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Title:
PYRROLIDINE AND PIPERIDINE DERIVATES AS NK1 ANTAGONISTS
Document Type and Number:
WIPO Patent Application WO/2003/051840
Kind Code:
A1
Abstract:
A NK¿1? antagonist having the formula (I), wherein Ar?1¿ and Ar?2¿ are optionally substituted phenyl or heteroaryl, X?1¿ is an ether, thio or imino linkage, R?4¿ and R?5¿ are not both H or alkyl, and the remaining variables are as defined in the specification, useful for treating a number of disorders, including emesis, depression, anxiety and cough. Pharmaceutical compositions. Methods of treatment and combinations with other agents are also disclosed.

Inventors:
PALIWAL SUNIL
REICHARD GREGORY A
WANG CHENG
XIAO DONG
TSUI HON-CHUNG
SHIH NENG-YANG
ARREDONDO JUAN D
WROBLESKI MICHELLE LACI
PALANI ANANDAN
Application Number:
PCT/US2002/040203
Publication Date:
June 26, 2003
Filing Date:
December 17, 2002
Export Citation:
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Assignee:
SCHERING CORP (US)
International Classes:
C07D491/107; A61K31/357; A61K31/40; A61K31/401; A61K31/4015; A61K31/402; A61K31/4025; A61K31/4166; A61K31/4178; A61K31/4188; A61K31/421; A61K31/435; A61K31/4355; A61K31/437; A61K31/438; A61K31/445; A61K31/454; A61K31/4545; A61K31/499; A61K31/505; A61K31/537; A61K31/5377; A61K31/664; A61K45/00; A61P1/00; A61P1/08; A61P3/04; A61P3/10; A61P9/10; A61P11/00; A61P11/14; A61P13/10; A61P15/00; A61P17/00; A61P25/00; A61P25/04; A61P25/06; A61P25/08; A61P25/18; A61P25/22; A61P25/24; A61P25/28; A61P25/30; A61P25/32; A61P25/36; A61P27/02; A61P29/00; A61P31/18; C07D207/14; C07D207/26; C07D207/50; C07D211/28; C07D211/30; C07D211/32; C07D211/34; C07D211/42; C07D211/56; C07D211/60; C07D211/72; C07D211/76; C07D401/04; C07D401/12; C07D401/14; C07D403/04; C07D413/12; C07D471/10; C07D487/10; C07D491/10; C07D498/10; C07D513/10; (IPC1-7): C07D211/60; C07D211/56; C07D471/10; C07D498/10; C07D401/04; C07D207/14; C07D403/04; C07D211/76; C07D413/12; C07D211/42; C07D211/72; C07D491/10; C07D401/12; C07D513/10; C07D211/32; C07D211/28; C07D401/14; C07D487/10; A61K31/4025; A61K31/407; A61K31/438; A61K31/445; A61P11/00; A61P1/08; A61P25/06; A61P25/24
Domestic Patent References:
WO1994010165A11994-05-11
WO2001044200A22001-06-21
Foreign References:
Other References:
WU X ET AL: "Stereoselective Transformation of 2H-1,4-Oxazin-2-ones into 2,(2),5,5-Tri- and Tetrasubstituted Analogues of cis-5-Hydroxy-2-piperidinemethanol and cis-5-Hydroxy-6-oxo-2-piperidi necarboxylic Acid", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 56, no. 19, May 2000 (2000-05-01), pages 3043 - 3051, XP004198015, ISSN: 0040-4020
ROGIERS J ET AL: "Stereoselective conversion of 2H-1,4-oxazin-2-ones into 2,5,5-substituted piperidine-2-carboxamides and 2-methanamines and related octahydro-2H-pyrido[1,2-a]pyrazines, potential substance P antagonists", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 57, no. 43, 22 October 2001 (2001-10-22), pages 8971 - 8981, XP004308865, ISSN: 0040-4020
GIARD T ET AL: "Pyrrolidines bearing a quaternary alpha-stereogenic center. Part 1: Synthesis of analogs of ABT-418, a powerful nicotinic agonist", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 40, no. 30, July 1999 (1999-07-01), pages 5495 - 5497, XP004171495, ISSN: 0040-4039
HARRISON T ET AL: "GEM- DISUBSTITUTED AMINO-ETHER BASED SUBSTANCE P ANTAGONISTS", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 4, no. 23, 1994, pages 2733 - 2734, XP000995889, ISSN: 0960-894X
WU X ET AL: "Generation of Cyclopenta[c]piperidines and Pyrrolo[3,4-c]piperidines- Potential Substance P Antagonists-from Adducts of Cyclic Dienophiles and 5-Chloro-6-methyl-3-phenyl-2H-1,4-oxazin-2-one", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 56, no. 34, 18 August 2000 (2000-08-18), pages 6279 - 6290, XP004214987, ISSN: 0040-4020
Attorney, Agent or Firm:
Magatti, Anita W. (K-6-1 1990 2000 Galloping Hill Road Kenilworth, NJ, US)
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Claims:
What is claimed is:
1. A compound having the formula (I) : or a pharmaceuticallyacceptable salt thereof, wherein Ar1 and Ar2 are each independently selected from the group consisting of R17heteroaryl and when X1 is SO, SO2, N(COR12) or N(SO2R15), then: R1 and R2 are each independently selected from the group consisting of H, CiCe alkyl, hydroxy (C1C3alkyl), C3C8 cycloalkyl CH2F,CHF2 andCF3 ; or R'and R, together with the carbon atom to which they are both attached, form a C3 to C6 alkylen ring; or when X1 is O, S or NR34, then: R1 and R2 are each independently selected from the group consisting of H, CiCe alkyl, hydroxy (C1C3alkyl), C3C8 cycloalkyl, CH2F, CHF2 and CF3 ; or R'and R2, together with the carbon atom to which they are both attached, form a C3 to C6 alkylen ring; or R1 and R2, together with the carbon atom to which they are both attached, form a C=O group; R3 is selected from the group consisting of H, CiCe alkyl, hydroxy (ClC3 alkyl), C3C8 cycloalkyl,CH2F,CHF2 andCF3 ; each R6 is independently selected from the group consisting of H, CiCe alkyl andOH; each R7 is independently selected from the group consisting of H and CiCe alkyl ;. n2 is 1 to 4; R4 and R5 are each independently selected from the group consisting of (CR28R29)n1G, where, ni is 0 to 5; and G is H, CF3, CHF2, CH2F, OH, O(C1C6 alkyl), OCH2F, OCHF2, OCF3,OCH2CF3,O(C3C8 cycloalkyl),O(C1C6) alkyl (C3C8 cycloalkyl), NR13R14, SO2NR13R14, NR12SO2R13, NR12C(O)R14, NR12C(O)OR13, R12 (C (O) NR13R14), C(O)NR13R15, C(O)OR13, C3C8 cycloalkyl, (R19)raryl, (R) rheteroaryl, OC(O)R14, OC(O)NR13R14, C(=NOR14)(R13), C(O)R13, C(OR12)(R13)(R14), heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of R30 and R31, R4 and R5 together are =O, =NOR12 ; or R4 and R5, together with the carbon atom to which they are both attached, form a 4to 8membered heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 groups independently selected from X2, provided that at least one X2 is NR35, 0,S,S (O) orS02, the ring being optionally substituted with from 1 to 6 substituents independently selected from the group consisting of R30 and R31 ; provided that R4 and R5 are not both selected from the group consisting of H, alkyl and cycloalkyl ; further provided that, when one of R4 and R5 is OH, then the other one of R4 and R 5is not alkyl or (R19)raryl ; R8, R9 and R10 are each independently selected from the group consisting of H, C1C6 alkyl, C3C8 cycloalkyl, OR12, halogen, CN, NO2, CF3, CHF2, CH2F, CH2CF3, OCF3, OCHF2, OCH2F, OCH2CF3, COOR12, CONR21R22, OC(O)NR21R22, OC(O)R12, NR21COR12, NR21CO2R15, NR21CONR21R22, NR21SO2R15, NR21R22, SO2NR21R22, S(O)n6R15, (R19)raryl and (R19)rheteroaryl; R12 is H, CiC6 alkyl or C3C8 cycloalkyl ; R13 and R14 are each independently selected from the group consisting of H, CiCe alkyl, C3C8 cycloalkyl, (C3C8) cycloalkyl (C1C6) alkyl,CH2CF3, aryl and heteroaryl ; or R and R, together with the nitrogen atom to which they are both attached, form a 4to 7membered saturated or unsaturated ring that is optionally substituted withOR, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting ofO,SandNR34; n6 is 0,1 or 2 ; R15 is CiCe alkyl, C3C8 cycloalkyl,CF3 orCH2CF3 ; R18 is H, CiC6 alkyl, C3C8 cycloalkyl, (C3C8) cycloalkyl (CC6) alkyl, hydroxy (C2C6) alkyl orP (O) (OH) 2; each R19 is a substituent on the aryl or heteroaryl ring to which it is attached, and is independently selected from the group consisting of H, ClC6 alkyl, C3C8 cycloalkyl, CiCe alkoxy,OH, halogen,CN,N02,CF3,CHF2,CH2F,OCF3, OCHF2,K OCH2F, O(C1C6 alkyl), O(C3C8 cycloalkyl), COOR12, CONR21R22, OC(O)NR21R22, OC(O)R12, NR21R22, NR21COR12, NR21CO2R12, NR21CONR21R22, NR21SO2R15 andS (O)n6R15 ; R21 and R22 are each independently selected from the group consisting of H, CiCe alkyl, C3C8 cycloalkyl and benzyl ; or R21 and R22, together with the nitrogen atom to which they are both attached, form a 4to 7membered saturated or unsaturated ring, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting ofO,SandNR34; R23 and R24 are each independently selected from the group consisting of H and ClC6 alkyl ; or R23 and R24, together with the carbon atom to which they are both attached, form a C=O or cyclopropyl group; R27 is H, OH or CiCe alkyl ; R28 and R29 are each independently selected from the group consisting of H and C1C2 alkyl ; R30 and R31 are each independently selected from the group consisting of H, OH, C1C6 alkyl, C3C8 cycloalkyl, (C3C8)cycloalkyl(C1C6)alkyl andC (O) NR13R14 ; or R30 and R31, together with the carbon atom to which they are both attached, form =O, =S, a cyclopropyl ring or =NR36 ; R32 and R33 are each independently selected from the group consisting of H and CiCe alkyl ; R34 is H, CiCe alkyl, C3C8 cycloalkyl, (C3C8)cycloalkyl(C1C6)alkyl or hydroxy (C2C6) alkyl ; R35 is H, CiCe alkyl, CsCg cycloalkyl, (C3C8) cycloalkyl (CC6) alkyl, P(O) (OH) 2, allyl, hydroxy(C2C6)alkyl, (C1C6)alkoxy(C1C6)alkyl, SO2R15 or (CH2)2N(R12)SO2R15 ; R36 is H, CiCe alkyl, C3C8 cycloalkyl, (C3C8) cycloalkyl (CC6) alkyl,N02, CN or OR12 ; R37 is 1 to 3 substituents independently selected from the group consisting of H, ClC6 alkyl,OH, CiCe alkoxy and halogen ; r is 1 to 3; X2 is NR35, O, S, S(O), SO2, CH2, CF2 or CR12F; X3 is NR34, N(CONR13R14), N(CO2R13), N(SO2R15), N(COR12), N(SO2NHR13), O, S, S(O), SO2, CH2, CF2 or CR12F; n3 is 1 to 5; and n5 is 1 to 3 ; or a diastereomer, enantiomer, stereoisomer, regiostereomer, rotomer, tautomer or prodrug thereof.
2. The compound or salt according to claim 1, where X1 is O.
3. The compound or salt according to claim 1, where Ar1 and Ar2 are each.
4. The compound or salt according to claim 3, where for Ar2, at least two of R8, R9 and R10 are eachCF3.
5. The compound or salt according to claim 3, where for Ar1, R8, R9 and R10 are each independently selected from the group consisting of H, OH and halogen.
6. The compound or salt according to claim 1 represented by the formula wherein X1 is O or NR34; for Ar2, R8 and R9 are independently selected from the group consisting of CF3, CHF2, CH2F, halogen, C1C6 alkyl, OCF3 andOR12 ; for Ar1, R9 and R10 are independently selected from the group consisting of H, OH and halogen; and n2 is 1 or 2.
7. The compound according to claim 6 wherein one of R4 and R5 is H and the other isC (R28R29)n1G, wherein ni is 0,1 or 2.
8. The compound according to claim 7 wherein one of R4 and R5 is H and the other is selected from the group consisting of NR13R14, NR12C(O)R14, C(O)NR13R14, OC(O)R14, OC(O)NR13R14, NR12C(O)OR13, C(O)OR13, NR12(C(O)NR13R14), NR12SO2R13, SO2NR13R14, R19heteroaryl,.
9. The compound or salt according to claim 6 wherein R4 is NR13R14, R12C (O) R14, NR12C(O)OR13, NR12(C(O)NR13R14), OH, O(C1C6)alkyl, O(C3C8)cycloalkyl, OC(O)R14, OC(O)NR13R14, NR12SO2R13, SO2NR13R14, R19heteroaryl, wherein X2 is O, S, CH2 or NR35; and R5 isC (O) OR" or (O) N R13R14.
10. The compound or salt according to claim 8, where R12 and R27 are independently selected from the group consisting of H andCH3 ; n3 is 2 or 3; and n5 is 1 or 2.
11. The compound or salt according to claim 9, wherein R12 and R27 are H; n3 is 2 or 3; and n5 is 1 or 2.
12. The compound or salt according to claim 6, wherein R4 and R5, together with the carbon atom to which they are both attached, form a 4to 8membered heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 groups independently selected from X2, provided that at least one X2 is NR35, O, S, S(O) or SO2, the ring being optionally substituted with from 1 to 6 substituents independently selected from the group consisting of R30 and R.
13. The compound or salt according to claim 12, where the 4to 8membered ring is selected from the group consisting of: wherein R35 is H, C1C6 alkyl, C3C8 cycloalkyl, (C3C8) cycloalkyl (C1C6) alkyl or hydroxy (CiCe) alkyl ; n5 is 1,2 or 3; X2 is NR35, CH2, O or S; R30 is H, CiCe alkyl or C3C8 cycloalkyl ; and R31 is H, OH or CiCe alkyl.
14. The compound or salt according to claim 12, where the 4to 8membered ring is selected from the group consisting of: wherein R30 is H, CiCe alkyl or C3C8 cycloalkyl ; R31 is H,OH or CiCe alkyl ; each R35 is independently selected from the group consisting of H, CiCe alkyl, C3C8 cycloalkyl, (C3C8) cycloalkyl (C1C6) alkyl and hydroxy (CiCe) alkyl ; n4 and n7 are independently 05, provided that the sum of n4 and n7 is 15.
15. The compound or salt according to claim 13 wherein the 4to 8membered ring is selected from the group consisting of.
16. The compound according to claim 14, wherein the 4to 8membered ring is selected from the group consisting of.
17. The compound or salt according to claim 1, wherein the compound is selected from the group consisting of Examples 3, 9,12a, 13,14, 15,20, 23, 29,36, 40,43b, 44b, 45,50, 53,56b, 57,60a, 61,62, 63,72a, 73b, 74a, 75b, 76a, 82a, 82b, 90,96, 105,106b, 109, 11 Oa, 111 a, 112 and 113, and the stereoisomers thereof.
18. The compound or salt according to claim 17, wherein the compound is:.
19. The compound or salt according to claim 17, wherein the compound is:.
20. The compound or salt according to claim 17, wherein the compound is:.
21. The compound or salt according to claim 17, wherein the compound is:.
22. The compound or salt according to claim 17, wherein the compound is:.
23. The compound or salt according to claim 17, wherein the compound is:.
24. The compound or salt according to claim 17, wherein the compound is:.
25. The compound or salt according to claim 17, wherein the compound is:.
26. The compound or salt according to claim 17, wherein the compound is:.
27. A pharmaceutical composition comprising a therapeutical effective amount of at least one compound of claim 1 in a pharmaceutical acceptable carrier.
28. The pharmaceutical composition according to claim 27, further comprising at least one selective serotonin reuptake inhibitor.
29. The pharmaceutical composition according to claim 27, further comprising at least one serotonin 5HT3 receptor antagonist, or at least one corticosteroid or at least one substituted benzamide.
30. The pharmaceutical composition according to claim 27, further comprising at least one serotonin 5HT3 receptor antagonist and at least one corticosteroid.
31. The pharmaceutical composition according to claim 27, further comprising at least one substituted benzamide and at least one corticosteroid.
32. The use of a compound of claim 1 for the preparation of a medicament for treating a physiological disorder, symptom or disease in a patient, where the physiological disorder, symptom or disease is a respiratory disease, cough, inflammatory disease, skin disorder, ophthalmalogical disorder, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AlDs related dementia, Towne's disease, stress related disorder, obsessive/compulsive disorder, bulemia, anorexia nervosa, binge eating, mania, premenstrual syndrome, gastrointestinal disorder, atherosclerosis, fibrosing disorder, obesity, Type II diabetes, headache, neuropathic pain, postoperative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, emesis or nausea.
33. The use according to claim 32 for treating asthma, emesis, nausea, depression, anxiety, cough or migraine.
34. The use of claim 33 for treating depression or anxiety further comprising at least one selective serotonin reuptake inhibitor.
35. The use of claim 33 for treating emesis further comprising at least one serotonin 5HT3 receptor antagonist or at least one corticosteroid or at least one substituted benzamide.
36. The use of claim 33 for treating emesis further comprising at least one serotonin 5HT3 receptor antagonist and at least one corticosteroid.
37. The use of claim 33 for treating emesis further comprising at least one corticosteroid and at least one substituted benzamide.
38. The use of a compoind of claim 1 for the preparation of a medicament for antagonizing an effect of a Substance P at a neurokinin1 receptor site or for blocking at least one neurokinin1 receptor.
Description:
PYRROLIDINE AND PIPERIDINE DERIVATES AS NK1 ANTAGONISTS BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to an antagonist of the neuropeptide neurokinin- 1 (NK1 or NK-1) receptor.

2. Description of Related Art Tachykinins are peptide ligands for neurokinin receptors. Neurokinin receptors, such as NK1, NK2 and NK3, are involved in a variety of biological processes. They can be found in a mammal's nervous and circulatory systems, as well as in peripheral tissues. Consequently, the modulation of these types of receptors have been studied to potentially treat or prevent various mammalian disease states. For instance, NK1 receptors have been reported to be involved in microvascular leakage and mucus secretion. Representative types of neurokinin receptor antagonists and their uses can be found in: U. S. 5,760, 018 (1998) (pain, inflammation, migraine and emesis), U. S. 5,620, 989 (1997) (pain, nociception and inflammation), WO 95/19344 (1995) (same), WO 94/13639 (1994) (same) and WO 94/10165 (1994) (same). Further types of NK1 receptor antagonists can be found in Wu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57, 8971-8981 (2001).

It would be beneficial to provide a NK1 antagonist that is potent, selective, and possesses beneficial therapeutic and pharmacological properties, and good metabolic stability. It would further be beneficial to provide a NK1 antagonist that is effective for treating a variety of physiological disorders, symptoms and diseases while minimizing side effects. The invention seeks to provide these and other benefits, which will become apparent as the description progresses.

SUMMARY OF THE INVENTION In one aspect of the invention, a compound is provided having the formula (I) :

or a pharmaceutically-acceptable salt thereof, wherein Ar1 and Ar2 are each independently selected from the group consisting of R17-heteroaryl and when X1 is-SO-,-S02-,-N (COR12)-or-N (SO2R15)-, then: R1 and R2 are each independently selected from the group consisting of H, Ci-Ce alkyl, hydroxy (C1-C3alkyl), C3-C8 cycloalkyl, -CH2F, -CHF2 and -CF3 ; or R'and R2, together with the carbon atom to which they are both attached, form a chemically feasible C3 to C6 alkylen ring; or when X is-0-,-S-or-NR, then: R1 and R2 are each independently selected from the group consisting of H, Ci-Ce alkyl, hydroxy (C1-C3alkyl), C3-C8 cycloalkyl, -CH2F, -CHF2 and -CF3 ; or R1 and R2, together with the carbon atom to which they are both attached, form a chemically feasible C3 to C6 alkylen ring; or R1 and R2, together with one another and the carbon atom to which they are both attached, form a C=O group; R3 is selected from the group consisting of H, Ci-Ce alkyl, hydroxy (Cl-C3 alkyl), C3-C8 cycloalkyl,-CH2F,-CHF2 and-CF3 ; each R6 is independently selected from the group consisting of H, Ci-Ce alkyl and-OH; each R7 is independently selected from the group consisting of H and Ci-Ce alkyl ;.

n2 is 1 to 4 ; R4 and R5 are each independently selected from the group consisting of - (CR28R29)n1-G, where, ni is 0 to 5 ; and G is H, -CF3-, -CHF2, -CH2F, -OH, -O-(C1-C6 alkyl), -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -O-(C3-C8 cycloalkyl), -O-(C1-C6)alkyl(C3-C8 cycloalkyl), -NR13R14, -SO2NR13R14, -NR12SO2R13, -NR12C(O)R14, -NR12C(O)OR13, - R12 (C (O) NR13R14), -C(O)NR13R14, -C(O)OR13, -C3-C8 cycloalkyl, (R19)r-aryl, (R19)r-heteroaryl, -OC(O)R14, -OC(O)NR13R14, -C(=NOR14)(R13), -C(O)R13, -C(OR12)(R13)(R14), heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of R30 and R31, R4 and R5 together are =O, =NOR12 ; or R4 and R5, together with the carbon atom to which they are both attached, form a chemically feasible 4-to 8-membered heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 groups independently selected from X2, provided that at least one X2 is -NR35-, -O-, -S-, -S(O)- or -SO2-, the chemically feasible ring being optionally substituted with from 1 to 6 substituents independently selected from the group consisting of R30 and R31 ; provided that R4 and R5 are not both selected from the group consisting of H, alkyl and cycloalkyl ; further provided that, when one of R4 and R5 is-OH, then the other one of R4 and R5 is not alkyl or (R19) r-aryl ; R8,R9 and R10 are each independently selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl, -OR12, halogen, -CN, -NO2, -CF3, -CHF2, -CH2F,

-CH2CF3,-OCF3,-OCHF2,-OCH2F,-OCH2CF3,-COOR,-CONR'R -OC(O)NR21R22, -OC(O)R12, -NR21COR12, -NR21CO2R15, -NR21CONR21R22, -NR21SO2R15, -NR21R22, -SO2NR21R22, -S(O)n6R15, (R19)r-aryl and (R19) r-heteroaryl ; R12 is H, Ci-Ce alkyl or C3-C8 cycloalkyl ; R13 and R14 are each independently selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C-C6) alkyl,-CH2CF3, aryl and heteroaryl ; or and R, together with the nitrogen atom to which they are both attached, form a chemically feasible 4-to 7-membered saturated or unsaturated ring that is -optionally substituted with-OR12, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting of-O-,-S- and-NR34 ; n6 is 0, 1 or 2 ; R15 is Ci-Ce alkyl, C3-C8 cycloalkyl,-CF3 or-CH2CF3 ; R18 is H, Ci-Ce alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C-C6) alkyl, hydroxy (C2-C6) alkyl or-P (O) (OH) 2; each R19 is a substituent on the aryl or heteroaryl ring to which it is attached, and is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl, Ci-Ce alkoxy,-OH, halogen,-CN,-NO2,-CF3,-CHF2,-CH2F,-OCF3, -OCHF2, -OCH2F, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -COOR12, -CONR21R22, -OC(O)NR21R22, -OC(O)R12, -NR21R22, -NR21COR12, -NR21CO2R12, - NR21CONR21R22, -NR21SO2R15 and-S (O) n6R 15 ; R21 and R22 are each independently selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl and benzyl ; or R21 and R22, together with the nitrogen atom to which they are both attached, form a chemically feasible 4-to 7-membered saturated or unsaturated ring, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting of-O-,-S-and-NR34-; R23 and R24 are each independently selected from the group consisting of H and Ci-Ce alkyl ; or R23 and R24, together with the carbon atom to which they are both attached, form a C=O or cyclopropyl group; R27 is H,-OH or C1-C6 alkyl ;

R 28 and R29 are each independently selected from the group consisting of H and C1-C2alkyl ; R30 and R31 are each independently selected from the group consisting of H, -OH, C1-C6 alkyl, C3-c8 cycloalkyl, (C3-C8) cycloalkyl(C1-C6)alkyl and-C (O) NR13R14; or R30 and R31, together with the carbon atom to which they are both attached, form =O, =S, a cyclopropyl ring or =NR36 ; R32 and R33 are each independently selected from the group consisting of H and Ci-Ce alkyl ; R34 is H, Ci-Ce alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or hydroxy (C2-C6) alkyl ; R35 is H, Ci-Ce alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl(C1-C6)alkyl, -P(O) (OH) 2, allyl, hydroxy (C2-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl, -SO2R15, or -(CH2)2-N(R12)-SO2-R15 ; R36 is H, Ci-Ce alkyl, C3-C8 cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -NO2, -CN or OR12 ; R37 is 1 to 3 substituents independently selected from the group consisting of H, Ci-Ce alkyl,-OH, C1-C6 alkoxy and halogen ; ris1 to3 ; X2 is-NR35-,-O-,-S-,-S (O)-,-SO2-,-CH2-,-CF2-or-CR12F-; X3 is -NR34-, -N(CONR13R14)-, -N(CO2R13)-, -N(SO2R15)-, -N(COR12)-, -N(SO2NHR13)-, -O-, -S-, -S(O)-, -SO2-, -CH2-, -CF2- or -CR12F-; n3 is 1 to 5; and n5 is 1 to 3.

The invention comprises at least one compound having the formula (I), including any and all diastereomers, enantiomers, stereoisomers, regiostereomers, rotomers, tautomers and prodrugs of the compounds having the formula (I) and their corresponding salts, solvates (e. g. , hydrates), esters, and the like. The compounds having the formula (I) can be useful for treating a variety of diseases, symptoms and physiological disorders, such as emesis, depression, anxiety and cough.

Another aspect of the invention comprises a pharmaceutical composition comprising a compound of formula (I), alone or with another active agent, and a pharmaceutically acceptable carrier or excipient therefor. The inventive compounds

and compositions can be used alone or in combination with other active agents and/or methods of treatment for treating a variety of diseases, symptoms and physiological disorders, such as the ones disclosed herein.

DETAILED DESCRIPTION -The--following-definitions--and terms--are-used--herein or-are-otherwise known--to-- a skilled artisan. Except where stated otherwise, the following definitions apply throughout the specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of"alkyl"applies to"alkyl"as well as the"alkyl" portions of"hydroxyalkyl,""haloalkyl,""alkoxy,"etc.

The term"substituted, "as used herein, means the replacement of one or more atoms, usually hydrogen atoms, in a given structure with an atom or radical selected from a specified group. in the situations where more than one atom may be replaced with a substituent selected from the same specified group, the substituents may be, unless otherwise specified, either the same or different at every position.

The term"heteroatom, "as used herein, means a nitrogen, sulfur, or oxygen atom. Multiple heteroatoms in the same group may be the same or different.

The term"alkyl,"as used herein, means a straight or branched, hydrocarbon chain having the designated number of carbon atoms. If the number of carbon atoms is not designated, the carbon chain is from one to twenty-four carbon atoms, more preferably, from one to twelve carbon atoms, and most preferably, from one to six carbon atoms.

The term"cycloalkyl"as used herein, means a saturated, stable, non- aromatic carbocyclic ring having from three to eight carbon atoms. The cycloalkyl may be attached at any endocyclic carbon atom that results in a stable structure.

Preferred carbocyclic rings have from three to six carbons. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term"aryl,"as used herein, means an aromatic, mono-or bicyclic, carbocyclic ring system having from one to two aromatic rings. The aryl moiety will generally have from 6 to 14 carbon atoms with all available substitutable carbon atoms of the aryl moiety being intended as possible points of attachment.

Representative examples include phenyl, cumenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The term"heteroaryl,"as used herein, means a mono-or bicyclic, chemically feasible ring system containing one or two aromatic rings and 1 to 4 nitrogen, oxygen or sulfur atoms in the aromatic ring. Typically, a heteroaryl group represents a cyclic group of five or six atoms, or a bicyclic group of nine or ten atoms, at least one of which is carbon, and having at least one oxygen, sulfur or nitrogen atom interrupting a carbocyclic ring having a sufficient number of pi (7C) electrons to provide aromatic character. Representative heteroaryl (heteroaromatic) groups are pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl, 1,3, 5-triazinyl and indolyl groups. The heteroaryl group can be joined to the rest of the molecule through a bond at any substitutable carbon or nitrogen.

The term"heterocycloalkyl"as used herein means a saturated cyclic ring having from 3 to 8 members, preferably 5 or 6 members, and comprising 2 to 7 carbon atoms and 1 to 3 heteroatoms independently selected from the group consisting of-O-,-S-,-S (O)-,-S02-and-NR35-. Typical heterocycloalkyl rings are pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. The heterocycloclkyl ring can be attached to the rest of the structure through either a substitutable ring carbon or a substitutable ring nitrogen.

The term"heterocycloalkenyl"as used herein means a cyclic ring having from 3 to 8 members, preferably 5 or 6 members, and comprising 2 to 7 carbon atoms and 1 to 3 heteroatoms independently selected from the group consisting of-O-,-S-, -S (O)-,-SO2-and-NR35-, and having at least one double bond in the ring, but not having aromatic characteristics. Examples of such rings are: wherein the ring can be attached to the rest of the structure through either a substitutable ring carbon or a substitutable ring nitrogen (e.g., in R4, when G is heterocycloalkenyl, it can be joined to the (CR28R29)n1 group through either a substitutable ring carbon or a substitutable ring nitrogen).

When R4 and Reform a ring with 1,2 or 3 groups independently selected from X2, and 1 or 2 of X2 are carbon, the variable size of the ring can be defined by n4 and n7, which are independently selected from 0-5, provided that the sum of n4 and n7 is 1 to 5. A typical structure wherein the heteroatom is-NR35-, x2 is-CH2-, and R30 and R31 together form a carbonyl group is represented by the formula When R4 and R5, together with the carbon to which they are attached, form a heterocycloalkenyl ring, examples of such rings are The term"alkoxy,"as used herein, means an oxygen atom bonded to a hydrocarbon chain, such as an alkyl or alkenyl group (e. g.,-O-alkyl or-O-alkenyl).

Representative alkoxy groups include methoxy, ethoxy, and isopropoxy groups.

The term"hydroxyalkyl,"as used herein, means a substituted hydrocarbon chain, preferably, an alkyl group, having at least one hydroxy substituent (i. e.,-OH).

Representative hydroxyalkyl groups include hydroxymethyl, hydroxyethyl and hydroxypropyl groups.

The term"halo"or"halogen"as used herein means a chloro, bromo, fluoro or iodo atom radical.

Unless otherwise known, stated or shown to be to the contrary, the point of attachment for a multiple term substituent (multiple terms that are combined to identify a single moiety) to a subject structure is through the last named term of the multiple term. For example, an"arylalkyl"substituent attaches to a targeted structure through the"alkyl"portion of the substituent. Conversely, when the substituent is"alkylaryl", it attaches to a targeted structure through the"aryl"portion of the substituent. Similarly, a cycloalkylalkyl substituent attaches to a targeted through the latter"alkyl"portion of the substituent (e. g., Structure-alkyl-cycloalkyl).

When a variable appears more than once in a structural formula, for example, R8, its definition at each occurrence is independent of its definition at every other occurrence.

The term"prodrug, "as used herein, represents compounds that are drug precursors which, following administration to a patient, release the drug in vivo via a chemical or physiological process (e. g. , a prodrug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form). A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of A. C. S. Symposium Series (1987), and in Bioreversible Carriers in Drug Design, E. B. Roche, ed. , American Pharmaceutical Association and Pergamon Press (1987), each of which is incorporated herein by reference in its entirety.

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

Other than as shown in the operating examples or where is otherwise indicated, all numbers used in the specification and claims expressing quantities of ingredients, reaction conditions, and so forth, are understood as being modified in all instances by the term"about." Referring to the compound having the formula (I) : or a pharmaceutically-acceptable salt thereof, preferred are compounds wherein Ar1 and Ar2 are each, preferably, where R8, R9 and R10 are each independently defined as above in the summary of the invention. More preferably, for Ar2, R10 is H, and R8 and R9 are independently

selected from the group consisting of-CF3,-CHF2,-CH2F, halogen, Ci-Ce alkyl, -OCF3 and -OR12 ; for Ar1, R9 and R10 are independently selected from the group consisting of H, -OH and halogen. The variable n2 is preferably 1 or 2.

X1 is, preferably-O-or-NR34-. More preferably, X1 is -O-.

R1 and R2 are each, preferably, independently selected from the group consisting of H and Ci-Ce alkyl. More preferably, R'and R2 are each independently selected from the group consisting of H and CH3.

R3 is preferably selected from the group consisting of H and C1-C6 alkyl.

More preferably, R3 is H.

Each R6 is preferably independently selected from the group consisting of H and Ci-Ce alkyl. Even more preferably, each R6 is H.

Each R7 is preferably independently selected from the group consisting of H and Ci-Ce alkyl. Even more preferably, each R7 is H.

More preferred are compounds of the structure 11 wherein X1 is -O- or -NR34-; R8 and R9 are independently selected from the group consisting of-CF3,-CHF2,-CH2F, halogen, Ci-Ce alkyl,-OCF3 and-OR12 ; R9 and R10 are independently selected from the group consisting of H, -OH and halogen ; and n2 is 1 or 2.

Preferred compounds of formula I and formula 11 are those wherein one of R4 and R5 is H and the other is-C (R28R29)n1-G, wherein ni is 0,1 or 2. More preferred are compounds wherein one of R4 and R5 is H and the other is selected from the group consisting of -NR13R14, -NR12C(O)R14, -C(O)NR13R14, -OC(O)R14, -OC(O)NR13R14, NR12C(O)OR13, -C(O)OR13, -NR12 (C (O) NR13R14), -NR12SO2R13, -SO2NR13R14, R19-heteroaryl,

Even more preferred are such compounds wherein R"and R"are independently selected from the group consisting of H and Ci-Ce alkyl, especially H and-CH3, and more especially, both are H; n3 is 2 or 3; and n5 is 1 or 2.

In another embodiment, preferred compounds of formula I and formula 11 are those wherein R is -NR13R14, -NR12C(O)R14, NR12C(O)OR13, -NR12 (C (O) 14 -OH, -O-(C1-C6)alkyl, -O-(C3-C8)cycloalkyl, -OC(O)R14, -OC(O)NR13R14, -NR12SO2R13, -SO2NR13R14, R19-heteroaryl, wherein X2 is -O-, -S-, -CH2- or -NR35-; and R5 is-C (O) OR" or-C (O) N R13R14 More preferred are compounds wherein R12 is independently selected from the group consisting of H, Ci-Ce alkyl and C3-C8 cycloalkyl ; R27 is H; n3 is 2 or 3; and n5 is 1 or 2.

Still another preferred embodiment of compounds of formula I and li is that wherein R4 and R5, together with the carbon atom to which they are both attached, form a 4-to 8-membered heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 groups independently selected from X2, provided that at least one X2 is -NR35-, - O-,-S-,-S (O)- or-S02-, the ring being optionally substituted with from 1 to 6 substituents independently selected from the group consisting of R30 and R31 ;. More preferred are compounds wherein the 4-to 8-membered ring is selected from the group consisting of:

wherein R35 is H, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl or hydroxy (Ci-C6) alkyl ; n5 is 1,2 or 3; X2 is -NR35-, -CH2-, -O- or -S-; R30 is H, C1-C6 alkyl or C3-C8 cycloalkyl ; and R31 is H, -OH or Ci-Ce alkyl. Especially preferred are 4-to 8-membered rings selected from the group consisting of The rings are optionally substituted with R30 and R31 Yet another group of preferred compounds wherein R4 and R5 form a ring is that wherein the ring is selected from the group consisting of

wherein R30 is H, Ci-Ce alkyl or C3-C8 cycloalkyl ; R31 is H, -OH or Ci-Ce alkyl ; each R35 is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C8 cycloalkyl, (C3-C8) CYCloalkyl (Cl-C6) alkyl and hydroxy (Ci-C6) alkyl ; n4 and n7 are independently 0-5, provided that the sum of n4 and n7 is 1-5. Especially preferred are 4-to 8-membered rings selected from the group consisting of

The rings are optionally substituted with R and R.

In still another embodiment of the invention, it is preferable for at least one of R4 and R5 to be in a cis orientation to the Ar1 substituent.

R15 is preferably Ci-Ce alkyl or-CF3. More preferably, R15 is Ci-Ce alkyl.

R18 is preferably H or-Ci-Ce alkyl. More preferably, R'8 is H or CH3. Even more preferably, R18 is H.

Each R19 is a substituent on the aryl or heteroaryl ring to which it is attached, and is, preferably, independently selected from the group consisting of H, Ci-Ce alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2 and-OCH2F. More preferably, each R19 is selected from the group consisting of H and Ci-Ce alkyl.

Preferably, r is 1 or 2. More preferably, r is 1.

R 21 and R22 are each, preferably, independently selected from the group consisting of H and Ci-Ce alkyl. More preferably, R21 and R22 are each independently selected from the group H and CH3.

R23 and R24 are each, preferably, independently selected from the group consisting of H and Ci-Ce alky, or R23 and R24 together are =O. More preferably, R23 and R24 are each independently selected from the group H and CH3.

R28 and R29 are preferably, independently selected from the group consisting of H and-CH3 R30 and R31 are preferably independently selected from the group consisting of H and C1-C2 alkyl, or R30 and R31 together are =O. More preferably, R30 and R3 are each independently selected from the group consisting of H and -CH3.

R32 and R33 are preferably independently selected from the group consisting of H and-CH3. Even more preferably, R32 and R33 are each H.

R36 is preferably H or Ci-Ce alkyl. More preferably, R36 is H or -CH3.

R37 is preferably 1 or 2 substituents selected from the group consisting of H, -CH3 and halogen.

Preferred compounds of the invention are those shown below in Examples 3, 9,12a, 13,14, 15,20, 23,29, 36,40, 43b, 44b, 45,50, 53,56b, 57,60a, 61,62, 63, 72a ! 73b, 74a, 75b, 76a, -82a, 82b, 90- ;-96, 105,-1066,--109,-110a,-111a, 112 and 113. More preferred are compounds of Examples 12a, 43b, 72a, 73b, 109, 110a and 111a.

Compounds having the formula (I) can be effective antagonists of the NK receptor, and of an effect of its endogenous agonist, Substance P, at the NK receptor site, and therefore, can be useful in treating conditions caused or aggravated by the activity of said receptor. The in vítro and in vivo NK1, NK2 and NK3 activities of the compounds having the formula (I) can be determined by various procedures known in the art, such as a test for their ability to inhibit the activity of the NK1 agonist Substance P. The percent inhibition of neurokinin agonist activity is the difference between the percent of maximum specific binding ("MSB") and 100%.

The percent of MSB is defined by the following equation, wherein"dpm"represents "disintegrations per minute" : <BR> <BR> <BR> <BR> <BR> <BR> % MSB (dpm of unknown) - (dpm of nonspecific binding)<BR> <BR> <BR> X 100 (dpm of total binding) - (dpm of nonspecific binding) The concentration at which the compound produces 50% inhibition of binding is then used to determine an inhibition constant ("Ki") using the Chang-Prusoff equation.

In vivo activity may be measured by inhibition of an agonist-induced foot tapping in a gerbil, as descibed in Science, 281,1640-1695 (1998), which is herein incorporated by reference in its entirety. It will be recognized that compounds having the formula (I) can exhibit NK1 antagonist activities of varying degrees. For instance, certain compounds can exhibit stronger NK1 antagonist activities than others.

The compounds of the invention exhibit potent affinities for the NK1 receptor as measured by Ki values (in nM). The activities (potencies) for the compounds of the invention are determined by measuring their Ki values. The smaller the Ki value, the more active is a compound for antagonizing the NK1 receptor. Compounds of the invention exhibit a wide range of activities. The NK1 average Ki values for

compounds having the formula (I) generally range from 0.01 nM to about 1000 nM, preferably, from about 0.01 nM to about 500 nM, with values of from about 0.01 nM to about 100 nM being more preferred. Even more preferred are compounds having average Ki values of from 0.01 nM to about 10 nM for the NK, receptor. The most preferred compounds have NK1 average Ki values of from 0.01 nM to about 3 nM.

The preferred compounds noted above have the-following Ki values : Exairaple-43-b :- 0.77nM ; 72a: 0. 66nM ; 73b: 0.2nM ; 109: 0. 1nM ; 110a : 0. 41nM ; and 111 a : 0. 38nM.

The inventive compounds are also highly selective for antagonizing a NK receptor as opposed to antagonizing (i) NK2 and/or (ii) NK3 receptors. When a compound's selection ratio is greater than about 100 for the Ki of the NK1 receptor to the Ki of the NK2 receptor, and/or, independently, the Ki of the NK3 receptor, then the compound is defined herein as a selective antagonist of the NIC receptor, as opposed to the NK2 and/or NK3 receptors, respectively.

Compounds having the formula (I) may have at least one asymmetrical carbon atom. All isomers, including stereoisomers, diastereomers, enantiomers, regiostereomers, tautomers and rotational isomers, are contemplated as being part of the invention. Prodrugs, salts, solvates, esters, etc. , derived from the compounds having the formula (I) or precursors thereof are aiso within the scope of the invention. The invention includes d-and/-isomers in pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound having the formula (I). Those skilled in the art will appreciate that for some compounds having the formula (I), particular isomers can show greater pharmacological activity than other isomers.

There are many uses for the compounds having the formula (I). For instance, compounds having the formula (I) can be useful as antagonists of neurokinin receptors, particularly, NK1 receptors in a mammal, such as a human.

As such, they may be useful in treating and preventing one or more of a variety of mammalian (human and animal) disease states (physiolgical disorders, symptoms and diseases), for instance, respiratory diseases (e. g., chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), inflammatory diseases (e. g. , arthritis and psoriasis), skin disorders (e. g. , atopic dermatitis and

contact dermatitis), ophthalmalogical disorders (e. g. , retinitis, ocular hypertension and cataracts), central nervous system conditions, such as depressions (e. g., neurotic depression), anxieties (e. g., general anxiety, social anxiety and panic anxiety disorders), phobias (e. g., social phobia), and bipolar disorder, addictions (e. g., alcohol dependence and psychoactive substance abuse), epilepsy, <BR> <BR> <BR> - nociception, psychosis, schizophrenia, Alzheimer's disease, AIDs related dementia, Towne's disease, stress related disorders (e. g. , post tramautic stress disorder), obsessive/compulsive disorders, eating disorders (e. g., bulemia, anorexia nervosa and binge eating), mania, premenstrual syndrome, gastrointestinal disorders (e. g., irritable bowel syndrome, Crohn's disease, colitis, and emesis), atherosclerosis, fibrosing disorders (e. g., pulmonary fibrosis), obesity, Type il diabetes, pain related disorders (e. g. , headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), bladder and genitourinary disorders (e. g., interstitial cystitis and urinary incontinence), and nausea. In particular, the compounds having the formula (I) are useful for treating disease states related to microvascular leakage and mucus secretion. Consequently, the compounds of the invention are especially useful in the treatment and prevention of asthma, emesis, nausea, depressions, anxieties, cough and pain related disorders.

In still another aspect of the invention, a method is provided for antagonizing an effect of a Substance P at a neurokinin-1 receptor site or for the blockade of one or more neurokinin-1 receptors in a mammal in need of such treatment, comprising administering to the mammal an effective amount of at least one compound having the formula (I).

In another embodiment of the invention, an effective amount of one or more of the inventive NK1 receptor antagonists may be combined with an effective amount of one or more selective serotonin reuptake inhibitors ("SSRIs") to treat depression or anxiety. SSRIs alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin. U. S. 6,162, 805, which is incorporated herein by reference in its entirety, discloses a method for treating obesity with a combination therapy of a NK1 receptor antagonist and an SSRI. An inventive compound (s) having the formula (I) can be combined together with an SSRI (s) in a single pharmaceutical composition or it can be administered simultaneously, concurrently or sequentially with an SSRI.

Numerous chemical substances are known to alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin. Representative SSRIs include, without limitation, the following : fluoxetine, fluvoxamine, paroxetine, sertaline, and pharmaceutically-acceptable salts thereof. Other compounds can readily be evaluated to determine their ability to ---selectively inhibit serotonin reuptake. Thus, the invention relates to a pharmaceutical composition comprising at least one NK1 receptor antagonist having the formula (I) and at least one SSRI, and a method of treating the above identified mammalian disease states, the method comprising administering to a patient in need of such treatment an effective amount of the pharmaceutical composition comprising at least one NK1 receptor antagonist having the formula (I) in combination with at least one SSRI, such as one of those recited above.

In another aspect, the invention relates to a method of treating emesis, comprising administering to a patient in need of such treatment an effective amount of at least one NK1 receptor antagonist having the formula (I). Compounds of the present invention are particularly useful in treatina delayed onset emesis such as that experienced 24 hours to several days after the administration of chemotherapy.

See Gonzales et al, Oncology Special Edition, Vol. 5 (2002), p. 53-58.

Combinations of at least one NK1 receptor antagonist and at least one other anti- emetic agent such as a serotonin 5-HT3 receptor antagonist, a corticosteroid or a substituted benzamide can be used to treat other forms of emesis, e. g. , acute emesis induced by chemotherapy, radiation, motion and alcohol (e. g., ethanol), and post-operative nausea and vomiting. Examples of serotonin 5-HT3 receptor antagonists are palonsetron, dolasetron, ondansetron and granisetron, or a . pharmaceutically-acceptable salts thereof. An examples of a suitable corticosteroid is dexamethasone. An example of a substituted benzamide is metoclopramide.

Preferred combinations for the treatment of emesis include a compound of formula I and a serotonin 5-HT3 receptor antagonist; a compound of formula I and a corticosteroid; a compound of formula I and a substituted benzamide; a compound of formula I,. a serotonin 5-HT3 receptor antagonist and a corticosteroid; and a compound of formula 1, a substituted benzamide and a corticosteroid.

When an inventive NK1 receptor antagonist is combined with an SSRI, a serotonin 5-HT3 receptor antagonist, a corticosteroid or a substituted benzamide for

administration to a patient in need of such treatment, the two or more active ingredients can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time).

Thus, the compounds of the invention may be employed alone or in combination with other agents ! n addition to the above described NK1 receptor antagonist/SSRI or serotonin 5-HT3 receptor antagonist combination therapy, the compounds having the formula (I) may be combined with other active agents, such as other types of NK1 receptor antagonists, prostanoids, H1 receptor antagonists, a- adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin il receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, rho kinase inhibitors, potassium channel modulators and/or inhibitors of multidrug resistance protein 5.

Preferable therapeutic agents for combination therapy with compounds of the invention are the following: prostanoids, such as prostaglandin Ei ; a-adrenergic agonists, such as phentolamine mesylate ; dopamine receptor agonists, such as apomorphine; angiotensin 11 antagonists, such as losartan, irbesartan, valsartan and candesartan; and ETA antagonists, such as bosentan and ABT-627. Dosage ranges for the other agent can be determined from the literature.

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

Gennaro (ed. ), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

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

Aerosol preparations suitable for inha ! atibn may indude solutions and solids- in powder form, which may be in combination with a pharmaceutical acceptable carrier, such as an inert compressed gas, e. g. nitrogen.

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

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

Preferably the compound is administered orally.

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

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 4,000 mg, preferably from about 0.02 mg to about 1000 mg, more preferably from about 0.03 mg to about 500 mg, and most preferably from about 0.04 mg to about 250 mg according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.

Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age,

condition and size of the patient as well as severity of the symptoms being treated.

A typical recommended daily dosage regimen for oral administration can range from about 0.02 mg/day to about 2000 mg/day, in two to four divided doses.

The quantity of NK1 receptor antagonist in combination with a SSRI or serotonin 5-HT3 receptor antagonist (5-HT3) in a unit dose of preparation may be varied or adjusted from about 10 to about 300 mg~ of-NK1 receptor antagonist combined with from about 10 to about 100 mg of SSRI or 5-HT3. A further quantity of NK1 receptor antagonist in combination with a SSRI or 5-HT3 in a unit dose of preparation may be varied or adjusted from about 50 to about 300 mg of NK1 receptor antagonist combined with from about 10 to about 100 mg of SSRI or 5-HT3.

An even further quantity of NK1 receptor antagonist in combination with SSRI or 5- HT3in a unit dose of preparation may be varied or adjusted from about 50 to about 300 mg of NK1 receptor antagonist combined with from about 20 to about 50 mg of SSRI or 5-HT3, depending on the particular application. Dosage levels for the corticosteroids and substituted benzamides can be determined form the literature.

Alternatively, separate dosage forms of the compounds of formula I and the other agents can be provided in a single package as a kit for the convenience of the patient. This is particularly useful when the separate components must be administered in different dosage forms (e. g. , a tablet and a capsuie) or at different dosage schedules.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of the invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

The inventive compounds can exist in unsolvated as well as solvate forms, including hydrated forms. In general, the solvate forms, with pharmaceutically- acceptable solvents, such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.

The inventive compounds may form pharmaceutically-acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are

hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in a conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.

Acidic compounds of the invention (e. g. , those compounds which possess a carboxyl group) form pharmaceutically-acceptable salts with inorganic and organic bases. Representative examples of such types of salts are sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically-acceptable amines, such as ammonia, alkyl amines, hydroxyalkylamines, N-methyiglucamine, and the like.

Following are general and specific methods of preparing compounds having the formula (I). As used herein, the following abbreviations are defined as follows : RBF is a round bottom flask ; RT is room temperature; Me is methyl ; Bu is butyl ; Ac is acetyl ; Et is ethyl ; Ph is phenyl ; THF is tetrahydrofuran; OAc is acetate; (Boc) 20 is di-tert-butyl dicarbonate; (Boc) is tert-butoxy carbonyl ; TLC is thin layer chromatography; LAH is lithium aluminum hydride; LDA is lithium diisopropyl amine; CDI is 1, 1-carbonyl diimidazole ;

HOBT is hydroxybenzotriazole ; DEC is 1 [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride ; TFA is trifluoroacetic acid; MTBE is t-butyl methyl ether; DIEA or i-Pr2EtN is diisopropylethyl amine; Prep plate is preparative thin layer chromatography; DMF is dimethyl formamide DMPU is 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H)-pyrimidinone TEMPO is a free radical of 2,2, 6,6-tetra methyl-1-piperidinyloxy ; BuLi is butyl lithium ; KHMDS is potasium bis (trimethylo silyl) amide; and DBU is 1, 8-diazabicyclo [5.4. 0] un dec-7-ene.

Compounds having the formula (I) can be prepared using methods known to those skilled in the art. Typical procedures are described below, although a skilled artisan will recognize that other procedures may be applicable, and that the procedure may be suitably modified to prepare other compounds within the scope of formula (I).

General Methods of Preparation Compounds having the formula (I) may be generally prepared from the corresponding protected oxazolidinone derivative A1 as shown under the following conditions, where Ar1 and Ar2 are each defined as in the summary of the invention; X1 is-O-; R1 through R33, independently of one another, are each defined as in the summary of the invention; and n2 is 1.

The stereoselective alkylation of a protected oxazolidinone A1 provides the protected oxazolidinone A2. Partial reduction with a reducing agent, such as LAH, provides the lactol A3. A Wittig reaction provides the corresponding olefin A4.

Hydrogenation of the olefin A4 and cyclization provides the lactam A5. If the protecting group (Pr) on the nitrogen is Cbz then it might cleave under hydrogenation conditions. The deprotection of the nitrogen of the lactam A5, if necessary, followed by reduction of the lactam with reducing agents such as LAH or LAH/AIC13, preferably LAH/AIC13, provides substituted pyrrolidines A6. 0 OMe Ph Ph. ph Ru PhYo Base Phf o reduction) oO Wittig p R4 H O N/ O 1 N H--- Pr-N Pr' Z X R Pr° J Ar R Ar Rs R Ar R R Ar A1 Zis-CI or-Br A2 A3 A4 X1 is-O- 0 R 0/R -/ hydrogenation 1. deprotection HN cyclization Pr 11 1 1 2. reduction Ar R3 3 R Ar A R A R R A5 A6 A A

Compounds having the formula 1, where n2 is 1 and R-is-NK'-R'-, - NR12SO2R13, -NR12C(O)R14, or -NR12(C(O)NR13R14) can also be prepared by conversion of lactol A3 to olefin A7 via Wittig reaction using a nitrogen protected (NPr') glycine ester Wittig reagent where Pr'can be a Boc or Cbz protecting group and Pr is preferably a Cbz protecting group. Palladium catalyzed hydrogenation and deprotection (if Pr is a Cbz group) of olefin A7, followed by spontaneous cyclization will provide lactam A8. When Pr is not Cbz or a protecting group readily cleaved under standard hydrogenation conditions, then hydrogenation of the olefin A7 is followed by deprotection of-NHPr and subsequent cyclization to provide lactam A8.

The deprotection of the N-Pr'group, if necessary, followed by the reduction of the lactam with reducing agents as LAH or LAH/AIC13, preferably LAH/AICI3, provides amino-pyrrolidines A9 which can further be functionalized using standard conditions to give N-substituted pyrrolidines A10. O H H OMe 1. hydroge ation/H, NPe Ph, O Pr'H \ cycli aion Wittig P-N H hydrogenation HN 4X'R'Witflg-y 1 Pr 1 X R 2. deprotection/ R3 R Ar R3 R Arz cyclization R3 R Ar A3 A7 A8 NH2 R4 1. deprotection 2. reduction HND functionalization HNr> X1 R1 R =-NR13Rl4> NR12S02R13 - 4 V 12C 14, 12 3 14) or 11-NR (O) R-NR (C (O) NR' R reduction R Ar R

A9 A10 Those skilled in the art will appreciate that the stereoselective hydrogenation of the double bond of olefin A7 are can also be performed using a chiral hydrogenation catalyst such as chiral Rhodium catalyst which can provide chiral

ester A11. Deprotection of the protecting group (if Pr, Pr'are Cbz groups) under standard hydrogenation conditions followed by spontaneous cyclization will provide chiral amino-lactam A12. The reduction of the chiral amino-lactam A12 with reducing agents as LAH or LAH/AIC13, preferably, LAH/AtCts, provides chiral amino- pyrrolidines A13 which can further be functionalized using standard conditions to give N-substituted pyrrolidines A14. 0 0 H OMe H OMe PRNH H Stereoselective Pr'N Pr-N 1 hydrogenation Pr-N xl deprotection HN A7 A11 A12 R R Ar R R Ar R R A7 A11 A12 (P, P'= Cbz) NH2 R4 * R4=_NR13R14 _NR2SZRs, reduction functionalization' No iN vi ol HN xi Ri-NR 12C (O) R 14,-NR 12 (C (O) NR 13R14) 2X'r2 2X r2 R ArZ R R Ar2 A13 A14

Compounds having the formula 1, where n2 is 2, 3 or 4, may be prepared by conversion of the lactol A3 to carbon homologated derivatives A15 (n is 1,2 or 3) using routine chemistry known to those skilled in the art. Particularly useful reagents for this carbon chain homologation include : Wittig chemistry using methoxymethyl triphenylphosphonium bromide or an analogous reagent, cyanomethyl triphenylphosphonium bromide and Horner-Emmons protocols, and aldol chemistry. Hydrogenation and cyclization to the 6-, 7-and 8-membered lactams A17, respectively, and deprotection and reduction to the 6-, 7-and 8- membered substituted reduced lactams A18, are analogous to the previously described procedures. 0 0 R4 OMe Ph Fts --s OH H rrR z is 1, 2 or 3 .. R homologation H Witti Ar1 N X, Ri ON PrN Xl R'H n2R n2isl, 2or3 N A3 A15 A16 A3 A15 A16 R6 Ar1 R3 R1 R2 R6Ar1 R3 R1 R2 1. hydrogenation R7eX1tAr2 1-deprotectiOn R7_+X1tAr2 /X Ara 2. c clization 2. R4 sat P 2. reduchon R4D$ (NH /5 0 n2is2, 3or4 R O n2is2, 30r4 A17 A18 Another method for preparing aldehyde A15 where R6, R7 = H involves Wittig homologation of lactol A3 to ethylene derivative A19 which upon hydroboration, preferably with 9-BBN, and subsequent oxidation provides aldehyde A20. 0 Ph O \ H H PH Wittig H 1 1. hydroboration XR--'Pr X RX_. Pr. ; N 1--Rl 10 Pr xl-R' Ar2 2. oxidation y R A3 A19 A20

Alternatively, compounds having the formula 1, where n2 is 2, and X1 is-O- can be prepared by means of transformation of ketone A21 to the sulfinamide using the appropriate sulfinamide (racemic or chiral) and titaniumisopropoxide, according to the protocol described in Cogan et al, Tetrahedron, 55,8883 (1999). The suifinamide A22 is then treated with a suitable allyl grignard reagent, followed by ozonolysis to provide the aldehyde A24. Those skilled in the art will recognize that addition of allyl grignard will provide A23 where R6, R7= H which can be further modified at the allylic position to incorporate functionalities from the definition of R6 and R7 using routine chemistry such as alkylation and hydroxylation. Wittig chemistry on aldehyde A24, followed by hydrogenation, deprotection and cyclization provides the lactam A26. Standard reduction of the lactam A26 provides the substituted piperidines A27, where n2 is 2. dz R' J%, XR R1, +SsN 1. allyl grignard 1 1 ozonolysis 1) ty R'30 Xl R 1 ON. A23 R3 R KA' ketone A21 sulfinamide A22 A23 R4 ° {/Rs o <tCO2Me R6 Ar1 R3 R1 R2 'R rR ! L S-NH F2 Wittig S-NH R 1. hydrogenation 2 1 1 1 1 r Ar 2. deprotection R3R A R3 R'Ar2 3. cyclization 0 2R5 H A24 A25 A26 R6 Ar1 R3 R1 R2 X Ar2 eduction R z a NH np is 2 A27 When X1 is as defined in the summary of the invention, the ketone A21 wherein X1 is an ether, thio or imino group may be prepared using several different

methods employing commercially available materials. Ketone A28 can be subjected to acylation (Q1 is -NH2, -OH or-SH), reductive amination (Q1 is -NH2), ether formation (Q'is-OH) by standard alkylation methods, thio ether formation (Q'is-SH) by standard alkylation methods, or esterification (Q'is-OH or- SH). Alternatively, the corresponding alcohol A29 can be oxidized to an aldehyde and treated with an aryl or heteroaryl organometallic reagent, followed by oxidation to give ketone A21. o o Standard Conditions xi Ri 1. oxidation Xi A/"Y-acylation-Arl/, Y-'2X HO R3 red amination R 2. Ar M R3 R Ar2 ether formation ketone A28 thio ether formation ketone A21 alcohol A29 Qr is-OH,-SH or-NH2 esterification Another method for preparing ketone A21 involves nucleophilic displacement of a leaving group, such as-Cl,-Br,-I,-OMs and-OTf, adjacent to the aryl or heteroaryl ketone, for example, see WO 01/44200 (2001), which is incorporated herein in its entirety by reference. Accordingly, a suitable substituted styrene or heteroaryl epoxide may be opened with the appropriate nucleophile to give the desired X1 : 0 0 1. Nu p R'R"2. oxidation ketone A30 ketone A21 epoxide A31 Q2 is a leaving group, such as -Cl,-Br,-I,-OMs and-OTf Compounds having the formula I where n2 is 2 and R4 or R5 is -NR13R14, -NR12SO2R13, -NR12C(O)R14, or -NR12 (C (O) NR13R14) can also be prepared from aldehyde A15 using the chemistry as described earlier for the pyrrolidine compounds (n2 = 1). H 0 H O Ru ,, \R' , 6 Ar'R'R'R' H n2R R6 R 1 2 H iX n2 is 1 HSn2is 1 1. hydrogenation R7g3xR15<RAr2 r2 IN Xl R'2. cyclization PrN Pr "A RAr H o"2is2 A15 A32 A33 s ArR3 R R s ArR3 R Ra 1. deprotection R R, R7 R 2. reduction R vX1tAr2 functionalizatjon R7+X1tAr2 NH NH R4 =-NR3R14,-NRZSO Ft3, nz is 2 R np is 2 2 reduction AS4 AS5-NC (0) R,-NR (C (0) NRR)

Those skilled in the art will appreciate that the stereoselective hydrogenation of the double bond of olefin A32 can also be performed using a chiral hydrogenation catalyst such as chiral Rhodium catalyst which can provide chiral ester A36. The chiral ester A36 can be converted to chiral functionalized amino-piperidine compounds A39 using the chemistry as described earlier for the chiral functionalized amino-pyrrolidine compounds (n2 = 1). H 0 H 0 Pr'N OMe Pr'N-OMe J 6 t'Y* s R6 ArR n2R7 n2 is 1hydrogenation n2R 7n2 is 11. hydrogenation-2"'-X' , R R 2. cyclization H't Ar1 t3 R% Ar2 Ar1 R3 R2 Ar o n2is2 A32 A36 A37 (if Pr, Pr'are Cbz) s Ar1R3 R1 R2 R6 Ar1R3 R1 R2 reduction R 7 xl Y'Ar2 functionalizafionR7tn4'-xl '-Ar2 * NH na is z , NH R4 = _NRl3Ra, _NRtaS2Rs nz is 2' ASS A39-NRC (0) R,-NR (C (0) NR"R) Those skilled in the art will appreciate that homologation of the aldehyde A15 followed by subsequent synthetic operations as described above will result in the cyclic reduced lactams, where n2 is 3 or 4.

Another method of preparing compounds having the formula 1, where n2 is 2, and X1 is-O-, involves the alkyation of amine derivative A40 with a suitable substituted allylic halide, preferably a 2-substituted allylic bromide, to bis olefin A41.

Treatment of the bis olefin A41 with Grubb's or Schrock's cati ! pst using standard olefin metathesis conditions provides the unsaturated piperidine derivative A42.

Deprotection of the nitrogen and hydrogenation provides the six-membered cyclic reduced lactams or substituted piperidines A43. If the protecting group (Pr) on the nitrogen is Cbz, then it might cleave under hydrogenation conditions. Those skilled in the art will appreciate that alkylation of amine A40 with an appropriate substituted alkyl halide of 4 to 5 carbon atoms in length containing a terminal olefin, followed by subsequent synthetic operations as described above will result in the substituted cyclic reduced lactams, where n2 is 3 or 4. Ra rua R' Ruz Pr-NH R 1 alkylation Pr-N R Grubb's cat. pr-N X R Ar1<3 R'Arl Vl D Ar 3 R 2) A Arl 2, x or r2 A40 A41 A42 4 1. deprotection _-Rs-- z 2. hydrogenation HN X R' Ar'*T X 7 R3 RAr2 A43

When R4 = COOCH3, the chemistry as described above provides A46 where ester group could be further transformed to other functional groups such as amide (R4 = CONR13R14) and alcohol (R4 = CH20H) using standard chemistry. In addition, the piperidine A46 can be further functionalized using chemistry such as alkylation followed by deprotection of the nitrogen, if necessary, to provide substituted piperidines A47. COOCH3 COOCH3 R% R% rR' R67 R6 6 Ar1 alkylafion Pr I Di Pr- N V Ar * R3 R2 <Ar2 Ar * R3 Ra <Ar2 Rs R Ar A40 A44 A45 COOCH3 R4 pS R 6 1. funcfionalization R67 7 4 F hydrogenation IX R 2. deprotection (if necessary) HN X R Ar IT (At *T ( R 3R 2 r2 R3 2X r2 A46 A47

Another method of preparing compounds having the formula (I), where n2 is 1, X1 is-O-and R4 is-OH,-O-(C1-C6 alkyl),-O-(C3-C8 cycloalkyl),-O-(C1-C6 alkyl)- (C3-C8 cycloalkyl),-OC (O) R14, or-OCONR13R14, from lactol A3 involves Wittig chemistry to provide the corresponding olefin ester A48. Hydrogenation of the olefin ester A48, followed by reduction to the alcohol using metal hydride reducing agents, preferably LiBH4, and subsequent oxidation, such as Swern or bleach, gives aldehyde A50. The cyclization of aldehyde A50 provides enamide A51 which upon hydroxylation, preferably using a borane gives alcohol A52. The alcohol A52 can be oxidized under standard oxidation conditions such as Swern oxidation to give ketone A53. Treatment of the ketone with a suitable organometallic reagent provides the tertiary alcohol A54. For instances where the desired R5 substituent cannot be

incorporated directly with an organometallic reagent, further functionalization at the R5 position may be necessary. The hydroxyl group of alcohol A54 can be further functionalized using standard chemistry followed by deprotection to give disubstituted pyrrolidines A55. Alternatively, the further modification of the secondary alcohol A52 under standard conditions and deprotection of the nitrogen provides the monosubstituted pyrrolidines A56. 0 0 OMe OMe Ph Phfo Wittig H \ hydrogenation H Pr'N OH 1 Pr N H R Fr N X R X R R3R A 3 A3 O A48 A49 H 1. reduction H cyclization PrNXi Ri hydroxylation - -°r-N-- = 2. oxidation R3R"Ar Ar R3 R2XAr2 A50 A51 OH, 0 OH R pr. N v, oxidation-N 1 ol 1. RM N VI El r V 0, Pr' Aj T A-. Ar T \-. 2. functiona !) zation. 1)'\, R R of R R A52 A53 A54 1 functionalization 1 functionalization 2. deprotection 2. deprotection or deprotection « For deprotection Ra Ra R4 R4 un xi RUZ HN) (1 Dl A56 Ar R3 R As" A55 R4=-0-alkyl,-0-cycloalkyl,-0-alkyl-cycloalkyl, R4=-0-alkyl,-0-cycloalkyl,-0-alkyl-cycloalkyl, - OC (O) R4,-OC (O) NR3R14,-OH-OC (O) R4,-OC (O) NR3R14,-OH Compounds having the formula 1, where n2 is 2, X1 is-O-and R4 is-OH, -O-(C1-C6 alkyl),-O-(C3-C8 cycloalkyl),),-O-(C1-C6 alkyl)-(C3-C8 cycloalkyl), - OC (O) R'4 or-OCONR'3R14, can be prepared from lactol A3. Wittig chemistry followed by hydrogenation and cyclization in weakly acidic conditions such as p- toluenesulfonic acid provides the enamide A59. Using the synthetic operations as described above from the enamide A51, the enamide A59 will result in the disubstituted piperidines A63 and monosubstituted piperidines A64. r Ph 00 00. )-0 OH Wittig hydrogenation cyclization N p lb-im--N Ri H R3 R Ar Pr'Pr'R A3 Ar 3R A Ar 3 R Ar2 A59 HO A57 O A58 Rs __. _-HO hydroxylation oxidabon 1. RM XR1 rN XR1 2. functionalization Ar 3 ; 2 Ar 3'R2<Ar2 Ar A50 A61 A62 1. functionalization 1. functionalization 2. deprotection 2. deprotection or deprotection R"4 R' n2=1 z= PrN'n2 X R1 PrN Ar 3 Ar Ar R 3R Ar Rs R Ar Rs R Ar A64 A63 R4 =-O-alkyl,-O-cycloalkyl,-O-alkylcycloalkyl, R4 =-O-alkyl,-O-cycloalkyl,-O-alkylcycloalkyl, -oC (o) R14,-oC (o) NR13R14.-OH. oC (o) R14,-oC (o) NR13R14,-OH

Those skilled in the art will appreciate that homologation of the lactol A3 to the aldehyde A15 where n2 is 2 or 3 followed by subsequent synthetic operations as described above will result in the monosubstituted cyclic amines A64 or disubstituted cyclic amines A63 where n2 is 2 or 3.

The compounds having the formula 1, where n2 is 1,2, 3 or 4, X1 is-O-and, R4 and R5, together with the carbon to which they are both attached, form a chemically feasible 5 membered ring can be prepared from corresponding ketones.

The ketone A65 is transformed into the corresponding hydantoin A66 by heating with KCN/ammonium carbonate in ethanol/water mixture or by using alternate standard conditions known to those skilled in the art. The amine is deprotected to give hydanotin A67 which can be converted to corresponding urea analogs A68 by reduction preferably with LAH/AICI3. Alternatively hydanotin A66 can be cleaved to amino-acid A69 using the protocol described in Kubik, S.; Meissner, R. S.; Rebek, J.

Tetrahedron Lett. 35,6635 (1994). Standard protection of the amino-acid A69 as a carbamate derivative (Pr') is followed by activation of the carboxylic acid. Treatment with phosgene or a phosgene equivalent, preferably triphosgene, is one such method for acid activation. The reduction of NBoc-UNCA A71 with reducing agents, preferably lithium borohydride, gives alcohol A72 which can be converted to five

membered cyclic compounds such as carbamate A73 by intramolecular cyclization (if Pr'is carbamate protecting group such as Boc) using base, preferably NaH, followed by deprotection. Alternatively, alcohol A72 can be oxidized to NBoc- aldehyde A74 by standard oxidation conditions such as Swern oxidation and using the routine chemistry known to those skilled in the art. The NBoc-aldehyde A74 can be converted to cyclic analogs such as the y-lactam A75. 0 0 0 0 HN NH HN NH HN NH npis1, 2, 3or4 \ N is N) pur 3 or 4) 0 deprotecbon 0 reduction Pr n'7 ( Ri Pr n ? 7C R I-IN t R1 XY, '7C R 1 2\ 1 2\ 1'\ 1 I 2\ Ar s R Ar'° 3 R A Ar 3 2 Ar s R A hydantoin R R A65 hydrolysis A66 A67 A68 O li HN OH Pr'-NH PH Pr--N 0 0) 0 0 n n Pr 1 N-Protection N n P 9 N - N'\f nz R Pr 27C R -Pr, 'X R-- Ar R3 R A Ar Rs R2 A Ar Rs R Ar A69 A70 A71 0 Prw NH OH Pro NH ° HN) % standard '\) oxidation'\) H transformation'\) Pr-R'Pr-n2X R' Ar R3 R2Ar2 Ar 3f'2 r2 r A72 A74 A75 l. NaH 2. deprotection 0 HN O n2 is 1, 2, 3 or4 Han iT X R Ar1 R3 R2 Ar2 A73

The compounds having the formula 1, where n2 is 1,2, 3, or 4, X1 is-O-and R is -NR13R14, -NR12SO24R13, -NR12COR14, -NR12C(O)OR13, or -NR12 (CoNR13R14), and R5 is-C (o) NR13R14 can be prepared by amidation of amino-acid A69 to give amino-amide A76 followed by functionalization of amino group and deprotection to provide disubstituted analogs A77. Alternatively, the NBoc-amino-acid A70 can be reacted with an amine, followed by deprotection of N- Pr'group to give amino-amide A76. The amino-amide A76 can also be deprotected to give analogs A78 where R4 is-NR13R14 and R13, R14 = H. H2N OH H2N NR13R14 R4 npis1, 2, 3or4 RS Pr-N) n 0 amidaflon-N 0 1. functionalization HN) n ) n) n ) n R3 R Ar Rs F2 Ar2 R3 R Ar A69 1. amidation A76 A77 2. deprotection/R4 =-NR13R14,-NR12SO2R13,-NR12CoR14, Pr'-NH OH deprotection-NR 12C (O) OR 13,-NR 12 (CONR 13R14) 13 14 R5-C (O) NR R 0 R 4 PrN n ( R R 5 R np is 1, 2, 3 or 4 Ar'R3 Rp, y.. pJ >nai A70 sq2X' X R'=-NRR"where R", R"= H Ar R3R A R5-C (O) NR R A78

Another method of preparing compounds having the formula 1, where n2 is 1, 2,3 or 4, X is-O-and R4 is -NR13R14, -NR12SO2R13, -NR12COR14, -NR12C(O)OR13, or -NR12(CONR13R14), involves treatment of ketone A65 with a protected amine under appropriate conditions to provide imine A79. Nucleophilic addition of compatible organometallic reagents such as grignard or reduction (if R5 = H) of imine A79 followed by deprotection of nitrogen (N-Pr') provides amine A80.

The functionalization of amine A80 under standard conditions and deprotection of nitrogen provides the substituted pyrrolidines A81.

Pr' 1. R5M NH2 nz is 1, 2, 3 or 4 p RS Pr, ! S) R5 NH2P'reduction A65 A79 A80 Ruz R R -<--R rua Rus 1. functionalization n2 is 1, 2, 3 or 4 --- 2. deprotection X R =-NR13R14,-NR12S02R13. Ar R3 R2 Ar2 NR12coR14-NR12C (o) oR13l-NR12 (CoNR13R14) A81 The compounds having the formula 1, where n2 is 1,2, 3 or 4, X1 is-O-, R5 is H, and R4 is a heterocyclic or heteroaryl group can be prepared by conversion of ketone A65 to nitrile A87, aldehyde A82 and a carboxylic acid A85 via aldehyde A82 using the standard oxidation conditions. Those who are skilled in the art will appreciate that the cyano, aldehyde and carboxylic acid compounds can provide the appropriate heterocyclic or heteroaryl functionality using standard chemistry. H Con 0 O r zis1, 2, 3or4 \/$ 0 rr is1, 2, 3or4 rr is1, 2, 3or4 pr-N) 1 1 NC Wittig i -' Ar Rs R Ar base p, ri Rs R A Ar Rs R Ar A87 A65 A82 oxidation 2. deprotection H-2 py I cri ''HO r c ! cl O NH n2 is 1, 2, 3 or4 H CO2Et ZON zon Pr ci n2 is 1, 2, 3 or 4 n2is1, 2, 3or4 1'\ Pr' R 2X r2 n2, 1 Ar Rs R A R r 1. EDC, NH2NHCONH2 A83 A88 2. cyclization 3. deprotection 1. NH2NH2 12. deprotection HN° i ION , N O NH nzis1, 2, 3or4 m) n2is1, 2, 30r4 X Pr-N) n Ar Ps R Ar A86 Ar R3 R2 Ar2 A86 AM P" A84

Another method of preparing the compounds having the formula 1, where n2 is 1, 2,3, or 4, X1 is-O-, R5 is H, and R4 is a heterocyclic or heteroaryl group involves conversion of the ketone A65 to a vinyl triflate A89 by using a base such as LDA and triflic anhydride as an electrophile. The triflate A89 could be coupled with suitable organometalic reagents, preferably boronic acid, to give heterocyclic or heteroaryl unsaturated compound A90. The reduction of the double bond followed- by deprotection of the amine (if necessary) provides heterocyclic or heteroaryl substituted cyclic amines A91. O OTf R4 n2 is 1, 2, 3 or 4 Pr N X R 1. bPr Nr (1 R R4B (OH) 2 r-N) n I Ri ri) r4i-) r4li-) A65 4 A89 A90 R4 A65 A89 A90 R n2 is 1, 2, 3 or 4 1. reduction 2. deprotection 1 R'R4=-heterocyclic or heteroaryl A R A91

The compounds having the formula 1, where n2 is 1,2, 3, or 4, X'is-O-and R4 is -C(OR12)(R13)(R14), where R14 is H, or-C (=NOR14) (R13) can be prepared by conversion of aldehyde A82 to an alcohol A92 via addition of an organometallic reagent. The alcohol A92 can be transformed to analogs such as A93 or it can be oxidized to ketone A94 which can provided analogs such as oxime A95 using the standard conditions. H R13 R13 0 OH 0 n2is1, 2, 3or4 RM nyis1, 2, 3or4 npis1, 2, 3or4 oxidized Pr, R'Pr Dl pr R 1 Ar R3 Rz Ar2 Ar R3 Rz Ar2 Ari R3 RAr2 A82 A92 A94 1. functionalization 1. NH20R 2. deprotection 2. deprotection 3 R13 ORiz NORA nzis1, 2, 3or4 n2is1, 2, 3or4 H N4) n, R'H N R 1 2 r2 r R R 3 R A93 A95

The compounds having the formula i', where n2 is 1,2, 3 or 4, X1 is-0-, R5 is H, and R4 is -C(R28R29)CONR13R14, where R28, R29 = H or methyl, can be prepared by conversion of ketone A65 to unsaturated ester A96 using Wittig chemistry.

Hydrogenation of the double bond and deprotection of the protecting group, if necessary, provides the ester A97. Conversion of the ester to amides A98 can be realized through treatment with amines, or transformation to the acid and subsequent coupling with amines using standard methods. In addition, the unsaturated ester A96 can also provide compounds where R4 and R5, together with the carbon to which they are attached, form a five membered cyclic ring such as lactam A100. MeO2C MeO2C 0 Wittig or n2 is 1, 2 or 3 hydrogenation n2 is 1, 2 or 3 Horner-Em deprotection Pr'N n ( R PrN ' ( R1 hiN a7C R "'Ar2 3 R2 r2 2 r2 Au R 3 R Ar R r R 3 R A65 n2 is 1, 2 or 3 A96 A97 NR'3R 14 nitromethane or 1. hydrolysis, H r r 2. NR13R14 1. hydrogenation NOZ 3RaFtNOC deprotection n2 is 1, 2 or 3 E CyCIIZatI0f1 ny is 1, 2 or 3 n2 is 1, 2 or 3 Pr-Pr N 2Xl Ri HN2VI Cl Ar1 2 2 2 Ar 2 r2 R R3 R Ar R3 R Ar2 R A R2\, 2 A/R2\, 2 A100 AM A98

Those skilled in the art will appreciate that functionalization of the nitrogen of cyclic ring formed by R4 and R5 when R4 and R5 together and to the carbon to which they are attached form cyclic rings such as hydantoin A67, urea A68 and lactam A100 may be performed at an appropriate point in the synthesis by deprotonation with a suitabie base and reaction of the necessary electrophile to provide the substitutents defined for R35. Those skilled in the art will appreciate that a substituted alkyl halide will afford the corresponding substituted Cl-C6 alkyl group and treatment with tetra benzyl pyrophosphate, followed by hydrogenation will serve to provide for R35 =-P (O) (OH) 2.

Functionalization of the reduced lactam nitrogen can be performed at an appropriate point in the synthesis by deprotonation with a suitable base and reaction of the necessary electrophile to provide the substitutents defined for R18. Those skilled in the art will appreciate that a substituted alkyl halide will afford the corresponding substituted Ci-Ce alkyl group and treatment with tetrabenzylpyrophosphate, followed by hydrogenation will serve to provide for pis =-P (O) (OH) 2. R6 Arl R3Ri R2 R6 Ari R3Ri R2 6 Ar'R'R. R' 6 Ar P'RR' R - R electrophile A101 A102 Those skilled in the art will recognize that certain additional protection and deprotection steps may be needed in order to accommodate different functional groups. Accordingly, the order of synthetic operations may be different in order to maintain functional group compatibility with the operational steps in the synthesis. Specific Methods Of Preparation-Examples Example 1a Example 1b Step 1: Compound 1 Compound 1 was prepared using a synthetic procedure reported by M. J.

O'Donnell, Z. Fang, X. Ma and J. C. Huffman, J. Am. Chem. Soc. , 1997,46, 617.

Step 2: KHMDS, THF I CF3 O _7g C p CbzN) F C ^ CbzN .", _ Y& Compound 1 f T <s8%) < ( Compound 2 L-I CF3 To a nitrogen purged solution of oxazolidinone Compound 1 (10.0g, 0. 027mol, 1 equiv) in THF (500ml) at-78 °C, a solution of KHMDS (0.5M in toluene, 64ml, 0. 032mol, 1. 18equiv) was added. After stirring at-78 °C for 30 min, a solution of bromomethyl ether (11.3g, 0. 032mol, 1.18equiv) in THF (100ml) at-78°C was cannulated into the reaction mixture. The solution was stirred at-78°C for 1 h before being quenched with a saturated NH4CI solution at-78°C. The reaction mixture was warmed to RT, and water and EtOAc were added. The aqueous layer was extracted with EtOAc (200moi x 2). The combined organic layers were dried (MgS04) and filtered, and solvents in the filtrate were removed by vacuum.

Purification using column chromatography [hexane-toluene, 1: 1 (v/v)] gave Compound 2 (11.7g, 68%) as a colorless oil.

Electrospray MS [M+1] +644. 1. Step 3 : CF3 LiAIH4, Et2O 9 OH A UA ! H,. Et, 0 "roH Compound 2 °°' (87%) CF3 Compound 3

To a solution of lactone Compound 2 (35.2g, 0. 055mol, 1equiv) in Et20 at 0°C, a 1M solution of LAH (17. 8ml, 0. 018mol, 0.32equiv) in Et20 was added. The reaction mixture was stirred at 0°C for 30 min before being quenched with saturated NH4CI solution. Water was added and the resulting layers were separated. The separated aqueous layer was extracted with EtOAc (300ml x 2), and the combined organic layers were dried (MgS04), and filtered. Solvents in the filtrate were removed in a vacuum to give a colorless oil. The oil was dissolved in HOAc (240ml) at RT, and water (60ml) was added. After being stirred at RT for 1 h, the white solid was filtered, washed with water and dried under a high vacuum. Recrystallization [hexane-toluene] gave Compound 3 (23g) as a white powder. All filtrates were combined, and the solvents removed in a vacuum to give a yellow oil. The above procedure [HOAc-H20, followed by recrystallization] was repeated to give another batch of lactol Compound 3 (3g). Solvents in the filtrate were removed in a vacuum, and the resulting oil was subjected to column chromatography [hexane- EtOAc, 6: 1 (v/v) ] to give a third batch (4g). The combined yield for Compound 3 was 30g, 87%.

Electrospray MS [Ms1] + 646. 2.

Step 4: 0 C02Me CF3 (MeO) PYCOMe gocHN- NHBoc DBU, CH2CI2 o I-CF3 Compound 3 r. t.-- (42%) \y Compound 4 To a solution of Compound 3 (0.98g, 1. 52mmol, 1 equiv) and NBoc-O- phosphonoglycine trimethylester (1.26g, 3. 80mmol, 2.5equiv) in CH2CI2 (5ml) at 23°C, DBU (0. 57mi, 3. 80mmol, 2.5equiv) was added dropwise. The mixture was stirred at 23°C for 4 h before it was quenched with saturated NH4CI solution. Et20 was added and layers were separated. The separated aqueous layer was extracted with Et20 (250ml x 2). The combined organic layers were dried (MgS04) and filtered. Removal of solvents in vacuum followed by chromatographic purification [hexane: ether, 3: 1 (v/v) ] gave Compound 4 (587mg, 52%) as white foam.

Electrospray MS [M+1] +745. 1.

Step 5: NH2 CF3 1. 10% Pd/C, H2 0 s EtOAc HNi"O+CF3 Compound 4 Fs 2. TFA, CH2Cl2 Compound 5 A solution of Compound 4 (1.4g, 1. 88mmol, 1. Oequiv.) in EtOAc (30ml) was flushed with N2. After the addition of Palladium on carbon (10%, 2g) a H2 balloon

was attached to the reaction flask. The reaction mixture was stirred for 18 h at 23°C under H2 atmosphere and then filtered and concentrated. The residue was dissolved in anhydrous CH2CI2 (45ml), cooled to 0°C, then treated with TFA solution (4. 5ml, 0. 059mmol, 30. Oequiv). The reaction mixture was stirred at 0°C for 30 min and then at 23°C for another 4 h. Reaction mixture was diluted with CH2CI2 (300ml) washed with saturated NaHC03 solution (100ml). The organic layer was dried (Na2SO4), filtered and concentrated to give Compound 5 (0.8g, 95%).

Step 6: NH2 CF3 LAH/AICI3 Compound 5 o">O CF3 _CFs 90%' Compound 6 In a flame dry 25ml RBF was placed AICI3 (0.089g, 0. 67mmol, 1.5equiv).

The reaction flask was cooled to 0°C and 1 M solution of LAH in Et20 (2ml, 1. 98mmol, 4.5equiv) was carefully added. The reaction mixture was cooled to-78°C and a solution of Compound 5 (0.2g, 0. 44mmol, 1. Oequiv) in dry THF (4ml) was slowly added. The reaction mixture was stirred at-78°C for 2 h, then slowly warmed to 23°C and stirred for 18 h. The reaction was then cooled to 0°C and quenched carefully with saturated aqueous sodium potassium tartrate solution. Reaction mixture was taken up in EtOAc (200ml) and extracted with saturated aqueous NaHC03 (100ml). Aqueous layer was extracted with EtOAc (150ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to give Compound 6 (180mg, 95%). Electrospray MS [M+1] + 433.1.

Step 7: To a solution of Compound 6 (0.21g, 0. 486mol, 1. Oequiv) in MeOH (3ml) at 0°C was added 2-trifluoromethyl-N, N-diacetylaniline (0.131g, 0. 535mmol, 1.1 equiv). The mixture was stirred at 0°C for 1 h, then warmed to 23°C and stirred for 18 h. The reaction mixture was then concentrated and purified using a Gilson with water/CH3CN to give a mixture of two compounds (0.16g). Purification of the mixture by HPLC using ChiralPak column (98: 2, hexane: lPA) gave less polar isomer Example 1 a (0.050g, 22%), Etectrospray MS [M+1] + 475.1, and more polar isomer Example 1 b (0. 015g, 7%), Electrospray MS [M+1] + 475. 1.

Preparation of Compound 9: Compound 9 Step 1 : Compound 7 Compound 7 was prepared using a procedure similar to that for Compound 4, using Compound 3 and PO (OEt) 2CH (NHCbz) CO2Me in place of PO (OMe) 2CH (NHBoc) CO2Me. Electrospray MS [M+1] + 745.1.

Step 2: CQZMe CbzHN/"g 3 Pd (OH) 2/C, H2 Rh (l)-S, S-EtDuPHOS CbzHN ß Pd (OH) 2/C, H2 Compound 7 > 2 zOv CF3 MeOH CF Compound 8 Compound 7 (3. 0g, 4. 03mmol, 1. Oequiv) was taken in MeOH (30ml) in a parr reaction bottle. The reaction bottle was degassed using N2 for 15 min. (+)-1, 2-Bis- ( (2S, 5S) -2, 5-diethylphospholano) benzene (cyclooctadiene) rhodium (l) trifluor- methanesulfonate (0. 12g, 0. 16mmol, 0.04equiv) was added to the reaction mixture in a glove box, and shaken under H2 at 60 psi for 96 h. The reaction mixture was transferred to a 200 ml RBF. 20% of Pd (OH) 2/C (1g) was added to the reaction mixture, which was stirred under H2 at 23°C for 18 h. The reaction was monitored by TLC 9/1 EtOAc/CH30H. Once the reaction was completed it was filtered through celite and concentrated. Purification was carried out using a silica plug 9: 1 EtOAc/MeOH (NH3) to give the Compound 9 (1.3g, 72%).

Electronspray MS [M+1] + 447.1.

Preparation of Compound 10: Compound 10 Compound 10 was prepared using similar procedure to Compound 6, using Compound 9 instead of Compound 5.

Example 2

To a solution of Compound 10 (0.05g, 0. 116mmol, 1. Oequiv) in MeOH (2ml) at-78°C was added cyclopropanecarbonyl chloride (1201, 0. 127mol, 1. 1equiv).

The mixture was stirred at-78°C for 5 min, then warmed to 23°C and stirred for 18 h. The reaction mixture was then concentrated and taken up in EtOAc (200 ml) and washed with sat. aq. NaHC03 (1 x 100ml). The organic layer was dried over Na2SO4, filtered and concentrated. Purification of the resulting mixture on a Biotage with 5% MeOH/ EtOAc gave Example 2 (0.04g, 69%). Electrospray MS [M+1] + 501.

Example 3 owt CAF 3 HN I i po step 1 : 0 0= C-L CF Step1 : - i MeOH HN.,, p I _CF3 Compound 11 To a solution of Compound 10 (0.05g, 0. 116mmol, 1. Oequiv) in MeOH (2ml) at-78°C was added 4-chlorobutyryl chloride (14µl, 0. 127mmol, 1. 1equiv). The mixture was stirred at-78°C for 5 min, then warmed to 23°C and stirred for 18 h.

The reaction mixture was then concentrated and taken up in EtOAc (200ml) and washed with sat. aq. NaHC03 (1 x 1 00ml). The organic layer was dried over Na2SO4, filtered and concentrated to provide the crude Compound 11, which was used in the next reaction without further purification.

Step 2: To a solution of crude Compound 11 in dry THF (2ml) was added NaH (60% dispersion in mineral oil, 0. 014g, 0. 347mmol, 3equiv) at 0°C and stirred for 5 min,

then heated at 60°C for 2 h. The reaction mixture was cooled to 0°C and quenched carefully with water (3ml). The mixture was poured into EtOAc (100 ml) and washed with saturated aqueous NaHC03 (100ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. Purification of the resulting mixture on Biotage with 5% MeOH/EtOAc gave Example 3 (0.20g, 34%).

Electrospray MS [M+1]+ 501.1.

Example 4

Example 4 (53% overall yield) was prepared from Compound 10 in a manner similar to that used to prepare the Example 3, but using 5-chlorovaleryl chloride in place of 4-chlorobutyryl chloride. Electrospray MS [M+1] + 515.1.

Example 5 4 Õ ° CF3 HN-S=O CF3 O xi / . 11 in / / HN-S--CF P-> o 0 i-Pr2EtN, CH2C12 $ ° CF3 han. 11 1 /YCF3 Compound 12

To a solution of Compound 9 (0. 13g, 0. 29mmol, 1. Oequiv) in CH2CI2 (3ml) at 0°C was added DIEA (0. 11 ml, 0.61 mmol, 2. 1 equiv) and CH3SO2CI (34p1, 0. 435mmol, 1.5equiv). The mixture was stirred at 0°C for 30 min, then poured into EtOAc (150mut) and washed with saturated aqueous NaHC03 (100moi). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to provide the crude Compound 12, which was used in the next reaction without further purification.

The crude Compound 12 was converted to Example 5 (80mg, 54% yield, two steps from Compound 9) using a method similar to the preparation Compound 6 from Compound 5. Electrospray MS [M+1] + 511.1.

Example 6a and Example 6b N-CF N-CF N N HN CF3 C CF3 id Example 6a Example 6b Step 1 : oE oE N CF3 N CF3 2M AlMe3 0 0 Compound 5 OEt HN, p I HN Br-*, ^ OEt y/1-0 CF3 0 CF3 ° Compound 13a Compound 13b To a solution of amino-lactam Compound 5 (0. 1 OOg, 0. 224mmol, 1equiv) in toluene (7ml) at 0°C, was added a solution of 2M AlMe3 in toluene (0. 14moi, 0. 28mmol, 1.25equiv). The reaction mixture was warmed to RT and stirred for 15 min. Ethyl 4-bromobutyrate was added, and the resulting mixture was heated at 100°C for 18 h. The reaction mixture was cooled to RT, poured into EtOAc c (20ml), and washed with of saturated aqueous NaHC03 (100moi) and saturated aqueous NaCI (100ml) successively. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. HPLC separation on ChiraiCel OD column using a (90/10) hexane/IPA mixture gave the Compound 13a (40mg, 35%), and the Compound 13b (20mg, 18%).

Electrospray MS [M+1]+ 515.1 for the Compound 13a.

Electrospray MS [M+1] + 515.1 for the Compound 13b.

Example 6a and Example 6b were prepared using a procedure similar to Compound 6, using Compound 13a and 13b instead of Compound 5.

Electrospray MS [M+1 ]+ 487. 11 for the Example 6a.

Electrospray MS [M+1]+ 487.11 for the Example 6b.

Example 7

Example 7 (74% overall yield) was prepared from Compound 10 in a manner similar to that used to prepare Example 29 from Example 13.

Electrospray MS [M+1] + 476. 1.

Example 8 Example 8 (94% overall yield) was prepared from Compound 10 in a manner similar to that used to prepare Example 33 from Example 13.

Electrospray MS [M+1] + 430.1.

Example 9 Example 9 (50% overall yield) was prepared from Compound 10 in a manner similar to that used to prepare Example 36 from Example 13.

Electrospray MS [M+1] + 502.1.

Example 10

To a solution of Compound 10 (0.15g, 0. 3mmol, 1 equiv) in CH2CI2 (2ml) was added methyl levulinate (0. 041ml, 0. 33mmol, 1. 1equiv) followed by sodium triacetoxyborohydride (0.127g, 0. 6mmol, 2equiv. ) and the reaction mixture was stirred at 23°C and stirred for 72 h. The reaction was quenched with saturated aq.

NaHC03 (100ml) and extracted with EtOAc (200ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated. The mixture was purified by chromatography over Gilson (1: 9, water: CH3CN) to give the title compound (0.070g, 47%). (Electrospray MS [M+1] + 515. 1.

Example 11 H2N CF3 / -O-YCF Step 1 : . CFs Step 1 : CF3 L OH F3C OH. CF3S22 O i I CH2CI2 CF3 Cl3 te compound 14 compound 15 Procedures for preparing Compound 14 and Compound 15 are shown in WO 01/44200.

Step 2: (R) tBUSvNH2 z", ßu CF3 S Compound 15 > 00-Up 0 N I Ti (OiPr) 4 CF3 56% v CF3 Compound 16 To a flask containing ketone Compound 15 (1.05g, 2. 8mmol, 1equiv) and (R)-t-butylsulfinamide (0.4g, 3. 3mmol, 1.8equiv), was applied a vacuum for 5 min.

Then, the flask was filled with N2. Ti (OiPr) 4 (1 ml) was added through a syringe dropwise to the reaction mixture. The reaction mixture was stirred at 23°C for 36 h.

The reaction mixture was then poured into brine (1 Oml) and EtOAc (20ml) and stirred vigorously for 10 min. The resulting suspension was passed through a pad of celite 545. The celite pad was washed with EtOAc several times. The combined organic solution was dried and concentrated under reduced pressure. Flash column chromatography afforded Compound 16 (0.75g, 56%).

Step 3: , tBu PhHN-S allylMgBr 0 Compound 16 CH2CI2 ON o 63% 0°C : 2 : 1 - 78 °C : 10 : 1 CF3 Compound 17

To a solution of sulfinimine Compound 16 (2.44g, 5. 1mmol, 1equiv) in CH2CI2 at-78°C, was added dropwise allylmagnesium bromide (6. 1 ml, 6. 1mmol, 1.2equiv, 1 M in Et20) through a syringe. After stirring for 3 h at-78°C, the reaction mixture was quenched with a saturated aqueous NH4CI and allowed to warm to 23°C. The layers were separated, and the aqueous layer was extracted with EtOAc.

The combined organic layers were dried and concentrated. Flash column chromatography gave Compound 17 (1.672g, 63%).

Step 4: , tBu Ph HN-S x \ 1. 03 0 0 Compound 17-- 2. TBAI < CF3 Compound 18 A 15ml RBF was charged with Compound 17 (245mg, 0. 47mmol, 1. Oequiv) and CH2CI2 (2ml). This pale orange solution was cooled to-78°C, and then 03 was bubbled in at 1.0 ml/min. After the solution turned pale blue, the reaction solution was stirred at-78°C for 10 min. Then it was flushed with N2 to get rid of 03.

Tetrabutylammonium iodide (177mg, 0. 47mmol, 1. Oequiv) was added to break the complex. Then it was quenched with saturated Na2S203, and extracted with CH2CI2.

The combined organic layers were dried, filtered, and concentrated, then re-taken up with Et20 and filtered. The residue on the filter was dissolved in water and extracted with Et20. The combined Et20 layer was dried, filtered and concentrated to give Compound 18 (243.5mg, 99%). Electrospray MS [M+1] + 524. 1.

Step 5: , tBu Ph HN-S NHBoc (MeOOPCOMe O-COe Compound ~t NHBoc Dû 50% (over two steps) Compound 19

To a solution of Compound 18 (1.2g, 2. 29mmol, 1. Oequiv) Boc-Phosphonate (818mg, 2. 75mmol, 1.2equiv) in DMF (20ml) was added Cs2CO3 (2.24g, 6. 87mmol, 3. 0equiv). After stirring at RT for 3h, the mixture was diluted with Et20, and washed with water (100mi 2 x), and brine. The combined aqueous layer was further extracted with Et20. The combined organic layer was dried, filtered and concentrated to give crude brownish oil, which was purified by column to give Compound 19 (830mg, 55%). Electrospray MS [M+1] + 695.2.

Step 6:

, tBu Ph HN-S O % 0 O G02Me Pd-C/H2 NHBoc < CF3 CF3 Compound 20 A solution of Compound 19 (830mg, 1. 19mmol, 1. Oequiv) in EtOH (20ml) was flushed with N2. After the addition of Palladium on carbon (10%, 1.27g, 1. 19mmol, 1. Oequiv), a H2 balloon was attached to the reaction flask. The reaction mixture was stirred for almost 24 h until TLC showed completion of the reaction. The mixture was filtered and concentrated to give Compound 20 as white solid (790mg, 95%). Electrospray MS [M+1] + 697. 2. Step 7: Ph NH2 N% 4M HCI C02Me Compound 20-NH2 vCF3 Compound 21

A solution of Compound 20 (400mg, 0. 57mmmol, 1. Oequiv) in anhydrous MeOH (4ml) was cooled to 0°C, then treated with 4 M solution of HCI in 1,4-dioxane (16ml). After 30 min at 0°C, it was stirred at RT for another 3 h. The solvent was evaporated under vacuum to give Compound 21 as pale brown solid. Electrospray MS [M+1] + 493. 1.

Step 8: 0 Ph HN -NH, zou NH2 o Compound z CF3 FsC Compound 22 To a solution of Compound 21 in MeOH (50ml) was added K2CO3 (4.5g).

The mixture was stirred for 30 min, then filtered and concentrated to give Compound 22 (199mg, 76%). Electrospray MS [M+1] + 461. 1.

Step 9: Aftame-dried 500m ! RBF was charged with ALCI3 (37.4mg, 0. 28mmol, 1.5 equiv). The reaction flask was cooled to 0°C and anhydrous THF (1 ml) was syringed in. After stirred for 5 min, 1 M solution of LAH in Et20 (0. 84moi, 0. 84mmol, 4.5 equiv) was cannulated in. The ice-bath was removed and the solution was stirred at RT for 30 min. Then the reaction mixture was cooled to-78°C and a solution of Compound 22 (50mg, 0. 187mmol, 1. Oequiv) in dry THF (1 mi) was slowly added. The reaction mixture was stirred at-78°C, and allowea to warm up to RT overnight. After TLC (MeOH/CH2CI2=1/9) indicated the reaction was completed, the reaction was then cooled to 0°C and diluted with EtOAc and quenched carefully with saturated aqueous sodium potassium tartarate solution. It was stirred at RT for over 30 min to get separation of the two layers. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated to give Example 11 (34mg, 41%). Electrospray MS [M+1] + 447. 1.

Example 12a and Example 12b o o HN CF3 HN CF3 HN O I HN, O f CF3 i CF3 Example 12a Example 12b

Step 1: To a solution of Example 11 (30mg, 0. 067mol, 1. Oequiv) in CH2CI2 (10mut) at 0°C was added ElEA(17.5µl, 0.10mmol, 1.5equiv) and Ac20 (6. 3µl, 0. 067mol, 1. Oequiv). The mixture was stirred at 0°C for 30 min. It was quenched with saturated aqueous NaHCO3 solution (4ml) and extracted with CH2CI2. The combined organic layers were dried, filtered and concentrated to give the crude product (39mg). Purification of the mixture by HPLC using ChiralPak AD column (2: 98, IPA : hexane) gave more polar isomer Example 12a, Electrospray MS [M+1] + 489.1, and less polar isomer Example 12b, Electrospray MS [M+1] + 489. 1.

Example 13 CF, ; CF3 w _CF3 Step 1 : PhsPCHgOMeCi KHMDS, Toluene 0°Cto r. t. Cbz ; HN caf3 Compound 3 then THF/10% aq. HC)/===\ t (1 : 1 v/v) Compound 23 r (61%) To a suspension of (methoxymethyl) triphenylphosphonium chloride (21. 3g, 0. 062mmol, 2.95equiv) in toluene (300mut) at 0°C under N2, a solution of potassium bis (trimethylsilyl) amide (125ml, 0. 062mol, 2.95equiv) was added. After being stirred at 0°C for 1 h, a solution of Compound 3 (13.4g, 0. 021mmol, 1equiv) in toluene (100ml) was added. The mixture was allowed to stir from 0°C to 23°C. in 1 h and then was quenched with saturated NH4CI solution. Et20 was added and layers were separated. The separated aqueous layer was extracted with Et20 (400ml x 2). The combined organic layers were dried (MgS04) and filtered.

Solvents were removed in vacuum to give crude enol ether as yellow oil.

The crude enol ether was dissolved in THF (100ml) at 23°C and aqueous HCI (100ml, 10% in water) was added. The mixture was stirred overnight and was quenched with saturated KHC03 solution. Et20 was added and layers were separated. The separated aqueous layer was extracted with Et20 (300mut x 2). The combined organic layers were dried (MgS04) and filtered. Removal of solvents in vacuum followed by chromatographic purification [hexane: EtOAc, 4: 1 (v/v)] gave Compound 23 (6.97g, 61 %) as yellow oil.

Step 2: 0 CbzHN MeO-p'SCO2Me CF3 Met C02Me M NHCbz CbzHN Compound 23 ON CF3 DBU, CH2C12 (72% over three steps)

Compound 24 was prepared from Compound 23 using a procedure similar to the preparation of Compound 4 from Compound 3 and using PO (OEt) 2CH (NHCbz) CO2Me in place of PO (OMe) 2CH (NHBoc) CO2Me.

Step 3: H2N CF3 O, 9Wo o CF3 w _CFs Compound 25 Compound 25 was prepared using a procedure similar to that for Compound 9 using Compound 24 instead of Compound 7. Electrospray MS [M+1] +461. 1.

Step 4: Example 13 (6.84g, 73%) was prepared using similar procedure to Compound 6 using Compound 25 instead of Compound 5.

Electrospray MS [M+1] +447. 1.

Example 14 To a solution of Example 13 (275mg, 0. 60mmol, 1. Oequiv) in anhydrous CH2CI2 (10mi) at-78°C was added propionyl chloride (52pL1, 0. 60mmol, 1. Oequiv).

The reaction was completed within 30 min. Reaction mixture was quenched with 7N ammonia in MeOH (0. 5moi), then loaded directly onto silica column and purified to give Example 14. (241.3mg, 80%). Electrospray MS [M+1] + 503.1.

Example 15

Example 15 (yield 89%) was prepared using similar procedure as for Example 14 using cyclopropanecarbonyl chloride in place of propionyl chloride.

Electrospray MS [M+1] + 515. 1.

Example 16 Example 16 (yield 89%) was prepared using similar procedure as for Example 14 using Example 13 and CH3SO2CI in place of propionyl chloride.

Electrospray MS [M+1] + 52. 1.

Example 17 Example 17 (overall yield 23%) was prepared using similar procedure as for Example 3 using Example 13 in place of Compound 10.

Electrospray MS [M+1] + 515.1.

Example 18

Example 18 (overall yield 42%) was prepared using similar procedure as for Example 4 using Example 13 in place of Compound 10.

Electrospray MS [M+1] + 529.1.

Preparation of Compounds 26, 27, 28 and 29: NH2 CF3 0 / . 11/--0 CF3 Compound 26 r Compound 26 was prepared from Compound 1 using similar procedure as for Compound 9. NH2 CF3 / HN, I 11 CF3 Compound 27 / Compound 27 was prepared using similar procedure as for Compound 10. H2N CF3 O/ 9 XCF3 Compound 28 s r Compound 28 (90% yield) was prepared using the similar procedure for Compound 25. Electrospray MS [M+1] + 447.1. H2N CF3 9 cl3 Compound 29 Compound 29 was prepared using similar procedure as for Example 13.

Electrospray MS [M+1] + 433. 1.

Example 19 Example 19 (40mg, 70% yield) was prepared using a procedure similar to Example 1a using Compound 27 instead of Compound 6.

Electrospray MS [M+1] + 461.1.

Example 20

Example 20 (99mg, 72%) was prepared using similar procedure as for Example 1a using Compound 29 instead of Compound 6.

Electrospray MS [M+1] + 475. 1.

Example 21 Example 21 (74mg, 66%) was prepared from Compound 29 using similar procedure as for Example 2 from Compound 10 using propionic anhydride in place of cyclopropanecarbonyl chloride. Electrospray MS [M+1] + 489.1.

Example 22 Example 22 (75mg, 78%) was prepared from Compound 29 using similar procedure as for Example 2 from Compound 10 using isobutyryl chloride in place of cyclopropanecarbonyl chloride. Electrospray MS [M+1] + 503.1.

Example 23 Example 23 (9mg, 35%) was prepared from Compound 29 using similar procedure as for Example 2 from Compound 10. Electrospray MS [M+1] + 501.1.

Example 24

Example 24 (31 mg, 71 %) was prepared from Compound 29 using similar procedure as for Example 3 from Compound 10. Electrospray MS [M+1] + 501. 1.

Example 25 Example 25 (68mg, 68%) was prepared from Compound 29 using similar procedure as for Example 4 from Compound 10. Electrospray MS [M+1] + 515.1.

Example 26 To a solution of Example 13 (0.14g, 0. 314mmol, 1equiv) in anhydrous DMF (1. 6ml) at 23°C was added N, N-dimethyl glycine (33.95mg, 0. 329mmol, 1.05equiv) followed by EDC. HCI (66.13mg, 0. 345mmol, 1. 1equiv) and the reaction mixture was stirred at 23°C for 18 h. The reaction mixture was diluted with DMF (2. 4moi) and purified using Gilson to give Example 26 (66mg, 40%). Electrospray MS [M+1] + 532.1.

Example 27 Example 27 (yield 62%) was prepared using similar procedure as for Example 14 using trimethylacetyl chloride in place of propionyl chloride.

Electrospray MS [M+1] + 531.1 Example 28

Example 28 (105mg, 74%) was prepared using similar procedure as for Example 14 using methyl isocyanate in place of propionyl chloride.

Electrospray MS [M+1] + 504.1 Example 29 Example 14 using trimethylsilyl isocyanate in place of propionyl chloride.

Electrospray MS [M+1] + 490. 1 Example 30 To a solution of Example 13 (100mg, 0. 224mol, 1equiv) in anhydrous CH2CI2 (2ml) was added 4-morpholinylcarbonyl chloride (28. 7111, 0. 246mmol, 1. 1 equiv) and DIEA (39µl, 0. 223mmol, 1 equiv). The reaction mixture was stirred at RT overnight. Aqueous work-up and purification by using silica column to afford Example 30 (53mg, 42%). Electrospray MS [M+1] + 560.1 Example 31

Example 31 (40% yield) was prepared using similar procedure as for Example 30 using dimethylcarbamyl chloride in place of 4-morpholinylcarbonyl chloride. Electrospray MS [M+1] + 518.1 Example 32 Example 32 (42% yield) was prepared using similar procedure as for Example 30 using 1-piperidinecarbonyl chloride in place of 4-morpholinylcarbonyl chloride. Electrospray MS [M+1] + 558. 1 Example 33 Example 33 (40% yield) was prepared using similar procedure as for Example 30 using 1-pyrrolidinecarbonyl chloride in place of 4-morpholinylcarbonyl chloride. Electrospray MS [M+1] + 544.1 Example 34 Step 1: Ph HN (NH I \-C) 0 0 c ! Example 13 CH2CIa _ Compound30 F3C Compound 30 (43% yield) was prepared using similar procedure as for Example 10 using chloroacetyl chloride in place of propionyl chloride.

Step 2 : To a solution of Compound 30 (90mg, 0. 17mmol, 1equiv) in anhydrous CH2CI2 (0. 5ml) was added pyrrolidine (17. 2µl, 0. 206mmol, 1.2equiv) and DIEA (30pL1, 0. 17mmol, 1equiv). The reaction mixture was stirred at RT overnight. Aqueous work-up and purification by using silica column to afford Example 34 (45mg, 47%).

Electrospray MS [M+1] + 558.1.

Example 35 Example 36 c N HN- PC t'3 t F3C HN I HN I CF, / Example 35 Example 36 Step 1: Ci -NH 0 Ph HN >=O N N H Ici Example Cl. + CH2CI v CF3 /Compound 31 rs Compound 31 was prepared using similar procedure as for Example 14 using 2-chloroethyl isocyanate in place of propionyl chloride.

Step 2: To a solution of Compound 31 in anhydrous THF (7ml), was added NaH (25mg, 0. 625mol, 1.7equiv, 60% dispersion in mineral oil) at 0°C. The resulting cloudy solution was heated at 60°C for 2 h. Aqueous work-up to give the crude

product which was purified by silica gel column to give the less polar title compound Example 35 (10mg, 5.4%), Electrospray MS [M+1] + 516. 1; and the more polar title compound Example 36 (122mg, 66%), Electrospray MS [M+1] +516. 1 Example 37 To a solution of Example 12b (200mg, 0. 41 mmol, 1 equiv) in anhydrous CH2CI2 (1 ml) at 0°C, was added trifluoromethanesulfonic anhydride (69su1, 0.41 mmol, 1 equiv). The reaction mixture was stirred for 40 min before NaN3 (26.6mg, 0.41 mmol, 1 equiv) was added. The mixture was warmed up to RT for 2 h.

The solvent was removed in vacuum. The residue was purified with prep-TLC (silica) to obtain Example 37 (4.5mg, 2%). Electrospray MS [M+1] + 514.1 Example 38 Step 1: ButOS y-COsEt Ph N C02Et Br- Compound 17 NaH, DMF t/CF3 /Compound 32 FISC To Compound 17 (0.3g, 0. 575mmol, 1equiv) under N2 in anhydrous DMF (3m !) at 0°C was added NaH (27.6mg, 0. 69mmol, 1.2equiv, 60% in mineral oil) and the reaction mixture was stirred for 1 h. To the resulting suspension under vigorous stirring was dropwise added ethyl-2-bromomethylacrylate (0. 088ml, 0. 629mmol, 1. 1 equiv). The reaction mixture was allowed to warm to 23°C and stirred for 18 h.

The reaction was quenched with saturated aqueous NH4CI solution and extracted

with Et20. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The crude product was purified using flash silica gel column to give titled Compound 32 (0.199g, 55%).

Step 2:

ButOS Pu N - X.. -C02Et \ Grubbs'cat. Compound 32-----" v CF3 /Compound 33 F3C To a solution of Compound 32 (50mg, 0. 078mmol, 1 equiv) in anhydrous CH2CI2 (0. 8ml) under N2 was added Grubbs'catalyst tricyclohexylphosphine [1,3- bis (2,4, 6-trimethyl-phenyl)-4, 5-dihydro-imidazol-2-ylidene] [benzylidine] ruthenium (IV) dichloride (6.7mg, 0. 0079mmol, 0. 1 equiv). The resulting brown solution was heated at 40-45°C for 2 h. The solvent was then removed and the residue was purified on a silica gel column to afford the titled Compound 33 (60mg, 63%). Electrospray MS [M+1] + 502. 1.

Step 3: PU HN --CCO2Et HO 0 HCI Compound 33 XCF3 /Compound 34 F3C To a solution of Compound 33 (30mg, 0. 05mmol, 1equiv) in absolute MeOH (0. 5mi) at 0°C was added a solution of 4N HCI in dioxane (0. 5moi). The resulting solution was stirred at 0°C for 4 h. The solvent was then removed and the residue was dissolved in CH2CI2 and passed through a short K2CO3 column. The residue of Compound 34 was taken directly to the next step without further purification.

Step 4: Ph HNn Y y-COzEt \-' H2 0 Compound 34- Pd-C < CF3 Compound 35 FsC

A solution of Compound 34 (30mg, 0. 06mmol) in EtOH (5ml) was treated with 10% Pd-C (32mg, 0. 03mmol) and was hydrogenated at 60 psig for 18 h. The catalyst was filtered and washed with EtOAc. The filtrate was concentrated and the resulting residue of Compound 35 was taken directly to the next step without further purification.

Step 5 : To a mixture of methylamine HCI salt (52mg, 0. 77mmol, 12.8 equiv) in toluene (0.2 ml) was added Me3AI (2M in toluene, 0. 36mi, 0. 72mmol) and the resulting mixture stirred for 30 min. A solution of Compound 35 (30mg, 0. 06mmol) in toluene (0. 5moi) was added to the reaction mixture via syringe. The resulting solution was heated at 100°C for 18 h. The reaction mixture was then poured into saturated aq. Na/K tartarate solution (1 Oml), stirred for 10 min and extracted with EtOAc (4 x 1 Oml). The combined organic layers were washed with brine and concentrated. The residue was subjected to prep TLC to afford the less polar isomer, Example 38a, Electrospray MS [M+1] + 489. 1 and the more polar isomer, Example 38b, Electrospray MS [M+1] + 489.1.

Example 39 Step 1: Ph NHCbz Ph3PCH3Br Ph3PCH3Br \ Compound dz KHMDS, tolu < CF3 Compound 36 Compound 36 (yield 63%) was prepared from Compound 23 using the procedure similar to the preparation of Compound 23 from Compound 3 and using methyltriphenyl-phosphonium bromide in place of (me. thoxymethyl) triphenylphosphonium chloride.

Step 2: f Et02C Ph NCbz EtOCBr O Compound zut NaH, DMF. F3C Compound 37 t-gU

Compound 37 (50% yield) was prepared using similar procedure as for Compound 32 using Compound 36 in place of Compound 17.

Step 3: Cbz Ph \ CO2Et U Grubbstcat. ° Compounct 37 > CF3 F3C Compound 38 rgU

To a solution of Compound 37 (2.46g, 3. 71 mmol, 1 equiv) in anhydrous CH2CI2 (50ml) under N2 was added Grubbs'catalyst (327mg, 0. 385mmol, 0. 1 equiv).

The resulting brown solution was heated at 40-45°C overnight. The solvent was then removed and the residue was purified on a silica gel column to afford Compound 38 (2. 1g, 89%).

Step 4 : Cbz Ph N 0 'N H FNH2 \0 NH Compound 38 AiMe3, tolu < CF3 Compound 39

To a mixture of cyclopropylamine (0. 24ml, 3. 45mmol, 4.2equiv) in toluene (1.0 ml) was added Me3AI (2M in toluene, 1. 71 ml, 3.41 mmol, 4.2 equiv) and the resulting mixture stirred for 30 min. A solution of Compound 38 (516mg, 0. 82mmol, 1 equiv) in toluene (2. 5ml) was added to the reaction mixture via syringe. The resulting solution was heated at 60°C for 18 h. The reaction mixture was then poured into saturated aq. Na, K tartarate solution, stirred for 10 min and extracted with EtOAc (1 Oml x 4). The combined organic layers were washed with brine and concentrated. The residue was purified on silica column to afford Compound 39 (360mg, 68%).

Step 5 : A solution of Compound 39 (360mg, 0. 556mmol, 1 equiv) in EtOH (25ml) was treated with 10% Pd-C (641 mg, 0. 613mmol, 1. 1equiv) and was hydrogenated at 50 psi for 6 h. The catalyst was filtered and washed with EtOAc. The residue was purified by silica gel column to afford the less polar isomer, Example 39a (54mg, 19%) Electrospray MS [M+1] + 515.1, and the more polar isomer, Example 39b (22mg, 8%) Electrospray MS [M+1] + 515.1 Example 40a and Example 40b Step 1: Cbz, Ph N 0 'NHPMB PMBNH2 0 Compound 38 AIMe3, tol. < CF3 F3C Compound 40 3 Compound 40 (yield 55%) was prepared using similar procedure as for Compound 39 using para-methoxylbenzylamine in place of cyclopropylamine.

Step 2: Cbz Ph No \t/N H2 CAN, CH3CN o Compound 40 pH7 buffer < CF3 po Compound 41

A solution of Compound 40 (1g, 1. 38mmol, 1equiv) in CH3CN (10moi) and pH7 buffer (3ml) was treated with ammonium cerium (IV) nitrate (2.17g, 3. 96mmol, 2.9equiv) at RT for 2 h. Aqueous work-up gave the crude product which was purified by silica gel column to give Compound 41 (760mg, 91%).

Step 3: Example 40a and Example 40b were prepared using a similar procedure as for Example 39a and Example 39b using Compound 41 instead of Compound 39.

Electrospray MS [M+1] + 475.1 for the Example 40a (less polar isomer); Electrospray MS [M+1] + 475.1 for the Example 40b (more polar isomer).

Example 41 Example 41a and Example 41b were prepared using a similar procedure as for Example 38a and Example 38b using ethylamin instead of methylamine.

Electrospray MS [M+1] + 503.1 for the Example 41 a (less polar isomer); Electrospray MS [M+1] + 503.1 for the Example 41 b (more polar isomer).

Example 42 The mixture of two isomers of Compound 35 was separated by column chromatography to give pure Example 42a and Example 42b Electrospray MS [M+1] + 504.1 for the Example 42a (less polar isomer); Electrospray MS [M+1] + 504.1 for the Example 42b (more polar isomer).

Example 43a Example 43b Step 1: Coo tOA PPh3Br C° KHMDS, Toluene CFs HOO C -78 OC to RT Compound 3 CF3 (68%) cl3 Compound 42 Compound 43 (minor)

To a suspension of lactol Compound 3 (60g, 93. Ommol, 1 equiv.) and Wittig Reagent (93.5g, 200. Ommol, 2.15equiv.) in toluene (800ml) stirred at-78°C under N2, a solution of KHMDS (0.5M in toluene, 558ml, 280. 0mmol), 3equiv. ) was added dropwise at-78°C. The cooling bath was removed and the yellow mixture was warmed to RT to form a red solution. The mixture was allowed to stir at 23°C for further 1 h before being quenched with saturated NH4CI solution. EtOAc was added and layers were separated. The separated aqueous layer was extracted with EtOAc (2 x 500ml). The combined organic layers were dried (MgSO4) and filtered.

Removal of solvents in vacuum followed by Biotage column chromatography [5% EtOAc-hexane to 10% EtOAc-hexane] gave alkene Compound 42 as white solid (40.5g, 68%), Electrospray MS [M+1] + 638.1. Continuous elution gave an impure cyclized product Compound 43.

Step 2: po Pt20, ETCH H2 (balloon) Rut Compound 42---CbzHN,.," caf3 Compound 44 A suspension of alkene Compound 42 (40.5g, 64mmol, 1 equiv.) and Pt02 (1.44g, 6. 4mmol, 0. 1equiv.) in EtOH (400ml) were stirred under a H2 balloon at 23°C for 24 h. Another batch of Pt02 (1.44g, 6. 4mmol, 0. 1 equiv) was added and the mixture was stirred for another 24 h at 23°C. The catalyst was filtered via a pad of Celite. This solution of alkane Compound 44 was used in the next step without further purification.

Step 3: CF3 p-TsOH (cat.) Compound 44 EtOH, reflux CbzN"", p CF Compound 44-----"yO (70%) g A Compound 45

p-TsOH. H20 (2.42g, 13. Ommol) was added to the ethanolic solution of alkane Compound 44 from above and the solution was heated to reflux for 4 h. The solution was cooled to RT and neutralized with Et3N. Solvents were removed in vacuum and EtOAc was added. Saturated NaHC03 solution was added and layers were separated. The separated aqueous layer was extracted with EtOAc (300ml x 2). The combined organic layers were dried (MgS04) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [10% ether- hexane] gave enamide Compound 45 (first batch) as yellow oil. Some intermediate and starting material were recovered as yellow oil by continuous elution with [50% EtOAc-hexane]. The yellow oil was dissolved in toluene and 10mol% p-TsOH was added. The mixture was heated to reflux for 2 h and cooled to RT. Work up was as above and the combined enamide Compound 45 (25g, 70%), Electrospray MS [M+1] + 564.1, was obtained as yellow oil.

Step 4: HO BH3. DMS, THF, r. t. then NaOH, H202 2) A Compound 45..", eo = (74%) < < 3 \/Compound 46 BH3. Me2S (13. 6m !, 133mmo, 3.02 equiv) was added to a solution of enamide Compound 4F (25g, 44. ammo, 1 equiv.) in THF at 23°C under N2. The mixture was stirred at 23°C for 18 h and then cooled over an ice-water bath. A solution of NaOH (500ml, 2N) was added slowly followed by a solution of H202 (500ml, 30% aqueous). The mixture was allowed to stir from 0°C to 23°C for 18 h. Layers were separated and the separated aqueous layer was extracted with Et20 (500mut x 2).

The combined organic layers were dried (MgS04) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-EtOAc, 3: 1 (v/v)] gave alcohol Compound 46 as colorless oil (19g, 74%), Electrospray MS [M+1] + 582.1.

Step 5: (COCI) 2, DMSO ~ CF3 CH2CI2,-78 °C ( Compound 46 then Et3N CbzN I CF3 Compound 47 Oxalyl chloride (5. 7moi, 65. 3mmol, 2equiv. ) was added to a solution of DMSO (9. 3ml, 131. 0mmol, 4equiv. ) in CH2CI2 (300ml) at-78°C under N2. The mixture was stirred at-78°C for 15 min before a solution of alcohol Compound 46 (19g,

32. 7mmol. 1 equiv.) in CH2CI2 (50ml) was added. The mixture was stirred at-78°C for a further 1 h and Et3N (32ml, 228. 9mmol, 7equiv. ) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHC03 solution. Layers were separated and the aqueous was extracted with CH2CI2 (300ml x 2). The combined organic layers were dried (MgS04) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-ether, 4: 1 (v/v) ] gave ketone Compound 47 as colorless oil (15g, 80%), Electrospray MS [M+1] + 580. 1.

Step 6: O+NH KCN, NH4 (C03) 2 HN 0 CF3 Compound 47 1 : 1, EtOH : H20, 56 OC,, 0 .,"O w CFs y<Cpg Compound 48 EtOH (150ml) was added to Cbz-ketone Compound 47 (15g, 25. 88mmol, lequiv.), followed by NH4 (CO3) 2 (9.95g, 103. 5mmol, 4equiv. ) and a solution of KCN (3.4g, 51. 77mmol, 2equiv. ). The resulting mixture was heated at 58°C under N2 for 72 h. TLC (1: 1 EtOAc : hexane) revealed complete consumption of the starting material. The reaction mixture was cooled to RT and poured into sat. aq. NaHC03 (200 ml) and extracted with EtOAc (3 x 200moi). The combined organic layers were dried over MgS04 and concentrated in vacuo to afford crude Cbz-hydantoin Compound 48 (16.5g, 98%), Electrospray MS [M+1] + 650.1. The crude material was used in the next reaction without further purification.

Step 7: The crude Cbz-hydantoin Compound 48 (16.5g, 25. 4mmol, 1 equiv.) was dissolved in MeOH (220mut) and 20% Pd (OH) 2-C (3.6g) was added. The reaction mixture was shaken in a parr shaker under H2 atmosphere at 40 psi for 18 h. TLC (1: 1 EtOAc: hexane) revealed complete consumption of the starting material. The reaction mixture was filtered through a pad of celite and the celite was washed with MeOH. The'resulting solution was concentrated in vacuo. The crude product was purified by column chromatography on a Biotage (3: 2, EtOAc: hex). Two major spots were collected. The less-polar spot corresponds to the isomer Example 43a (3 g, overall 20% over two steps), Electrospray MS [M+1] + 516. 1. The more polar spot corresponds to the isomer Example 43b (4.5 g, overall 30% over two steps), Electrospray MS [M+1] + 516. 1.

Examples 44a and 44b

Example 44a Example 44b A flame-dried 25ml RBF was charged with AIC13 (0. 01 g, 0. 776mmol, 4equiv).

The reaction flask was cooled to 0°C and 1 M solution of LAH in Et20 (0. 58ml, 0. 58mmol, 3equiv) was added. The mixture was stirred at 0°C for 10 min and then a solution of Example 43b (0. 1g, 0. 194mmol, 1equiv.) in dry THF (3ml) was slowly added via canula. The reaction mixture was stirred at 0°C for 1 h and then allowed to warm up to RT stirred for 18 h. The reaction was then cooled to 0°C and quenched carefully with saturated aqueous sodium potassium tartarate solution. It was then stirred at 0°C for over 30 min. The mixture was extracted with EtOAc (2 x 200ml). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on a Biotage (1: 9, MeOH: EtOAc) to afford Example 44b (0. 066g, 68%), Electrospray MS [M+1]+ 502. 1.

Example 44a was prepared from Example 43a using the procedure described for the preparation of Example 44b from Example 43b.

Electrospray MS [M+1] + 502.1 for the Example 44a.

Example 45

Step 1: CF3 KHMDS Compound 47 Ph3PCH3Br Ph//}/O < CF 3 Compound 49 To a suspension of (methyl) triphenylphosphonium bromide (0.37g, 1. 04mmol, 3equiv) in toluene (5ml) at 0°C under N2, a solution of KHMDS (1. 73moi, 0. 863mmol, 2.5equiv) was added. After being stirred at 0°C for 1 h, a solution of Compound 47 (0. 2g, 0. 35mmol, 1 equiv) in toluene (7ml) was added. The mixture

was stirred at 0°C for 1.5 h and then quenched with saturated NaHC03 (150moi).

The mixture was extracted with EtOAc (100mol x 3). The combined organic layers were dried (MgS04), filtered and concentrated. The crude product was purified by column chromatography on a Biotage (4: 1, hexane: EtOAc) to afford Compound 49 (0. 196g, 98%).

Step 2 : To a solution of Compound 49 (0.196g, 0. 34mmol, 1 equiv) in dry Et2O (3ml) at 0°C was added chlorosulfonylisocyanate (0. 045ml, 0. 51 mmol, 1.5equiv). The reaction mixture was stirred at 0°C for 1 h and then warmed to 23°C. Another equivalent of chlorosulfonylisocyanate was added and the mixture was stirred 23°C for 18 h. The reaction mixture was diluted with Et20 (12ml), 10% aqueous Na2SO3 solution was added and pH of the reaction mixture was adjusted to 8 using 2M aqueous KOH solution. The mixture was stirred for 1.5 h and then washed with brine. The organic layer was dried (MgS04), filtered and concentrated. The crude product was purified by column chromatography on a Biotage (2: 1, hexane: EtOAc) to afford the crude NCbz-lactam product (20mg) which was converted to mixture of desired products Example 45a and 45b using a procedure similar to the preparation of Example 43a and Example 43b from Compound 48. The mixture of two products was separated on prep. plate (5: 95, MeOH; EtOAc) to afford the less polar isomer, Example 45a (0.006g, 3. 5°/(, over four steps), Electrospray MS [M+1] 487. 1 and the more poiar isomer, Example 45b (0.003g, 1. 79% over four steps), Electrospray MS [M+1] + 487. 1.

Examples 46 Example 46a and Example 46b were prepared from Compound 46 using a procedure similar to the preparation of Example 43a and Example 43b from Compound 48.

Electrospray MS [M+1] + 448. 1 for the Example 46a (less polar isomer); Electrospray MS [M+1] + 448. 1 for the Example 46b (more polar isomer).

Example 47

To a solution of NCbz-alcohol Compound 46 (0.125g, 0. 215mmol, 1equiv) in dry DMF (3ml) at 0°C was added NaH (60% in mineral oil, 0.017g, 0. 43mmol, 2equiv). The reaction mixture was stirred at 0°C for 20 min and then CH31 (0. 04moi, 0. 645mmol, 3equiv) added and the mixture was stirred at 23°C for 18 h. The crude was poured into CH2CI2 (100ml) and washed with brine (100ml x 2). The organic layer was dried (MgS04), filtered and concentrated. The crude product was purified by column chromatography over Biotage (4: 1, hexane: EtOAc) to afford the crude NCbz-methylether product (69mg) which was hydrogenated to the mixture of desired products Example 47a and 47b using a procedure similar to the preparation of Example 43a and Example 43b from Compound 48. The mixture of two products was purified by column chromatography over Biotage (1: 4, hexane: EtOAc) to afford the less polar isomer, Example 47a, Electrospray MS [M+1] + 462.1 and the more polar isomer, Example 47b, Electrospray MS [M+1] + 462.1.

Example 48 Example 48a and Example 48b were prepared from Compound 46 using the procedure similar to the preparation of Example 47a and Example 47b and using ethyl iodide in place of methyl iodide.

Electrospray MS [M+1] + 476.1 for the Example 48a (less polar isomer); Electrospray MS [M+1] + 476.1 for the Example 48b (more polar isomer) Example 49 To a solution of NCbz-alcohol Compound 46 (0.118g, 0. 20mmol, 1 equiv) in dry CH2CI2 (3ml) at 0°C was added dry pyridine (0. 026ml, 0. 325mol, 1.6equiv), followed by acetyl chloride (0. 023moi, 0. 325mol, 1.6equiv). The reaction mixture was warmed to 23°C for and stirred for 18 h. The mixture was then concentrated and purified by column chromatography on a Biotage (4: 1, hexane: EtOAc) to afford the crude NCbz-acetate product (108mg) which was hydrogenated to the crude desired product using a procedure similar to the preparation of Example 23a and Example 23b from Compound 48. The crude product was purified by column chromatography on a Biotage (5: 95 MeOH: EtOAc) to afford Example 49 (0.079g, 79% over two steps), Electrospray MS [M+1] + 490.1.

Examples 50a and 50b

Example 50a Example 50b To a solution of NCbz-alcohol Compound 46 (0.223g, 0. 385mmol, 1equiv) in CH2CI2 (8ml) at 0°C was added trichloroacetyl isocyanate (0. 055ml, 0. 46mmol, 1.2equiv). The reaction mixture was stirred at 0°C for 15 min and then concentrated in vacuo. The residue was dissolved in CH30H (ml) and water (5 ml) was added.

The mixture was cooled to 0°C and K2CO3 (0.16g, 1. 16mmol, 3equiv) was added.

The reaction mixture was stirred at 0°C for 1 h and then warmed to 23°C and stirred for 18 h. The reaction mixture was then concentrated in vacuo and water (100ml) was added to the residue and the mixture was extracted with CH2CI2 (100ml x 2).

The combined organic layers were dried (Na2SO4), filtered and concentrated to afford the crude NCbz-carbamate product (232mg) which was hydrogenated to the mixture of desired products Example 50a and 50b using a procedure simiiar to the preparation of Example 43a and Example 43b from Compound 48. The mixture of two products was purified by column chromatography over Biotage (1: 4, hexane: EtOAc) to afford pure Example 50a and pure Example 50b.

Electrospray MS [M+1] + 491. 1 for the Example 50a (less polar isomer); Electrospray MS [M+1] + 491.1 for the Example 50b (more polar isomer) Example 51 A mixture of NCbz-alcohol Compound 46 (0.2g, 0. 344mmol, 1equiv.), 1,4- dioxane (3ml), 1-pyrrolidine carbonyl chloride (0. 076ml, 0. 69mmol, 2equiv. ) and dry pyridine (0. 084moi, 1. 03mmol, 3equiv. ) was heated in a sealed tube at 100°C for 18 h. The reaction mixture was cooled to 23°C and diluted with EtOAc (150mol). The

mixture was washed with water (100mol) and the organic layer was dried (Na2SO4), filtered and concentrated to afford the crude NCbz-carbamate product (232mg) which was hydrogenated to the mixture of desired products Example 51 a and 51 b using a procedure similar to the preparation of Example 43a and Example 43b from Compound 48. The mixture of two products was purified by column chromatography over Biotage (2 : 3, hexane: EtOAc) to afford the less polar isomer, Example 51 a and the more polar isomer, Example 51 b.

Electrospray MS [M+1] + 545.1 for the Example 51 a ; Electrospray MS [M+1] + 545.1 for the Example 51 b.

Example 52 Example 52a and Example 52b were prepared from Compound 46 using the procedure similar to that used for the preparation of Example 51a and Example 51 b and using 1-piperidine carbonyl chloride in place of 1-pyrrolidine carbonyl chloride.

Electrospray MS [M+1] + 559.1 for the Example 52a (less polar isomer); Electrospray MS [M+1] + 559. 1 for the Example 52b (more polar isomer).

Example 53 Example 53a and Example 53b were prepared from Compound 46 using the procedure similar to that used for the preparation of Example 51 a and Example 51 b and using methylisocyanate in place of 1-pyrrolidine carbonyl chloride.

Electrospray MS [M+1] + 505.1 for the Example 53a (less polar isomer); Electrospray MS [M+1] + 505.1 for the Example 53b (more polar isomer).

Example 54 OC Ph'j, CF3 HN \ J/0 l--Cd OH CF3 V-CFs 1. CeC13. 7H20 Compound 47 CbzN 2. MeMgl /p/ Ph"CF3 Compound 50

CeCI3 (0. 186g, 0. 5mmol, 2. 1equiv) was added to a 25ml RBF and heated in vacuo at 140°C for two h. The flask was cooled to 23°C under N2, dry THF (2ml) was added and the resulting suspension was stirred at 23°C for 18 h. The mixture was then cooled to 140°C and CH3Mgl (0. 159mol, 0. 476mmol, 2equiv.) was added and stirred at 0°C for 1 h. A solution of Compound 47 (0.138g, 0. 238mmol, 1 equiv) in dry THF (2. 5ml) was added dropwise and the reaction mixture was stirred under N2 at 0°C for 0.5 h. The mixture was quenched with saturated aq. NH4CI solution (50ml) and extracted with EtOAc (100mi x 2). The combined organic layers were dried (MgS04), filtered and concentrated. The mixture was purified by column chromatography over Biotage (4: 1, hexane: Et20) to afford the NCbz-alcohol Compound 50 (0. 115g, 80%).

The NCbz-alcohol Compound 50 was converted to the desired product Example 54 (63% yield over two steps) using a procedure similar to the preparation of Example 49 from Compound 46.

Electrospray MS [M+1] + 504.1 for the Example 54.

Example 55 To a solution of Compound 47 (0. 1g, 0. 173mmol, 1equiv) in dry pyridine (1 ml) was added methoxylamine hydrochloride (0.058g, 0. 69mmol, 4equiv) and the reaction mixture was stirred 23°C for 18 h. The mixture was quenched with water (50mi) and extracted with CH2CI2 (100mol x 2). The combined organic layers were dried (Na2SO4), filtered and concentrated to give NCbz-oxime (0. 102g, 97%) which was hydrogenated to afford the crude product Example 55 using a procedure similar to the preparation of Example 43a and Example 43b from Compound 48, except that the reaction was carried out in a H2 balloon atmosphere at RT instead of

a parr shaker at 40psi. The crude product was purified by column chromatography over Biotage (4: 1, EtOAc: hexane) to afford Example 55 (0.063g, 79%), Electrospray MS [M+1] + 475.1.

Examples 56a and 56b Example 56a Example 56b Step 1: C02Me (EtO) 2P (O) CH2CO2Me Compound 47 NaH, THF u D) z I IN4.., 3 Compound 51 To a suspension of NaH (1.8g, 44. 5mmol, 60% in oil) in THF (200ml) at 0°C under N2, methyl diethylphosphonoacetate (8. 2ml, 44. 5moo !) was added. The mixture was stirred at 0°C for 15 min and a solution of ketone Compound 47 (8.6g, 14. 8mol) in THF (50ml) was added. The mixture was allowed to warm to RT and stirred for 1 h before it was quenched with saturated NH4Ci solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200ml x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4: 1 (v/v)] gave unsaturated ester Compound 51 (9.2g, 98%) as colorless oil. Electrospray MS [M+1] +=636. 1.

Step 2: O N C°2Me MeN02 n Compound 51 (50O/) cb>", O<acF3 3 Compound 52 A mixture of unsaturated ester Compound 51 (9.2g, 14. 5mmol) and tetrabutylammonium fluoride (145m1, 1. OM in THF) in CH3N02 were heated to reflux for 2 h. The mixture was cooled to RT and quenched with saturated NH4CI solution.

Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (X2). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum and purification by

column chromatography [hexane-acetone, 9: 1 (v/v) ] gave the less polar alkene (4. 1g, 45%) as colorless oil. Continuous elution with the same solvent system gave the more polar nitroester Compound 52 (5. 1g, 50%) as colorless oil. Electrospray MS [M+1] +=670. 1.

Step 3: A mixture of Compound 52 (5.1g, 7. 32mol), a catalytic amount of Pd (OH) 2 (20% on carbon) and a catalytic amount of Raney Ni (50% slurry in water) were shaken in a Parr hydrogenator at 50 psi overnight. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a mixture of Example 56a and 56b as colorless oil (3.5g, 95%). Separation by HPLC using Chiralcel OD [hexane-isopropanol, 9: 1 (v/v) ] gave less polar isomer Example 56a as white foam.

Electrospray MS [M+1] +=501. 1. Continuous elution with the same solvent system gave the more polar isomer Example 56b as colorless oil. Electrospray MS [M+1] +=501. 1.

Example 57 To a solution of ethyl propiolate (0. 27mol, 2. 69mmo !) in THF (10ml) at-78°C under N2, t-butyllithium (1. 6ml, 2. 69mmol, 1.7M in pentane) was added. The mixture was stirred at-78°C for 10 min and a solution of Compound 47 (519mg, 0. 90mmol) in THF (5ml) was added. The mixture was stirred at-78°C for 1 h, then quenched with HOAc at-78°C. Water and EtOAc were added to the mixture.

Layers were separated and the aqueous layer was extracted with EtOAc (200moi x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4: 1 (v/v) ] gave a colorless oil. The oil was dissolved in EtOH and a catalytic amount of palladium (10% on carbon) was added. The mixture was shaken in a Parr hydrogenator at 45 psi overnight. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a colorless oil. The oil was dissolved in toluene and catalytic amount of p-TsOH was added. The mixture was heat to reflux overnight. After being cooled to RT, the mixture was quenched with saturated NaHC03 solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (250ml x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed

in vacuum to give a mixture of Example 57a and 57b as colorless oil. Separation by column chromatography [hexane-ether, 1: 2 (v/v) ] gave the less polar minor isomer Example 57a (67mg, 15%) as white foam. Electrospray MS [M+1] +=502. 1.

Continuous elution with the same solvent system gave the more polar major isomer Example 57b (134mg, 30%) as white solid. Electrospray MS [M+1] +=502. 1.

Example 58 To a solution of Example 57a (112mg, 0. 22mmol) in THF (5ml) at-78°C under N2, lithium bis (trimethylsilyl) amide (1. 1ml, 1. 12mmol, 1. 0M in THF) was added. The mixture was stirred at-78°C for 1 h and CH31 (701l1, 1. 12mmol) was added. The mixture was stirred at-78°C for 1 h before quenched with saturated NH4CI solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (100mol x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-ether, 3: 1 (v/v) ] gave Example 58 (92mg, 78%) as colorless oil. Electrospray MS [M+1] +=530. 1.

Example 59 Example 59 (75%) was prepared from Example 57b in a manner similar to that used to prepare Example 58 from Example 57a. Electrospray MS [M+1] +=530. 1.

Examples 60a and 60b HN. 11 HN- AcHN sgO CF3 + CF3 N, J Han 4 Han 11 1 Example 60a Example 60b Step 1: OH 1. Boc20, CH2CI2 H2N 0 CF3 Compound 48-1 Compound 53 p°Y-cFs Ph <

To a solution of Compound 48 (0.5g, 0. 77mmol, 1 equiv) in CH2CI2 (30ml) was added di tert-butyl dicarbonate (0.37g, 1. 69mmol, 2.2equiv) followed by DMAP (0.035g, 0. 286mol, 0.37equiv) and the reaction mixture was stirred at 23°C for 18 h. The reaction mixture was then filtered through a short pad of silica using (1: 1 hexane: EtOAc) and concentrated in vacuo to afford diBoc-hydantoin (0.59g, 90%).

The diBoc-hydantoin (0.59g, 0. 7mmol, 1equiv) was dissolved in THF (30moi) and 1M aq. LiOH solution (5. 56ml, 5. 56mmol, 8equiv) was added. The reaction mixture was stirred at 23°C for 18 h. Saturated aq. NaHC03 was added to the reaction mixture and extracted with EtOAc (100ml x 3). The combined organic layers were dried (Na2SO4), filtered and concentrated to give crude Compound 53 (0.52g) which was used in the next reaction without further purification.

Step 2: To a mixture of crude Compound 53 (0.52g) in pyridine (3ml) and THF (2ml) at 0°C was added acetyl chloride (0. 072moi, 1 mmol, 1. 2equiv) and the reaction mixture was warmed to 23°C and stirred for 18 h. The reaction mixture was then concentrated and purified by column chromatography over Biotage (5: 95, MeOH : EtOAc) to afford a yellow oil of N-acelyated product (0.31g, 0. 456mol, 1equiv.) which was dissolved in THF (10moi). A 2M solution of CH3NH2 in THF (2. 3ml, 4. 6mmol, 10equiv) was added and the reaction mixture was stirred at 23°C for 18 h. The mixture was diluted with EtOAc (100ml) and washed with saturated aq. NaHC03 (100mol). The organic layer was were dried (Na2SO4), filtered and concentrated to give crude NCbz-amide which was hydrogenated to afford the mixture of two isomers Example 60a and 60b using a procedure similar to the preparation of Example 43a and Example 43b from Compound 48. The mixture of two products was separated on HPLC"ChiralPak AD column"using (1: 9, IPA : hexane) to afford the more polar isomer pure Example 60a, Electrospray MS [M+1] =546. 1 and less polar isomer pure Example 60b, Eiectrospray MS [M+1] =546. 1.

Example 61

Example 61 was prepared from Example 43a using the procedure similar to the preparation of Examples 60a and 60b from Compound 48, but using a solution of ammonia (0.5M in 1,4-dioxane) in place of CH3NH2 solution (2M in THF).

Electrospray MS [M+1] +=532. 1.

Example 62 Step 1 : OH 1. Boc20, CH2CI2 2"2Q CFs Compound 43a l Compound 54 2. 1M aq. LiOH, THF Ph CF3 Ph CF3 Compound 54 was prepared from Example 43a using the procedure similar to the preparation of Compound 53 from Compound 48. Compound 54 was used in the next reaction without further purification.

Step 2: UH Boc20 BocHN) to CF3 Compound 54 THF, sat. NaHC03 HN Compound 55 /,, O Ph d CF3 To a mixture of Compound 54 (0.5g, 1. 02mmol, 1equiv) in THF (30mi) was added sat. aq. NaHC03 followed by di tert-butyl dicarbonate (0.58g, 2. 65mmol, 2.6equiv). The reaction mixture was stirred at 23°C for 18 h. The mixture was cooled to 0°C and 10% aq. citric acid (20moi) was added and the resulting mixture was extracted with EtOAc (100mol x 3). The combined organic layers were dried (Na2SO4), filtered and concentrated to give crude Compound 55 (0.93g) which was used in the next reaction without further purification.

Step 3: To a solution of Compound 55 (0.93g, 1. 57mmol, 1equiv) in CH2CI2 (15MI) was added DIEA (0. 83ml, 4. 72mmol, 3equiv) followed by PyBOP (1.23g, 2. 4mmol, 1.3equiv). After 15 min, 0.5M solution of ammonia in 1,4-dioxane (31. 5ml, 15. 75mmol, 10equiv) was added to the reaction mixture and stirred at for 23°C for 18 h. The reaction mixture was quenched with water (100ml) and extracted with EtOAc (100ml x 3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography over Biotage (1: 10: 89, Et3N: MeOH: EtOAc) to afford NBoc-amide which was dissolved in CH2CI2 (1 Oml) and cooled to 0°C. TFA (6ml) was added and the reaction mixture was warmed to 23°C and stirred for 2 h. The reaction was quenched carefully with sat. aq. NaHC03 (100ml) and diluted with CH2CI2 (100ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography over Biotage (10: 90, MeOH: EtOAc) to afford the desired product Example 62 (0.18g, 35% over three steps), Electrospray MS [M+1]+=490. 1.

Example 63

Example 63 was prepared from Example 62 using the procedure similar to the preparation of Example 14 from Example 13 and using cyclopropyl acid chloride in place of propionyl chloride and also using DIEA (1.3equiv).

Electrospray MS [M+1] +=558. 1.

Example 64

Example 64 was prepared from Example 62 using the procedure similar to the preparation of Example 14 from Example 13 and using t-butyl chloride in place of propionyl chloride.

. Electrospray MS [M+1] +=574. 1.

Example 65 OH nu2 HNo CF HN HN f !) Ph CF3 Step-) : OCOCH3 0 NH2 CI'O HN, O I Example 62 > HN Compound 56 i-Pr2EtN, CH2CI2 Ph CF old Compound 56 was prepared from Example 62 using the procedure similar to the preparation of Example 14 from Example 13 but using acetoxyacetyl chloride in place of propionyl chloride. The crude Compound 56 was used in the next reaction without further purification.

Step 2: The crude Compound 56 was dissolved in MeOH (5ml), KHC03 (3equiv) was added and the reaction mixture was stirred at 23°C for 18 h. The reaction mixture was concentrated and purified by column chromatography over Biotage (10: 90, MeOH: EtOAc) to afford the desired product Example 65, Electrospray MS [M+1] +=548. 1.

Example 66 Example 66 was prepared from Example 62 using the procedure similar to the. preparation of Example 14 from Example 13 and using CH3SO2CI in place of propionyl chloride.

Electrospray MS [M+1] +=568. 1 for the Example 66.

Example 67

Example 67 was prepared from Example 62 using the procedure similar to the preparation of Example 14 from Example 13 but using cyclopropylsulfonyl chloride in place of propionyl chloride. Electrospray MS [M+1] +=594. 1.

Example 68 Example 68 was prepared from Example 62 using the procedure similar to the preparation of Example 14 from Example 13 but using trifluoromethanesulfonic anhydride in place of propionyl chloride.

Electrospray MS [M+1] +=622. 1 for the Example 68.

- Example 69 Example 69 was prepared from Example 62 using the procedure similar to the preparation of Example 14 from Example 13 and using nicotinoyl chloride in place of propionyl chloride.

Electrospray MS [M+1] +=595. 1 for the Example 69.

Examples 70a and 70b OH OH 2 z H2Nt S I'll 7 HO J . HN J/ , Ph, Ph CF3 CF3 Example 70a Example 70b Step 1 : OMe TMSCH N BcHN CF3 Compound 53-Compound 57 Compound 57 toluene, CbzN MeOH pht98/°<, CF3 3

To a mixture of Compound 53 (4g, 5. 52mmol, lequiv), toluene (46ml) and MeOH (18mut) at 0°C was added TMSCH2N2 (2M solution in hexane, 13. 8moi, 27. 6mmol, 5equiv) and the resulting solution was stirred at 0°C for 30 min. The reaction mixture was then concentrated and purified by column chromatography over Biotage (2: 1, hexane: EtOAc) to give Compound 57 (1.8g, 44%).

Step 2 : -0 OH HN CF3 BocHN CF3 CH3MgBr \ \ Compound 57-'CbN \ CbzN CbzN 0 11 CbzN 11 1 3 3 Compound 58 Compound 59 To a mixture of Compound 57 (1 g, 1. 35mmol, 1 equiv) in dry THF (18ml) at 0°C was added CH3MgBr (1 M solution in n-butylether, 3. 24moi, 3. 24mmol, 2.4equiv.) and the resulting solution was stirred at 0°C for 30 min. The reaction mixture was then warmed to 23°C and stirred for 18 h. The reaction was quenched with saturated aq. NaHC03 (100ml) and extracted with EtOAc (200ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated. The mixture was purified by column chromatography over Biotage (2: 1, hexane: EtOAc) to give more polar Compound 58 (0.52g, 56%) and less polar Compound 59 (0. 31g, 34%).

Step 3: Compound 59 was deprotected with TFA using the procedure described in the preparation of Example 62. The resulting NCbz-aminoalcohol compound was hydrogenated to afford the mixture of two isomers Example 70a and 70b using a procedure similar to the preparation of Examples 43a and 43b from Compound 48.

The mixture of two products was separated on HPLC"ChiraICel OD column"using (1: 9, IPA : hexane) to afford less polar isomer Example 70a, Electrospray MS [M+1] + 505.1, and more polar isomer Example 70b, Electrospray MS [M+1] + 505.1.

Example 71

Compound 58 was hydrogenated to a mixture of desired products Example 71 a and 71 b using a procedure similar to the preparation of Examples 43a and 43b from Compound 48. The mixture of two products was purified by column chromatography over Biotage (1: 1, hexane: EtOAc) to afford pure less polar isomer Example 71a, Electrospray MS [M+1] + 531.1 and pure more polar isomer Example 71b, Electrospray MS [M+1] + 531. 1.

Examples 72a and 72b Example 72a Example 72b Step 1: o Triphosgene p CF Compound 53 iPrNEt, CH2CI2 P CbzN..,,, o F3 caf3 Compound 60 To a solution of crude Compound 53 (19g) in CH2CI2 (300ml) at RT, DIEA (15mol, 0. 087mol) was added, followed by triphosgene (4. 34g, 0. 015mol). The mixture was stirred at RT for 18 h and was filtered through a pad of silica. Solvents were removed in vacuum to give crude Compound 60 as yellow oil which was used in the next reaction without further purifications.

Step 2: LiBH4, THF BocHN>COH CF3 0 °C to RT Compound 60--. CbzN ",, i CF3 Compound 61 To the crude Compound 60 in THF (200ml) at 0°C, LiBH4 (1.26g, 0. 058mol) was added in small portions. The mixture was stirred at RT for 18 h before

quenching with saturated NH4CI solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (100 x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane- EtOAc, 4: 1 (v/v) ] gave Compound 61 (12.9g, 62% overall) as white foam.

Step 3: Oxalyl chloride (4. 2ml, 0. 048mol) was added to a solution of DMSO (6. 8moi, 0.096) in CH2CI2 (300ml) at-78°C under N2. The mixture was stirred at-78°C for 15 min before a solution of Compound 61 (8.5g, 0. 012mol) in CH2CI2 (100moi) was added. The mixture was stirred at-78°C for a further 1 h and Et3N (23. 5ml) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHC03 solution. Layers were separated and the aqueous was extracted with CH2CI2 (150ml x 2). The combined organic layers were dried (MgS04) and filtered. Removal of solvents in vacuum gave an aldehyde as yellow oil. To a mixture of NaH (1.44g, 0. 036mol) in THF at 0°C, methyl diethylphosphonoacetate (6. 6ml, 0. 036mol) was added. The mixture was stirred at 0°C for 15 min and a solution of aldehyde in THF (100mi) was added. The cooling bath was removed and the mixture was stirred at RT for 1 h. The reaction was quenched with saturated NH4CI solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200ml x 2). The combined organic layers were dried (MgS04) and. filtered.

Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4: 1 (v/v) ] gave an ester as white foam. The ester was dissolved in EtOH (1 00ml) and a catalytic amount of palladium (1.28g, 10% on carbon) was added. The mixture was shaken under H2 (50 psi) for 2 days. Catalytic amount of Pd (OH) 2 (20% on carbon) was then added to the mixture and the mixture was again shaken under H2 (50 psi) for 5 h. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a white foam. The foam was then dissolved in CH2CI2 (200ml) and TFA (8. 9moi, 0. 12mol) was added. The mixture was stirred at RT for 18 h and was cooled at 0°C before it was neutralized with saturated NaHC03 solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200moi x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum to give a yellow oil. The oil was dissolved in CH30H (50ml) and a catalytic amount of K2CO3 (166mg, 0. 0012mol) was added. The mixture was heated at 60°C for 2 h. After being cooled to RT, the mixture was filtered through a pad of silica and solvents were removed in vacuum. Purification by column

chromatography (EtOAc) gave the mixture of two isomers Example 72a and 72b (2.3g, 38% overall) as white foam. Separation by HPLC using Chiralcel OD [hexane-isopropanol, 95: 5 (v/v) ] gave the less polar major isomer Example 72a as white foam. Electrospray MS [M+1] +=501. 1. Continuous elution with the same solvent system gave the more polar minor isomer Example 72b as colorless oil.

Electrospray MS [M+1] +=501. 1.

Examples 73a and 73b Example 73a Example 73b To a solution of Compound 61 (3g, 4. 22mmol, 1 equiv) in DMF (60ml) at 0°C was added NaH (60% in mineral oil, 0.122g, 5. 07mmol, 1.2equiv) and the mixture was allowed to warm to 23°C and stirred for 45 min. The reaction was quenched with water (100ml) and extracted with EtOAc (100ml x 3). The combined organic layers were dried (MgS04), filtered and concentrated. The crude product purified by column chromatography over Biotage (2: 1, hexane: EtOAc) to afford the desired product which was hydrogenated to afford the mixture of two isomers Example 73a and 73b using a procedure similar to the preparation of Examples 43a and 43b from Compound 48. The mixture of two products was separated on HPLC "ChiralPak AD column"using (5: 95, IPA : hexane) to afford pure less polar isomer Example 73a and more polar isomer Example 73b.

Electrospray MS [M+1] +=503. 1 for Example 73a.

Electrospray MS [M+1] +=503. 1 for Example 73b.

Example 74 Compound 61 (1. 68g, 2. 36mmol, 1 equiv) was dissolved in CH2CI2 (50ml), TFA (5. 46ml, 70. 9mmol, 30equiv) was added and the reaction mixture was stirred at 23°C for 2.5 h. The reaction was quenched carefully with sat. aq. NaHCO3 (150ml) and diluted with CH2CI2 (100ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated to give crude amino-alcohol product (1. 4g, 97%). The

product (0. 32g, 0. 524mol, 1equiv) was dissolved in dry THF (10ml) and NaH (60% in mineral oil, 0. 025g, 0. 63mmol, 1.2equiv.) was added. The reaction mixture was stirred at 23°C for 5 min and then ethyl chloroacetate (0. 062ml, 0. 576mol, 1. 1equiv) was added and the reaction mixture was stirred for 2.5 h. The reaction was quenched carefully with sat. aq. NaHC03 (100mol) and diluted with EtOAc (200moi). The organic layer was separated, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography over Biotage (2: 3, hexane: EtOAc) to give the product (0. 1g, 32%) which was hydrogenated to afford the mixture of two isomers Example 74a and 74b using a procedure similar to the preparation of Examples 43a and 43b from Compound 48.

The mixture of two products was separated on HPLC"ChiralCel OD column"using (1: 9, IPA : hexane) to afford pure Example 74a, Electrospray MS [M+1] + 517.1, and pure Example 74b, Electrospray MS [M+1] + 517.1.

Example 75 Step 1 : NH2 ' OMe 1. PyBOP, i-Pr2EtN, HOOC^NHBoc HOOC NHBoc r" J. Compound 57 Compound 62 2. TFA, CH2CI2 CbzN\ J Ph d CF3 Ph" Y"-"CF3 Compound 57 was converted to Compound 62 (72% yield over two steps) using the PyBOP coupling followed by TFA deprotection procedures as described in the preparation of Example 62 from Compound 55 but using Compound 57 (1equiv.) in place of ammonia and NH-Boc-glycine (2equiv. ) in place of Compound 55.

Step 2: Compound 62 (0.5g, 0. 72mmol, 1 equiv) was dissolved in MeOH (10mol) and Et3N (1 ml, 7. 2mmol, 10equiv) was added. The resulting mixture was heated at 23°C for 18 h. The reaction mixture was then concentrated and purified by column chromatography over Biotage (EtOAc) to give NCbz-diketopiperazine (0.33g) which was hydrogenated to afford the mixture of two isomers Example 75a and 75b using a procedure similar to the preparation of Examples 43a and 43b from Compound

48. The mixture of two products was separated on HPLC"ChiralPak AD column" using (5: 95, IPA : hexane) to afford pure less polar isomer Example 75a (0. 03g, 8% over two steps), Electrospray MS [M+1] + 530.1, and more polar isomer Example 75b, (0.04g, 11 % over two steps), Electrospray MS [M+1] + 530. 1.

Examples 76a and 76b Example 76a Example 76b Compound 51 (3.66g, 5. 76mmol, 1 equiv.) was hydrogenated using a procedure similar to the preparation of Examples 43a and 43b from Compound 48 and the hydrogenated product (2. 85g) was treated with CH3NH2 (2M solution in CH30H, 200ml) and stirred at 23°C for 18 h. The reaction mixture was then concentrated and purified by column chromatography over Biotage (1: 9, MeOH: EtOAc) to give the mixture of two isomers Example 76a and 76b. The mixture of two isomers was separated on HPLC"ChiralPak AD column"using (5: 95, IPA : hexane) to afford less polar isomer Example 76b, Electrospray MS [M+1] + 503.1, and more polar isomer Example 76a, Electrospray MS [M+1] + 503.1.

Example 77 Example 62 (0.07g, 0. 133mmol, 1equiv) was dissolved in CH2CI2 (3ml) and DIEA (0. 03ml, 0. 147mmol, 1. 1 equiv) was added followed by 4-methoxyphenyl (pmb) -isocyanate (0. 021 ml, 0. 147mmol, 1. 1 equiv) and the reaction mixture was stirred at 23°C for 18 h. The reaction mixture was then concentrated and treated with CH3CN (3ml) and water (1 ml) and the mixture was cooled to 0°C. Ammonium cerium nitrate (0.24g, 0. 44mmol, 4equiv) was added and the reaction mixture was stirred at 0°C for 45 min. The reaction was quenched with saturated aq. NaHC03 (100ml) and extracted with EtOAc (200ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated. The mixture was purified by column chromatography over Biotage (15: 85, MeOH: EtOAc) to give Example 77 (0.03g, 42%), Electrospray MS [M+1] + 533.1.

Examples 78a and 76b

Example 78a Example 78b Step 1 : OH ZON BrOH HN O Compound 48 K2CO3, DMF Cbz Compound 63 In a flame dry 15ml RBF Compound 48 (0. 25g, 0. 385mmol, 1equiv) in DMF (1ml) was added to K2CO3 (0.106g, 0. 77mmol, 2equiv) followed by 2-bromoethanol (0. 033moi, 0. 46mmol, 1.2equiv) and the mixture was stirred for 2h at RT, then heated to 50 °C for 6 h. The reaction was monitored by TLC (60/40 EtOAc/Hexane). The reaction mixture was cooled to 0°C, quenched with H20, diluted with EtOAc and washed with brine. The organic layer was combined and dried over Na2SO4, filtered and concentrated. The reaction mixture was purified using Biotage using 2: 3 EtOAc/Hexane to 3: 2 EtOAc/Hexane to elute Compound 63 as a mixture of two isomers (0.258g, 97%), Electrospray MS [M+1] + 694. 1.

Step 2: To a solution of Compound 63 (0.25g, 0. 36mmol, 1 equiv) in anhydrous MeOH was added (5. 5moi) 20% Pd (OH) 2/C (0.08g). The reaction mixture was purged with N2 followed by H2 and stirred for 18 h under H2. The reaction was monitored by TLC (60/40 EtOAc/Hexane). The catalyst was filtered through a plug of celite and the solution was concentrated to give crude product. The material was subjected to flash chromatography using a Biotage (80: 20 EtOAc/Hexane). The isomers were separated to give Example 78a and Example 78b (0. 13g, 63%).

Electrospray MS [M+1] + 560.1 for Example 78a (less polar isomer); Electrospray MS [M+1] + 560. 1 for Example 78b (more polar isomer).

Examples 79a and 79b

Example 79a Example 79b Step 1 : \ o N-Boc NS N-Boc O H HN CF3 Compound 63 PPH3, DEAD i Compound 64 THF Cbz CF3 N- (Boc)-methanesulfonamide (0. 041g, 0. 43mmol, 1.5equiv) was dissolved in dry THF (1 ml) and triphenyl phosphine (0. 228g, 0. 43mmol, 3equiv) was added. The resulting solution was stirred under N2 and a solution of Compound 63 (0.2g, 0. 29mmol, 1equiv) in THF followed by diethyl azodicarboxylate (DEAD) (0. 12ml, 0. 26mmol, 2.5equiv) were added. The reaction monitored by TLC (60/40 EtOAc/ Hexane). Upon completion, the reaction mixture was concentrated to give a yellow oil which was subjected to flash chromatography using a Biotage (1: 1 EtOAc/Hexane) to elute the product, Compound 64, as a mixture of two isomers (0.24g, 95%), Electrospray MS [M+1] + 871.1.

Step : 2 O=SO NH 4M HCI/Dioxane \ N - Compound 65 3 Compound 65 CbzN zN. o ; cF3 \/

To a solution of Compound 64 (0. 25g, 0. 29mmol, 1equiv) in dry CH2Cl2 (10mut) at 0°C was added 4M HCI in dioxane (0. 755mut, 2. 9mmol, 10equiv). The reaction was warmed to RT and monitored by TLC (60/40 EtOAc/Hexane). Upon completion the reaction was quenched with water, diluted with CH2CI2, washed with saturated NaHC03, and dried over Na2SO4 to give crude Compound 65 as a mixture of two isomers (0.2g, 89%). The crude material was carried forward without any purification.

Electrospray MS [M+1] + 771.1 for Compound 65.

Step: 3 To a solution of Compound 65 (0.2g, 0. 26mmol, 1equiv) in MeOH (5ml) was added10% Pd/C followed by ammonium formate (0.082g, 1. 3mmol, 5equiv). The reaction was refluxed under N2 for 3 h, then cooled to RT, filtered through celite, and concentrated. The residue was dissolved in EtOAc, washed with NaHC03 and dried over Na2SO4. The crude material was subjected to prep plate chromatography.

Both of the isomers were isolated to give pure Example 79a and Example 79b (0.06g, 36% total for both isomers).

Electrospray MS [M+1] + 637.1 for Example 79a (less polar isomer); Electrospray MS [M+1] + 637.1 for Example 79b (more polar isomer).

Example 80 To a solution of Example 62 (0. 079g, 0. 127mmol, 1equiv) in dry CH2CI2 (1ml) was added Et3N (0. 108ml, 0. 76mmol, 6equiv). The reaction mixture was cooled to 0 C and stirred for 15 min. S02CI2 (0. 011 ml, 0. 133mmol, 1.05equiv) was added very slowly to the reaction over 5 min. The reaction stirred for 10 h and was

monitored by TLC (9: 1 EtOAc/CH30H). The reaction mixture was diluted with EtOAc, washed with NaHC03, and dried over Na2SO4. The crude product was subjected to prep plate chromatography to isolate Example 80 (0. 015g, 20%), Electrospray MS [M+1] + 552. 1.

Example 81 Step 1: H2N o H2N CF3 i CbzN p Compound 66a and 66b , 0 Compounds 66a and 66b were prepared from Compound 48 using a procedure similar to the preparation of Example 62 from Example 43a.

Step 2: H Triethyl ortho- formate Compound 66a Acetic Acid 0. Compound 67a Toluene CbzN Reftux/'"yCF3 To a solution of Compound 66a (0.34g, 0. 545mmol, 1 equiv) in dry toluene (14ml) was added HOAc (0. 17mi) followed by triethyl orthoformate (0. 363ml, 2. 18mmol, 4equiv). The solution was refluxed for 12 h and monitored by TLC (9: 1 EtOAc/CH30H). The reaction was cooled to 0 C, quenched with H20, diluted with EtOAc, washed with NaHC03, and dried over Na2SO4. The crude was subjected to flash chromatography using a Biotage (60: 40 EtOAc/Hexane) to elute Compound 67a (0.272g, 79%), Electrospray MS [M+1] + 634. 1.

Step3 : Example 81 was prepared from Compound 67a using a similar procedure as for Examples 79a and 79b from Compound 65.

Electrospray MS [M+1] + 500.1 for Example 81.

Example 82

Step 1: H ruz HN CF3 HN CF, NaBH4 MeOH Compound 67a and 67b CbzN Compound 68 To a solution of a mixture of the two isomers of Compound 67 (0.27g, 0. 426mmol, 1 equiv) in dry CH30H (3ml) was added NaBH4 (0.048g, 1. 28mmol, 3equiv). The reaction mixture bubbled upon the addition of the reagent, and was stirred for 5 h under N2. The reaction was monitored by TLC (60/40 EtOAc/Hexane), and upon completion was quenched with HOAc, concentrated, diluted with EtOAc, washed with NaHC03 and dried over Na2SO4. The crude product was a mixture of two isomers, Compound 68, (0.25g, 92%) and was carried forward without any purification.

Electrospray MS [M+l] + 636.1 for the Compound 68.

Step2: Example 82a (less polar isomer) and Example 82b (more polar isomer) (0.12g, 61%) were prepared from Compound 68 using a similar procedure as for preparing Examples 79a and 79b from Compound 65.

Electrospray MS [M+1] + 502.1 for Example 82a, Electrospray MS [M+1] + 502.1 for Example 82b.

Example 83 Step 1: 0 _X N zozo i Compound 66a-. CbzN.,,, p-p-TsOH Compound 69

To a solution of Compound 66a (0. 1g, 0. 16mmol, 1equiv) in a 25ml RBF in MeOH (0. 5moi) was added acetone (0. 352moi, 0. 48mmol, 3equiv) and p-TsOH (0.06g, 0. 32mmol, 2equiv). The reaction mixture was refluxed for 12 h and was monitored by mass spectrum analysis. Reaction upon completion was concentrated, diluted with EtOAc, washed with NaHC03, and dried over Na2SO4 to give Compound 69 (0. 1 g, 94%). The crude product was carried forward without any purification.

Step 2: Example 83 (0.026g, 33%) was prepared from Compound 69 using a similar procedure as forpreparing Examples 79a and 79b from Compound 65.

Electrospray MS [M+1] + 530.1 for Example 83.

Examples 84a and Example 84b Example 84a Example 84b Examples 84a and Example 84b were prepared using a similar procedure as for Examples 78a and 78b, but using 2-bromoethyl methyl ether instead of 2- bromoethanol.

Electrospray MS [M+1] + 574. 1 for Example 84a, Electrospray MS [M+1] + 574.1 for Example 84b.

Example 85 Example 85 (46mg, 88%) was prepared from Example 43b using a similar procedure as for Compound 63, but using allyl bromide instead of 2-bromoethanol.

Electrospray MS [M+1] + 556.1.

Examples 86a and Example 86b

Example 86a Example 86b Step 1: n PMB 0 PMB zu HN CF3 CbzN. Cbz .,. i0 CF3 Compound 70 Compound 70 (1.14, 99%) was prepared from Compound 48 using a similar procedure as for Compound 63 but using para-methoxybenzyl chloride instead of 2-bromoethanol. Electrospray MS [M+1] + 770.2.

Step 2: 0 PMB N CF3 'W/N CF, Compound 70 NaH, DMF cbzN bon Bu Compound 71 To a solution of Compound 70 (0.19g, 0. 25mmol, 1 equiv) in 1. 0mu of anhydrous DMF at 0°C was added NaH (60% dispersion in mineral oil, 0.012g, 0. 30mmol, 1.2equiv). After 5 min, the ice bath was removed and the reaction mixture was allowed to stir for 30 min before the addition of bromomethyl cyclopropane (0. 029ml, 0. 30mmol, 1.2equiv). After 20 h, the reaction mixture was quenched with saturated NH4CI solution and diluted with EtOAc. The layers were separated and the organic layer was washed once with brine, dried over Na2SO4, filtered and concentrated to give Compound 71 (0. 11g, 99%) Electrospray MS [M+1] + 824. 2.

Step 3: o NM B ZEN HN / CF, '°. i Compound 72 Compound 72 (0.24g, 90%) was prepared from Compound 71 using a similar procedure as for Examples 78a and 78b from Compounds 63. Electrospray MS [M+1] + 690. 1.

Step 4 : To a solution of Compound 72 (0.24g, 0. 34mmol, 1 equiv) in 5. 0m ! of CH3CN and 1. 7m1 of water at 0°C was added ammonium cerium nitrate (0.79g, 1. 4mmol, 4equiv). After 5 min the ice bath was removed and the reaction mixture was allowed to stir at RT for 17 h. The reaction mixture was quenched with water and diluted with EtOAc. The layers were separated and the organic layer was washed with water (100mol x 2), dried over Na2SO4, filtered and concentrated to give a yellow oil.

Purification by chromatography on a Biotage eluting with the solvent gradient 20% EtOAc/hexane to 30% EtOAc/hexane to 50% EtOAc/hexane gave a diastereomeric mixture of Examples 86a and 86b (15mg, 8%), isomerically pureless polar Example 86a (14mg, 7%) Electrospray MS [M+1] + 570.1, and isomerically pure more polar Example 86b (16mg, 9%) Electrospray MS [M+1] + 570.1.

Example 87 Step 1: 0 PMB zon M/0 HOw/ß CF3 ,, 0 Compound 73 '''. i \/ Compound 73 (0.20, 64%) was prepared from Compound 48 using a similar procedure as for Compound 63. Electrospray MS [M+1] + 814. 19.-

Step 2: 0 PMB zon i/0 HO~ ß CF3 ZU Compound 74 W . -/_

Compound 74 (0.16g, 96%) was prepared from Compound 73 using a similar procedure as for Examples 78a and 78b from Compound 63. Electrospray MS [M+1] + 680. 1.

Step3: Examples 87a and 87b were prepared from Compound 74 using a similar procedure as for Example 86a and 86b from Compound 72, but purification using a Gilson with water/CH3CN was used instead of chromatography on a Biotage to isolate a diastereomeric mixture of Examples 87a and 87b (92mg, 71 %). HPLC separation on 50mg of the mixture on a ChiraICel OD column using a (90/10) hexane/IPA as the eluent gave a diastereomeric mixture of Example 87a and 87b (11 mg), isomerically pure first-eluted product Example 87a (1 Omg) Electrospray MS [M+1] + 560.1, and isomerically pure second-eluted product Example 87b (11mg) Electrospray MS [M+1] + 570. 1.

Example 88 A diastereomeric mixture of Example 88a and 88b (22% overall yield in three steps from Compound 70) was prepared using a similar procedure as for Example 86a and 86b, but using 2-bromoethyl methyl ether instead of bromomethyl cyclopropane. HPLC separation on 50mg of the diastereomeric mixture on a ChiralCel OD column using a (90/10) hexane/ ! PA as the eluent gave isomerically pure first-eluted product Example 88a (16mg) Electrospray MS [M+1] + 574.3, and isomerically pure second-eluted product Example 88b (29mg) Electrospray MS [M+1] + 574. 3.

Example 89 ° POs'- zon HN,,, 0 CF3 (N-Me-D-glucamine) 2 Han phO-YcFs

To a solution of Example 43b (0.68g, 1. 32mmol, 1equiv) in DMF (7ml) at 0°C was added NaH (60% in mineral oil, 0. 105g, 2. 64mmol, 2equiv) and the mixture was stirred at 0°C for 15 min. Tetravbenzyl pyrophosphate (1.42g, 2. 64mmol, 2equiv) was added and the reaction mixture stirred at 0°C for 15 min, then warmed to 23°C and stirred for 1 h. The reaction was quenched with saturated aq. NaHC03 (100mol) and extracted with EtOAc (100ml x 3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product purified by column chromatography over Biotage (2: 1, hexane: EtOAc) to afford the N-phosphorated hydantoin product (0. 24g) which was dissolved in MeOH (10ml) ; N-Me-D-glucamine (0.119, 0. 619mmol, 2equiv) was added, followed by 10% Pd-C (0. 021g). The resulting mixture was shaken in a parr shaker under H2 atmosphere at 40 psi for 18 h. The reaction mixture was filtered through a pad of celite and the celite was washed with MeOH. The resulting solution was concentrated in vacuo. The residue was dissolved in EtOAc (100ml) and extracted with water (100mi) and the aqueous layer was lyophilized to give the desired product Example 89 as N-Me-D-glucamine salt (0. 22g, 21 % over two steps).

Example 90 Step1 : HN 0 H2N CF3 i C b) z N.., 0 1 Compound 75 Compound 75 was prepared from Compound 48 using a procedure similar to the preparation of Compound 66 from Compound 48.

Step 2:

MeHN MeHN 0 C, H 0 Compound 75 CbzN Et3N, CH2CI2-CF3 Compound 76 To a solution of the diastereomeric Compound 75 (0. 1 Og, 0. 16mmol, 1equiv) in 2. Oml of anhydrous CH2CI2 at 0°C was added Et3N (0. 033ml, 0. 24mmol, 1.5equiv) and 4-chlorobutyrylchloride (0. 017ml, 0. 17mmol, 1.1 equiv). After 6 h, the reaction mixture was quenched with saturated NH4CI solution and diluted with EtOAc. The layers were separated and the organic layer was washed once with brine, dried over Na2SO4, filtered and concentrated to give Compound 76 as a diastereomeric mixture (0.12g, 100%) Electrospray MS [M+1] + 742.2.

Step3: MeHN N O CAF3 The Compound 76 NaH, CbzN y -YcFg Compound 77 To a solution of Compound 76 (0.12g, 0. 16mmol, 1 equiv) in 1. Oml of anhydrous THF at RT was added NaH (60% dispersion in mineral oil, 0. 010g, 0. 24mmol, 1.5equiv). After 3 h, the reaction mixture was quenched with saturated NH4CI solution and diluted with EtOAc. The layers were separated and the organic layer was washed once with brine, dried over Na2SO4, filtered and concentrated to give Compound 77 (0. 10g, 88%) Electrospray MS [M+1] + 706.2.

Step 4: Examples 90a and 90b were prepared from Compound 77 using a similar procedure as for preparing Example 83 from Compound 69, but purification used chromatography on a Biotage instead of a Prep plate. A diastereomeric mixture of Examples 90a and 90b (26mg, 32%) was obtained: less polar product Example 90a (20mg, 25%) Electrospray MS [M+1] + 572.1, more polar product Example 90b (14mg, 17%) Electrospray MS [M+1] + 572. 1.

Example 91 Step 1: Cbz Ph N ; CN -N=C 0 Compound 47 (Compound 78 tBuOK, DME, MeOH F3C F3C To a solution of Compound 47 (1g, 1. 73mmol, 1 equiv) and tosylmethyl- isocyanide (374mg, 1.9mmo !, 1. 1equiv) in anhydrous ethylene glycol dimethylether (11 ml) at-30 °C, was added anhydrous MeOH (0. 15ml) followed by addition of potassium tert-butoxide (426mg, 3. 8mmol, 2.2equiv). After stirring at-30°C to 10°C for 7 h, the reaction mixture was passed through celite. The celite pad was thoroughly washed with Et20. The filtrate was concentrated and the residue was purified on silica gel column to afford the titled Compound 78 (470mg, 46%).

Step 2: Cbz N-A/N i Ph<} 4N-N NaN3, NH4CI N Compound 78 ° DMF (Compound 79 DMF CFs F3C A solution of Compound 78 (125.7mg, 0. 21 mmol, 1 equiv) and NH4CI (68.3mg, 1/28mol, 6equiv) and NaN3 (69.2mg, 1. 06mmol, 5equiv) in anhydrous DMF (1. 2ml) under N2 was heated at 115°C overnight. The mixture was concentrated, then acidified with HCI (6N, 10ml) and extracted with EtOAc (15ml x 3). The combined organic solvent was dried over Na2SO4, filtered and evaporated in vacuum. The residue was purified on a silica gel column to afford Compound 79 (67mg, 50%).

Step 3: A solution of Compound 79 (65mg, 0. 103mmol, 1equiv) in EtOH (1. 5moi) was treated with 10% Pd-C (107mg, 0. 1mol, 1. equiv) and 1, 4-cyclohexadiene (0. 5ml, 5. 29mmol, 50equiv). The mixture was heated at 85°C for 10 min, then passed through celite. The celite pad was washed with MeOH. The filtrate was concentrated in vacuum and the residue was purified by silica gel column to afford Example 91 (11 mg, 21 %) Electrospray MS [M+1] + 500.1.

Example 92 Step 1: Cbz Ph3PCH3OMeCl Ph KHMDS, Toluene 0°C to r. t. then Compound 47 THF/10% aq. HCI (1 : 1 V/V)-CF3 Compound 80 F3C Compound 80 (72% yield) was prepared by similar procedure as for Compound 23 using Compound 47 in place of Compound 3.

Step 2: Cbz Pu II qCO2Et \f} >CO2Et (Et0) z-P Cl Compound 80 Compound 81 \/C LiHMDS, THF F3C To a solution of triethyl 2-chloro-2-phophonoacetate (73µl, 0. 34mmol, 1.05equiv) in anhydrous THF (1. 5moi) at-78°C, was added dropwise of LiHMDS (0. 35ml. 0. 35mmol, 1. 1 equiv, 1 N solution in THF). The solution was stirred for 20 min before a solution of Compound 80 (192mg, 0. 32mmol, 1 equiv). in dry THF (1 ml)

was cannulated in. It was stirred at-78°C for 2 h then quenched with saturated NH4CI aqueous solution, and extracted with Et20. The organic layer was dried over MgS04, filtered and concentrated to give the crude product which was purified by silica gel column to give Compound 81 (127mg, 57%).

Step 3: To a solution of Compound 81 (127mg, 0. 18mmol, 1. Oequiv) in EtOH (1ml) was added H2NNH2 (351l1, 1.1 mmol, 6equiv). It was stirred for 3 h and then concentrated in vacuum. The crude product was retaken up into EtOH (3ml) and treated with 10% Pd/C (40mg, 0. 036mol, 0.2equiv) and hydrogenated overnight.

The catalyst was filtered off and washed with MeOH. The filtrate was concentrated to give the crude residue which was purified on silica gel column to afford less polar isomer Example 92a (14.2mg, 15%), Electrospray MS [M+1] +514. 1; and more polar isomer Example 92b (28. 1mg, 30%), Electrospray MS [M+1] +514. 1 Example 93

Of NXH HN oBN HN i N CFg un Step 1 : HOOC CF3 Compound 80 EDC, HOOBt semicarbazide-HCI CbzN.,,, p caf3 DIEA, CH2CI2 Compound 82

Compound 80 (0.74g, 1. 25mmol, 1 equiv), was dissolved in t-BuOH (20moi) and 2-methyl-2-butadiene (7ml). To this solution was added a fresh solution of NaC102 (1.13g, 12. 5mmol, 10equiv. ) in 20% (v/w) aq. NaH2PO4 solution. The reaction mixture was stirred at RT for 2 h. It was then diluted with EtOAc (200ml) and the organic layer was separated, dried (Na2SO4), filtered and concentrated to give the crude Compound 82 which was used in the next reaction without further purification.

Step 2 : H2N -NH 0 0 FiN C F3 Compound 82 EDC, HOOBt CF3 semicarbazide-HCI CbzN DIEA, CH2CI2'' D ! EA, CH2Ci2 (t Compound 83

To a solution of the diastereomeric Compound 82 (0.33g, 0. 54mmol, 1 equiv) in 2 mi of anhydrous CH2CI2 at RT was sequentially added DIEA (0. 11 ml, 0. 65mmol, 1.2equiv), DEC (0. 21 g, 1. 1mmol, 2equiv), 3-hydroxy-1,2, 3-benzotriazin-4 (3H)-one (0.18g, 1. 1mmol, 2equiv), and semicarbazide hydrochloride (0.072g, 0. 65mmol, 1.2equiv). After 3 h, the starting carboxylic acid was present by TLC [Hexane- EtOAc 1: 1 (v/v)] and an additional amount of DIEA (0. 11 mL, 0. 65mmol, 1.2equiv) was added. After 2 days, the reaction mixture was quenched with saturated NaHC03 solution and diluted with EtOAc. The layers were separated and the organic layer was washed once with water and brine, dried over Na2SO4, filtered and concentrated to give an orange oil. Purification by chromatography on a Biotage eluting with the solvent gradient 50% EtOAc/hexane to 80% EtOAc/hexane to EtOAc to 5% MeOH/EtOAc gave Compound 83 as a diastereomeric mixture (0. 19g, 54%) Electrospray MS [M+11+ 667. 07.

Step 3: v -NH Oif N, H CF3 Compound 83 2M NaOH Cbz CF3 Compound 84 A solution of Compound 83 (0.17g, 0. 26mmol, 1 equiv) in 8ml of 2. 0M NaOH solution was heated to reflux. After 15 h, the mixture was allowed to cool to RT and was neutralized with 1. OM HCI to pH6. The aqueous solution was diluted with EtOAc and the layers were separated. The organic layer was washed once with brine, dried over Na2SO4, filtered and concentrated to give a yellow oil (0. 16g).

Purification by chromatography on a Biotage eluting with 3% MeOH/EtOAc gave Compound 84 as a diastereomeric mixture (0. 12g, 71%) Electrospray MS [M+1] + 649.2.

Step 4: Less polar product Example 93a and more polar product Example 93b (32mg and 44mg, total 88% for both isomers) were prepared from Compound 84 using a similar procedure as for preparing Examples 79a and 79b from Compound 65, but purification used chromatography on a Biotage instead of a Prep plate.

Electrospray MS [M+1] + 515.3 for Example 93a.

Electrospray MS [M+1] + 515.3 for Example 93b.

Example 94 Step 1: Cbz Ph OH \ OH 0 MeMgBr, THF (Compound 85 Compound 80 XCF3 F3C To a solution of Compound 80 (550mg, 0. 98mmol, 1equiv) in anhydrous THF (6ml) at-10°C, was added dropwise CH3MgBr (1. 24moi, 3. 7mmol, 4equiv, 3. 0M solution in Et20). The solution was stirred at-10°C to 10°C for 30 min. Aqueous work-up gave the crude product which was purified on silica gel column to afford Compound 85 (236mg, 42%).

Step 2: Ubz Ph N I 0 0 (COCI) 2, DMSO Compound 86 Compound 85- CH2CI2, Et3N CF3 F3C To a solution of DMSO (0.11 ml, 1. 55mmol, 4equiv) in anhydrous CH2C12 (5ml) at-78°C, was added dropwise oxalyl chloride (0. 067moi, 0. 78mmol, 2equiv).

The solution was stirred for 15 min before a solution of Compound 85 (236mg, 0. 387mmol, 1 equiv) in dry CH2Cl2 (1 ml) was cannulated in. It was stirred at-78°C

for 1 h, then Et3N (0. 37moi, 2. 71 mmol, 7equiv) was added dropwise. After stirring at - 78°C for 30 min, the cooling bath was removed and the reaction was warmed up to RT. It was quenched with saturated NH4CI aqueous solution, and extracted with CH2CI2. The organic layer was dried over MgS04, filtered and concentrated to give the crude product, which was purified by silica gel column to give Compound 86 (140mg, 60%).

Step 3: To a solution of Compound 86 (1. Oequiv) in EtOH (3moi) was added 10% Pd/C (0.4equiv) and the mixture hydrogenated overnight in a H2 balloon atmosphere. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated to give the crude residue which was purified on silica gel column to affordless polar isomer Example 94a (24mg, 22%), Electrospray MS [M+1] + 474.1 ; and more polar isomer Example 94b (32mg, 29%), Electrospray MS [M+1] + 474.1 Example 95 To a solution of Example 94a (16mg, 0. 033mmol, 1equiv) in anhydrous EtOH (1 ml) was added hydroxylamine hydrochloride salt (18mg, 0. 26mmol, 7.7equiv), and NaOAc (5mg, 0.061 mmol, 1.8equiv). The reaction mixture was stirred at RT overnight, then concentrated to dryness. The residue was retaken up with Et20, and washed with saturated NaHC03 aqueous solution. The organic layers were dried over MgS04, filtered and concentrated in vacuum. The crude product was purified on silica gel column to afford Example 95 (12mg, 74%), Electrospray MS [M+1] + 489. 1 Example 96 Example 96 (13mg, 50%) was prepared by similar procedure as for Example 95 but using Example 94b in place of Example 94a. Electrospray MS [M+1] + 489.1.

Example 97 Step 1: Cbz Ph N So OH (WO 1 om 1) EOEt tBuLi (Compound 87 Compound 47 2) HCI 10% aq. Y/3 THF F3C To a solution of ethyl vinylether (0. 5moi, 4. 83mmol, 12equiv) in anhydrous THF (6ml) at-78°C, was added dropwise tBuLi (0. 73ml, 1. 24mmol, 3equiv, 1.7N solution in pentane). The solution was stirred at-10°C bath until the orange color faded away. It was cooled to-78°C again, and a solution of Compound 47 (240mg, 0. 41 mmol, 1 equiv) in dry THF (1 ml) was cannulated in. It was stirred at-78°C for 1.5 h then was quenched with saturated NH4CI aqueous solution and extracted with Et20. The organic layer was dried over MgS04, filtered and concentrated to give the crude product, which was retaken up into THF (6ml) and treated with 10% HCI aqueous solution (0. 8ml). It was stirred at RT overnight. Alkaline aqueous work-up gave the crude product which was purified on silica gel column to afford Compound 87 (100mg, 39%).

Step 2: Ph HN- Fh HN _ O H OH Pd/C, EtOH,/ Compound 87 \/F3 \/ r F3C Compound 88a F3C Compound 88b Compound 88a and Compound 88b were prepared using a similar procedure as for Examples 94a and 94b using Compound 87 instead of Compound 86. Separation by chiral HPLC column afforded Compound 88a (13mg, 18%), and Compound 88b (10mg, 14%).

Step 3: PhHN-L. OH N OH H2NOHHCì w° Compound 88a _ NaOAc, EtOH ) ~ Example 97a F3C

Example 97a (9.7mg, 71 %) was prepared using similar procedure as for Example 95 using Compound 88a in place of Example 94a. Electrospray MS [M+1] +505. 1 Step 4: PhHNLOH (WO -OH 0 ... HsNOHHC !-\ Example 88b H2NOHHCI- NaOAc, EtOH XCF3 Example 97b F3C F3C Example 97b (10.7mg, 100%) was prepared using similar procedure as for Example 95 using Compound 88b in place of Example 94a. Electrospray MS [M+1] +505. 1 Example 98 and Example 99 P bNH bN 0 (}-N zon \/CF3 \ F3C Example 98 F3C Example 99 To Example 13 (340mg, 0. 76mmol) in 1 ml toluene was added Pd2 (dba) 3 (27.8 mg, 0. 03mol), BINAP (37.8 mg, 0. 06mol), 2-bromopyridine (73ll, 0. 76mmol) and NaOtBu (102mg, 1. 065mol). The mixture was concentrated in vacuo and the flask filled with N2. The process was repeated once. The dark-brown solution was heated at 90°C for 16h. It was cooled to 23°C and quenched with 2ml pH7 buffer. The solution was extracted with EtOAc (1 Oml x 2). The organic layers were dried over Na2SO4 and concentrated. HPLC separation give Example 98, Electrospray MS M+1] + 524.1 ; and Example 99, Electrospray MS [M+1] + 601.1.

Example 100

Example 100 was prepared using a similar procedure to Example 98, using 2-bromopyrimidine in place of 2-bromopyridine. Electrospray MS [M+1] + 525.1.

Example 101 Example 101 was prepared using a similar procedure to Example 98, using 2-chloro-3-cyanopyridine in place of 2-bromopyridine. Electrospray MS [M+1] + 549.1.

Example 102 Step 1: Cbz o Cbz o NH2 0 1) Ci3CONCO/ Compound 85 q Lv 2) K2CO3 CF3 MEOH-& Compound 88 F3C To Compound 85 (429mg, 0. 704mmol) in CH2Ci2 (3. 5mi) at 0°C was added CI3CONCO (1 00ml, 0. 844mmol) dropwise. The solution was stirred at 0°C for 2 h.

The solvent was then removed and the residue was dissolved in MeOH (4ml) and H20 (1 ml). K2CO3 (1. 0g) was added and the suspension was stirred for 14 h. The mixture was then diluted with 3ml of water, concentrated to remove MeOH. The residue was extracted with EtOAc (10mi x 3). The combined organic layers were concentrated and passed through a short silica gel column to give product Compound 88 (420mg, 91%).

Step 2: UI) Z Ph N 0 "I-il- Ph N9o Phl (OAc) 2 OH Rh (OAc) 2 MgO \ Compound 88 ego _ ifs Compound 89

To Compound 88 (290mg, 0. 446mmol) in CH2CI2 (3ml) was added Phl (OAc) 2 (131mg, 0. 625mol), Rh2 (OAc) 4 (12.9mg, 0. 022mmol) and MgO (26.4mg, 1. Ommol). The suspension was heated at 40°C for 16 h then cooled to 23°C. Celite (0.5g) was added and the suspension was stirred for 5 min. The mixture was filtered and washed with EtOAC. The combined filtrate was concentrated and purified by chromatography on silica gel to give Compound 89 (60mg, 31%).

Step 3: Compound 89 transferred to a Parr shaker using 5ml EtOH. 10% Pd-C (10%, 60mg) was added and the suspension was hydrogenated at 40psi overnight.

The reaction mixture was filtered and concentrated. The residue was separated using HPLC on OD column eluted with 1: 9 IPA/hexane to give two isomers, less polar isomer Example 102a, Electrospray MS [M+1] + 517. 1 and more polar isomer Example 102b, Electrospray MS [M+1] + 517.1.

Example 103

02CH3 CF3 (OEt) 2P (O) CH2C02CH3 CbZHNß C NaH, THF-16 NaH, THF- Compound 90

To a mixture of methyl diethylphosphonoacetate (9. 5ml, 51. 77mmol, 3equiv) in dry THF (100ml) at 0°C under N2 was added NaH (60% in mineral oil, 1.24g, 51. 77ml, 3equiv. ). After being stirred at 0°C for 15 min, a solution of Compound 3 (10g, 17. 26mmol, 1 equiv) in THF (250mi) was added. The mixture was warmed to 23°C and stirred for 1 h and then quenched with saturated aq. NaHC03 solution

(100ml). The mixture was extracted with EtOAc (1 00ml x 3). The combined organic layers were dried (MgS04) and filtered. The crude product was purified by column chromatography over Biotage (4: 1, hexane: EtOAc then 1: 1, hexane: EtOAc) to afford the Compound 90 (8.88g, 86%), Electrospray MS [M+1] + 596.1.

Step 2: C02CH3 CF3 Pt02, Ho Compound 90 CbzHN caf3 Compound 91 Compound 91 was prepared from Compound 90 using the procedure similar to the preparation of Compound 44 from Compound 42. The crude Compound 91 was used in the next reaction without further purification.

Step 3: HO CF3 NaBH4 Compound91. CbzH/, oßcF3 caf3 Compound 92 To a solution of Compound 91 (8.8g, 14. 73mmol, 1equiv.) in dry THF (1 50ml) was added LiBH4 (0.58g, 26. 51 mmol, 1.8 equiv. ) and the reaction mixture was stirred at 0°C for two h. The reaction mixture was cooled to 0°C over an ice bath and quenched with saturated NaHCO3 (50ml). The reaction mixture was extracted with EtOAc (3x100 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to give crude Compound 92 (8.2g), Electrospray MS [M+1] + 570.1, which was used in the next reaction without further purification.

Step 4: 0 H CF3 TEMPO I Compound 92 CbzHN,,, I Naomi CF3 NaOC !/== Y '3 Compound 93 To a solution of Compound 92 (8.2g, 14. 4mmol, 1. Oequiv.) in EtOAc (150mol) at 0°C was added saturated aq. NaHC03 (1 50ml) and the reaction mixture was stirred for 10 min at 0°C. NaBr (1.5g, 14. 4mmol, 0. 01equiv.) was added to the reaction mixture, followed by TEMPO (0.0225g, 0. 144mmol, 0.1 equiv), and bleach (5.25% in H2O, 20. 4ml, 14. 4mmol, 1. Oequiv.). The reaction mixture was stirred for 15 min at 0°C. The reaction was monitored by TLC in 1: 2 EtOAc/hexane which indicted presence of starting material. Additional NaOCI (2ml) was added to the

reaction mixture and was stirred for 15 min at 0°C and then it was quenched with saturated Na2S203 (20ml). The reaction mixture was extracted with EtOAc (1 50mol x 3). The combined organic layers were dried over (MgS04), filtered and concentrated to give crude Compound 93 (8g) which was used in the next reaction without further purification.

Step 4: ..-CF3 HMPA CbzN I Compound 93 PA Cb0) oAcF3 Compound 94 A mixture of Compound 93 (8g, 14. 1 mmol, 1. Oequiv. ) and HMPA (50ml) was heated at 170°C for two h. The reaction mixture was cooled to 23°C and quenched with water (50moi). The reaction mixture was extracted with Et20 (1 50mol x 3). The combined organic layers were dried over (MgS04), filtered and concentrated. The crude product purified by column chromatography over Biotage (7: 3, hexane: EtOAc) to afford Compound 94 (3.8g, 40% over three steps), Electrospray MS [M+1] + 550. 1.

Step 5: 0 CF3 1. BH2. SMe2, H202, NaOH CbzN I Compound 94 '' CF3 2. (COCI) 2, DMSO, Et3N Compound 95 Compound 95 was prepared from Compound 94 using the procedure similar to the preparation of Compound 47 from Compound 45. Electrospray MS [M+1] + 566. 1.

Step 6: Compound 95 was converted toless polar isomer Example 103a, Electrospray MS [M+1] + 502.1, andmore polar isomer Example 103b, Electrospray MS [M+1] + 502.1, using the procedure similar to the preparation of Example 43a and Example 44b from Compound 47.

Example 104 Step 1: KHMUS, TH i I CFg o L L r Com ound 1-7$ "1'0 F C CbzN"" O Br-CF3 Compound 96 3

Compound 96 was prepared from Compound 1 using the procedure similar to the preparation of Compound 3 from Compound 1. Electrospray MS [M+1] + 566.1 for the Compound 106.

Step 2: Compound 96 was converted to a mixture of Example 104a and Example 104b using the procedure similar to the preparation of Examples 43a and 44b from Compound 2. The mixture of two isomers was separated on HPLC"ChiralPak AD column"using (5: 95, IPA : hexane) to afford pure less polar isomer Example 104a, Electrospray MS [M+1] + 502.1 and more polar isomer Example 104b, Electrospray MS [M+1] + 502.1.

Example 105 Example 105 was prepared from Compound 54 using the procedure similar to the preparation of Compound 62 from Compound 54, but using CH3NH2 (2M in THF) in place of ammonia (0.5M in 1,4-dioxane). Electrospray MS [M+1] + 504.1.

Example 106a and Example 106b Example 106a Example106b Step1 : 1. Et t-BuLi, THF 0 2. 03, CH2CI2 HO OEt CF3 then Me2S - 3. Pd (OH), H."'CF3 Compound 47 Compound 97

To a solution of ethyl vinyl ether (2. 51ml, 26. 1mmol) in THF (50ml) at-78°C underN2, t-BuLi (6. 6ml, 11. 2mmol, 1.7M in pentane) was added. The mixture was warmed to 0°C and stirred until the color of the solution turned pale yellow. The mixture was then re-cooled at-78°C and a solution of Compound 47 (2.16g, 3. 73mmol) in THF (20ml) was added. The mixture was stirred at-78°C for 1 h before quenched with saturated NaHC03 solution. Water and Et20 were added to the mixture. Layers were separated and the aqueous layer was extracted with Et20 (200ml x 2). The combined organic layers were dried (K2CO3, Na2SO4) and filtered.

Solvents were removed in vacuum to give an alcohol as yellow oil. The alcohol was dissolved in CH2CI2 (20ml) and ozone was, bubbled through the solution at-78°C until pale blue color persisted. (CH3) 2S (2. 7moi, 37. 3mmol) was added and the mixture was warmed to RT. Solvents were removed in vacuum and purification by column chromatography [CH2CI2] gave an ester as colorless oil. The ester was dissolved in EtOH (20ml) and a catalytic amount of Pd (OH) 2 (20% on carbon) was added. The mixture was shaken in a Parr hydrogenator at 45 psi overnight. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a colorless oil. Separation by column chromatography [hexane-EtOAc, 4: 1 (v/v)] gave Compound 97 as colorless oil.

Step 2: Compound 97 was dissolved in CH3OH (10ml) and ammonia was bubbled through the solution for 30 min. The mixture was stirred at RT overnight and solvents were removed in vacuum to give a yellow oil. Separation by HPLC using Chiralcel OD [hexane-isopropanol, 9: 1 (v/v.)] gave the less polar major isomer Example 106a (15% overall) as white foam. Electrospray MS [M+1] +=491. 1.

Continuous elution with the same solvent system gave the more polar minor isomer Example 106b (10% overall) as white foam. Electrospray MS [M+1] +=491. 1.

Example 107 To a solution of cyclopropylamine (17111, 0. 20mmol) in toluene (1 ml) at RT under N2, Al (CH3) 3 (0. 1ml, 0. 20mmol, 2. 0M in toluene) was added. The mixture was allowed to stir at RT for 20 min. and a solution of Compound 97 (20mg, 0. 040mmol) in toluene (1 ml) was added. The mixture was heated at 60°C overnight and was cooled to RT. EtOAc was added and the mixture was quenched with

saturated potassium sodium tartarate solution. The layers were separated and the aqueous layer was extracted with EtOAc (100ml x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 2: 1 (v/v) ] gave Example 107 (11 mg, 56%) as colorless oil. Electrospray MS [M+1] +=531.

Example 108 Example 108a and Example 108b were prepared from Compound 97 using the procedure similar to the preparation of Example 107 from Compound 97 but using 2,2, 2-trifluoroethylamine in place of cyclopropylarnine. Electrospray MS [M+1] + 573.1 for the less polar isomer Example 108a and Electrospray MS [M+1] + 573.1 for the more polar isomer Example 108b.

Example 109 Step 1: CF3 0" Example 13 NH THF CF3 HN-ro Compound 98 HN p Compound 98 NHNHBoc To a solution of diamine Example 13 (150mg, 0. 336mol, 1 equiv) in anhydrous THF (5ml) at 0°C was added tert-butylcarbazine (44.4mg, 0. 336mol, 1 equiv) followed by CDI (65.4mg, 0. 404mmol, 1.2equiv). The reaction mixture was warmed to RT and stirred for 2 h. The reaction mixture was then concentrated and purified on a biotage (5: 95 MeOH/EtOAc) to give Compound 98 (170mg, 84%), Electrospray MS [M+1] + 605. 3.

Step 2: CF3 0" Ph 4M HCI/dioxane NH q Compound 98 CF3 HN>o Compound 99 NHNH2

To a solution of Compound 98 (170mg, 0.281 mmol, 1 equiv) in anhydrous CH2CI2 (15mi) at 0°C was added a 4M HCI solution in 1,4-dioxane (0. 7ml, 2.81 mmol, 1 Oequiv). The reaction mixture was warmed to RT and stirred for 18 h.

The reaction mixture was quenched with sat. aq. NaHC03 (100ml) and extracted with EtOAc (2 x 150mut). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product Compound 99 was used in the next reaction without further purification.

Step 3: To a solution of Compound 99 (160mg, 0. 317mmol, 1equiv) in anhydrous DMF (5ml) was added formaimidine acetate (165mg, 1. 6mmol, 5equiv) and the reaction mixture was stirred at RT for 30 min. HOAc (0.091 ml, 1. 6mmol, 5equiv) was added and the reaction mixture was heated at 80°C for 6 h. The reaction mixture was then cooled to RT, poured into EtOAc (200ml) and washed with water (3 x 100mi). The organic layer was dried (Na2SO4), filtered and concentrated. The crude mixture was purified on Gilson (1: 9 H20/CH3CN) to give Example 109 (50mg, 35%), Electrospray MS [M+1] + 515. 3.

Example 110a and Example 11 Ob 0 0 ,, ion, CF3 CF3 HN i HN i ''Vi 'i zozo Example 110a Example 110b Step 1: t ; Dz Ph tBuSONH Compound 47 Ti (/PrO) 4 0 CF3 Compound 100 CF3 Using a procedure similar to Example 11, step 2, Compound 47 was converted to the corresponding sulfinimine, Compound 100.

Step 2:

Cbz Cbz Ph N NHSOtBu Ph MgBr Compound 100 THF CF3 XCF3 - 78toO°C J t ! J Compound 101a Compound 101b CF3 CF3 Following a procedure similar to Example 11, Step 3, Compound 100 was converted to sulfinamide Compounds 101 a and 101b.

Step 3: Cbz PhvN NHSOtBu C02Me \C°2Me n Compound 101b- Grubbs'cat <CF3 Compound 102 CF3 A 15ml pear-shaped flask was charged with Compound 101b (140mg, 0. 193mmol, 1equiv) and CH2CI2 (1 ml). To this pale yellow solution was added Grubbs'catalyst (13.7mg, 0.016 mmol, 0.084 equiv), and methyl acrylate (21 , I, 0.232 mmol, 1.2 equiv). The resulting reddish solution was heated at 40 °C overnight and quenched with methylsulfoxide (0. 2ml). After stirring at RT for 20 h, it was diluted with Et2O and washed with water. The organic layer was dried over MgS04, filtered, and concentrated. The residue was purified by silica column to give Compound 102 (100mg, 66%).

Step 4: A RBF was charged with Compound 102 (100mg, 0. 128mol, 1 equiv) in EtOH (3ml), and Pd (OH) 2 on carbon (90mg, 0.128 mmol, 1equiv, 20% wt). A hydrogen balloon was attached on the top and the mixture was hydrogenated overnight. The reaction mixture was carefully passed through a celited funnel and the celite pad was washed thoroughly with MeOH. The filtrate was concentrated, then re-taken up into MeOH (2ml), treated with HCI (2ml, 4. 0M in 1,4-dioxane), stirred at RT for 2 h, then concentrated again, retaken up again into MeOH (5ml), treated with an excess amount of K2CO3, and heated at 50°C for 3 h, filtered, concentrated, and the resulted residue was purified on a silica column to afford Example 110a (42mg, 64%), Electrospray MS [M+1] + 515.1 Example 11 Ob (49%) was prepared by a similar procedure, but using Compound 101a. Electrospray MS [M+1] + 515.1 Example 111 a and Example 111 b

0 0 ki y I J CF HN CF3 CF3 HN'i HN i 'i0 /i0 CF3 /CF3 Example 111a Example 111b Step 1: Cbz . 0 Ph NHSOtBu PHHN HN4 1) HCI 0 0 OH2) (Cl3CO) 2O ° O Compounds 1) 03 7'q CF3 DIEA-CF3 + CF3 101 a and 101 b 2 NaBH4 3) H2, Pd/C separation CF3 CF3 CF3 Compound 103 Example 111a Example 111b An RBF was charged with a mixture of Compound 101 a and 101b (180mg, 0. 248mmol, 1. Oequiv) and CH2CI2 (2ml). This pale orange solution was cooled to -78°C, and then 03 was bubbled in. After the solution turned pale blue, the reaction solution was stirred at-78°C for 10 min, then it was flushed with N2 to get rid of 03.

The solvent was then removed carefully. The residue was dissolved in EtOH followed by addition of NaBH4 (120mg). The solution was stirred at RT for 12h. It was quenched with NH4CI solution. The reaction was extracted with EtOAc (3 x 10mi). The organic solution was washed with brine, dried and concentrated to give Compound 103, which was used in the next reaction without further purification.

The crude Compound 103 was dissolved in MeOH (2ml) and cooled to 0°C, followed by the addition of HCI (6ml, 4N in dioxane). After stirring for 3 h, the solvent was removed and the residue was redissolved in 3ml CH2CI2, followed by the addition of DIEA (1781l1). The solution was cooled to 0°C, triphosgene (36mg) was added, and the reaction was allowed to warm to RT and stirred for 3h. It was then diluted with EtOAc, washed with 5% HCI, NaHC03 (aq. ) and brine. The organic layers were dried with Na2SO4, filtered and concentrated. The crude product was hydrogenated to give a mixture of Example 111 a and 111b. The mixture was separated using prep TLC (5% MeOH in CH2CI2) to give Example 111a (less polar) and Example 111b (more polar). Electrospray MS Example 111a [M+1] + 517.1 ; Example 111a [M+1] + 517.1.

Example 112

To a solution of ethyl propiolate (83p1, 0. 82mmol) in THF (2ml) at-78°C under N2, t-butyllithium (0. 48moi, 0. 82mmol, 1.7M in pentane) was added. The mixture was stirred at-78°C for 10 min and a solution of Compound 47 (158mg, 0. 27mmol) in THF (1 ml) was added. The mixture was stirred at-78°C for 1 h before quenching with HOAc at-78°C. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200moi x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexanes-EtOAc, 4: 1 (v/v)] gave a colorless oil (112mg, 61 %). The oil was dissolved in EtOH and catalytic amount of palladium (10% on charcoal) was added. The mixture was shaken in a Parr hydrogenator at 45 psi overnight. The mixture was filtered through a pad of celite and solvents were removed in vacuum to give an ester as a colorless oil. The oil was dissolved in CH30H (1 Oml) and ammonia was bubbled through the solution for 30 min. The mixture was stirred at RT overnight and solvents were removed in vacuum. Purification by column chromatography [CH30H-EtOAc, 1: 9 (v/v) ] gave Example 112 as a colorless oil (54mg, 61%). Electrospray MS [M+1] +=519. 1.

Examples 113a and 113b Example 113a Example 113b To a solution of Compound 51 (1.97g, 3. 10mmol) in CH2CI2 (50ml) at-78°C, DIBAL-H (9. 3ml, 9. 3mmol, 1. OM in toluene) was added. The mixture was stirred at - 78°C for 1 h before it was quenched with saturated potassium sodium tartrate solution. The mixture was warmed to RT and water and EtOAc were added. Layers were separated and the aqueous layer was extracted with EtOAc (200 mi x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed

in vacuum and column chromatography [hexane-EtOAc, 3: 1 (v/v) ] gave the allylic alcohol (1.6g, 85%) as colorless oil.

The allylic alcohol (1.6g, 2. 63mmol) was dissolved in triethylorthoacetate (30ml) and catalytic amount of propanoic acid was added. The mixture was heated in a sealed-tube at 130°C overnight. Solvents were removed in vacuum and column chromatography [hexane-Et2O, 5: 1 (v/v) ] gave the alkene (891 mg, 50%) as colorless oil.

The alkene (891 mg, 1. 31 mmol) was dissolved in CH2CI2 (20ml) and was cooled at-78°C. 03 was bubbled through the solution until a pale blue color persisted in the solution. The mixture was purged with N2 until a colorless solution was obtained. Methyl sulfide (1 ml) was added and the mixture was warmed to RT.

Solvents were removed in vacuum and column chromatography [Hexanes-EtOAc, 5: 1 (v/v) ] gave the aldehyde (800mg, 90%) as colorless oil.

The aldehyde (280mg, 0.41 mmol) was dissolved in isoprene (2. 4ml) and t- butyl alcohol (7ml) at RT. A solution of sodium chlorite (414mg, 4. 12mmol) in sodium dihydrogenphosphate (4ml, 20% wt. in water) was added. The mixture was stirred at RT vigorously for 2 h. Water and EtOAc were added. Layers were separated and the aqueous layer was extracted with EtOAc (250ml x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum to give a crude acid as yellow oil.

The crude acid was dissolved in CH2CE2 (1 Oml) at RT and diisopropylamine (0. 22ml, 1. 24mmol), followed by PyBOP (322mg, 0. 62mmol) were added. The mixture was stirred at RT for 20 min. before a solution of ammonia in dioxane (8ml, 4. 12mmol) was added. The mixture was stirred at RT overnight before it was quenched with saturated NaHC03 solution. Water and EtOAc were added. Layers were separated and the aqueous layer was extracted with EtOAc (250mut x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum to give the crude amide as yellow oil.

The crude amide was dissolved in CH30H (1 Oml) and Pd (OH) 2 (20% on carbon) was added. The mixture was stirred under H2 (balloon) for 4 h. Solid was filtered through a pad of celite and solvents were removed in vacuum to give the crude amino-amide as yellow oil.

The crude amino-amide was dissolved in CH30H and excess NaOCH3 was added. The mixture was heated at 60°C for 1 h before it was quenched with saturated with saturated NH4CI solution. Water and EtOAc were added. Layers were separated and the aqueous layer was extracted with EtOAc (250ml x 2). The combined organic layers were dried (MgS04) and filtered. Solvents were removed

in vacuum and column chromatography [hexane-EtOAc, 2: 1 (v/v) ] gave the less polar isomer Example 113a (20mg, 9%, 4 steps overall) as white foam. Electrospray MS [M+1] +=515. 1. Continuous elution with the same solvent system gave the more polar isomer Example 113b (25mg, 12%, 4 steps overall) as colorless oil.

Electrospray MS [M+1] +=515. 1.

The above description is not intended to detail all modifications and variations of the invention. It will be appreciated by those skilled in the art that changes can be made to the embodiments described above without departing from the inventive concept. It is understood, therefore, that the invention is not limited to the particular embodiments described above, but is intended to cover modifications that are within the spirit and scope of the invention, as defined by the language of the following claims.