CIS-MORPHOLINONE AND OTHER COMPOUNDS AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER

FIELD OF THE INVENTION

The present invention relates to compounds that are MDM2 inhibitors that are useful as therapeutic agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions that contain a MDM2 inhibitor.

BACKGROUND OF THE INVENTION

p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which have infrequent cause for p53 activation, tumor cells are under constant cellular stress from various insults including hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective advantage for inactivation of the p53 pathway in tumors, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. In support of this notion, three groups of investigators have used mouse models to demonstrate that absence of p53 function is a continuous requirement for the maintenance of established tumors. When the investigators restored p53 function to tumors with inactivated p53, the tumors regressed.

p53 is inactivated by mutation and/or loss in 50% of solid tumors and 10% of liquid tumors. Other key members of the p53 pathway are also genetically or

epigenetically altered in cancer. MDM2, an oncoprotein, inhibits p53 function, and it is activated by gene amplification at incidence rates that are reported to be as high as 10%. MDM2, in turn, is inhibited by another tumor suppressor, pl4ARF. It has been suggested that alterations downstream of p53 may be responsible for at least partially inactivating the p53 pathway in p53 tumors (p53 wildtype). In support of this concept, some p53 tumors appear to exhibit reduced apoptotic capacity, although their capacity to undergo cell cycle arrest remains intact. One cancer treatment strategy involves the use of small molecules that bind MDM2 and neutralize its interaction with p53. MDM2 inhibits p53 activity by three mechanisms: 1) acting as an E3 ubiquitin ligase to promote p53 degradation; 2) binding to and blocking the p53 transcriptional activation domain; and 3) exporting p53 from the nucleus to the cytoplasm. All three of these mechanisms would be blocked by neutralizing the MDM2-p53 interaction. In particular, this therapeutic strategy could be applied to tumors that are p53 ^WT , and studies with small molecule MDM2 inhibitors have yielded promising reductions in tumor growth both in vitro and in vivo. Further, in patients with p53 -inactivated tumors, stabilization of wildtype p53 in normal tissues by MDM2 inhibition might allow selective protection of normal tissues from mitotic poisons.

The present invention relates to compounds capable of inhibiting the interaction between p53 and MDM2 and activating p53 downstream effector genes. As such, compounds of the present invention would be useful in the treatment of cancers, bacterial infections, viral infections, ulcers and inflammation. In particular, the compounds of the present invention are useful to treat solid tumors such as: breast, colon, lung and prostate tumors; and liquid tumors such as lymphomas and leukemias. As used herein, MDM2 means a human MDM2 protein and p53 means a human p53 protein. It is noted that human MDM2 can also be referred to as HDM2 or hMDM2.

SUMMARY OF THE INVENTION

In embodiment 1, the present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof,

wherein,

X is O or -S(=0) ₂ -;

R is hydrogen, Ci_ ₆ alkyl, -(CR ^e R ^e ) _n C ₆ -8 _; ;aryl, -(CR ^e R ^e ) _n C ₃ - ₈ cycloalkyl, -(CR ^e R ^e )„3-8membered heterocycloalkyl,

-S(=0) ₂ C ₃ _ ₈ cycloalkyl, -C(=0)C ₃ _ ₈ cycloalkyl, or

R ^f

C (CR ^e R ^e ) _n -Q

R ^a

wherein any heteroaryl or heterocycloalkyl group has one or more heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from d_ ₆ alkyl, halo, -CN, -CF ₃ , -SR ^e , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, or -OR ^e ;

Q is -(CR ^e R ^e ) _n C ₆ - ₈ aryl, -(CR ^e R ^e )„3-8membered heterocycloalkyl,

-(CR ^e R ^e )„5-8membered heteroaryl, -(CR ^e R ^e )„C ₃ _ ₈ cycloalkyl,

-CN, -(CR ^e R ^e ) _n OH, -C(=0)OH, -NR ^e R ^e , -(CR ^e R ^e ) _n OR ^e , -C(=0)N(R ^e )S(=0) ₂ R ^e , -C(=0)NR ^e R ^e , -C(=0)NR ^e (CR ^e R ^e ) _n C(=0)OR ^e , -C(=0)NR ^e (CR ^e R ^e ) _n C(=0)NR ^e R ^e , -N(R ^e )(CR ^e R ^e ) _n C(=0)OR ^e , -OC(=0)NR ^e R ^e , -S(=0) ₂ C ₃ _ ₈ cycloalkyl,

-C(=0)N(R ^e )(CR ^e R ^e ) _n OH, -C(=0)N(R ^e )(CR ^e R ^e ) _n 3-8membered heterocycloalkyl, -N(R ^e )C(=0)(CR ^e R ^e ) _n OH, -N(R ^e )S(=0) ₂ R ^e , -N(R ^e )C(=0)(CR ^e R ^e ) _n C(=0)OR ^e ,

-C(=0)3-8membered heterocycloalkyl, -S(=0) ₂ 3-8membered heterocycloalkyl,

-C(=0)N(R ^e )S(=0) ₂ C ₃ _ ₈ cycloalkyl, -0(CR ^e R ^e ) _n C(=0)R ^e ,

-C(=0)N(R ^e )(CR ^e R ^e ) _n 5-8membered heteroaryl, -N(R ^e )C(=0)(CR ^e R ^e ) _n 5-8membered heteroaryl, -C(=0)3-8memberedheterocycloalkyl(CR ^e R ^e )„ C(=0)OR ^e , or

-C(=0)(CR ^e R ^e ) _n C(=0)OR ^e , wherein any heteroaryl or heterocycloalkyl group has one or more heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from Ci_ ₆ alkyl, halo, -CN, -SR ^e , -C(=0)OR ^e , -CF ₃ , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, or -OR ^e ; R ² is hydrogen, Ci_ ₆ alkyl, -(CR ^e R ^e ) _n C(=0)OR ^e , -(CR ^e R ^e ) _n NR ^e R ^e , -(CR ^e R ^e ) _n C(=0)NR ^e R ^e , -(CR ^e R ^e ) _n OH, -(CR ^e R ^e ) _n C(=0)H, -(CR ^e R ^e ) _n C ₆ _ ₈ aryl, -(CR ^e R ^e ) _n 3-8membered

heterocycloalkyl, -(CR ^e R ^e )„5-8membered heteroaryl, -(CR ^e R ^e )„CN,

-(CR ^e R ^e )„C(=0)5-8membered heterocycloalkyl,

-(CR ^e R ^e ) _n C(=0)N(R ^e )(CR ^e R ^e ) _n 3-8membered heterocycloalkyl,

-(CR ^e R ^e ) _n _CH(OH)CH ₂ OH, -CH=CH5-8membered heteroaryl, -(CR ^e R ^e ) _n CH=CR ^e R ^e , wherein any heteroaryl or heterocycloalkyl group has one or two heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from Ci_ ₆ alkyl, halo, -(CR ^e R ^e )„halo, -OCi_ ₆ alkyl, -OCF ₃ , -OCF ₂ H, -OCFH ₂ , -CN, -S(=0) ₂ CF ₃ , -C(=0)NR ^e R ^e , -5-8membered heteroaryl, -C(=0)OR ^e , C ₆ - ₈ aryl, 5- 8membered heteroaryl, -CF ₃ , -SR ^e , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , or -OR ^e ; R ³ is hydrogen or Ci_ ₆ alkyl;

R ⁴ is C ₆ - ₈ aryl or 5-9membered heteroaryl, wherein any heteroaryl group has one or more heteroatom independently selected from O, N or S, and wherein the aryl or heteroaryl group is substituted with from 1 to 3 substituents indpendently selected from Ci_ ₆ alkyl, halo, -CF ₃ , -CN, C ₃ _ ₈ cycloalkyl, -SR ^e , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, or -OR ^e ;

R ⁵ is C ₆ - ₈ aryl or 5 -9membered heteroaryl, wherein any heteroaryl group has one or more heteroatom independently selected from O, N or S, and wherein the aryl or heteroaryl group is substituted with from 1 to 3 substituents indpendently selected from Ci_ ₆ alkyl, halo, -CF ₃ , -CN, C ₃ _ ₈ cycloalkyl, -SR ^e , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , -OCF ₃ , - OCHF ₂ , -OCH ₂ F, or -OR ^e ;

R ⁶ is hydrogen or Ci_ ₆ alkyl;

R ⁷ is hydrogen or Ci_ ₆ alkyl; each R ^a is independently hydrogen, Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, -(CR ^e R ^e ) _n C ₃ _ ₈ cycloalkyl, or -(CR ^e R ^e ) _n C6- ₈ aryl, wherein any cycloalkyl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from Ci_ ₆ alkyl, halo, -CN, -SR ^e , -C(=0)OR ^e -CF ₃ , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, or -OR ^e ; each R ^e is independently hydrogen, Ci_ ₆ alkyl, or -OH; each R is independently hydrogen, Ci_ ₆ alkyl, or -OH; each n is independently 0, 1 , 2, 3 or 4; and each m is independently 0, 1 , 2, 3 or 4, provided that R ² and R ³ are not both hydrogen.

In embodiment 2, the present invention provides compounds in accordance with embodiment 1 wherein X is O.

In embodiment 3, the present invention provides compounds in accordance with embodiment 1 wherein X is -S(=0) ₂ -.

In embodiment 4, the present invention provides compounds in accordance with any one of embodiments 1 to 3 wherein R ³ is hydrogen.

In embodiment 5, the present invention provides compound in accordance with any one of embodiments 1 to 3 wherein R ³ is Ci_ ₆ alkyl.

In embodiment 6, the present invention provides compounds in accordance with one of embodiments 1 to 3 wherein R ³ is methyl. In embodiment 7, the present invention provides compounds in accordance with any one of embodiments 1 to 6 wherein R ⁶ is hydrogen. In embodiment 8, the present invention provides compounds in accordance with any one of embodiments 1 to 6 wherein R ⁶ is methyl.

In embodiment 9, the present invention provides compounds in accordance with any one of embodiments 1 to 8 wherein R ⁷ is hydrogen.

In embodiment 10, the present invention provides compounds in accordance with any one of embodiments 1 to 8 wherein R ⁷ is methyl.

In embodiment 11 , the present invention provides compounds in accordance with any one of embodiments 1 to 10 wherein R ⁴ is substituted C ₆ -8aryl.

In embodiment 12, the present invention provides compounds in accordance with any one of embodiments 1 to 10 wherein R ⁴ is substituted phenyl. In embodiment 13, the present invention provides compounds in accordance with any one of embodiments 1 to 10 wherein R ⁴ is phenyl substituted with from 1 to 3 halo groups.

In embodiment 14, the present invention provides compounds in accordance with any one of embodiments 1 to 10 wherein R ⁴ is phenyl substituted with a fluorine.

In embodiment 15, the present invention provides compounds in accordance with any one of embodiments 1 to 10 wherein R ⁴ is phenyl substituted with a bromine. In embodiment 16, the present invention provides compounds in accordance with any one of embodiments 1 to 10 wherein R ⁴ is 4-chlorophenyl or 4-bromophenyl. In embodiment 17, the present invention provides compounds in accordance with any one of embodiments 1 to 16 wherein R ⁵ is substituted C ₆ -8aryl.

In embodiment 18, the present invention provides compounds in accordance with any one of embodiments 1 to 16 wherein R ⁵ is substituted phenyl.

In embodiment 19, the present invention provides compounds in accordance with any one of embodiments 1 to 16 wherein R ⁵ is phenyl substituted with from 1 to 3 halo groups.

In embodiment 20, the present invention provides compounds in accordance with any one of embodiments 1 to 16 wherein R ⁵ is phenyl substituted with a fluorine.

In embodiment 21, the present invention provides compounds in accordance with any one of embodiments 1 to 16 wherein R ⁵ is phenyl substituted with a bromine.

In embodiment 22, the present invention provides compounds in accordance with any one of embodiments 1 to 16 wherein R ⁵ is 4-chlorophenyl or 4-bromophenyl.

In embodiment 23, the present invention provides compounds in accordance with any one of embodiments 1 to 16 wherein R ⁵ is 3-chlorophenyl or 3-bromophenyl.

In embodiment 24, the present invention provides compounds in accordance with any one of embodiments 1 to 23 wherein R ² is hydrogen.

In embodiment 25, the present invention provides compounds in accordance with any one of embodiments 1 to 23 wherein R ² is Ci_6alkyl.

In embodiment 26, the present invention provides compounds in accordance with any one of embodiments 1 to 23 wherein R ² is -CH ₂ C(=0)OH. In embodiment 27, the present invention provides compounds in accordance with any one of embodiments 1 to 23 wherein R ² is -CH ₂ phenyl. In embodiment 28, the present invention provides compounds in accordance with any one of embodiments 1 to 23 wherein R ² is -CH ₂ phenyl substituted with from 1 to 3 substituents independently selected from Ci_ ₆ alkyl, halo, -(CR ^e R ^e ) _n halo, -OCi_ ₆ alkyl, -OCF ₃ , -OCF ₂ H, -OCFH ₂ , -CN, -S(=0) ₂ CF ₃ , -C(=0)NR ^e R ^e , -C(=0)OR ^e , C ₆ - ₈ aryl, -CF ₃ , -SR ^e , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , or -OR ^e .

In embodiment 29, the present invention provides compounds in accordance with any one of embodiments 1 to 23 wherein R ² is -CH ₂ phenyl substituted with from 1 to 3 substituents independently selected from Ci_ ₆ alkyl, halo, -OCi_ ₆ alkyl, -OCF ₃ , -OCF ₂ H, -OCFH ₂ , -CN, -CF ₃ , -SR ^e , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , or -OR ^e .

In embodiment 30, the present invention provides compounds in accordance with any one of embodiments 1 to 23 wherein R ² is -CH ₂ pyridyl.

In embodiment 31 , the present invention provides compounds in accordance with any one of embodiments 1 to 23 wherein R ² is -CH ₂ pyridyl substituted with from 1 to 3 substituents independently selected from Ci_ ₆ alkyl, halo, -OCi_ ₆ alkyl, -OCF ₃ , -OCF ₂ H, - OCFH ₂ , -CN, -CF ₃ , -SR ^e , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , or -OR ^e .

In embodiment 32, the present invention provides compounds in accordance with any one of embodiments 1 to 31 wherein R ¹ is Ci_ ₆ alkyl.

In embodiment 33, the present invention provides compounds in accordance with any one of embodiments 1 to 31 wherein R ¹ is methyl. In embodiment 34, the present invention provides compounds in accordance with any one of embodiments 1 to 31 wherein R ¹ is -(CR ^e R ^e ) _n C ₃ _ ₈ cycloalkyl. In embodiment 35, the present invention provides compounds in accordance with any one of embodiments 1 to 31 wherein R ¹ is -CH ₂ cyclopropyl, -CH ₂ cyclobutyl or -CH ₂ cyclohexyl. In embodiment 36, the present invention provides compounds in accordance with any one of embodiments 1 to 31 wherein R ¹ is

R ^f C (CR ^e R ^e ) _n -Q

R ^a

In embodiment 37, the present invention provides compounds in accordance with any one of embodiments 1 to 31 wherein R ¹ is

H C (CR ^e R ^e ) _n -Q

C _-6 alkyl

In embodiment 38, the present invention provides compounds in accordance with any one of embodiments 1 to 31 wherein R ¹ is

H C (CR ^e R ^e ) _n -Q C _1-6 alkyl _and

Q is -C(=0)OR ^e , -C(=0)NR ^e (CR ^e R ^e ) _n C(=0)OR ^e , or 5-8memberedheteroaryl.

In embodiment 39, the present invention provides compounds in accordance with any one of embodiments 1 to 31 wherein R ¹ is 5-8membered heteroaryl.

In embodiment 40, the present invention provides compounds in accordance with embodiment 1 wherein: X is O;

R ³ is hydrogen or methyl; R ⁴ is phenyl substituted with from 1 to 3 halo groups; R ⁵ is phenyl substituted with from 1 to 3 halo groups; R ⁶ is hydrogen or methyl; and

R ⁷ is hydrogen or methyl.

In embodiment 41, the present invention provides compounds in accordance with embodiment 40 wherein: R ² is -CH ₂ C(=0)OH.

In embodiment 42, the present invention provides compounds in accordance with embodiment 40 wherein: R ² is -CH ₂ phenyl substituted with from 1 to 3 substituents independently selected from Ci_ ₆ alkyl, halo, -OCi_ ₆ alkyl, -OCF ₃ , -OCF ₂ H, -OCFH ₂ , -CN, -CF ₃ , -SR ^e , -S(=0) ₂ R ^e , -CHF ₂ , -CH ₂ F, -NR ^e R ^e , or -OR ^e .

In embodiment 43, the present invention provides the compounds, or a pharmaceutically acceptable salts, selected from:

(25',5i?,65)-2-benzyl-5,6-bis(4-bromophenyl)-4-methylmorphol in-3-one;

(2i?,55',6i?)-2-benzyl-5,6-bis(4-bromophenyl)-4-methylmorpho lin-3-one;

(25',5i?,65)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmor pholin-3-one;

(2i?,55',6i?)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmorph olin-3-one;

(25',5i?,65)-2-(4-bromobenzyl)-5,6-bis(4-bromophenyl)-4-meth ylmorpholin-3-one;

(2i?,55',6i?)-2-(4-bromobenzyl)-5,6-bis(4-bromophenyl)-4-met hylmorpholin-3-one;

(25',5i?,65)-5,6-bis(4-bromophenyl)-2-(4-fluorobenzyl)-4-met hylmorpholin-3-one;

(2i?,55',6i?)-5,6-bis(4-bromophenyl)-2-(4-fluorobenzyl)-4 -methylmorpholin-3-one;

(25',5i?,65)-5,6-bis(4-bromophenyl)-2-(4-methoxybenzyl)-4-me thylmorpholin-3-one; (2i?,55',6i?)-5,6-bis(4-bromophenyl)-2-(4-methoxybenzyl)-4-m ethylmorpholin-3-one;

(2S,5R,6S)-5,6-bis(4-bromophenyl)-4-methyl-2-^^

3 -one;

(2i?,55',6i?)-5,6-bis(4-bromophenyl)-4-methyl-2-(4-(trifluor omethoxy)benzyl)morpholm 3 -one;

(25',5i?,65)-5,6-bis(4-bromophenyl)-2-(3-methoxybenzyl)-4-me thylmorpholin-3-one;

(2i?,55',6i?)-5,6-bis(4-bromophenyl)-2-(3-methoxybenzyl)- 4-methylmorpholin-3-one;

(i?)-2-((2 _l S,5i?,65)-2-(4-fluorobenzyl)-5,6-bis(4-chlorophenyl)-3 - oxomorpholino)pentanoic acid;

(5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-methylmo rpholin-3-one;

(55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-methylmorp holin-3-one;

(5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)morpholin-3-one;

(55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclop ropylmethyl)morpholin-3-one;

(25',5i?,65)-2-benzyl-6-(3-chlorophenyl)-5-(4-chloropheny l)-4-methylmorpholin-3-one; (2i?,55',6i?)-2-benzyl-6-(3-chlorophenyl)-5-(4-chlorophenyl) -4-methylmorpholin-3-one;

(25 ^* ,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-2-((5)-2,3- dihydroxypropyl)morpholin-3-one;

(25 ^* ,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-2-((i?)-2,3- dihydroxypropyl)morpholin-3-one;

(2^,5^,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-2-((5)-2,3- dihydroxypropyl)morpholin-3-one;

(25 ^* ,55 ^* ,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-2-((i?)-2,3- dihydroxypropyl)morpholin-3-one;

(2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cy clopropylmethyl)-3- oxomorpholin-2-yl)acetaldehydeacetaldehyde;

(2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)acetaldehydeacetaldehyde;

(25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclop ropylmethyl)-2-(2- hydroxyethyl)morpholin-3 -one;

(2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cy clopropylmethyl)-2-(2- hydroxyethyl)morpholin-3 -one; (2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cy clopropylmethyl)-3- oxomorpholin-2-yl)acetic acid;

(2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)acetic acid;

(25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lopropylmethyl)-2-(2- (methylamino)ethyl)morpholin-3-one;

(2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-2-(2- (methylamino)ethyl)morpholin-3-one;

(25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclop ropylmethyl)-2-(3- hydroxypropyl)morpholin-3-one;

(2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-2-(3- hydroxypropyl)morpholin-3-one;

3-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lopropylmethyl)-3- oxomorpholin-2-yl)propanoic acid;

3-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-3- oxomorpholin-2-yl)propanoic acid;

2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lopropylmethyl)-3- oxomorpholin-2-yl)acetic acid;

2-((2i?,55',6i?)-6-(3-chlophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-3- oxomorpholin-2-yl)acetic acid;

2-((25 ^* ,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycl obutylmethyl)-3- oxomorpholin-2-yl)acetic acid;

2-((2i?,55 ^* ,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclobu tylmethyl)-3- oxomorpholin-2-yl)acetic acid;

(2S,5i?,65)-6-(3-chlorophenyl)-5-(4-cM

acid;

(2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-isobut yl-3-oxomorpholin-2- yl)acetic acid;

2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lohexylmethyl)-3- oxomorpholin-2-yl)acetic acid; 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cy clohexylmethyl)-3- oxomorpholin-2-yl)acetic acid;

2-((25',5i?,65)-4-benzyl-6-(3-chlorophenyl)-5-(4-chloropheny l)-3-oxomorpholin-2- yl)acetic acid;

2-((2i?,55',6i?)-4-benzyl-6-(3-chlorophenyl)-5-(4-chlorop henyl)-3-oxomorpholin-2- yl)acetic acid;

(i?)-2 (25 ^* ,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5- oxomorpholino)-N- (methylsulfonyl)pentanamide;

(5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzy l)-5-oxomorpholino)-N- (methylsulfonyl)pentanamide;

l-((i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)pentanoyl)azetidine-3-carboxylic acid;

l-((5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-fluor obenzyl)-5- oxomorpholino)pentanoyl)azetidine-3-carboxylic acid;

(i?)-2 (2^,3i?,65)-2-(4-chloro-3-fluorophenyl)-3-(4-chlorophenyl)-6 -(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid;

(5)-2-((2i?,3S,6i?)-2-(4-chloro-3-fluorophenyl)-3-(4-chlorop henyl)-6-(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid;

(5)-2-((2^,3i?,65)-2-(4-chloro-3-fluorophenyl)-3-(4-chloroph enyl)-6-(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid;

(i?)-2 (2i?,3S,6i?)-2-(4-chloro-3-fluorophenyl)-3-(4-chlorophenyl)- 6-(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid;

(i?)-2-((2 _l S,3i?,65)-2-(4-chloro-2-methylphenyl)-3-(4-chloropheny l)-6-(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid;

(5)-2-((2i?,3S,6i?)-2-(4-chloro-2-methylphenyl)-3-(4-chlo rophenyl)-6-(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid;

(5)-2-((2 _l S,3i?,65)-2-(4-chloro-2-methylphenyl)-3-(4-chloropheny l)-6-(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid;

(i?)-2 (2i?,3S,6i?)-2 4-chloro-2-methylphenyl)-3-(4-chlorophenyl)-6-(4-fluorobenzy l)-5- oxomorpholino)pentanoic acid; (i?)-4-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)heptanoic acid;

(5)-4-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzy l)-5- oxomorpholino)heptanoic acid;

4-((i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)pentanamido)butanoic acid;

3- ((i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)pentanamido)propanoic acid;

(i?)-N-(2-amino-2-oxoethyl)-2 (25 ^* ,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5^ oxomorpholino)pentanamide;

(5)-N-(2-amino-2-oxoethyl)-2-((2i?,3S,6i?)-2,3-bis(4-chlorop henyl)-6-(4-cyanobenzyl)-5- oxomorpholino)pentanamide;

4- (((2 _l S,5i?,65)-4-((i?)-l-(lH-tetrazol-5-yl)butyl)-5,6-bis(4 -chlorophenyl)-3- oxomorpholin-2-yl)methyl)-2-fluorobenzonitrile;

(2 _l S,5i?,65)-4-((i?)-l-(lH-tetrazol-5-yl)butyl)-5,6-bis(4 -chlorophenyl)-2-(4- iodobenzyl)morpholin-3-one;

(2i?,5 _l S,6i?)-4-((5)-l-(lH-tetrazol-5-yl)butyl)-5,6-bis(4-chl orophenyl)-2-(4- iodobenzyl)morpholin-3-one;

(i?)-2-((25',3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)pe ntanoic acid;

(5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-fluorobe nzyl)-5- oxomorpholino)pentanoic acid;

(2i?,55',6i?)-5,6-bis(4-chlorophenyl)-4-methyl-2-(2-morpholi noethyl)morph^

(25',5i?,65)-5,6-bis(4-chlorophenyl)-4-methyl-2-(2-morpho linoethyl)morph^

(2i?,55',6i?)-5,6-bis(4-chlorophenyl)-4-methyl-2-(pyridin -4-ylmethyl)morphoi

(25',5i?,65)-5,6-bis(4-chlorophenyl)-4-methyl-2-(pyridin- 4-ylmethyl)morph^

(5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-5-oxo-6-(pyri din-4- ylmethyl)morpholino)pentanoic acid;

(i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-5-oxo-6-(pyridin-4- ylmethyl)morpholino)pentanoic acid;

(i?)-2-((25',3i?)-2-(4-chlorophenyl)-3-(lH-indol-2-yl)-5- oxomorpholino)pentanoic acid; (5)-2-((2i?,3S)-2-(4-Chlorophenyl)-3-(lH-indol-2-yl)-5-oxomo rpholino)pentanoic acid; (i?)-2-((25',5i?,65)-2-benzyl-5,6-bis(4-chlorophenyl)-3-oxom orpholino)pentanoic acid; (i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(2-cyano-4-fluorob enzyl)-5- oxomorpholino)pentanoic acid;

(i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(2-cyanobenzyl)-5- oxomorpholino)pentanoic acid;

(i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(2-fluorobenzyl)-5 - oxomorpholino)pentanoic acid;

(i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-fluorobenzyl)-5 - oxomorpholino)pentanoic acid;

(i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-cyanobenzyl)-5- oxomorpholino)pentanoic acid;

(^)-2-((2^,3^,65)-2,3^ί8(4-ΰ1ι1θΓορ1 6η 1)-6-(3-(ηΐ6 ΐ8υ1&η 1^εηζ 1)-5- oxomorpholino)pentanoic acid;

(^)-2-((2^,3^,65)-2,3^ί8(4-ΰ1ι1θΓορ1 6η 1)-6-(2-(ηΐ6 ΐ8υ1&η 1^εηζ 1)-5- oxomorpholino)pentanoic acid;

(i?)-2 (2^,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-fluoro-2-(methylsul fonyl)benzyl)-5- oxomorpholino)pentanoic acid;

(i?)-2 (2^,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-fluoro-4-(methylsul fonyl)benzyl)-5- oxomorpholino)pentanoic acid;

(^)-2-((2^,3^,65)-2,3^ί8(4-ΰ1ι1θΓορ1 6η 1)-6-(4-(ηΐ6 ΐ8υ1&η 1^εηζ 1)-5- oxomorpholino)pentanoic acid;

(i?)-2-((2^3i?,65)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4- ((trifluoromethyl)sulfonyl)benzyl)morpholino)pentanoic acid;

(R)-2 (2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4- ((trifluoromethyl)sulfonyl)benzyl)morpholino)pentanoic acid;

(i?)-2-((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-morpholino propyl)-5- oxomorpholino)pentanoic acid;

(25 ^* ,5i?,65)-5,6-bis(4-chlorophenyl)-4-(2-chloropyridin-4- yl)-2-(4- fluorobenzyl)morpholin-3 -one;

(2i?,5 _l S,6i?)-5,6-bis(4-chlorophenyl)-4-(2-chloropyridin-4-yl )-2-(4- fluorobenzyl)morpholin-3 -one; (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-ph enylmorpholin-3-one;

(2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)- 4-phenylmorpholin-3-one;

(25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4 -(lH-pyrazol-4-yl)morpholin- one;

(2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)- 4-(lH-pyrazol-4-yl)morpholin- one;

(2S,5i?,65)-5,6-bis(4-chlorophenyl)-2-(4-fl

(2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-( pyridin-4-yl)morpholin-3 (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4-(methylsulfonyl)be nzyl)-4-(pyridin-3- yl)morpholin-3-one;

(2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-(methylsulfonyl)b enzyl)-4-(pyridin-3- yl)morpholin-3 -one;

(25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(2-fluoro-4-(methylsu lfonyl)benzyl)-4-(pyridin-3- yl)morpholin-3 -one;

(2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(2-fluoro-4-(meth ylsulfonyl)benzyl)-4-(pyridin-3- yl)morpholin-3 -one;

(25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclop ropylmethyl)-2-(2-(4- methylpiperazin- 1 -yl)-2-oxoethyl)morpholin-3 -one;

(2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-2-(2-(4- methylpiperazin-l-yl)-2-oxoethyl)morpholin-3-one;

2- ((2S,5R,6S)-4-((R)- 1 -amino- 1 -oxopentan-2-yl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-

3- oxomorpholin-2-yl)acetic acid;

2- ((2R,5S,6R)-4-((S)- 1 -amino- 1 -oxopentan-2-yl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-

3- oxomorpholin-2-yl)acetic acid;

2-((25 ^* ,5i?,65)-4-((5)-l-amino-l-oxopentan-2-yl)-6-(3-chlorop henyl)-5-(4-chlorophenyl)- 3-oxomorpholin-2-yl)acetic acid;

2- ((2i?,55',6i?)-4-((i?)-l-amino-l-oxopentan-2-yl)-6-(3-chloro phenyl)-5-(4-chlorophenyl)-

3- oxomorpholin-2-yl)acetic acid;

2-((2 _l S,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((i? )-l-cyanobutyl)-3- oxomorpholin-2-yl)acetic acid; 2-((2i?,5 _l S,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5)-l- cyanobutyl)-3- oxomorpholin-2-yl)acetic acid;

2-((2 _l S,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-cyanobutyl)-3- oxomorpholin-2-yl)acetic acid;

2-((2i?,5 _l S,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((i?)-l -cyanobutyl)-3- oxomorpholin-2-yl)acetic acid;

2-((25,5R,6S)-4-((R) -(lH-tetrazol-5-yl)butyl)-6-(3-cMoro^^

oxomorpholin-2-yl)acetic acid;

2-((2i?,5^,6i?)-4-((5)-l-(lH-tetrazol-5-yl)butyl)-6-(3-chlor ophenyl)-5-(4-chlorophenyl)-3^ oxomorpholin-2-yl)acetic acid;

2-((2^,5i?,65)-4-((5)-l-(lH-tetrazol-5-yl)butyl)-6-(3-chloro phenyl)-5-(4-chlorophenyl)-3 oxomorpholin-2-yl)acetic acid;

2- ((2i?,5^,6i?)-4-((i?) -(lH-tetrazol-5-yl)butyl)-6-(3-chlorophenyl)-5-(4-chlorophen y

3- oxomorpholin-2-yl)acetic acid;

2-((2^,5^,65)-6-(3-ΰΜθΓορ1ΐ6η 1)-5-(4-ΰ1ι1θΓορ1ΐ6η 1)-4-((^)-1-(5-ηΐ6 1-1,3,4- oxadiazol-2-yl)butyl)-3-oxomorpholin-2-yl)acetic acid;

2-((2^,5^,6^)-6-(3-ΰΜθΓορ1ΐ6η 1)-5-(4-ΰ1ι1θΓορ1ΐ6η 1)-4-((5)-1-(5-ηΐ6 1-1,3,4- oxadiazol-2-yl)butyl)-3-oxomorpholin-2-yl)acetic acid;

2-((2^,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5)- l-(5-methyl-l,3,4-oxadiazol- 2-yl)butyl)-3-oxomorpholin-2-yl)acetic acid;

2-((2^,5^,6^)-6-(3-ΰΜθΓορ1ΐ6η 1)-5-(4-ΰ1ι1θΓορ1ΐ6η 1)-4-((^)-1-(5-ηΐ6 1-1,3,4- oxadiazol-2-yl)butyl)-3-oxomorpholin-2-yl)acetic acid;

2-((25 ^* ,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((i?) -cyclopropyl(5-methyl-l,3,4- oxadiazol-2-yl)methyl)-3-oxomorpholin-2-yl)acetic acid;

2-((2i?,5^,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-( (5)-cyclopropyl(5-methyl-l,3,4- oxadiazol-2-yl)methyl)-3-oxomorpholin-2-yl)acetic acid;

2-((2^,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5)- cyclopropyl(5-methyl-l,3,4- oxadiazol-2-yl)methyl)-3-oxomorpholin-2-yl)acetic acid;

2-((2i?,55 ^* ,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((i?)-cy clopropyl(5-methyl-l,3,4- oxadiazol-2-yl)methyl)-3-oxomorpholin-2-yl)acetic acid; (5)-2-((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl )-5-oxomorpholino)-2- cyclopropylacetic acid;

(i?)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzy l)-5-oxomorpholino)-2- cyclopropylacetic acid;

(i?)-2-((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobe nzyl)-5-oxomorpholino)-2- cyclopropylacetic acid;

(5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl )-5-oxomorpholino)-2- cyclopropylacetic acid;

(5)-2-((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl )-5-oxomorpholino)-2- cyclopropylacetic acid;

(i?)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzy l)-5-oxomorpholino)-2- cyclopropylacetic acid;

(i?)-2-((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzy l)-5-oxomorpholino)-2- cyclopropylacetic acid;

(5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-cyanoben zyl)-5-oxomorpholino)-2- cyclopropylacetic acid;

(5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)thiomorpholin-3- one;

(5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)-2,2- dimethylthiomorpholin-3 -one 1,1 -dioxide;

(5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-isopropylth iomorpholin-3-one;

2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-i sopropyl- 1 , 1 -dioxido-3- oxothiomorpholin-2-yl)acetic acid;

2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-isopro pyl-l,l-dioxido-3- oxothiomorpholin-2-yl)acetic acid;

2-((2 _l S,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-hydroxybutan-2-yl)-3- oxomorpholin-2-yl)acetic acid;

2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-hydroxybutan-2-yl)-3- oxomorpholin-2-yl)acetic acid;

2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-( (5)- 1 -hydroxybutan-2-yl)-3- oxomorpholin-2-yl)acetic acid; 2-((2 _l S,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-hydroxybutan-2-yl)-3- oxomorpholin-2-yl)acetic acid;

(25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)morph olin-3-one;

(2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)m orpholin-3-one; or

2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-( cyclopropylmethyl)-5-methyl-3- oxomorpholin-2-yl)acetic acid.

In embodiment 44, the present invention provides the compounds, or a pharmaceutically acceptable salts, selected from:

1,1 -dimethylethyl (2R,3S)-2,3-bis(4-bromophenyl)-5-oxo- 1 -piperazinecarboxylate;

1 , 1 -dimethylethyl (2S,3R)-2,3-bis(4-bromophenyl)-5-oxo- 1 -piperazinecarboxylate;

(2R,5S,6R)-5,6-bis(4-bromophenyl)-4-methyl-2-(2-propen-l- yl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-bromophenyl)-4-methyl-2-(2-propen-l-yl) -3-morpholinone;

(5R,6S)-5,6-bis(4-bromophenyl)-4-cyclopropyl-3-morpholinone;

(5S,6R)-5,6-bis(4-bromophenyl)-4-cyclopropyl-3-morpholino ne

(2S,5R,6S)-5,6-bis(4-bromophenyl)-2,4-dimethyl-3-morpholinon e;

(2R,5R,6S)-5,6-bis(4-bromophenyl)-2,4-dimethyl-3-morpholinon e;

(2R,5S,6R)-5,6-bis(4-bromophenyl)-4-cyclopropyl-2-(phenylmet hyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-bromophenyl)-4-cyclopropyl-2-(phenyl methyl)-3-morpholinone; (2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-(methylsulfo nyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-(methylsulfo nyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2R,5S,6R)-5,6-bis(4-bromophenyl)-4-methyl-2-phenyl-3-morpho linone;

(2S,5R,6S)-5,6-bis(4-bromophenyl)-4-methyl-2-phenyl-3-mor pholinone;

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyano-3-f luorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)glycine;

(5R,6S)-5 ,6-bis(4-bromophenyl)- 1 -methyl-4-(phenylmethyl)-2-piperazinone;

(5S,6R)-5,6-bis(4-bromophenyl)-l-methyl-4-(phenylmethyl)- 2-piperazinone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(3-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoic acid; (2R,5S,6R)-5,6-bis(4-bromophenyl)-4-methyl-2-(3-methyl-2-but en-l-yl)-3- morpholinone;

(2S,5R,6S)-5,6-bis(4-bromophenyl)-4-methyl-2-(3-methyl-2-but en-l-yl)-3- morpholinone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyano-3-f luorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(5R,6S)-5,6-bis(4-bromophenyl)-4-(phenylmethyl)-2-piperazino ne;

(5S,6R)-5,6-bis(4-bromophenyl)-4-(phenylmethyl)-2-piperaz inone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl) -5-oxo-4- morpholinyl)pentanoic acid;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-2-hydroxy-l-phenylet hyl)-3-morpholinone;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lS)-2-hydroxy-l-pheny lethyl)-3-morpholinone; (5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)-2-hydroxy- 1 -phenylethyl)-3-morpholinone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-((lS)-2-hydroxy-l-pheny lethyl)-3-morpholinone;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-3-phenylpropanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-3-phenylpropanoic acid;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-3-phenylpropanoic acid; (2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -3-phenylpropanoic acid;

(5R,6S)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 -(hydroxymethyl)butyl)-3-morpholinone;

(5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 S)- 1 -(hydroxymethyl)butyl)-3-morpholinone;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lS)-l-(hydroxymethyl) butyl)-3-morpholinone;

(5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 -(hydroxymethyl)butyl)-3-morpholinone (2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2-methoxybenzy l)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl)(4 -chlorophenyl)ethanoic acid;

(2S)-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl)(4 -chlorophenyl)ethanoic acid; (2S)-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl)(4 -chlorophenyl)ethano acid;

(2R)-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl)(4 -chlorophenyl)ethanoi acid;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-3-phenylpropanoic acid; (2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -3-phenylpropanoic acid; (2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -3-phenylpropanoic acid; (2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -3-phenylpropanoic acid (2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lS )-l- (hydroxymethyl)butyl)-3 -morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lR )-l- (hydroxymethyl)butyl)-3-morpholinone;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lR )-l- (hydroxymethyl)butyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-( (lS)-l-(hydroxymethyl)butyl)- 3 -morpholinone;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-l-(4-chlorophenyl)-2 -hydroxyethyl)-3- morpholinone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-((l S)-l-(4-chlorophenyl)-2-hydroxyethyl)-3- morpholinone;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((l S)-l-(4-chlorophenyl)-2-hydroxyethyl)-3- morpholinone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-((lR)-l-(4-chlorophenyl)-2 -hydroxyethyl)-3- morpholinone;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-l-(l-hydroxy-l-me thylethyl)butyl)-3- morpholinone;

(5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 S)- 1 -( 1 -hydroxy- 1 -methylethyl)butyl)-3 - morpholinone;

(5R,6S)-5 ,6-bis(4-chlorophenyl)-4-(( 1 S)- 1 -(1 -hydroxy- 1 -methylethyl)butyl)-3- morpholinone; (5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 - ( 1 -hydroxy- 1 -methylethyl)butyl)-3 - morpholinone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentanamide;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentanamide;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentanamide;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentanamide;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-( (lR)-l-

(hydroxymethyl)butyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lS )-l-(hydroxymethyl)butyl)- 3 -morpholinone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentyl carbamate;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentyl carbamate;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentyl carbamate;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentyl carbamate;

(2R)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(3,4-dichlorophen yl)-6-(4-fluorobenzyl)-5-oxo- 4-morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl) -6-(4-fluorobenzyl)-5-oxo- 4-morpholinyl)pentanoic acid; (2S)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl) -6-(4-fluorobenzyl)-5-oxo- 4-morpholinyl)pentanoic acid;

(2R)-2-((2R,3S,6R)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl) -6-(4-fluorobenzyl)-5- oxo-4-morpholinyl)pentanoic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-3 -oxo-2- morpholinyl)acetic acid;

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l- methylbutyl)-3-oxo-2- morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS) -l-methylbutyl)-3-oxo-2- morpholinyl)acetic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l- methylbutyl)-3-oxo-2- morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l- methylbutyl)-3-oxo-2- morpholinyl)acetic acid;

(2R)-2-((2S,3R)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanamide;

(2S)-2-((2R,3S)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanamide;

(2S)-2-((2S,3R)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl) -5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2R,3S)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanamide;

(2R)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)(4- chlorophenyl)ethanoic acid; (2S)-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)(4- chlorophenyl)ethanoic acid;

(2S)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)(4- chlorophenyl)ethanoic acid;

(2R)-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzy l)-5-oxo-4-morpholinyl)(4- chlorophenyl)ethanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-2- (4-chlorophenyl)ethanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-2- (4-chlorophenyl)ethanamide;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-2- (4-chlorophenyl)ethanamide;

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-2- (4-chlorophenyl)ethanamide;

methyl 4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-(methyls ulfonyl)benzyl)-5- oxo-4-morpholinyl)pentanoyl)amino)butanoate;

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2R)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2S)-2,3- dihydroxypropyl)-5 -oxo-4-morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2R)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2S)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-((2S)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2R)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2S)-2,3- dihydroxypropyl)-5 -oxo-4-morpholinyl)pentanamide; (2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2R)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-2-(4- chlorophenyl)ethanamide;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-2-(4- chlorophenyl)ethanamide;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -2-(4- chlorophenyl)ethanamide;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -2-(4- chlorophenyl)ethanamide;

(2R)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl) -6-(4-fluorobenzyl)-5-oxo- 4-morpholinyl)pentanamide;

(2S)-2-((2R,3S,6S)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl) -6-(4-fluorobenzyl)-5-oxo- 4-morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(3,4-dichlorophen yl)-6-(4-fluorobenzyl)-5-oxo- 4-morpholinyl)pentanamide;

(2R)-2-((2R,3S,6S)-3-(4-chlorophenyl)-2-(3,4-dichlorophenyl) -6-(4-fluorobenzyl)-5-oxo- 4-morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2-(4-methyl-l- piperazinyl)ethyl)-5-oxo- 4-morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-methylpentanamide;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-N-methylpentanamide;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-N-methylpentanamide;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-N-methylpentanamide; (2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-(2- hydroxyethyl)pentanamide;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-(2- hydroxyethyl)pentanamide;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-(2- hydroxyethyl)pentanamide; (2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-(2- hydroxyethyl)pentanamide;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N,N- dimethylpentanamide;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-N,N- dimethylpentanamide;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N,N- dimethylpentanamide;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N,N- dimethylpentanamide;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-(2-(4- morpholinyl)ethyl)pentanamide;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-(2-(4- morpholinyl)ethyl)pentanamide;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-N-(2-(4- morpholinyl)ethyl)pentanamide;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-(2-(4- morpholinyl)ethyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(3-(lH-imidazol -l-yl)propyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -N-propylpentanamide;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-N-propylpentanamide;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-N-propylpentanamide;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-N-propylpentanamide; (5R,6S)-4-((lR)-l-(aminomethyl)butyl)-5,6-bis(4-chlorophenyl )-3-morpholinone;

(5 S ,6R)-4-(( 1 S)-l -(aminomethyl)butyl)-5 ,6-bis(4-chlorophenyl)-3 -morpholinone;

(5R,6S)-4-((lS)-l-(aminomethyl)butyl)-5,6-bis(4-chlorophenyl )-3-morpholinone;

(5S,6R)-4-((lR)-l-(aminomethyl)butyl)-5,6-bis(4-chlorophenyl )-3-morpholinone;

(2R)-2-((2S,3R,6S)-2-(4-chloro-3-fluorophenyl)-3-(4-chloroph enyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)pentanamide; (2S)-2-((2R,3S,6R)-2-(4-chloro-3-fluorophenyl)-3-(4-chloroph enyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2-(4-chloro-3-fluorophenyl)-3-(4-chloroph enyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)pentanamide;

(2R)-2-((2R,3S,6R)-2-(4-chloro-3-fluorophenyl)-3-(4-chlor ophenyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6-(2-propen -l-yl)-4- morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(2-propen -l-yl)-4- morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6-(2-propen -l-yl)-4- morpholinyl)pentanamide;

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(2-propen -l-yl)-4- morpholinyl)pentanamide;

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)pentanoic acid;

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentyl)-2- hydroxyacetamide;

N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpho linyl)pentyl)-2- hydroxyacetamide;

N-((2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentyl)-2- hydroxyacetamide;

N-((2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentyl)-2- hydroxyacetamide; (2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(3-methoxybenzy l)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2-(4-chloro-2-methylphenyl)-3-(4-chloropheny l)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2-(4-chloro-2-methylphenyl)-3-(4-chloroph enyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2-(4-chloro-2-methylphenyl)-3-(4-chloropheny l)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2R,3S)-2-(4-chloro-2-methylphenyl)-3-(4-chloropheny l)-5-oxo-4- morpholinyl)pentanoic acid;

(3R)-3-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6-(2-propen -l-yl)-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(2-pro pen-l-yl)-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2R)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-((2R)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-((2R)-2,3-di hydroxypropyl)-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanamide; (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2R)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-((2R)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3-di hydroxypropyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2R)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3-dihyd roxypropyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,5R,6S)-2-(2-amino-2-oxoethyl)-5,6-bis(4-chloroph enyl)-3-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,5S,6R)-2-(2-amino-2-oxoethyl)-5,6-bis(4-chloroph enyl)-3-oxo-4- morpholinyl)pentanoic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS) -l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l- (((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo-2- morpholinyl)acetic acid; ((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l- (((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo-2- morpholinyl)acetic acid; ((2R,5 S ,6R)-4-(( 1 S)- 1 -carbamoylbutyl)-5 ,6-bis(4-chlorophenyl)-3 -oxo-2- morpholinyl)acetic acid;

((2S,5R,6S)-4-((lR)-l-carbamoylbutyl)-5,6-bis(4-chlorophenyl )-3-oxo-2- morpholinyl)acetic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS) -l-(ethoxycarbonyl)butyl)-3- oxo-2-morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l- (ethoxycarbonyl)butyl)-3- oxo-2-morpholinyl)acetic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l- (ethoxycarbonyl)butyl)-3- oxo-2-morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l- (ethoxycarbonyl)butyl)-3- oxo-2-morpholinyl)acetic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-N- (2-(4-morpholinyl)ethyl)pentanamide;

(2S)-2 (2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxo- 4-morpholinyl)-N- (2-(4-morpholinyl)ethyl)pentanamide;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-l-(4-morpholinylmeth yl)butyl)-3- morpholinone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-((l S)-l-(4-morpholinylmethyl)butyl)-3- morpholinone;

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentyl)methanesulfonamide; N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentyl)methanesulfonamide;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(( IS)- 1 -((4-methyl- 1- piperazinyl)carbonyl)butyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-( (lR)-l-((4-methyl-l- piperazinyl)carbonyl)butyl)-3-morpholinone;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lS )-l-(4- morpholinylcarbonyl)butyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lR )-l-(4- morpholinylcarbonyl)butyl)-3 -morpholinone;

(2R,5 S,6R)-4-(( 1 S)- 1 -(aminomethyl)butyl)-5 ,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)- 3 -morpholinone;

(2S,5R,6S)-4-((lR)-l-(aminomethyl)butyl)-5,6-bis(4-chlorophe nyl)-2-(4-fluorobenzyl)- 3 -morpholinone;

(5R,6S)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methyl-3-morph olinone;

(5S,6R)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methyl-3-morph olinone;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylsulfonyl)-3-oxo-2- morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylsulfonyl)-3-oxo-2- morpholinyl)acetic acid;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lS )-l-(4- morpholinylmethyl)butyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lR )-l-(4- morpholinylmethyl)butyl)-3-morpholinone;

(2R)-2-((2S,3R,6S)-3-(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-2-phenyl-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-3-(4-chlorophenyl)-6-(4-fluorobenzyl)-5-o xo-2-phenyl-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R,6S)-3-(4-chlorophenyl)-6-(4-fluorobenzyl)-5-o xo-2-phenyl-4- morpholinyl)pentanoic acid; (2R)-2-((2R,3S,6R)-3-(4-chlorophenyl)-6-(4-fluorobenzyl)-5-o xo-2-phenyl-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2-(4-morpholin yl)ethyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzy l)-5-oxo-4- morpholinyl)(phenyl)ethanoic acid;

(2S)-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4- morpholinyl)(phenyl)ethanoic acid;

(2S)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4- morpholinyl)(phenyl)ethanoic acid;

(2R)-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4- morpholinyl)(phenyl)ethanoic acid;

(2R)-2-((2S,3R)-2-(4-chlorophenyl)-3-(3,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2-(4-chlorophenyl)-3-(3,4-dichlorophenyl) -5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2-(4-chlorophenyl)-3-(3,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2R,3S)-2-(4-chlorophenyl)-3-(3,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanoic acid;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(l-methyleth yl)-3-thiomorphoi^^ 1,1 -dioxide;

(2R)-2-((2S,3R,6S)-2 3-chlorophenyl)-3-(4-chlorophenyl)-6-(2-(4-morpholinyl)-2- oxoethyl)-5-oxo-4-morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-(2-(4-morpholinyl)-2- oxoethyl)-5-oxo-4-morpholinyl)pentanoic acid;

(2S)-2 (2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(2-(4-mor pholinyl)-2- oxoethyl)-5-oxo-4-morpholinyl)pentanoic acid;

(2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 2-(4-morpholinyl)-2- oxoethyl)-5-oxo-4-morpholinyl)pentanoic acid; (2R)-2-((2S,3R)-3-(4-bromophenyl)-2-(4-chlorophenyl)-5-oxo-4 -morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-3-(4-bromophenyl)-2-(4-chlorophenyl)-5-oxo-4 -morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-3-(4-bromophenyl)-2-(4-chlorophenyl)-5-ox o-4-morpholinyl)pentanoic acid;

(2R)-2-((2R,3S)-3-(4-bromophenyl)-2-(4-chlorophenyl)-5-oxo-4 -morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6-(2-(l-pip eridinyl)ethyl)-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2-(4-chlorophenyl)-3-(4-cyclopropylphenyl)-5 -oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2-(4-chlorophenyl)-3-(4-cyclopropylphenyl)-5 -oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2-(4-chlorophenyl)-3-(4-cyclopropylphenyl )-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2R,3S)-2-(4-chlorophenyl)-3-(4-cyclopropylphenyl)-5 -oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-3-(4-bromophenyl)-2-(4-chlorophenyl)-6-(4 -fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-3-(4-bromophenyl)-2-(4-chlorophenyl)-6-(4 -fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R,6S)-3-(4-bromophenyl)-2-(4-chlorophenyl)-6-(4 -fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2R,3S,6R)-3-(4-bromophenyl)-2-(4-chlorophenyl)-6 -(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

2-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzonitrile;

2-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzonitrile; (2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2-fluoro-4-(me thylsulfonyl)benzyl)-5- oxo-4-morpholinyl)pentanoic acid

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(2-fluoro-4-(me thylsulfonyl)benzyl)-5- oxo-4-morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)hexanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)hexanoic acid;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)hexanoic acid;

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4- morpholinyl)hexanoic acid;

(2R,5 S,6R)-5 ,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(( 1 S)- 1 -( 1 H-tetrazol-5 - yl)butyl)-3 -morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((lR )-l-(lH-tetrazol-5- yl)butyl)-3 -morpholinone;

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluoro benzyl)-5-oxo-4- morpholinyl)pentanoyl)glycine;

N-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoyl)glycine;

(2R)-2-((2S,3R,6S)-3-(4-bromophenyl)-2-(4-chlorophenyl)-6-(4 -cyanobenzyl)-5-oxo-4- morpholinyl)pentanoic acid; (2S)-2-((2R,3S,6R)-3-(4-bromophenyl)-2-(4-chlorophenyl)-6-(4 -cyanobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

3-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3-oxo-2- morpholinyl)propanenitrile;

3-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cy clopropylmethyl)-3-oxo-2- morpholinyl)propanenitrile;

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-3-oxo-2- morpholinyl)acetic acid;

2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cy clopropylmethyl)-3-oxo-2- morpholinyl)-N-(2-(4-morpholinyl)ethyl)acetamide;

2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3-oxo-2- morpholinyl)-N-(2-(4-morpholinyl)ethyl)acetamide;

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4-f luorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4-f luorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4-f luorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(S)-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid;

(R)-2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid; (R)-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid;

(S)-2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid;

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-((2S)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2R)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2S)-2,3- dihydroxypropyl)-5 -oxo-4-morpholinyl)pentanamide;

(2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2R)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2R)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-((2S)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2S)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2R)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanamide;

(2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( (2S)-2,3- dihydroxypropyl)-5 -oxo-4-morpholinyl)pentanamide;

((2R,5S,6R)-6-(3-chloro-2-fluorophenyl)-5-(4-chlorophenyl)-4 -(cyclopropylmethyl)-3- oxo-2-morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chloro-2-fluorophenyl)-5-(4-chlorophenyl)-4 -(cyclopropylmethyl)-3- oxo-2-morpholinyl)acetic acid;

((2R,5S,6R)-4-butyl-6-(3-chlorophenyl)-5-(4-chlorophenyl) -3-oxo-2-morpholinyl)acetic acid; ((2S,5R,6S)-4-butyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3- oxo-2- morpholinyl)acetic acid;

(2R)-2-((2S,3R)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl) -5-oxo-4- morpholinyl)pentanoic acid; (2S)-2-((2S,3R)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2R,3S)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5- oxo-4- morpholinyl)pentanoic acid;

N'-acetyl-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophe nyl)-4-(cyclopropylmethyl)- 3-0X0-2 -morpholinyl)acetohydrazide;

N'-acetyl-2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl )-4-(cyclopropylmethyl)- 3-0X0-2 -morpholinyl)acetohydrazide;

(2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopro pylmethyl)-2-(2-(4- morpholinyl)-2-oxoethyl)-3-morpholinone;

(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopro pylmethyl)-2-(2-(4- morpholinyl)-2-oxoethyl)-3-morpholinone;

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo- 4- morpholinyl)pentanamide;

(2S)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-o xo-4- morpholinyl)pentanamide;

(2S)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo- 4- morpholinyl)pentanamide;

(2R)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo- 4- morpholinyl)pentanamide;

2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3-oxo-2- morpholinyl)ethyl carbamate;

2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3-oxo-2- morpholinyl)ethyl carbamate;

(2R)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzy l)-5-oxo-4-morpholinyl)(3- chlorophenyl)ethanoic acid;

(2S)-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)(3- chlorophenyl)ethanoic acid;

(2S)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)(3- chlorophenyl)ethanoic acid; (2R)-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)- 5-oxo-4-morpholinyl)(3- chlorophenyl)ethanoic acid;

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; (2R)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl) -6-(4-fluorobenzyl)-5-oxo 4-morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl) -6-(4-fluorobenzyl)-5-oxo 4-morpholinyl)pentanoic acid;

(2S)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl) -6-(4-fluorobenzyl)-5-oxo 4-morpholinyl)pentanoic acid;

(2R)-2-((2R,3S,6R)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl) -6-(4-fluorobenzyl)-5- oxo-4-morpholinyl)pentanoic acid;

4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-(methyls ulfonyl)benzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)butanoic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS) -l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid and ((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l- (((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo-2- morpholinyl)acetic acid; ((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; (S)-2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid;

(R)-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid;

(R)-2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid;

(S)-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid;

3-((2R,3S)-3-(4-chlorophenyl)-4-(cyclopropylmethyl)-5-oxo-2- morpholinyl)benzonitrile; 3-((2S,3R)-3-(4-chlorophenyl)-4-(cyclopropylmethyl)-5-oxo-2- morpholinyl)benzonitrile; (2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid; (2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)glycine;

N-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanob enzyl)-5-oxo-4- morpholinyl)pentanoyl)glycine;

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentanoyl)glycine; N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentanoyl)glycine; 2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3-oxo-2- morpholinyl)-N,N-dimethylacetamide;

2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3-oxo-2- morpholinyl)-N,N-dimethylacetamide;

ethyl (2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(3-(4-morpholin yl)propyl)-5-oxo-4- morpholinyl)pentanoate;

(2R)-2-((2S,3R)-3-(4-chlorophenyl)-2-(4-cyanophenyl)-5-ox o-4-morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-3-(4-chlorophenyl)-2-(4-cyanophenyl)-5-oxo-4 -morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-3-(4-chlorophenyl)-2-(4-cyanophenyl)-5-oxo-4 -morpholinyl)pentanoic acid;

(2R)-2-((2R,3S)-3-(4-chlorophenyl)-2-(4-cyanophenyl)-5-oxo-4 -morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(3-hydroxypropy l)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzy l)-5-oxo-4- morpholinyl)pentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)- 5-oxo-4- morpholinyl)pentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-4- pentenoic acid; (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-4- pentenoic acid;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-4- pentenoic acid;

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4-morpholinyl)-4- pentenoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)- 5-oxo-4- morpholinyl)pentanenitrile;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)- 5-oxo-4- morpholinyl)pentanenitrile;

4-(((2R,5 S,6R)-5 ,6-bis(4-chlorophenyl)-3 -oxo-4-(( 1 S) - 1 -( 1 H-tetrazol-5 -yl)butyl)-2- morpholinyl)methyl)benzonitrile;

4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-3-oxo-4-((lR)-l-(lH-t etrazol-5-yl)butyl)-2- morpholinyl)methyl)benzonitrile;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopro pylmethyl)-3-morpholinone;

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopro pylmethyl)-3-morpholinone;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(((lR,2R) -2- methylcyclopropyl)methyl)-3-morpholinone;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(((lS,2S)-2- methylcyclopropyl)methyl)-3 -morpholinone;

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(((lR,2R)-2- methylcyclopropyl)methyl)-3-morpholinone;

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(((lS,2S)-2- methylcyclopropyl)methyl)-3-morpholinone;

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanob enzyl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine;

N-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine;

N-((2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine; N-((2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine;

N-((2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine;

N-((2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanob enzyl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine;

N-((2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine;

N-((2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine;

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentanoyl)-beta- alanine;

N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentanoyl)-beta- alanine;

N-((2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpho linyl)pentanoyl)-beta- alanine;

N-((2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentanoyl)-beta- alanine;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropyl sulfonyl)-3-morpholinone; (5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropyl sulfonyl)-3-morpholinone; 4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzamide;

4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzamide;

(3R)-3-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid;

(((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholiny l)pentyl)oxy)acetic acid; (((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholiny l)pentyl)oxy)acetic acid; (2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-(methylsulfo nyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid; (2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-(methylsulfo nyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid;

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-morp holinyl)methyl)-2- fluorobenzonitrile;

4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-m orpholinyl)methyl)-2 fluorobenzonitrile;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(4-p yridinyl)-3-morpholinone; (2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(4-p yridinyl)-3-morpholinone; (2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopro pylmethyl)-2-((5-methyl- l,3,4-oxadiazol-2-yl)methyl)-3-morpholinone;

(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopro pylmethyl)-2-((5-methyl- l,3,4-oxadiazol-2-yl)methyl)-3-morpholinone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyano-2-fluo robenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyano-2-f luorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid;

(5R,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-2,2,6-trimethy l-4-(l-methylethyl)-3- thiomorpholinone 1,1 -dioxide;

(5S,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-2,2,6-trimethy l-4 l-methylethy thiomorpholinone 1,1 -dioxide;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-2,2,6-trimethy l-4-(l-methylethyl)-3- thiomorpholinone 1,1 -dioxide;

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-2,2,6-trimethy l-4-(l-methylethyl)-3- thiomorpholinone 1,1 -dioxide;

3-(((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morph olinyl)pentyl)amino)-3- oxopropanoic acid;

3-(((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholi nyl)pentyl)amino)-3- oxopropanoic acid;

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentyl)glycine;

N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpho linyl)pentyl)glycine; ((2R,5S,6R)-6-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4 -(cyclopropylmethyl)-3- oxo-2-morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4 -(cyclopropylmethyl)-3- oxo-2-morpholinyl)acetic acid;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-2-(4-(methyls ulfonyl)benzyl)-3- morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-2-(4-(methylsulf onyl)benzyl)-3- morpholinone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl) -5-oxo-4-morpholinyl)-N- (1 H-tetrazol-5 -ylmethyl)pentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl) -5-oxo-4-morpholinyl)-N- ( 1 H-tetrazol-5 -ylmethyl)pentanamide;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylcarbonyl)-3-oxo-2- morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylcarbonyl)-3-oxo-2- morpholinyl)acetic acid;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropyl methyl)-3- thiomorpholinone 1,1 -dioxide;

2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3-oxo-2- morpholinyl)ethyl methanesulfonate;

2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3-oxo-2- morpholinyl)ethyl methanesulfonate;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl) -5-oxo-4-morpholinyl)-N- (2-( 1 H-tetrazol-5 -yl)ethyl)pentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4-morpholinyl)-N- (2-( 1 H-tetrazol-5 -yl)ethyl)pentanamide;

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentyl)-2-(lH- tetrazol-5-yl)acetamide;

N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentyl)-2-(lH-tetrazol- 5-yl)acetamide; 4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanoben zyl)-5-oxo-4- morpholinyl)pentanoyl)amino)butanoic acid;

4-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanoben zyl)-5-oxo-4- morpholinyl)pentanoyl)amino)butanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoic acid;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(2-(methylsulfanyl)-4-pyri midinyl)-3-morpholm^ (5S,6R)-5,6-bis(4-chlorophenyl)-4-(2-(methylsulfanyl)-4-pyri midinyl)-3-morpholm^ l-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentanoyl)-4- piperidinecarboxylic acid;

l-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpho linyl)pentanoyl)-4- piperidinecarboxylic acid;

(4-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholi nyl)pentanoyl)-l- piperazinyl)acetic acid;

(4-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morph olinyl)pentanoyl)-l- piperazinyl)acetic acid;

(2S)-4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cya nobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2-hydroxybutanoic acid;

(2S)-4-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cya nobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2-hydroxybutanoic acid;

(3R)-4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cya nobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-3 -hydroxybutanoic acid;

(3R)-4-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cya nobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-3 -hydroxybutanoic acid;

(3S)-4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-3 -hydroxybutanoic acid;

(3S)-4-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cya nobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-3 -hydroxybutanoic acid;

(2R)-3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cya nobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2-methylpropanoic acid; (2R)-3-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cya nobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2-methylpropanoic acid;

(2S)-3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cya nobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2-methylpropanoic acid;

(2S)-3-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2-methylpropanoic acid;

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanob enzyl)-5-oxo-4- morpholinyl)pentanoyl)-L-alanine;

N-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)-D-alanine;

(2R)-2-((2R,3S)-2-(4-chlorophenyl)-3-(lH-indol-2-yl)-5-oxo-4 -morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2-(4-chlorophenyl)-3-(lH-indol-2-yl)-5-oxo-4 -morpholinyl)pentanoic acid;

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanob enzyl)-5-oxo-4- morpholinyl)pentanoyl)-D-alanine;

N-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4- morpholinyl)pentanoyl)-L-alanine;

methyl 4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzoate;

methyl 4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzoate;

3- (((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzy l)-5-oxo-4- morpholinyl)pentanoyl)amino)-N-(tert-butoxycarbonyl)-D-alani ne;

3-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyano benzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-N-(tert-butoxycarbonyl)-D-alani ne;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclobut ylmethyl)-3-morpholinone; (5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclobutylm ethyl)-3-morpholinone;

4- (((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzonitrile; 4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzonitrile;

(4-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanoben zyl)-5-oxo-4- morpholinyl)pentanoyl)- 1 -piperazinyl)acetic acid;

(4-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyano benzyl)-5-oxo-4- morpholinyl)pentanoyl)- 1 -piperazinyl)acetic acid;

3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanoben zyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2,2-dimethylpropanoic acid;

3-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanoben zyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2,2-dimethylpropanoic acid;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(2-chloro-4-pyridinyl)-3-m orpholinone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-(2-chloro-4-pyridinyl)-3-m orpholinone;

3-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzamide;

3-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzamide;

3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanoben zyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-D-alanine;

3-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanoben zyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-D-alanine;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-methoxybenzy l)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-methoxybenzy l)-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-o xo-4-morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo- 4-morpholinyl)pentanoic acid;

3-(4-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpho linyl)pentanoyl)-l- piperazinyl)propanoic acid; 3- (4-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholi nyl)pentanoyl)-l- piperazinyl)propanoic acid;

(2R)-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid;

(2S)-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6- (4-fluorobenzyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid;

(2S)-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid;

(2R)-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(l -methyl- lH-imidazo 1-4-yl)- 3 -morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(l -methyl- lH-imidazol-4-yl)- 3 -morpholinone;

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-m orpholinyl)methyl)benzoic acid;

4- (((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-morpho linyl)methyl)benzoic acid;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(2-methylpro pyl)-3-morpholinone; (5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(2-methylpro pyl)-3-morpholinone; l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoyl)-D-proline;

l-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoro benzyl)-5-oxo-4- morpholinyl)pentanoyl)-D-proline;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(2-pyrazinyl)-3-morphol inone;

(5 S,6R)-5,6-bis(4-chlorophenyl)-4-(2-pyrazinyl)-3 -morpholinone;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-(cyclopropylmethyl)- 2-((2R)-2,3- dihydroxypropyl)-3-morpholinone;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-(cyclopropylmethyl)-2-( (2S)-2,3- dihydroxypropyl)-3 -morpholinone; (2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-(cyclopropylmethyl)-2-( (2R)-2,3- dihydroxypropyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-(cyclopropylmethyl)-2-( (2S)-2,3- dihydroxypropyl)-3-morpholinone;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-cyclopent yl-3-morpholinone; (5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-cyclopentyl- 3-morpholinone; methyl l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoyl)-L-prolinate;

methyl l-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoyl)-L-prolinate;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-morpholinone;

l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-iodobe nzyl)-5-oxo-4- morpholinyl)pentanoyl)-4-piperidinecarboxylic acid;

l-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-iodobe nzyl)-5-oxo-4- morpholinyl)pentanoyl)-4-piperidinecarboxylic acid;

(2R)-2-((2S,5R,6S)-2-(4-chlorobenzyl)-5,6-bis(4-chlorophenyl )-3-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,5S,6R)-2-(4-chlorobenzyl)-5,6-bis(4-chlorophenyl )-3-oxo-4- morpholinyl)pentanoic acid;

(2R,5S,6R)-2-(4-(aminomethyl)benzyl)-5,6-bis(4-chlorophen yl)-4-methyl-3- morpholinone;

(2S,5R,6S)-2-(4-(aminomethyl)benzyl)-5,6-bis(4-chlorophenyl) -4-methyl-3- morpholinone;

3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-iodobenz yl)-5-oxo-4- morpholinyl)pentyl)amino)-3-oxopropanoic acid;

3-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-iodobenz yl)-5-oxo-4- morpholinyl)pentyl)amino)-3 -oxopropanoic acid;

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(l,3-thiazol -4-ylmethyl)-3- morpholinone;

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(l,3-thia zol-4-ylmethyl)-3- morpholinone; (5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(2-hydroxy-2 -methylpropyl)-3- morpholinone; (5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(2-hydroxy-2 - methylpropyl)-3 -morpholinone;

(5S,6R)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methyl-3-morpholi none;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((l-c yanocyclopropyl)methyl)-3- oxo-2-morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((l-cyan ocyclopropyl)methyl)-3- oxo-2-morpholinyl)acetic acid;

l-((((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyan obenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)methyl)cyclopentanecarboxylic acid;

l-((((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyan obenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)methyl)cyclopentanecarboxylic acid;

(3S)-3-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid;

(3S)-3-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid;

(2R)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo- 4-morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo- 4-morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo- 4-morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo- 4-morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzy l)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)- 5-oxo-4- morpholinyl)pentanoic acid;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(4-pyridinyl)-3-morpholino ne;

(5 S,6R)-5,6-bis(4-chlorophenyl)-4-(4-pyridinyl)-3 -morpholinone; (2R)-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid;

(2R)-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo -4- morpholinyl)(cyclopropyl)ethanoic acid;

(2S)-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo -4- morpholinyl)(cyclopropyl)ethanoic acid;

(2S)-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo -4- morpholinyl)(cyclopropyl)ethanoic acid;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)pentanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentanoic acid;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) pentanoic acid;

(2R)-2-((2S,5R,6S)-2-(4-biphenylylmethyl)-5,6-bis(4-chloroph enyl)-3-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,5S,6R)-2-(4-biphenylylmethyl)-5,6-bis(4-chlor ophenyl)-3-oxo-4- morpholinyl)pentanoic acid;

ethyl (2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyano-2-fluo robenzyl)-5-oxo-4- morpholinyl)pentanoate;

ethyl (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyano-2-fluo robenzyl)-5-oxo-4- morpholinyl)pentanoate;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-((dimethylamino)meth yl)benzyl)-4-methyl-3- morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-((dimethylamino)meth yl)benzyl)-4-methyl-3- morpholinone;

(5R,6S)-5,6-bis(4-chlorophenyl)-6-methyl-3-morpholinone and (5S,6R)-5,6-bis(4- chlorophenyl)-6-methyl-3-morpholinone

(2R)-2-((2S,5R,6S)-2-(4-carbamoylbenzyl)-5,6-bis(4-chlorophe nyl)-3-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,5S,6R)-2-(4-carbamoylbenzyl)-5,6-bis(4-chlorophe nyl)-3-oxo-4- morpholinyl)pentanoic acid; (2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4-(lH-py razol-l-yl)benzyl)-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4-(lH-py razol-l-yl)benzyl)-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4-(lH -pyrrol-l-yl)benzyl)-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4-(lH-py rrol-l-yl)benzyl)-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) hexanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)hexanoic acid;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) hexanoic acid;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) hexanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-2-methyl-5-oxo-4-mor pholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-2-methyl-5-oxo-4- morpholinyl)pentanoic acid; (2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-2-methyl-5-oxo-4-mor pholinyl)pentanoic acid;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-2-methyl-5-oxo-4- morpholinyl)pentanoic acid;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(3-pyridinyl)-3-morphol inone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-(3-pyridinyl)-3-morpholino ne;

(5S,6R)-5,6-bis(4-bromophenyl)-4-(l-methylethyl)-3-morpholin one;

(5R,6S)-5,6-bis(4-bromophenyl)-4-(l-methylethyl)-3-morpho linone;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-2-methyl-5-oxo-4-mor pholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-2-methyl-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-2-methyl-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-2-methyl-5-oxo-4- morpholinyl)pentanoic acid; (5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(2-methoxyet hyl)-3-morpholinone;

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(2-methox yethyl)-3-morpholinone;

(2R)-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl )(phenyl)ethanoic acid;

(2S)-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl )(phenyl)ethanoic acid;

(2S)-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl )(phenyl)ethanoic acid; (2R)-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl)(p henyl)ethanoic acid; (2R)-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid;

(2S)-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo -4- morpholinyl)(cyclopropyl)ethanoic acid;

(2S)-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo -4- morpholinyl)(cyclopropyl)ethanoic acid;

(2R)-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxo -4- morpholinyl)(cyclopropyl)ethanoic acid;

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(2-fluoro-4-(me thylsulfonyl)benzyl)-5- oxo-4-morpholinyl)pentanoic acid;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2-fluoro-4-(me thylsulfonyl)benzyl)-5- oxo-4-morpholinyl)pentanoic acid;

((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-morphol inyl)acetonitrile;

((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-morp holinyl)acetonitrile;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-phenyl-3-morpholinone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-phenyl-3-morpholinone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4-(lH-l, 2,4-triazol-l-yl)benzyl)-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4-(lH-l, 2,4-triazol-l-yl)benzyl)-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-2-methyl-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-2-methyl-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-2-methyl-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-2-methyl-5-oxo-4- morpholinyl)pentanoic acid;

(2R,5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-methyl-2-( 1 H-tetrazol-5 -ylmethyl)-3- morpholinone; (2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-2-(lH-tetrazol-5 -ylmethyl)-3- morpholinone;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) hexanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)hexanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)hexanoic acid;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)hexanoic acid;

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-2-m ethyl-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-2-meth yl-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-2-meth yl-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-2-meth yl-5-oxo-4- morpholinyl)pentanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-4-methylpentanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-4-methylpentanoic acid;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-4-methylpentanoic acid;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)-4-methylpentanoic acid;

4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-iodob enzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)butanoic acid;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-6-methyl-3- oxo-2-morpholinyl)acetic acid;

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-6-methyl-3- oxo-2-morpholinyl)acetic acid;

(4R)-4-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)heptanoic acid;

and (4S)-4-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) heptanoic acid;

(4R)-4-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)heptanoic acid;

(4S)-4-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) heptanoic acid;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) butanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)butanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) butanoic acid; (2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) butanoic acid;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(cyclopropylmethyl)-3-m orpholinone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-(cyclopropylmethyl)-3-m orpholinone;

(5S,6R)-5,6-bis(4-bromophenyl)-4-ethyl-3-morpholinone;

(5R,6S)-5,6-bis(4-bromophenyl)-4-ethyl-3-morpholinone;

2-((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-morph olinyl)acetamide; 2-((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-morph olinyl)acetamide;

(2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)-2-(4-fluorobenzyl)pentanoic acid;

(2S)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)-2-(4-fluorobenzyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)-2-(4-fluorobenzyl)pentanoic acid;

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-( 4-fluorobenzyl)-5-oxo-4- morpholinyl)-2-(4-fluorobenzyl)pentanoic acid;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(2-hydroxyethyl)-4-meth yl-3-morpholinone; (2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(2-hydroxyethyl)-4-meth yl-3-morpholinone; (2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-((2R)-2,3-dihydroxyprop yl)-4-methyl-3- morpholinone;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-((2S)-2,3-dihydroxyp ropyl)-4-methyl-3- morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-((2R)-2,3-dihydroxyprop yl)-4-methyl-3- morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-((2S)-2,3-dihydroxyprop yl)-4-methyl-3- morpholinone;

l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluoro benzyl)-5-oxo-4- morpholinyl)pentyl)-4-piperidinecarboxylic acid;

l-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoro benzyl)-5-oxo-4- morpholinyl)pentyl)-4-piperidinecarboxylic acid;

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluoro benzyl)-5-oxo-4- morpholinyl)pentanoyl)-N-methylglycine; N-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoyl)-N-methylglycine;

(3R,5R,6S)-5,6-bis(4-chlorophenyl)-3-propyl-2,5,6,8-tetrahyd ro-3H-imidazo[2,l- c][l,4]oxazine;

(3S,5S,6R)-5,6-bis(4-chlorophenyl)-3-propyl-2,5,6,8-tetra hydro-3H-imidazo[2,l- c][l,4]oxazine;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2-(dimethylami no)ethyl)-5-oxo-4- morpholinyl)pentanoic acid;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(2-(dimethylami no)ethyl)-5-oxo-4- morpholinyl)pentanoic acid;

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoyl)-N-methyl-beta-alanine;

N-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluoroben zyl)-5-oxo-4- morpholinyl)pentanoyl)-N-methyl-beta-alanine;

4-(((2S,5R,6S)-5-(4-chlorophenyl)-4-methyl-6-(2-methylpro pyl)-3-oxo-2- morpholinyl)methyl)-2-fluorobenzonitrile;

4-(((2R,5S,6R)-5-(4-chlorophenyl)-4-methyl-6-(2-methylpropyl )-3-oxo-2- morpholinyl)methyl)-2-fluorobenzonitrile;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) propanoic acid;

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholin yl)propanoic acid;

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) propanoic acid;

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) propanoic acid;

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(2,6-dichloro-4-pyridinyl) -3-morpholinone;

(5S,6R)-5,6-bis(4-chlorophenyl)-4-(2,6-dichloro-4-pyridinyl) -3-morpholinone;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzy l)-5-oxo-4-morpholinyl)-N- hydroxypentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)- 5-oxo-4-morpholinyl)-N- hydroxypentanamide;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-N- (cyclopropylsulfonyl)pentanamide; (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl )-5-oxo-4-morpholinyl)-N- (cyclopropylsulfonyl)pentanamide;

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -3-methylbutanoic acid; (2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -3-methylbutanoic acid; (2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -3-methylbutanoic acid; (2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl) -3-methylbutanoic acid; (2R,5R,6S)-5,6-bis(4-chlorophenyl)-2-hydroxy-4-methyl-3-morp holinone;

(2S,5S,6R)-5,6-bis(4-chlorophenyl)-2-hydroxy-4-methyl-3-m orpholinone;

(2R,5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-((l S)- 1 -((4-(cyclopropylmethyl)- 1 - piperazinyl)carbonyl)butyl)-2-(4-iodobenzyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-l-((4-(cyclopropy lmethyl)-l- piperazinyl)carbonyl)butyl)-2-(4-iodobenzyl)-3-morpholinone;

(3R,5S,6R)-5,6-bis(4-chlorophenyl)-3-propyl-2,5,6,8-tetra hydro-3H-imidazo[2,l- c][l,4]oxazine;

(3S,5R,6S)-5,6-bis(4-chlorophenyl)-3-propyl-2,5,6,8-tetra hydro-3H-imidazo[2,l- c][l,4]oxazine;

l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanob enzyl)-5-oxo-4- morpholinyl)pentanoyl)-3 -azetidinecarboxylic acid;

l-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanob enzyl)-5-oxo-4- morpholinyl)pentanoyl)-3 -azetidinecarboxylic acid;

3-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-morp holinyl)methyl)benzoic acid;

3- (((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2-morpho linyl)methyl)benzoic acid;

(2R,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-( 3-pyridinyl)-3-morpholinone; (2S,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(3-p yridinyl)-3-morpholinone;

4- (((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-((lS)-l-((4-(cyclopro pylmethyl)-l- piperazinyl)carbonyl)butyl)-3-oxo-2-morpholinyl)methyl)benzo nitrile;

4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-l-((4-(cyc lopropylmethyl)-l- piperazinyl)carbonyl)butyl)-3 -oxo-2-morpholinyl)methyl)benzonitrile; 3-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzonitrile;

3-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzonitrile;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenz yl)-5-oxo-4-morpholinyl)-N- (methylsulfonyl)pentanamide; or

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl) -5-oxo-4-morpholinyl)-N- (methylsulfonyl)pentanamide. In embodiment 45, the present invention provides the compounds, or a pharmaceutically acceptable salts, selected from:

(55',6i?,Z)-5,6-bis(4-chlorophenyl)-4-methyl-2-(pyridin-3-yl methylene)morpholin-3-one; (5i?,65',Z)-5,6-bis(4-chlorophenyl)-4-methyl-2-(pyridin-3-yl methylene)morpholin-3-one; (3R,4S,SR)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-isopropyl tetrahydropyrrolo[l,2- a]pyrazine-l,6(2H,7H)-dione;

(3i?,45',85)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-isoprop yltetrahydropyrrolo[l,2- ajpyrazine- 1 ,6(2H,7H)-dione;

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2R,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo -2-morpholinyl)acetic acid; ((2S,5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lS)-l- (((cyclopropylsulfonyl)(phenyl)amino)methyl)propyl)-3-oxo-2- morpholinyl)acetic acid; (2R)-2-((2R,3S)-2-(4-chlorophenyl)-3-(lH-indol-2-yl)-5-oxo-4 -morpholinyl)pentanoic acid;

(2S)-2-((2S,3R)-2-(4-chlorophenyl)-3-(lH-indol-2-yl)-5-oxo-4 -morpholinyl)pentanoic acid;

3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyano benzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-N-(tert-butoxycarbonyl)-D-alani ne; 3- (((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzy l)-5-oxo-4- morpholinyl)pentanoyl)amino)-N-(tert-butoxycarbonyl)-D-alani ne;

l-((((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-cyan obenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)methyl)cyclopentanecarboxylic acid;

l-((((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyan obenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)methyl)cyclopentanecarboxylic acid;

(2R,3R)-3-(4-chlorophenyl)-4-(cyclopropylmethyl)-N-(2-hyd roxyphenyl)-5-oxo-2- morpholinecarboxamide;

(3R,5R,6S)-5,6-bis(4-chlorophenyl)-3-propyl-2,5,6,8-tetrahyd ro-3H-imidazo[2,l- c][l,4]oxazine;

(3S,5S,6R)-5,6-bis(4-chlorophenyl)-3-propyl-2,5,6,8-tetrahyd ro-3H-imidazo[2,l- c][l,4]oxazine;

4- (((2S,5R,6S)-5-(4-chlorophenyl)-4-methyl-6-(2-methylpropyl)- 3-oxo-2- morpholinyl)methyl)-2-fluorobenzonitrile;

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzy l)-5-oxo-4-morpholinyl)-N- hydroxypentanamide;

(2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)- 5-oxo-4-morpholinyl)-N- hydroxypentanamide;

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-((lS)-l-((4-(cyclopropy lmethyl)-l- piperazinyl)carbonyl)butyl)-2-(4-iodobenzyl)-3-morpholinone;

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-l-((4-(cyclopropy lmethyl)-l- piperazinyl)carbonyl)butyl)-2-(4-iodobenzyl)-3-morpholinone;

(3R,5S,6R)-5,6-bis(4-chlorophenyl)-3-propyl-2,5,6,8-tetra hydro-3H-imidazo[2,l- c][l,4]oxazine, (3S,5R,6S)-5,6-bis(4-chlorophenyl)-3-propyl-2,5,6,8-tetrahyd ro-3H- imidazo[2,l-c][l,4]oxazine;

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-((lS)-l-((4-(cyclop ropylmethyl)-l- piperazinyl)carbonyl)butyl)-3-oxo-2-morpholinyl)methyl)benzo nitrile; or

4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-l-((4-(cyc lopropylmethyl)-l- piperazinyl)carbonyl)butyl)-3-oxo-2-morpholinyl)methyl)benzo nitrile. In embodiment 46, the present invention provides pharmaceutical compositions comprising a compound of any one of embodiments 1 to 45, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable exipient.

In embodiment 47, the present invention provides methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject an effective dosage amount of a compound according to any one of embodiments 1 to 45, or a pharmaceutically acceptable salt thereof.

In embodiment 48, the present invention provides the methods of embodiment 47, wherein the cancer is selected from bladder, breast, colon, rectum, kidney, liver, small cell lung cancer, non-small-cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, skin, acute lymphocytic leukemia, chronic

myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell- lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute and chronic myelogenous leukemia, melanoma, endometrial cancer, head and neck cancer, glioblastoma, or osteosarcoma.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of Formula I, as defined above, or pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions comprising a compound of Formula I, or pharmaceutically acceptable salts thereof, and methods of treating diseases and/or conditions, such as cancer, using compounds of Formula I, or pharmaceutically acceptable salts thereof.

The term "alkyl" means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, sec-butyl, pentyl and hexyl. Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, which groups are commonly represented as Ci-galkyl.

The term "alkoxy" means an alkyl group bonded to an oxygen atom.

Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy. Common alkoxy groups are Ci- ₈ alkoxy. The term "halogen" or "halo" means chlorine, fluorine, bromine or iodine.

The term "alkenyl" means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds. Representative examples of alkenyl groups include ethenyl, propenyl, allyl, butenyl and 4-methylbutenyl. Common alkenyl groups are C ₂ - galkenyl.

The term "alkynyl" means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds. Representative examples of alkynyl groups include ethynyl, propynyl (propargyl) and butynyl. Common alkynyl groups are C ₂ -g alkynyl.

The term "cycloalkyl" means a cyclic, nonaromatic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A cycloalkyl group can contain one or more double bond. Examples of cycloalkyl groups that contain double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl. Common cycloalkyl groups are C3-8 cycloalkyl groups. A cycloalkyl group can also be a bicyclic group comprising a cycloalkyl ring fused to an aryl or heteroaryl ring. An example of such a fused bicyclic group is tetrahy dronaphthalene .

The term "perfluoroalkyl" means an alkyl group in which all of the hydrogen atoms have been replaced with fluorine atoms. Common perfluoroalkyl groups are Ci- sperfluoroalkyl. An example of a common perfluoroalkyl group is CF ₃ .

The term "acyl" means a group derived from an organic acid by removal of the hydroxy group (-OH). For example, the acyl group CH ₃ C(=0)- is formed by the removal of the hydroxy group from CH ₃ C(=0)OH .

The term "aryl" means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six to thirteen membered rings.

The term "heteroatom" as used herein means an oxygen, nitrogen or sulfur atom.

The term "heteroaryl" means a cyclic, aromatic hydrocarbon in which one or more carbon atoms of an aryl group have been replaced with a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo[b]thienyl. Common heteroaryl groups are five to thirteen membered rings that contain from 1 to 4 heteroatoms. Heteroaryl groups that are five and six membered rings that contain 1 to 3 heterotaoms are particularly common.

The term "heterocycloalkyl" means a cycloalkyl group in which one or more of the carbon atoms has been replaced with a heteroatom. If the heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different.

Examples of heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl. It is also possible for the heterocycloalkyl group to have one or more double bonds, but is not aromatic. Examples of heterocycloalkyl groups containing double bonds include dihydrofuran. Common heterocycloalkyl groups are three to ten membered rings containing from 1 to 4 heteroatoms. Heterocycloalkyl groups that are five and six membered rings that contain 1 to 2 heterotaoms are particularly common. A heterocycloalkyl group can also be a bicyclic group comprising a

heterocycloalkyl ring fused to an aryl or heteroaryl ring. Examples of such fused bicyclic ring include tetrahydroquinoline or tetrahydroisoquinoline.

It is also noted that the cyclic ring groups, i.e., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, can comprise more than one ring. For example, the naphthyl group is a fused bicyclic ring system. It is also intended that the present invention include ring groups that have bridging atoms, or ring groups that have a spiro orientation.

Representative examples of five to six membered aromatic rings, optionally having one or two heteroatoms, are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, and pyrazinyl.

Representative examples of partially saturated, fully saturated or fully unsaturated five to eight membered rings, optionally having one to three heteroatoms, are

cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3- dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl,

imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1 ,2- dithiolyl, 1,3-dithiolyl, 3H-l,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, l,3,4oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl, 3H- 1.2.3- dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5- oxathiazolyl, and 1,3-oxathiolyl.

Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1 ,2-dioxinyl, 1,3-dioxinyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, pyndazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4- triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-l,2-oxazinyl, 2H-l,3-oxazinyl, 6H-1,3- oxazinyl, 6H-l,2-oxazinyl, 1 ,4-oxazinyl, 2H-l,2-oxazinyl, 4H-l,4-oxazinyl, 1,2,5- oxathiazinyl, 1 ,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, l,2,6-(3 oxathiazinyl, and 1,4,2-oxadiazinyl.

Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and

1.2.4- triazepinyl.

Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.

Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, optionally having one to four heteroatoms, are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H- indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1- benzopyranyl, pyrido(3,4-b)pyridinyl, pyrido(3,2-b)pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-l,3-benzoxazinyl, 2H-l,4-benzoxazinyl, lH-2,3-benzoxazinyl, 4H-3,l-benzoxazinyl, 2H-l,2-benzoxazinyl and 4H-l,4-benzoxazinyl.

A cyclic ring group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term "pyridyl" includes 2-, 3-, or 4-pyridyl, and the term "thienyl" includes 2-, or 3-thienyl.

The term "substituted" means that a hydrogen atom on a molecule or group is replaced with a group or atom. Typical substitutents include: halogen, Ci-galkyl, hydroxyl, Ci-galkoxy, -NR ^X R ^X , nitro, cyano, halo or perhaloCi-galkyl, C ₂ -galkenyl, C ₂ - ₈ alkynyl, -SR ^X , -S(=0) ₂ R ^x , -C(=0)OR ^x , -C(=0)R ^x , wherein each R ^x is independently hydrogen or Ci-Cg alkyl. It is noted that when the substituent is -NR ^X R ^X , the R ^x groups may be joined together with the nitrogen atom to form a ring.

The term "oxo", when used as a substituent, means the =0 group, which is typically attached to a carbon atom.

A group or atom that replaces a hydrogen atom is also called a substituent.

Any particular molecule or group can have one or more substituent depending on the number of hydrogen atoms that can be replaced.

The symbol "-" represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.

The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements.

The term "therapeutically effective amount" means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.

The terms "patient" and "subject" may be used interchangeably and mean animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals. The term patient includes males and females.

The term "pharmaceutically acceptable" means that the referenced substance, such as a compound of Formula I, or a salt of a compound of Formula I, or a formulation containing a compound of Formula I, or a particular excipient, are suitable for administration to a patient.

The terms "treating", "treat" or "treatment" and the like include preventative (e.g., prophylactic) and palliative treatment.

The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient.

The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.

In addition, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other

pharmaceutically active compounds. The other pharmaceutically active compounds can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously, or sequentially. For example, in the case of tablets, the active compounds may be found in one tablet or in separate tablets, which can be administered at once or sequentially in any order. In addition, it should be recognized that the compositions may be different forms. For example, one or more compound may be delivered via a tablet, while another is administered via injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.

The term "cancer" means a physiological condition in mammals that is characterized by unregulated cell growth. General classes of cancers include carcinomas, lymphomas, sarcomas, and blastomas.

The compounds of the present invention can be used to treat cancer. The methods of treating a cancer comprise administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be used to treat tumors. The methods of treating a tumor comprise administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

The invention also concerns the use of a compound of the present invention in the manufacture of a medicament for the treatment of a condition such as a cancer.

Cancers which may be treated with compounds of the present invention include, without limitation, carcinomas such as cancer of the bladder, breast, colon, rectum, kidney, liver, lung (small cell lung cancer, and non-small-cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute

lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplasia syndrome and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma). Other cancers that can be treated with a compound of the present invention include endometrial cancer, head and neck cancer, glioblastoma, malignant ascites, and hematopoietic cancers.

Particular cancers that can be treated by the compounds of the present invention include soft tissue sarcomas, bone cancers such as osteosarcoma, breast tumors, bladder cancer, Li-Fraumeni syndrome, brain tumors, rhabdomyosarcoma, adrenocortical carcinoma, colorectal cancer, non-small cell lung cancer, and acute myeleogenous leukemia (AML).

In a particular embodiment of the invention that relates to the treatment of cancers, the cancer is identified as p53wildtype (p53 ^WT ). In another particular embodiment, the cancer is identified as p53 ^WT and CDKN2A mutant. In another aspect, the present invention provides a diagnostic for determining which patients should be administered a compound of the present invention. For example, a sample of a patient's cancer cells may be taken and analyzed to determine the status of the cancer cells with respect to p53 and/or CDKN2A. In one aspect, a patient having a cancer that is p53 ^WT will be selected for treatment over patients having a cancer that is mutated with respect to p53. In another aspect, a patient having a cancer that is both p53 ^WT and has a mutant CDNK2A protein is selected over a patient that does not have these characteristics. The taking of a cancer cells for analyses is well known to those skilled in the art. The term "p53 " means a protein encoded by genomic DNA sequence no. NC 000017 version 9 (7512445..7531642)(GenBank); a protein encoded by cDNA sequence no. NM_000546 (GenBank); or a protein having the GenBank sequence no. NP 000537.3. The term "CDNK2A mutant" means a CDNK2A protein that in not wildtype. The term "CDK 2A wildtype" means a protein encoded by genomic DNA sequence no. 9:21957751- 21984490 (Ensembl ID); a protein encoded by cDNA sequence no. NM 000077

(GenBank) or NM 058195 (GenBank) or; or a protein having the GenBank sequence no. NP 000068 or NP 478102.

The compounds of the present invention can also be used to treat

hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein- Leventhal syndrome)).

The compounds of the present invention can also be used to treat the following diseases or conditions: asthma, chronic obstructive pulmonary disease (COPD), emphysema, psoriasis, contact dermatitis, conjunctivitis, allergic rhinitis, systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, atherosclerosis and

Huntington's disease.

The compounds of the present invention can also be used to treat inflammatory diseases, hypoxia, ulcers, viral infections, bacterial infections, and bacterial sepsis.

The compounds of Formula I, or the pharmaceutically acceptable salts thereof, may also be administered in combination with one or more additional pharmaceutically active compounds/agents. In a particular embodiment, the additional pharmaceutically active agent is an agent that can be used to treat a cancer. For example, an additional pharmaceutically active agent can be selected from antineoplastic agents, anti-angiogenic agents, chemotherapeutic agents and peptidal cancer therapy agents. In yet another embodiment, the antineoplastic agents are selected from antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, kinase inhibitors, miscellaneous agents and combinations thereof. It is noted that the additional pharmaceutically active compounds/agents may be a traditional small organic chemical molecules or can be macromolecules such as a proteins, antibodies, peptibodies, DNA, R A or fragments of such macromolecules.

Examples of specific pharmaceutically active agents that can be used in the treatment of cancers and that can be used in combination with one or more compound of the present invention include: methotrexate; tamoxifen; fluorouracil; 5-fluorouracil;

hydroxyurea; mercaptopurine; cisplatin; carboplatin; daunorubicin; doxorubicin;

etoposide; vinblastine; vincristine; pacitaxel; thioguanine; idarubicin; dactinomycin; imatinib; gemcitabine; altretamine; asparaginase; bleomycin; capecitabine; carmustine; cladisat. aq. NaCl solution; cyclophosphamine; cytarabine; decarazine; docetaxel;

idarubicin; ifosfamide; irinotecan; fludarabine; mitosmycin; mitoxane; mitoxantrone; topotecan; vinorelbine; adriamycin; mithram; imiquimod; alemtuzmab; exemestane; bevacizumab; cetuximab; azacitidine; clofarabine; decitabine; desatinib; dexrazoxane; docetaxel; epirubicin; oxaliplatin; erlotinib; raloxifene; fulvestrant; letrozole; gefitinib; gemtuzumab; trastuzumab; gefitinib; ixabepilone; lapatinib; lenalidomide; aminolevulinic acid; temozolomide; nelarabine; sorafenib; nilotinib; pegaspargase; pemetrexed;

rituximab; dasatinib; thalidomide; bexarotene; temsirolimus; bortezomib; vorinostat; capecitabine; zoledronic acid; anastrozole; sunitinib; aprepitant and nelarabine, or a pharmaceutically acceptable salt thereof.

Additional pharmaceutically active agents that can be used in the treatment of cancers and that can be used in combination with one or more compound of the present invention include: vascular endothelial growth factor (VEGF) inhibitors, hepatocyte growth factor/scatter factor (HGF/SF) inhibitors, angiopoietin 1 and/or 2 inhibitors, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonists, recombinant human apo2 ligand (TRAIL), insulin- like growth factor 1 receptor (IGFR-1) inhibitors, cFMS inhibitors, HER 2 inhibitors, c-met inhibitors, aurora kinase inhibitors, CDK 4 and/or 6 inhibitors, and B-raf inhibitors.

Further additional pharmaceutically active agents that can be used in the treatment of cancers and that can be used in combination with one or more compound of the present invention include antibody drug conjugates (ADCs) whereby an antibody that binds to a protein, preferably on a cancer cell, is conjugated using a linker with a chemical compound that is detrimental to the cancer cell. Examples of chemical compounds that are detrimental to a cancer cell include maytansinoids derivatives and auristatin derivatives.

Still further additional pharmaceutically active agents that can be used in the treatment of cancers and that can be used in combination with one or more compound of the present invention include: epoetin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG 102; AMG 319; AMG 386; AMG 479 (Ganitumab); AMG 511, AMG 900, AMG 655 (Conatumumab); AMG 745; AMG 951 ; and AMG 706 (Motesanib), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to the use of the compounds of the present invention in combination with one or more pharmaceutical agent that is an inhibitor of a protein in the phosphatidylinositol 3-kinase (PI3K) pathway. Combinations of compounds of the present invention along with inhibitors of proteins in the PI3K pathway have shown synergy in cancer cell growth assays, including enhanced apoptosis and cell killing. Examples of proteins in the PI3K pathway include PI3K, mTOR and PKB (also known as Akt). The PI3K protein exists in several isoforms including α, β, δ, or γ. It is contemplated that a PI3K inhibitor that can be used in combination with a compound of the present invention can be selective for one or more isoform. By selective it is meant that the compounds inhibit one or more isoform more that other isoforms. Selectivity is a concept well known to those is the art and can be measured with well known activity in vitro or cell-based assays. Preferred selectivity includes greater than 2 fold, preferably 10 fold, or more preferably 100 fold greater selectivity for one or more isoform over the other isoforms. In one aspect, the PI3K inhibitors that can be used in combination with compounds of the present invention is a PI3K a selective inhibitor. In another aspect the compound is a PI3K δ selective inhibitor.

Examples of PI3K inhibitors that can be used in combination with one or more compounds of the present invention include those disclosed in the following: PCT published application no. WO2010/151791; PCT published application no.

WO2010/151737;

PCT published application no.WO2010/151735; PCT published application no.

WO2010151740; PCT published application no. WO2008/118455; PCT published application no. WO2008/118454; PCT published application no. WO2008/118468; U.S. published application no. US20100331293; U.S. published application no.

US20100331306; U.S. published application no. US20090023761; U.S. published application no. US20090030002; U.S. published application no. US20090137581; U.S. published application no. US2009/0054405; U.S. published application no. U.S. 2009/0163489; U.S. published application no. US 2010/0273764; U.S. published application no. U.S. 2011/0092504; or PCT published application no. WO2010/108074.

Preferred PI3K inhibitors for use in combination with compounds of the present invention include:

, or a pharmaceutically acceptable salt thereof.

Also preferred is a compound of Formula Ila below, or a pharmaceutically acceptable salt thereof,

Ila

wherein X ¹ is fluorine or hydrogenjY ¹ is hydrogen or methyl; and Z ¹ is hydrogen or methyl.

Compounds that inhibit both PI3K and mTOR (dual inhibitors) are known. In still another aspect, the present invention provides the use of dual PI3K and mTOR inhibitors for use in combination with a compound of the present invention.

mTOR is a protein in the PI3K pathway. It is another aspect of the present invention to use an mTOR inhibitor in combination with one or more compounds of the present invention. mTOR inhibitors that can be used in combination with compounds of the present invention include those disclosed in the following documents: PCT published application no. WO2010/132598 or PCT published application no. WO2010/096314.

PKB (Akt) is also a protein in the PI3K pathway. It is another aspect of the present invention to use an mTOR inhibitor in combination with one or more compounds of the present invention. PKB inhibitors that can be used in combination with compounds of the present invention include those disclosed in the following documents: U.S. patent no. 7,354,944; U.S. patent no. 7,700,636; U.S. patent no. 7,919,514; U.S. patent no.

7,514,566; U.S. patent application publication no. US 2009/0270445 Al; U.S. patent no. 7,919,504; U.S. patent no. 7,897,619; or PCT published application no. WO 2010/083246 Al .

The compounds of the present invention can be used in combination with CDK4 and/or 6 inhibitors. CDK 4 and/or 6 inhibitors that can be used in combination with compounds of the present invention include those disclosed in the following documents: PCT published application no. WO 2009/085185 or U.S. patent application publication no. US2011/0097305.

The compounds of the present invention can also be used in combination with pharmaceutically active agents that treat nausea. Examples of agents that can be used to treat nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or a pharmaceutically acceptable salt thereof.

In addition, the compounds of the present invention can be used in combination with other agents that can be used to treat cancer such as acemannan; aclarubicin;

aldesleukin; alitretinoin; amifostine; amrubicin; amsacrine; anagrelide; arglabin; arsenic trioxide; BAM 002 (Novelos); bicalutamide; broxuridine; celmoleukin; cetrorelix;

cladribine; clotrimazole; DA 3030 (Dong-A); daclizumab; denileukin diftitox; deslorelin; dilazep; docosanol; doxercalciferol; doxifluridine; bromocriptine; cytarabine; HIT diclofenac; interferon alfa; tretinoin; edelfosine; edrecolomab; eflornithine; emitefur; epirubicin; epoetin beta; etoposide phosphate; exisulind; fadrozole; finasteride;

fludarabine phosphate; formestane; fotemustine; gallium nitrate; gemtuzumab zogamicin; gimeracil/oteracil/tegafur combination; glycopine; goserelin; heptaplatin; human chorionic gonadotropin; human fetal alpha fetoprotein; ibandronic acid; interferon alfa; interferon alfa natural; interferon alfa-2; interferon alfa-2a; interferon alfa-2b; interferon alfa-Nl; interferon alfa-n3; interferon alfacon-1; interferon alpha natural; interferon beta; interferon beta-la; interferon beta-lb; interferon gamma natural; interferon gamma-la; interferon gamma-lb; interleukin-1 beta; iobenguane; irsogladine; lanreotide; LC 9018

(Yakult); leflunomide; lenograstim; lentinan sulfate; letrozole; leukocyte alpha interferon; leuprorelin; levamisole + fluorouracil; liarozole; lobaplatin; lonidamine; lovastatin;

masoprocol; melarsoprol; metoclopramide; mifepristone; miltefosine; mirimostim;

mismatched double stranded RNA; mitoguazone; mitolactol; mitoxantrone;

molgramostim; nafarelin; naloxone + pentazocine; nartograstim; nedaplatin; nilutamide; noscapine; novel erythropoiesis stimulating protein; NSC 631570 octreotide; oprelvekin; osaterone; paclitaxel; pamidronic acid; peginterferon alfa-2b; pentosan polysulfate sodium; pentostatin; picibanil; pirarubicin; rabbit antithymocyte polyclonal antibody; polyethylene glycol interferon alfa-2a; porfimer sodium; raltitrexed; rasburicase; rhenium

Re 186 etidronate; RII retinamide; romurtide; samarium (153 Sm) lexidronam;

sargramostim; sizofiran; sobuzoxane; sonermin; strontium-89 chloride; suramin;

tasonermin; tazarotene; tegafur; temoporfm; teniposide; tetrachlorodecaoxide;

thymalfasin; thyrotropin alfa; toremifene; tositumomab-iodine 131; treosulfan; tretinoin; trilostane; trimetrexate; triptorelin; tumor necrosis factor alpha natural; ubenimex;

bladder cancer vaccine; Maruyama vaccine; melanoma lysate vaccine; valrubicin;

verteporfin; virulizin; zinostatin stimalamer; abarelix; AE 941 (Aeterna); ambamustine; antisense oligonucleotide; bcl-2 (Genta); APC 8015 (Dendreon); dexaminoglutethimide; diaziquone; EL 532 (Elan); EM 800 (Endorecherche); eniluracil; etanidazole; fenretinide; filgrastim SD01 (Amgen); galocitabine; gastrin 17 immunogen; HLA-B7 gene therapy

(Vical); granulocyte macrophage colony stimulating factor; histamine dihydrochloride; ibritumomab tiuxetan; ilomastat; IM 862 (Cytran); interleukin-2; iproxifene; LDI 200

(Milkhaus); leridistim; lintuzumab; CA 125 monoclonal antibody(MAb) (Biomira); cancer MAb (Japan Pharmaceutical Development); HER-2 and Fc MAb (Medarex); idiotypic 105AD7 MAb (CRC Technology); idiotypic CEA MAb (Trilex); LYM-1- iodine 131 MAb (Techniclone); polymorphic epithelial mucin-yttrium 90 MAb

(Antisoma); marimastat; menogaril; mitumomab; motexafm gadolinium; MX 6

(Galderma); nolatrexed; P 30 protein; pegvisomant; porfiromycin; prinomastat; RL 0903

(Shire); rubitecan; satraplatin; sodium phenylacetate; sparfosic acid; SRL 172 (SR

Pharma); SU 5416 (Pfizer); TA 077 (Tanabe); tetrathiomolybdate; thaliblastine;

thrombopoietin; tin ethyl etiopurpurin; tirapazamine; cancer vaccine (Biomira);

melanoma vaccine (New York University); melanoma vaccine (Sloan Kettering

Institute); melanoma oncolysate vaccine (New York Medical College); viral melanoma cell lysates vaccine (Royal Newcastle Hospital); or valspodar. It is noted that the agents recited above may also be administered as pharmaceutically acceptable salts when appropriate.

The compounds of the present invention may also be used in combination with radiation therapy, hormone therapy, surgery and immunotherapy, which therapies are well known to those skilled in the art.

Since one aspect of the present invention contemplates the treatment of the disease/conditions with a combination of pharmaceutically active compounds that may be administered separately, the invention further relates to combining separate

pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes and bags. Typically, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician or veterinarian.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday,

. . . etc . . . Second Week, Monday, Tuesday, . . . " etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a compound of the present invention can consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this and aid in correct administration of the active agents.

In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

The compounds of the present invention and other pharmaceutically active compounds, if desired, can be administered to a patient either orally, rectally,

parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracisternally, intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin,

polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, as for example, paraffin; (f) absorption accelerators, as for example, quatemary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active

compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administration are preferable suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants. The active compound or fit compounds are admixed under sterile condition with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required. Opthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient. The specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill in the art.

The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs. The term "salts" refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. The salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non- toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al, "Pharmaceutical Salts," J Pharm Sci, 66: 1-19 (1977).

Examples of pharmaceutically acceptable esters of the compounds of the present invention include Ci-Cg alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl. C ₁ -C4 alkyl esters are commonly used. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.

Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary Ci-Cs alkyl amines, and secondary Ci-Cg dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C ₁ -C ₃ primary alkyl amines and C ₁ -C ₂ dialkyl secondary amines are commonly used. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.

The term "prodrug" means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various

mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

To illustrate, if the compound of the invention 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 (Ci-Cg alkyl, (C ₂ - Cl ₂ )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl- l-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms,

alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C ₂ )alkylamino(C ₂ -C ₃ )alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C ₂ )alkyl, N,N-di(Ci-C ₂ )alkylcarbamoyl-(Ci- C ₂ )alkyl and piperidino-, pyrrolidino- or morpholino(C ₂ -3)alkyl.

Similarly, if a compound of the present invention comprises 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 (Ci-C ₆ )alkanoyloxymethyl, l-((Ci-C ₆ )alkanoyloxy)ethyl, 1- methyl-l-((Ci-C ₆ )alkanoyloxy)ethyl, (Ci-C ₆ )alkoxycarbonyloxymethyl, N-(Ci- C ₆ )alkoxycarbonylaminomethyl, succinoyl, (Ci-C ₆ )alkanoyl, a-amino(Ci-C4)alkanoyl, arylacyl and a-aminoacyl, or α-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(0)(OH) ₂ , - P(0)(0(Ci-Ce)alkyl) ₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate). The compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention

contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated as Z and E,

respectively), as well as mixtures, are contemplated.

Mixture of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods such as chromatography and/or fractional crystallization. Enantiomers can can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydro lyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some compounds may be atropisomers (e.g., substituted biaryls).

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like. The present invention contemplates and encompasses both the solvated and unsolvated forms.

It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the tetrazole moiety are included in this invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention.

Those skilled in the art will recognize that the compound names and structures contained herein may be based on a particular tautomer of a compound. While the name or structure for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the present invention, unless stated otherwise.

It is also intended that the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

The present invention also includes isotopically-labelled compounds, 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, phosphorous, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁶ 0, ¹⁷ 0, ¹⁸ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ C1. In one aspect, the present invention relates to compounds wherein one or more hydrogen atom is replaced with deuterium ( ² H) atoms.

Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug 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 detection. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half- life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

The compounds of the present invention may exist in various solid states including crystalline states and as an amorphous state. The different crystalline states, also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.

In synthesizing compounds of the present invention, it may be desirable to use certain leaving groups. The term "leaving groups" ("LG") generally refer to groups that are displaceable by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, CI), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH ₃ ), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like.

All patents, published patent applications and other publications recited herein are hereby incorporated by reference.

The examples presented below illustrate specific embodiments of the present invention. These examples are meant to be representative and are not intended to limit the scope of the claims in any manner. Unless otherwise noted, when a percent is used herein with respect to a solid, the percent is by weight with respect to the referenced solid composition. When a percent is used herein with respect to a liquid, the percent is by volume with respect to the referenced solution.

1H-NMR spectra were typically acquired on a Bruker Avance III 500

spectrometer system (Bruker, Bilerica, MA) operating at a 1H frequency of 500.13 MHz, equipped with a Bruker 5 mm PABBI probe with a z-axis gradient; or on a Bruker

Avance II or Avance III 400 spectrometer operating at a 1H frequency of 400.23 MHz, equipped with a Bruker 5 mm PABBO probe with a z-axis gradient. Samples were typically dissolved in 500 μΐ. of either DMSO-d ₆ or CD ₃ OD for NMR analysis. 1H chemical shifts are referenced, for example, to the residual solvent signals from DMSO- d ₆ at 5 2.50 and CD ₃ OD at 5 3.30.

Significant peaks are tabulated and typically include: number of protons, multiplicity (s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; m, multiplet; br s, broad singlet) and coupling constant(s) in Hertz.

Electron Ionization (EI) mass spectra were typically recorded on an Agilent Technologies 6140 Quadrupole LC/MS mass spectrometer. Mass spectrometry results are reported as the ratio of mass over charge, sometimes followed by the relative abundance of each ion (in parentheses). Starting materials in the Examples below are typically either available from commercial sources such as Sigma- Aldrich, St. Louis, MO, or via literature procedures. The following abbreviations may be used herein:

about

+ve or pos. ion positive ion

Δ heat

Ac acetyl

Ac ₂ 0 acetic anhydride

aq aqueous

AcOH acetic acid

9-BBN 9-borabicylo[3.3.1] nonane

Bn benzyl

Boc tert-butyloxycarbonyl

BSA bovine serum albumin

Bu butyl

Burgess Reagent Methyl N-(triethylammoniumsulfonyl) carbamate Bz benzoyl

Calcd or Calc'd calculated

Cone. concentrated

CSA camphor- 10-sulfonic acid

d day(s)

DBU 1 , 8-diazabicyclo [5.4.0]undec-7-ene

DCE dichloroethane

DCM dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone

DEA diethylamine

Dess-Martin periodinane;

1 , 1 ,1 -triacetoxy- 1 , 1 -dihydro- 1 ,2-benziodoxol-3 -( \H)- ^■ one Dess-Martin reagent

DIBAL diisobutylaluminum hydride

DIEA or DIPEA diisopropylethylamine

DMAP 4-dimethylaminopyridine

DME 1 ,2-dimethoxyethane

DMF N,N-dimethylformamide DMSO dimethyl sulfoxide

DPPA diphenylphosphoryl azide

dr diastereomeric ratio

DTT dithiothreitol

DVB divinylbenzene

EDC N-ethyl-N ' -(3 -dimethylaminopropy l)carbodiimide ee or e.e. enantiomeric excess

eq equivalent

ESI or ES electrospray ionization

Et ethyl

Et ₂ 0 diethyl ether

Et ₃ N triethylamine

EtOAc ethyl acetate

EtOH ethyl alcohol

g gram(s)

h hour(s)

HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N ' ,N ' - tetramethyluronium hexafiuorophosphate

HBTU 0-benzotriazole-N,N,N',N'-tetramethyl-uronium- hexafluorophosphate

Hex hexanes

HMPA hexamethylphosphoramide

HOAt 1 -hydroxy-7-azabenzotriazole

HOBt hydroxybenzotriazole

HRMS high resolution mass spectrometry

HPLC high pressure liquid chromatography

IPA or iPrOH isopropyl alcohol

Jones reagent solution of chromium(IV)oxide and sulfuric acid in KHMDS potassium hexamethyldisilazide

KOAc potassium acetate

LCMS, LC-MS or LC/MS liquid chromatography mass spectrometry

LDA lithium diisopropylamide LHMDS or LiHMDS lithium hexamethyldisilazide

lithium tri-sec-butylborohydride (Sigma-Aldrich, St. L-Selectride ^®

Louis)

M molar (mol L ^"1 )

mCPBA m-chloroperoxybenzoic acid

Me methyl

MeCN acetonitrile

Mel iodomethane

MeOH methyl alcohol

mg milligram(s)

min minute(s)

mL milliliter(s)

M mole(s)

MS mass spectrometry

MsCl methanesulfonyl chloride

MTBE or MtBE methyl tert-butyl ether

m/z mass-to-charge ratio

NaHMDS sodium hexamethyldisilazide

NaOtBu sodium tert-butoxide

NBS N-bromosuccinimide

nBuLi n-butyl lithium

NMO N-methylmorpholine-N-oxide

NMP 1 -methyl-2-pyrrolidinone

NMR nuclear magnetic resonance

sodium tri-sec-butylborohydride (Sigma-Aldrich, St.

N-Selectride ^®

Louis)

PBS phosphate buffered saline

PMB paramethoxybenzyl

Pr propyl

ppm parts per million

PTFE polytetrafluoroethylene p-tol para-toluoyl

rac racemic

RP-HPLC or RPHPLC reversed phase high pressure liquid chromatography

RT or rt or r.t. room temperature

sat. or sat'd or satd saturated

SFC supercritical fluid chromatography

Sml ₂ samarium (II) iodide

TBAF tetrabutylammonium fluoride

TBDMS iert-b ^' ULyldimel ^' hylsilyl

TBDMS-C1 tert-buiyldimethylsilyl chloride

TBDPS tert-butyldiphenylsilyl

TEMPO (2,2,6,6-tetramethylpiperidin- 1 -yl)oxidanyl tert or t tertiary

TFA triflouroacetic acid

TFAA triflouroacetic acid anhydride

THF tetrahydrofuran

TIPS triisopropylsilyl

TLC thin layer chromatography

TMEDA tetramethylethylenediamine

TMS trimethylsilyl or trimethylsilane

TPAP tetrapropylammonium perruthenate

t _R retention time

tBuOH tert-butyl alcohol

v/v volume per volume

EXAMPLES

General Synthetic Schemes

Compounds of the present invention generally can be prepared beginning with commercially available starting materials and using synthetic techniques known to those of skill in the art. Outlined below are some reaction schemes suitable for preparing compounds of the present invention. Further exemplification is found in the specific examples provided. Examples 1 to 3

Examples 4 to 9 and 11 to 13

Examples 10, 29 to 30, 38 and 44 to 49

Examples 14 to 22

Examples 23 to 26

Example 28

Example 32

Example 33

Example 34

Example 37 Example 40

Example 43 Example 55 to 56

Example 57

Examples 58 to 63

Example 64

xamples 67 to 69

Example 70 to 71

Examples 72 to 75

Examples 78 to 79

Examples 80 and 81

EXAMPLE 1

(2S, 5R, 65)-2-Benzyl-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one

(2i?,55',6i?)-2-benzyl- -bis(4-bromophenyl)-4-methylmorpholin-3-one

Step A. (15, 2i?)-l,2-Bis(4-bromophenyl)-2-(methylamino)ethanol and (1R, 2S)-1,2- bis(4-bromophenyl)-2-(methylamino)ethanol

Methylamine (5.2 mL, 60 mmol) was added to a solution of l ,2-bis(4- bromophenyl)ethane-l ,2-dione (7.3 g, 20 mmol) in MeOH (45 mL) at room temperature. The mixture was refluxed for 5 hours, and the solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL) and sodium borohydride (3.8 g, 99 mmol) was added in portions over 10 minutes. After stirring for 1 hour, the mixture was quenched with water and extracted with 10%

MeOH/DCM. The combined organic layers were washed with saturated aqueous sodium chloride, dried over Na ₂ S0 ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 10% MeOH in DCM) to afford the title compounds.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.32-7.40 (m, 4H), 6.92-6.96 (m, 4H), 4.83 (d, J = 5.0 Hz, 1H), 3.66 (s, J = 5.0 Hz, 1H), 3.42 (s, 1H), 2.24 (s, 3H); MS (ESI) 383.9 [M + H] ⁺ .

Step B. (5R, 65)-5,6-Bis(4-bromophenyl)-4-methylmorpholin-3-one and (5S, 6i?)-5,6- bis(4-bromophenyl)-4-methylmorpholin-3-one

2-Chloroacetyl chloride (0.25 mL, 3.1 mmol) was added to a stirring solution of (IS, 2R)- l ,2-bis(4-bromophenyl)-2-(methylamino)ethanol and (IR, 25)-l ,2-bis(4-bromophenyl)-2- (methylamino)ethanol (1.2 g, 3.1 mmol, Example 1 , Step A) and triethylamine (0.65 mL, 4.65 mmol) in THF (30 mL) at 0 °C under nitrogen. After stirring at 0 °C for 1 hour, the reaction was quenched with saturated aqueous NH ₄ C1 and extracted with ethyl acetate (2x). The combined organic layers were washed with saturated NaCl solution, dried over Na ₂ S0 ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (50 mL), and sodium hydride (0.31 g, 7.8 mmol, 60% suspension in oil) was added at room temperature over 5 minutes. After stirring at room temperature overnight, the reaction was quenched with saturated aqueous NH ₄ C1 solution and extracted with ethyl acetate (2x). The combined organic layers were washed with saturated NaCl solution, dried over Na ₂ S0 ₄ , filtered, and the filtrate was concentrated under reduced pressure. The purification of the residue by silica gel flash

chromatography (eluent: 70% ethyl acetate/hexanes) gave the title compounds as a white solid.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.25-7.35 (m, 4H), 6.81 (d, J= 5.0 Hz, 2H), 6.71 (d, J = 5.0 Hz, 2H), 5.15 (d, J = 5.0 Hz, 1H), 4.63 (s, J = 5.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.35 (d, J = 12.0 Hz, 1H), 2.89 (s, 3H); MS (ESI) 426.0 [M + H] ⁺ .

Step C. (2S, 5R, 65)-2-Benzyl-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one and

-2-Benz -5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one

Sodium bis(trimethylsilyl)amide (1.0 M in THF, 1023 μΐ,, 1023 μιηοΐ) was added dropwise to a solution of (5R, 65)-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one and (5S, 6i?)-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one (90 mg, 682 μιηοΐ, Example 1 , Step B) in THF (5 mL) at -78 °C. The bright yellow solution was stirred for 20 minutes at -78 °C, after which a solution of l-(bromomethyl)benzene (89 μΐ,, 750 μιηοΐ) in THF (0.5 mL) was added. The reaction mixture was stirred at -78 °C for 30 minutes, the cooling bath was removed, and the mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. The solution was diluted with ethyl acetate, extracted, washed with brine, dried over MgS0 ₄ and concentrated. The purification of the residue by flash chromatography on silica gel (eluent: 40% ethyl acetate/hexanes) provided the title compounds as a white solid.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.36-7.24 (m, 9H), 6.80 (d, J= 10.0 Hz, 2H), 6.72 (d, J= 5.0 Hz, 2H), 5.22 (d, J= 5.0 Hz, 1H), 4.80-4.90 (m, 1H), 4.34 (d, J= 5.0 Hz, 1H), 3.43-3.34 (m, 2H), 2.96 (s, 3H); HRMS calcd for C ₂₄ H ₂ iBr ₂ N0 ₂ , 514.0012; found, 514.0009.

EXAMPLE 2

(25',5i?,65)-2-Benzyl-5,6-bis(4-bromophenyl)-4-methylmorphol in-3-one

The enantiomers (2S, 5R, 65)-2-benzyl-5,6-bis(4-bromophenyl)-4-methylmorpholin-3- one and (2R, 5S, 6i?)-2-benzyl-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one (150 mg, Example 1, Step C) were separated by chiral HPLC (OD-H column, flow rate: 18 mL/min on a Chiralcel ^® OD-H 30 mm I.D.X250 mm, 5 μιη column (Daicel Inc., Fort Lee, NJ), eluent: 10%> IPA in hexanes) to give the title compound as the first (faster) eluting isomer, [a] _D ²³ +160.2° (c 0.65, DCM).

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.36-7.24 (m, 9H), 6.80 (d, J= 10.0 Hz, 2H), 6.72 (d, J= 5.0 Hz, 2H), 5.22 (d, J= 5.0 Hz, 1H), 4.80-4.90 (m, 1H), 4.34 (d, J= 5.0 Hz, 1H), 3.43-3.34 (m, 2H), 2.96 (s, 3H); HRMS calcd for C ₂₄ H ₂ iBr ₂ N0 ₂ , 514.0012; found, 514.0009. EXAMPLE 3

(2i?,55',6i?)-2-Benzyl-5,6-bis(4-bromophenyl)-4-methylmorpho lin-3-one

Further elution from Example 2 provided the title compound as the second (slower) eluting isomer, [a] _D ²³ -154.7° (c 1.0, DCM).

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.36-7.24 (m, 9H), 6.80 (d, J= 10.0 Hz, 2H), 6.72 (d, J= 5.0 Hz, 2H), 5.22 (d, J= 5.0 Hz, 1H), 4.80-4.90 (m, 1H), 4.34 (d, J= 5.0 Hz, 1H), 3.43-3.34 (m, 2H), 2.96 (s, 3H); HRMS calcd for C ₂₄ H ₂ iBr ₂ N02, 514.0012; found, 514.0009.

EXAMPLE 4

(25',5i?,65)-2-Benzyl-5,6-bis(4-chlorophenyl)-4-methylmorpho lin-3-one and (2R,5S,6R)- 2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one

CI CI and

Step A. (i?)-2-((fert-Butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid and (S)-2- ((fert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid

A 1 N sodium hydroxide solution (100 mL, 100 mmol) was added to a stirring solution of 2-amino-2-(4-chlorophenyl)acetic acid (20 g, 108 mmol) in dioxane:water (200 mL: 100 mL) at 0 °C. After 5 minutes di-tert-butyl dicarbonate (35 g, 162 mmol) and sodium hydrogen carbonate (4.2 mL, 108 mmol) were added in one portion. After stirring at room temperature for 24 hours, the reaction was evaporated under a vacuum and then acidified to pH 4 with KHS0 ₄ . The separated organic layer was extracted with ethyl acetate, and the separated organic layer was dried over MgS0 ₄ , filtered and evaporated under a vacuum to give the title compounds as a clear oil.

1H NMR (500 MHz, DMSO-<¾, δ ppm): 12.91 (s, 1H), 7.66 (d, J= 5.0 Hz, 1H), 7.43 (brs, 4H), 5.14 (d, J= 5.0 Hz, 1H), 1.39 (s, 9H).

Step B. (R)-tert-Butyl l-(4-chlorophenyl)-2-(methoxy(methyl)amino)-2- oxoethylcarbamate and (S)-tert-butyl l-(4-chlorophenyl)-2-(methoxy(methyl) oxoethylcarbamate -OMe

CI and CI

A solution of N,O-dimethylhydroxylamine hydrochloride (4.8 g, 49 mmol) and Hunig's base (8.5 mL, 49 mmol) in DCM (40 mL) was added dropwise over 10 minutes to a stirring solution of (i?)-2-((fert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid and (5)-2-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid (14 g, 49 mmol, Example 4, Step A), HTBU (19 g, 49 mmol), HOBT (7.5 g, 49 mmol) and Hunig's base (8.5 mL, 49 mmol) at 0 °C in DCM (200 mL). The reaction was allowed to warm to room temperature overnight. After the solvent was removed under a vacuum, the resulting oil was dissolved in ethyl acetate (400 mL) and washed with saturated aqueous NH ₄ CI. The separated, organic layer was washed with NaCl (saturated solution, 100 mL). The organic layer was dried over MgS0 ₄ , filtered and the solvent was removed under a vacuum. Flash column chromatography (Si0 ₂ , gradient elution of 0% to 50% ethyl acetate in hexanes) afforded the title compounds as a white solid.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.35 (s, 4H), 5.80-5.88 (m, 1H), 5.65-5.73 (m, 1H), 3.52 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H). Step C. (R)-tert-Butyl l,2-bis(4-chlorophenyl)-2-oxoethylcarbamate and (S)-tert-butyl l,2-bis(4-chlorophenyl)-2-oxoethylcarbamate

4-Chlorophenylmagnesium bromide (30 mL, 30 mmol) was added dropwise over 5 minutes to a stirring solution of l-(4-chlorophenyl)-2-

(methoxy(methyl)amino)-2-oxoethylcarbamate and (S)-tert-butyl l-(4-chlorophenyl)-2- (methoxy(methyl)amino)-2-oxoethylcarbamate (4 g, 12 mmol, Example 4, Step B) in anhydrous THF (50 mL) at 0 °C. The reaction was allowed to warm to rt over a period of 3 h and then treated with ethyl acetate (250 mL) and water (100 mL). The separated organic layer was washed with sat'd. NaCl solution (50 mL), dried over MgS0 ₄ , filtered and evaporated under reduced pressure. Flash column chromatography (Si0 ₂ , gradient elution with 0 to 25% ethyl acetate in hexanes) gave the title compounds as a white solid. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.86 (d, J= 8.6 Hz, 2H), 7.34 (d, J= 8.6 Hz, 2H), 7.20-7.26 (m, 4H), 6.22 (d, J= 7.0 Hz, 1H), 6.12 (d, J= 7.0 Hz, 1H), 1.41 (s, 9H). Step D. tert-Butyl ((li?,25)-l,2-bis(4-chlorophenyl)-2-hydroxyethyl)carbamate and tert- butyl (( 1 S,2R)- 1 ,2-bis(4-chlorophenyl)-2-hydroxyethyl)carbamate

A solution of sodium borohydride (0.10 g, 3 mmol) in THF (10 mL) was added dropwise to a stirring solution of 1 ,2-bis(4-chlorophenyl)-2-oxoethylcarbamate and (S)-tert-butyl l,2-bis(4-chlorophenyl)-2-oxoethylcarbamate (1 g, 3 mmol, Example 4, Step C) in anhydrous THF (30 mL). After the reaction was stirred at room temperature for 2 hours, it was treated with ethyl acetate (200 mL) and saturated aqueous Na ₂ CC"3 (10 mL) and water (40 mL). The separated organic layer was washed with brine (40 mL), dried over MgSC^, filtered, and evaporated under reduced pressure to give the title compounds as a white solid.

1H NMR (400 MHz, OMSO-d ₆ , δ ppm): 7.39-7.25 (m, 8H), 5.48 (d, J= 4.0 Hz, 1H), 4.75-4.83 (m, 1H), 3.95 (d, J= 4.0 Hz, 1H), 1.43 (s, 9H).

Step E. (15',2i?)-2-Amino-l,2-bis(4-chlorophenyl)ethanol and (li?,25)-2-amino-l,2- bis(4-chlorophenyl)ethanol

TFA (3 mL) was added dropwise over 5 minutes to a stirring solution of tert-butyl

((li?,25)-l,2-bis(4-chlorophenyl)-2-hydroxyethyl)carbamat e and tert-butyl ((15 ^* ,2i?)-l,2- bis(4-chlorophenyl)-2-hydroxyethyl)carbamate (700 mg, 1831 μιηοΐ, Example 4, Step D) in CH ₂ C1 ₂ (10 mL) at 0 °C. After stirring at room temperature for 1.5 hours, the reaction was evaporated under a vacuum, dissolved in DCM (50 mL) and basified with aqueous NaOH until pH 14. The organic layer was dried over MgSC^, filtered and evaporated under a vacuum. Flash column chromatography (Si0 ₂ , eluent: DCM : MeOH 9: 1) provided the title compounds as a white solid.

1H NMR (400 MHz, OMSO-d ₆ , δ ppm): 7.30-7.13 (m, 8H), 5.42 (d, J= 8.1 Hz, 1H), 4.66-4.70 (m, 1H), 4.60-4.65 (m, 1H).

Step F. (5i?,65)-5,6-Bis(4-chlorophenyl)morpholin-3-one and (55 ^* ,6i?)-5,6-bis(4- chlorophenyl)morpholin-3 -one

Triethylamine (0.70 mL, 5.1 mmol) was added a stirring solution of (15',2i?)-2-amino-l,2- bis(4-chlorophenyl)ethanol and (li?,25)-2-amino-l,2-bis(4-chlorophenyl)ethanol (0.95 g, 3.4 mmol, Example 4, Step E) in anhydrous THF (20 mL) at 0 °C. The reaction was stirred for 5 minutes and then 2-chloroacetyl chloride (0.27 mL, 3.4 mmol) was added dropwise over 3 minutes. After stirring at room temperature for 1 hour, the reaction was quenched with aqueous NH ₄ C1 and diluted with ethyl acetate. The separated organic layer was dried over MgS0 ₄ , filtered and evaporated under a vacuum to give a residue. The crude residue (400 mg, 1115 μιηοΐ) was diluted in anhydrous THF (20 mL), and sodium hydride (58.9 mg, 2454 μιηοΐ, 60% suspension in oil) was added portionwise at room temperature over 3 minutes under a N ₂ atmosphere. After stirring at room temperature for 3 hours, the reaction was quenched with saturated NH ₄ C1 solution and extracted with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na ₂ S0 ₄ , and filtered. The filtrate was concentrated under reduced pressure. Flash column chromatography (Si0 ₂ , eluent: 5% MeOH in DCM) gave the title compounds as a white solid. 1H NMR (400 MHz, OMSO-d ₆ , δ ppm): 8.75 (s, 1H), 7.26-7.20 (m, 4H), 7.05 (d, J= 8.4 Hz, 2H), 6.91 (d, J= 8.6 Hz, 2H), 5.35 (d, J= 3.3 Hz, 1H), 4.75 (s, 1H), 4.48 (d, J= 12.0 Hz, 1H), 4.37 (d, J= 3.1 Hz, 1H). Step G. (5i?,65)-5,6-Bis(4-chlorophenyl)-4-methylmorpholin-3-one and (5S,6R)-5,6- bis(4-chlorophenyl)-4-methylmorpholin-3-one

Sodium hydride (9.7 mg, 403 μιηοΐ, 60% suspension in oil) was added portionwise over 2 minutes to a stirring solution of (5i?,65)-5,6-bis(4-chlorophenyl)morpholin-3-one and (55',6i?)-5,6-bis(4-chlorophenyl)morpholin-3-one (100 mg, 310 μιηοΐ, Example 4, Step F) in DMF (3 mL) at 0 °C. After 10 minutes at this temperature, iodomethane (25 μί, 403 μιηοΐ) was added dropwise over 1 minute. The reaction was allowed to warm to room temperature over 4 hours. The reaction was then treated with ethyl acetate and water. The separated organic layer was washed with brine, dried, filtered and evaporated under a vacuum. Flash column chromatography (Si0 ₂ , gradient elution of 0% to 75% ethyl acetate in hexanes) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.09 (d, J= 8.2 Hz, 4H), 6.78 (d, J= 8.6 Hz, 2H), 6.69 (d, J= 8.6 Hz, 2H), 5.09 (d, J= 3.1 Hz, 1H), 4.56 (d, J= 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.28 (d, J= 3.1 Hz, 1H), 2.82 (s, 3H); HRMS calcd for Ci ₇ Hi ₅ Cl ₂ N02, 336.0553; found, 336.0564.

Step H. (25',5i?,65)-2-Benzyl-5,6-bis(4-chlorophenyl)-4-methylmorpho lin-3-one and (2i?,55',6i?)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmorph olin-3-one

The title compounds were prepared from (5i?,6S)-5,6-bis(4-chlorophenyl)-4- methylmorpholin-3-one and (55',6i?)-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one (Example 4, Step G) as described for Example 1, Step C.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.09-6.93 (m, 9H), 6.63 (d, J= 8.2 Hz, 2H), 6.55 (d, J=8.6Hz, 2H), 5.01 (d,J=2.7 Hz, 1H), 4.67 (dd, J= 8.2, 3.9 Hz, 1H),4.13 (d,J=3.1 Hz, 1H), 3.22-3.11 (m, 2H), 2.74 (s, 3H); MS (ESI) 426.1 [M + H] ⁺ .

Examples 5 to 9 were prepared from (5R, 6S)-5,6-bis(4-bromophenyl)-4- methylmorpholin-3-one and (5S, 6i?)-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one (Example 1, Step B) as described in Example 1, Step C substituting 1- (bromomethyl)benzene in Example 1 , Step C with an equivalent amount of the appropriate alk l bromide.

and

EXAMPLE 5

(25',5i?,65)-2-(4-Bromobenzyl)-5,6-bis(4-bromophenyl)-4-meth ylmorpholin-3-one and (2i?,55',6i?)-2-(4-bromobenzyl)-5,6-bis(4-bromophenyl)-4-met hylmorpholin-3-one

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.38-7.24 (m, 8H), 7.02 (d, J = 5.0 Hz, 2H), 6.94 (d, J = 5.0 Hz, 2H), 5.15 (d, J = 2.5 Hz, 1H), 4.73-4.81 (m, 1H), 4.29 (d, J = 2.5 Hz, 1H), 3.40-3.25 (m, 2H), 3.03 (s, 3H).

EXAMPLE 6

(25',5i?,65)-5,6-Bis(4-bromophenyl)-2-(4-fiuorobenzyl)-4- methylmorpholin-3-one and (2i?,55',6i?)-5,6-bis(4-bromophenyl)-2-(4-fluorobenzyl)-4-me thylmorpholin-3-one

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.33-7.28 (m, 4H), 7.14-7.19 (m, 2H), 6.80-6.95 (m, 2H), 6.76 (d, J= 5.0 Hz, 2H), 6.66 (d, J = 5.0 Hz, 2H), 5.15 (d, J = 2.5 Hz, 1H), 4.75- 4.84 (m, 1H), 4.29 (d, J = 2.5 Hz, 1H), 3.40-3.25 (m, 2H), 2.92 (s, 3H), HRMS calcd for C ₂₄ H ₂ oBr ₂ FNO 2, 531.9918; found, 531.9928.

EXAMPLE 7 (25',5i?,65)-5,6-Bis(4-bromophenyl)-2-(4-methoxybenzyl)-4-me thylmorpholin-3-one and (2i?,55',6i?)-5,6-bis(4-bromophenyl)-2-(4-methoxybenzyl)-4-m ethylmorpholin-3-one

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.34-7.28 (m, 4H), 7.13 (d, J = 10.0 Hz, 2H), 6.75- 6.80 (m, 4H), 6.69 (d, J= 10.0 Hz, 2H), 5.19 (d, J= 5.0 Hz, 1H), 4.77-4.83 (m, 1H), 4.30 (d, J= 5.0 Hz, 1H), 3.79 (s, 3H), 3.36-3.24 (m, 2H), 2.93 (s, 3H); MS (ESI) 546.0 [M + H] ⁺ .

EXAMPLE 8

(25',5i?,65)-5,6-Bis(4-bromophenyl)-4-methyl-2-(4-(trifluoro methoxy)benzyl)morpholin- 3-one and (2i?,55 ^* ,6i?)-5,6-bis(4-bromophenyl)-4-methyl-2-(4- (trifluoromethoxy)benzyl)morpholin-3-one

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 77.41-7.28 (m, 6H), 6.90-6.76 (m, 6H), 4.55-4.65 (m, 1H), 4.47 (d, J= 10.0 Hz, 1H), 4.21 (d, J= 10.0 Hz, 1H), 3.30-3.40 (m, 1H), 3.17- 3.23 (m, 1H), 2.61 (s, 3H); MS (ESI) 600.0 [M + H] ⁺ .

EXAMPLE 9

(25',5i?,65)-5,6-Bis(4-bromophenyl)-2-(3-methoxybenzyl)-4-me thylmorpholin-3-one and (2i?,55',6i?)-5,6-bis(4-bromophenyl)-2-(3-methoxybenzyl)-4-m ethylmorpholin-3-one

1H NMR (500 MHz, CDCI ₃ , δ ppm): 7.31-7.28 (m, 4H), 7.13-7.16 (m, 1H), 6.79-6.75 (m, 5H), 6.68 (d, J= 5.0 Hz, 2H), 5.15 (d, J= 5.0 Hz, 1H), 4.83-4.86 (m, 1H), 4.29 (d, J = 5.0 Hz, 1H), 3.63 (s, 3H), 3.35 (dd, J= 15.0, 10.0 Hz, 1H), 3.28 (dd, J= 15.0, 10.0 Hz, 1H), 2.92 (s, 3H); MS (ESI) 546.0 [M + H] ⁺ .

EXAMPLE 10

(i?)-2-((2 _l S,5i?,65)-2-(4-Fluorobenzyl)-5,6-bis(4-chlorophenyl)-3 - oxomorpholino)pentanoic acid

Step A. ( ?)-Ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)pentano ate and (5)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)pentanoa te

Sodium hydride (436 mg, 10913 μιηοΐ, 60% in mineral oil) was added to a solution of (5i?,65)-5,6-bis(4-chlorophenyl)morpholin-3-one and (5S,6R)-5,6-bis(4- chlorophenyl)morpholin-3-one (2930 mg, 9094 μιηοΐ, Example 4, Step F) in DMF (23 mL) at 0 °C. After stirring for 20 minutes, ethyl 2-bromovalerate (2326 μί, 13641 μιηοΐ) was added in portions at 0 °C, and the resulting solution was stirred at 25 °C for 16 hours. The reaction was quenched with saturated NH ₄ C1 solution, extracted with ethyl acetate (3x) and washed with brine (3x). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under the reduced pressure. Purification of the residue by flash chromatography (Si0 ₂ , gradient elution of 30% to 50%> MTBE in hexanes) provided (R)- ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)pentano ate and (5)-ethyl 2- ((2i?,3S)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)pentanoate as the less polar products.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.17-7.14 (m, 4H), 6.85-6.81 (m, 4H), 5.24 (s, 1H), 4.90-4.97 (m, 1H), 4.71 (d, J= 17.2 Hz, 1H), 4.60 (s, 1H), 4.59 (d, J= 17.2 Hz, 1H),

4.08-4.14 (m, 2H), 1.70-1.81 (m, 1H), 1.32-1.45 (m, 1H), 1.33 (t, J= 7.6, 3H), 1.20-1.26 (m, 1H), 1.00-1.10 (m, 1H), 0.62 (t, J= 7.2 Hz, 3H); MS (ESI) 422.0 [M + H]. Step B. ( ?)-Ethyl 2-((25',3i?)-2,3-bis 4-chlorophenyl)-5-oxomorpholino)pentanoate

(i?)-Ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)pentano ate and (S)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)pentanoa te (Example 10, Step A) were separated by chiral HPLC OD-H column (flow rate: 18 mL/min on a Chiralcel ^® OD-H 30 mm l.D.x 250 μιη, 5 μιη column (Daicel Inc., Fort Lee, NJ) eluting with 5% IPA in hexanes) to give the title compound as the first (faster) eluting isomer.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.17-7.14 (m, 4H), 6.85-6.81 (m, 4H), 5.24 (s, 1H), 4.90-4.97 (m, 1H), 4.71 (d, J= 17.2 Hz, 1H), 4.60 (s, 1H), 4.59 (d, J= 17.2 Hz, 1H), 4.08-4.14 (m, 2H), 1.70-1.81 (m, 1H), 1.32-1.45 (m, 1H), 1.33 (t, J= 7.6, 3H), 1.20-1.26 (m, 1H), 1.00-1.10 (m, 1H), 0.62 (t, J= 7.2 Hz, 3H); MS (ESI) 422.0 [M + H].

Step C. (i?)-Ethyl 2-((2 _l S,5i?,65)-2-(4-fluorobenzyl)-5,6-bis(4-chlorophi

oxomorpholino)pentanoate

Lithium bis(trimethylsilyl)amide (2.7 mL, 2.70 mmol, 1.0 M in THF) was added dropwise to a solution of (i?)-ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (1.15 g, 2.45 mmol, Example 10, Step B) and 1- (bromomethyl)-4-fluorobenzene (464 L, 3.68 mmol) in THF (8.2 mL, 0.3 M) at -78 °C. After stirring at -78 °C for 2 hours, the reaction was quenched with saturated NH ₄ C1 solution, extracted with ethyl acetate (2x) and washed with brine. The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under the reduced pressure. Purification of the residue by flash chromatography (Si0 ₂ , gradient elution of 10% to 15% ethyl acetate in hexanes) provided the title compound as a colorless film.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.16-7.13 (m, 6H), 6.80-6.70 (m, 6H), 5.08 (s, 1H), 5.00-4.82 (m, 2H), 4.47 (s, 1H), 4.10-4.25 (m, 2H), 3.39-3.20 (m, 2H), 1.63-1.75 (m, 1H), 1.25-1.38 (m, 1H), 1.31 (t, J= 7.0 Hz, 3H), 1.10-1.20 (m, 1H), 0.90-1.05 (m, 1H), 0.65 (t, J= 8.0 Hz, 3H); MS (ESI) 558.1 [M + H] ⁺ .

Step D. (i?)-2-((2 _l S,5i?,65)-2-(4-Fluorobenzyl)-5,6-bis(4-chlorophenyl)-3 - oxomorpholino)pentanoic acid

A solution of 2 M lithium hydroxide in H ₂ 0 (202 μΐ,, 405 μιηοΐ) was added to a solution of (i?)-ethyl 2-((2 _l S,5i?,65)-2-(4-fiuorobenzyl)-5,6-bis(4-chlorophenyl)-3 - oxomorpholino)pentanoate (113 mg, 202 μιηοΐ, Example 10, Step C) in MeOH/THF/H ₂ 0 (1/1/1, 2 mL, 0.1 M). After stirring at 25 °C for 4 hours, the reaction was concentrated under reduced pressure and acidified with 1 N aqueous HCl. The product was extracted with DCM (3x) and washed with brine. The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure to provide the title compound as a white solid. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.20-7.10 (m, 6H), 6.80-6.90 (m, 2H), 6.80-6.70 (m, 4H), 5.02 (s, 1H), 4.85-4.91 (m, 1H), 4.60-4.70 (m, 1H), 4.40 (s, 1H), 3.30-3.38 (m, 1H), 3.15-3.23 (m, 1H), 1.75-1.85 (m, 1H), 1.40-1.55 (m, 1H), 1.10-1.25 (m, 1H), 0.90-1.15 (m, 1H), 0.68 (t, J = 7.2 Hz, 3H); HRMS calcd for C ₂₈ H ₂₆ CI ₂ FNO ₄ , 530.1296; found, 530.1316.

EXAMPLE 1 1

(5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-methylmo rpholin-3-one and (5S,6R)-6- (3-chlorophenyl)-5-(4- hlorophenyl)-4-methylmorpholin-3-one

CI and CI

Step A. tert-Butyl (i?)-2-(3-chlorophenyl)-l-(4-chlorophenyl)-2-oxoethylcarbama te and tert-butyl (S)-2-(3 -chlorophenyl)- 1 -(4-chlorophenyl)-2-oxoethylcarbamate

3-Chlorophenylmagnesium bromide (200 mL, 99 mmol, 0.5 M in THF) was slowly added to a solution of (R)-tert- utyl l-(4-chlorophenyl)-2-(methoxy(methyl)amino)-2- oxoethylcarbamate and (S)-tert-butyl l-(4-chlorophenyl)-2-(methoxy(methyl)amino)-2- oxoethylcarbamate (13.00 g, 40 mmol, Example 4, Step B) in THF (180 mL) at 0 °C. After stirring at 25 °C overnight, the mixture was quenched with saturated NH ₄ CI solution (500 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgS0 ₄ and concentrated under reduced pressure. Flash column chromatography (Si0 ₂ , gradient elution of 5% to 20% ethyl acetate in hexanes) gave the title compounds. 1H NMR (400 MHz, CDCI ₃ , δ ppm): 7.93 (s, 1H), 7.78 (d, J= 7.8 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.26 - 7.38 (m, 5H), 6.20 (d, J= 7.4 Hz, 1H), 6.00 (d, J= 7.0 Hz, 1H), 1.45 (s, 9H).

Step B. tert-Butyl ((li?,25)-2-(3-chlorophenyl)-l-(4-chlorophenyl)-2- hydroxyethyl)carbamate and tert-butyl ((15',2i?)-2-(3-chlorophenyl)-l-(4-chlorophenyl)- 2-hydroxyethyl)carbamate

Sodium borohydride (0.7 g, 18 mmol) in THF (20 mL) was added dropwise over 3 minutes to a stirring solution of tert-butyl (i?)-2-(3-chlorophenyl)-l-(4-chlorophenyl)-2- oxoethylcarbamate and tert-butyl (5)-2-(3-chlorophenyl)-l-(4-chlorophenyl)-2- oxoethylcarbamate (7 g, 18 mmol, Example 11, Step A) in THF (100 mL) at 0 °C. The reaction was stirred while warming to 25 °C for 3 hours. After this time the reaction was treated with ethyl acetate and saturated sodium carbonate solution. The separated organic layer was washed with brine, dried over MgS0 ₄ and concentrated under reduced pressure to give the title compounds as a white solid.

1H NMR (400 MHz, DMSO-d ₆ , δ ppm): 7.20-7.38 (m, 8H), 5.50 (d, J

(dd, J= 8.4, 5.3 Hz, 1H), 4.53 (d, J= 9.4 Hz, 1H), 1.21 (s, 9H).

Step C. (15',2i?)-2-Amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethan ol and (lR,2S)-2- amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethanol

Trifluoroacetic acid (20 mL, 260 mmol) was added slowly over 20 minutes to a solution of tert-butyl ((li?,25)-2-(3-chlorophenyl)-l-(4-chlorophenyl)-2-hydroxyeth yl)carbamate and tert-butyl (( 1 S,2R)-2-(3 -chlorophenyl)- 1 -(4-chlorophenyl)-2-hydroxyethyl)carbamate (6.2 g, 16 mmol, Example 11, Step B) in DCM (30 mL) at 0 °C. After stirring at 25 °C for 3 hours, the reaction mixture was quenched with 4 M NaOH (pH 14), extracted with DCM (3x), washed with brine, dried over MgSC^ and concentrated under reduced pressure. Flash column chromatography (Si0 ₂ , eluent: 5% MeOH in DCM) gave the title compounds.

1H NMR (400 MHz, MeOH- ¼, δ ppm): 6.95 - 7.21 (m, 8H), 4.72 (d, J= 5.48 Hz, 1H), 3.94 (d, J= 5.28 Hz, 1H).

Step D. (5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)morpholin-3-on e and (5S,6R)-6- (3-chlorophenyl)-5-( -

C ^Cl

The title compounds were prepared from (15',2i?)-2-amino-l-(3-chlorophenyl)-2-(4- chlorophenyl)ethanol and (li?,25)-2-amino-l-(3-chlorophenyl)-2-(4- chlorophenyl)ethanol (Example 11, Step C) using the procedure described in Example 4, Step F.

¹ HNMR (400 MHz, CDC1 ₃ , δ ppm): 7.02 - 7.19 (m, 4H), 6.88 - 7.00 (m, 1H), 6.73 - 6.88 (m, 3H), 5.07 (d, J= 3.33 Hz, 1H), 4.51-4.66 (m, 2H), 4.40 (d, J= 16.82 Hz, 1H); MS (ESI) 322.0 [M + H] ⁺ . Step E. (5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-methylmorph olin-3- (55',6i?)-6-(3-chloroph nyl)-5-(4-chlorophenyl)-4-methylmorpholin-3-one

The title compounds were prepared from (5i?,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (5i?,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one (Example 11, Step D) using the procedure described in Example 4, Step G.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.06 - 7.22 (m, 4H), 6.96 (t, J= 1.96 Hz, 1H), 6.72 - 6.87 (m, 3H), 5.16 (d, J = 3.13 Hz, 1H), 4.65 (d, J = 16.82 Hz, 1H), 4.49 (d, J = 16.82 Hz, 1H), 4.38 (d, J= 3.13 Hz, 1H), 2.87 - 2.97 (s, 3H); MS (ESI) 336.1 [M + H] ⁺ .

EXAMPLE 12

(5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)morpholin-3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cycloprop ylmethyl)morpholin-3- one

CI and CI

Sodium hydride (0.2 g, 6 mmol, 60% suspension in oil) was added portionwise over 2 minutes to a stirring solution of (5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one (1.6 g, 5 mmol, Example 11, Step D) in DMF (6 mL) at 0 °C. The reaction was stirred at this temperature for 20 minutes and treated with cyclopropylmethyl bromide (0.8 mL, 6 mmol). After stirring at 25 °C for 4 hours, the reaction mixture was diluted with ethyl acetate and saturated NH ₄ C1 solution. The separated organic layer was dried, filtered and evaporated under a vacuum. Flash column chromatography (Si0 ₂ , gradient elution of 0% to 60% ethyl acetate in hexanes) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.02 - 7.20 (m, 4H), 6.87 - 7.00 (m, 1H), 6.68 - 6.87 (m, 3H), 5.13 (d, J= 3.13 Hz, 1H), 4.56 - 4.71 (m, 2H), 4.41 - 4.52 (m, 1H), 3.82 (dd, J = 14.28, 6.46 Hz, 1H), 2.54 (dd, J= 14.18, 7.73 Hz, 1H), 0.79 - 0.97 (m, 1H), 0.44 - 0.57 (m, 1H), 0.31 - 0.44 (m, 1H), 0.11 - 0.21 (m, 1H), -0.01 - 0.11 (m, 1H); HRMS calcd for C ₂ oHi ₉ Cl ₂ N02, 376.0868; found, 376.0868.

EXAMPLE 13

(25',5i?,65)-2-Benzyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-methylmorpholin-3-one and (2i?,55',6i?)-2-benzyl-6-(3-chlorophenyl)-5-(4-chlorophenyl) -4-methylmorpholin-3- one

CI and CI A solution of sodium bis(trimethylsilyl)amide (803 μί, 803 μιηοΐ, 1.0 M in THF) in THF (1.5 mL) was added dropwise via syringe to a solution of (5i?,65)-6-(3-chlorophenyl)-5- (4-chlorophenyl)-4-methylmorpholin-3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-methylmorpholin-3-one (180 mg, 535 μιηοΐ, Example 11, Step E) in THF (2.0 mL) over 4 minutes at -78 °C. The reaction was stirred for 20 minutes at this temperature and then l-(bromomethyl)benzene (95 μΐ,, 803 μιηοΐ) was added. After stirring at -78 °C for 2 hours, the reaction was quenched with saturated NH ₄ C1 solution and ethyl acetate. The separated organic layer was washed with brine, dried, filtered and evaporated under a vacuum. Flash column chromatography (Si0 ₂ , gradient elution of 0% to 50% ethyl acetate in hexanes) gave the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.09-6.93 (m, 9H), 6.63 (d, J= 8.2 Hz, 2H), 6.55 (d, J= 8.6 Hz, 2H), 5.01 (d, J= 2.7 Hz, 1H), 4.67 (dd, J= 8.2, 3.9 Hz, 1H), 4.13 (d, J= 3.1 Hz, 1H), 3.22-3.11 (m, 2H), 2.74 (s, 3H); MS (ESI) 426.1 [M + H] ⁺ .

EXAMPLE 14

(2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lopropylmethyl)-2-((5)-2,3- dihydroxypropyl)morpholin-3-one and (25',5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-2-((i?)-2,3-dihydroxypro pyl)morpholin-3-one and (25 ^* ,55 ^* ,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-2-((5)-2,3- dihydroxypropyl)morpholin-3-one and (25',55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-2-((i?)-2,3-dihydroxypro pyl)morpholin-3-one

Step A. (2S,5R,6S)-2-Allyl-6-(3-chlorophenyl)-5-(4-chloiophe-iyl)-4- (cyclopropylmethyl)morpholin-3-one and (2i?,55',6i?)-2-allyl-6-(3-chlorophi

chlorophenyl)-4-(cyclopropylmethyl)morpholin-3-one

CI and CI

A solution of (5i?,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)morpholin-3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)morpholin-3-one (330 mg, 877 μηιοΐ, Example 12) in THF (2.5 mL) was added dropwise over 4 minutes to a stirring solution of sodium bis(trimethylsilyl)amide (965 pL, 965 μπιοΐ, 1.0 M in THF) in THF (1.0 mL) at -78 °C. The reaction was stirred at this temperature for 25 minutes, and then treated with allyl bromide (83 μΐ,, 965 μιηοΐ). After stirring at -78 °C for 4 hours, the reaction was quenched with saturated NH ₄ C1 solution and ethyl acetate. The separated organic layer was washed with brine, dried, filtered and evaporated under a vacuum. Flash column chromatography (Si0 ₂ , gradient elution of 0% to 30% ethyl acetate in hexanes) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.05 - 7.23 (m, 4H), 6.93 - 7.05 (m, 1H), 6.83 (dt, J = 7.63, 1.76 Hz, 1H), 6.68 - 6.80 (m, 2H), 5.91 (ddt, J= 17.09, 10.15, 7.02, 7.02 Hz, 1H), 5.37 (d, J= 3.13 Hz, 1H), 5.04 - 5.20 (m, 2H), 4.60 - 4.76 (m, 2H), 3.83 (dd, J= 14.09, 6.46 Hz, 1H), 2.74 - 2.92 (m, 2H), 2.59 (dd, J= 14.28, 7.63 Hz, 1H), 0.78 - 0.94 (m, 1H), 0.46 - 0.60 (m, 1H), 0.14 - 0.27 (m, 1H), 0.33 - 0.46 (m, 1H), -0.01 - 0.14 (m, 1H); MS (ESI) 416.0 [M + H] ⁺ . Step B. (25',5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclop ropylmethyl)-2- ((S)-2,3-dihydroxypropyl)morpholin-3-one and (25',5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-2-((i?)-2,3-dihydroxypro pyl)morpholin-3-one and (25 ^* ,55 ^* ,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-2-((5)-2,3^ dihydroxypropyl)morpholin-3-one and (25',55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-2-((i?)-2,3-dihydroxypro pyl)morpholin-3-one

Potassium osmate(VI) dihydrate (10.6 mg, 28.8 μιηοΐ) and a solution of (2S,5R,6S)-2- allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylme thyl)morpholin-3-one and (2i?,5 _l S,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4 -

(cyclopropylmethyl)morpholin-3-one (240 mg, 576 μιηοΐ, Example 14, Step A) in acetone (1 mL) were added to a stirring solution of 4-methylmorpholine N-oxide (540 mg, 4612 μιηοΐ) in tert- uOH (3 mL) and water (3 mL). After stirring at 25 °C overnight, the reaction was quenched with saturated NH ₄ C1 solution, extracted with DCM, dried, and filtered. The solvent was removed under a vacuum and flash column chromatography (Si0 ₂ , gradient elution of 0% to 67% ethyl acetate in hexanes) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.10-7.21 (m, 4H), 6.96 (d, J= 1.8 Hz, 1H), 6.72- 6.83 (m, 1H), 5.28 (d, J= 2.9 Hz, 1H), 4.87-4.95 (m, 1H), 4.65 (d, J= 2.8 Hz, 1H), 4.01- 4.19 (m, 1H), 3.83 (dd, J= 14.2, 6.4 Hz, 1H), 3.31-3.67 (m, 1H), 2.58-2.66 (m, 1H), 2.21-2.40 (m, 2H), 2.00-2.07 (m, 1H), 0.86 - 0.99 (m, 1H), 0.51 - 0.58 (m, 1H), 0.39 - 0.46 (m, 1H), 0.17 - 0.23 (m, 1H), 0.06 - 0.13 (m, 1H); MS (ESI) 450.1 [M + H] ⁺ . EXAMPLE 15

(2-((25 ^* ,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-3- oxomorpholin-2-yl)acetaldehydeacetaldehyde and (2-((2i?,55',6i?)-6-(3-chlorophenyl)-5- (4-chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)a cetaldehydeacetaldehyde

Sodium periodate (47 mg, 222 μηιοΐ) and aqueous pH 7 buffer (0.5 mL) was added to a stirring solution of (25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-2-((5)-2,3-dihydroxypropyl)morpholin-3-o ne and (25 ^* ,5i?,65)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)-2-((i ?)-2,3- dihydroxypropyl)morpholin-3-one and (25',55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-2-((5)-2,3-dihydroxyprop yl)morpholin-3-one and (2 _l S ^* ,55 ^* ,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-2-((i?)-2,3- dihydroxypropyl)morpholin-3-one (20 mg, 44 μιηοΐ, Example 14, Step B) in THF (1.0 mL). The reaction was stirred at 25 °C for 4 hours and then diluted with DCM. The separated aqueous layer was extracted with DCM and the combined organic layers were dried, filtered and evaporated under a vacuum to give the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 9.83 (t, J= 1.66 Hz, 1H), 7.05 - 7.24 (m, 4H), 6.89 - 7.01 (m, 1H), 6.64 - 6.84 (m, 3H), 5.21 - 5.40 (m, 2H), 4.59 - 4.72 (m, 1H), 3.71 - 3.86 (m, 1H), 3.07 - 3.30 (m, 2H), 2.69 (dd, J= 14.09, 7.83 Hz, 1H), 0.83 - 0.97 (m, 1H), 0.49 - 0.59 (m, 1H), 0.38 - 0.46 (m, 1H), 0.13 - 0.27 (m, 1H), 0.02 - 0.13 (m, 1H). EXAMPLE 16

(25',5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclop ropylmethyl)-2-(2- hydroxyethyl)morpholin-3-one and (2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-2-(2-hydroxyethyl)morpholin-3-one

Sodium borohydride (1.8 mg, 48 μιηοΐ) was added to a stirring solution of (2- ((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3- oxomorpholin-2-yl)acetaldehydeacetaldehyde and (2-((2R,5S,6R)-6-(3-chlorophenyi)-5- (4-chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)a cetaldehydeacetaldehyde (20 mg, 48 μιηοΐ, Example 15) in THF. After stirring at 25 °C for 3 hours, the reaction was quenched with saturated NH ₄ C1 solution and ethyl acetate. The separated organic layer was washed with brine, dried, filtered and evaporated under a vacuum. Flash column chromatography (Si0 ₂ , gradient eluent of 0% to 70% ethyl acetate in hexanes) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.06 - 7.22 (m, 4H), 6.95 - 7.01 (m, 1H), 6.82 (dt, J = 7.63, 1.76 Hz, 1H), 6.72 - 6.78 (m, 2H), 5.33 (d, J= 3.13 Hz, 1H), 4.81 - 4.87 (m, 1H), 4.65 (d, J= 2.93 Hz, 1H), 3.78 - 3.92 (m, 3H), 2.62 (dd, J= 14.18, 7.73 Hz, 1H), 2.30 - 2.46 (m, 1H), 2.16 - 2.25 (m, 1H), 0.85 - 0.96 (m, 1H), 0.50 - 0.58 (m, 1H), 0.38 - 0.46 (m, 1H), 0.20 (dq, J= 9.76, 4.83 Hz, 1H), 0.05 - 0.13 (m, 1H); HRMS calcd for

C ₂ 2H ₂₃ C1 ₂ N0 ₃ , 420.1128; found, 420.1132.

EXAMPLE 17

(2-((25 ^* ,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-3- oxomorpholin-2-yl)acetic acid and (2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)acet ic acid

An aqueous solution of sodium chlorite (30 mg, 330 μιηοΐ) and monosodium dihydrogen phosphate (34 mg, 287 μιηοΐ) was added to a stirring solution of (2-((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)-3-oxo morpholin-2- yl)acetaldehydeacetaldehyde and (2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)acetaldehydeacetal dehyde (60 mg, 143 μιηοΐ, Example 15) in tert- uOH (2.5 mL) and 2-methyl-2-butene (1.5 mL) at 0 °C. The reaction was stirred in the dark while warming to 25 °C for 4 hours. After this time the reaction was diluted with ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried, filtered and evaporated under a vacuum. Flash column chromatography (Si0 ₂ , gradient elution of 0% to 70% ethyl acetate in hexanes) gave the title compounds as a white solid.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.08 - 7.20 (m, 4H), 6.95 - 6.98 (m, 1H), 6.81 (dt, J = 7.63, 1.56 Hz, 1H), 6.72 - 6.77 (m, 2H), 5.29 - 5.36 (m, 1H), 5.15 - 5.20 (m, 1H), 4.66 (d, J= 3.13 Hz, 1H), 3.78 (dd, J= 14.09, 6.46 Hz, 1H), 3.22 (dd, J= 16.24, 5.09 Hz, 1H), 3.02 (dd, J= 16.24, 7.83 Hz, 1H), 2.71 (dd, J= 14.09, 7.63 Hz, 1H), 0.84 - 0.97 (m, 1H), 0.50 - 0.58 (m, 1H), 0.38 - 0.46 (m, 1H), 0.20 (dq, J= 9.76, 4.77 Hz, 1H), 0.05 - 0.13 (m, 1H); MS (ESI) 434.0 [M + H] ⁺ .

EXAMPLE 18

(25',5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclop ropylmethyl)-2-(2- (methylamino)ethyl)morpholin-3-one and (2i?,55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-2-(2-(methylamino)ethyl) morpholin-3-one

Methylamine (251 μί, 502 μηιοΐ) and methylamine hydrochloride (23 mg, 335 μηιοΐ) were added to a stirring solution of (2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)acet aldehydeacetaldehyde and (2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)acetaldehydeacetaldehyde (70 mg, 167 μιηοΐ, Example 15) in MeOH (2 mL). The reaction was stirred for 1 hour, cooled to 0 °C, and treated with sodium cyanoborohydride (13 μί, 251 μιηοΐ) in MeOH (1.0 mL). The reaction was stirred for 2 hours and the solvent was evaporated under a vacuum. Flash column chromatography (Si0 ₂ , eluent: 5% MeOH in DCM) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.10 - 7.21 (m, 4H), 6.90 - 6.99 (m, 2H), 6.71 - 6.80 (m, 2H), 5.48 (d, J= 3.13 Hz, 1H), 4.68 - 4.83 (m, 2H), 3.68 (dd, J= 14.08, 6.46 Hz, 1H), 3.15 - 3.35 (m, 2H), 2.66 - 2.90 (m, 5H), 2.27 - 2.44 (m, 1H), 0.84 - 0.95 (m, 1H), 0.51 - 0.59 (m, 1H), 0.38 - 0.46 (m, 1H), 0.11 - 0.18 (m, 1H), -0.03 - 0.07 (m, 1H); MS (ESI) 433.1 [M + H] ⁺ . EXAMPLE 19

(25',5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclop ropylmethyl)-2-(3- hydroxypropyl)morpholin-3-one and (2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclopropylmethyl)-2-(3 -hydroxypropyl)morpholin-3 -one

9-Borabicyclo(3.3.1)nonane (1441 μΐ,, 721 μηιοΐ, 0.5 M in THF) was added dropwise over 2 minutes to a stirring solution of (25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)morpholin-3-one and (2R,5S,6R)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)morpho lin-3-one (100 mg, 240 μιηοΐ, Example 14, Step A) in THF at 0 °C. The reaction was stirred at this temperature for 3 hours, treated with additional 9-borabicyclo(3.3.1)nonane (1441 μΐ _^ , 721 μιηοΐ) and warmed to 25 °C. After 2 hours hydrogen peroxide (44 μΐ,, 1441 μιηοΐ) and 3 M aqueous NaOH (0.5 mL) were added. After 2 hours 25 °C, the reaction was quenched with aqueous Na ₂ S ₂ 0 ₃ and diluted with ether. The separated organic layer was washed with brine, dried, filtered and evaporated under a vacuum. Reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA, using a gradient elution of 0% to 100% acetonitrile, both eluents containing 0.1% TFA, 45 minutes) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.07 - 7.22 (m, 4H), 6.99 (t, J= 1.96 Hz, 1H), 6.83 (dt, J= 7.63, 1.76 Hz, 1H), 6.71 - 6.79 (m, 2H), 5.31 (d, J= 3.13 Hz, 1H), 4.61 - 4.71 (m, 2H), 3.84 (dd, J= 14.18, 6.36 Hz, 1H), 3.65 - 3.76 (m, 2H), 2.56 (dd, J= 14.18, 7.73 Hz, 1H), 2.18 - 2.28 (m, 1H), 1.95 - 2.15 (m, 1H), 1.71 - 1.87 (m, 2H), 0.84 - 0.97 (m, 1H), 0.49 - 0.58 (m, 1H), 0.37 - 0.46 (m, 1H), 0.15 - 0.23 (m, 1H), 0.05 - 0.13 (m, 1H).

EXAMPLE 20

3-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lopropylmethyl)-3- oxomorpholin-2-yl)propanoic acid and 3-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)prop anoic acid

Step A. (3-((25 ^* ,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-3- oxomorpholin-2-yl)propanal and (3-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)propanal

CI and CI

Sodium hydrogen carbonate (17 mg, 207 μιηοΐ) and Dess-Martin periodinane (26 mg, 62 μιηοΐ) were added to a stirring solution of (25',5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-2-(3 -hydroxypropyl)morpholin-3 -one and

(2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cy clopropylmethyl)-2-(3- hydroxypropyl)morpholin-3-one (18 mg, 41 μιηοΐ, Example 19) in DCM (4.0 mL). The reaction was stirred at room temperature for 3 hours, then treated with additional Dess- Martin reagent (26 mg, 62 μιηοΐ). After stirring at 25 °C for 1 hour, the reaction was diluted with ethyl acetate and treated with aqueous Na ₂ S ₂ 0 ₃ and NaHC0 ₃ . The mixture was stirred for 30 minutes, and then the separated organic layer was dried, filtered and evaporated under a vacuum to give the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 9.74 (t, J= 1.27 Hz, 1H), 7.08 - 7.23 (m, 4H), 6.91 - 6.99 (m, 1H), 6.82 (dt, J= 7.63, 1.76 Hz, 1H), 6.65 - 6.76 (m, 2H), 5.28 (d, J= 3.13 Hz, 1H), 4.58 - 4.70 (m, 2H), 3.84 (dd, J= 14.09, 6.46 Hz, 1H), 2.63 - 2.74 (m, 2H), 2.57 (dd, J= 14.08, 7.63 Hz, 1H), 2.32 - 2.51 (m, 2H), 0.84 - 0.96 (m, 1H), 0.50 - 0.59 (m, 1H), 0.38 - 0.47 (m, 1H), 0.15 - 0.23 (m, 1H), 0.05 - 0.13 (m, 1H).

Ste B. (3-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lopropylmethyl)-3- oxomorpholin-2-yl)propanoic acid and (3-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)prop anoic acid

An aqueous solution of sodium chlorite (5 mg, 52 μιηοΐ) and monosodium dihydrogen phosphate (6 mg, 52 μιηοΐ) was added to a stirring solution of (3-((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)-3-oxo morpholin-2-yl)propanal and (3-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(c yclopropylmethyl)-3- oxomorpholin-2-yl)propanal (9 mg, 21 μιηοΐ, Example 20, Step A) in tert- uOH (2.5 mL) and 2-methyl-2-butene (1.5 mL) at 0 °C. The reaction was stirred in the dark for 4 hours while warming slowly to 25 °C. The reaction was diluted with ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried, filtered and evaporated under a vacuum. Preparative reverse phase HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA, using a gradient elution of 10% to 90% acetonitrile in water, where both solvents contain 0.1 %> TFA, 45 minutes) gave the title compounds as a white solid.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.02 - 7.19 (m, 4H), 6.96 (t, J= 1.96 Hz, 1H), 6.80 (dt, J= 7.48, 1.74 Hz, 1H), 6.69 - 6.76 (m, 2H), 5.28 (d, J= 3.13 Hz, 1H), 4.60 - 4.66 (m, 2H), 3.83 (dd, J= 14.18, 6.36 Hz, 1H), 2.32 - 2.61 (m, 5H), 0.84 - 0.96 (m, 1H), 0.50 - 0.58 (m, 1H), 0.38 - 0.46 (m, 1H), 0.15 - 0.23 (m, 1H), 0.05 - 0.12 (m, 1H); HRMS calcd for C2 ₃ H ₂₃ C1 ₂ N04, 448.1077; found, 448.1081.

EXAMPLE 21

2-((25',5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lopropylmethyl)-3- oxomorpholin-2-yl)acetic acid

The enantiomers from (2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-3-oxomorpholin-2-yl)acetic acid and (2-((2R,5S,6R)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)-3-oxo morpholin-2-yl)acetic acid (Example 17) were separated by chiral HPLC (flow rate: 18 mL/min, Chiralcel® OD-H 30 mm I.D.x250 mm, 5 μιη column (Daicel Inc., Fort Lee, NJ), eluent: 40% isopropyl alcohol in hexanes) to give the title compound as the first (faster) eluting isomer (t _R = 8.2 minutes, [a] _D ²³ +158° (c 1.12, MeOH).

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.08 - 7.20 (m, 4H), 6.95 - 6.98 (m, 1H), 6.81 (dt, J = 7.63, 1.56 Hz, 1H), 6.72 - 6.77 (m, 2H), 5.29 - 5.36 (m, 1H), 5.15 - 5.20 (m, 1H), 4.66 (d, J= 3.13 Hz, 1H), 3.78 (dd, J= 14.09, 6.46 Hz, 1H), 3.22 (dd, J= 16.24, 5.09 Hz, 1H), 3.02 (dd, J= 16.24, 7.83 Hz, 1H), 2.71 (dd, J= 14.09, 7.63 Hz, 1H), 0.84 - 0.97 (m, 1H), 0.50 - 0.58 (m, 1H), 0.38 - 0.46 (m, 1H), 0.20 (dq, J= 9.76, 4.77 Hz, 1H), 0.05 - 0.13 (m, 1H); MS (ESI) 434.0 [M + H] ⁺ .

EXAMPLE 22

2-((2i?,55 ^* ,6i?)-6-(3-Chlophenyl)-5-(4-chlorophenyl)-4-(cycloprop ylmethyl)-3- oxomorpholin-2-yl)acetic acid

Further elution from Example 21 provided the title compound as the second (slower) eluting isomer (t _R = 12.4 minutes, [a] _D ²³ -156° (c 1.13, MeOH).

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.08 - 7.20 (m, 4H), 6.95 - 6.98 (m, 1H), 6.81 (dt, J = 7.63, 1.56 Hz, 1H), 6.72 - 6.77 (m, 2H), 5.29 - 5.36 (m, 1H), 5.15 - 5.20 (m, 1H), 4.66 (d, J= 3.13 Hz, 1H), 3.78 (dd, J= 14.09, 6.46 Hz, 1H), 3.22 (dd, J= 16.24, 5.09 Hz, 1H), 3.02 (dd, J= 16.24, 7.83 Hz, 1H), 2.71 (dd, J= 14.09, 7.63 Hz, 1H), 0.84 - 0.97 (m, 1H), 0.50 - 0.58 (m, 1H), 0.38 - 0.46 (m, 1H), 0.20 (dq, J= 9.76, 4.77 Hz, 1H), 0.05 - 0.13 (m, 1H); MS (ESI) 434.0 [M + H] ⁺ .

EXAMPLE 23

2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lobutylmethyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclobutylmethyl)-3-oxomorpholin-2-yl)acetic acid

CI and CI

Step A. (5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclobutyl methyl)morpholin- 3 -one and (55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4- (cyclobutylmethyl)mor holin-3 -one

CI and CI The title compounds were prepared from (5i?,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one (Example 11, Step D) using the method described in Example 12, substituting cyclobutylmethyl bromide for cyclopropylmethyl bromide.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.18-7.07 (m, 5H), 6.92 (s, 1H), 6.80-6.73 (m, 2H), 5.08 (d, J= 4.0 Hz, 1H), 4.63 (d, J= 16.0 Hz, 1H), 4.48 (d, J= 16.0 Hz, 1H), 4.39 (d, J = 4.0 Hz, 1 Hz, 1H), 3.85-3.95 (m, 1H), 2.75-2.80 (m, 1H), 2.53-2.65 (m, 1H), 2.04-1.60 (m, 6H); MS (ESI) 390.7 [M + H] ⁺ .

Step B. (2 _l S,5i?,65)-2-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-4- (cyclobutylmethyl)morpholin-3-one and (2i?,55',6i?)-2-Allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclobutylmethyl)morpholin-3-one

The title compounds were prepared from (25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclobutylmethyl)morpholin-3-one and (2i?,55',6i?)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-(cyclobutylmethyl)morphol in-3-one (Example 23, Step A) using the method described in Example 14, Step A.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.20-7.07 (m, 4H), 6.95 (s, 1H), 6.75-6.85 (m, 1H), 6.72 (d, J= 12.0 Hz, 2H), 5.80-6.00 (m, 1H), 5.31 (s, 1H), 5.17-5.08 (m, 2H), 4.65-4.73 (m, 1H), 4.38 (s, 1H), 3.90-4.00 (m, 1H), 2.85-2.56 (m, 3H), 2.50-2.60 (m, 1H), 2.09- 1.66 (m, 4H), 1.65-1.75 (m, 2H); MS (ESI) 430.1 [M + H] ⁺ . Ste C. 2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lobutylmethyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclobutylmeth l)-3-oxomorpholin-2-yl)acetic acid

Sodium periodate (60 mg, 279 μιηοΐ) and ruthenium trichloride hydrate (0.8 mg, 3.6 μιηοΐ) were added to a stirring solution of (25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclobutylmethyl)morpholin-3-one and (2R,5S,6R)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-(cyclobutylmethyl)morphol in-3-one (30 mg, 70 umol, Example 23, Step B) in CCUiacetonitrileiwater (1 mL: l mL:2 mL). The reaction was stirred at room temperature for 4 hours, treated with ethyl acetate, and acidified to pH 2 with 1 M HCl. The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were dried, filtered and evaporated under a vacuum. The residue was purified by preparative reverse phase HPLC (Gemini™ Prep C18 5 μιη column, Phenomenex, Torrance, CA, gradient elution of 0% to 100% acetonitrile, both eluents containing 0.1 % TFA, 45 minutes) to give the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 1.61 - 1.75 (m, 2H), 1.77 - 1.96 (m, 3H), 1.96 - 2.05 (m, 1H), 2.48 - 2.59 (m, 1H), 2.87 - 3.03 (m, 2H), 3.17 (dd, J= 16.14, 5.38 Hz, 1H), 3.83 (dd, J= 13.79, 7.53 Hz, 1H), 4.40 (d, J= 2.93 Hz, 1H), 5.12 - 5.17 (m, 1H), 5.23 - 5.28 (m, 1H), 6.66 - 6.75 (m, 2H), 6.75 - 6.81 (m, 1H), 6.90 - 6.95 (m, 1H), 7.05 - 7.13 (m, 1H), 7.13 - 7.22 (m, 3H). MS (ESI) 448.1 [M + H] ⁺ . EXAMPLE 24

(25',5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-isobuty l-3-oxomorpholin-2- yl)acetic acid and (2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-isobut yl-3- xomorpholin-2-yl)acetic acid

The title compounds were prepared from (5i?,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one (Example 11, Step D) using the methods described in Example 23, Steps A to C, substituting isobutyl bromide for cyclopropylmethyl bromide in Step A.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 0.89 - 1.00 (m, 6H), 1.97 - 2.08 (m, 1H), 2.42 (dd, J = 13.60, 6.94 Hz, 1H), 3.05 (dd, J= 16.33, 7.73 Hz, 1H), 3.20 (dd, J= 16.33, 4.99 Hz, 1H), 3.80 (dd, J= 13.50, 8.41 Hz, 1H), 4.44 (d, J= 2.93 Hz, 1H), 5.14 (dd, J= 7.73, 4.99 Hz, 1H), 5.29 - 5.36 (m, 1H), 6.70 - 6.76 (m, 2H), 6.81 (dt, J= 7.63, 1.66 Hz, 1H), 6.96 (t, J= 1.96 Hz, 1H), 7.08 - 7.21 (m, 4H); MS (ESI) 436.1 [M + H] ⁺ .

EXAMPLE 25

2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyc lohexylmethyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclohexylmethyl)-3-oxomorpholin-2-yl)acetic acid

and

The title compounds were prepared from (5i?,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one (Example 11, Step D) using the methods described in Example 23, Steps A to C, substituting cyclohexylmethylbromide for cyclopropylmethyl bromide in Step A.

1H NMR (400 MHz, MeOH- ¼, δ ppm): 0.89 - 1.07 (m, 2H), 1.13 - 1.22 (m, 2H), 1.58 - 1.80 (m, 6H), 2.60 (dd, J= 13.69, 6.85 Hz, 1H), 2.96 - 3.12 (m, 2H), 3.64 (dd, J= 13.69, 7.63 Hz, 1H), 4.68 (d, J= 3.13 Hz, 1H), 4.80-4.90 (m, 1H), 5.18 (dd, J= 9.10, 4.01 Hz, 1H), 5.55 (d, J= 3.13 Hz, 1H), 6.86 - 6.94 (m, 2H), 6.96 - 7.04 (m, 2H), 7.13 - 7.23 (m, 4H). MS (ESI) 476.2 [M + H] ⁺ .

EXAMPLE 26

2-((25',5i?,65)-4-Benzyl-6-(3-chlorophenyl)-5-(4-chloropheny l)-3-oxomorpholin-2- yl)acetic acid and 2-((2i?,55',6i?)-4-benzyl-6-(3-chlorophenyl)-5-(4-chlorophen yl)-3- oxomorpholin-2-yl)acetic acid

CI and CI The title compounds were prepared from (5i?,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one (Example 1 1 , Step D) using the methods described in Example 23, Steps A to C, substituting benzylbromide for cyclopropylmethyl bromide in Step A.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 3.00-3.25 (m, 2H), 3.51 (d, J = 14.48 Hz, 1H), 4.28 - 4.35 (m, 1H), 5.22 (dd, J = 2.35, 0.59 Hz, 1H), 5.25 - 5.34 (m, 1H), 5.45 - 5.59 (m, 1H), 6.66 - 6.79 (m, 3H), 6.81 - 6.88 (m, 1H), 7.01 - 7.09 (m, 1H), 7.09 - 7.25 (m, 5H), 7.33 - 7.45 (m, 3H). MS (ESI) 470.0 [M + H] ⁺ .

EXAMPLE 27

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-fiuorobenzyl)-5 -oxomorpholino)-N- (methylsulfonyl)pentanamide and (5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxomorpholino)-N-(methylsulfonyl)pentanamide

CI CI and CI CI

Step A. (i?)-2-((2^,5i?,65)-2-(4-fluorobenzyl)-5,6-bis(4-chloropheny l)-3- oxomorpholino)pentanoic acid and (5)-2-((2i?,5S,6i?)-2-(4-fluorobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomor holino)pentanoic acid

The title compounds were prepared from ( ?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate and (5)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 10, Step A) using the methods described in

Example 10, Steps C and D.

Step B. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)-N-(methylsulfonyl)pentanamide and (5)-2-((2i?,3S,6i?)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)-N-(methyls ulfonyl)pentanamide

Methanesulfonamide (65 mg, 679 μιηοΐ) was added to a solution of Ι,Γ- carbonyldiimidazole (110 mg, 679 μιηοΐ), N-ethyl-N-isopropylpropan-2-amine (151 μί, 848 μπιοΐ) and (i?)-2-((2^,5i?,65)-2-(4-fluorobenzyl)-5,6-bis(4-chloropheny l)-3- oxomorpholino)pentanoic acid and (5)-2-((2i?,5S,6i?)-2-(4-fluorobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanoic acid (90 mg, 0.17 mmol, Example 27, Step A) in THF (2 mL). The reaction was stirred at reflux for 12 hours, quenched with saturated NH ₄ CI solution, and extracted with ethyl acetate. The organic layer was dried over MgS0 ₄ and concentrated under reduced pressure. The residue was purified by

preparative reverse phase HPLC (Gemini™ Prep CI 8 5 μιη column (Phenomenex, Torrance, CA), (40 minutes, elution gradient of 50% to 90% acetonitrile in water, where both solvents contain 0.1% TFA) to give the title compounds as a white solid.

1H NMR (400 MHz, OMSO-d ₆ , δ ppm): 7.26 - 7.18 (m, 6H), 7.05 - 6.95 (m, 4H), 6.88 (d, J= 8.0 Hz, 2H), 5.30 (d, J= 4.0 Hz, 1H), 5.06 (m, 1H), 5.0 (d, J= 4.0 Hz, 1H), 4.93 (m, 1H), 3.32 (s, 3H), 3.29 (m, 1H), 3.15-3.25 (m, 1H), 1.50-1.65 (m, 1H), 1.40-1.45 (m, 1H), 0.95-1.10 (m, 1H), 0.65-0.80 (m, 1H), 0.41 (t, J= 8.0 Hz, 3H); MS (ESI) 607.2 [M + H] ⁺ .

EXAMPLE 28

l-((i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)pentanoyl)azetidine-3-carboxylic acid and l-((5)-2-((2i?,3S,6i?)-2,3- bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)penta noyl)azetidine-3- carboxylic acid

CI CI and CI CI

Step A. Methyl l-((i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-fiuorobenzyl)-5 - oxomorpholino)pentanoyl)azetidine-3-carboxylate and methyl l-((5)-2-((2i?,3S,6i?)-2,3- bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)penta noyl)azetidine-3- carboxylate

CI CI and CI CI

N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.158 mmol), HOAt (22 mg, 0.158 mmol) and sodium bicarbonate (22 mg, 0.264 mmol) were successively added to a solution of (i?)-2-((25',5i?,65)-2-(4-fluorobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanoic acid and (S)-2-((2R,5S,6R)-2-(4- fluorobenzyl)-5,6-bis(4-chlorophenyl)-3-oxomorpholino)pentan oic acid (70 mg, 0.132 mmol, Example 27, Step A) and methyl azetidine-3-carboxylate (18 mg, 0.158 mmol) in DMF (1.5 mL). After stirring at room temperature for 18 hours, the reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over MgS0 ₄ and concentrated. Purification of the residue by flash chromatography (Si0 ₂ , eluent 50% ethyl acetate/hexanes) provided the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.16-7.06 (m, 6H), 6.85-6.95 (m, 2H), 6.80-6.85 (m, 2H), 6.68-6.75 (m, 2H), 5.23 (s, 1H), 5.06 (s, 1H), 5.05 (s, 1H), 4.83-4.93 (m, 1H), 4.62- 4.75 (m, 1H), 4.40-4.20 (m, 3H), 3.01 (s, 3H), 3.52-3.22 (m, 3H), 1.35-1.50 (m, 1H), 1.15-1.25 (m, 3H), 0.60 (t, J= 8.0 Hz, 3H); MS (ESI) 627.1 [M+H] -

Step B. l-((i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)pentanoyl)azetidine-3-carboxylic acid and l-((5)-2-((2i?,3S,6i?)-2,3- bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)penta noyl)azetidine-3- carboxylic acid

The title compounds were prepared from methyl l-((R)-2-((2S,3R _> 6S)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)pentanoyl)a zetidine-3-carboxylate and methyl l-((5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-fiuorobe nzyl)-5- oxomorpholino)pentanoyl)azetidine-3-carboxylate (Example 28, Step A) using the method described in Example 10, Step D.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.16-7.30 (m, 6H), 7.00-7.10 (m, 2H), 6.75-6.95 (m, 4H), 4.85-5.50 (m, 4H), 3.90-4.60 (m, 5H), 3.20-3.60 (m, 3H), 1.25-1.40 (m, 1H), 0.95- 1.10 (m, 1H), 0.80-0.95 (m, 1H), 0.50 (t, J= 8.0 Hz, 3H); MS (ESI) 613.2 [M + H] ⁺ .

EXAMPLE 29

(i?)-2-((2 _l S,3i?,65)-2-(4-Chloro-3-fluorophenyl)-3-(4-chloropheny l)-6-(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid and (5)-2-((2i?,3S,6i?)-2-(4-chloro-3-fluorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)pentanoic acid or (5)-2-((25',3i?,65)- 2-(4-chloro-3-fluorophenyl)-3-(4-chlorophenyl)-6-(4-fluorobe nzyl)-5- oxomorpholino)pentanoic acid and (i?)-2-((2i?,3S,6i?)-2-(4-chloro-3-fluorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)pentanoic acid

Step A. (5i?,65)-6-(4-Chloro-3-fluorophenyl)-5-(4-chlorophenyl)morph olin-3- (55',6i?)-6-(4-chloro-3-fluorophenyl)-5-(4-chlorophenyl)morp holin-3-one

The title compounds were prepared as described in Example 4, Steps A to F, substituting 3-fluoro-4-chlorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide in Step C. 1H NMR (400 MHz, DMSO-< , 5 ppm): 8.77 (d, J= 4.0 Hz, 1H), 7.35-7.45 (m, 1H), 7.24 (d, J= 4.0 Hz, 2H), 7.05 (d, J= 4.0 Hz, 1H), 6.95-6.80 (m, 3H), 5.28 (d, J= 4.0 Hz, 1H), 4.81 (d, J= 4.0 Hz, 1H), 4.49 (d, J= 12.0 Hz, 1H), 4.38 (d, J= 12.0 Hz, 1H); MS (ESI) 340.0 [M + H] ⁺ . Ste B. (R)-2-((2S R,6S)-2 4-CMoro-3-fluorophenyl)-3-(4-chloropheiiyl)-6-(4- fluorobenzyl)-5-oxomorpholino)pentanoic acid and (5)-2-((2i?,3S,6i?)-2-(4-Chloro-3- fluorophenyl)-3-(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomor pholino)pentanoic acid or (5)-2-((2^,3i?,65)-2 4-chloro-3-fluorophenyl)-3-(4-chlorophenyl)-6-(4-fluorobenzy l)-5- oxomorpholino)pentanoic acid and (i?)-2-((2i?,3S,6i?)-2-(4-chloro-3-fluorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)pentanoic acid

The title compounds were prepared from (5i?,6S)-6-(4-chloro-3-fluorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (55',6i?)-6-(4-chloro-3-fluorophenyl)-5-(4- chlorophenyl)morpholin-3-one (Example 29, Step A) by the methods described in Example 10, Steps A, C and D.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.15-7.04 (m, 5H), 6.75-6.85 (m, 2H), 6.65-6.75 (m, 2H), 6.56-6.49 (m, 2H), 4.91 (s, 1H), 4.85 (s, 1H), 4.45-4.65 (m, 1H), 4.40 (s, 1H), 3.10-3.30 (m, 2H), 1.75-1.90 (m, 1H), 1.35-1.55 (m, 1H), 1.10-1.20 (m, 1H), 0.90-1.10 (m, 1H), 0.60 (s, 3H); MS (ESI) 548.0 [M + H] ⁺ .

EXAMPLE 30

(i?)-2-((2 _l S,3i?,65)-2-(4-Chloro-2-methylphenyl)-3-(4-chloropheny l)-6-(4-fluorobenzyl)- 5-oxomorpholino)pentanoic acid and (5)-2-((2i?,3S,6i?)-2-(4-chloro-2-methylphenyl)-3- (4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)pentanoi c acid or (5)-2- ((25 ^* ,3i?,65)-2-(4-chloro-2-methylphenyl)-3-(4-chlorophenyl )-6-(4-fluorobenzyl)-5- oxomorpholino)pentanoic acid and (R)-2-((2R,3S,6R)-2-(4-chloro-2-methylphenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)pentanoic acid

CI CI and CI CI

Step A. (5i?,65)-6-(4-Chloro-2-methylphenyl)-5-(4-chlorophenyl)morph olin-3- (55',6i?)-6-(4-chloro-2-methylphenyl)-5-(4-chlorophenyl)morp holin-3-one

The title compounds were prepared as described in Example 4, Steps A to F, substituting 4-chloro-2-methylphenylmagnesium bromide for 4-chlorophenylmagnesium bromide in Step C.

1H NMR (400 MHz, OMSO-d ₆ , δ ppm): 8.70 (s, 1H), 7.20-7.25 (m, 3H), 6.80-6.90 (m, 3H), 6.43 (d, J= 8.0 Hz, 1H), 5.33 (d, J= 4.0 Hz, 1H), 4.65-4.75 (m, 1H), 4.30-4.50 (m, 2H), 2.42 (s, 3H).

Step B. (i?)-2-((2 _l S,3i?,65)-2-(4-Chloro-2-methylphenyl)-3-(4-chloropheny l)-6-(4- fluorobenzyl)-5-oxomorpholino)pentanoic acid and (5)-2-((2i?,3S,6i?)-2-(4-chloro-2- methylphenyl)-3-(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomor pholino)pentanoic acid or (5)-2-((25 ^* ,3i?,65)-2-(4-chloro-2-methylphenyl)-3-(4-chlorophenyl )-6-(4-fluorobenzyl)- 5-oxomorpholino)pentanoic acid and (i?)-2-((2i?,3S,6i?)-2-(4-chloro-2-methylphenyl)-3- (4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)pentanoi c acid

The title compounds were prepared from (5i?,6S)-6-(4-chloro-2-methylphenyl)-5-(4- chlorophenyl)morpholin-3-one and (55',6i?)-6-(4-chloro-2-methylphenyl)-5-(4- chlorophenyl)morpholin-3-one (Example 30, Step A) by the methods described in Example 10, Steps A, C and D.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.32-7.24 (m, 5H), 7.10-7.07 (m, 2H), 6.80-7.01 (m, 3H), 6.55 (d J= 4.0 Hz, 1H), 5.19 (d, J= 4.0 Hz, 1H), 5.11 (s, 1H), 4.75-4.90 (m, 1H), 4.57 (s, 1H), 3.65-3.75 (m, 1H), 3.30-3.45 (m, 1H), 2.27 (s, 3H), 1.95-2.10 (m, 1H), 1.70- 1.85 (m, 1H), 1.45-1.55 (m, 1H), 1.20-1.35 (m, 1H), 0.60 (t, J= 8.0 Hz, 3H); MS (ESI) 542.0 [M - H] ⁺ .

EXAMPLE 31

(i?)-4-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)heptanoic acid and (5)-4-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenz l)-5-oxomorpholino)heptanoic acid

CI CI and CI CI

Step A. (i?)-Ethyl 2-((2 _l S,5i?,65)-2-(4-fluorobenzyl)-5,6-bis(4-chlorophenyl)-3 - oxomorpholino)pentanoate and (5)-ethyl 2-((2i?,5S,6i?)-2-(4-fluorobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanoate

The title compounds were prepared from ( ?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate and (5)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 10, Step A) by the method described in Example 10, Step C.

Step B . (2S,5R,6S)-5 ,6-Bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((i?)- 1 -hydroxypentan- 2-yl)morpholin-3-one and (2i?,55 ^, ,6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-((i ?)- 1 -hydroxypentan-2-yl)morpholin-3 -one

CI CI and CI CI

Sodium borohydride (81.3 mg, 2149 μιηοΐ) was added to a solution of (i?)-ethyl 2- ((25',5i?,65)-2-(4-fluorobenzyl)-5,6-bis(4-chlorophenyl)-3-o xomorpholino)pentanoate and (S)-ethyl 2-((2i?,5 _l S,6i?)-2-(4-fiuorobenzyl)-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanoate (400 mg, 716 μιηοΐ, Example 31 , Step A) in DME/MeOH (5 : 1 , 15 mL) at 0 °C. After stirring at room temperature for 16 hours, the reaction was quenched with saturatedNH4Cl, extracted with ethyl acetate, and washed with 1 N NaOH and brine. The organic layer was dried over MgSC^ and concentrated to give the title compounds as a white solid. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.20-7.12 (m, 6H), 6.90-7.00 (m, 2H), 6.75-6.72 (m, 4H), 4.89 (d, J= 4.0 Hz, 1H), 4.85-4.90 (m, 1H), 4.26 (d, J= 4.0 Hz, 1H), 3.75-3.85 (m, 1H), 3.70-3.60 (m, 2H), 3.45-3.60 (m, 1H), 3.35-3.45 (m, 1H), 3.20-3.30 (m, 1H), 1.70- 1.59 (m, 2H), 1.40-1.10 (m, 2H), 0.89 (t, J= 8.0 Hz, 3H).

Step C. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)pentanal and (S)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)- -oxomorpholino)pentanal

Dimethylsulfoxide (45 μί, 639 μηιοΐ) in DCM (1 mL) was added to a solution of oxalyl dichloride (28 μί, 320 μιηοΐ) in DCM (1 mL) at -60 °C under N ₂ . The mixture was stirred at -60 °C for 2 minutes, and a solution of (25',5i?,65)-2-(4-fluorobenzyl)-5,6-bis(4- chlorophenyl)-4-((i?)- 1 -hydroxypentan-2-yl)morpholin-3-one and (2R,5S,6R)-2-(4- fluorobenzyl)-5,6-bis(4-chlorophenyl)-4-((i?)-l-hydroxypenta n-2-yl)morpholin-3-one (150 mg, 290 μιηοΐ, Example 31, Step B) in DCM (1 mL) was added. The resulting solution was stirred for 15 minutes and triethylamine (203 μΐ,, 1452 μιηοΐ) was added. After stirring at -60 °C for 5 minutes, the reaction was allowed to warm to room temperature, then 5 mL of water was added. The solution was extracted with DCM and washed with brine. The organic layer was dried over MgS0 ₄ and concentrated to give the title compounds as a white solid.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 9.46 (s, 1H), 7.20-7.12 (m, 6H), 6.90-7.00 (m, 2H), 6.81-6.75 (m, 4H), 5.04 (d, J= 4.0 Hz, 1H), 4.90-4.95 (m, 1H), 4.24 (d, J= 4.0 Hz, 1H), 3.75-3.85 (m, 1H), 3.35-3.48 (m, 1H), 3.20-3.30 (m, 1H), 1.90-2.10 (m, 1H), 1.70-1.85 (m, 1H), 1.40-1.26 (m, 2H), 0.89 (t, J= 8.0 Hz, 3H); MS (ESI) 514.2 [M+H] - Step D. (R)-Ethyl 4-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)hept-2-enoate and (5)-ethyl 4-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl) fluorob

A solution of ethyl 2-(diethoxyphosphoryl)acetate (62 μΐ,, 303 μηιοΐ) and DMPU (0.3 mL) in THF (1 mL) was added to a well stirred suspension of sodium hydride (1 1 mg, 278 μηιοΐ, 60% dispersion in mineral oil) in THF (1 mL) at 0 °C. The mixture was stirred for 30 minutes, and treated with a solution of (R)-2-((2S,5R,6S)-2-(4- fluorobenzyl)-5,6-bis(4-chlorophenyl)-3-oxomorpholino)pentan al and (S)-2-((2R,5S,6R)- 2-(4-fluorobenzyl)-5,6-bis(4-chlorophenyl)-3-oxomorpholino)p entanal (130 mg, 253 μιηοΐ, Example 31 , Step C) in THF (1 mL). After stirring for 12 hours, the reaction was quenched with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over MgSC^ and concentrated to give the title compounds.

Step E. (R)-Ethyl 4-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-fiuorobenzyl)-5 - oxomorpholino)heptanoate and (5)-ethyl 4-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4- fluorob

10% Palladium on carbon (15 mg, 14 μιηοΐ) was added to a solution of (i?)-ethyl 4- ((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-o xomorpholino)hept-2-enoate and (S)-ethyl 4-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5 - oxomorpholino)hept-2-enoate (80 mg, 137 μιηοΐ, Example 31, Step D) in EtOH (4.4 mL) at room temperature. The reaction mixture was hydrogenated under atmospheric pressure at room temperature. After stirring at room temperature for 1 hour, the mixture was filtered through a short plug of silica gel, and the solid was washed with ethyl acetate. The filtrate was concentrated to give the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.15-7.05 (m, 6H), 6.75-6.85 (m, 2H), 6.70-6.65 (m, 4H), 4.80-4.85 (m, 1H), 4.67-4.68 (m, 1H), 4.20-4.35 (m, 1H), 4.10-4.20 (m, 1H), 4.00- 4.08 (m, 2H), 3.25-3.35 (m, 1H), 3.10-3.20 (m, 1H), 2.10-2.20 (m, 1H), 1.90-2.05 (m, 1H), 1.80-1.90 (m, 2H), 1.25-0.75 (m, 7H), 0.56 (t, J= 8.0 Hz, 3H). Step F. (25 ^* ,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4- ((i?)-l-hydroxypentan- 2-yl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-( (i?)- 1 -hydroxypentan-2-yl)morpholin-3 -one

CI CI and CI CI The title compounds were prepared from (i?)-ethyl 4-((25',3i?,65)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholino)heptanoate and (5)-ethyl 4- ((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-o xomorpholino)heptanoate (Example 31, Step E) by the method described in Example 10, Step D.

1H NMR (400 MHz, OMSO-d ₆ , δ ppm): 7.24-7.15 (m, 6H), 7.10-7.00 (m, 4H), 7.00-6.90 (m, 2H), 5.29 (s, 1H), 4.88-4.98 (m, 1H), 4.65 (s, 1H), 3.30-3.40 (m, 1H), 3.15-3.25 (m, 1H), 2.50-2.65 (m, 1H), 2.10-2.20 (m, 1H), 1.95-2.05 (m, 1H), 1.75-1.85 (m, 1H), 1.10- 0.60 (m, 5H), 0.49 (t, J = 8.0 Hz, 3H); MS (ESI) 558.1 [M+H] -

EXAMPLE 32

4-((i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)pentanamido)butanoic acid

Step A. (R)-Ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)-5- oxomorpholino)pentanoate

The title compound was prepared from (i?)-ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 10, Step B) by the method described in Example 10, Step C, substituting 4-iodobenzyl bromide for 4-fluorobenzyl bromide.

Step B. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-iodobenzyl)-5- oxomorpholino)pentanoic acid

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?,6S)-2,3-bis(4-chlorophenyl)- 6-(4-iodobenzyl)-5-oxomorpholino)pentanoate (Example 32, Step A) by the method described in Example 10, Step D.

Step C. Ethyl 4-((i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)-5- oxomorpholino)pentanamido)butanoate

A solution of (i?)-2-((2 _l S,5i?,65)-2-(4-iodobenzyl)-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanoic acid (2.00 g, 3.13 mmol, Example 32, Step B) and ethyl 4- aminobutanoate hydrochloride (1.58 g, 9.40 mmol) in DMF (12.0 mL) was treated, successively, with N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.80 g, 9.40 mmol), HOAt (1.28 g, 9.40 mmol) and sodium bicarbonate (1.58 g, 18.8 mmol). After stirring at 25 °C for 12 hours, the reaction was diluted with water, extracted with ethyl acetate (2x) and washed with saturated NaHC0 ₃ and brine (2x). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under the reduced pressure to give the title compounds as a white solid. Step D. Ethyl 4-((i?)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)pentanamido)butanoate

A solution of ethyl 4-((i?)-2-((2 _l S,5i?,65)-2-(4-iodobenzyl)-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanamido)butanoate (1.250 g, 1.66 mmol, Example 32, Step C), dppf (0.0461 g, 0.0832 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0381 g, 0.0416 mmol), and zinc cyanide (0.195 g, 1.66 mmol) in DMF (5.0 mL) was charged with argon and stirred at 120 °C overnight. The reaction was quenched with saturated NH ₄ C1 solution, extracted with ethyl acetate (2x), and washed with brine. The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure to give the title compound as a brown oil. Step E. 4-((i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-iodobenzyl)-5- oxomorpholino)pentanamido)butanoic acid

Trimethyltin hydroxide (0.945 g, 5.23 mmol) was added to a solution of ethyl 4-((R)-2- ((2 _l S,5i?,65)-2-(4-cyanobenzyl)-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanamido)butanoate (0.850 g, 1.31 mmol, Example 32, Step D) in DCE (6.0 mL). After stirring at 80 °C for 18 hours, the reaction was concentrated. The residue was diluted with ethyl acetate and washed with IN aqueous HCl (2x) and brine. The separated organic layer was dried over Na ₂ S0 ₄ and concentrated under the reduced pressure. The residue was purified by preparative reverse phase HPLC (Gemini™ Prep CI 8 5 μιη column (Phenomenex, Torrance, CA), 45 minutes, gradient elution of 10% to 90% acetonitrile in water, where both solvents contain 0.1% TFA) to provide the title compound as a white solid.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.53 (m, J= 8.22 Hz, 2H), 7.32 (m, J= 8.22 Hz, 2H), 7.11 - 7.21 (m, 4H), 6.65-6.75 (m, J= 8.02 Hz, 3H), 6.67 (d,J= 8.00 Hz, 2H), 5.04 (d, J= 2.35 Hz, 1H), 4.97 (dd, J= 7.82, 4.30 Hz, 1H), 4.79 (dd, J= 9.39, 5.48 Hz, 1H), 4.43 (d, J= 2.74 Hz, 1H), 3.35 - 3.48 (m, 2H), 1.81 - 1.95 (m, 1H), 1.53 (td, J= 9.49, 4.50 Hz, 1H), 0.86 - 0.91 (m, 2H), 1.23 - 1.33 (m, 4H), 0.71 (t, J= 7.43 Hz, 3H); MS (ESI) 620.0[M-H] ^" . EXAMPLE 33

3-((i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)pentanamido)propanoic acid

Step A. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)pentanoic acid

A solution of (R)-ethyl 2-((2 _l S,5i?,65)-2-(4-iodobenzyl)-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanoate (539 mg, 809 μηιοΐ, Example 32, Step A), zinc cyanide (104 mg, 890 μιηοΐ), tris(dibenzylideneacetone)dipalladium(0) (37.0 mg, 40.4 μιηοΐ) and Ι,Γ- bis(diphenylphosphino)ferrocene (22.4 mg, 40.4 μιηοΐ) in DMF (1.35 mL, 0.6 M) was charged with argon and stirred at 120 °C for 6 hours. The reaction was diluted with H ₂ 0, extracted with ethyl acetate (2x), and washed with brine. The combined organic layer was dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (Si0 ₂ , gradient elution of 20% to25% ethyl acetate in hexanes) to give (i?)-ethyl 2-((25',5i?,65)-2-(4-cyanobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanoate as a yellowish soild. The solid was dissolved in DCE (5 mL) and trimethyltin hydroxide (276 mg, 1528 μιηοΐ) was added. The mixture was warmed to 80 °C. After stirring at 80 °C for 16 hours, the reaction was diluted with DCM, washed with IN aqueous HC1 (3x) and brine. The separated organic layer was dried over Na ₂ S0 ₄ and concentrated under the reduced pressure. Separation by preparative reverse phase HPLC (Gemini™ Prep CI 8 5 μιη column (Phenomenex, Torrance, CA), 45 minutes, gradient elution 65% to 90% acetonitrile in water, where both solvents contain 0.1% TFA) provided the title compound as a white foam.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.52 (d, J= 8.2 Hz, 2H), 7.33 (d, J= 8.2 Hz, 2H), 7.15 (dd, J= 8.6, 7.0 Hz, 4H), 6.75 (dd, J= 15.1, 8.4 Hz, 4H), 4.94 - 5.12 (m, 2H), 4.79 (dd, J= 9.4, 5.1 Hz, 1H), 4.43 (d, J= 2.7 Hz, 1H), 3.23 - 3.60 (m, 2H), 1.81 - 1.98 (m, 1H), 1.49 - 1.61 (m, 1H), 1.25 - 1.35 (m, 1H), 1.03 - 1.16 (m, 1H), 0.71 (t, J= 7.2 Hz, 3H). MS (ESI) 537.1 [M + H] ⁺ . Ste B. 3-((i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)pentanamido)propanoic acid

A solution of (i?)-2-((25 ^* ,5i?,65)-2-(4-cyanobenzyl)-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanoic acid (114 mg, 212 μηιοΐ) and β-alanine ethyl ester

hydrochloride (48.9 mg, 318 μηιοΐ, Example 33, Step A) in DMF (0.53 mL, 0.4 M) at 0 °C was successively treated with N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (81.3 mg, 424 μιηοΐ), 3H-[l,2,3]triazolo[4,5-b]pyridin-3-ol (57.7 mg, 424 μιηοΐ), and sodium bicarbonate (53.5 mg, 636 μιηοΐ). After stirring at 25 °C for 14 hours, the reaction was diluted with water, extracted with ethyl acetate (2x), and washed with aqueous 1 N HCl, saturated NaHC0 ₃ , and brine. The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The residue was dissolved in DCE (2 mL, 0.1 M), and trimethyltin hydroxide (115 mg, 636 μιηοΐ) was added. The mixture was stirred at 90 °C for 6 hours and cooled to room temperature. The reaction was diluted with DCM and washed with IN aqueous HCl (3x) and brine. The separated organic layer was dried over Na ₂ S0 ₄ and concentrated under reduced pressure.

Separation by preparative reverse phase HPLC (Gemini™ Prep CI 8 5 μιη column (Phenomenex, Torrance, CA), 25 minutes, gradient elution of 65% to 90% acetonitrile in water, where both solvents contain 0.1% TFA) provided the title compound as a white foam.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.44 - 7.58 (m, 3H), 7.25 (d, J= 8.2 Hz, 2H), 7.16 (d, J= 8.6 Hz, 2H), 7.12 (d, J= 8.6 Hz, 2H), 6.78 (d, J= 8.2 Hz, 2H), 6.69 (d, J= 8.6 Hz, 2H), 5.21 (d, J= 2.7 Hz, 1H), 5.05 (dd, J= 8.8, 6.1 Hz, 1H), 4.96 (d, J= 2.7 Hz, 1H), 4.88 (t, J= 6.1 Hz, 1H), 3.71 (ddd, J= 10.4, 7.0, 3.3 Hz, 1H), 3.49 - 3.59 (m, 1H), 3.29 - 3.37 (m, 2H), 2.67 (ddd, J= 11.7, 7.4, 3.9 Hz, 2H), 1.50 - 1.63 (m, 1H), 1.07 - 1.18 (m, 2H), 0.92 - 1.04 (m, 1H), 0.70 (t, J= 7.2 Hz, 3H). MS (ESI) 607.8[M + H] ⁺ . EXAMPLE 34

(i?)-N-(2-Amino-2-oxoethyl)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)- 5-oxomorpholino)pentanamide and (5)-N-(2-amino-2-oxoethyl)-2-((2i?,3S,6i?)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxomorpholino)pentanamide

CI CI and CI CI

Step A. (i?)-2-((2 _l S,5i?,65)-2-(4-Cyanobenzyl)-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanoic acid and (S)-2-((2R,5S,6R)-2-(4-cyanobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanoic acid

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate and (5)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 10, Step A) as described in Example 32, Steps A, D, and E.

Step B. (i?)-N-(2-Amino-2-oxoethyl)-2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxomorpholino)pentanamide and (S)-N-(2-amino-2-oxoethyl)-2- ((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5-ox omorpholino)pentanamide

CI CI and

A solution of (i?)-2-((25 ^* ,5i?,65)-2-(4-cyanobenzyl)-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanoic acid and (S)-2-((2R,5S,6R)-2-(4-cyanobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanoic acid (0.030 g, 0.056 mmol, Example 34, Step A) in DMF (0.5 mL, 0.1 M) at 50 °C was treated with sodium bicarbonate (0.04 g, 0.17 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.016 g, 0.084 mmol), 3H-[l,2,3]triazolo[4,5-b]pyridin-3-ol (0.011 g, 0.084 mmol) and glycinamide hydrochloride (0.019 g, 0.17 mmol) were successively added. After stirring at 50 °C for 12 hours, the reaction was diluted with water, extracted with ethyl acetate (2x), and washed with saturated NaHC0 ₃ and brine (2x). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (Gemini™ Prep CI 8 5 μιη column (Phenomenex, Torrance, CA), 45 minutes, gradient elution of 10% to 90% acetonitrile in water, where both solvents contain 0.1% TFA) to give the title compounds as a white solid.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.51 (d, J= 8.2 Hz, 2H), 7.49 (br s, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.16 (2d, J= 8.6 Hz, 2H), 7.12 (d, J= 8.6 Hz, 2H), 6.78 (d, J= 8.2 Hz, 2H), 6.69 (d, J= 8.6 Hz, 2H), 5.21 (d, J= 2.3 Hz, 1H), 5.05 (dd, J= 8.6, 5.9 Hz, 1H), 4.96 (d, J= 2.0 Hz, 1H), 4.88 (t, J= 6.1 Hz, 1H), 3.65 - 3.77 (m, 1H), 3.48 - 3.58 (m, 1H), 3.29 - 3.36 (m, 2H), 2.58 - 2.78 (m, 2H), 1.51 - 1.63 (m, 1H), 1.04 - 1.20 (m, 2H), 0.89 - 1.04 (m, 1H), 0.62 (t, J= 7.0 Hz, 3H).

EXAMPLE 35

4-(((2 _l S,5i?,65)-4-((i?)-l-(lH-Tetrazol-5-yl)butyl)-5,6-bis(4 -chlorophenyl)-3- oxomorpholin-2-yl)methyl)-2-fluorobenzonitrile

Step A. (R)-Ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-fluoro-4-iodobe nzyl)-5- oxomorpholino)pentanoate

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 10, Step B) using the method described in Example 10, Step C, substituting 3-fluoro-4-iodobenzyl bromide for 4-fluorobenzyl bromide.

Step B. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(3-fluoro-4-iodobe nzyl)-5- oxomorpholino)pentanamide

In a sealed tube, (R)-ethyl 2-((25 ^* ,5i?,65)-2-(3-fiuoro-4-iodobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanoate (0.30 g, 0.44 mmol, Example 35, Step A) was treated with ammonia (15 mL, 7 N in MeOH). The tube was sealed and stirred at 25 °C for 7 days. NH ₃ and MeOH were removed under reduced pressure to give the title compound as a colorless oil.

Step C. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(3-fluoro-4-iodobe nzyl)-5- oxomorpholino)pentanenitrile

A solution of (i?)-2-((2 _l S,5i?,65)-2-(3-fluoro-4-iodobenzyl)-5,6-bis(4-chloroph enyl)-3- oxomorpholino)pentanamide (0.140 g, 0.21 mmol, Example 35, Step B) and

triethylamine (0.15 mL, 1.1 mmol) in THF (3 mL, 0.05 M) was treated with

trifluoroacetic acid anhydride (0.075 mL, 0.53 mmol) at 0 °C. After stirring at 0 °C for 3 hours, the reaction was quenched with 10% citric acid, extracted with ethyl acetate (2x) and washed with brine. The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Purification of the residue by flash

chromatography (Si0 ₂ , gradient elution of 15% to 20% ethyl acetate in hexanes) provided the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.65-7.69 (m, 1H), 7.27-7.24 (m, 4H), 7.09 (d, J = 8.0 Hz, 1H), 6.98-6.92 (m, 4H), 6.84 (d, J= 4.0 Hz, 1H), 5.58 (d, J= 4.0 Hz, 1H), 5.05 (d, J= 4.0 Hz, lH), 4.90 (d, J= 4.0 Hz, 1H), 4.35-4.48 (m, 1H), 3.30-3.40 (m, 1H), 3.10- 3.25 (m, 1H), 1.75-1.95 (m, 2H), 1.41-1.25 (m, 2H), 0.87 (t, J= 8.0 Hz, 3H).

Step D. (2S,5R,6S)-4-((R)-l -(lH-Tetrazol-5-yl)butyl)-5,6-bis(4-chlorophenyl)-2-(3- fluoro-4-iodobenzyl)morpholin-3-one

Sodium azide (15 mg, 0.23 mmol) and ammonium chloride (12.9 mg, 241 μιηοΐ) were added to a solution of (i?)-2-((25 ^* ,5i?,65)-2-(3-fluoro-4-iodobenzyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanenitrile (0.115 g, 0.18 mmol, Example 35, Step C) in DMF (0.5 mL, 0.4 M). The resulting mixture was stirred at 90 °C for 16 hours. Additional sodium azide (16 mg) and ammonium chloride (13 mg) were added. After stirring at 90 °C for another 8 hours, the reaction was acidified with aqueous 10% citric acid solution, extracted with ethyl acetate (2x), and washed with brine. The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure to give the title compound. MS (ESI) 678.1 [M-H] -

Step E. 4-(((2 _l S,5i?,65)-4-((i?)-l-(lH-Tetrazol-5-yl)butyl)-5,6-bis(4 -chlorophenyl)-3- oxomorpholin-2-yl)methyl)-2-fluorobenzonitrile

A solution of (2 _l S,5i?,65)-4-((i?)-l-(lH-tetrazol-5-yl)butyl)-5,6-bis(4 -chlorophenyl)-2-(3- fluoro-4-iodobenzyl)morpholin-3-one (0.094 g, 0.14 mmol, Example 35, Step D), dppf (0.0015 g, 0.0028 mmol), zinc cyanide (0.016 g, 0.14 mmol), and

tris(dibenzylideneacetone)dipalladium(0) (0.0013 g, 0.0014 mmol) in DMF (0.5 mL, 0.3 M) was charged with argon and stirred at 120 °C overnight. The reaction was acidified with aqueous 10%> citric acid, extracted with ethyl acetate (2x), and washed with brine. The combined organic layers were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (Gemini Prep CI 8 5 μιη column (Phenomenex, Torrance, CA), 45 minutes, gradient elution of 10% to 90% acetonitrile in water, where both solvents contain 0.1% TFA) to give the title compound as a white solid.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.25-7.45 (m, 1H), 7.00-7.15 (m, 4H), 6.87 (d, J = 8.0 Hz, 2H), 6.65-6.68 (m, 4H), 5.75-5.85 (m, 1H), 4.85-4.90 (m, 2H), 4.82 (s, 1H), 3.30- 3.24 (m, 2H), 1.75-1.90 (m, 1H), 1.50-1.60 (m, 1H), 0.90-1.10 (m, 2H), 0.63 (t, J= 8.0 Hz, 3H); MS (ESI) 577.2[M-H] ^~ .

EXAMPLE 36

(2 _l S,5i?,65)-4-((i?)-l-(lH-Tetrazol-5-yl)butyl)-5,6-bis(4 -chlorophenyl)-2-(4- iodobenzyl)morpholin-3-one and (2i?,55 ^* ,6i?)-4-((5)-l-(lH-tetrazol-5-yl)butyl)-5,6-bis(4- chlorophenyl)-2-(4-iodobenzyl)morpholin-3-one

CI CI and CI CI

Step A. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-iodobenzyl)-5- oxomorpholino)pentanoic acid and (5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophi

iodobenzyl)-5

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate and (5)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 10, Step A) as described in Example 32, Steps A and B.

Step B. (2 _l S,5i?,65)-4-((i?)-l-(lH-Tetrazol-5-yl)butyl)-5,6-bis(4 -chlorophenyl)-2-(4- iodobenzyl)morpholin-3-one and (2i?,55 ^* ,6i?)-4-((5)-l-(lH-tetrazol-5-yl)butyl)-5,6-bis(4- chlorophenyl)-2-(4-iodobenzyl)morpholin-3-one

The title compounds were prepared from (i?)-ethyl 2-((25',3i?,65)-2,3-bis(4- chlorophenyl)-6-(4-iodobenzyl)-5-oxomorpholino)pentanoate and (5)-ethyl 2- ((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-iodobenzyl)-5-oxo morpholino)pentanoate (Example 36, Step A) as described in Example 35, Steps A through E.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.54 (d, J= 8.2 Hz, 2H), 7.16 (d, J= 8.6 Hz, 2H), 7.09 (d, J= 8.6 Hz, 2H), 6.90 (d, J= 8.2 Hz, 2H), 6.74 (d, J= 8.6 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 5.31 - 5.53 (m, 1H), 4.90 (dd, J = 7.2, 4.9 Hz, 1H), 4.81 - 4.88 (m, 1H), 4.72 (d, J= 2.7 Hz, 1H), 3.17 - 3.33 (m, 2H), 1.97 - 2.18 (m, 2H), 1.03 - 1.27 (m, 2H), 0.81 (t, J= 7.2 Hz, 3H). MS (ESI) 661.7 [M+H] ^~ .

EXAMPLE 37

(i?)-2-((25',3i?)-2,3-Bis(4-chlorophenyl)-5-oxomorpholino)pe ntanoic acid

An aqueous solution of NaOH (1 M, 0.250 mL, 0.250 mmol) was added to a solution of ( ?)-ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)pentano ate (584 mg, 2.793 mmol, Example 10, Step B) in THF (0.7 mL). The mixture was stirred at room temperature overnight. The mixture was acidified with 2 N HC1 and extracted with DCM. The organic layer was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution of 1% to 10% MeOH in DCM) to give the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.16 (d, J = 8.6 Hz, 4H), 6.80 - 6.87 (m, 4H), 5.23 (dd, J = 2.5, 0.4 Hz, 1H), 4.69 - 4.83 (m, 2H), 4.57 - 4.66 (m, 1H), 4.54 (d, J = 0.4 Hz, 1H), 1.80 - 1.94 (m, 1H), 1.52 (dtd, J = 14.3, 9.6, 4.9 Hz, 1H), 1.24 - 1.34 (m, 1H), 1.07 - 1.18 (m, 1H), 0.83 - 0.92 (m, 1H), 0.69 (t, J = 7.3 Hz, 3H). Spectrum (ESI) m/z = 422 [M+l]. EXAMPLE 38 (Reserved)

EXAMPLE 39

(55',6i?,Z)-5,6-Bis(4-chlorophenyl)-4-methyl-2-(pyridin-3-yl methylene)morpholin-3-one and (5i?,65',Z)-5,6-bis(4-chlorophenyl)-4-methyl-2-(pyridin-3-yl methylene)morpholin-3- one

CI and CI CI

Sodium hydride (12 mg, 0.518 mmol, 60%> dispersion in mineral oil) was added to a solution of (5i?,65)-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one and (5S,6R)-5,6- bis(4-chlorophenyl)-4-methylmorpholin-3-one (29 mg, 0.086 mmol; Example 4, Step G) and nicotinaldehyde (14 mg, 0.129 mmol) in THF (1.0 mL) at room temperature. The mixture was heated to 70 °C overnight, cooled, and quenched with saturated NH ₄ C1 solution. The residue was purified by flash chromatography on silica gel (gradient elution of 50% to 100% ethyl acetate in hexanes) to give the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 8.88 (dd, J = 1.8, 0.6 Hz, 1H), 8.45 (dd, J = 4.8, 1.7 Hz, 1H), 7.97 - 8.06 (m, 1H), 7.24 - 7.30 (m, 2H), 7.15 - 7.24 (m, 3H), 7.08 (s, 1H), 6.95 - 7.03 (m, 2H), 6.71 - 6.80 (m, 2H), 5.64 (d, J = 3.3 Hz, 1H), 4.50 (d, J = 3.1 Hz, 1H), 3.06 (s, 3H). Spectrum (ESI) m/z = 425 [M+l].

EXAMPLE 40

(2i?,55',6i?)-5,6-Bis(4-chlorophenyl)-4-methyl-2-(2-morpholi noethyl)morpholin-3-one and (25',5i?,65)-5,6-bis(4-chlorophenyl)-4-methyl-2-(2-morpholin oethyl)morpholin-3-one

Sodium bis(trimethylsilyl)amide (1.285 mL, 1.285 mmol, 1 M in THF) was added to a solution of (55',6i?)-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one and (5R,6S)-5,6- bis(4-chlorophenyl)-4-methylmorpholin-3-one (360 mg, 1.07 mmol, Example 4, Step G) in THF (1 mL) at -78 °C. After stirring at -78 °C for 20 minutes, allyl bromide (0.130 mL, 1.50 mmol) was added. The mixture was stirred at -78 °C for 90 minutes. The mixture was quenched with saturated NH ₄ C1 solution and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over MgSC^ and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution of 30% to 90% ethyl acetate in hexanes) to give the title compounds.

Step B. 2-((2i?,55',6i?)-5,6-Bis(4-chlorophenyl)-4-methyl-3-oxomorph olin-2- yl)acetaldehyde and 2-((25',5i?,65)-5,6-Bis(4-chlorophenyl)-4-methyl-3-oxomorpho lin-2- yl)acetaldehyde

and

4-Methylmorpholine-N-oxide (230 mg, 1.967 mmol) and potassium osmate (7.3 mg, 0.020 mmol)were added to a slurried solution of (2i?,55',6i?)-2-allyl-5,6-bis(4- chlorophenyl)-4-methylmorpholin-3-one and (25',5i?,65)-2-allyl-5,6-bis(4-chlorophenyl)- 4-methylmorpholin-3-one (148 mg, 0.393 mmol, Example 40, Step A) in tert- uOH (1 mL), water (1 mL) and acetone (2 mL) under N ₂ (g) at room temperature. The mixture was stirred at room temperature overnight and quenched with saturated Na ₂ S ₂ 03. After stirring at room temperature for 10 minutes, the mixture was extracted with DCM (2). The combined organic layers were washed with brine, dried over MgSC^ and

concentrated. The residue was diluted with THF (2 mL) and potassium phosphate monobasic/sodium hydroxide buffer (1 mL, pH 7.00 Buffer Concentrate). Then sodium periodate (136 mg, 0.634 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated NaHCOs. Saturated Na ₂ S ₂ 03 was added and the mixture was stirred at room temperature for 20 minutes. The mixture was extracted with DCM. The organic layer was washed with brine, dried over MgS0 ₄ and concentrated to give the title compounds.

Step C. (2i?,55',6i?)-5,6-Bis(4-chlorophenyl)-4-methyl-2-(2-morpholi noethyl)morpholin- 3-one and (25 ^* ,5i?,65)-5,6-bis(4-chlorophenyl)-4-methyl-2-(2- morpholinoethyl)morpholin-3 -one

Morpholine (13 mg, 0.147 mmol) and sodium triacetoxyborohydride (42 mg, 0.198 mmol) were added to a solution of 2-((2i?,55',6i?)-5,6-bis(4-chlorophenyl)-4-methyl-3- oxomorpholin-2-yl)acetaldehyde and 2-((25',5i?,65)-5,6-bis(4-chlorophenyl)-4-methyl-3- oxomorpholin-2-yl)acetaldehyde (50 mg, 0.132 mmol, Example 40, Step B) in THF (1.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with saturated NaHC0 ₃ and diluted with ethyl acetate. The organic layer was dried over MgS0 ₄ and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution of 2% to 5% MeOH in DCM) to give the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.11 - 7.19 (m, 4H), 6.84 - 6.90 (m, 2H), 6.71 - 6.78 (m, 2H), 5.32 (d, J= 3.1 Hz, 1H), 4.75 (dd, J= 10.3, 3.2 Hz, 1H), 4.33 (d, J= 3.1 Hz, 1H), 3.69 (t, J= 4.7 Hz, 4H), 2.88 (s, 3H), 2.40 - 2.55 (m, 6H), 2.25 - 2.36 (m, 1H), 2.01 - 2.14 (m, 1H). Spectrum (ESI) m/z = 449.

EXAMPLE 41

(2i?,55',6i?)-5,6-Bis(4-chlorophenyl)-4-methyl-2-(pyridin-4- ylmethyl)morpholin-3-one and (25',5i?,65)-5,6-bis(4-chlorophenyl)-4-methyl-2-(pyridin-4-y lmethyl)morpholin-3-one

Step A. (2R,5S,6R)-5 ,6-Bis(4-chlorophenyl)-2-((5)-hydroxy(pyridin-4-yl)methyl)-4 - methylmorpholin-3-one and (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-((i?)-hydroxy(pyridin - 4-yl)methyl)-4-methylmorpholin-3-one

LiHMDS (1.0 M in THF, 0.326 niL, 0.326 mmol) was added to a solution (55,6R)-5,6- bis(4-chlorophenyl)-4-methylmorpholin-3-one and (5i?,6S)-5,6-bis(4-chlorophenyl)-4- methylmorpholin-3-one (73 mg, 0.217 mmol, Example 4, Step G) in THF (1 mL) at -78 °C. The mixture was stirred at -78 °C for 15 minutes and then 4-pyridinecarboxaldehyde (0.037 mL, 0.391 mmol) was added. The color of the mixture turned from yellow to colorless after the addition of 4-pyridinecarboxaldehyde. The mixture was stirred at -78 °C for 30 minutes, quenched with saturated NH ₄ C1 solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSC^, and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution of 50% to 100% ethyl acetate in hexanes, and then 3% Et ₃ N in ethyl acetate) to give the title compounds. Ste B. ( _l S)-((2i?,55 ^* ,6i?)-5,6-Bis(4-chlorophenyl)-4-methyl-3-oxomorpholin- 2- yl)(pyridin-4-yl)methyl acetate and (i?)-((25',5i?,65)-5,6-bis(4-chlorophenyl)-4-methyl-3- oxomorpholin-2-yl)(pyridin-4-yl)methyl acetate

Acetic anhydride (0.035 mL, 0.372 mmol) was added to a solution of (2i?,55 ^* ,6i?)-5,6- bis(4-chlorophenyl)-2-((5)-hydroxy(pyridin-4-yl)methyl)-4-me thylmorpholin-3-one and (25 ^* ,5i?,65)-5,6-bis(4-chlorophenyl)-2-((i?)-hydroxy(pyrid in-4-yl)methyl)-4- methylmorpholin-3-one (55 mg, 0.124 mmol, Example 41, Step A) in pyridine (0.7 mL). The mixture was stirred at room temperature overnight, quenched with water, and extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgS0 ₄ and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution of 0% to 3% Et ₃ N in ethyl acetate) to give the title compounds. Step C. (2i?,55',6i?)-5,6-Bis(4-chlorophenyl)-4-methyl-2-(pyridin-4- ylmethyl)morpholin- 3-one and (25',5i?,65)-5,6-bis(4-chlorophenyl)-4-methyl-2-(pyridin-4- ylmethyl)morpholin-3 -one

Samarium (II) iodide (0.1 M in THF, 6.3 mL, 0.63 mmol) and tert-BuOU (0.030 mL, 0.315 mmol) were added to (5)-((2i?,5^,6i?)-5,6-bis(4-chlorophenyl)-4-methyl-3- oxomorpholin-2-yl)(pyridin-4-yl)methyl acetate and (R)-((2S,5R,6S)-5,6-bis(4- chlorophenyl)-4-methyl-3-oxomorpholin-2-yl)(pyridin-4-yl)met hyl acetate (102 mg, 0.210 mmol, Example 41, Step B) at room temperature. The color of the samarium (II) iodide solution turned from blue to yellow upon addition. The mixture was stirred at room temperature for 10 minutes, quenched with water, and diluted with saturated

NaHC0 ₃ and ethyl acetate. The organic layer was washed with brine, dried over MgS0 ₄ and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution of 1% to 2% MeOH in DCM). The residue was further purified by reverse phase preparative HPLC (gradient elution of 45% to 80% acetonitrile in water, where both solvents contain 0.1% TFA, 25 minutes) to give the title compounds.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 8.37 - 8.61 (m, 2H), 7.19 - 7.24 (m, 2H), 7.11 - 7.19 (m, 4H), 6.62 - 6.68 (m, 2H), 6.48 - 6.54 (m, 2H), 4.51 (dd, J = 5.1, 1.0 Hz, 1H), 3.38 - 3.49 (m, 2H), 3.08 - 3.16 (m, 1H), 2.98 (dd, J = 13.7, 10.5 Hz, 1H), 2.88 (s, 3H). Spectrum (ESI) m/z = 427.

EXAMPLE 42

(5)-2-((2i?,3S,6i?)-2,3-Bis(4-chlorophenyl)-5-oxo-6-(pyridin -4- ylmethyl)morpholino)pentanoic acid and (i?)-2-((25',3i?,65)-2,3-bis(4-chlorophi oxo-6-(pyridin- -ylmethyl)morpholino)pentanoic acid

Step A. (5)-Ethyl 2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-((5)-hydroxy(pyrid in-4- yl)methyl)-5-oxomorpholino)pentanoate and (i?)-ethyl 2-((2S,3R _> 6S)-2,3-bis(4- chlorophenyl)-6-((i?)-hydroxy(pyridin-4-yl)methyl)-5-oxomorp holino)pentanoate

The title compounds were prepared from (5)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate and ( ?)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 10, Step A) by a procedure similar to the one described in (Example 41 , Step A). The residue was purified by flash chromatography on silica gel (eluent: 25% ethyl acetate in hexanes, then 10% MeOH in DCM) to provide the title compounds.

Step B. (S)-Ethyl 2-((2i?,5 _l S,6i?)-2-((5)-acetoxy(pyridin-4-yl)methyl)-5,6-bis(4- chlorophenyl)-3-oxomorpholino)pentanoate and (S)-ethyl 2-((2R,5S,6R)-2-((S)- acetoxy(pyridin- -yl)methyl)-5,6-bis(4-chlorophenyl)-3-oxomorpholino)pentanoa te

The title compounds were prepared from (5)-ethyl 2-((2i?,3S,6i?)-2,3-bis(4- chlorophenyl)-6-((5)-hydroxy(pyridin-4-yl)methyl)-5-oxomorph olino)pentanoate and (R)-ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-((i?)-hydroxy(pyri din-4-yl)methyl)-5- oxomorpholino)pentanoate (Example 42, Step B) by a procedure similar to the one described in (Example 41 , Step B). The residue was purified by flash chromatography on silica gel (gradient elution of 50% to 100% ethyl acetate in hexanes) to provide the title compounds. Step C. (S)-Ethyl 2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-5-oxo-6-(pyridin-4- ylmethyl)morpholino)pentanoate and (i?)-ethyl 2-((2S',3i?,6S)-2,3-bis(4-chlorophi oxo-6-(pyrid -4-ylmethyl)morpholino)pentanoate

The title compounds were prepared from (S)-ethyl 2-((2i?,55',6i?)-2-((5)-acetoxy(pyridin- 4-yl)methyl)-5,6-bis(4-chlorophenyl)-3-oxomorpholino)pentano ate and (i?)-ethyl 2- ((25 ^* ,5i?,65)-2-((i?)-acetoxy(pyridin-4-yl)methyl)-5,6-bis( 4-chlorophenyl)-3- oxomorpholino)pentanoate (Example 42, Step B) by a procedure similar to the one described in (Example 41, Step C). The residue was purified by flash chromatography on silica gel (gradient elution of 50% to 100% ethyl acetate in hexanes) to provide the title compounds.

Step D. (5)-2-((2i?,3S,6i?)-2,3-Bis(4-chlorophenyl)-5-oxo-6-(pyridin -4- ylmethyl)morpholino)pentanoic acid and (R)-2-((2S,3R,6S)-2,3-bis(4-chloroph( oxo-6-(pyridin- -ylmethyl)morpholino)pentanoic acid

The title compounds were prepared from (5)-ethyl 2-((2i?,3S,6i?)-2,3-bis(4- chlorophenyl)-5-oxo-6-(pyridin-4-ylmethyl)morpholino)pentano ate and (i?)-ethyl 2- ((25',3i?,65)-2,3-bis(4-chlorophenyl)-5-oxo-6-(pyridin-4-ylm ethyl)morpholino)pentanoate (Example 42, Step C) by a procedure similar to the one described in (Example 10, Step D). The residue was purified by flash chromatography on silica gel (eluent: 10% MeOH in DCM with 2.5% Et ₃ N) to provide the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 8.35 - 8.49 (m, 2H), 7.15 - 7.20 (m, 2H), 7.10 - 7.16 (m, 2H), 7.08 (d, J= 8.6 Hz, 2H), 6.80 (d, J= 8.6 Hz, 2H), 6.75 (d, J= 8.6 Hz, 2H), 5.33 (br s, 1H), 5.15 (dd, J= 10.0, 4.3 Hz, 1H), 4.93 (d, J= 4.3 Hz, 1H), 4.76 (dd, J= 2.3, 0.4 Hz, 1H), 3.31 - 3.43 (m, 2H), 1.73 - 1.86 (m, 1H), 1.21 (s, 2H), 0.84 - 0.97 (m, 1H), 0.49 (t, J= 7.2 Hz, 3H). Spectrum (ESI) m/z = 513.

EXAMPLE 43

(i?)-2-((25',3i?)-2-(4-Chlorophenyl)-3-(lH-indol-2-yl)-5-oxo morpholino)pentanoic acid and (5)-2-((2i?,3S)-2-(4-Chlorophenyl)-3-(lH-indol-2-yl)-5-oxomo rpholino)pentanoic acid

Step A. (li?,2i?)-l-(4-Chlorophenyl)-l-(methoxymethoxy)-4-(triisopro pylsilyl)but-3-yn- 2-ol and ( 1 S,2S)- 1 -(4-chlorophenyl)- 1 -(methoxymethoxy)-4-(triisopropylsilyl)but-3 -yn- 2-ol

n-Butyllithium (32.6 mL, 82 mmol, 1.6 M solution in hexanes) was added dropwise over 15 minutes from an addition funnel to a solution of (triisopropylsilyl)acetylene (17.15 mL, 76 mmol) in anhydrous ether (100 mL) at -78 °C under argon. In a separate flask 1 ,2-dibromoethane (17.57 mL, 204 mmol) was added slowly to a mixture of magnesium (4.95 g, 204 mmol) in anhydrous ether (100 mL) at room temperature at a rate that maintained a gentle reflux. Once the MgBr ₂ solution had cooled to room temperature, it was added via cannula to the solution containing the lithiated acetylene at -78 °C under argon. A large amount of solid white material formed. The solution was warmed to 0 °C. The solid dissolved providing a greenish-gray solution. In a separate flask, DIBAL (40.8 mL, 61.2 mmol, 1.5 M solution in toluene) was added dropwise over 35 minutes from an addition funnel to a solution of methoxymethyl 2-(4-chlorophenyl)-2- (methoxymethoxy)acetate (14.00 g, 51.0 mmol) (Haddad, M.; Imogai, H.; Larcheveque, M. The First Enantioselective Synthesis of the cis-2-carboxy-5-phenylpyrrolidine. J. Org. Chem. 1998, 63, 5680-5683.) in anhydrous ether (200 mL) at -78 °C under argon. After 1.5 hours the Grignard solution was added to the DIBAL solution via cannula over 15 minutes. During the addition, a large amount of white precipitate formed. Once the addition was complete, the reaction mixture was removed from the dry-ice bath and allowed to warm to room temperature. After 8 hours the reaction mixture was cooled to - 20 °C and quenched with 10% HC1 (200 mL) and diluted with water (300 mL). The layers were separated and the organic layer was washed with brine, dried over MgS0 ₄ , filtered and concentrated under a vacuum to provide a pale yellow liquid. Flash column chromatography (750 g Si0 ₂ , gradient elution with 0% to 35% ethyl acetate/hexanes) provided a colorless oil. Step B. (li?,2i?)-l-(4-Chlorophenyl)-l-(methoxymethoxy)-4-(triisopro pylsilyl)but-3-yn- 2-yl methanesulfonate and (15',25)-l-(4-chlorophenyl)-l-(methoxymethoxy)-4- (triisopropylsilyl)but-3 -yn-2-yl methanesulfonate

Triethylamine (4.81 mL, 34.5 mmol) was added to a solution of (li?,2i?)-l-(4- chlorophenyl)- 1 -(methoxymethoxy)-4-(triisopropylsilyl)but-3 -yn-2-ol and ( 1 S,2S)- 1 -(4- chlorophenyl)-l-(methoxymethoxy)-4-(triisopropylsilyl)but-3- yn-2-ol (9.14 g, 23.02 mmol, Example 43, Step A) and methanesulfonyl chloride (1.973 mL, 25.3 mmol) in anhydrous DCM (230 mL) at 0 °C. After the addition was complete, the ice bath was removed. After two hours the reaction mixture was washed with saturated aqueous NaHCC"3, brine, dried over MgSC^, filtered and concentrated under a vacuum to provide a pale yellow oil.

Step C . ((3 S,4R)-3 -Azido-4-(4-chlorophenyl)-4-(methoxymethoxy)but- 1 -yn- 1 - yl)triisopropylsilane and ((3i?,45)-3-azido-4-(4-chlorophenyl)-4-(methoxymethoxy)but- 1 - yn- 1 -yl)triisopropylsilane

Sodium azide (1.647 g, 25.3 mmol) was added to a solution of (li?,2i?)-l-(4- chlorophenyl)- 1 -(methoxymethoxy)-4-(triisopropylsilyl)but-3-yn-2-yl methanesulfonate and ( 1 S,2S)- 1 -(4-chlorophenyl)- 1 -(methoxymethoxy)-4-(triisopropylsilyl)but-3 -yn-2-yl methanesulfonate (10.94 g, 23.02 mmol, Example 43, Step B) in anhydrous DMF (230 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hours and then heated to 60 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and water (400 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x), and the organics were pooled, washed with brine, dried over MgSC^, filtered and concentrated under a vacuum to provide a colorless liquid. The liquid was adsorbed onto Si0 ₂ and purified by flash column chromatography (330 g Si0 ₂ , gradient elution with 0% to 25% ethyl acetate in hexanes) to provide a colorless oil.

Step D . ( IR,2S)- 1 -(4-Chlorophenyl)- 1 -(methoxymethoxy)-4-(triisopropylsilyl)but-3 -yn- 2-amine and ( 1 S,2R)- 1 -(4-chlorophenyl)- 1 -(methoxymethoxy)-4-(triisopropylsilyl)but-3 - yn-2-amine

Lithium aluminum hydride (10.66 mL, 21.33 mmol, 2 M in THF) was added dropwise to a solution of ((3S,4i?)-3-azido-4-(4-chlorophenyl)-4-(methoxymethoxy)but-l - ynyl)triisopropylsilane and ((3i?,45)-3-azido-4-(4-chlorophenyl)-4- (methoxymethoxy)but-l-ynyl)triisopropylsilane (6.00 g, 14.22 mmol, Example 43, Step C) in anhydrous THF (142 mL) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 1 hour 40 minutes and was quenched by the sequential addition of water (0.9 mL), 15% NaOH (0.9 mL) and water (2.7 mL). The ice-bath was removed and the mixture stirred vigorously at room temperature for 30 minutes, filtered under a vacuum and concentrated under a vacuum to provide an orange oil. Flash column

chromatography (330 g Si0 ₂ , gradient elution with 0% to 5% MeOH/CH ₂ Cl ₂ ) provided a yellow oil.

Step E. (li?,25)-2-Amino-l-(4-chlorophenyl)-4-(triisopropylsilyl)but -3-yn-l-ol and ( 1 S,2R)-2- Amino- 1 -(4-chlorophenyl)-4-(triisopropylsilyl)but-3 -yn- 1 -ol

Hydrochloric acid (10% in MeOH) was added to a solution of (lR,2S)-l-(4- chlorophenyl)- 1 -(methoxymethoxy)-4-(triisopropylsilyl)but-3 -yn-2-amine and ( 1 S,2R)- 1 - (4-chlorophenyl)- 1 -(methoxymethoxy)-4-(triisopropylsilyl)but-3-yn-2-amine (4.32 g, 10.9 mmol, Example 1, Step D) in MeOH (25 mL) at room temperature. The reaction mixture was heated at 50 °C for 22 hours and then concentrated under a vacuum to provide a beige solid. The solid was taken up in DCM and saturated aqueous NaHC0 ₃ , and the layers were separated. The aqueous layer was extracted with DCM (2x), and the organics were pooled, washed with brine, dried over MgSC^, filtered and concentrated under a vacuum to provide a beige solid.

Step F. 2-Chloro-N-((li?,25)- 1 -(4-chlorophenyl)- 1 -hydroxy-4-(triisopropylsilyl)but-3-yn- 2-yl)acetamide and 2-chloro-N-(( IS,2R)- 1 -(4-chlorophenyl)- 1 -hydroxy-4- (triisopropylsilyl)but-3-yn-2-yl)acetamide

Chloroacetyl chloride (0.616 mL, 7.69 mmol) was added to a solution of (lS,2R)-2- amino- 1 -(4-chlorophenyl)-4-(triisopropylsilyl)but-3 -yn- 1 -ol and ( li?,25)-2-amino- 1 -(4- chlorophenyl)-4-(triisopropylsilyl)but-3-yn-l-ol (2.46 g, 6.98 mmol, Example 43, Step E) and triethylamine (1.461 mL, 10.48 mmol) in anhydrous THF (69.9 mL) at 0 °C under nitrogen. After 2 hours the reaction was quenched with saturated aqueous NH ₄ CI and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x) and the organics were pooled, washed with brine, dried over MgSC^, filtered and concentrated under a vacuum to provide a beige solid. Flash column chromatography (330 g Si0 ₂ , gradient elution with 5% to 35% ethyl acetate in hexanes provided an off- white solid.

Step G. (55',6i?)-6-(4-Chlorophenyl)-5-((triisopropylsilyl)ethynyl)m orpholin-3-one and (5i?,65)-6-(4-chlorophenyl)-5-((triisopropylsilyl)ethynyl)mo rpholin-3-one

Sodium hydride (0.829 g, 20.73 mmol, 60% dispersion in mineral oil) was added to a solution of 2-chloro-N-((15',2i?)-l-(4-chlorophenyl)-l-hydroxy-4-(triiso propylsilyl)but-3- yn-2-yl)acetamide and 2-chloro-N-(( IR,2S)- 1 -(4-chlorophenyl)- 1 -hydroxy-4-

(triisopropylsilyl)but-3-yn-2-yl)acetamide (2.22 g, 5.18 mmol, Example 43, Step F) in anhydrous THF (51.8 mL) under nitrogen at 0 °C. The ice bath was removed after the addition was complete. After 17 hours at room temperature, the reaction was quenched by the addition of ice cold water (50 mL) and saturated aqueous NH ₄ C1 (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x). The organics were pooled, washed with brine, dried over MgS0 ₄ , filtered and concentrated under a vacuum to provide a yellow oil. Flash column chromatography (,120 g Si0 ₂ , gradient elution with 30% to 70% ethyl acetate in hexanes) provided an off- white solid. Step H. (5)-Ethyl 2-((2i?,3S)-2-(4-chlorophenyl)-5-oxo-3-

((triisopropylsilyl)ethynyl)morpholino)pentanoate and (i?)-ethyl 2-((2S,3R)-2-(4- chlorophenyl)-5-oxo-3-((triisopropylsilyl)ethynyl)morpholino )pentanoate

Sodium hydride (0.1 17 g, 2.92 mmol, 60% dispersion in mineral oil) was added to a solution of (5i?,65)-6-(4-chlorophenyl)-5-((triisopropylsilyl)ethynyl)mo rpholin-3-one and (55',6i?)-6-(4-chlorophenyl)-5-((triisopropylsilyl)ethynyl)m orpholin-3-one (0.764 g, 1.95 mmol, Example 43, Step G) in anhydrous DMF (19.49 mL) at 0 °C under nitrogen. After 30 minutes, ethyl 2-bromovalerate (0.668 mL, 3.90 mmol) was added, and the reaction mixture was stirred at 0 °C for 2 hours before the reaction was quenched by the addition of saturated aqueous NH ₄ C1 and extracted with ethyl acetate (3x). The organics were pooled, washed with brine, dried over MgSC^, filtered and concentrated under a vacuum to provide a pale yellow oil. Purification by flash column chromatography ( 80 g Si0 ₂ , eluent: 30% MTBE in hexanes) provided separation of the desired isomer (title compound shown above) from its diastereomer with the propyl group syn to the alkyne. The desired product eluted first to provide a colorless oil and the diastereomer eluted second to provide a white solid. Step I. (iS)-Ethyl 2-((2i?,3S)-2-(4-chlorophenyl)-3-ethynyl-5-oxomorpholino)pen tanoate and (i?)-Ethyl 2-((25',3i?)-2-(4-chlorophenyl)-3-ethynyl-5-oxomorpholino)pe ntanoate

Tetra-n-butylammonium fluoride (0.414 mL, 0.414 mmol) was added to a solution of (R)-ethyl 2-((2S R)-2-(4-cWorophenyl)-5-oxo-3-

((triisopropylsilyl)ethynyl)morpholino)pentanoate and (5)-ethyl 2-((2i?,3S)-2-(4- chlorophenyl)-5 -oxo-3 -((triisopropylsilyl)ethynyl)morpholino)pentanoate (0.196 g, 0.376 mmol, Example 43, Step H) in anhydrous THF (3.77 mL) at 0 °C under argon. After 15 minutes the reaction mixture was quenched with NH ₄ C1 and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x) and the organic layers were pooled, washed with brine, dried over MgS0 ₄ , filtered and concentrated under a vacuum to provide a colorless oil. Purification by flash column chromatography (12 g Si0 ₂ , gradient elution with 0% to 30% ethyl acetate in hexanes provided a colorless oil. Step J. (S)-Ethyl 2-((2i?,3S)-3-((2-acetamidophenyl)ethynyl)-2-(4-chlorophenyl )-5- oxomorpholino)pentanoate and (i?)-ethyl 2-((25',3i?)-3-((2-acetamidophenyl)ethynyl)-2- (4-chlorophenyl)-5-oxomorpholino)pentanoate

A solution of (R)-ethyl 2-((2S,3i?)-2-(4-chlorophenyl)-3-ethynyl-5- oxomorpholino)pentanoate and (S)-ethyl 2-((2i?,3S)-2-(4-chlorophenyl)-3-ethynyl-5- oxomorpholino)pentanoate (0.222 g, 0.610 mmol, Example 43, Step I) in anhydrous THF (6.10 mL) was degassed by bubbling argon through the solution for 10 minutes.

Triethylamine (0.255 mL, 1.830 mmol), N-(2-iodophenyl)acetamide (0.159 g, 0.610 mmol), bis(triphenylphosphine)palladium(II) chloride (0.021 g, 0.031 mmol) and copper(I) iodide (5.81 mg, 0.031 mmol) were added and the solution was degassed for an additional 10 minutes. The reaction mixture was heated at 80 °C under argon for 12 hours. The reaction mixture was cooled to room temperature and diluted with water (20 mL). This solution was extracted with ethyl acetate (3x) and the organic layers were pooled, washed with brine, dried over MgS0 ₄ , filtered and concentrated under a vacuum to provide a yellow oil. Purification by flash column chromatography (40 g Si0 ₂ , gradient elution with 10% to 50% ethyl acetate in hexanes provided a colorless oil. Step K. (R)-2-((2S,3R)-2-(4-Chlorophenyl)-3-(lH-indol-2-yl)-5- oxomorpholino)pentanoic acid and (5)-2-((2i?,3S)-2-(4-chlorophenyl)-3-(lH-indol-2-yl)- 5-oxomorpholino)pentanoic acid

A solution of LiOH (100 mg) in water (1 mL) was added to a solution of ( ?)-ethyl 2- ((25',3i?)-3-((2-acetamidophenyl)ethynyl)-2-(4-chlorophenyl) -5- oxomorpholino)pentanoate and (5)-ethyl 2-((2i?,3S)-3-((2-acetamidophenyl)ethynyl)-2- (4-chlorophenyl)-5-oxomorpholino)pentanoate (0.046 g, 0.092 mmol, Example 43, Step J) in MeOH at room temperature. The reaction mixture was heated at 90 °C for 4 days. The reaction mixture was cooled, diluted with water (3 mL), and acidified (pH = 4) by addition of 1 N HCl. This solution was extracted with ethyl acetate (3x) and the organic layers were pooled, washed with brine, dried over MgS0 ₄ , filtered and concentrated under a vacuum to provide a brown oil. Purification by reverse phase preparative HPLC (C-18 column, gradient elution with 40% to 70% acetonitrile/water) provided the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 0.62 (t, J= 7.4 Hz, 3H) 0.84 - 0.92 (m, 1H) 0.99 - 1.15 (m, 1H) 1.46 (m, 1H) 1.96 - 2.12 (m, 1H) 4.26 (d, J= 17.0 Hz, 1H) 4.40 (d, J= 17.0 Hz, 1H) 4.83 (d, J= 6.5 Hz, 1H) 4.99 (d, J= 6.3 Hz, 1H) 6.33 (s, 1H) 7.02 - 7.11 (m, 3H) 7.12 - 7.18 (m, 1H) 7.29 (m, 2H) 7.44 - 7.52 (m, 2H) 8.50 (br s, 1H).

EXAMPLE 44

(i?)-2-((25',5i?,65)-2-Benzyl-5,6-bis(4-chlorophenyl)-3-oxom orpholino)pentanoic acid

Step A. ( ?)-Ethyl 2-((25',3i?)-2,3-bi -chlorophenyl)-5-oxomorpholino)pentanoate

Sodium hydride (3.73 g, 93.2 mmol, 60% dispersion in mineral oil) was added to a solution of (5i?,65)-5,6-bis(4-chlorophenyl)morpholin-3-one and (5S,6R)-5,6-bis(4- chlorophenyl)morpholin-3-one (20.0 g, 62.2 mmol, Example 4, Step F) in anhydrous DMF (150 mL) at 0 °C under nitrogen. After 1 hour, rac-ethyl 2-bromo valerate (21.2 mL, 124 mmol) was added. After 3 hours the reaction was quenched by the addition of saturated aqueous NH ₄ CI and extracted with ethyl acetate (3x). The organic layers were pooled, washed with brine, dried over MgS0 ₄ , filtered and concentrated under a vacuum to provide an orange oil. The compound was adsorbed onto Si0 ₂ (140 mL) and purified by flash column chromatography (3 stacked 330 g Si0 ₂ columns) to provide 11.38 g of the desired isomer. Further purification by chiral SFC (250 x 30 mm Chiralpak® IC and OD-H columns in series (Chiral Technologies, Inc., West Chester, PA, USA) with 28 g/min MeOH + 0.2% diethylamine + 72 g/min C0 ₂ on a Thar 350 SFC (Thar

Technologies, Inc., Pittsburg, PA)) provided the title compound as the first eluting enantiomer (5.02 g), [a] _D ²² = +196. .

Step B. (R)-Ethyl 2-((2 _l S,5i?,65)-2-benzyl-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanoate

A 10 mL round-bottomed flask was charged with (R)-ethyl 2-((2S,3R)-2,3-bis(4- chlorophenyl)-5-oxomorpholino)pentanoate (0.165 g, 0.366 mmol, Example 44, Step A), anhydrous THF (2.443 mL) and benzyl bromide (0.048 mL, 0.403 mmol). This solution was degassed by bubbling argon through the solution for 10 minutes. The reaction mixture was cooled to -78 °C and LHMDS (0.403 mL, 0.403 mmol, 1 M in THF) was added dropwise. The reaction mixture was stirred at -78 °C under argon for three hours. The reaction mixture was quenched by the addition of saturated aqueous NH ₄ C1. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x). The organic layers were pooled, washed with brine, dried over MgS0 ₄ , filtered and concentrated under a vacuum to provide a colorless glass. Purification by flash column chromatography ( 12 g Si0 ₂ , eluent: 2.5% ethyl acetate in benzene provided a colorless oil. Step C. (i?)-2-((25',5i?,65)-2-Benzyl-5,6-bis(4-chlorophenyl)-3-oxom orpholino)pentanoic acid

Lithium hydroxide (100.0 mg, 4.18 mmol) in water (1 mL) was added to a solution of (i?)-ethyl 2-((25',5i?,65)-2-benzyl-5,6-bis(4-chlorophenyl)-3-oxomorpho lino)pentanoate (0.082 g, 0.152 mmol, Example 44, Step B) in MeOH (3 mL) at room temperature. After 2 hours the pH was adjusted to 1 by addition of 1 N HC1 and the mixture was stirred vigorously. The resulting precipitate was collected by vacuum filtration to provide the title compound as a white solid.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.22 (m, 5H), 7.12 (m, 4H), 6.78 (d, J= 8.6 Hz, 2H), 6.73 (d, J= 8.2 Hz, 2H), 5.02 (m, 1H), 4.96 (m, 1H), 4.60 m, 1H), 4.39 (d, J= 2.4 Hz, 1H), 3.42 (dd, J= 7.8 and 14.1 Hz, 1H), 3.31 (dd, J= 3.9 and 14.1 Hz, 1H), 1.95- 1.88 (m, 1H), 1.64-1.60 (m, 1H), 1.31-1.26 (m, 1H), 1.15-1.05 (m, 1H), 0.74 (t, J= 7.0 Hz, 3H).

EXAMPLE 45

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(2-cyano-4-fluorob enzyl)-5- oxomorpholino)pentanoic acid

Step A. 2-(Bromomethyl)-5-fluorobenzonitrile

A solution of 5-fluoro-2-methylbenzonitrile (500 mg, 3700 μιηοΐ), NBS (659 mg, 3700 μιηοΐ), and AIBN (30.4 mg, 185 μιηοΐ) in carbon tetrachloride (37 mL) was heated at reflux for 3 hours. The mixture was quenched with water (10 mL) and cooled to room temperature. The mixture was extracted with DCM (2x, 100 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 0% to 40% DCM in hexanes) to give the title compound.

Step B. (R)-Ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(2-cyano-4-f uorobenzyl)-5- oxomorpholino)pentanoat

The title compound was prepared from (i?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 44, Step A) and 2-(bromomethyl)-5- fluorobenzonitrile (Example 45, Step A) by a procedure similar to the that described in Example 10, Step C.

Step C. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(2-cyano-4-fiuorob enzyl)-5- oxomorpholino)pentanoic acid

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?,6S)-2,3-bis(4-chlorophenyl)- 6-(2-cyano-4-fluorobenzyl)-5-oxomorpholino)pentanoate (Example 45, Step B) by a procedure similar to the one described in (Example 10, Step D).

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.40 - 7.46 (m, J= 5.4 Hz, 1H), 7.19 - 7.26 (m, 2H), 7.13 (d, J= 8.3 Hz, 4H), 6.71 - 6.81 (m, 4H), 5.39 (dd, J= 2.2, 0.5 Hz, 1H), 4.89 - 4.97 (m, 1H), 4.80 (dd, J= 9.3, 5.6 Hz, 1H), 4.53 (d, J= 2.7 Hz, 1H), 3.61 - 3.69 (m, 1H), 3.54 (dd, J= 14.5, 9.9 Hz, 1H), 1.85 - 1.96 (m, 1H), 1.52 - 1.59 (m, 1H), 1.24 - 1.36 (m, 1H), 1.08 - 1.20 (m, 1H), 0.71 (t, J= 7.3 Hz, 3H). Spectrum (ESI) m/z = 555 [M+l]. Examples 46 through 49 were also prepared from (i?)-ethyl 2-((25',3i?)-2,3-bis(4- chlorophenyl)-5-oxomorpholino)pentanoate (Example 44, Step A) as described in (Example 10, Steps C and D) substituting 1 -(bromomethyl)4-fluorobenzene in Example 10, Step C with an equivalent amount of the appropriate alkyl bromide.

EXAMPLE 46

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(2-cyanobenzyl)-5- oxomorpholino)pentanoic acid

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.48 - 7.55 (m, 2H), 7.42 - 7.47 (m, 1H), 7.28 - 7.34 (m, 1H), 7.07 - 7.15 (m, 4H), 6.73 - 6.81 (m, 4H), 5.46 (dd, J= 2.0, 0.8 Hz, 1H), 4.96 (dd, J= 9.9, 3.8 Hz, 1H), 4.79 - 4.87 (m, J= 1 1.7 Hz, 1H), 4.57 (dd, J= 2.2, 0.6 Hz, 1H), 3.65 - 3.71 (m, 1H), 3.52 - 3.61 (m, 1H), 1.81 - 1.98 (m, 1H), 1.45 - 1.59 (m, 1H), 1.25 - 1.35 (m, 1H), 1.04 - 1.17 (m, 1H), 0.64 - 0.72 (m, 3H). Spectrum (ESI) m/z = 537

[M+l].

EXAMPLE 47

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(2-fluorobenzyl)-5 - oxomorpholino)pentanoic acid

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.15 - 7.24 (m, 2H), 7.07 - 7.14 (m, 4H), 6.98 - 7.05 (m, 1H), 6.89 - 6.97 (m, 1H), 6.79 (dd, J= 8.5, 1.9 Hz, 4H), 5.33 - 5.39 (m, 1H), 4.93 (dd, J= 9.9, 3.8 Hz, 1H), 4.45 - 4.55 (m, 1H), 3.42 - 3.52 (m, 1H), 3.31 - 3.41 (m, 1H), 1.75 - 1.98 (m, 1H), 1.44 - 1.65 (m, 1H), 1.26 (d, J= 4.5 Hz, 2H), 1.02 - 1.17 (m, 1H), 0.66 - 0.76 (m, 3H). Spectrum (ESI) m/z = 530 [M+l].

EXAMPLE 48

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(3-fluorobenzyl)-5 - oxomorpholino)pentanoic acid 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.08 - 7.21 (m, 5H), 6.88 - 6.98 (m, 3H), 6.72 - 6.81 (m, 4H), 5.04 - 5.11 (m, 1H), 4.94 (dd, J= 7.8, 3.9 Hz, 1H), 4.62 - 4.74 (m, 1H), 4.44 - 4.51 (m, 1H), 3.25 - 3.43 (m, 2H), 1.80 - 1.97 (m, 1H), 1.47 - 1.62 (m, 1H), 1.24 - 1.33 (m, 1H), 1.00 - 1.15 (m, 1H), 0.64 - 0.73 (m, 3H). Spectrum (ESI) m/z = 530 [M+l].

EXAMPLE 49

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(3-cyanobenzyl)-5- oxomorpholino)pentanoic acid 1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.50 - 7.58 (m, 2H), 7.43 (dt, J= 7.9, 1.5 Hz, 1H), 7.30 - 7.35 (m, 1H), 7.09 - 7.18 (m, 4H), 6.68 - 6.80 (m, 4H), 4.94 - 5.01 (m, 2H), 4.86 (dd, J= 9.3, 5.4 Hz, 1H), 4.45 (d, J= 2.7 Hz, 1H), 3.42 - 3.52 (m, 1H), 3.31 - 3.39 (m, 1H), 1.82 - 1.93 (m, 1H), 1.47 - 1.54 (m, 1H), 1.22 - 1.31 (m, 1H), 1.01 - 1.14 (m, 1H), 0.69 (t, J= 7.3 Hz, 3H). Spectrum (ESI) m/z = 537 [M+l].

EXAMPLE 50

(^)-2-((2^,3^,65)-2,3-ΒΪ8(4-ΰ1ι1θΓορ1ΐ6η 1)-6-(3-^6 ΐ8ώ&η 1^6ηζ 1)-5- oxomorpholino)pentanoic ac

Step A. (i?)-Ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-iodobenzyl)-5- oxomorpholino)pentanoate

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 44, Step A) and l-(bromomethyl)-3-iodobenzene by a procedure similar to the one described in (Example 10, Step C).

Step B. (R)-Ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-(methylsulfonyl )benzyl)-5- oxomorpholino)pentanoate

A solution of (R)-ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-iodobenzyl)-5- oxomorpholino)pentanoate (81 mg, 0.122mmol, Example 50, Step A), sodium

methanesulfinate (49.6 mg, 486 μιηοΐ), and copper(I) iodide (34.7 mg, 182 μιηοΐ) in DMF (1216 μί) in a capped vial was stirred at 125 °C overnight. The mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with saturated NaHC0 ₃ (3x, 50 mL). The organic layer was washed with brine, dried over Na ₂ S0 ₄ , and concentrated. The crude residue was purified by preparative thin layer silica gel chromatography (eluent: 50% ethyl acetate/hexanes) to provide the title compound. Ste C. (^)-2-((2^,3^,65)-2,3-ΒΪ8(4-ο1ι1θΓορ1ΐ6η 1)-6-(3-(ηΐ6ΐ1ι ΐ8ώβ3η 1^6ηζ 1)-5- oxomorpholino)pentanoic acid

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?,6S)-2,3-bis(4-chlorophenyl)- 6-(3-(methylsulfonyl)benzyl)-5-oxomorpholino)pentanoate (Example 50, Step B) by a procedure similar to the one described in (Example 32, Step E).

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.72 - 7.83 (m, 2H), 7.45 - 7.52 (m, 1H), 7.36 - 7.44 (m, 1H), 7.04 - 7.16 (m, 4H), 6.70 - 6.81 (m, 4H), 5.06 - 5.16 (m, 1H), 4.98 (td, J= 8.2, 4.7 Hz, 2H), 4.55 (dd, J= 2.1, 0.7 Hz, 1H), 3.46 - 3.56 (m, 1H), 3.39 - 3.46 (m, 1H), 2.83 (s, 3H), 1.76 - 1.90 (m, 1H), 1.32 - 1.46 (m, 1H), 1.15 - 1.30 (m, 1H), 0.95 - 1.10 (m, 1H), 0.57 - 0.65 (m, 3H). Spectrum (ESI) m/z = 590 [M+l].

Examples 51 to 54 were also prepared from (i?)-ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)- 5-oxomorpholino)pentanoate (Example 44, Step A) as described in (Example 50, Steps A through C) substituting l-(bromomethyl)-3-iodobenzene in Example 50, Step A with an equivalent amount of the appropriate alkyl bromide. The required alkyl bromides are prepared as described in the individual examples.

EXAMPLE 51

(^)-2-((2^,3^,65)-2,3-Βί8(4-ο1ι1θΓο 1ιεη 1)-6-(2-(ηΐ6 ΐ8υ1&η 1^6ηζ 1)-5- oxomorpholino)pentanoic acid

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 8.00 (dt, J= 7.8, 0.8 Hz, 1H), 7.44 - 7.50 (m, 1H), 7.32 - 7.44 (m, 2H), 7.06 - 7.13 (m, 4H), 6.81 (dd, J= 8.3, 3.4 Hz, 4H), 5.53 (br s, 1H), 5.07 - 5.17 (m, 1H), 4.78 - 4.87 (m, 1H), 4.61 - 4.68 (m, 1H), 3.94 - 4.04 (m, 1H), 3.74 (dd, J= 14.7, 9.8 Hz, 1H), 3.02 (s, 3H), 1.80 - 1.96 (m, 1H), 1.48 (ddt, J= 14.5, 9.7, 4.8 Hz, 1H), 1.20 - 1.34 (m, 1H), 1.02 - 1.15 (m, 1H), 0.61 - 0.70 (m, 3H). Spectrum (ESI) m/z = 590 [M+l].

EXAMPLE 52

(i?)-2-((2^,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-fluoro-2-(m ethylsulfonyl)benzyl)-5- oxomorpholino)pentanoic acid 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.79 (t, J= 7.7 Hz, 1H), 7.07 - 7.21 (m, 6H), 6.70 - 6.82 (m, 4H), 5.10 - 5.19 (m, 1H), 4.90 - 5.04 (m, 2H), 4.46 - 4.55 (m, 1H), 3.43 (d, J = 6.1 Hz, 2H), 3.19 (s, 3H), 1.74 - 1.87 (m, 1H), 1.34 (ddd, J= 14.3, 9.7, 4.5 Hz, 1H), 1.14 - 1.25 (m, 1H), 0.93 - 1.05 (m, 1H), 0.55 - 0.62 (m, 3H). Spectrum (ESI) m/z = 608

[M+l].

Synthesis of l-(bromomethyl)-4-fluoro-2-iodobenzene

The title compound was prepared from 4-fluoro-2-iodotoluene by a procedure similar to the one described in Example 45, Step A.

EXAMPLE 53

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(3-fiuoro-4-(methy lsulfonyl)benzyl)-5- oxomorpholino)pentanoic acid

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.71 - 7.85 (m, 1H), 7.10 - 7.22 (m, 6H), 6.70 - 6.81 (m, 4H), 4.89 - 5.07 (m, 3H), 4.40 - 4.46 (m, 1H), 3.46 - 3.58 (m, 1H), 3.35 - 3.46 (m,

1H), 3.20 (s, 3H), 1.77 - 1.94 (m, 1H), 1.44 (dq, J = 9.6, 4.8 Hz, 1H), 1.18 - 1.25 (m, 1H), 0.95 - 1.14 (m, 1H), 0.65 (t, J= 7.3 Hz, 3H).

Synthesis of 4-(bromomethyl)-2-fluoro-l-iodobenzene

The title compound was prepared from 2-fluoro-4-iodotoluene (Alfa Aesar, Ward Hill, MA) by a procedure similar to the one described in (Example 45, Step A). EXAMPLE 54

(^)-2-((2^,3^,65)-2,3-ΒΪ8(4-ο1ι1θΓο 1ΐ6η 1)-6-(4-(ηΐ6 ΐ8ώ&η 1^6ηζ 1)-5- oxomorpholino)pentanoic acid

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.79 (d, J= 8.3 Hz, 2H), 7.41 (d, J= 8.3 Hz, 2H), 7.13 (t, J= 8.6 Hz, 4H), 6.74 (dd, J= 17.0, 8.4 Hz, 4H), 4.94 - 5.05 (m, 2H), 4.80 - 4.91 (m, 1H), 4.41 - 4.52 (m, 1H), 3.45 - 3.57 (m, 1H), 3.35 - 3.45 (m, 1H), 2.98 - 3.09 (m, 3H), 1.77 - 1.94 (m, 1H), 1.45 (ddt, J= 14.5, 9.7, 5.0 Hz, 1H), 1.18 - 1.31 (m, 1H), 0.98 - 1.12 (m, 1H), 0.65 (t, J = 7.3 Hz, 3H). Spectrum (ESI) m/z = 590 [M+l].

EXAMPLE 55

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(2-cyano-4-(methyl sulfonyl)benzyl)-5- oxomorpholino)pentanoic acid

Step A. 2-methyl-5-(methylthio)benzonitrile

To a solution of 5-fluoro-2-methylbenzonitrile (3.770 g, 27.9 mmol) in DMF (279 mL) was added sodium thiomethoxide (7.82 g, 112 mmol) at room temperature. The mixture was heated to 100 °C and stirred at 100 °C for 2 hours. The mixture was cooled to room temperature and diluted with ether (2 L). The mixture was washed with saturated NaHCC"3 (3x, 300 mL) and brine. The organic layer was dried over Na ₂ S0 ₄ and concentrated to give the title compound.

Step B. 2-(Bromomethyl)-5-(meth lthio)benzonitrile

The title compound was prepared from 2-methyl-5-(methylthio)benzonitrile (Example 55, Step A) by a procedure similar to the one described in Example A.

Step C. (R)-Ethyl 2-((2^,3i?,65)-2,3-bis(4-chlorophenyl)-6-(2-cyano-4- (methylthio)benzyl)-5-oxomorpholino)pentanoate

The title compound was prepared from (i?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl) oxomorpholino)pentanoate (Example 44, Step A) and 2-(bromomethyl)-5- (methylthio)benzonitrile (Example 55, Step B) by a procedure similar to the one described in Example 10, Step C.

Step D. (R)-Ethyl 2-((2^,3i?,65)-2,3-bis(4-chlorophenyl)-6-(2-cyano-4- (methylsulfonyl)benzyl)-5-oxomorpholino)pentanoate

4-Chlorobenzoperoxoic acid (127 mg, 0.736 mmol) was added to a solution of (i?)-ethyl 2-((25 ^* ,3i?,65)-2,3-bis(4-chlorophenyl)-6-(2-cyano-4-(methylt hio)benzyl)-5- oxomorpholino)pentanoate (125 mg, 0.204 mmol, Example 55, Step C) in DCM (2 mL) at room temperature. After stirring at room temperature overnight, the mixture was quenched with saturated aq. NaHC0 ₃ (50 mL) and diluted with DCM (150 mL). The layers were separated and the aqueous layer was back extracted with DCM (100 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution with 0% to 3% MeOH in DCM) to give the title compound.

Step E. (i?)-2-((2^,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(2-cyano-4- (methylsulfonyl)benzyl)-5 -oxomorpholino)pentanoic acid

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?,6S)-2,3-bis(4-chlorophenyl)- 6-(2-cyano-4-(methylsulfonyl)benzyl)-5-oxomorpholino)pentano ate (Example 55, Step D) by a procedure similar to the one described in Example 32, Step E. 1H NMR (500 MHz, CDC1 ₃ , δ ppm): 8.03 - 8.12 (m, 2H), 7.71 (d, J= 8.1 Hz, 1H), 7.08 - 7.15 (m, 4H), 6.76 (d, J= 8.6 Hz, 4H), 5.37 - 5.47 (m, 1H), 5.00 (dd, J= 9.9, 3.8 Hz, 1H), 4.89 - 4.97 (m, 1H), 4.53 - 4.60 (m, 1H), 3.79 (dd, J= 14.3, 3.8 Hz, 1H), 3.64 (dd, J = 14.3, 9.9 Hz, 1H), 3.06 (s, 3H), 1.78 - 1.94 (m, 1H), 1.36 - 1.51 (m, 1H), 1.18 - 1.31 (m, 1H), 0.97 - 1.12 (m, 1H), 0.60 - 0.66 (m, 3H). Spectrum (ESI) m/z = 615 [M+l].

EXAMPLE 56

(i?)-2-((2^,3i?,65)-2,3-Bis(4-chlorophenyl)-5-oxo-6-(4- ((trifluoromethyl)sulfonyl benzyl)morpholino)pentanoic

Step A. (i?)-Ethyl 2-((2^3i?,65)-2,3-bis(4-chlorophenyl)- ((trifluoromethyl)thio)benzyl)morpholino)pentanoate

The title compound was prepared from ( ?)-ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (Example 44, Step A) and 4-(trifluoromethylthiol)benzyl bromide by a procedure similar to the one described in Example 10, Step C.

Step B. (R)-Ethyl 2-((2^,3i?,65)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4- ((trifluoromethyl)sulfonyl)benzyl)morpholino)pentanoate

The title compound was prepared from (i?)-ethyl 2-((25',3i?,65)-2,3-bis(4-chlorophenyl)- 5-oxo-6-(4-((trifluoromethyl)thio)benzyl)morpholino)pentanoa te (Example 56, Step A) by a procedure similar to the one described in Example 55, Step D. Step C. (i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-5-oxo-6-(4- ((trifluoromethyl)sulfonyl)benzyl)morpholino)pentanoic acid

The title compound was prepared from (i?)-ethyl 2-((25',3i?,65)-2,3-bis(4-chlorophenyl)- 5-oxo-6-(4-((trifluoromethyl)sulfonyl)benzyl)morpholino)pent anoate (Example 56, Step B) by a procedure similar to the one described in Example 32, Step E.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.88 (d, J= 8.3 Hz, 2H), 7.47 - 7.55 (m, 2H), 7.08 - 7.18 (m, 4H), 6.64 - 6.80 (m, 4H), 4.99 - 5.06 (m, 1H), 4.91 - 4.99 (m, 1H), 4.67 - 4.82 (m, 1H), 4.45 - 4.51 (m, 1H), 3.51 - 3.58 (m, 1H), 3.41 - 3.47 (m, 1H), 1.79 - 1.93 (m, 1H), 1.47 - 1.60 (m, 1H), 1.25 - 1.34 (m, 1H), 1.00 - 1.12 (m, 1H), 0.65 - 0.72 (m, 3H). Spectrum (ESI) m/z = 644 [M+l].

EXAMPLE 57

(i?)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(3-morpholinopropy l)-5- oxomorpholino)pentanoic acid

Step A. (i?)-Ethyl 2-((2S,5^6S)-2-allyl-5,6-bis(4-chlorophi

oxomorpholino)pentanoate

In an oven-dried flask, (i?)-Ethyl 2-((2S',3i?)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)pentanoate (1.0 g, 2.22 mmol, Example 44, Step A) and allyl bromide (0.376 mL, 4.44 mmol) were dissolved in THF (14.8 mL) and degassed by bubbling argon through the solution for 10 minutes. The mixture was cooled to -78 °C under argon. Then, LiHMDS (3.33 mL, 3.33 mmol, 1.0 M in THF) was added to the mixture and the mixture was stirred at -78 °C for 3 hours. The mixture was quenched with 50% saturated NH ₄ C1 solution and diluted with 50 mL of ethyl acetate. The mixture was warmed to room temperature and stirred overnight. The layers were separated and the aqueous layer was back-extracted with ethyl acetate (2x, 100 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution with 50% to 100% DCM in hexanes) to give the title compound.

Step B. (R)-Ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-hydroxypropyl)- 5- oxomorpholino)pentanoate

9-Borabicyclo[3.3.1]nonane (1622 μΐ,, 0.81 1 mmol, 0.5 M in THF) was added dropwise to a solution of (R)-ethyl 2-((2 _l S,5i?,65)-2-allyl-5,6-bis(4-chlorophenyl)-3- oxomorpholino)pentanoate (234 mg, 0.477 mmol, Example 57, Step A) in THF (795 μί, 0.477 mmol) at 0 °C under N ₂ (g). The mixture was stirred at 0 °C for 5 minutes and then warmed to room temperature. The mixture was stirred at room temperature for 2 days. Aqueous hydrogen peroxide (14.62 μί, 0.477 mmol, 30%> solution) and pH 7 buffer were added to the solution and the reaction was allowed to stir at 60 °C for 3 hours. The mixture was diluted with water (10 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution with 60% to 100% ethyl acetate in hexanes) to give the title compound.

Step C. (R)-Ethyl 2-((2^,3i?,65)-2,3-bis(4-chlorophenyl)-5-oxo-6-(3- oxopropyl)morpholino)pentanoate

Dess-Martin periodinane (222 mg, 0.523 mmol) was added to a stirring solution of (R)- ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-hydroxypropyl)- 5- oxomorpholino)pentanoate (190 mg, 0.374 mmol, Example 57, Step B) in

dichloromethane (3737 μί, 0.374 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (10 mL) and DCM (100 mL). The layers were separated and the aqueous layer was back-extracted with 100 mL DCM. The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated. The crude residue was purified by preparative thin layer chromatography (eluent: 100% ethyl acetate) to provide the title compound.

Step D. (R)-Ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(3-morpholinopropy l)-5- oxomorpholino)pentanoate

Sodium triacetoxyborohydride (64.4 mg, 0.341 mmol) was added to a solution of (R)- ethyl 2-((2^,3i?,65)-2,3-bis(4-chlorophenyl)-5-oxo-6-(3- oxopropyl)morpholino)pentanoate (75 mg, 0.148 mmol; Example 57, Step C) and morpholine (25.6 μί, 0.296 mmol) in 1 ,2-dichloroethane (14.66 mg, 0.148 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with water (10 mL) and extracted with DCM (2x, 100 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated. The crude residue was purified by preparative thin layer chromatography (eluent: 2% MeOH in DCM) to provide the title compound.

The title compound was prepared from (i?)-ethyl 2-((25',3i?,65)-2,3-bis(4-chlorophenyl)- 6-(3-morpholinopropyl)-5-oxomorpholino)pentanoate (Example 57, Step D) by a procedure similar to the one described in (Example 10, Step D).

1H NMR (400 MHz, MeOH- ¼, δ ppm): 7.08 - 7.23 (m, 4H), 6.95 - 7.07 (m, 2H), 6.85 - 6.98 (m, 2H), 5.52 (dd, J= 2.2, 0.8 Hz, 1H), 5.04 (dd, J= 10.5, 4.2 Hz, 1H), 4.82 - 4.84 (m, 1H), 4.77 (dd, J= 9.1, 4.4 Hz, 1H), 3.76 (t, J= 4.9 Hz, 4H), 2.80 - 2.92 (m, 6H), 2.08 - 2.19 (m, 2H), 1.82 - 1.92 (m, 1H), 1.70 - 1.81 (m, 1H), 1.04 - 1.25 (m, 2H), 0.83 - 0.95 (m, 2H), 0.46 (t, J= 7.3 Hz, 3H). Spectrum (ESI) m/z = 549 [M+l].

EXAMPLE 58

(2 _l S,5i?,65)-5,6-Bis(4-chlorophenyl)-4-(2-chloropyridin-4 -yl)-2-(4- fluorobenzyl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-4-(2- chloropyridin-4-yl)-2-(4-fiuorobenzyl)morpholin-3-one

A solution of (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)morph olin-3-one and (2i?,55 ^, ,6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)morpho lin-3-one (7 mg, 0.0065 mmol; Example 80, Step C), TMEDA (0.00098 mL, 0.0065 mmol), 2-chloro-4- iodopyridine (12 mg, 0.049 mmol), and potassium phosphate dibasic (11 mg, 0.065 mmol) in 1,4-dioxane (0.163 mL) was degassed by bubbling argon through the solution for 10 minutes. Copper(I) iodide (0.62 mg, 0.0033 mmol) was added, and the mixture was heated to 110 °C overnight. After cooling to room temperature, the crude residue was concentrated under a vacuum and purified by preparative thin layer chromatography (eluent: 100% ethyl acetate) to provide the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 8.25 (d, J= 5.7 Hz, 1H), 7.35 - 7.49 (m, 1H), 7.08 - 7.22 (m, 6H), 6.94 (dd, J= 5.5, 2.0 Hz, 1H), 6.82 - 6.91 (m, 4H), 5.99 - 6.16 (m, 2H), 5.36 (d, J= 3.5 Hz, 1H), 4.77 - 4.85 (m, 2H), 3.60 (d, J= 5.1 Hz, 1H), 3.40 (d, J= 4.5 Hz, 1H). Spectrum (ESI) m/z = 542, 544 [M+l].

Examples 59, 60 and 61 were also prepared from (25',5i?,65)-5,6-bis(4-chlorophenyl)-2- (4-fluorobenzyl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4- fluorobenzyl)morpholin-3-one (Example 80, Step C) as described in Example 58 substituting 2-chloro-4-iodopyridine in Example 58 with an equivalent amount of the appropriate iodide.

Example R Reagent used

59 3-iodopyridine

4-iodo-lH-pyrazole

60

N />-|- 4-iodopyridine

61

EXAMPLE 59

(2S,5R,6S)-5 ,6-Bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-phenylmorpholin- 3 -one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-p henylmorpholin-3-one

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 8.43 (dd, J= 4.6, 1.7 Hz, 1H), 8.33 (dd, J= 2.5, 0.6 Hz, 1H), 7.43 - 7.50 (m, 2H), 7.25 (dd, J= 2.5, 1.6 Hz, 1H), 7.11 - 7.23 (m, 5H), 6.79 - 6.89 (m, 4H), 6.02 - 6.09 (m, 2H), 5.44 (s, 1H), 4.85 (t, J= 4.3 Hz, 1H), 4.73 (s, 1H), 3.60 - 3.69 (m, 1H), 3.31 - 3.41 (m, 1H). Spectrum (ESI) m/z = 507 [M+l].

EXAMPLE 60

(25 ^, ,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4- (lH-pyrazol-4-yl)morpholin-3- one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-( lH-pyrazol-4- yl)morpholin-3 -one 1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.08 - 7.20 (m, 6H), 6.89 - 7.00 (m, 2H), 6.79 - 6.87 (m, 2H), 6.72 - 6.79 (m, 2H), 6.55 (d, J= 4.4 Hz, 2H), 5.12 (dd, J= 2.9, 0.5 Hz, 1H), 4.84 (dd, J= 8.6, 3.7 Hz, 1H), 4.54 (dd, J= 4.4, 3.4 Hz, 1H), 3.40 - 3.53 (m, 1H), 3.31 - 3.40 (m, 1H), 3.19 - 3.29 (m, 1H).

EXAMPLE 61

(25',5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(p yridin-4-yl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-( pyridin-4-yl)morpholin-3- one

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 8.33 - 8.60 (m, 2H), 7.38 - 7.49 (m, 2H), 7.09 - 7.23 (m, 4H), 6.98 - 7.07 (m, 2H), 6.76 - 6.91 (m, 4H), 5.98 - 6.11 (m, 2H), 5.38 (d, J= 3.5 Hz, 1H), 4.79 - 4.94 (m, 2H), 3.64 (dd, J= 14.2, 4.6 Hz, 1H), 3.37 (dd, J= 14.2, 4.4 Hz, 1H). Spectrum (ESI) m/z = 507 [M+l].

EXAMPLE 62

(25 ^* ,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-(methylsulfonyl) benzyl)-4-(pyridin-3- yl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4- (methy

Step A. (2 _l S,5i?,65)-5,6-Bbis(4-chlorophenyl)-2-(4-iodobenzyl)-4- (4- methoxybenzyl)morpholin-3-one and (2i?,55',6i?)-5,6-Bis(4-chlorophenyl)-2-(4- iodobenzyl)-4-(4-methoxybenzyl)morpholin-3-one —

CI CI and CI CI

The title compounds were prepared from (5i?,65)-5,6-bis(4-chlorophenyl)-4-(4- methoxybenzyl)morpholin-3-one and (55',6i?)-5,6-bis(4-chlorophenyl)-4-(4- methoxybenzyl)morpholin-3-one (Example 80, Step A) and l-(bromomethyl)-4- iodobenzene by a procedure similar to the one described in (Example 80, Step B).

Step B. (25',5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-iodobenzyl)morphol in-3-one and (2i?,55',6i?)-5,6-Bis(4-chlorophenyl)-2-(4-i

C CI CI

The title compounds were prepared from (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4- iodobenzyl)-4-(4-methoxybenzyl)morpholin-3-one and (2R,5S,6R)-5,6-bis(4- chlorophenyl)-2-(4-iodobenzyl)-4-(4-methoxybenzyl)morpholin- 3-one (Example 62, Step A) by a procedure similar to the one described in (Example 80, Step C). Ste C. (2 _l S,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-iodobenzyl)-4-( pyridin-3- yl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(4-iodobenzyl)-4-(py ridin- 3 -yl)morp

The title compounds were prepared from (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4- iodobenzyl)morpholin-3-one and (2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- iodobenzyl)morpholin-3-one (Example 62, Step B) by a procedure similar to the one described in Example 58.

Step D. (25 ^* ,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-(methylsulfonyl) benzyl)-4-(pyridin-3- yl)morpholin-3-one and (2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- (methylsulfonyl)benzyl)-4-(pyridin-3 -yl)morpholin-3 -one The title compounds were prepared from (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4- iodobenzyl)-4-(pyridin-3-yl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2- (4-iodobenzyl)-4-(pyridin-3-yl)morpholin-3-one (Example 62, Step C) by a procedure similar to the one described in Example 50, Step B.. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 8.43 - 8.53 (m, 1H), 8.33 - 8.42 (m, 1H), 7.97 - 8.05 (m, 2H), 7.64 - 7.75 (m, 2H), 7.21 - 7.25 (m, 2H), 7.15 - 7.19 (m, 2H), 6.88 - 6.95 (m, 2H), 6.82 - 6.88 (m, 2H), 6.12 - 6.24 (m, 2H), 5.45 (d, J= 3.5 Hz, 1H), 4.87 - 4.94 (m, 1H), 4.75 (d, J= 3.5 Hz, 1H), 3.65 - 3.75 (m, 1H), 3.56 (dd, J= 13.9, 4.3 Hz, 1H), 3.14 (s, 3H). Spectrum (ESI) m/z = 567 [M+l]. EXAMPLE 63

(25',5i?,65)-5,6-Bis(4-chlorophenyl)-2-(2-fluoro-4-(methylsu lfonyl)benzyl)-4-(pyridin-3- yl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(2-fluoro-4- (methy

Step A. (2 _l S,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(2-fluoro-4-iodobe nzyl)-4-(4- methoxybenzyl)morpholin-3-one and (2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(2 iodobenz l)-4-(4-methoxybenzyl)morpholin-3-one

ci ci _and CI CI

The title compounds were prepared from (5i?,6S)-5,6-bis(4-chlorophenyl)-4-(4- methoxybenzyl)morpholin-3-one and (55',6i?)-5,6-bis(4-chlorophenyl)-4-(4- methoxybenzyl)morpholin-3-one (Example 80, Step A) and l-(bromomethyl)-2-fluoro-4- iodobenzene (Example 53) by a procedure similar to the one described in Example 80, Step B.. Step B. (25 ^, ,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(2-fluoro4-iodobenz yl)morpholin-3-one and (2i?,55', 3-one

The title compounds were prepared from (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(2-fluoro- 4-iodobenzyl)-4-(4-methoxybenzyl)morpholin-3-one and (2R,5S,6R)-5,6-bis(4- chlorophenyl)-2-(2-fluoro-4-iodobenzyl)-4-(4-methoxybenzyl)m orpholin-3-one

(Example 63, Step A) by a procedure similar to the one described in Example 80, Step C.

Step C. (25 ^* ,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(2-fluoro-4-iodoben zyl)-4-(pyridin-3- yl)morpholin-3-one and (2i?,55 ^, ,6i?)-5,6-bis(4-chlorophenyl)-2-(2-fluoro-4-iodobenzyl )-4- (pyridin-3 -yl)morpholin-3 -one

The title compounds were prepared from (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(2-fluoro- 4-iodobenzyl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(2-fluoro-4- iodobenzyl)morpholin-3-one (Example 63, Step B) by a procedure similar to the one described in Example 58. Ste D. (25 ^* ,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(2-fluoro-4-(methyl sulfonyl)benzyl)-4- (pyridin-3-yl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)-2-(2-fluoro-4- (methylsulfonyl)benzyl)-4-(pyridin-3 -yl)morpholin-3 -one

The title compounds were prepared from (25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(2-fluoro- 4-iodobenzyl)-4-(pyridin-3-yl)morpholin-3-one and (2i?,55',6i?)-5,6-bis(4-chlorophenyl)- 2-(2-fluoro-4-iodobenzyl)-4-(pyridin-3-yl)morpholin-3-one (Example 63, Step C) by a procedure similar to the one described in Example 50, Step B.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 8.38 - 8.57 (m, 2H), 7.64 - 7.83 (m, 3H), 7.36 (d, J = 8.3 Hz, 1H), 7.11 - 7.20 (m, 3H), 7.00 (d, J= 8.6 Hz, 2H), 6.82 - 6.90 (m, 2H), 6.37 - 6.45 (m, 2H), 5.43 - 5.54 (m, 1H), 4.87 - 4.95 (m, 1H), 4.73 - 4.83 (m, 1H), 3.75 - 3.83 (m, 1H), 3.52 - 3.60 (m, 1H), 3.12 (s, 3H). Spectrum (ESI) m/z = 585 [M+l].

EXAMPLE 64

(25 ^* ,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-2-(2-(4- methylpiperazin- 1 -yl)-2-oxoethyl)morpholin-3-one and (2i?,55',6i?)-6-(3-chlorophenyl)-5- (4-chlorophenyl)-4-(cyclopropylmethyl)-2-(2-(4-methylpiperaz in-l-yl)-2- oxoethyl)morpholi -3 -one

CI and CI

4-Methylpiperazine (28 mg, 0.28 mmol), HO At (29 mg, 0.21 mmol), EDC (40 m mmol), and NaHC0 ₃ (35 mg, 0.42 mmol) were added to a stirring solution of 2- ((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclo propylmethyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclopropylmethyl)-3-oxomorpholin-2-yl)acetic acid (61 mg, 0.14 mmol, Example 17) in DMF (2.5 mL). The reaction was stirred at room temperature overnight. After this time the reaction was partitioned between ethyl acetate and water. The separated organic layer was washed with LiCl (1 M aqueous solution), dried over MgSC^, filtered and evaporated under a vacuum. Purification by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; gradient elution with 10% to 90%> acetonitrile in water, with both eluents containing 0.1% TFA) provided the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.07 - 7.20 (m, 4H), 6.99 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 5.52 (d, J = 2.7 Hz, 1H), 5.23 (dd, J = 7.9, 3.0 Hz, 1H), 4.68 (d, J = 2.9 Hz, 1H), 3.79 (dd, J = 14.1 , 6.3 Hz, 1H), 3.66 (br s, 2H), 3.51 (br s, 2H), 3.15 (dd, J = 16.0, 8.0 Hz, 1H), 3.04 (dd, J = 16.0, 3.1 Hz, 1H), 2.72 (dd, J = 14.2, 7.7 Hz, 1H), 2.35 (br s, 4H), 2.27 (s, 3H), 0.82 - 0.95 (m, 1H), 0.53 (td, J = 8.5, 4.6 Hz, 1H), 0.35 - 0.45 (m, 1H), 0.19 (dt, J = 9.6, 4.8 Hz, 1H), 0.08 (td, J = 9.8, 4.8 Hz, 1H). MS (ESI) 516.3 [M + H] ⁺ .

EXAMPLE 65

2- ((25 ^* ,5i?,65)-4-((i?)-l-Amino-l-oxopentan-2-yl)-6-(3-chloro phenyl)-5-(4-chlorophenyl)-

3- oxomorpholin-2-yl)acetic acid and 2-((2R,5S,6R)-4-((S)-l -amino- 1 -oxopentan-2-yl)-6- (3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl)acet ic acid or 2-((2S,5R,6S)-

4- ((S)-l -amino- l-oxopentan-2-yl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2R,5S,6R)-4-((R)- 1 -amino- 1 -oxopentan-2-yl)-6- (3 -chlorophenyl)-5 -(4-chlorophenyl)-3 -oxomorpholin-2-yl)acetic acid

Step A. (R)-Ethyl 2-((2^3i?)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5- oxomorpholino)pentanoate and (5)-ethyl 2-((2i?,3S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-5-oxomorpholino)pentanoate or (5)-ethyl 2-((25',3i?)-2-(3-chlorophi (4-chlorophenyl)-5-oxomorpholino)pentanoate and ( ?)-ethyl 2-((2i?,3S)-2-(3- chlorophenyl)-3- -chlorophenyl)-5-oxomorpholino)pentanoate

Sodium hydride (56 mg, 1.40 mmol, 60% dispersion in oil) was added portionwise over 1 minute to a stirring solution of (5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)morpholin- 3-one and (55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)morpholin-3-o ne (450 mg, 1.40 mmol, Example 1 1 , Step D) in DMF (10 mL) at 0 °C under a N ₂ atmosphere. The reaction was stirred at this temperature for 15 minutes and ethyl-2-bromovalerate (292 μί, 1.40 mmol) was added in one portion. The reaction was stirred at room temperature for 4 hours and then quenched with saturated aqueous NH ₄ C1 and diluted with ethyl acetate. The separated organic layer was washed with brine, dried over MgS0 ₄ , filtered and evaporated under a vacuum. Flash column chromatography (12 g Si0 ₂ , gradient elution of 1 :0 to 1 : 1 hexanes: ethyl acetate) gave one pair of the title compounds as the first eluting product.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.04 - 7.19 (m, 4H), 6.92 (s, 1H), 6.70 - 6.86 (m, 3H), 5.23 (d, J= 2.5 Hz, 1H), 4.91 (dd, J= 9.5, 5.2 Hz, 1H), 4.67 - 4.75 (m, 1H), 4.60 (d, J = 2.7 Hz, 1H), 4.52 - 4.59 (m, 1H), 4.18 - 4.27 (m, 2H), 1.70 - 1.84 (m, 1H), 1.39 (ddt, J = 14.3, 9.5, 4.8, 4.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.16 - 1.27 (m, 1H), 1.00 - 1.12 (m, 1H), 0.61 (t, J= 7.3 Hz, 3H). Step B. (i?)-Ethyl 2-((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)pentanoate and (5)-ethyl 2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanoate or (5)-ethyl 2-((25',5i?,65)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanoate and (i?)-ethyl 2- ',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomo rpholino)pentanoate

CI and CI Lithium bis(trimethylsilyl)amide (179 μΐ,, 179 μmol, 1.0 M solution in THF) was added dropwise over 1 minute to a stirring solution of (i?)-ethyl 2-((25',3i?)-2-(3-chlorophenyl)- 3-(4-chlorophenyl)-5-oxomorpholino)pentanoate and (S)-ethyl 2-((2i?,3S)-2-(3- chlorophenyl)-3-(4-chlorophenyl)-5-oxomorpholino)pentanoate or (5)-ethyl 2-((2S,3R)-2- (3-chlorophenyl)-3-(4-chlorophenyl)-5-oxomorpholino)pentanoa te and (i?)-ethyl 2- ((2i?,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxomorphol ino)pentanoate (70 mg, 155 μmol, first eluting isomers of Example 65, Step A) and allyl bromide (13 μί, 155 μιηοΐ) in THF (2.0 mL) at -78 °C under a N ₂ atmosphere. The reaction was stirred at -78 °C for 2 hours. The reaction was treated with saturated aqueous NH ₄ CI and ethyl acetate. The separated aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over MgSC^, filtered and evaporated under a vacuum. Flash column chromatography (4 g Si0 ₂ , gradient elution of 1 :0 to 2: 1 hexanes:ethyl acetate) gave the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.07 - 7.19 (m, 4H), 6.92 - 6.97 (m, 1H), 6.77 - 6.85 (m, 3H), 5.93 (ddt, J= 17.1, 10.1, 7.0, 7.0 Hz, 1H), 5.40 - 5.46 (m, 1H), 5.12 - 5.18 (m, 1H), 5.06 - 5.11 (m, 1H), 4.93 (dd, J= 9.6, 5.3 Hz, 1H), 4.78 (t, J= 6.4 Hz, 1H), 4.55 (d, J= 2.9 Hz, 1H), 4.16 - 4.32 (m, 2H), 2.82 (tt, J= 6.7, 0.8 Hz, 2H), 1.72 - 1.88 (m, 1H), 1.34 - 1.47 (m, 1H), 1.32 (t, J= 7.1 Hz, 3H), 1.12 - 1.26 (m, 1H), 0.94 - 1.10 (m, 1H), 0.62 (t, J= 7.3 Hz, 3H).

Step C. (i?)-2-((2 _l S,5i?,65)-2-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)pentanamide and (5)-2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanamide or (S)-2-((2S,5R,6S)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanamide and (R)-2-((2R,5S,6R)- 2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin o)pentanamide

an

A solution of ammonia in methanol (3.1 mL, 183.5 mmol, 7 N) was added to (i?)-ethyl 2- ((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 3-oxomorpholino)pentanoate and (S)-ethyl 2-((2i?,5^,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)pentanoate or (5)-ethyl 2-((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanoate and (i?)-ethyl 2-((2i?,5 _l S,6i?)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanoate (30 mg, 61 μιηοΐ, Example 65, Step B), and the reaction was stirred at room temperature for 2 days. The solvent was evaporated under a vacuum and the product was purified by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA;

gradient elution with 10% to 90% acetonitrile in water, both eluents containing 0.1% TFA) to give the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.06 - 7.20 (m, 4H), 6.93 (s, 1H), 6.81 (d, J= 7.6 Hz, 1H), 6.76 (d, J= 8.4 Hz, 2H), 6.20 (br s, 1H), 5.90 (ddt, J= 17.1 , 10.1 , 7.0, 7.0 Hz, 1H), 5.40 (br s, 1H), 5.22 (d, J= 2.5 Hz, 1H), 5.15 (dd, J= 17.0, 1.6 Hz, 1H), 5.09 (d, J = 10.2 Hz, 1H), 5.01 (dd, J = 8.7, 6.2 Hz, 1H), 4.83 (d, J= 2.7 Hz, 1H), 4.79 (t, J = 6.2 Hz, 1H), 2.80 (t, J = 6.7 Hz, 2H), 1.57 - 1.76 (m, 1H), 0.97 - 1.22 (m, 3H), 0.66 (t, J= 7.1 Hz, 3H).

Step D. 2-((2 _l S,5i?,65)-4-((i?)-l-Amino-l-oxopentan-2-yl)-6-(3-chlor ophenyl)-5-(4- chlorophenyl)-3-oxomorpholin-2-yl)acetic acid and 2-((2R,5S,6R)-4-((S)-l -amino- 1 - oxopentan-2-yl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxom orpholin-2-yl)acetic acid or 2-((2S,5R,6S)-4-((S)- 1 -amino- 1 -oxopentan-2-yl)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholin-2-yl)acetic acid and 2-((2R,5S, 6R)-4-((R)-l -amino- 1 - oxopentan-2-yl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxom orpholin-2-yl)acetic acid

Sodium periodate (19 mg, 87 μηιοΐ), followed by ruthenium(III) chloride hydrate (0.5 mg, 2 μιηοΐ), was added to a rapidly stirring solution of (R)-2-((2S,5R,6S)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanamide and (S)-2-((2R,5S,6R)- 2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin o)pentanamide or (S)-2- ((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)pentanamide and (R)-2-((2R,5S,6R)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanamide (10 mg, 22 μιηοΐ, Example 65, Step C) in a mixture of water (1 mL), acetonitrile (0.5 mL) and CC1 ₄ (0.5 mL). After stirring vigorously for 2 hours, the reaction was acidified with 10% citric acid and diluted with ethyl acetate. The separated organic layer was dried over MgS0 ₄ , filtered, and evaporated under a vacuum. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; gradient elution of 10% to 90% acetonitrile in water, with both eluents containing 0.1% TFA) to give the title compounds as a colorless film.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.11 - 7.21 (m, 4H), 6.93 (s, 1H), 6.88 (d, J= 7.0 Hz, 1H), 6.70 (d, J= 8.2 Hz, 2H), 5.70 (br s, 2H), 5.33 (br s, 1H), 4.93 (br s, 1H), 3.35 (dd, J= 17.5, 3.2 Hz, 1H), 2.96 (d, J= 16.6 Hz, 1H), 0.97 - 1.40 (m, 4H), 0.62 - 0.75 (m, 3H). MS (ESI) 479.1 [M + H] ⁺ . EXAMPLE 66

2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((i? )-l-cyanobutyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((5)-l-cyanobutyl)-3-oxomorpholin-2-yl)acetic acid or 2-((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((iS)- 1 -cyanobutyl)-3-oxomorpholin-2-yl)acetic acid and 2-((2i?,5 _l S,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((i?)- 1 -cyanobutyl)-3- oxomorpholin-2-yl)acetic acid

CI and CI

Step A. (^)-2-((2^,5^,65)-2-Α11 1-6-(3-ΰ1ι1θΓορ1ΐ6η 1)-5-(4-ΰ1ι1θΓορ1ΐ6η 1)-3- oxomorpholino)pentanenitrile and (5)-2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5 chlorophenyl)-3-oxomorpholino)pentanenitrile or (S)-2-((2S,5R,6S)-2-allyl-6-(3- chlorophenyl)-5 -(4-chlorophenyl)-3 -oxomorpholino)pentanenitrile and (R)-2- ((2R,5S,6R)-2-allyl-6-(3-chlorophenyl)-5-(4-chlon)phe-iyl)-3 - oxomorpholino)pentanenitrile

or

Trifluoroacetic acid anhydride (0.17 mL, 1.25 mmol) was added to a stirring solution of (i?)-2-((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)pentanamide and (5)-2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanamide or (S)-2-((2S,5R,6S)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanamide and (R)-2-((2R,5S,6R)- 2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin o)pentanamide (230 mg, 0.50 mmol, Example 65, Step C) and Et ₃ N (0.35 mL, 2.49 mmol) in THF (5 mL) at 0 °C. The reaction was stirred at 0 °C for 3 hours, and then it was partitioned between ethyl acetate and 10% aqueous citric acid. The separated aqueous layer was extracted with ethyl acetate (2 x 20 mL), and the combined organic extracts were washed with brine, dried over MgSC^, filtered and concentrated under a vacuum to give the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.06 - 7.21 (m, 4H), 6.93 - 6.98 (m, 1H), 6.78 - 6.88 (m, 3H), 5.90 (ddt, J = 17.1 , 10.1 , 7.0, 7.0 Hz, 1H), 5.43 - 5.50 (m, 1H), 5.36 (d, J = 2.9 Hz, 1H), 5.07 - 5.21 (m, 2H), 4.76 - 4.84 (m, 1H), 4.69 - 4.75 (m, 1H), 2.75 - 2.86 (m, 2H), 1.30 - 1.40 (m, 2H), 1.17 - 1.28 (m, 2H), 0.73 - 0.83 (m, 3H). MS (ESI) 443.1 [M + H] ⁺ .

Step B. 2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((i? )-l-cyanobutyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((5)-l-cyanobutyl)-3-oxomorpholin-2-yl)acetic acid or 2-((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((S)- 1 -cyanobutyl)-3-oxomorpholin-2-yl)acetic acid and 2-((2i?,5^,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((i? )- 1 -cyanobutyl)-3- oxomorpholin-2-yl)acetic acid The title compound was prepared from (i?)-2-((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5- (4-chlorophenyl)-3-oxomorpholino)pentanenitrile and (S)-2-((2R,5S,6R)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanenitr ile or (S)-2-((2S,5R,6S)- 2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin o)pentanenitrile and (R)- 2-((2i?,5^,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)pentanenitrile (Example 66, Step A) according to the procedure used for Example 65, Step D. The product was purified by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; gradient elution with 10% to 90% acetonitrile in water, both eluents containing 0.1% TFA) to give the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.19 (d, J= 8.4 Hz, 3H), 7.12 (t, J= 7.8 Hz, 1H), 6.94 (s, 1H), 6.79 - 6.86 (m, 3H), 5.45 - 5.52 (m, 1H), 5.37 (d, J= 2.5 Hz, 1H), 5.26 (dd, J= 8.2, 4.1 Hz, lH), 4.76 (d, J= 2.7 Hz, 1H), 3.04 - 3.21 (m, 2H), 1.17 - 1.44 (m, 4H), 0.67 - 0.84 (m, 3H). MS (ESI) 461.0 [M + H] ⁺ .

EXAMPLE 67

2-((2 _l S,5i?,65)-4-((i?)-l-(lH-Tetrazol-5-yl)butyl)-6-(3-chlo rophenyl)-5-(4-chlorophenyl)- 3-oxomorpholin-2-yl)acetic acid and 2-((2i?,55 ^* ,6i?)-4-((5)-l-(lH-tetrazol-5-yl)butyl)-6- (3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl)acet ic acid or 2-((25 ^* ,5i?,65)- 4-((5)-l-(lH-tetrazol-5-yl)butyl)-6-(3-chlorophenyl)-5-(4-ch lorophenyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-4-((i?)-l-(lH-tetrazol-5-yl)butyl)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl)acetic acid

or

Step A. (25,5R,6S)-4-((R)-l -(lH-Tetrazol-5-yl)butyl)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (2R,55,6R)-4-((S)- 1 -(lH-tetrazol-5-yl)butyl)-2-allyl- 6-(3-chlorophenyl)-5-(4-chlorophenyl)morpholin-3-one or (25,5R,6S)-4-((S)- 1 -(1H- tetrazol-5-yl)butyl)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorop henyl)morpholin-3-one and (2i?,5^6i?)-4-((i?)-l-(lH-tetrazol-5-yl)butyl)-2-allyl-6-(3- chlorophenyl)-5-(4- chlorophenyl)morpholin-3 -one

Sodium azide (17 mg, 0.26 mmol) and NH ₄ C1 (14 mg, 0.26 mmol) were added to a stirring solution of (i?)-2-((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorop henyl)-3- oxomorpholino)pentanenitrile and (5)-2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanenitrile or (5)-2-((25',5i?,65)-2-allyl-6-(3- chlorophenyl)-5 -(4-chlorophenyl)-3 -oxomorpholino)pentanenitrile and (R)-2- ((2^,5^,6^)-2-α11 1-6-(3-οΜθΓορ1ΐ6η 1)-5-(4-ο1ι1θΓορ1ΐ6η 1)-3- oxomorpholino)pentanenitrile (90 mg, 0.20 mmol, Example 66, Step A) in DMF (3 mL). The mixture was heated at 90 °C for 24 hours. The reaction was treated with an additional portion of sodium azide (17 mg, 0.26 mmol) and NH ₄ C1 (14 mg, 0.26 mmol) and heated at 95 °C for another 3 hours. An additional portion of sodium azide (85 mg, 1.3 mmol) was added and the reaction was stirred at 95 °C overnight. The reaction was allowed to cool to room temperature and partitioned between ethyl acetate and citric acid (0.1 M aqueous solution). The separated aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSC^, filtered and evaporated under a vacuum to give the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.05 - 7.17 (m, 5H), 6.88 (s, 1H), 6.78 (d, J= 8.4 Hz, 3H), 5.94 (t, J= 7.5 Hz, 1H), 5.83 (ddt, J= 17.1, 10.1, 6.9, 6.9 Hz, 1H), 5.20 (d, J = 2.5 Hz, 1H), 5.00 - 5.15 (m, 2H), 4.84 (d, J= 2.5 Hz, 1H), 4.79 (dd, J= 7.6, 5.1 Hz, 1H), 2.69 - 2.78 (m, 2H), 1.81 - 1.93 (m, 1H), 1.51 - 1.65 (m, 1H), 1.19 - 1.29 (m, 1H), 1.02 - 1.17 (m, 1H), 0.60 - 0.70 (m, 3H). MS (ESI) 486.1 [M + H] ⁺ .

Step B. 2-((2 _l S,5i?,65)-4-((i?)-l-(lH-Tetrazol-5-yl)butyl)-6-(3-chlo rophenyl)-5-(4- chlorophenyl)-3-oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-4-((5)-l-(lH-tetrazol- 5-yl)butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorph olin-2-yl)acetic acid or 2- ((2^,5i?,65)-4-((5)-l-(lH-tetrazol-5-yl)butyl)-6-(3-chloroph enyl)-5-(4-chlorophenyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55 ^* ,6i?)-4-((i?)-l-(lH-tetrazol-5-yl)butyl)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl)acetic acid The title compounds were prepared from (25',5i?,65)-4-((i?)-l-(lH-tetrazol-5-yl)butyl)-2- allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)morpholin-3-one and (2R,5S,6R)-4-((S)-l- (lH-tetrazol-5-yl)butyl)-2-allyl-6-(3-chlorophenyl)-5-(4-chl orophenyl)morpholin-3-one or (2S,5R,6S)-4-((S)- 1 -(lH-tetrazol-5-yl)butyl)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)morpholin-3-one and (2i?,55',6i?)-4-((i?)-l-(lH-tetrazol-5-yl)butyl)-2-allyl- 6-(3-chlorophenyl)-5-(4-chlorophenyl)morpholin-3-one (Example 67, Step A) according to the procedure used for Example 2, Step D. The product was purified by reverse phase preparative HPLC (Gemini Prep CI 8 5 μηι column, Phenomenex, Torrance, CA; gradient elution with 10% to 90% acetonitrile in water, both eluents containing 0.1% TFA) to give the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.06 - 7.22 (m, 5H), 6.72 - 6.86 (m, 4H), 6.05 (br s, 1H), 5.51 (br s, 1H), 5.20 (t, J= 4.5 Hz, 1H), 4.79 (br s, 1H), 3.37 (dd, J= 17.4, 4.3 Hz, 1H), 3.11 (dd, J= 17.5, 3.6 Hz, 1H), 1.98 - 2.11 (m, 1H), 1.54 - 1.70 (m, 1H), 0.89 - 1.21 (m, 2H), 0.65 (t, J= 7.2 Hz, 3H). MS (ESI) 504.1 [M + H] ⁺ .

EXAMPLE 68

2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((i? )-l-(5-methyl-l,3,4- oxadiazol-2-yl)butyl)-3-oxomorpholin-2-yl)acetic acid and 2-((2i?,55 ^* ,6i?)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((5)-l -(5 -methyl- 1,3, 4-oxadiazol-2-yl)butyl)-3 - oxomorpholin-2-yl)acetic acid or 2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((5)-l-(5-methyl-l,3,4-oxadiazol-2-yl)butyl)-3-oxomorpholi n-2-yl)acetic acid and 2- ((2i?,5^,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((i?)- l-(5-methyl-l,3,4-oxadiazol- 2-yl)butyl)-3-oxomorpholin-2-yl)acetic acid

Step A. (^)-2-((2^,5^,65)-2-Α11 1-6-(3-ο1ι1θΓορ1ΐ6η 1)-5-(4-ο1ι1θΓορ1ΐ6η 1)-3- oxomorpholino)pentanoic acid and (5)-2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanoic acid or (S)-2-((2S,5R,6S)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanoic acid and ( ?)-2-

((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophen yl)-3-oxomorpholino)pentanoic acid

To a stirring solution of (R)-ethyl 2-((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanoate and (S)-ethyl 2-((2i?,55',6i?)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanoate or (5)-ethyl 2- ((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 3-oxomorpholino)pentanoate and (R)-ethyl 2-((2i?,5 _l S,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3 - oxomorpholino)pentanoate (220 mg, 0.45 mmol, Example 65, Step B) in THF (2.0 mL) was added lithium hydroxide (10.7 mg, 0.45 mmol) and water (2 mL). The reaction was stirred at room temperature overnight. The reaction was treated with another portion of lithium hydroxide (10.7 mg, 0.45 mmol) and the mixture was stirred for 1 hour. Finally, the reaction was treated with an additional portion of lithium hydroxide (21.4 mg, 0.90 mmol) and the reaction was stirred for 3 hours. After this time the reaction was diluted with ethyl acetate and 0.1 M aqueous citric acid. The separated organic layer was washed with brine, dried over MgS0 ₄ , filtered and evaporated under a vacuum to give the title compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 9.66 (br s, 1H), 7.06 - 7.22 (m, 4H), 6.89 - 6.97 (m, 1H), 6.74 - 6.86 (m, 3H), 5.91 (ddt, J = 17.1 , 10.1 , 7.0, 7.0 Hz, 1H), 5.42 (d, J = 2.5 Hz, 1H), 5.03 - 5.20 (m, 2H), 4.74 - 4.94 (m, 2H), 4.49 - 4.57 (m, 1H), 2.81 (t, J = 6.7 Hz, 2H), 1.81 - 1.93 (m, 1H), 1.49 (dtd, J = 14.3, 9.6, 9.6, 4.8 Hz, 1H), 1.24-1.28 (m, 1H), 1.04 - 1.18 (m, 1H), 0.61 - 0.71 (m, 3H). MS (ESI) 462.1 [M + H] ⁺ .

Step B. (i?)-N'-Acetyl-2-((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)pentanehydrazide and (5)-N'-acetyl-2-((2i?,55',6i?)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanehydr azide or (5)-N"-acetyl-2- ((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)pentanehydrazide and (i?)-N'-acetyl-2-((2i?,55',6i?)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanehydr azide

Acetohydrazide (38.5 mg, 0.52 mmol), NaHC0 ₃ (109 mg, 1.3 mmol), HO At (88 mg, 0.65 mmol), and EDC (124 mg, 0.65 mmol) were added to a stirring solution of (i?)-2- ((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 3-oxomorpholino)pentanoic acid and (5)-2-((2i?,5 _l S,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3 - oxomorpholino)pentanoic acid or (5)-2-((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)pentanoic acid and (R)-2-((2R,5S,6R)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanoic acid (200 mg, 0.43 mmol, Example 68, Step A) in DMF (5 mL). The reaction was stirred at room temperature overnight, then diluted with ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate (2 x 50 mL) and the combined organic layers were washed with 1 M aqueous LiCl, dried over MgSC^, filtered and evaporated under a vacuum. Purification by column chromatography (24 g Si0 ₂ , gradient elution of 1 : 1 to 0: 1 hexanes:ethyl acetate) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 8.38 (br s, 1H), 7.01 - 7.17 (m, 4H), 6.93 (s, 1H), 6.82 (d, J= 7.4 Hz, 1H), 6.75 (d, J= 8.4 Hz, 2H), 5.87 (ddt, J= 17.1, 10.1, 6.9, 6.9 Hz, 1H), 5.50 (d, J= 2.5 Hz, 1H), 5.17 (dd, J= 8.5, 6.4 Hz, 1H), 5.10 (dd, J= 17.1, 1.7 Hz, 1H), 5.02 (dd, J= 10.2, 1.8 Hz, 1H), 4.75 (dd, J = 8.8, 4.3 Hz, 1H), 4.71 (d, J= 2.7 Hz, 1H), 2.71 - 2.84 (m, 2H), 2.07 (s, 3H), 1.48 - 1.64 (m, 1H), 0.88 - 1.16 (m, 3H), 0.44 - 0.62 (m, 3H). MS (ESI) 518.2 [M + H] ⁺ .

Step C. (2 _l S,5i?,65)-2-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-4-((i?)-l-(5-methyl- 1 ,3,4-oxadiazol-2-yl)butyl)morpholin-3-one and (2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)- 5-(4-chlorophenyl)-4-((5)-l-(5-methyl-l,3,4-oxadiazol-2-yl)b utyl)morpholin-3-one or (2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-4-((5)-l-(5-methyl-l,3,4- oxadiazol-2-yl)butyl)morpholin-3-one and (2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((i?)- 1 -(5 -methyl- 1 ,3 ,4-oxadiazol-2-yl)butyl)morpholin-3 -one

CI and CI

Burgess reagent (368 mg, 1.54 mmol) was added to a stirring solution of (R)-N-acetyl-2- ((2S,5R,6S)-2-allyl-6 3-cMorophenyl)-5-(4-chlorophenyl)-3- oxomorpholino)pentanehydrazide and (S)-N-acetyl-2-((2R,5S,6R)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanehydr azide or (5)-N"-acetyl-2- ((2S,5R,6S)-2-allyl-6 3-cMorophenyl)-5-(4-chlorophenyl)-3- oxomorpholino)pentanehydrazide and (R)-N-acetyl-2-((2R,5S,6R)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)pentanehydr azide (200 mg, 0.39 mmol, Example 68, Step B) in DCM (2 mL). The reaction was heated at 120 °C for 20 minutes in a microwave reactor, then diluted with DCM and saturated aqueous NaHC0 ₃ . The separated organic layer was washed with brine, dried over MgS0 ₄ , filtered and evaporated under a vacuum. Column chromatography (12 g Si0 ₂ , gradient elution of 1 :0 to 1 :2 hexanes: ethyl acetate) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.12 - 7.19 (m, 3H), 7.04 - 7.11 (m, 1H), 6.87 - 6.93 (m, 1H), 6.76 - 6.84 (m, 3H), 5.83 - 5.96 (m, 2H), 5.37 (dd, J= 2.3, 0.6 Hz, 1H), 5.13 (dq, J= 17.2, 1.6 Hz, 1H), 5.07 (dd, J= 10.2, 1.8 Hz, 1H), 4.81 (t, J= 6.4 Hz, 1H), 4.72 (d, J= 2.7 Hz, 1H), 2.74 - 2.87 (m, 2H), 2.54 - 2.61 (m, 3H), 1.69 - 1.82 (m, 1H), 1.36 - 1.49 (m, 1H), 1.15 - 1.24 (m, 1H), 0.99 - 1.14 (m, 1H), 0.61 (t, J= 7.3 Hz, 3H). MS (ESI) 500.0 [M + H] ⁺ .

Ste D. 2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((i? )-l-(5-methyl-l,3,4- oxadiazol-2-yl)butyl)-3-oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((5)-l-(5-methyl-l,3,4-ox adiazol-2-yl)butyl)-3- oxomorpholin-2-yl)acetic acid or 2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((5)-l-(5-methyl-l,3,4-oxadiazol-2-yl)butyl)-3-oxomorpholi n-2-yl)acetic acid and 2- ((2i?,5^,6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((i?)- l-(5-methyl-l,3,4-oxadiazol- 2-yl)butyl)-3-oxomorpholin-2-yl)acetic acid

The title compounds were prepared from (25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((i?)-l-(5-methyl-l,3,4-oxadiazol-2-yl)butyl )morpholin-3-one and (2i?,5 _l S,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4 -((5)- 1 -(5-methyl- 1 ,3 ,4- oxadiazol-2-yl)butyl)morpholin-3-one or (25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((5)-l-(5-methyl-l,3,4-oxadiazol-2-yl)butyl) morpholin-3-one and (2i?,5^,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4 -((i?)-l-(5-methyl-l,3,4- oxadiazol-2-yl)butyl)morpholin-3-one (Example 68, Step C) by a procedure similar to the one described in Example 65, Step D. The product was purified by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; gradient elution of 10% to 90% acetonitrile in water, with both eluents containing 0.1% TFA) to give the title compounds.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.13 - 7.19 (m, 3H), 7.04 - 7.11 (m, 1H), 6.88 (s, 1H), 6.75 - 6.82 (m, 3H), 5.90 (t, J= 7.3 Hz, 1H), 5.35 - 5.41 (m, 1H), 5.27 (dd, J= 7.6,

4.6 Hz, 1H), 4.77 (d, J= 2.2 Hz, 1H), 3.16 (dd, J= 16.5, 4.5 Hz, 1H), 3.04 (dd, J= 16.5,

7.7 Hz, 1H), 2.57 (s, 3H), 1.69 - 1.82 (m, 1H), 1.37 - 1.48 (m, 1H), 1.13 - 1.23 (m, 1H), 1.00 - 1.10 (m, 1H), 0.61 (t, J= 7.3 Hz, 3H). MS (ESI) 518.2 [M + H] ⁺ . EXAMPLE 69

2-((25 ^* ,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((i?) -cyclopropyl(5-methyl- l,3,4-oxadiazol-2-yl)methyl)-3-oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((5)-cyclopropyl(5-methyl -l,3,4-oxadiazol-2- yl)methyl)-3-oxomorpholin-2-yl)acetic acid or 2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((5)-cyclopropyl(5 -methyl- 1,3, 4-oxadiazol-2-yl)methyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((i?)-cyclopropyl(5 -methyl- 1, 3, 4-oxadiazol-2-yl)methyl)-3-oxomorpholin-2-yl)acetic acid

Step A. Ethyl 2-bromo-2-cyclopropylacetate

Methyl 2-cyclopropylacetate (4 g, 35 mmol) in THF (10 mL) was added dropwise over 5 minutes to a stirring solution of LDA (23 mL, 35 mmol, 1.8 M solution) in THF (80 mL) at -78 °C. The reaction was stirred at this temperature for 20 minutes, and then trimethylchlorosilane (7 mL, 53 mmol) was added dropwise over 2 minutes. The reaction was stirred at -78 °C for 20 minutes, and a solution of NBS (14 g, 77 mmol) in THF (10 mL) was added dropwise over 3 minutes. The reaction was allowed to warm to room temperature overnight. The reaction was treated with ethyl acetate and water. The separated organic layer was washed with brine, dried over MgS0 ₄ , filtered and evaporated under a vacuum. Flash column chromatography (80 g, Si0 ₂ , gradient elution with 1 :0 to 1 : 1 hexanes: ethyl acetate) gave the racemic title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 4.26 (q, J= 7.1 Hz, 2H), 3.45 (d, J= 10.4 Hz, 1H), 1.54 - 1.66 (m, 1H), 1.24 - 1.36 (m, 3H), 0.79 - 0.89 (m, 2H), 0.50 - 0.60 (m, 1H), 0.39 - 0.49 (m, 1H).

Step B. (i?)-Ethyl 2-((25',3i?)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxomorp holino)- 2-cyclopropylacetate and (5)-ethyl 2-((2i?,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5- oxomorpholino)-2-cyclopropylacetate or (S)-ethyl 2-((25',3i?)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-5-oxomorpholino)-2-cyclopropylacetate and (i?)-ethyl 2-((2i?,3S)-2-(3- chlorophenyl)-3- 4-chlorophenyl)-5-oxomorpholino)-2-cyclopropylacetate

Sodium hydride (150 mg, 3.72 mmol, 60% dispersion in oil) was added to a stirring solution of (5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)morpholin-3-on e and (55 ^* ,6i?)- 6-(3-chlorophenyl)-5-(4-chlorophenyl)morpholin-3-one (1.0 g, 3.14 mmol, Example 11, Step D) in DMF (7.5 mL). The reaction was stirred for 10 minutes, at room temperature and treated with (±)-ethyl 2-bromo-2-cyclopropylacetate (707 mg, 3.41 mmol, Example 69, Step A). After 16 hours the reaction was treated with NH ₄ C1 (saturated aqueous solution) and ethyl acetate. The separated organic layer was washed with 1.0 M aqueous LiCl, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. Flash column chromatography (silica gel; gradient elution with 1 :0 to 2: 1 hexanes:ethyl acetate) gave one pair of the the title compounds as the first eluting isomers.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.16 - 7.20 (m, 1H), 7.11 (dd, J= 8.4, 7.0 Hz, 3H), 6.95 (t, J= 2.0 Hz, 1H), 6.81 (dt, J= 7.6, 1.7 Hz, 1H), 6.76 (d, J= 8.3 Hz, 2H), 5.24 - 5.28 (m, 1H), 4.90 (d, J= 2.7 Hz, 1H), 4.70 (d, J= 17.4 Hz, 1H), 4.56 (d, J= 17.4 Hz, 1H), 4.34 (d, J= 10.5 Hz, 1H), 4.27 (q, J= 7.1 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H), 0.46 - 0.68 (m, 3H), -0.09 - 0.02 (m, 1H), -0.32 - -0.23 (m, 1H).

Step C. (i?)-Ethyl 2-((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)-2-cyclopropylacetate and (5)-ethyl 2-((2i?,5 _l S,6i?)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)-2-cyclopro pylacetate or (5)-ethyl 2- ((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 3-oxomorpholino)-2- cyclopropylacetate and (i?)-ethyl 2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)-2-cyclopropylacetate

r

CI and CI The title compounds were prepared from ( ?)-ethyl 2-((2S',3i?)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-5-oxomorpholino)-2-cyclopropylacetate and (5)-ethyl 2-((2i?,3S)-2-(3- chlorophenyl)-3-(4-chlorophenyl)-5-oxomorpholino)-2-cyclopro pylacetate or (5)-ethyl 2- ((25',3i?)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxomorpho lino)-2-cyclopropylacetate and ( ?)-ethyl 2-((2i?,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-5-oxomorph olino)-2- cyclopropylacetate (Example 69, Step B) by a procedure similar to the one described in Example 2, Step B. The product was purified by flash column chromatography (Si0 ₂ , gradient elution of 1 :0 to 1 :1 hexanes: ethyl acetate). 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.16 - 7.20 (m, 1H), 7.09 - 7.14 (m, 3H), 6.97 (t, J = 2.0 Hz, 1H), 6.83 (dt, J= 7.6, 1.8 Hz, 1H), 6.68 - 6.77 (m, 2H), 5.91 (ddt, J= 17.1, 10.1, 6.9, 6.9 Hz, 1H), 5.44 - 5.49 (m, 1H), 5.14 (dq, J= 17.2, 1.6 Hz, 1H), 5.04 - 5.10 (m, 1H), 4.85 (dd, J= 2.5, 0.4 Hz, 1H), 4.76 (dd, J= 7.8, 5.1 Hz, 1H), 4.32 (d, J= 10.2 Hz, 1H), 4.23 - 4.30 (m, 2H), 2.72 - 2.88 (m, 2H), 1.35 (t, J= 7.2 Hz, 3H), 0.45 - 0.72 (m, 3H), -0.10 - 0.02 (m, 1H), -0.37 - -0.20 (m, 1H).

Step D. (i?)-2-((2 _l S,5i?,65)-2-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)-2-cyclopropylacetic acid and (5)-2-((2i?,55',6i?)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)-2-cyclopro pylacetic acid or (S)-2- ((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 3-oxomorpholino)-2- cyclopropylacetic acid and (i?)-2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3 -

The title compounds were prepared from ( ?)-ethyl 2-((25',5i?,65)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)-2-cyclopro pylacetate and (5)-ethyl 2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chloropheny l)-3-oxomorpholino)-2- cyclopropylacetate or (5)-ethyl 2-((2S',5i?,6S)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)-2-cyclopropylacetate and (i?)-ethyl 2- (2R,5S,6K)-2- allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino) -2-cyclopropylacetate (Example 69, Step C) by a procedure similar to the one described in Example 68, Step A. MS (ESI) 460.1 [M + H] ⁺ .

Step E. (i?)-N'-Acetyl-2-((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)-2-cyclopropylacetohydrazide and (5)-N'-Acetyl-2-((2i?,55',6i?)-2-allyl-6- (3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)-2-cyclo propylacetohydrazide or (5)-N ^* -Acetyl-2-((2 _l S,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-3- oxomorpholino)-2-cyclopropylacetohydrazide and (R)-N-Acetyl-2-((2R,5S,6R)-2-allyl-6- (3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)-2-cyclo propylacetohydrazide

The title compounds were prepared from (i?)-2-((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5- (4-chlorophenyl)-3-oxomorpholino)-2-cyclopropylacetic acid and (S)-2-((2R,5S,6R)-2- allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino) -2-cyclopropylacetic acid or (5)-2-((25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chloroph enyl)-3-oxomorpholino)-2- cyclopropylacetic acid and (i?)-2-((2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxomorpholino)-2-cyclopropylacetic acid (Example 69, Step D) by a procedure similar to the one described in Example 68, Step B. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.00 - 7.19 (m, 4H), 6.95 (s, 1H), 6.79 - 6.88 (m, 1H), 6.65 - 6.77 (m, 2H), 5.88 (ddt, J= 17.1, 10.1, 7.0, 7.0 Hz, 1H), 5.49 (d, J= 2.5 Hz, 1H), 4.98 - 5.18 (m, 2H), 4.80 - 4.88 (m, 1H), 4.74 (dd, J= 8.9, 4.0 Hz, 1H), 4.39 (d, J = 10.6 Hz, 1H), 2.66 - 2.84 (m, 2H), 2.08 (s, 3H), 0.69 - 0.88 (m, 1H), 0.49 - 0.62 (m, 1H), 0.33 (dq, J= 9.8, 5.0 Hz, 1H), -0.10 - 0.10 (m, 1H), -0.44 - -0.25 (m, 1H).

Step F. (2 _l S,5i?,65)-2-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-4-((i?)-cyclopropyl(5- methyl-1 ,3,4-oxadiazol-2-yl)methyl)morpholin-3-one and (2i?,55',6i?)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((5)-cyclopropyl(5-methyl -l,3,4-oxadiazol-2- yl)methyl)morpholin-3-one or (25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((S)-cyclopropyl(5 -methyl- 1 ,3,4-oxadiazol-2-yl)methyl)morpholin-3-one and

(2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((i?)-cyclopropyl(5-methyl- l,3,4-oxadiazol-2-yl)methyl)morpholin-3-one

The title compounds were prepared from (R)-N-acetyl-2-((2S,5R,6S)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)-2-cyclopro pylacetohydrazide and (5)-N ^* -acetyl-2-((2i?,5 _l S,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3 - oxomorpholino)-2-cyclopropylacetohydrazide or (S)-N-acetyl-2-((2S,5R,6S)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholino)-2-cyclopro pylacetohydrazide and (i?)-N'-acetyl-2-((2i?,5 _l S,6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3 - oxomorpholino)-2-cyclopropylacetohydrazide (Example 69, Step E) by a procedure similar to the one described in Example 68, Step C.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.05 - 7.20 (m, 4H), 6.97 (s, 1H), 6.69 - 6.87 (m, 3H), 5.89 (ddt, J= 17.1, 10.1, 7.0, 7.0 Hz, 1H), 5.43 - 5.50 (m, 1H), 5.21 (d, J= 10.4 Hz, 1H), 5.13 (dd, J= 17.1, 1.5 Hz, 1H), 5.07 (d, J= 10.2 Hz, 1H), 4.98 (d, J= 2.5 Hz, 1H), 4.77 - 4.82 (m, 1H), 2.73 - 2.84 (m, 2H), 2.59 (s, 3H), -0.21-0.77 (m, 5H).

Step G. 2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((i? )-cyclopropyl(5- methyl-l,3,4-oxadiazol-2-yl)methyl)-3-oxomorpholin-2-yl)acet ic acid and 2-((2R,5S,6R)- 6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5)-cyclopropyl(5-m ethyl-l,3,4-oxadiazol-2- yl)methyl)-3-oxomorpholin-2-yl)acetic acid or 2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((5)-cyclopropyl(5 -methyl- 1,3, 4-oxadiazol-2-yl)methyl)-3- oxomorpholin-2-yl)acetic acid and 2-((2i?,55',6i?)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((i?)-cyclopropyl(5 -methyl- 1, 3, 4-oxadiazol-2-yl)methyl)-3-oxomorpholin-2-yl)acetic acid

The title compounds were prepared from (25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((i?)-cyclopropyl(5-methyl-l,3,4-oxadiazol-2 -yl)methyl)morpholin-3- one and (2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((5)-cyclopropyl(5- methyl-l,3,4-oxadiazol-2-yl)methyl)morpholin-3-one or (25',5i?,65)-2-allyl-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((5)-cyclopropyl(5-methyl -l,3,4-oxadiazol-2- yl)methyl)morpholin-3-one and (2i?,55',6i?)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((i?)-cyclopropyl(5-methyl-l,3,4-oxadiazol-2 -yl)methyl)morpholin-3- one (Example 69, Step F) by a procedure similar to the one described in Example 65, Step D. The product was purified by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; gradient elution with 10% to 90%> acetonitrile in water, with both eluents containing 0.1% TFA) to give the title

compounds. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.07 - 7.20 (m, 4H), 6.96 (s, 1H), 6.84 (d, J= 7.6 Hz, 1H), 6.77 (d, J= 8.2 Hz, 2H), 5.47 (br s, 1H), 5.28 (br s, 1H), 5.17 (d, J= 9.4 Hz, 1H), 5.03 (br s, 1H), 3.17 (d, J= 15.7 Hz, 1H), 3.03 (dd, J= 16.0, 8.0 Hz, 1H), 2.46 - 2.65 (m, 3H), 0.92 (br s, 1H), 0.59 (d, J= 5.1 Hz, 1H), 0.50 (d, J= 4.5 Hz, 1H), 0.09 - 0.22 (m, 1H), -0.25 - -0.12 (m, 1H).

EXAMPLE 70

(5)-2-((25',3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-cyanobenzyl )-5-oxomorpholino)-2- cyclopropylacetic acid and (i?)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxomorpholino)-2-cyclopropylacetic acid or (R)-2-((2S,3R,6S)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxomorpholino)-2-cycloprop ylacetic acid and (5)-2- ((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5-ox omorpholino)-2- cyclopropyl

Step A. ( ?)-Ethyl 2-((2 _l S,3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)-2- cyclopropylacetate and (5)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)- 2-cyclopropylacetate or (5)-ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)- 2-cyclopropylacetate and (i?)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5- oxomorpholino)-2-cyclopropylacetate

The title compounds were prepared from (5i?,65)-5,6-bis(4-chlorophenyl)morpholin-3- one and (55',6i?)-5,6-bis(4-chlorophenyl)morpholin-3-one (Example 4, Step F) by a procedure similar to the one described in Example 69, Step B, to give one pair of the the title compounds as the first eluting isomers.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.15 - 7.20 (m, 2H), 7.09 - 7.14 (m, 2H), 6.83 - 6.89 (m, 2H), 6.72 - 6.77 (m, 2H), 5.26 (d, J= 2.7 Hz, 1H), 4.88 (d, J= 2.7 Hz, 1H), 4.70 (d, J = 17.2 Hz, 1H), 4.57 (d, J= 17.2 Hz, 1H), 4.34 (d, J= 10.2 Hz, 1H), 4.26 (q, J= 7.0 Hz, 2H), 1.30 - 1.39 (m, 3H), 0.44 - 0.69 (m, 3H), -0.08 - 0.01 (m, 1H), -0.33 - -0.23 (m, 1H).

Step B. (i?)-Ethyl 2-((2 _l S,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)-2-cyclopropylacetate and (5)-ethyl 2-((2i?,3S,6i?)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxomorpholino)-2-cycloprop ylacetate or (S)

((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5 -oxomorpholino)-2- cyclopropylacetate and (i?)-ethyl 2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxomorpholino)-2-cyclopropylacetate

( ?)-ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)-2-cycl opropylacetate and (5)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)-2-cyclo propylacetate or (iS)-ethyl 2-((25',3i?)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)-2-cycl opropylacetate and (i?)-ethyl 2-((2i?,3S)-2,3-bis(4-chlorophenyl)-5-oxomorpholino)-2- cyclopropylacetate (60 mg, 134 μηιοΐ, first eluting isomers, Example 70, Step A) in THF (1.5 mL) were added to a stirring solution of lithium bis(trimethylsilyl)amide (147 μί, 147 μιηοΐ, 1.0 M solution in tetrahydrofuran) in THF (1.5 mL) at -78 °C. The reaction was stirred at -78 °C for 20 minutes and treated with a solution of 4- (iodomethyl)benzonitrile (39 mg, 161 μιηοΐ) in THF (1.0 mL). After stirring at -78 °C for 1 hour, the reaction was treated with saturated aqueous NH ₄ C1 and ethyl acetate. The separated aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSC^, filtered and evaporated under a vacuum. Flash column chromatography (12 g Si0 ₂ , gradient elution of 1 :0 to 2: 1 hexanes:ethyl acetate) gave the title compounds.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.48 - 7.56 (m, 2H), 7.28 - 7.34 (m, 2H), 7.08 - 7.19 (m, 4H), 6.74 - 6.83 (m, 4H), 5.03 - 5.07 (m, 1H), 4.91 - 4.97 (m, 1H), 4.68 (d, J= 2.9

Hz, 1H), 4.04 (dq, J= 10.8, 7.1 Hz, 1H), 3.88 (dq, J= 10.8, 7.1 Hz, 1H), 3.53 (d, J= 10.4 Hz, 1H), 3.34 - 3.42 (m, 2H), 1.31 - 1.43 (m, 1H), 1.20 (t, J= 7.1 Hz, 3H), 0.72 (tdd, J = 8.6, 8.6, 6.1, 4.9 Hz, 1H), 0.47 - 0.55 (m, 1H), 0.37 - 0.46 (m, 1H), -0.10 - 0.00 (m, 1H). MS (ESI) 563.2 [M + H] ⁺ .

Ste C. (5)-2-((2 _l S,3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)-2-cyclopropylacetic acid and (i?)-2-((2i?,3S,6i?)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxomorpholino)-2-cycloprop ylacetic acid or (i?)-2- ((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5-ox omorpholino)-2- cyclopropylacetic acid and (5)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl )- 5 -oxomorpholino)-2-cyclopropylacetic acid

Lithium hydroxide (53 μί, 106 μιηοΐ, 2 M aqueous solution) was added to a stirring solution of (R)-ethyl 2-((25 ^* ,3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxomorpholino)-2-cyclopropylacetate and (5)-ethyl 2-((2i?,3S,6i?)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxomorpholino)-2-cycloprop ylacetate or (5)-ethyl 2- ((25',3i?,65)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5-ox omorpholino)-2- cyclopropylacetate and (i?)-ethyl 2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxomorpholino)-2-cyclopropylacetate (30 mg, 53 μmol, Example 70, Step B) in MeOH (0.7 mL), THF (0.7 mL) and water (0.7 mL). The reaction was stirred at room temperature overnight, then acidified with 1 M HC1 and treated with ethyl acetate. The separated aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried, filtered and evaporated under a vacuum. The product was purified by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; gradient elution of 10% to 90% acetonitrile in water, both eluents containing 0.1% TFA) to give one pair of the title compounds as the first eluting isomers.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.52 - 7.59 (m, 2H), 7.32 (d, J= 8.2 Hz, 2H), 7.10 - 7.20 (m, 4H), 6.73 - 6.86 (m, 4H), 5.02 - 5.08 (m, 1H), 4.99 (dd, J= 6.6, 5.6 Hz, 1H), 4.54 - 4.63 (m, 1H), 3.35 - 3.44 (m, 2H), 3.21 - 3.29 (m, 1H), 1.46 - 1.59 (m, 1H), 0.74 (d, J= 0.6 Hz, 2H), 0.42 - 0.52 (m, 1H), 0.31 - 0.42 (m, 1H). MS (ESI) 535.2 [M + H] ⁺ . EXAMPLE 71

(5)-2-((25',3i?,65)-2,3-Bis(4-chlorophenyl)-6-(4-cyanobenzyl )-5-oxomorpholino)-2- cyclopropylacetic acid and (i?)-2-((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxomorpholino)-2-cyclopropylacetic acid or (R)-2-((2S,3R,6S)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxomorpholino)-2-cycloprop ylacetic acid and (5)-2- ((2i?,3S,6i?)-2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5-ox omorpholino)-2- cyclopropylacetic acid

CI CI and CI CI

Further elution of Example 70 provided a pair of the title compounds as the second eluting set of isomers: 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.52 (d, J= 8.0 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz, 2H), 6.78 (d, J= 8.4 Hz, 2H), 6.70 (d, J = 8.2 Hz, 2H), 5.10 (br s, 1H), 4.96 (dd, J= 7.3, 3.6 Hz, 1H), 4.76 (br s, 1H), 4.26 (d, J = 10.0 Hz, 1H), 3.30 - 3.51 (m, 2H), 0.77 (br s, 1H), 0.67 (br s, 1H), 0.58 (br s, 1H), -0.03 (br s, 1H), -0.18 (br s, 1H). MS (ESI) 535.2 [M + H] ⁺ . EXAMPLE 72

(5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)thiomorpholin-3- one

Step A. l-Chloro-4-(nitromethyl)benzene

A suspension of AgN0 ₂ (392 g) in diethyl ether (1.6 L) was cooled to 0 °C, and a solution of 4-chlorobenzylbromide (395 g, 1.92 mol) in diethyl ether (1.6 L) was added dropwise over 1 hour (temperature maintained below 3 °C during addition). The reaction mixture was stirred for 16 hours at 0 °C in the dark. The mixture was filtered, the solids were washed with diethyl ether (3x), and the combined filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution with 0% to 10% ethyl acetate in heptane) to give the title compound.

Step B. (li?,2i?)-2-Amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethan ol hydrochloride and (15',25)-2-amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethano l hydrochloride

HCI

HCI

l-Chloro-4-(nitromethyl)-benzene (205 g, 1.19 mol, Example 72, step A), alumina (135 g), pyridine (96 mL, 1.19 mol) and chlorotriethylsilane (200 mL, 180 g, 1.19 mol) were added to a flask containing 3-chlorobenzaldehyde (135 mL, 168 g, 1.19 mol). The flask was covered in aluminium foil and spun for 16 hours on a rotary evaporator in the dark at room temperature. The thick paste was filtered and washed with isopropanol. The filtrate was divided into two equal batches which were processed in parallel. To each batch, hydrochloric acid (7 L, 7 mol, 1 M) was added, followed by zinc powder (800 g, 12.3 mol) in several portions. The reaction mixture was stirred for 90 minutes until the observed exothermic (to 35 °C) reaction was complete. The mixture was cooled to 0 °C and basified to pH 10 with 30% NaOH. The suspension was filtered through a pad of diatomaceous earth and washed with DCM. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried over Na ₂ S0 ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MTBE (1.5 L) and cooled to 0 °C. Then, HC1 (375 mL, 1.5 mol, 4 N in dioxane) was added dropwise. The solid was collected by filtration and purified by crystallization from dioxane/ethanol to give the title compounds as a racemic mixture.

Step C. (li?,2i?)-2-Amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethan ol and (\S,2S)-2- amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethanol

CI and CI

Aqueous sodium hydroxide (500 mL, 1 mol, 2 M) was added to a mixture of (lR,2R)-2- amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethanol hydrochloride and (lS,2S)-2- amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethanol hydrochloride (65.5 g, 0.205 mol, Example 72, Step B) in ethyl acetate (500 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated under a vacuum to give the racemic title compounds as a white solid.

Mass Spectrum (ESI) m/z = 282.0 (M+H). Step D. (li?,2i?)-2-Amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethan ol

A mixture of (li?,2i?)-2-amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethan ol and (15',25)-2-amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethano l (57 g, 0.2 mol; Example 72, Step C) was dissolved in ethanol (2.65 L) and (+)-di-p-toluoyl-D-tartaric acid (68.4 g, 0.169 mol) was added. The mixture was heated to reflux, and water (175 mL) was added until the solution became clear. The mixture was seeded with seeding crystals (e.e. 95%) and cooled to room temperature over a period of 16 hours. The mixture was filtered, and the solid was washed with ethanol and dried to give the salt, ee. 75%. This salt was recrystallized twice from 12.5: 1 EtOH: water (36 mL/gram of salt) using seed crystals to initialize crystallization to provide the salt in 97.6% ee. The salt was dissolved in 1 :1 ethyl acetate: aqueous NaOH (2 N). The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , filtered, and the filtrate was concentrated under reduced pressure to give the title compound in 97.8% ee. Enantiomeric excess was determined by HPLC using an 250 x 46 mm Chiralpak® AD-H column (Chiral Technologies, Inc., West Chester, PA, USA) and eluting with 5% IPA/hexanes at room temperature; t _¾ = 21.7 minutes. [α]ο ^23'5 + 92.7° (c 0.385, MeOH). (lS,2S)-2-amino-l-(3-chlorophenyl)-2-(4- chlorophenyl)ethanol: room temperature; t¾ = 20.1 minutes.

Step E. (li?,2i?)-l-(3-Chlorophenyl)-2-(4-chlorophenyl)-2- ((cyclopropylmethyl)amino)ethanol

Cyclopropanecarboxaldehyde (89 μΐ,, 1.19 mmol) was added to a stirring solution of 335 mg (1.19 mmol) of ( li?,2i?)-2-amino- 1 -(3-chlorophenyl)-2-(4-chlorophenyl)ethanol

(Example 72, Step D) in MeOH (3 mL), and the reaction was stirred at room temperature overnight under a N ₂ atmosphere. An additional portion of sodium borohydride (79 mg, 2.078 mmol) was added and the reaction was stirred at room temperature. After 10 minutes, the reaction mixture was acidified to pH 2 with aqueous HC1 (1 M) and concentrated under reduced pressure. The resulting residue was partitioned between

DCM and aqueous NaHC0 ₃ . The separated aqueous layer was extracted with DCM (2x) and the combined organic extracts were dried over MgSC^, filtered and evaporated under reduced pressure to give the title compound. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.13 - 7.24 (m, 4H), 7.05 - 7.11 (m, 1H), 6.92 - 6.97 (m, 2H), 6.81 (dt, J= 7.6, 1.6 Hz, 1H), 4.47 (d, J= 8.6 Hz, 1H), 3.57 (d, J= 8.6 Hz, 1H), 2.44 (dd, J= 11.9, 6.5 Hz, 1H), 2.23 (dd, J= 12.0, 7.3 Hz, 1H), -0.09 - 0.99 (m, 5H). MS (ESI) 336.1 [M + H] ⁺ . Step F. (4i?,5i?)-5-(3-Chlorophenyl)-4-(4-chlorophenyl)-3-(cycloprop ylmethyl)-l,2,3- oxathiazolidine 2-oxide

Imidazole (323 mg, 4.75 mmol) and triethylamine (367 μί, 2.61 mmol) were added to a stirring solution of (li?,2i?)-l-(3-chlorophenyl)-2-(4-chlorophenyl)-2- (cyclopropylmethylamino)ethanol (399 mg, 1.19 mmol, Example 72, Step E) in DCM (12 mL). The reaction was cooled to 0 °C and thionyl chloride (100 μί, 1.365 mmol) was added dropwise over 2 minutes. The reaction was stirred at 0 °C for 80 minutes and quenched with water. The separated organic layer was dried over MgSC^, filtered and evaporated under a vacuum to give the title compound. The product was used

immediately in the next step without further purification.

Step G. (4i?,5i?)-5-(3-Chlorophenyl)-4-(4-chlorophenyl)-3-(cycloprop ylmethyl)- 1 ,2,3- oxathiazolidine 2,2-dioxide

Ruthenium(III) chloride hydrate (2.65 mg, 0.012 mmol), sodium periodate (302 mg, 1.412 mmol) and water (6 mL)were added to a stirring solution of (4R,5R)-5-(3- chlorophenyl)-4-(4-chlorophenyl)-3-(cyclopropylmethyl)-l ,2,3-oxathiazolidine 2-oxide (450 mg,1.177 mmol, Example 72, Step F) in acetonitrile (6 mL) at 0 °C. The reaction mixture was warmed to room temperature, stirred for 3 hours, and partitioned between ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSC^, filtered and evaporated under a vacuum. Column chromatography (12 g Si0 ₂ , gradient elution of 1 :0 to 2: 1 hexanes: ethyl acetate) gave the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.28 - 7.33 (m, 3H), 7.1 1 - 7.24 (m, 4H), 6.94 (dt, J = 7.7, 1.5 Hz, 1H), 5.26 (d, J = 9.2 Hz, 1H), 4.44 (d, J = 9.2 Hz, 1H), 2.98 (dd, J = 14.1 , 5.9 Hz, 1H), 2.67 (dd, J = 14.1 , 8.2 Hz, 1H), 0.92 - 1.04 (m, 1H), 0.45 - 0.53 (m, 1H), 0.32 - 0.44 (m, 1H), -0.15 - 0.06 (m, 2H).

Step H. Methyl 2-(((l^,2i?)-l-(3-chlorophenyl)-2-(4-chlorophenyl)-2- ((cyclopropylmethyl)amino)ethyl)thio)acetate

Methyl 2-mercaptoacetate (51.2 μΐ _^ , 0.565 mmol) and cesium carbonate (184 mg, 0.565 mmol) were added to a stirring solution of (4i?,5i?)-5-(3-chlorophenyl)-4-(4- chlorophenyl)-3-(cyclopropylmethyl)-l,2,3-oxathiazolidine 2,2-dioxide (150 mg, 0.38 mmol, Example 72, Step G) in DMF (4 mL) and the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with 1 M aqueous LiCl, dried over MgS0 ₄ , filtered and evaporated under reduced pressure to give the title compound. MS (ESI) 424.0 [M + H] ⁺ .

Step I. (5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)thiomorpholin-3-one

Water (1.0 mL) and aqueous sodium hydroxide (0.121 g, 3.02 mmol, 1.0 mL water) were sequentially added to a stirring solution of methyl 2-(((15',2i?)-l-(3-chlorophenyl)-2-(4- chlorophenyl)-2-((cyclopropylmethyl)amino)ethyl)thio)acetate (0.16 g, 0.38 mmol, Example 72, Step H) in THF (2.0 mL) at room temperature. After three hours, the reaction was diluted with ethyl acetate and acidified to pH 2 with 1.0 M aqueous HC1. The separated organic layer was dried over MgS0 ₄ , filtered and evaporated under a vacuum. The resulting intermediate was dissolved in DCM (35 mL) and cooled to 0 °C under a N ₂ atmosphere. Oxalyl chloride (0.19 mL, 0.38 mmol) was added followed by DMF (2 drops) and the reaction was warmed to room temperature and stirred for 30 minutes. Additional oxalyl chloride (0.19 mL) and DMF (2 drops) were added, and the reaction was stirred at room temperature. After 2 hours the reaction mixture was partitioned between DCM (40 mL) and water (10 mL). The separated organic layer was dried over MgSC^, filtered and evaporated under a vacuum. Flash column chromatography (12 g Si0 ₂ , gradient elution of 1 :0 to 7:3 hexanes:ethyl acetate) gave the title compound.

1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.21 - 7.25 (m, 1H), 7.14 - 7.18 (m, 2H), 7.07 - 7.13 (m, 1H), 6.86 (t, J= 2.1 Hz, 1H), 6.75 - 6.82 (m, 2H), 6.60 (dt, J= 7.8, 1.3 Hz, 1H), 4.97 (d, J= 3.9 Hz, 1H), 4.65 - 4.73 (m, 1H), 3.86 - 3.95 (m, 2H), 3.44 - 3.55 (m, 1H), 2.36 (dd, J= 14.2, 7.8 Hz, 1H), 1.20 - 1.35 (m, 1H), 0.48 - 0.56 (m, 1H), 0.36 - 0.45 (m, 1H), 0.11 - 0.20 (m, 1H), 0.00 - 0.09 (m, 1H). MS (ESI) 392.0 [M + H] ⁺ .

EXAMPLE 73

(5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)-2,2- dimethylthiomorpholin-3 -one 1 , 1 -dioxide

Step A. (5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)-2,2- dimethylthiomorpholin-3 -one

Lithium bis(trimethylsilyl)amide (382 μί, 0.382 mmol, 1.0 M in THF) was added THF (0.5 mL) under a N ₂ atmosphere, and the solution was cooled to. (5i?,65)-6-(3- Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropylmethyl)thiomo rpholin-3-one (50 mg, 0.127 mmol, Example 72, Step I) in THF (2.5 mL) was added dropwise via syringe over 5 minutes. After stirring for 15 minutes at -78 °C, methyl iodide (19.92 μΐ _^ , 0.319 mmol) in THF (0.3 mL) was added dropwise via syringe over 3 minutes. The reaction was stirred at -78 °C for 3 hours and at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ C1 and ethyl acetate. The separated organic layer was washed with MgS0 ₄ , filtered and evaporated under a vacuum. Column

chromatography (Si0 ₂ , 4 g, gradient elution with 1 :0 to 4: 1 hexanes:ethyl acetate) gave the title compound. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.21 - 7.25 (m, 1H), 7.16 (d, J= 8.6 Hz, 2H), 7.07 - 7.13 (m, 1H), 6.90 (t, J= 1.9 Hz, 1H), 6.74 (d, J= 8.2 Hz, 2H), 6.62 (d, J= 7.6 Hz, 1H), 4.99 (d, J= 4.1 Hz, 1H), 4.82 (d, J= 3.9 Hz, 1H), 3.89 (dd, J= 14.1, 6.1 Hz, 1H), 2.33 (dd, J= 14.1, 7.4 Hz, 1H), 1.84 (s, 3H), 1.70 (s, 3H), 0.85 - 1.02 (m, 1H), 0.49 - 0.58 (m, 1H), 0.35 - 0.45 (m, 1H), 0.16 (dq, J= 9.4, 4.8 Hz, 1H), 0.07 (td, J= 9.7, 5.0 Hz, 1H). MS (ESI) 420.0 [M + H] ⁺ .

Step B. (5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)-2,2- dimethylthiomorpholin-3 -one 1 , 1 -dioxide Sodium periodate (8.95 mg, 0.042 mmol), ruthenium(III) chloride hydrate (0.429 mg, 1.903 μιηοΐ), and water (0.4 mL) were sequentially added to a stirring solution of (5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)-2,2- dimethylthiomorpholin-3-one (8 mg, 0.019 mmol, Example 73, Step A) in acetonitrile (0.6 mL). After 1 hour at room temperature, the reaction was partitioned between ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate and the combined organics extracts were washed with water and brine, dried over MgS0 ₄ , filtered and evaporated under a vacuum to give the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.34 - 7.40 (m, 1H), 7.14 - 7.23 (m, 4H), 6.97 (dt, J = 7.9, 1.3 Hz, 1H), 6.70 (d, J= 8.0 Hz, 2H), 5.09 (d, J= 6.1 Hz, 1H), 4.93 (d, J= 6.1 Hz, 1H), 4.04 - 4.11 (m, 1H), 2.30 (dd, J= 14.3, 7.6 Hz, 1H), 1.89 (s, 3H), 1.82 (s, 3H), 0.89 - 0.98 (m, 1H), 0.52 - 0.61 (m, 1H), 0.41 - 0.52 (m, 1H), 0.05 - 0.17 (m, 2H). MS (ESI) 452.0 [M + H] ⁺ .

EXAMPLE 74

(5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-isopropylth iomorpholin-3-one

Step A. (li?,2i?)-l-(3-Chlorophen -2-(4-chlorophenyl)-2-(isopropylamino)ethanol

Acetone (78 μί, 1.063 mmol), acetic acid (154 μΕ, 2.69 mmol), and sodium

cyanoborohydride (111 mg, 1.77 mmol) were sequentially added to a stirring solution of (li?,2i?)-2-amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethan ol (200 mg, 0.71 mmol, Example 72, Step D) in methanol (7 mL). The reaction was heated at 65 °C for 14 hours. The reaction was then cooled to room temperature and evaporated under a vacuum. The resulting white solid was partitioned between ethyl acetate and saturated aqueous NaHC0 ₃ . The separated aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over MgS0 ₄ and filtered under reduced pressure to give the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.18 - 7.25 (m, 3H), 7.12 - 7.18 (m, 1H), 7.05 - 7.10 (m, 1H), 6.92 - 6.97 (m, 2H), 6.79 (dt, J= 7.6, 1.5 Hz, 1H), 4.43 (d, J= 8.8 Hz, 1H), 3.58 (d, J= 9.0 Hz, 1H), 2.70 (dt, J= 12.5, 6.2 Hz, 1H), 1.07 (d, J= 6.1 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H). Step B. (4i?,5i?)-5-(3-Chlorophenyl)-4-(4-chlorophenyl)-3-isopropyl- l ,2,3- oxathiazolidine 2-oxide

The title compound was prepared from (li?,2i?)-l-(3-chlorophenyl)-2-(4-chlorophenyl)- 2-(isopropylamino)ethanol (Example 74, Step A) by a procedure similar to the one described in Example 72, Step F. MS (ESI) 392.0 [M + Na] ⁺ .

Step C. (4i?,5i?)-5-(3-Chlorophenyl)-4-(4-chlorophenyl)-3-isopropyl- l ,2,3- oxathiazolidine 2,2-dioxide

The title compound was prepared from (4i?,5i?)-5-(3-chlorophenyl)-4-(4-chlorophenyl)- 3-isopropyl-l,2,3-oxathiazolidine 2-oxide (Example 74, Step B) by a procedure similar to the one described in Example 72, Step G.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.37 - 7.48 (m, 3H), 7.21 - 7.34 (m, 4H), 7.03 (dt, J = 7.6, 1.6 Hz, 1H), 5.34 (d, J= 8.8 Hz, 1H), 4.60 (d, J= 9.0 Hz, 1H), 3.56 (quin, J= 6.8 Hz, 1H), 1.45 (d, J= 6.8 Hz, 3H), 1.17 (d, J= 6.7 Hz, 3H).

Step D. Methyl 2-(((l _l S,2i?)-l-(3-chlorophenyl)-2-(4-chlorophenyl)-2- (isopropylamino)ethyl)thio)acetate

The title compound was prepared from (4i?,5i?)-5-(3-chlorophenyl)-4-(4-chlorophenyl)- 3-isopropyl-l,2,3-oxathiazolidine 2,2-dioxide (Example 74, Step C) by a procedure similar to the one described in Example 72, Step H. MS (ESI) 412.0 [M + H] ⁺ .

Step E. (5i?,65)-6-(3-Chloropheny -5-(4-chlorophenyl)-4-isopropylthiomorpholin-3-one

The title compound was prepared from methyl 2-(((15',2i?)-l-(3-chlorophenyl)-2-(4- chlorophenyl)-2-(isopropylamino)ethyl)thio)acetate (Example 74, Step D), by a procedure similar to the one described in Example 72, Step I.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.22 - 7.26 (m, 1H), 7.15 - 7.19 (m, 2H), 7.10 - 7.15 (m, 1H), 6.86 (t, J= 1.9 Hz, 1H), 6.75 - 6.82 (m, 2H), 6.62 (d, J= 7.8 Hz, 1H), 4.76 (d, J = 3.5 Hz, 1H), 4.55 (d, J= 3.5 Hz, 1H), 4.27 - 4.40 (m, 1H), 3.88 (d, J= 17.8 Hz, 1H), 3.55 (d, J= 17.6 Hz, 1H), 1.24 (d, J= 6.7 Hz, 3H), 0.92 (d, J= 7.0 Hz, 3H). MS (ESI) 380.0 [M + H] ⁺ .

EXAMPLE 75

2-((2i?,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-i sopropyl-l,l-dioxido-3- oxothiomorpholin-2-yl)acetic acid and 2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-isopropyl- 1 , 1 -dioxido-3 -oxothiomorpholin-2-yl)acetic acid

Step A. (25,5R,6S)-2-Allyl-6-(3-chloropheiiyl)-5-(4-chloioph(

isopropylthiomorpholin-3 -one

To a stirring solution of lithium bis(trimethylsilyl)amide (1 M solution in THF, 526 μί, 0.526 mmol) in THF (1.0 mL) at -78 °C under a N ₂ atmosphere was added dropwise via syringe over 3 minutes a solution of 200 mg (0.526 mmol) of (5i?,65)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-isopropylthiomorpholin-3- one (Example 74, Step E) in THF (1.5 mL). The reaction was stirred at this temperature for 10 minutes and then a solution of allyl bromide (45.5 μί, 0.526 mmol) in THF (0.5 mL) was added dropwise via syringe over 1 minute. The reaction was stirred at -78 °C for 40 minutes and then it was quenched by the addition of NH ₄ C1 (saturated aqueous solution). The mixture was allowed to warm to room temperature and then it was partitioned between ethyl acetate and water. The separated organic layer was dried over MgS0 ₄ , filtered and evaporated under a vacuum. Column chromatography (12 g Si0 ₂ , hexanes:ethyl acetate, 1 :0 t o 8:2) gave the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.21 - 7.27 (m, 1H), 7.10 - 7.19 (m, 3H), 6.89 - 6.93 (m, 1H), 6.73 - 6.79 (m, 2H), 6.65 (dt, J= 7.8, 1.5 Hz, 1H), 5.94 (ddt, J= 17.1, 10.1, 7.0, 7.0 Hz, 1H), 5.10 - 5.27 (m, 2H), 4.77 (d, J= 3.5 Hz, 1H), 4.59 - 4.67 (m, 1H), 4.43 (dt, J = 13.7, 6.8 Hz, 1H), 3.71 (dd, J= 8.0, 4.5 Hz, 1H), 2.79 - 3.00 (m, 2H), 1.19 - 1.34 (m, 3H), 0.85 - 0.96 (m, 3H). MS (ESI) 420.0 [M + H] ⁺ . Step B. 2-((2i?,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-isop ropyl-l,l-dioxido-3- oxothiomorpholin-2-yl)acetic acid and 2-((25',5i?,65)-6-(3-Chlorophenyl)-5-(4- chlorophenyl)-4-isopropyl- 1 , 1 -dioxido-3 -oxothiomorpholin-2-yl)acetic acid

To a stirring solution of 70 mg (0.167 mmol) of (25',5i?,65)-2-allyl-6-(3-chlorophenyl)-5- (4-chlorophenyl)-4-isopropylthiomorpholin-3-one (Example 75, Step B) in

CCl ₄ :acetonitrile:water (0.6 mL:0.6 mL: l mL) was added sodium periodate (178 mg, 0.833 mmol) and ruthenium(III) chloride hydrate (3.75 mg, 0.017 mmol). The reaction was stirred at room temperature for 2 hours. After this time the reaction was partitioned between ethyl acetate and water. The separated organic layer was dried over MgS0 ₄ , filtered and evaporated under a vacuum. Purification by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; eluent 20 to 70% acetonitrile in water + 0.1% TFA, gradient elution) provided the title compound as a 1 : 1 mixture of stereoisomers. 1H NMR (500 MHz, CDC1 ₃ , δ ppm): 7.35 - 7.44 (m, 1H), 7.24 - 7.31 (m, 2H), 7.14 - 7.22 (m, 2H), 7.02 - 7.09 (m, 1H), 6.78 - 6.91 (m, 2H), 4.75 - 5.04 (m, 2H), 4.45 - 4.60 (m, 1H), 3.82 - 4.38 (m, 1H), 3.31-3.53 (m, 1H), 3.17 - 3.25 (m, 1H), 0.97 - 1.32 (m, 6H). MS (ESI) 470.0 [M + H] ⁺ . EXAMPLE 76

(3i?,45',Si?)-4-(3-Chlorophenyl)-3-(4-chlorophenyl)-2-iso propyltetrahydropyrrolo[l,2- ajpyrazine- 1 ,6(2H,7H)-dione

Step A. (R)-Ethyl l-((lS,2R)-l-(3-chlorophenyl)-2-(4-chlon)ph(

(isopropylamino)ethyl)-5-oxopyrrolidine-2-carboxylate

Sodium hydride (36.4 mg, 0.835 mmol, 60% dispersion in oil) was added to a stirring solution of (4i?,5i?)-5-(3-chlorophenyl)-4-(4-chlorophenyl)-3-isopropyl- 1 ,2,3- oxathiazolidine 2,2-dioxide (215 mg, 0.557 mmol, Example 74, Step C) and (i?)-ethyl 5- oxopyrrolidine-2-carboxylate (87 mg, 0.557 mmol) in DMF (1.0 mL) under a N ₂ atmosphere. After heating at 80 °C in an oil bath for 2 hours, the reaction was cooled to room temperature, treated with an additional portion of NaH (36.4 mg, 0.835 mmol, 60% dispersion in oil) and heated at 80 °C for 1 hour. The reaction was cooled and partitioned between ethyl acetate and 1.0 M LiCl. The separated organic layer was washed with 1.0 M aqueous LiCl and the combined organic extracts were dried over MgSC^, filtered and evaporated under a vacuum to give the title compound. MS (ESI) 463.0 [M + H] ⁺ .

Step B. (i?)-l-((l _l S,2i?)-l-(3-Chlorophenyl)-2-(4-chlorophenyl)-2- (isopropylamino)ethyl)-5-oxopyrrolidine-2-carboxylic acid

Sodium hydroxide (216 mg, 5.39 mmol) in water (1.0 mL) was added to a stirring solution of (R)-ethyl 1 -((\S,2R)- 1 -(3-chlorophenyl)-2-(4-chlorophenyl)-2- (isopropylamino)ethyl)-5-oxopyrrolidine-2-carboxylate (250 mg, 0.54 mmol, Example 76, Step A) in THF:water (1.0 mL:0.5 mL) at room temperature The reaction was stirred at room temperature for 1 hour then heated at reflux for 5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The separated aqueous layer was acidified to pH 2 with 1.0 M HCl and extracted with DCM (2x). The separated organic layer was dried over MgS0 ₄ , filtered and evaporated under a vacuum to give the title compound. MS (ESI) 435.0 [M + H] ⁺ .

Step C. (3i?,4^,Si?)-4-(3-Chlorophenyl)-3-(4-chlorophenyl)-2- isopropyltetrahydropyrrolo[l ,2-a] dione

Oxalyl chloride (0.053 mL, 0.107 mmol) and DMF (3 drops) were added to a stirring solution of (i?)-l-((l^,2i?)-l-(3-chlorophenyl)-2-(4-chlorophenyl)-2- (isopropylamino)ethyl)-5-oxopyrrolidine-2-carboxylic acid (31 mg, 0.071 mmol, Example 76, Step B) in DCM (7 mL) under a N ₂ atmosphere. After stirring for 1 hour at room temperature, the reaction was partitioned between DCM and NaHC0 ₃ . The separated organic layer was dried over MgS0 ₄ , filtered and evaporated under a vacuum. Purification by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; gradient elution with 20% to 75% acetonitrile in water, both eluents containing 0.1 %> TFA) provided the title compound. 1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.21 - 7.27 (m, 3H), 7.04 - 7.12 (m, 1H), 6.80 (s, 1H), 6.65 (t, J = 5.9 Hz, 3H), 4.78 (br s, 1H), 4.64 (br s, 1H), 4.35 (dd, J= 10.1 , 6.9 Hz, 1H), 3.93 (br s, 1H), 2.25-2.60 (m, 4H), 1.22 - 1.40 (d, J= 6.5 Hz, 3H), 0.98 (d, J= 6.5 Hz, 3H). MS (ESI) 417.1 [M + H] ⁺ .

EXAMPLE 77

(3i?,45',85)-4-(3-Chlorophenyl)-3-(4-chlorophenyl)-2-isoprop yltetrahydropyrrolo[l,2- ajpyrazine- 1 ,6(2H,7H)-dione

Step A. (S)-Methyl l-((lS,2i -l-(3-chlorophenyl)-2-(4-chlorophi

(isopropylamino)ethyl)-5-oxopyrrolidine-2-carboxylate

The title compound was prepared from (4i?,5i?)-5-(3-chlorophenyl)-4-(4-chlorophenyl)- 3-isopropyl-l,2,3-oxathiazolidine 2,2-dioxide (Experiment 74, Step C) and (5)-methyl 5- oxopyrrolidine-2-carboxylate by a procedure similar to the one described in Example 76, Step A. MS (ESI) 449.0 [M + H] ⁺ .

Step B. (5)-l-((l _l S,2i?)-l-(3-Chlorophenyl)-2-(4-chlorophenyl)-2- (isopropylamino)ethyl)-5-oxopyrrolidine-2-carboxylic acid

The title compound was prepared from (S)-methyl l-((lS,2R)-l-(3-chlorophenyi)-2-(4- chlorophenyl)-2-(isopropylamino)ethyl)-5-oxopyrrolidine-2-ca rboxylate (Example 77, Step A), by a procedure similar to the one described in Example 76, Step B. MS (ESI) 435.1 [M + H] ⁺ .

Step C. (3i?,4 _l S,85)-4-(3-Chlorophenyl)-3-(4-chlorophenyl)-2- isopropyltetrahydropyrrolo[l ,2-a] dione

The title compound was prepared from (S)-l-((lS,2R)-l-(3-chlorophenyl)-2-(4- chlorophenyl)-2-(isopropylamino)ethyl)-5-oxopyrrolidine-2-ca rboxylic acid (Example 77, Step B) by a procedure similar to the one described in Example 76, Step C.

Purification by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column, Phenomenex, Torrance, CA; gradient elution with 25% to 70% acetonitrile in water, both eluents containing 0.1 % TFA) provided the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.23 - 7.28 (m, 1H), 7.15 - 7.22 (m, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.97 (br s, 1H), 6.87 (d, J= 7.4 Hz, 1H), 6.50 (d, J= 8.4 Hz, 2H), 5.21 (d, J= 6.5 Hz, 1H), 4.84 - 5.03 (m, 2H), 4.52 - 4.70 (m, 1H), 2.69 - 2.83 (m, 1H), 2.27 - 2.54 (m, 3H), 1.21 - 1.35 (d, J= 6.8 Hz, 3H), 0.88 (d, J= 6.8 Hz, 3H). MS (ESI) 417.1 [M + H] ⁺ .

EXAMPLE 78

2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-hydroxybutan-2-yl)-3- oxomorpholin-2-yl)acetic acid or 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((5)-l-hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetic acid

Step A. tert-Butyl ((li?,25)-2-(3-chlorophenyl)-l-(4-chlorophi

hydroxyethyl)carbamate

tert-Butyl ((li?,25)-2-(3-chlorophenyl)-l-(4-chlorophenyl)-2-hydroxyeth yl)carbamate and tert-butyl (( 1 S,2R)-2-(3 -chlorophenyl)- 1 -(4-chlorophenyl)-2-hydroxyethyl)carbamate (Example 11, Step B) were separated by chiral SFC (150 x 50 mm Chiralpak® AD column (Chiral Technologies, Inc., West Chester, PA, USA) with 50 g/min MeOH + 20 mM NH ₃ + 125 g/min C0 ₂ on a Thar 350 SFC (Thar Technologies, Inc., Pittsburg, PA)) to give the title compound as the second (slower) eluting isomer.

Step B. (15',2i?)-2-Amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)ethan ol 2,2,2- trifluoroacetate

Trifluoroacetic acid (576 μΐ,, 7.48 mmol) was added to a solution of tert-butyl {{\R,2S)- 2-(3 -chlorophenyl)- l-(4-chlorophenyl)-2-hydroxyethyl)carbamate (286 mg, 0.748 mmol, Example 78, Step A) in DCM (2.5 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under a vacuum to give the title compound.

Step C. tert-Butyl 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3- oxomorpholin-2-yl)acetate and tert-butyl 2-((25',5i?,65)-6-(3-chlorophenyl)-5

chlorophenyl)-3-oxomorpholin-2-yl)acetate

(E)-4-(tert-Butoxy)-4-oxobut-2-enoic acid (148 mg, 0.859 mmol; AMRI, Albany, NY), N-ethyl-N-isopropylpropan-2-amine (390 μί, 2.241 mmol) and HATU (327 mg, 0.859 mmol) were added to a solution of (15',2i?)-2-amino-l-(3-chlorophenyl)-2-(4- chlorophenyl)ethanol 2,2,2-trifluoroacetate (296 mg, 0.747 mmol, Example 78, Step B) in DMF (7.5 mL) at room temperature. After 8 hours, the mixture was diluted with ethyl acetate and washed with 1 M LiCl, 1 M HCl, saturated NaHC0 ₃ , and brine. The organic layer was dried over Na ₂ S0 ₄ , filtered and the filtrate was concentrated under a vacuum. The residue was dissolved in THF (7.5 mL) and sodium hydride (44.8 mg, 1.121 mmol, 60% dispersion in mineral oil) was added. The mixture turned yellowish orange and gas evolution was observed. The mixture was stirred at room temperature for 2 hours and became cloudy. The reaction was quenched with saturated NH ₄ C1 and extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ , filtered and the filtrate was concentrated under a vacuum to give the title compounds as a mixture of diastereomers.

Step D. (i?)-l-((3,4-Dimethoxybenzyl)oxy)butan-2-ol

A solution of 3,4-dimethoxybenzyl alcohol (29.4 mL, 202 mmol) in DMF (100 mL) was added dropwise over 30 minutes to a suspension of sodium hydride (8.91 g, 223 mmol, 60% dispersion in mineral oil) in DMF (300 mL) at 60 °C. The mixture was stirred at 60 °C for 0.5 hours until gas evolution ceased. The mixture was cooled to 45 °C, and (R)-2- ethyloxirane (17.61 mL, 202 mmol) was added dropwise. After stirring at 45 °C overnight, the mixture was cooled to room temperature, diluted with saturated aqueous NaHCC"3 (300 mL) and extracted with diethyl ether (3 x 300 mL). The combined organic extracts were washed with water (3x), dried over MgSC^, filtered, and the filtrate was concentrated under a vacuum. The residue was divided into 3 parts and purified by flash chromatography on silica gel (330 g column; gradient elution with 10% to 40% acetone in hexanes) to give the title compound as an off-white oil.

Step E. (i?)-l-((3,4-Dimethoxybenz l)oxy)butan-2-yl 4-bromobenzenesulfonate

4-Bromobenzene-l-sulfonyl chloride (20.74 g, 81 mmol) was added to a solution of DMAP (14.54 g, 1 19 mmol) and (i?)-l-((3,4-dimethoxybenzyl)oxy)butan-2-ol (13.0 g, 54.1 mmol, Example 78, Step D) in CH ₂ CI ₂ (180 mL). The mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate (50 mL) and saturated NaHCC"3 (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 0.1 M HCl (2x), brine, dried over MgSC^, filtered and the filtrate was concentrated under a vacuum. The residue was divided into 2 parts and purified by flash chromatography on silica gel (330 g column; gradient elution of 10% to 30% acetone in hexanes) to give the title compound. Step F. tert-Butyl 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-((3,4- dimethoxybenzyl)oxy)butan-2-yl)-3-oxomorpholin-2-yl)acetate and tert-butyl 2- ((25,5R,6S)-6-(3-cMorophenyl)-5 4-cMoiophenyl)-4 (S)-l-((3,4-

Sodium tert-butoxide (30.3 mg, 0.315 mmol) was added to a solution of tert-butyl 2- ((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomor pholin-2-yl)acetate and tert-butyl 2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxom orpholin-2- yl)acetate (125 mg, 0.286 mmol, Example 78, Step C) and (R)-l-((3,4- dimethoxybenzyl)oxy)butan-2-yl 4-bromobenzenesulfonate (145 mg, 0.315 mmol, Example 78, Step E) in dioxane (716 μί) at room temperature. The light orange slurry was stirred at 85 °C overnight, then cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate (3x). The combined organic layers were dried over Na ₂ SC"4, filtered and the filtrate was concentrated under a vacuum. The residue was purified by flash chromatography on silica gel (12 g column; gradient elution with 0% to 50% ethyl acetate in hexanes) to give the title compounds as a mixture of diastereomers. Step G. tert-Butyl 2-((2 _l S,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l- hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetate or tert-butyl 2-((2i?,5i?,65)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((5)-l-hydroxybutan-2-yl) -3-oxomorpholin-2- yl)acetate

2,3-Dichloro-5,6-dicyano-l ,4-benzoquinone (39.7 mg, 0.175 mmol) was added to a 0 °C solution of tert-butyl 2-((2 _l S,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-((3,4- dimethoxybenzyl)oxy)butan-2-yl)-3-oxomorpholin-2-yl)acetate and tert-butyl 2- ((25,5R,6S)-6-(3-cMorophenyl)-5 4-cMoiophenyl)-4 (S)-l-((3,4- dimethoxybenzyl)oxy)butan-2-yl)-3-oxomorpholin-2-yl)acetate (96 mg, 0.146 mmol, Example 78, Step F) in DCM (1385 μί) and water (72.9 μί). The dark green mixture was stirred at 0 °C for 2 hours, quenched with saturated NaHC0 ₃ solution, and extracted with DCM (3x). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and the filtrate was concentrated under a vacuum. The residue was purified by flash

chromatography on silica gel (4 g column; gradient elution with 70% to 90% MTBE in hexanes) to give one of the title compounds as the first (faster) eluting isomer.

Step H. 2-((2 _l S,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((5) - 1 -hydroxybutan-2- yl)-3-oxomorpholin-2-yl)acetic acid or 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((i - 1 -hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetic acid

Trifluoroacetic acid (15 μί, 0.197 mmol) was added to a solution of tert-butyl 2- ((2 _l S,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-hydroxybutan-2-yl)-3 oxomorpholin-2-yl)acetate or tert-butyl 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((5)-l-hydroxybutan-2-yl)-3-oxomorpholin-2-y l)acetate (10 mg, 0.020 mmol, Example 78, Step G) in DCM (197 μί) at room temperature. After stirring at room temperature for 4.5 hours, the mixture was concentrated, and the residue was dissolved in ethyl acetate (172 μΐ,) and water (35 μί). Sodium bicarbonate (12 mg, 0.103 mmol) was added and the mixture was heated at 70 °C for 30 minutes. The mixture was cooled to room temperature and acetic acid (12 μΐ _^ , 0.207 mmol) was slowly added. The mixture was partitioned between DCM and brine, and the aqueous layer was back extracted with DCM and ethyl acetate. The combined organic layers were dried over Na ₂ S0 ₄ , filtered and the filtrate was concentrated under a vacuum. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep CI 8 5 μιη column

(Phenomenex, Torrance, CA), gradient elution with 0% to 100% acetonitrile in water, both eluents containing 0.1% TFA, 20 minutes) to give the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.13 - 7.22 (m, 2H), 6.89 - 7.13 (m, 4H), 6.76 - 6.87 (m, 2H), 5.41 (dd, J = 2.6, 0.5 Hz, 1H), 5.20 (t, J= 5.7 Hz, 1H), 4.48 (d, J= 3.1 Hz, 1H), 3.70 - 3.82 (m, 1H), 3.13 - 3.18 (m, 2H), 1.79 - 1.94 (m, 1H), 1.48 - 1.60 (m, 1H), 0.95 (d, J= 6.7 Hz, 2H), 0.75 (t, J= 7.5 Hz, 3H). Spectrum (ESI) m/z = 452 [M+l].

EXAMPLE 79

2-((2i?,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-( (5)- 1 -hydroxybutan-2-yl)-3- oxomorpholin-2-yl)acetic acid or 2-((25',5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-((5)-l-hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetic acid

Step A. tert-Butyl 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l- hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetate or tert-butyl 2-((2S,5R,6S)-6-(3- Lyl)-5-(4-chlorophenyl)-4-((5)-l-hydroxybutan-2-yl)-3-oxomor pholin-2-

The title compound was isolated in Step G, Example 78 as the second (slower) eluting isomer.

Step B. 2-((2i?,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-((5) -l-hydroxybutan-2- yl)-3-oxomorpholin-2-yl)acetic acid or 2-((2S',5i?,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((iS)- 1 -hydroxybutan-2-yl)-3-oxomorpholin-2-yl)acetic acid

The title compound was obtained by a procedure analogous to the one described in Example 78, Step H using tert-butyl 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((5)-l-hydroxybutan-2-yl)-3-oxomorpholin-2-y l)acetate or tert-butyl 2- ((2 _l S,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((5) - 1 -hydroxybutan-2-yl)-3- oxomorpholin-2-yl)acetate (Example 79, Step A) as the starting material.

1H NMR (400 MHz, CD ₃ CN, δ ppm): 7.02 - 7.18 (m, 6H), 6.87 - 6.97 (m, 2H), 5.27 - 5.29 (m, 1H), 4.85 - 4.92 (m, 1H), 4.59 (d, J= 3.5 Hz, 1H), 3.19 - 3.29 (m, 1H), 3.01 - 3.1 1 (m, 1H), 2.89 - 2.99 (m, 1H), 1.48 - 1.68 (m, 2H), 1.23 - 1.30 (m, 3H), 0.72 (t, J = 7.6 Hz, 3H). Spectrum (ESI) m/z = 452 [M+l].

EXAMPLE 80

(25',5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-fluorobenzyl)mo rpholin-3-one

Step A. (5i?,65)-5,6-Bis(4-chlorophenyl)-4-(4-methoxybenzyl)morpholi n-3- 55',6i?)-5,6-Bis(4-chlorophenyl)-4-(4-methoxybenzyl)morpholi n-3-one

Sodium hydride (0.358 g, 14.90 mmol, 60% dispersion in mineral oil) was added to a solution of (5i?,65)-5,6-bis(4-chlorophenyl)morpholin-3-one and (5S,6R)-5,6-bis(4- chlorophenyl)morpholin-3-one (2.000 g, 6.21 mmol, Example 4, Step F) in DMF (24.83 mL, 12.42 mmol). After stirring at room temperature for 20 minutes, l-(bromomethyl)- 4-methoxybenzene (2.147 mL, 14.90 mmol) was added dropwise. The mixture was stirred at room temperature for 2 days. The mixture was diluted with saturated NaHCC"3 and ethyl acetate and the layers were separated. The organic layer was washed with saturated NaHCC"3 (2x). The combined aqueous layers were back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ S0 _4, filtered and the filtrate was concentrated under a vacuum. The residue was purified by flash chromatography on silica gel (40 g column; gradient elution with 0% to 30% ethyl acetate in hexanes) to give the title compounds as a racemic mixture.

Step B. (2 _l S,5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4 -(4- methoxybenzyl)morpholin-3-one and (2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- fluorobenzyl)-4-(4-methoxybenzyl)morpholin-3-one

In an oven dried flask, a solution of (5i?,6S)-5,6-bis(4-chlorophenyl)-4-(4- methoxybenzyl)morpholin-3-one and (55',6i?)-5,6-bis(4-chlorophenyl)-4-(4- methoxybenzyl)morpholin-3-one (1.000 g, 2.261 mmol, Example 80, Step A) in degassed THF (30.1 mL, 4.52 mmol) was cooled to -78 °C under N ₂ . l-(Bromomethyl)-4- f uorobenzene (1.239 mL, 9.95 mmol) was added, and the mixture was stirred at -78 °C for 5 minutes. LiHMDS (6.78 mL, 6.78 mmol, 1.0 M in THF) was added and the mixture was stirred at -78 °C for 3 hours. The mixture was quenched with saturated NH ₄ C1 soultion, diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , filtered and the filtrate was concentrated under a vacuum. The residue was purified by flash chromatography on silica gel (40 g column; gradient elution with 0% to 30% ethyl acetate in hexanes) to give the title compounds as a racemic mixture.

Step C. (25',5i?,65)-5,6-Bis(4-chlorophenyl)-2-(4-fluorobenzyl)morph olin-3-one

Ammonium cerium(IV) nitrate (6573 mg, 11.99 mmol) was added to a solution of

(25',5i?,65)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4 -(4-methoxybenzyl)morpholin- 3-one and (2i?,55 ^* ,6i?)-5,6-bis(4-chlorophenyl)-2-(4-fluorobenzyl)-4-(4- methoxybenzyl)morpholin-3-one (825 mg, 1.499 mmol, Example 80, Step B) in MeCN (50 mL) and water (10 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was quenched with water, diluted with ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over Na ₂ S0 _4i filtered, and the filtrate was concentrated under a vacuum. The residue was purified by flash

chromatography on silica gel (40 g column; gradient elution with 50% to 70% ethyl acetate in hexanes). The product was further purified by chiral SFC (250 x 30 mm Chiralpak® AD column (Chiral Technologies, Inc., West Chester, PA, USA) with 48 g/min MeOH + 72 g/min C0 ₂ on a Thar 350 SFC (Thar Technologies, Inc., Pittsburg, PA)) to give the title compound as the final (slowest) eluting isomer.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.10 - 7.21 (m, 6H), 6.93 (t, J= 8.7 Hz, 2H), 6.82 (d, J= 8.4 Hz, 2H), 6.77 (d, J= 8.4 Hz, 2H), 6.36 (br. s, 1H), 5.08 - 5.16 (m, 1H), 4.85 (dd, J= 8.5, 3.8 Hz, 1H), 4.54 (t, J= 3.6 Hz, 1H), 3.31 - 3.41 (m, 1H), 3.21 - 3.29 (m, 1H). Mass Spectrum (ESI) m/z = 430 [M+l].

EXAMPLE 81

(2i?,55 ^, ,6i?)-5,6-Bis(4-chlorophenyl)- -(4-fluorobenzyl)morpholin-3-one

The fast eluting peak from Example 80, Step C was further purified by flash

chromatography on silica gel (40 g column; gradient elution with 0% to 10% ethyl acetate in hexanes) to give the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.11 - 7.19 (m, 6H), 6.90 - 6.96 (m, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.77 (d, J= 8.4 Hz, 2H), 6.36 (br. s, 1H), 5.12 (d, J= 3.3 Hz, 1H), 4.85 (dd, J= 8.6, 3.5 Hz, 1H), 4.54 (t, J= 3.7 Hz, 1H), 3.34 (d, J= 8.6 Hz, 1H), 3.19 - 3.30 (m, 1H). Mass Spectrum (ESI) m/z = 430 [M+l].

EXAMPLE 82

2-((25',5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-( cyclopropylmethyl)-5-methyl- 3-oxomorpholin-2-yl)acetic aci

Step A. (i?)-4-(4-Chlorophenyl)-4-methyloxazolidin-2-one

A solution of triphosgene (1.670 mL, 11.26 mmol) in DCM (20 mL) was added dropwise over 1 hour to a solution of (2i?)-2-amino-2-(4-chlorophenyl))propan-l-ol HC1 salt (5 g, 22.51 mmol, Net Chem, Brantford, Ontario, Canada) and triethylamine (9.4 mL, 67.5 mmol) in CH ₂ CI ₂ (45.0 mL) at 0 °C. The mixture was stirred for 2 hours at 0 °C and at room temperature overnight. The mixture was quenched with saturated NaHC0 ₃ and stirred for 1 hour. The layers were separated. The aqueous layer was extracted with DCM (3x). The combined organic layers were dried over MgS0 ₄ , filtered, and the filtrate was concentrated under a vacuum. The residue was purified by flash

chromatography on silica gel (120 g column; gradient elution with 10% to 30% acetone in hexanes) to provide the title compound as a light-yellow oil.

Step B. (R)-tert-Butyl 4-(4-chlorophenyl)-4-methyl-2-oxooxazolidine-3-carboxylate

Di-tert-butyl dicarbonate (6.98 mL, 32.6 mmol) was added to a solution of (R)-4-(4- chlorophenyl)-4-methyloxazolidin-2-one (4.6 g, 21.73 mmol, Example 82, Step A), DMAP (0.266 g, 2.173 mmol) and triethylamine (4.53 mL, 32.6 mmol) in THF (43.5 mL) at 0 °C. The mixture was stirred at room temperature overnight, then it was diluted with saturated NaHC0 ₃ (30 mL) and extracted with diethyl ether ( x). The combined organic layers were dried over MgSC^, filtered and the filtrate was concentrated under a vacuum. The residue was further purified by flash chromatography on silica gel (120 g column; gradient elution with 10% to 30% acetone in hexanes) to provide the title compound as a white solid.

Step C. (R)-tert- utyl (2-(4-chlorophenyl)-l-hydroxypropan-2-yl)carbamate

Potassium carbonate (2.76 g, 45.7 mmol) was added to a solution of 4-(4- chlorophenyl)-4-methyl-2-oxooxazolidine-3-carboxylate (5.7 g, 18.28 mmol, Example 82, Step B) in MeOH (73 mL). After stirring at room temperature overnight, the mixture was diluted with dichloromethane (80 mL) and washed with brine (3 x 30 mL). The organic extract was washed with water (30 mL) and dried over MgSC^. The solution was filtered and concentrated under a vacuum. The residue was adsorbed onto a plug of silica gel and purified by flash chromatography on silica gel (120 g column; gradient elution of 5%> to 35%) acetone in hexanes) to provide the title compound as white solid.

Step D. (R)-tert-Butyl (2-(4-chlorophenyl)-l-oxopropan-2-yl)carbamate Dess-Martin periodinane (13.36 g, 31.5 mmol) was added to a suspension of (R)-tert- butyl (2-(4-chlorophenyl)-l-hydroxypropan-2-yl)carbamate (4.5 g, 15.75 mmol, Example 82, Step C) in DCM (3120 μί) and water (312 μί) at room temperature. After stirring at 25 °C for 2 hours, the mixture was diluted with ether (40 mL), and a solution of Na ₂ S ₂ 0 ₃ (25 g, 158 mmol) in saturated aqueous NaHC0 ₃ (40 mL) was added. The mixture was stirred vigorously for 10 minutes and the layers were separated. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSC^, filtered, and the filtrate was concentrated under a vacuum to give the title compound as an off- white solid.

Step E . tert- utyl (( 1 S,2R)- 1 -(3 -chlorophenyl)-2-(4-chlorophenyl)- 1 -hydroxypropan-2- yl)carbamate and tert-butyl ((li?,2i?)-l-(3-chlorophenyl)-2-(4-chlorophenyl)-l- hydroxypropan-2-yl)carbamate

A solution of (3-chlorophenyl)magnesium bromide (40 mL, 40 mmol, 1.0 M in Et ₂ 0) was added to a solution of {R)-tert-bvXy\ (2-(4-chlorophenyl)-l-oxopropan-2- yl)carbamate (5.66 g, 19.95 mmol, Example 82, Step D) in Et ₂ 0 (20 mL) at room temperature. After stirring overnight, the mixture was quenched with saturated NH ₄ C1 and extracted with ethyl acetate (3x). The combined organic layers were dried over MgS04, filtered, and the filtrate was concentrated under a vacuum. The residue was purified by flash chromatography on silica gel (330 g column; gradient elution with 0% to 40% ethyl acetate in hexanes) to provide the title compounds as a 3 : 1 mixture of isomers. Step F. ((15',2i?)-2-Amino-l-(3-chlorophenyl)-2-(4-chlorophenyl)prop an-l-ol

Hydrochloric acid (34.1 mL, 136 mmol, 4.0 M in dioxane) was added to tert-butyl (( 1 S,2R)- 1 -(3 -chlorophenyl)-2-(4-chlorophenyl)- 1 -hydroxypropan-2-yl)carbamate and tert-butyl ((IR,2R)- 1 -(3-chlorophenyl)-2-(4-chlorophenyl)- 1 -hydroxypropan-2- yl)carbamate (3.0 g, 7.57 mmol, Example 82, Step E). After stirring at room temperature for two hours, the mixture was basified with saturated NaHC0 ₃ . The layers were separated, and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over MgSC^, filtered, and the filtrate was concentrated under a vacuum. The residue was adsorbed onto a plug of silica gel and purified by flash chromatography on silica gel (120 g column; eluent: 70:25:5 DCM:acetone:MeOH + 0.1 % triethylamine) to provide the title compound as the second (slower) eluting isomer.

Step G. (15)-l-(3-Chlorophenyl)-2-(4-chlorophenyl)-2- ((cyclopropylmethyl)amino)propa - 1 -ol

Acetic acid (143 μί, 2.496 mmol) and cyclopropanecarboxaldehyde (199 μί, 2.67 mmol) were added to a stirring solution of (IS, 2i?)-2-amino-l-(3-chlorophenyl)-2-(4- chlorophenyl)propan-l-ol (264 mg, 0.891 mmol, Example 82, Step F) in MeOH (2971 μΕ) at room temperature. Then, sodium cyanoborohydride (140 mg, 2.228 mmol) was added, and evolution of gas was observed. The mixture was warmed to 60 °C and stirred overnight. The reaction was cooled to room temperature and acidified to pH 2 with 1 M HC1. The mixture was concentrated, and the residue was partitioned between DCM and saturated NaHC0 ₃ . The separated aqueous layer was extracted with DCM (3x) and the combined organic extracts were dried over Na ₂ S0 ₄ , filtered, and the filtrate

concentrated under a vacuum to provide the title compound.

Step H. Methyl 2-((15, 2i?)-l-(3-chlorophenyl)-2-(4-chlorophenyl)-2- ((cyclopopylmethyl)amino)propoxy)acetate

Sodium hydride (35.6 mg, 0.891 mmol, 60% dispersion in mineral oil) was added to a solution of (15)-l-(3-chlorophenyl)-2-(4-chlorophenyl)-2-

((cyclopropylmethyl)amino)propan-l-ol (312 mg, 0.891 mmol, Example 82, Step G) in THF (4454 μΐ.) at room temperature. The light yellow/gray slurry was stirred at room temperature for 30 minutes, and methyl 2-bromoacetate (85 μΐ,, 0.891 mmol) was added dropwise. After 4 hours at room temperature, sodium hydride (35.6 mg, 0.891 mmol, 60% dispersion in mineral oil) and methyl 2-bromoacetate (85 μί, 0.891 mmol) were added. The mixture was stirred at room temperature overnight, and additional sodium hydride (35.6 mg, 0.891 mmol, 60% dispersion in mineral oil) and methyl 2- bromoacetate (85 μί, 0.891 mmol) were added. The mixture was heated to 35 °C for 6.5 hours. The mixture was cooled to room temperature, quenched with saturated NH ₄ C1 and extracted with ethyl acetate (2x). The combined organic layers were dried over Na ₂ S0 ₄ , filtered, and the filtrate was concentrated under a vacuum to provide the title compound.

Step I. (5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopropy lmethyl)-5- methylmorpholin-3 -one

3 A Molecular sieves were added to a solution of methyl 2-((15)-l-(3-chlorophenyl)-2-(4- chlorophenyl)-2-((cyclopropylmethyl)amino)propoxy)acetate (376 mg, 0.890 mmol, Example 82, Step H) in distilled xylenes (18 mL) at room temperature. The mixture was heated at 135 °C for 2 days. The mixture was cooled to room temperature and filtered. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (12 g column; gradient elution with 0% to 50% ethyl acetate in hexanes) to give the title compound. Step J. (2 _l S,5i?,65)-2-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl )-4- (cyclopropylmethyl)-5 -methylmorpholin-3 -one

(5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(cyclopr opylmethyl)-5- methylmorpholin-3 -one (64 mg, 0.164 mmol; Example 82, Step I) was dissolved in toluene and concentrated under a vacuum thrice. The resulting residue was dissolved in THF (1640 μί) and degassed by bubbling argon through the solution for 10 minutes. Then, the mixture was cooled to -78 °C under argon and lithium bis(trimethylsilyl)amide (590 μί, 0.590 mmol, 1.0 M in THF) was added dropwise. The mixture turned orange. Allyl bromide (51.1 μί, 0.590 mmol) was added and the mixture was stirred at -78 °C for 1 hour. The mixture was quenched with saturated NH ₄ CI soultion, warmed to room temperature, and extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ , filtered, and the filtrate was concentrated under a vacuum. The residue was purified by flash chromatography on silica gel (4 g column; gradient elution with 0% to 25% ethyl acetate in hexanes) to give the title compound. Step K. 2-((25 ^* ,5i?,65)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-(cycl opropylmethyl)-5- methyl-3 -oxomorpholin-2-yl)acetic acid

Sodium periodate (113 mg, 0.530 mmol) and ruthenium(III) chloride hydrate (0.438 mg, 1.943 μπωφλνβτβ added to a solution of (25 ^* ,5i?,65)-2-allyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-5-methylmorpholin-3-one (38 mg, 0.088 mmol, Example 82, Step J) in ethyl acetate (631 μί) and acetonitrile (631 μί) and water (946 μΐ.) at room temperature. After stirring for 1 hour, the mixture was diluted with water and extracted with ethyl acetate (3x). The organic layer was dried over Na ₂ S0 ₄ , filtered, and the filtrate was concentrated under a vacuum. The residue was purified by reverse phase preparative HPLC (Gemini™ Prep C18 5 μιη column (Phenomenex, Torrance, CA), gradient elution of 0% to 100% acetonitrile, both eluents containing 0.1% TFA, 20 minutes) to give the title compound.

1H NMR (400 MHz, CDC1 ₃ , δ ppm): 7.17 - 7.25 (m, 3H), 7.06 (t, J= 7.9 Hz, 1H), 6.76 6.83 (m, 2H), 6.64 - 6.71 (m, 1H), 6.58 (dt, J= 7.8, 1.4 Hz, 1H), 5.16 (dd, J= 8.2, 4.9 Hz, 1H), 4.85 (s, 1H), 3.37 (dd, J= 14.3, 6.7 Hz, 1H), 3.12 - 3.22 (m, 1H), 2.94 - 3.06 (m, 2H), 1.72 (s, 3H), 0.83 - 0.98 (m, 1H), 0.36 - 0.49 (m, 2H), 0.15 - 0.28 (m, 2H). Spectrum (ESI) m/z = 448 [M+l]. Biological Assays

Compounds of the present invention display inhibition of the interaction between HDM2 and p53 in the following assays. Homogenous time-resolved fluorescence assay (HTRF1 assay)

The standard assay conditions for the in vitro HTRF assay consisted of a 50 ul total reaction volume in black 384-well Costar polypropylene plates in IX PBS buffer pH 7.4, 1 mM DTT, 0.1% BSA, 2.5 nM GST-hMDM2 (aa 1-188), 5 nM biotinylated-p53 (aa 1-83), 1.8 nM SA-XLent (Cisbio; Bedford, MA), 0.6 nM anti-GST cryptate monoclonal antibody (Cisbio; Bedford, MA) and 200 mM KF. Amino acid residues 1-188 of human MDM2 were expressed as an amino-terminal glutathione-S-transferase (GST) fusion protein (GST-hMDM2) in Escherichia coli. Residues 1-83 of human p53 were expressed as an amino-terminal AviTag™-TrxA-6xHis fusion protein (biotinylated p53) in E. coli. Each protein was purified from cell paste by affinity chromatography.

Specifically, 10 uL of GST-hMDM2 was incubated with 10 ul of diluted compound (various concentrations, serially diluted) in 10% DMSO for 20 minutes at room temperature. 20 uL of biotinylated-p53 was added to the GST-hMDM2 + compound mixture, and then incubated at room temperature for 60 min. 10 uL of detection buffer consisting of SA-XLent, anti-GST cryptate antibody and KF was added to GST-hMDM2, biotinylated-p53 and compound reaction and left at room temperature to reach equilibrium for >4 hrs. The final concentration of DMSO in the reaction was 2%. Time -resolved fluorescence readings were measured on a microplate multilabel reader. Percentage of inhibition was calculated relative to nutlin-3. HTRF2 Assay

As the potencies of the HDM2 inhibitors increased, an improved HTRF assay (HTRF2 assay) was developed. All assay conditions remained the same as described above, with the exception of the following changes in reagent concentrations: 0.2 nM GST-hMDM2 (1-188), 0.5 nM biotinylated-p53 (1-83), 0.18 nM SA-XLent, and 100 mM KF. HTRF3 Assay

This assay was run using the same conditions as the HTRFl assay except that 20 uL of GST-hMDM2 was incubated with 1.0 ul of diluted compound.

Results are provided in Table 1 below.

Table 1

37 2.13 8.87 11.1

39 6.64 10.4

40 6.59 19.1

41 4.53 5.6

42 0.947 0.539

43 1.29

44 0.757

45 0.466

46 0.259

47 0.4

48 0.42

49 0.561

50 0.568

51 0.676

52 0.279

53 0.276

54 0.196

55 0.179

56 0.453

57 0.391

58 5

59 10

60 12.5

61 15.8

62 15.8

63 20

64 0.322 2.74

65 0.361

66 0.697 0.718

67 0.425 0.426

68 0.659 0.488

69 0.924 0.617

70 8.8 6.99

71 0.952 0.544

72 1.25 6.17

73 0.466 2.74

74 1.68

75 2.41

76 3.63

77 3.18

78 0.611

79 1

80 0.973 4.94

81 2.34 8.75

82 6.26 The following compounds were made using processes analogous to those of Examples 1 to 82 and have been tested in the various HTRF assays described above. The results are set forth below in Table 2. Table 2

-p peraz none (2R,5S,6R)-5,6-bis(4-bromophenyl)-4-methyl-2- 25 13.2 (3 -methyl-2-buten- 1 -yl)-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-bromophenyl)-4-methyl-2- (3 -methyl-2-buten- 1 -yl)-3 -morpholinone

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.539 0.443 cyano-3-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid

(5R,6S)-5,6-bis(4-bromophenyl)-4- 84.4 (phenylmethyl)-2-piperazinone and (5S,6R)-5,6- bis(4-bromophenyl)-4-(phenylmethyl)-2- piperazinone

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.465 0.596 cyanobenzyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoic acid

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-2- 38.2 hydroxy- 1 -phenylethyl)-3 -morpholinone and

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lS)-2- hydroxy- 1 -phenylethyl)-3 -morpholinone and

(5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)-2- hydroxy- 1 -phenylethyl)-3 -morpholinone and

(5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 S)-2- hydroxy- 1 -phenylethyl)-3 -morpholinone

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 69.1 morpholinyl)-3-phenylpropanoic acid and (2S)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3-phenylpropanoic acid or (2S)-2- ((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3-phenylpropanoic acid and (2R)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3 -phenylpropanoic acid

(5R,6S)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 - 5.12 6.35 (hydroxymethy l)butyl)-3 -morpholinone and

(5 S ,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 S)- 1 - (hydroxymethy l)butyl)-3 -morpholinone or

(5R,6S)-5,6-bis(4-chlorophenyl)-4-((lS)-l- (hydroxymethy l)butyl)-3 -morpholinone and

(5 S ,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 - (hydroxymethyl)butyl)-3-morpholinone

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2- 0.496 methoxybenzyl)-5-oxo-4-morpholinyl)pentanoic

acid

(2R)-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 16.8 19.8 morpholinyl)(4-chlorophenyl)ethanoic acid and

(2S)-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)(4-chlorophenyl)ethanoic acid or

(2S)-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)(4-chlorophenyl)ethanoic acid and

(2R)-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)(4-chlorophenyl)ethanoic acid

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- 61.3 morpholinyl)-3-phenylpropanoic acid and (2S)-2- ((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3-phenylpropanoic acid or (2S)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3-phenylpropanoic acid and (2R)-2- ((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3 -phenylpropanoic acid

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- 2.07 1.28 fluorobenzyl)-4-(( 1 S)-l -(hydroxymethyl)butyl)-3 - morpholinone and (2S,5R,6S)-5,6-bis(4- chlorophenyl)-2-(4-fluorobenzyl)-4-(( 1 R)- 1 - (hydroxymethy l)butyl)-3 -morpholinone or

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- fluorobenzyl)-4-(( 1 R)- 1 -(hydroxymethyl)butyl)- 3 -morpholinone and (2S,5R,6S)-5,6-bis(4- chlorophenyl)-2-(4-fluorobenzyl)-4-(( 1 S)- 1 - (hydroxymethyl)butyl)-3-morpholinone

(5R,6S)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 -(4- 5 7.88 chlorophenyl)-2-hydroxyethyl)-3-morpholinone

and (5 S ,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 S)- 1 - (4-chlorophenyl)-2-hydroxyethyl)-3- morpholinone or (5R,6S)-5,6-bis(4- chlorophenyl)-4-((lS)-l-(4-chlorophenyl)-2- hydroxyethyl)-3 -morpholinone and (5S,6R)-5,6- bis(4-chlorophenyl)-4-(( 1 R)- 1 -(4-chlorophenyl)- 2-hydroxy ethyl)-3 -morpholinone

(5R,6S)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 -( 1 - 12.6 16.1 hydroxy- 1 -methylethyl)butyl)-3 -morpholinone

and (5 S ,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 S)- 1 - ( 1 -hydroxy- 1 -methylethyl)butyl)-3 -morpholinone

or (5R,6S)-5 ,6-bis(4-chlorophenyl)-4-(( 1 S)- 1 -( 1 - hydroxy- 1 -methylethyl)butyl)-3 -morpholinone

and (5 S ,6R)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 - ( 1 -hydroxy- 1 -methylethyl)butyl)-3 -morpholinone

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- s 0.838 0.506 fluorobenzyl)-5-oxo-4-morpholinyl)pentanamide

and (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-

6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide or (2S)-2-((2S,3R,6S)-

2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5- oxo-4-morpholinyl)pentanamide and (2R)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)pentanamide

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 4.29 3.19 morpholinyl)pentanamide and (2S)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanamide or (2S)-2-((2S,3R)-2,3- bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanamide and (2R)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanamide

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4- 0.644 0.744 fluorobenzyl)-4-(( 1 R)- 1 -(hydroxymethyl)butyl)- 3-morpholinone or (2S,5R,6S)-5,6-bis(4- chlorophenyl)-2-(4-fluorobenzyl)-4-(( 1 S)- 1 - (hydroxymethyl)butyl)-3-morpholinone

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.623 0.507 fluorobenzyl)-5-oxo-4-morpholinyl)pentanamide

or (2S)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6- (4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 3.61 3.72 morpholinyl)pentyl carbamate and (2S)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentyl carbamate or (2S)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentyl carbamate and (2R)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentyl carbamate

(2R)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(3,4- 3.69 3.58 dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acidand (2S)-2- ((2R,3S,6R)-3-(4-chlorophenyl)-2-(3,4- dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid or (2S)-2- ((2S,3R,6S)-3-(4-chlorophenyl)-2-(3,4- dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acidand (2R)-2- ((2R,3S,6R)-3-(4-chlorophenyl)-2-(3,4- dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 0.66

chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetic acid and ((2S,5S,6R)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-3-oxo-2-morpholinyl)acetic acid or ((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetic acid and ((2R,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-

(cyclopropylmethyl)-3-oxo-2-morpholinyl)acetic

acid

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 0.677 0.677 chlorophenyl)-4-(( 1 R)- 1 -methylbutyl)-3 -oxo-2- morpholinyl)acetic acid and ((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((l S)- 1 - methylbutyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)- 1 -methylbutyl)-3-oxo-2- morpholinyl)acetic acid and ((2S,5R,6S)-6-(3- chlorophenyl)-5 -(4-chlorophenyl)-4-(( 1 R)- 1 - methylbutyl)-3-oxo-2-morpholinyl)acetic acid

(2R)-2-((2S,3R)-3-(4-chlorophenyl)-2-(3,4- 9.16 15.7 dichlorophenyl)-5-oxo-4- morpholinyl)pentanamide and (2S)-2-((2R,3S)-3-

(4-chlorophenyl)-2-(3,4-dichlorophenyl)-5-oxo-4- morpholinyl)pentanamide or (2S)-2-((2S,3R)-3-

(4-chlorophenyl)-2-(3,4-dichlorophenyl)-5-oxo-4- morpholinyl)pentanamide and (2R)-2-((2R,3S)-3-

(4-chlorophenyl)-2-(3,4-dichlorophenyl)-5-oxo-4- morpholinyl)pentanamide

(2R)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 1.41 3.65 fluorobenzyl)-5-oxo-4-morpholinyl)(4- chlorophenyl)ethanoic acid and (2S)-((2R,3S,6R)- 2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5- oxo-4-morpholinyl)(4-chlorophenyl)ethanoic acid

or (2S)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)(4- chlorophenyl)ethanoic acid and (2R)- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)(4- chlorophenyl)ethanoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 5 11.3 fluorobenzyl)-5-oxo-4-morpholinyl)-2-(4- chlorophenyl)ethanamide and (2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)-2-(4- chlorophenyl)ethanamide or (2S)-2-((2S,3R,6S)-

2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5- oxo-4-morpholinyl)-2-(4- chlorophenyl)ethanamide and (2R)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)-2-(4- chlorophenyl)ethanamide

methyl 4-(((2R)-2-((2S,3R,6S)-2,3-bis(4- 0.749 chlorophenyl)-6-(4-(methylsulfonyl)benzyl)-5- oxo-4-morpholinyl)pentanoyl)amino)butanoate

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- 0.752 1.69 chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide and (2S)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2S)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide or (2S)-2-

((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide and (2R)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2S)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide or (2R)-2-

((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2S)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide and (2S)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide or (2S)-2-

((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2S)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide and (2R)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 7.44 13.7 morpholinyl)-2-(4-chlorophenyl)ethanamide and

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-2-(4-chlorophenyl)ethanamide or

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-2-(4-chlorophenyl)ethanamide and

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-2-(4-chlorophenyl)ethanamide

(2R)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(3,4- 2.38 1.95 dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide and (2S)-2-

((2R,3S,6S)-3-(4-chlorophenyl)-2-(3,4- dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide or (2S)-2-((2S,3R,6S)-

3-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)pentanamide

and (2R)-2-((2R,3S,6S)-3-(4-chlorophenyl)-2- (3,4-dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2- 0.79

(4-methyl- 1 -piperazinyl)ethyl)-5-oxo-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 2.87 4.45 morpholinyl)-N-methylpentanamide and (2S)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-methylpentanamide or (2S)-2- ((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-methylpentanamide and (2R)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-methylpentanamide

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 3.44 5.25 morpholinyl)-N-(2-hydroxyethyl)pentanamide

and (2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5- oxo-4-morpholinyl)-N-(2- hydroxyethyl)pentanamide or (2S)-2-((2S,3R)-

2,3-bis(4-chlorophenyl)-5-oxo-4-morpholinyl)-N-

(2-hydroxyethyl)pentanamide and (2R)-2-

((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-(2-hydroxyethyl)pentanamide

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 4.16 5.09 morpholinyl)-N,N-dimethylpentanamide and

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N,N-dimethylpentanamide or (2S)- 2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N,N-dimethylpentanamide and

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N,N-dimethylpentanamide

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 4.53 4.75 morpholinyl)-N-(2-(4- morpholinyl)ethyl)pentanamide and (2S)-2-

((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-(2-(4- morpholinyl)ethyl)pentanamide or (2S)-2-

((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-(2-(4- morpholinyl)ethyl)pentanamide and (2R)-2-

((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-(2-(4- morpholinyl)ethyl)pentanamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(3- 0.973

( 1 H-imidazol- 1 -yl)propyl)-5 -oxo-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 5 6.55 morpholinyl)-N-propylpentanamide and (2S)-2-

((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-propylpentanamide or (2S)-2-

((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-propylpentanamide and (2R)-2-

((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-N-propylpentanamide

(5R,6S)-4-(( 1 R)- 1 -(aminomethyl)butyl)-5 ,6- 6.09 6.88 bis(4-chlorophenyl)-3-morpholinone and (5S,6R)- 4-(( 1 S)- 1 -(aminomethyl)butyl)-5 ,6-bis(4- chlorophenyl)-3-morpholinone or (5R,6S)-4- ((1 S)- 1 -(aminomethyl)butyl)-5 ,6-bis(4- chlorophenyl)-3-morpholinone and (5S,6R)-4- (( 1 R)- 1 -(aminomethyl)butyl)-5 ,6-bis(4- chlorophenyl)-3 -morpholinone

(2R)-2-((2S,3R,6S)-2-(4-chloro-3-fluorophenyl)- 2 1.21

3-(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide and (2S)-2-

((2R,3S,6R)-2-(4-chloro-3-fluorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide or (2S)-2-((2S,3R,6S)-

2-(4-chloro-3-fluorophenyl)-3-(4-chlorophenyl)-

6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide and (2R)-2-

((2R,3S,6R)-2-(4-chloro-3-fluorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5- 1.94 1.25 oxo-6-(2-propen- 1 -yl)-4- morpholinyl)pentanamide and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(2- propen-l-yl)-4-morpholinyl)pentanamide or (2S)- 2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5-oxo-6- (2-propen- 1 -yl)-4-morpholinyl)pentanamide and

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5- oxo-6-(2-propen- 1 -yl)-4- morpholinyl)pentanamide

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- 1.3 1.05 fluorobenzyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2R)-2-((2S,3R,6S)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2S,3R,6S)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 3.71 4.56 oxo-4-morpholinyl)pentyl)-2-hydroxyacetamide

and N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-

5-oxo-4-morpholinyl)pentyl)-2-hydroxyacetamide

or N-((2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- oxo-4-morpholinyl)pentyl)-2-hydroxyacetamide

and N-((2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-

5-oxo-4-morpholinyl)pentyl)-2-hydroxyacetamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(3- 1.11 methoxybenzyl)-5-oxo-4-morpholinyl)pentanoic

acid

(2R)-2-((2S,3R)-2-(4-chloro-2-methylphenyl)-3- 7.67 8.53

(4-chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,3S)-2-(4-chloro-2- methylphenyl)-3-(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanoic acid or (2S)-2-((2S,3R)-2-

(4-chloro-2-methylphenyl)-3-(4-chlorophenyl)-5- oxo-4-morpholinyl)pentanoic acid and (2R)-2-

((2R,3S)-2-(4-chloro-2-methylphenyl)-3-(4- chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid

(3R)-3-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- 1.15 chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5- 0.997 2.03 oxo-6-(2-propen- 1 -yl)-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-5-oxo-6-(2-propen- 1 -yl)-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6- 1.76 2.4 ((2S)-2,3-dihydroxypropyl)-5-oxo-4- morpholinyl)pentanamide and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2R)-2,3- dihydroxypropyl)-5 -oxo-4- morpholinyl)pentanamide or (2R)-2-((2S,3R,6S)- 2,3-bis(4-chlorophenyl)-6-((2R)-2,3- dihydroxypropyl)-5 -oxo-4- morpholinyl)pentanamide and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3- dihydroxypropyl)-5 -oxo-4- morpholinyl)pentanamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6- 2.38 2.57 ((2R)-2,3-dihydroxypropyl)-5-oxo-4- morpholinyl)pentanamide and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3- dihydroxypropyl)-5 -oxo-4- morpholinyl)pentanamide or (2R)-2-((2S,3R,6S)- 2,3-bis(4-chlorophenyl)-6-((2S)-2,3- dihydroxypropyl)-5 -oxo-4- morpholinyl)pentanamide and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2R)-2,3- dihydroxypropyl)-5 -oxo-4- morpholinyl)pentanamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6- 3.52 8.22

((2R)-2,3-dihydroxypropyl)-5-oxo-4- morpholinyl)pentanoic acid and (2R)-2-

((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanoic acid and (2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-((2S)-2,3- dihydroxypropyl)-5-oxo-4-morpholinyl)pentanoic

acid

(2R)-2-((2S,5R,6S)-2-(2-amino-2-oxoethyl)-5,6- 3.85 5.49 bis(4-chlorophenyl)-3-oxo-4- morpholinyl)pentanoic acid and (2S)-2-

((2R,5S,6R)-2-(2-amino-2-oxoethyl)-5,6-bis(4- chlorophenyl)-3-oxo-4-morpholinyl)pentanoic

acid

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 1.27

chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid

((2R,5 S ,6R)-4-(( 1 S)- 1 -carbamoylbutyl)-5 ,6-bis(4- 7.82 13.5 chlorophenyl)-3-oxo-2-morpholinyl)acetic acid

and ((2S,5R,6S)-4-((lR)-l-carbamoylbutyl)-5,6- bis(4-chlorophenyl)-3-oxo-2-morpholinyl)acetic

acid

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.31 1.3 chlorophenyl)-4-(( 1 S)-l -(ethoxy carbonyl)butyl)- 3-oxo-2-morpholinyl)acetic acid and ((2S,5R,6S)- 6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((lR)-l- (ethoxycarbonyl)butyl)-3 -oxo-2- morpholinyl)acetic acid or ((2R,5S,6R)-6-(3- chlorophenyl)-5 -(4-chlorophenyl)-4-(( 1 R)- 1 - (ethoxycarbonyl)butyl)-3 -oxo-2- morpholinyl)acetic acid and ((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-((l S)- 1 - (ethoxycarbonyl)butyl)-3 -oxo-2- morpholinyl)acetic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.691 0.706 fluorobenzyl)-5-oxo-4-morpholinyl)-N-(2-(4- morpholinyl)ethyl)pentanamide and (2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)-N-(2-(4- morpholinyl)ethyl)pentanamide

(5R,6S)-5 ,6-bis(4-chlorophenyl)-4-(( 1 R)- 1 -(4- 4 12.1 morpholinylmethyl)butyl)-3 -morpholinone and

(5 S,6R)-5 ,6-bis(4-chlorophenyl)-4-(( lS)-l-(4- morpholinylmethyl)butyl)-3-morpholinone

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4- 1.33

chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetic acid and ((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-3-oxo-2-morpholinyl)acetic

acid or ((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetic acid, ((2S,5S,6R)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-

(cyclopropylmethyl)-3-oxo-2-morpholinyl)acetic

acid

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 5.12 7.15 oxo-4-morpholinyl)pentyl)methanesulfonamide

and N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)- 5-oxo-4-morpholinyl)pentyl)methanesulfonamide

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- 0.922 0.583 fiuorobenzyl)-4-(( 1 S)- 1 -((4-methyl- 1 - piperazinyl)carbonyl)butyl)-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4- fluorobenzyl)-4-((l R)- 1 -((4-methyl- 1 - piperazinyl)carbonyl)butyl)-3-morpholinone

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- 1.05 1.27 fiuorobenzyl)-4-(( lS)-l-(4- morpholinylcarbonyl)butyl)-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4- fiuorobenzyl)-4-(( 1 R)- 1 -(4- morpholinylcarbonyl)butyl)-3-morpholinone

(2R,5S,6R)-4-((lS)-l-(aminomethyl)butyl)-5,6- 4.65 3.09 bis(4-chlorophenyl)-2-(4-fluorobenzyl)-3- morpholinone and (2S,5R,6S)-4-((lR)-l- (aminomethyl)butyl)-5,6-bis(4-chlorophenyl)-2- (4-fluorobenzyl)-3 -morpholinone

(5R,6S)-2-benzyl-5,6-bis(4-chlorophenyl)-4- 1.45 4.88 8.31 methyl-3 -morpholinone or (5S,6R)-2-benzyl-5,6- bis(4-chlorophenyl)-4-methyl-3-morpholinone

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 4.21 1.47 chlorophenyl)-4-(cyclopropylsulfonyl)-3-oxo-2- morpholinyl)acetic acid and ((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-

(cyclopropylsulfonyl)-3-oxo-2-morpholinyl)acetic

acid

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- 55.1 fluorobenzyl)-4-(( lS)-l-(4- morpholinylmethyl)butyl)-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4- fhiorobenzyl)-4-(( 1 R)- 1 -(4- morpholinylmethyl)butyl)-3-morpholinone

(2R)-2-((2S,3R,6S)-3-(4-chlorophenyl)-6-(4- 1.47

fluorobenzyl)-5-oxo-2-phenyl-4- morpholinyl)pentanoic acid and (2S)-2-

((2R,3S,6R)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-2-phenyl-4- morpholinyl)pentanoic acid or (2S)-2-

((2S,3R,6S)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-2-phenyl-4- morpholinyl)pentanoic acid and (2R)-2- ((2R,3S,6R)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-2-phenyl-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2- 1.49

(4-morpholinyl)ethyl)-5-oxo-4- morpholinyl)pentanoic acid

(2R)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 1.52 fluorobenzyl)-5-oxo-4- morpholinyl)(phenyl)ethanoic acid and (2S)- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4- morpholinyl)(phenyl)ethanoic acid or (2S)- ((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4- morpholinyl)(phenyl)ethanoic acid and (2R)- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4- morpholinyl)(phenyl)ethanoic acid

(2R)-2-((2S,3R)-2-(4-chlorophenyl)-3-(3,4- 48.9 dichlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acidand (2S)-2-((2R,3S)-2-(4-chlorophenyl)-3- (3,4-dichlorophenyl)-5-oxo-4- morpholinyl)pentanoic acid or (2S)-2-((2S,3R)-2- (4-chlorophenyl)-3-(3,4-dichlorophenyl)-5-oxo-4- morpholinyl)pentanoic acidand (2R)-2-((2R,3S)- 2-(4-chlorophenyl)-3-(3,4-dichlorophenyl)-5-oxo- 4-morpholinyl)pentanoic acid

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 1.56

4-( 1 -methylethyl)-3 -thiomorpholinone 1,1- dioxide

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- 1.6 4.31 chlorophenyl)-6-(2-(4-morpholinyl)-2-oxoethyl)- 5-oxo-4-morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(2-(4-morpholinyl)-2-oxoethyl)- 5-oxo-4-morpholinyl)pentanoic acid or (2S)-2- ((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(2-(4-morpholinyl)-2-oxoethyl)- 5-oxo-4-morpholinyl)pentanoic acid and (2R)-2- ((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(2-(4-morpholinyl)-2-oxoethyl)- 5-oxo-4-morpholinyl)pentanoic acid

(2R)-2-((2S,3R)-3-(4-bromophenyl)-2-(4- 2.69 11.6 chlorophenyl)-5-oxo-4-morpholinyl)pentanoic acidand (2S)-2-((2R,3S)-3-(4-bromophenyl)-2-(4- chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid or (2S)-2-((2S,3R)-3-(4-bromophenyl)-2-(4- chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2R)-2-((2R,3S)-3-(4-bromophenyl)-2-

(4-chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5- 1.73 oxo-6-(2-(l-piperidinyl)ethyl)-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R)-2-(4-chlorophenyl)-3-(4- 64.9 cyclopropylphenyl)-5 -oxo-4- morpholinyl)pentanoic acid and (2S)-2-((2R,3S)- 2-(4-chlorophenyl)-3-(4-cyclopropylphenyl)-5- oxo-4-morpholinyl)pentanoic acid or (2S)-2- ((2S,3R)-2-(4-chlorophenyl)-3-(4- cyclopropylphenyl)-5 -oxo-4- morpholinyl)pentanoic acid and (2R)-2-((2R,3S)- 2-(4-chlorophenyl)-3-(4-cyclopropylphenyl)-5- oxo-4-morpholinyl)pentanoic acid

(2R)-2-((2S,3R,6S)-3-(4-bromophenyl)-2-(4- 0.707 1.28 chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-3-(4-bromophenyl)-2-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid or (2S)-2- ((2S,3R,6S)-3-(4-bromophenyl)-2-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2R)-2- ((2R,3S,6R)-3-(4-bromophenyl)-2-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid

2-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 1.77 8.03 methyl-3-oxo-2-morpholinyl)methyl)benzonitrile

and 2-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- methyl-3-oxo-2-morpholinyl)methyl)benzonitrile

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- 2.5 1.81 chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide and (2S)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide or (2S)-2-((2S,3R,6S)-

2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)pentanamide

and (2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2- 1.82

fluoro-4-(methylsulfonyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(2-fluoro- 4-(methylsulfonyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 2.13 1.86 fluorobenzyl)-5-oxo-4-morpholinyl)hexanoic acid

and (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)- 6-(4-fluorobenzyl)-5-oxo-4-morpholinyl)hexanoic

acid or (2S)-2-((2S,3R,6S)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid and (2R)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)hexanoic acid

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- 1.33 0.845 fluorobenzyl)-4-((lS)-l-(lH-tetrazol-5-yl)butyl)- 3-morpholinone and (2S,5R,6S)-5,6-bis(4- chlorophenyl)-2-(4-fluorobenzyl)-4-(( 1 R)- 1 -( 1 H- tetrazol-5 -yl)butyl)-3 -morpholinone

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.909

6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)glycine and N-((2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)glycine

(2R)-2-((2S,3R,6S)-3-(4-bromophenyl)-2-(4- 0.358 0.584 chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-3-(4-bromophenyl)-2-(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoic acid

3-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.01 6.3 16.3 chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)propanenitrile and 3-((2S,5R,6S)-6-

(3-chlorophenyl)-5-(4-chlorophenyl)-4-

(cyclopropylmethyl)-3-oxo-2- morpholinyl)propanenitrile

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.04

chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetic acid or ((2R,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-

(cyclopropylmethyl)-3-oxo-2-morpholinyl)acetic

acid or ((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetic acid or ((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-3-oxo-2-morpholinyl)acetic

acid

2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.05 3.58 chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)-N-(2-(4- morpholinyl)ethyl)acetamide and 2-((2S,5R,6S)- 6-(3-chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-3-oxo-2-morpholinyl)-N-(2- (4-morpholinyl)ethyl)acetamide

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4- 3.92 2.09 chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2-((2R,3S)-

2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)pentanoic

acid or (2S)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2R)-2-((2R,3S)-

2-(3-chlorophenyl)-3-(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)pentanoic

acid

(S)-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.09 2.56 chlorophenyl)-4-(cyclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid and

(R)-2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid or (R)- 2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid and

(S)-2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid

(2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- 2.1 2.25 chlorophenyl)-6-((2S)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide and (2S)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide or (2S)-2-

((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2S)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide and (2R)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide or (2R)-2-

((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamideand (2S)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2S)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide or (2S)-2-

((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2R)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamideand (2R)-2-

((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-((2S)-2,3-dihydroxypropyl)-5- oxo-4-morpholinyl)pentanamide

((2R,5S,6R)-6-(3-chloro-2-fluorophenyl)-5-(4- 32.6 chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetic acid and ((2S,5R,6S)-6-(3- chloro-2-fluorophenyl)-5-(4-chlorophenyl)-4-

(cyclopropylmethyl)-3-oxo-2-morpholinyl)acetic

acid

((2R,5S,6R)-4-butyl-6-(3-chlorophenyl)-5-(4- 2.35 2.14 chlorophenyl)-3-oxo-2-morpholinyl)acetic acid

and ((2S,5R,6S)-4-butyl-6-(3-chlorophenyl)-5-(4- chlorophenyl)-3-oxo-2-morpholinyl)acetic acid

(2R)-2-((2S,3R)-3-(4-chlorophenyl)-2-(2,4- 33.3 dichlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid, (2S)-2-((2R,3S)-3-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid or (2S)-2-((2S,3R)-3-(4-chlorophenyl)-2- (2,4-dichlorophenyl)-5-oxo-4- morpholinyl)pentanoic acid, (2R)-2-((2R,3S)-3- (4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-oxo-4- morpholinyl)pentanoic acid

N ^* -acetyl-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 6.06 2.15 chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetohydrazide and N'-acetyl-2-

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetohydrazide

(2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.92 2.18 chlorophenyl)-4-(cyclopropylmethyl)-2-(2-(4- morpholinyl)-2-oxoethyl)-3-morpholinone and

(2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-2-(2-(4- morpholinyl)-2-oxoethyl)-3-morpholinone

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4- 2.78 2.19 chlorophenyl)-5-oxo-4-morpholinyl)pentanamide and (2S)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-5-oxo-4-morpholinyl)pentanamide

or (2S)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-5-oxo-4-morpholinyl)pentanamide

and (2R)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-5-oxo-4-morpholinyl)pentanamide

2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.25 4.46 chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)ethyl carbamateand 2-((2S,5R,6S)-6-

(3-chlorophenyl)-5-(4-chlorophenyl)-4-

(cyclopropylmethyl)-3-oxo-2-morpholinyl)ethyl

carbamate

(2R)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 2.25 fluorobenzyl)-5-oxo-4-morpholinyl)(3- chlorophenyl)ethanoic acid and (2S)-((2R,3S,6R)- 2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5- oxo-4-morpholinyl)(3-chlorophenyl)ethanoic acid

or (2S)-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)(3- chlorophenyl)ethanoic acid and (2R)- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)(3- chlorophenyl)ethanoic acid

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.32

chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro pyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid

(2R)-2-((2S,3R,6S)-3-(4-chlorophenyl)-2-(2,4- 2.16 1.23 dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-3-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid or (2S)-2- ((2S,3R,6S)-3-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2R)-2- ((2R,3S,6R)-3-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid

4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 2.44

6-(4-(methylsulfonyl)benzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)butanoic acid

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 2.57

chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid and

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid and

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 -

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid and

((2S,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l R)- 1 - (((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid or

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid and

((2R,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-((l S)-l-

(((cyclopropylsulfonyl)(phenyl)amino)methyl)pro

pyl)-3-oxo-2-morpholinyl)acetic acid

(S)-2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- 2.59 3.19 chlorophenyl)-4-(cyclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid and

(R)-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid or (R)- 2-((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid and

(S)-2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3- oxomorpholin-2-yl)-2-hydroxyacetic acid

3-((2R,3S)-3-(4-chlorophenyl)-4- 19 29.8 (cyclopropylmethyl)-5-oxo-2- morpholinyl)benzonitrile and 3-((2S,3R)-3-(4- chlorophenyl)-4-(cyclopropylmethyl)-5-oxo-2- morpholinyl)benzonitrile

(2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- 2.66 12.7 7.21 chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid or (2S)-2- ((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2R)-2- ((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.63 0.446

6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)glycine and N-((2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)glycine N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 5.05 7.64 oxo-4-morpholinyl)pentanoyl)glycine and N- ((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo- 4-morpholinyl)pentanoyl)glycine

2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 7.56 2.78 chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)-N,N-dimethylacetamide and 2-

((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)-N,N-dimethylacetamide

ethyl (2R)-2-((2S,3R,6S)-2,3-bis(4- 2.79

chlorophenyl)-6-(3-(4-morpholinyl)propyl)-5- oxo-4-morpholinyl)pentanoate

(2R)-2-((2S,3R)-3-(4-chlorophenyl)-2-(4- 66.4 cyanophenyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,3S)-3-(4-chlorophenyl)-2- (4-cyanophenyl)-5-oxo-4-morpholinyl)pentanoic

acid or (2S)-2-((2S,3R)-3-(4-chlorophenyl)-2-(4- cyanophenyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2R)-2-((2R,3S)-3-(4-chlorophenyl)-2- (4-cyanophenyl)-5-oxo-4-morpholinyl)pentanoic

acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(3- 3.01

hydroxypropyl)-5-oxo-4-morpholinyl)pentanoic

acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.912 1.16 iodobenzyl)-5-oxo-4-morpholinyl)pentanamide

and (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-

6-(4-iodobenzyl)-5-oxo-4- morpholinyl)pentanamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 2.82 2.62 fluorobenzyl)-5-oxo-4-morpholinyl)-4-pentenoic

acid and (2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)-4-pentenoic acid or (2S)-2- ((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)-4-pentenoic

acid and (2R)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)-4-pentenoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 58.5 iodobenzyl)-5-oxo-4-morpholinyl)pentanenitrile

and (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-

6-(4-iodobenzyl)-5-oxo-4- morpholinyl)pentanenitrile

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-3-oxo-4- 0.415 0.391 ((1S)-1-(1 H-tetrazol-5 -yl)butyl)-2- morpholinyl)methyl)benzonitrile and 4- (((2S,5R,6S)-5,6-bis(4-chlorophenyl)-3-oxo-4- ((lR)-l-(lH-tetrazol-5-yl)butyl)-2- morpholinyl)methyl)benzonitrile

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 3.52 6.96 4-(cyclopropylmethyl)-3 -morpholinone or

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclopropylmethyl)-3-morpholinone

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 70.5 4-(((lR,2R)-2-methylcyclopropyl)methyl)-3- morpholinone and (5R,6S)-6-(3-chlorophenyl)-5- (4-chlorophenyl)-4-(((l S,2S)-2- methylcyclopropyl)methyl)-3 -morpholinone and

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(((lR,2R)-2-methylcyclopropyl)methyl)-3- morpholinone and (5S,6R)-6-(3-chlorophenyl)-5- (4-chlorophenyl)-4-(((l S,2S)-2- methylcyclopropyl)methyl)-3-morpholinone

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.428 0.263

6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine and N-((2S)-

2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4-morpholinyl)pentanoyl)- beta-alanine or N-((2S)-2-((2S,3R,6S)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine and N-

((2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-

(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine

N-((2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)- 2.66 8.53

6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine and N-((2S)-

2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4-morpholinyl)pentanoyl)- beta-alanine or N-((2R)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-beta-alanine and N-((2S)-

2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4-morpholinyl)pentanoyl)- beta-alanine

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 3.05 3.78 oxo-4-morpholinyl)pentanoyl)-beta-alanine and

N-((2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5- oxo-4-morpholinyl)pentanoyl)-beta-alanine or N- ((2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo- 4-morpholinyl)pentanoyl)-beta-alanine and N-

((2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-

4-morpholinyl)pentanoyl)-beta-alanine

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 7.9 3.66 4-(cyclopropylsulfonyl)-3-morpholinone and

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclopropylsulfonyl)-3-morpholinone

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 3.66 5.8 methyl-3-oxo-2-morpholinyl)methyl)benzamide

and 4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- methyl-3-oxo-2-morpholinyl)methyl)benzamide

(3R)-3-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- 3.66

chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid

(((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo- 6.58 7.22 4-morpholinyl)pentyl)oxy)acetic acid and (((2S)- 2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentyl)oxy)acetic acid

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- 3.75

(methylsulfonyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- (methylsulfonyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 6.3 3.8 methyl-3-oxo-2-morpholinyl)methyl)-2- fluorobenzonitrile and 4-(((2S,5R,6S)-5,6-bis(4- chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)-2-fluorobenzonitrile

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- 3.86

fluorobenzyl)-4-(4-pyridinyl)-3-morpholinone

and (2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4- fluorobenzyl)-4-(4-pyridinyl)-3-morpholinone

(2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 4.96 3.87 chlorophenyl)-4-(cyclopropylmethyl)-2-((5- methyl- 1 ,3 ,4-oxadiazol-2-yl)methyl)-3 - morpholinone and (2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethy l)-2-((5 -methyl- 1 ,3 ,4- oxadiazol-2-yl)methyl)-3-morpholinone

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 1.12 0.927 cyano-2-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyano-

2-fluorobenzyl)-5-oxo-4-morpholinyl)pentanoic

acid 3-(((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 5.5 6.99 oxo-4-morpholinyl)pentyl)amino)-3- oxopropanoic acid and 3-(((2S)-2-((2R,3S)-2,3- bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentyl)amino)-3 -oxopropanoic acid

N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 7.12 10 oxo-4-morpholinyl)pentyl)glycine and N-((2S)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentyl)glycine

((2R,5S,6R)-6-(3-chloro-4-fluorophenyl)-5-(4- 4.22 6.24 chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)acetic acid and ((2S,5R,6S)-6-(3- chloro-4-fluorophenyl)-5-(4-chlorophenyl)-4-

(cyclopropylmethyl)-3-oxo-2-morpholinyl)acetic

acid

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-2- 4.33 7.97 (4-(methylsulfonyl)benzyl)-3-morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-2- (4-(methylsulfonyl)benzyl)-3-morpholinone

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.61 0.484 cyanobenzyl)-5-oxo-4-morpholinyl)-N-(lH- tetrazol-5-ylmethyl)pentanamide and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4-morpholinyl)-N-(lH- tetrazol-5 -ylmethyl)pentanamide

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 10.8 4.65 chlorophenyl)-4-(cyclopropylcarbonyl)-3-oxo-2- morpholinyl)acetic acid and ((2S,5R,6S)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylcarbonyl)-3-oxo-2- morpholinyl)acetic acid

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4.76 22.4

4-(cyclopropylmethyl)-3 -thiomorpholinone 1,1- dioxide

2-((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 4.81 6.86 chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)ethyl methanesulfonate and 2- ((2S,5R,6S)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(cyclopropylmethyl)-3-oxo-2- morpholinyl)ethyl methanesulfonate

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 2.03 0.425 cyanobenzyl)-5-oxo-4-morpholinyl)-N-(2-(lH- tetrazol-5-yl)ethyl)pentanamide and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4-morpholinyl)-N-(2-(lH- tetrazol-5 -yl)ethyl)pentanamide N-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 10.9 8.12 oxo-4-morpholinyl)pentyl)-2-(lH-tetrazol-5- yl)acetamide and N-((2S)-2-((2R,3S)-2,3-bis(4- chlorophenyl)-5-oxo-4-morpholinyl)pentyl)-2- ( 1 H-tetrazol-5 -yl)acetamide

4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.452 0.339 6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)butanoic acid and

4-(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)- 6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)butanoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.393 0.297 cyanobenzyl)-5-oxo-4-morpholinyl)pentanoic

acid

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(2- 5

(methylsulfanyl)-4-pyrimidinyl)-3-morpholinone

and (5S,6R)-5,6-bis(4-chlorophenyl)-4-(2- (methylsulfanyl)-4-pyrimidinyl)-3-morpholinone

l-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 3.36 5.5 oxo-4-morpholinyl)pentanoyl)-4- piperidinecarboxylic acid and l-((2S)-2-((2R,3S)-

2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanoyl)-4-piperidinecarboxylic

acid

(4-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 4.82 6.61 oxo-4-morpholinyl)pentanoyl)- 1 - piperazinyl)acetic acid and (4-((2S)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanoyl)- 1 -piperazinyl)acetic acid

(2S)-4-(((2R)-2-((2S,3R,6S)-2,3-bis(4- 0.459 0.294 chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2- hydroxybutanoic acid and (2S)-4-(((2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2- hydroxybutanoic acid

(3R)-4-(((2R)-2-((2S,3R,6S)-2,3-bis(4- 0.428 0.328 chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-3 - hydroxybutanoic acid and (3R)-4-(((2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-3 - hydroxybutanoic acid and (3S)-4-(((2R)-2- ((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-3 - hydroxybutanoic acid and (3S)-4-(((2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-3 - hydroxybutanoic acid

(2R)-3-(((2R)-2-((2S,3R,6S)-2,3-bis(4- 0.386 0.358 chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2- methylpropanoic acid and (2R)-3-(((2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2- methylpropanoic acid and (2S)-3-(((2R)-2-

((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2- methylpropanoic acid and (2S)-3-(((2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2- methylpropanoic acid

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.419 0.365

6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-L-alanine and N-((2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4-morpholinyl)pentanoyl)-D- alanine

(2R)-2-((2R,3 S)-2-(4-chlorophenyl)-3 -( 1 H-indol- 5.9

2-yl)-5-oxo-4-morpholinyl)pentanoic acid and

(2S)-2-((2S,3R)-2-(4-chlorophenyl)-3-(lH-indol- 2-yl)-5-oxo-4-morpholinyl)pentanoic acid

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.44 0.537

6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-D-alanine and N-((2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4-morpholinyl)pentanoyl)-L- alanine

methyl 4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 6.14 8.6 methyl-3-oxo-2-morpholinyl)methyl)benzoate

and methyl 4-(((2S,5R,6S)-5,6-bis(4- chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)methyl)benzoate

3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.66 0.795 6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-N-(tert- butoxycarbonyl)-D-alanine and 3-(((2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-N-(tert- butoxycarbonyl)-D-alanine

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 6.25 18.2 4-(cyclobutylmethyl)-3 -morpholinone and

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-(cyclobutylmethyl)-3-morpholinone

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 6.3 7 methyl-3-oxo-2-morpholinyl)methyl)benzonitrile

and 4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- methyl-3-oxo-2-morpholinyl)methyl)benzonitrile

(4-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.674 0.441 6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)- 1 -piperazinyl)acetic acid

and (4-((2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)- 1 -piperazinyl)acetic acid

3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.633 0.345 6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2,2- dimethylpropanoic acid and 3-(((2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-2,2- dimethylpropanoic acid

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(2-chloro-4- 7.18

pyridinyl)-3 -morpholinone and (5S,6R)-5,6-bis(4- chlorophenyl)-4-(2-chloro-4-pyridinyl)-3- morpholinone

3-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 7.39 12.4 methyl-3-oxo-2-morpholinyl)methyl)benzamide

and 3-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- methyl-3-oxo-2-morpholinyl)methyl)benzamide

3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.95 0.542

6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-D-alanine and 3-

(((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-

(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)-D-alanine

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 1.34 1.93 methoxybenzyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-methoxybenzyl)-5-oxo-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4- 7.81 19 chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,3S)-2-(3-chlorophenyl)-3- (4-chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid

3-(4-((2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5- 3.6 4.59 oxo-4-morpholinyl)pentanoyl)- 1 - piperazinyl)propanoic acid and 3-(4-((2S)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanoyl)- 1 -piperazinyl)propanoic

acid

(2R)-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- 7.85 8.35 chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid and (2S)- ((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid or (2S)- ((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid and (2R)- ((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- 7.9

fluorobenzyl)-4-(l -methyl- lH-imidazol-4-yl)-3- morpholinone and (2S,5R,6S)-5,6-bis(4- chlorophenyl)-2-(4-fluorobenzyl)-4-(l-methyl- lH-imidazol-4-yl)-3-morpholinone

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 7.99 13.3 methyl-3 -oxo-2-morpholinyl)methyl)benzoic acid

and 4-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- methyl-3 -oxo-2-morpholinyl)methyl)benzoic acid

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 8.75 20.2 4-(2-methylpropyl)-3-morpholinone and (5S,6R)- 6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(2- methylpropyl)-3 -morpholinone

l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6- 1.05 1.01 (4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-D-proline and l-((2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)pentanoyl)- D-proline

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(2-pyrazinyl)- 9.3

3 -morpholinone and (5S,6R)-5,6-bis(4- chlorophenyl)-4-(2-pyrazinyl)-3-morpholinone (2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 9.94 18.2 (cyclopropylmethyl)-2-((2R)-2,3- dihydroxypropyl)-3 -morpholinone and

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- (cyclopropylmethyl)-2-((2S)-2,3- dihydroxypropyl)-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- (cyclopropylmethyl)-2-((2R)-2,3- dihydroxypropyl)-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- (cyclopropylmethyl)-2-((2S)-2,3- dihydroxypropyl)-3 -morpholinone

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 10 16.6 4-cyclopentyl-3 -morpholinone and (5S,6R)-6-(3- chlorophenyl)-5-(4-chlorophenyl)-4-cyclopentyl- 3 -morpholinone

methyl l-((2R)-2-((2S,3R,6S)-2,3-bis(4- 1.39 1.83 chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-L-prolinate and methyl

l-((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-

(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-L-prolinate

(5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3- 11.8 38.6 morpholinone

l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6- 0.892 0.583 (4-iodobenzyl)-5-oxo-4-morpholinyl)pentanoyl)- 4-piperidinecarboxylic acid and l-((2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- iodobenzyl)-5-oxo-4-morpholinyl)pentanoyl)-4- piperidinecarboxylic acid

(2R)-2-((2S,5R,6S)-2-(4-chlorobenzyl)-5,6-bis(4- 1.26 1.19 chlorophenyl)-3-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,5S,6R)-2-(4-chlorobenzyl)- 5,6-bis(4-chlorophenyl)-3-oxo-4- morpholinyl)pentanoic acid

(2R,5S,6R)-2-(4-(aminomethyl)benzyl)-5,6-bis(4- 12.7 15.9 chlorophenyl)-4-methyl-3 -morpholinone and

(2S,5R,6S)-2-(4-(aminomethyl)benzyl)-5,6-bis(4- chlorophenyl)-4-methyl-3-morpholinone

3-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 18.4 17.7 6-(4-iodobenzyl)-5-oxo-4- morpholinyl)pentyl)amino)-3 -oxopropanoic acid

and 3-(((2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-iodobenzyl)-5-oxo-4- morpholinyl)pentyl)amino)-3 -oxopropanoic acid

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 13.7 17.7 4-(l ,3-thiazol-4-ylmethyl)-3-morpholinone and

(5S,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 4-( 1 ,3 -thiazol-4-ylmethyl)-3 -morpholinone

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 14.5 15.9 4-(2-hydroxy-2-methylpropyl)-3-morpholinone

and (5S,6R)-6-(3-chlorophenyl)-5-(4- chlorophenyl)-4-(2-hydroxy-2-methylpropyl)-3- morpholinone

(5S,6R)-2-benzyl-5,6-bis(4-chlorophenyl)-4- 15.6 >100 [3] methyl-3 -morpholinone

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 16.1 28.3 chlorophenyl)-4-((l -cyanocyclopropy l)methyl)-3- oxo-2-morpholinyl)acetic acid and ((2S,5R,6S)-6- (3 -chlorophenyl)-5 -(4-chlorophenyl)-4-(( 1 - cyanocyclopropyl)methyl)-3-oxo-2- morpholinyl)acetic acid

l-((((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.646 0.56

6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)methyl)cyclopenta

necarboxylic acid and l-((((2S)-2-((2R,3S,6R)-

2,3-bis(4-chlorophenyl)-6-(4-cyanobenzyl)-5- oxo-4- morpholinyl)pentanoyl)amino)methyl)cyclopenta

necarboxylic acid

(3S)-3-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- 16.4

chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid and (3S)-3- ((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)hexanoic acid

(2R)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4- 16.8 19.5 chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2R)-2-((2S,3R)-2-(3-chlorophenyl)-3- (4-chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2R,3S)-2-(3-chlorophenyl)-3- (4-chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid and (2S)-2-((2S,3R)-2-(3-chlorophenyl)-3- (4-chlorophenyl)-5-oxo-4-morpholinyl)pentanoic

acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.789

iodobenzyl)-5-oxo-4-morpholinyl)pentanoic acid

and (2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)- 6-(4-iodobenzyl)-5-oxo-4-morpholinyl)pentanoic

acid

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(4-pyridinyl)- 16.8 24.2 3 -morpholinone and (5S,6R)-5,6-bis(4- chlorophenyl)-4-(4-pyridinyl)-3-morpholinone

(2R)-((2R,3S)-2-(3-chlorophenyl)-3-(4- 16.9 17 chlorophenyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid and (2R)- ((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 5-oxo-4-morpholinyl)(cyclopropyl)ethanoic acid

and (2S)-((2R,3S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid and (2S)- ((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 5-oxo-4-morpholinyl)(cyclopropyl)ethanoic acid

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- 18.1 17.2 morpholinyl)pentanoic acid and (2R)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)pentanoic acid

(2R)-2-((2S,5R,6S)-2-(4-biphenylylmethyl)-5,6- 1.44 bis(4-chlorophenyl)-3-oxo-4- morpholinyl)pentanoic acid and (2S)-2-

((2R,5S,6R)-2-(4-biphenylylmethyl)-5,6-bis(4- chlorophenyl)-3-oxo-4-morpholinyl)pentanoic

acid

ethyl (2R)-2-((2S,3R,6S)-2,3-bis(4- 17.4 chlorophenyl)-6-(4-cyano-2-fluorobenzyl)-5-oxo- 4-morpholinyl)pentanoate and ethyl (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4-cyano- 2-fluorobenzyl)-5-oxo-4-morpholinyl)pentanoate

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- 17.5 22.5 ((dimethylamino)methyl)benzyl)-4-methyl-3- morpholinone and (2S,5R,6S)-5,6-bis(4- chlorophenyl)-2-(4-

((dimethylamino)methyl)benzyl)-4-methyl-3- morpholinone

(5R,6S)-5,6-bis(4-chlorophenyl)-6-methyl-3- 100 morpholinone and (5S,6R)-5,6-bis(4- chlorophenyl)-6-methyl-3-morpholinone

(2R)-2-((2S,5R,6S)-2-(4-carbamoylbenzyl)-5,6- 0.816 bis(4-chlorophenyl)-3-oxo-4- morpholinyl)pentanoic acid and (2S)-2-

((2R,5S,6R)-2-(4-carbamoylbenzyl)-5,6-bis(4- chlorophenyl)-3-oxo-4-morpholinyl)pentanoic

acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5- 1.01 oxo-6-(4-( 1 H-pyrazol- 1 -yl)benzyl)-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4- ( 1 H-pyrazol- 1 -yl)benzyl)-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5- 1.3

oxo-6-(4-(l H-pyrrol- 1 -yl)benzyl)-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4- ( 1 H-pyrrol- 1 -yl)benzyl)-4-morpholinyl)pentanoic

acid

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 23.4 27.5 morpholinyl)hexanoic acid and (2S)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)hexanoic acid or (2S)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)hexanoic acid and (2R)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)hexanoic acid

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-2- 5.04 methyl-5-oxo-4-morpholinyl)pentanoic acid and

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-2- methyl-5-oxo-4-morpholinyl)pentanoic acid or

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-2- methyl-5-oxo-4-morpholinyl)pentanoic acid and

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-2- methyl-5-oxo-4-morpholinyl)pentanoic acid

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(3-pyridinyl)- 29.6 23.9 3-morpholinone and (5S,6R)-5,6-bis(4- chlorophenyl)-4-(3 -pyridinyl)-3 -morpholinone

(5 S,6R)-5 ,6-bis(4-bromophenyl)-4-( 1 - >100 24.6 methylethyl)-3 -morpholinone and (5R,6S)-5,6- bis(4-bromophenyl)-4-(l-methylethyl)-3- morpholinone

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-2- 16.1 methyl-5-oxo-4-morpholinyl)pentanoic acid and

(2S)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-2- methyl-5-oxo-4-morpholinyl)pentanoic acid or

(2S)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-2- methyl-5-oxo-4-morpholinyl)pentanoic acid and

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-2- methyl-5-oxo-4-morpholinyl)pentanoic acid

(5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)- 27.1 26.2 4-(2-methoxyethyl)-3-morpholinone and (5S,6R)- 6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-(2- methoxyethyl)-3 -morpholinone (2R)-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 26.6 27.8 morpholinyl)(phenyl)ethanoic acid and (2S)- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)(phenyl)ethanoic acid or (2S)- ((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)(phenyl)ethanoic acid and (2R)- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)(phenyl)ethanoic acid

(2R)-((2S,3R)-2-(3-chlorophenyl)-3-(4- 28.9 27.9 chlorophenyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid and (2S)- ((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 5-oxo-4-morpholinyl)(cyclopropyl)ethanoic acid

or (2S)-((2S,3R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-5-oxo-4- morpholinyl)(cyclopropyl)ethanoic acid and (2R)- ((2R,3S)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 5-oxo-4-morpholinyl)(cyclopropyl)ethanoic acid

(2R)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(2- 29.6

fluoro-4-(methylsulfonyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2-fluoro- 4-(methylsulfonyl)benzyl)-5-oxo-4- morpholinyl)pentanoic acid

((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-3- 30.6 oxo-2-morpholinyl)acetonitrile and ((2S,5R,6S)- 5,6-bis(4-chlorophenyl)-4-methyl-3-oxo-2- morpholinyl)acetonitrile

(5R,6S)-5,6-bis(4-chlorophenyl)-4-phenyl-3- 31.6 >100 [2] morpholinone and (5S,6R)-5,6-bis(4- chlorophenyl)-4-phenyl-3-morpholinone

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-5- 1.15

oxo-6-(4-(l H- 1 ,2,4-triazol- 1 -yl)benzyl)-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-5-oxo-6-(4- ( 1 H- 1 ,2,4-triazol- 1 -yl)benzyl)-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 17.9

fluorobenzyl)-2-methy 1-5-0X0-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-2-methy 1-5-0X0-4- morpholinyl)pentanoic acid or (2S)-2- ((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-2-methy 1-5-0X0-4- morpholinyl)pentanoic acid and (2R)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-2-methy 1-5-0X0-4- morpholinyl)pentanoic acid

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl-2- 32.6 ( 1 H-tetrazol-5 -ylmethyl)-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-2- ( 1 H-tetrazol-5 -ylmethyl)-3 -morpholinone

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- 33.1 morpholinyl)hexanoic acid and (2R)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)hexanoic acid and (2S)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)hexanoic acid and (2S)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)hexanoic acid

(2R)-2-((2S,3R)-2-(3-chlorophenyl)-3-(4- 20

chlorophenyl)-2-methyl-5-oxo-4- morpholinyl)pentanoic acid and (2S)-2-((2R,3S)- 2-(3-chlorophenyl)-3-(4-chlorophenyl)-2-methyl- 5-oxo-4-morpholinyl)pentanoic acid or (2S)-2- ((2S,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)- 2-methyl-5-oxo-4-morpholinyl)pentanoic acid

and (2R)-2-((2R,3S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-2-methyl-5-oxo-4- morpholinyl)pentanoic acid

(2R)-2-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 34.5 morpholinyl)-4-methylpentanoic acid and (2S)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-4-methylpentanoic acid or (2S)-2- ((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-4-methylpentanoic acid and (2R)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-4-methylpentanoic acid

4-(((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.388

6-(4-iodobenzyl)-5-oxo-4- morpholinyl)pentanoyl)amino)butanoic acid

((2R,5S,6R)-6-(3-chlorophenyl)-5-(4- 35.9 chlorophenyl)-4-(cyclopropylmethyl)-6-methyl-3- oxo-2-morpholinyl)acetic acid and ((2S,5R,6S)-6- (3-chlorophenyl)-5-(4-chlorophenyl)-4- (cyclopropylmethyl)-6-methyl-3-oxo-2- morpholinyl)acetic acid

(4R)-4-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- 4.14 morpholinyl)heptanoic acid and (4S)-4-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)heptanoic acid (4R)-4-((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- 24.7 morpholinyl)heptanoic acid and (4S)-4-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)heptanoic acid

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- 40.2 morpholinyl)butanoic acid and (2R)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)butanoic acid and (2S)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)butanoic acid and (2S)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)butanoic acid

(5R,6S)-5,6-bis(4-chlorophenyl)-4- 41.8 (cyclopropylmethyl)-3 -morpholinone and

(5 S ,6R)-5 ,6-bis(4-chlorophenyl)-4- (cyclopropylmethyl)-3-morpholinone

(5S,6R)-5,6-bis(4-bromophenyl)-4-ethyl-3- 42.4 morpholinone and (5R,6S)-5,6-bis(4- bromophenyl)-4-ethyl-3-morpholinone

2- ((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-methyl- 43.9

3- oxo-2-morpholinyl)acetamideand 2- ((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-methyl-3- oxo-2-morpholinyl)acetamide

(2R)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- 44.8 chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)-2-(4-fluorobenzyl)pentanoic acid

and (2S)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)-2-(4-fluorobenzyl)pentanoic acid or

(2S)-2-((2R,3S,6R)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)-2-(4-fluorobenzyl)pentanoic acid

and (2R)-2-((2S,3R,6S)-2-(3-chlorophenyl)-3-(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)-2-(4-fluorobenzyl)pentanoic acid

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-(2- 45.4 hydroxyethyl)-4-methyl-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-(2- hydroxyethyl)-4-methyl-3-morpholinone

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-((2R)-2,3- 46.5 dihydroxypropyl)-4-methyl-3 -morpholinone and

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-2-((2S)-2,3- dihydroxypropyl)-4-methyl-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-((2R)-2,3- dihydroxypropyl)-4-methyl-3 -morpholinone and

(2S,5R,6S)-5,6-bis(4-chlorophenyl)-2-((2S)-2,3- dihydroxypropyl)-4-methyl-3-morpholinone

l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6- 2.12

(4-fluorobenzyl)-5-oxo-4-morpholinyl)pentyl)-4- piperidinecarboxylic acid and l-((2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)pentyl)-4- piperidinecarboxylic acid

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 6.15

6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-N-methylglycine and N-

((2S)-2-((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-

(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-N-methylglycine

(3R,5R,6S)-5,6-bis(4-chlorophenyl)-3-propyl- 11

2,5 ,6,8-tetrahydro-3H-imidazo[2, 1 -c] [ 1 ,4]oxazine

and (3S,5S,6R)-5,6-bis(4-chlorophenyl)-3-propyl- 2,5 ,6,8-tetrahydro-3H-imidazo[2, 1 -c] [ 1 ,4]oxazine

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(2- 56.1 (dimethylamino)ethyl)-5 -oxo-4- morpholinyl)pentanoic acid and (2S)-2- ((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(2- (dimethylamino)ethyl)-5 -oxo-4- morpholinyl)pentanoic acid

N-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)- 0.498

6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-N-methyl-beta-alanine

and N-((2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-fluorobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-N-methyl-beta-alanine

4-(((2S,5R,6S)-5-(4-chlorophenyl)-4-methyl-6-(2- 59.3 methylpropyl)-3-oxo-2-morpholinyl)methyl)-2- fluorobenzonitrile or 4-(((2R,5S,6R)-5-(4- chlorophenyl)-4-methyl-6-(2-methylpropyl)-3- oxo-2-morpholinyl)methyl)-2-fluorobenzonitrile

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- 61.7 morpholinyl)propanoic acid and (2R)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)propanoic acid and (2S)-2-((2R,3S)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)propanoic acid and (2S)-2-((2S,3R)- 2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)propanoic acid

(5R,6S)-5,6-bis(4-chlorophenyl)-4-(2,6-dichloro- 63

4-pyridinyl)-3-morpholinone and (5S,6R)-5,6- bis(4-chlorophenyl)-4-(2,6-dichloro-4-pyridinyl)- 3-morpholinone (2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 1.66 iodobenzyl)-5-oxo-4-morpholinyl)-N- hydroxypentanamide and (2S)-2-((2R,3S,6R)-2,3- bis(4-chlorophenyl)-6-(4-iodobenzyl)-5-oxo-4- morpholinyl)-N-hydroxypentanamide

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 1.21 fluorobenzyl)-5-oxo-4-morpholinyl)-N-

(cyclopropylsulfonyl)pentanamide and (2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- fluorobenzyl)-5-oxo-4-morpholinyl)-N-

(cyclopropylsulfonyl)pentanamide

(2R)-2-((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- 66.9 morpholinyl)-3-methylbutanoic acid and (2R)-2- ((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3-methylbutanoic acid and (2S)-2- ((2R,3S)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3-methylbutanoic acid and (2S)-2- ((2S,3R)-2,3-bis(4-chlorophenyl)-5-oxo-4- morpholinyl)-3 -methylbutanoic acid

(2R,5R,6S)-5,6-bis(4-chlorophenyl)-2-hydroxy-4- 67.5 methyl-3-morpholinone and (2S,5S,6R)-5,6- bis(4-chlorophenyl)-2-hydroxy-4-methyl-3- morpholinone

(2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-((l S)-l- 1.53

((4-(cyclopropylmethyl)- 1 - piperazinyl)carbonyl)butyl)-2-(4-iodobenzyl)-3- morpholinone and (2S,5R,6S)-5,6-bis(4- chlorophenyl)-4-(( 1 R)- 1 -((4-(cyclopropylmethyl)- l-piperazinyl)carbonyl)butyl)-2-(4-iodobenzyl)-3- morpholinone

(3R,5S,6R)-5,6-bis(4-chlorophenyl)-3-propyl- 39.9

2,5 ,6,8-tetrahydro-3H-imidazo[2, 1 -c] [ 1 ,4]oxazine

and (3S,5R,6S)-5,6-bis(4-chlorophenyl)-3-propyl- 2,5 ,6,8-tetrahydro-3H-imidazo[2, 1 -c] [ 1 ,4]oxazine

l-((2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6- 0.479

(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-3-azetidinecarboxylic

acid and l-((2S)-2-((2R,3S,6R)-2,3-bis(4- chlorophenyl)-6-(4-cyanobenzyl)-5-oxo-4- morpholinyl)pentanoyl)-3-azetidinecarboxylic

acid

3-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 76.4 methyl-3 -oxo-2-morpholinyl)methyl)benzoic acid

and 3-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- methyl-3 -oxo-2-morpholinyl)methyl)benzoic acid

(2R,5R,6S)-5,6-bis(4-chlorophenyl)-2-(4- 79 fluorobenzyl)-4-(3 -pyridinyl)-3 -morpholinone

and (2S,5S,6R)-5,6-bis(4-chlorophenyl)-2-(4- fluorobenzyl)-4-(3 -pyridinyl)-3 -morpholinone

4-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4-((lS)- 1.38

1 -((4-(cyclopropy lmethyl)- 1 - piperazinyl)carbonyl)butyl)-3-oxo-2- morpholinyl)methyl)benzonitrile and 4- (((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4-((lR)-l- ((4-(cyclopropylmethyl)- 1 - piperazinyl)carbonyl)butyl)-3-oxo-2- morpholinyl)methyl)benzonitrile

3-(((2R,5S,6R)-5,6-bis(4-chlorophenyl)-4- 93.5 methyl-3-oxo-2-morpholinyl)methyl)benzonitrile

and 3-(((2S,5R,6S)-5,6-bis(4-chlorophenyl)-4- methyl-3-oxo-2-morpholinyl)methyl)benzonitrile

(2R)-2-((2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4- 0.305 cyanobenzyl)-5-oxo-4-morpholinyl)-N-

(methylsulfonyl)pentanamide and (2S)-2-

((2R,3S,6R)-2,3-bis(4-chlorophenyl)-6-(4- cyanobenzyl)-5-oxo-4-morpholinyl)-N-

(methylsulfonyl)pentanamide