

354.2

3962

443.2

3963

408.2

3964

351.2

3965

357.2

3966

397.2

3967

559.3

3968

465.3

3969

455.3

3970

459.3

3971

341.2

3972

504.3

3973

490.1

3974

429.2

3975

459.3

3976

386.2

3977

440.2

3978

409.2

3979

402.2

3980

354.2

3981

490.3

3982

457.3

3983

330.3

3984

419.2

3985

369.2

3986

412.2

3987

447.3

3988

460.3

3989

436.2

3990

461.3

3991

466.1

3992

468.0

3993

359.2

3994

299.2

3995

432.2

3996

293.2

3997

422.2

3998

329.1

3999

389.4

4000

4001

515.3

4002

370.0

4003

463.3

4004

314.3

4005

489.3

4006

399.2

4007

431.4

4008

472.3

4009

4010

427.2

4011

4012

359.9

4013

385.2

4014

372.0

4015

300.2

4016

657.1

4017

345.1

4018

387.2

4019

358.2

4020

401.2

4021

350.2

4022

415.0

4023

392.0

4024

4025

497.3

4026

442.2

4027

286.2

4028

516.3

4029

336.2

4030

396.2

4031

408.2

4032

330.0

4033

383.2

4034

287.0

4035

4036

354.1

4037

493.3

4038

481.3

4039

389.2

4040

501.3

4041

476.3

4042

416.2

4043

344.2

4044

423.8

4045

483.3

4046

452.3

4047

537.7

4048

469.0

4049

501.3

4050

326.0

4051

361.0

4052

495.3

4053

470.3

4054

459.0

4055

393.2

4056

337.2

4057

342.2

4058

422.2

4059

367.2

4060

452.3

4061

357.2

4062

186.2

4063

477.3

4064

351.2

4065

409.2

4066

340.2

4067

408.1

4068

447.0

4069

372.2

4070

405.2

4071

359.2

4072

4073

351.2

4074

311.2

4075

515.3

4076

4077

444.1

4078

417.2

4079

323.2

4080

4081

389.1

4082

539.3

4083

363.0

4084

395.2

4085

408.2

4086

4087

309.2

4088

395.2

4089

455.3

4090

386.2

4091

447.3

4092

463.3

4093

436.2

4094

340.2

4095

505.3

4096

433.2

4097

347.1

4098

376.2

4099

299.1

4100

411.1

4101

426.1

4102

375.1

4103

496.3

4104

352.2

4105

394.2

4106

369.2

4107

311.2

4108

377.2

4109

372.2

4110

341.2

4111

459.3

4112

423.0

4113

351.1

4114

481.3

4115

350.2

4116

420.2

4117

330.1

4118

407.2

4119

426.1

4120

393.2

4121

446.3

4122

338.2

4123

336.2

4124

405.1

4125

408.2

4126

449.3

4127

396.2

4128

461.3

4129

365.2

4130

404.2

4131

470.3

4132

428.2

4133

425.2

4134

382.2

4135

445.2

4136

509.3

4137

426.2

4138

313.1

4139

385.2

4140

483.3

4141

326.1

4142

500.3

4143

427.2

4144

489.3

4145

334.2

4146

359.0

4147

315.3

4148

373.2

4149

462.3

4150

453.3

4151

371.2

4152

410.2

4153

450.3

4154

380.2

4155

407.2

4156

297.1

4157

350.2

4158

390.2

4159

326.0

4160

4161

397.2

4162

340.3

4163

419.2

4164

377.2

4165

397.2

4166

399.2

4167

330.2

4168

392.0

4169

469.3

4170

472.3

4171

416.2

4172

481.3

4173

325.1

4174

4175

528.3

4176

322.1

4177

398.2

4178

374.2

4179

421.2

4180

392.2

4181

409.5

4182

364.2

4183

386.1

4184

339.2

4185

286.2

4186

547.3

4187

359.2

4188

354.2

4189

301.2

4190

436.0

4191

472.3

4192

380.2

4193

315.2

4194

4195

316.2

4196

390.1

4197

393.1

4198

516.3

4199

404.2

4200

452.3

4201

337.8

4202

397.1

4203

350.1

4204

496.3

4205

417.1

4206

458.3

4207

4208

343.0

4209

434.3

4210

357.2

4211

476.3

4212

4213

511.3

4214

342.2

4215

254.1

4216

360.2

4217

344.2

4218

4219

469.3

4220

325.3

4221

322.2

4222

344.2

4223

364.2

4224

285.9

4225

465.3

4226

386.2

4227

427.2

4228

4229

337.2

4230

426.2

4231

343.2

4232

501.3

4233

404.9

4234

210.1

4235

507.3

4236

467.3

4237

336.2

4238

249.1

4239

368.2

4240

426.2

4241

399.2

4242

480.3

4243

360.2

4244

403.2

4245

375.2

4246

340.2

4247

4248

357.0

4249

286.2

4250

341.2

4251

444.2

4252

361.2

4253

432.1

4254

499.3

4255

356.0

4256

310.0

4257

426.2

4258

388.1

4259

428.0

4260

313.9

4261

410.2

4262

443.2

4263

359.0

4264

335.2

4265

411.2

4266

250.0

4267

391.2

4268

490.3

4269

309.2

4270

475.9

4271

449.3

4272

316.0

4273

482.3

4274

497.1

4275

331.2

4276

320.1

4277

509.3

4278

444.2

4279

373.2

4280

541.3

4281

493.3

4282

359.0

4283

300.2

4284

359.2

4285

338.0

4286

446.3

4287

396.2

4288

4289

419.2

4290

444.2

4291

337.3

4292

568.3

4293

375.2

4294

297.0

4295

4296

340.2

4297

4298

482.3

4299

397.2

4300

383.2

4301

382.2

4302

406.2

4303

434.1

4304

359.2

4305

274.2

4306

320.2

4307

308.2

4308

394.2

4309

323.1

4310

356.2

4311

354.2

4312

500.3

4313

4314

384.2

4315

463.3

4316

441.2

4317

346.2

4318

403.2

4319

449.3

4320

476.3

4321

4322

389.2

4323

312.2

4324

439.1

4325

335.2

4326

323.1

4327

380.2

4328

409.2

4329

378.2

4330

340.2

4331

394.2

4332

378.2

4333

434.1

4334

465.3

4335

356.2

4336

443.2

4337

403.2

4338

4339

329.2

4340

423.0

4341

368.2

4342

369.0

4343

326.3

4344

332.0

4345

4346

4347

486.3

4348

433.2

4349

469.3

4350

260.1

4351

393.2

4352

4353

4354

459.3

4355

335.1

4356

351.0

4357

486.3

4358

250.3

4359

379.2

4360

332.2

4361

342.1

4362

4363

562.3

4364

370.2

4365

360.0

4366

402.7

4367

487.1

4368

427.2

4369

421.0

4370

272.2

4371

316.2

4372

4373

409.0

4374

301.9

4375

358.2

4376

326.2

4377

429.2

4378

357.0

4379

363.2

4380

4381

380.2

4382

357.2

4383

4384

369.2

4385

310.0

4386

332.2

4387

375.2

4388

283.3

4389

384.0

4390

302.0

4391

4392

469.3

4393

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)

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-NH 2 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.

structure

The following compound

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/H is 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 900-11 medium (Invitrogen) supplemented with 3% heat inactivated FBS and 0.5× penicillin/streptomycin solution (Invitrogen). Five milliliters of high titer plaque purified sBACEmyc/H is virus was used to infect 1 L of logarithmically growing sf9 cells using CeilFectin (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^((Log EC50−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 IC 50 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:

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-1 Ki 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]-1-[[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-THIENYYL]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]METHYL]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]METHYL]-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]ETHANESULFONAMIDE (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-M ETHOXYETHYL)-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 V5-6H is 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.

Compound

1% of hRenin at 100 μM

68.8

75.3

76.9

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

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

W is —C(═O)—;

X is —N(R 5 )—;

U is a bond;

R 1 , R 2 and R 5 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;

R 3 and R 4 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;

R 15 , R 16 and R 17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -cycloalkylalkyl, R 18 -heterocycloalkyl, R 18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 18 -heteroarylalkyl; or

R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO 2 , halo, heteroaryl, HO-alkyoxyalkyl, —CF 3 , —CN, alkyl-CN, —C(O)R 19 , —C(O)OH, —C(O)OR 19 , —C(O)NHR 20 , —C(O)NH 2 , —C(O)NH 2 —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 19 , —S(O) 2 R 20 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OCF 3 , —OH, —OR 20 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 20 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 20 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 20 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

or two R 18 moieties on adjacent carbons can be linked together to form

R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R 20 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 R 1 , R 2 , R 3 , R 4 , and R 5 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —CH(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(R 16 ), —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —S(O)R 15 , ═NOR 15 , —N 3 , —NO 2 and —S(O) 2 R 15 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 21 are independently unsubstituted or substituted by 1 to 5 R 22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , -alkyl-C(O)OR 15 , C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —N 3 , ═NOR 15 , —NO 2 , —S(O)R 15 and —S(O) 2 R 15 ;

or two R 21 or two R 22 moieties on adjacent carbons can be linked together to form

and when R 21 or R 22 are selected from the group consisting of —C(═NOR 15 )R 16 , —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 and —CH 2 —N(R 15 )C(O)OR 16 , R 15 and R 16 together can be a C 2 to C 4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R 15 and R 16 , together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R 23 ;

R 23 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, —OR 24 , —C(O)R 24 , —C(O)OR 24 , —C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 23 are independently unsubstituted or substituted by 1 to 5 R 27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 24 , —C(O)R 24 , —C(O)OR 24 , alkyl-C(O)OR 24 , C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ;

R 24 , R 25 and R 26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R 27 -alkyl, R 27 -cycloalkyl, R 27 -cycloalkylalkyl, R 27 -heterocycloalkyl, R 27 -heterocycloalkylalkyl, R 27 -aryl, R 27 -arylalkyl, R 27 -heteroaryl and R 27 -heteroarylalkyl;

R 27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO 2 , halo, —CF 3 , —CN, alkyl-CN, —C(O)R 28 , —C(O)OH, —C(O)OR 28 , —C(O)NHR 29 , —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 28 , —S(O) 2 R 29 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 28 , —S(O) 2 NH(aryl), —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OH, —OR 29 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 29 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)(heteroarylalkyl), —NHC(O)R 29 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 29 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R 29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

provided that when R 1 is methyl, X is —N(R 5 )—, R 2 is H, W is —C(O)— and U is a bond, (R 3 , R 4 ) is not (H, H), (benzyl, H) or (i-butyl, H).

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

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

W is —C(═O)—;

X is —N(R 5 )—;

U is a bond;

R 1 , R 2 and R 5 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;

R 3 is independently selected from the group consisting of aryl and heteroaryl;

R 4 is independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;

R 15 , R 16 and R 17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -cycloalkylalkyl, R 18 -heterocycloalkyl, R 18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 18 -heteroarylalkyl; or

R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO 2 , halo, heteroaryl, HO-alkyoxyalkyl, —CF 3 , —CN, alkyl-CN, —C(O)R 19 , —C(O)OH, —C(O)OR 19 , —C(O)NHR 20 , —C(O)NH 2 , —C(O)NH 2 —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 19 , —S(O) 2 R 20 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OCF 3 , —OH, —OR 20 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 20 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 20 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 20 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

or two R 18 moieties on adjacent carbons can be linked together to form

R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R 20 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 R 1 , R 2 , R 3 , R 4 and R 5 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —CH(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —(P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(R 16 ), —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —S(O)R 15 , ═NOR 15 , —N 3 , —NO 2 and —S(O) 2 R 15 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 21 are independently unsubstituted or substituted by 1 to 5 R 22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , -alkyl-C(O)OR 15 , C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —N 3 , ═NOR 15 , —NO 2 , —S(O)R 15 and —S(O) 2 R 15 ;

or two R 21 or two R 22 moieties on adjacent carbons can be linked together to form

and when R 21 or R 22 are selected from the group consisting of —C(═NOR 15 )R 16 , —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 and —CH 2 —N(R 15 )C(O)OR 16 , R 15 and R 16 together can be a C 2 to C 4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R 15 and R 16 , together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R 23 ;

R 23 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, —OR 24 , —C(O)R 24 , —C(O)OR 24 , —C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 23 are independently unsubstituted or substituted by 1 to 5 R 27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 24 , —C(O)R 24 , —C(O)OR 24 , alkyl-C(O)OR 24 , C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ;

R 24 , R 25 and R 26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R 27 -alkyl, R 27 -cycloalkyl, R 27 -cycloalkylalkyl, R 27 -heterocycloalkyl, R 27 -heterocycloalkylalkyl, R 27 -aryl, R 27 -arylalkyl, R 27 -heteroaryl and R 27 -heteroarylalkyl;

R 27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO 2 , halo, —CF 3 , —CN, alkyl-CN, —C(O)R 28 , —C(O)OH, —C(O)OR 28 , —C(O)NHR 29 , —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), SR 28 , —S(O) 2 R 29 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 28 , —S(O) 2 NH(aryl), —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OH, —OR 29 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 29 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)(heteroarylalkyl), —NHC(O)R 29 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 29 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R 29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

provided that when R 1 is methyl, X is —N(R 5 )—, R 2 is H, W is —C(O)— and U is a bond, (R 3 , R 4 ) is not (phenyl, phenyl), (H, phenyl), (benzyl, phenyl), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH 3 O-phenyl, NO 2 -phenyl);

provided that when X is —N(R 5 )—, R 1 and R 5 are each H, W is —C(O)— and U is a bond, (R 3 , R 4 ) 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

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

W is —C(═O)—;

X is —N(R 5 )—;

U is a —(C(R 6 )(R 7 ))—;

R 1 , R 2 and R 5 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;

R 3 and R 4 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, —SH, —SR 19 , —CN, —OR 9 , —N(R 11 )(R 12 ) and halo;

R 6 and R 7 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;

R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR 15 , —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ;

R 9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;

R 10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R 15 )(R 16 );

R 11 and R 12 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —C(O)R 8 , —C(O)OR 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 15 )(R 16 ), —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ) and —CN;

R 15 , R 16 and R 17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -cycloalkylalkyl, R 18 -heterocycloalkyl, R 18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 18 -heteroarylalkyl; or

R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO 2 , halo, heteroaryl, HO-alkyoxyalkyl, —CF 3 , —CN, alkyl-CN, —C(O)R 19 , —C(O)OH, —C(O)OR 19 , —C(O)NHR 20 , —C(O)NH 2 , —C(O)NH 2 —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 19 , —S(O) 2 R 20 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OCF 3 , —OH, —OR 20 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 20 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 20 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 20 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

or two R 18 moieties on adjacent carbons can be linked together to form

R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R 20 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 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —CH(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(R 16 ), —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —S(O)R 15 , ═NOR 15 , —N 3 , —NO 2 and —S(O) 2 R 15 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 21 are independently unsubstituted or substituted by 1 to 5 R 22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , -alkyl-C(O)OR 15 , C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —N 3 , ═NOR 15 , —NO 2 , —S(O)R 15 and —S(O) 2 R 15 ;

or two R 21 or two R 22 moieties on adjacent carbons can be linked together to form

and when R 21 or R 22 are selected from the group consisting of —C(═NOR 15 )R 16 , —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 and —CH 2 —N(R 15 )C(O)OR 16 , R 15 and R 16 together can be a C 2 to C 4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R 15 and R 16 , together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R 23 ;

R 23 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, —OR 24 , —C(O)R 24 , —C(O)OR 24 , —C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 23 are independently unsubstituted or substituted by 1 to 5 R 27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 24 , —C(O)R 24 , —C(O)OR 24 , alkyl-C(O)OR 24 , C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ;

R 24 , R 25 and R 26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R 27 -alkyl, R 27 -cycloalkyl, R 27 -cycloalkylalkyl, R 27 -heterocycloalkyl, R 27 -heterocycloalkylalkyl, R 27 -aryl, R 27 -arylalkyl, R 27 -heteroaryl and R 27 -heteroarylalkyl;

R 27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO 2 , halo, —CF 3 , —CN, alkyl-CN, —C(O)R 28 , —C(O)OH, —C(O)OR 28 , —C(O)NHR 29 , —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 28 , —S(O) 2 R 29 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 28 , —S(O) 2 NH(aryl), —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OH, —OR 29 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 29 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)(heteroarylalkyl), —NHC(O)R 29 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 29 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R 29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.

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

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

W is —O—;

X is —N(R 5 )—;

U is a —(C(R 6 )(R 7 ))—;

R 1 , R 2 and R 5 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;

R 3 and R 4 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl and —CN;

R 6 and R 7 are independently selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryalkyl and arylalkyl;

R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR 15 , —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ;

R 10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R 15 )(R 16 );

R 15 , R 16 and R 17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -cycloalkylalkyl, R 18 -heterocycloalkyl, R 18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 18 -heteroarylalkyl; or

R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO 2 , halo, heteroaryl, HO-alkyoxyalkyl, —CF 3 , —CN, alkyl-CN, —C(O)R 19 , —C(O)OH, —C(O)OR 19 , —C(O)NHR 20 , —C(O)NH 2 , —C(O)NH 2 —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 19 , —S(O) 2 R 20 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OCF 3 , —OH, —OR 20 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 20 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 20 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 20 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

or two R 18 moieties on adjacent carbons can be linked together to form

R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R 20 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 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —CH(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(R 16 ), —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —S(O)R 15 , ═NOR 15 , —N 3 , —NO 2 and —S(O) 2 R 15 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 21 are independently unsubstituted or substituted by 1 to 5 R 22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , -alkyl-C(O)OR 15 , C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —N 3 , ═NOR 15 , —NO 2 , —S(O)R 15 and —S(O) 2 R 15 ;

or two R 21 or two R 22 moieties on adjacent carbons can be linked together to form

and when R 21 or R 22 are selected from the group consisting of —C(═NOR 15 )R 16 , —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 and —CH 2 —N(R 15 )C(O)OR 16 , R 15 and R 16 together can be a C 2 to C 4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R 15 and R 16 , together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R 23 ;

R 23 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, —OR 24 , —C(O)R 24 , —C(O)OR 24 , —C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 23 are independently unsubstituted or substituted by 1 to 5 R 27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 24 , —C(O)R 24 , —C(O)OR 24 , alkyl-C(O)OR 24 , C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 (O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ;

R 24 , R 25 and R 26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R 27 -alkyl, R 27 -cycloalkyl, R 27 -cycloalkylalkyl, R 27 -heterocycloalkyl, R 27 -heterocycloalkylalkyl, R 27 -aryl, R 27 -arylalkyl, R 27 -heteroaryl and R 27 -heteroarylalkyl;

R 27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO 2 , halo, —CF 3 , —CN, alkyl-CN, —C(O)R 28 , —C(O)OH, —C(O)OR 28 , —C(O)NHR 29 , —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 28 , —S(O) 2 R 29 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 28 , —S(O) 2 NH(aryl), —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OH, —OR 29 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 29 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)(heteroarylalkyl), —NHC(O)R 29 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 29 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R 29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.

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

the process comprising the steps of:

(a) reacting the compound of Formula A:

with R 3 —X in a solvent in the presence of a base, optionally with ZnCl 2 , 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 —;

R 1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl and heteroaryl;

R 3 is selected from the group consisting of aryl, heteroaryl and alkenyl; and

R 6 and R 7 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 Pd 2 (dba) 3 , PdCl 2 , PdOAc 2 /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 m 1 agonist or m 2 antagonist can be used. Examples of m 1 agonists are known in the art. Examples of m 2 antagonists are also known in the art; in particular, m 2 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; GABA A 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.