AU2015202475A1 - Piperidine derivatives as nk1 antagonists - Google Patents

Abstract

OF THE INVENTION A compound having the general structure shown in Formula 1: R' R2 Ar2 5 Ar' O R3 (I) or pharmaceutically acceptable salts and/or solvates thereof are useful in treating diseases or conditions mediated by NK1 receptors, for example 10 various physiological disorders, symptoms or diseases, including emesis, depression, anxiety and cough.

Description

NK

1 ANTAGONISTS This application claims the benefit of U.S. Provisional Application No. 5 60/584,502, filed July 1, 2004. FIELD OF THE INVENTION The present invention relates to novel neurokinin-1 (NK 1 or NK-1) receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds, to treat NK 1 10 receptor mediated diseases and conditions, including, for example, emesis, depression, anxiety and cough. BACKGROUND OF THE INVENTION Tachykinins are peptide ligands for neurokinin receptors. Neurokinin 15 receptors, such as NK1, NK 2 and NK 3 , 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 has been studied to potentially treat or prevent various mammalian disease states. For instance, NK1 receptors have been 20 reported to be involved in microvascular leakage and mucus secretion. Representative types of neurokihin receptor antagonists and the disorders that can be treated with them include, for example, sleep, pain, migraine, emesis, nociception anI inflammation; see, for example, U.S. 6,329,401, U.S. 5,760,018, U.S. 5,620,989, WO 95/19344, WO 94/13639, WO 94/10165, Wu 25 et al., Tetrahedron, 56, 6279-6290 (2000), Rombouts et al., Tetrahedron, 59, 47_21-4731 (2003),_andRogiers et al., Tetrahedron, 57, 8971-8981 (2001). It would be beneficial to provide a NK 1 antagonist that is potent, selective, and possesses beneficial therapeutic and pharmacological properties, and good metabolic stability. It would further be beneficial to 30 provide a NK 1 antagonist that is effective for treating a variety of physiological disorders, symptoms and diseases, while minimizing side effects. This invention provides such NK 1 antagonists. -1- SUMMARY OF THE INVENTION In one embodiment, the present invention is directed to a compound of Formula I: R'

R

2 Ar 2 RN )n Ari O R3 5 (1) or pharmaceutically acceptable salts and/or solvates thereof, wherein: . R 1 and R 2 are each independently selected from the group consisting of H, alkyl, haloalkyl, alkyl substituted with one or more hydroxyl groups, -CN, alkynyl, -N(R 6

)

2 , -N(R 6 )-S(0 2 )-alkyl, -N(R 6

)-C(O)-N(R

9

)

2 , -alkylene-CN, 10 -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR)-alkyl,

-C(O)-N(R

9

)

2 , -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R 9

)

2 , 0 Y N H N N N )mn 1W N OL N N N i~, ir- jiliand -Ii, Y X, >()m N with the proviso that at least one of R 1 and R 2 is -CN, 'r , 0 N NN N.N O HN N o N 4 -N 0N 15 J , , or W is =C(R 8 )- or =N-; X is -C(0)- or -S(0 2 )-; Y is selected from the group consisting of -OH 2 -, -0-, and -N(R)-C(0)-, with the proviso that: 20 (a) the nitrogen atom of -N(R 6 )-C(O)- is bonded to X, and -2- Y N (b) if R' and/or R 2 is a and Y is -O-, X is not -S(0 2 )-; Z is -C(R 7

)

2 -, -N(R)-, or -0-;

R

3 is selected from the group consisting of H, -CH 2

OR

5 , and alkyl;

R

4 is selected from the group consisting of H, alkyl, cycloalkyl, 5 heterocycloalkyl, heteroaryl, aryl, acyl, aroyl, alkylsulfonyl, and arylsulfonyl;

R

5 is H or alkyl;

R

6 is selected from the group consisting of H, alkyl, cycloalkyl, and aryl; each R 7 is independently H or alkyl; or each R , together with the ring carbon to which they are shown 10 attached, form a cycloalkylene ring;

R

8 is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -N(R 6

)

2 , -N(R)-S(0 2 )-alkyl,

-N(R

6

)-S(O

2 )-aryl, -N(R 6 )-C(O)-alkyl, -N(R 6 )-C(O)-aryl, alkylene-O-alkyl, and -CN; 15 R 9 is selected from the group consisting of H, alkyl, and aryl, or each

R

9 , together with the nitrogen to which they are shown attached, form a heterocycloalkyl ring; Arl and Ar 2 are each independently selected from the group consisting of unsubstituted aryl and aryl substituted with 0 to 3 substituents selected 20 from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -CN, -OH, and -NO 2 ; n is 0, 1, or 2; and m is 1, 2, or 3. In another embodiment,~the present invention is directed to a 25 pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable carrier. In another embodiment, the present invention is directed to a kit comprising two or more containers in a single package, wherein each 30 container in the package comprises a pharmaceutical composition. At least one container of the package comprises an effective amount of the compound -3of Formula 1, or a pharmaceutically acceptable salt and/or solvate thereof in a pharmaceutically acceptable carrier, and at least one other container of the package comprises another therapeutic agent in a pharmaceutically acceptable carrier. The pharmaceutical compositions of the kit may be used 5 in combination. In another embodiment, the present invention is directed to a method for affecting an NK 1 receptor in a patient. The method comprises administering to the patient an effective amount of at least one compound of -Formula I or a pharmaceutically acceptable salt and/or solvate thereof. 10 In another embodiment, the present invention is directed to a method for treating an NK, receptor mediated condition or disease (i.e., a disease associated with an NK 1 receptor, or a disease involving an NK 1 receptor in part of the disease process) in a patient in need of such treatment The method comprises administering to the patient an effective amount of at least 15 one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. 20 DETAILED DESCRIPTION OF THE INVENTION In a first embodiment, the present invention is directed to a compound of Formula 1, or a solvate and/or salt thereof, as described herein. In yet another embodiment, the compounds of Formula I have the following structure IA:

R

1 RA Ar 2 N) 25 Ar 1 - 0 Ra (IA) In yet another embodiment of the compounds of Formula 1, R 3 is C1.6 alkyl; R4 is H; 30 Ar is phenyl; -4- Ar 2 is a phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1.6 alkyl, C 1

.

6 alkoxy, C 1

.

6 haloalkyl, C 1

..

6 haloalkoxy, -CN, and -NO 2 ; and n is 1. 5 In yet another embodiment of the compounds of Formula I, R 3 is alkyl;

R

4 is H; Ar is phenyl; Ar2 is phenyl substituted with I to 3 substituents selected from the group consisting of halogen, C1.6 alkyl, C1.e alkoxy, C1.e haloalkyl, C1.6 10 haloalkoxy, -CN, and -NO 2 ; and n is 1. In yet another embodiment, the compounds of Formula I have the following structure IA: R' R 2 R 4'N )n Ar - R 3 15 (IA)

R

3 is C1..e alkyl; R4 is H; Ar 1 is phenyl; Ar2 is phenyl substituted with 1 to 3 substituents selected from the 20 group consisting of halogen, C1.6 alkyl, C1.e alkoxy, C1..e haloalkyl, C1.6 haloalkoxy, -CN, and -NO 2 ; and n is 1. ln-yet another embodiment, -the compounds of Formula I have the following structure IA: Ar 2 R R 25 Ar O R3 (IA) wherein R 1 and R 2 are each independently selected from the group consisting of H, -CH 3 , -CH 2

CH

2

CH

3 , -CH 2 CI, -CH 2 F, -CHC1 2 , -CHF 2 , -CF 3 , -5-

-CH

2 OH, -CH 2

CH

2 OH, -CH 2

CH(OH)CH

3 , -CH 2

C(OH)(CH

3

)

2 , -CN, -CH 2 CN,

-NH

2 , -NH-S(0 2

)-CH

3 , -NH-C(O)-NH 2 , -CH 2 0CH 3 , -C(O)-CH 3 ,

-C(O)-CH

2

CH

3 , -C(=N-OH)-CH 3 , -C(=N-OH)-CH 2

CH

3 , -C(=N-OCH 3

)-CH

3 ,

-C(O)-NH

2 , -C(O)-NH(CH 3 ), -C(O)-O-CH 3 or -C(O)-O-CH 2

CH

3 , 5 -CH 2

-C(O)-CH

3 , -CH 2

-C(O)O-CH

3 , -CH 2

-C(O)O-CH

2

CH

3 ,

-CH

2

C(O)-NH(CH

2

CH

3 ), -CH 2

C(O)-NH

2 , 0, 0 0 OH O N -N --- -- - N NH --- NH \--- N H 0, 0 , 0 , 0 , 0 0

OCH

3 -CH 3

H

2 N HN N -N \N ,NN= NH -- N NH --N>NH N NH -N CH 3 Y CH 3 0 , 0 , 0 -- HN 0 , J-, %--NyN, and 10 R3 is -CH 3 ;

R

4 is H; Ar is phenyl; Ar 2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1.6 alkyl, C1.6 alkoxy, C1.6 haloalkyl, C1.6 15 haloalkoxy, -CN, and -NO 2 ; and n is 1. In yet another embodiment of the compounds of Formula 1, Ar' is unsubstituted phenyl or phenyl substituted with I to 3 substituents selected - 6from the group consisting of Cl, F, Br, -OH, C1.6 alkyl, C1.6 alkoxy, C1.6 haloalkyl, C1.

6 haloalkoxy, -CN, and -NO 2 . In yet another embodiment of the compounds of Formula I, Ar' is unsubstituted phenyl. 5 In yet another embodiment of the compounds of Formula I, Ar 2 is unsubstituted phenyl or phenyl substituted with 1 to 3 substituents selected from the group consisting of Cl, F, Br, -OH, C1.6 alkyl, C1.6 alkoxy, C1.6 haloalkyl, C1.

6 haloalkoxy, -CN, and -NO 2 . In yet another embodiment of the compounds of Formula I, Ar2 is 10 substituted phenyl. In yet another embodiment of the compounds of Formula I, Ar2 is 3,5 bis(trifluoromethyl)phenyl. In yet another embodiment of the compounds of Formula I, R' is H. In yet another embodiment of the compounds of Formula I, R1 is a C1.6 15 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl. In yet another embodiment of the compounds of Formula I, R' is a C1.6 haloalkyl, for example -CH 2 CI, -CH 2 F, -CHCl 2 , -CHF 2 , -CF 3 . In yet another embodiment of the compounds of Formula I, R' is a C2-6 20 alkynyl, for example -CeC-H, -CeC-CH 3 , -CeC-CH 2

CH

3 , etc. In yet another embodiment of the compounds of Formula 1, R' is a C1.6 alkyl substituted with one or more hydroxy groups, for example -CH 2 OH,

-CH

2

CH

2 OH, -CH 2 CH(OH)CH3, or -CH 2

C(OH)(CH

3

)

2 . In yet another embodiment of the compounds of Formula I, R' is -CN 25 or -C1.6 alkylene-CN, for example -CH 2 CN. .-- In-yet-another-embodiment of the compounds of Formula I, R' is -NH 2 . In yet another embodiment of the compounds of Formula I, R' is -NH-S(0 2

)-C

1

.

6 alkyl, for example -NH-S(0 2

)-CH

3 . In yet another embodiment of the compounds of Formula I, R1 is 30 -NH-C(O)-NH 2 . In yet another embodiment of the compounds of Formula I, R' is -C1.6 alkylene-O-C 1

.

6 alkyl, for example -CH 2 0CH 3 . In yet another embodiment of the compounds of Formula 1, R 1 is -C(O)-C1.6 alkyl, for example -C(O)-CH 3 or -C(O)-CH 2

CH

3 . -7- In yet another embodiment of the compounds of Formula 1, R' is

-C(=N-OH)-C

1

.

6 alkyl or -C(=N-O-C 1

.

6 alkyl)-C1.e alkyl, for example

-C(=N-OH)-CH

3 , -C(=N-OH)-CH 2

CH

3 , or -C(=N-OCH 3

)-CH

3 . In yet another embodiment of the compounds of Formula I, R' is 5 -C(O)-NH(C 1 .E alkyl), -C(O)-N(C.e alkyl) 2 , -C(O)-NH(C 6

.

1 o aryl), -C(O)-N(C 6 .10 aryl) 2 , -C(O)-N(CP6 alkyl)( C.10 aryl), or -C(O)-NH 2 , for example -C(O)-NH 2 or -C(O)-NH(CH 3

)

In yet another embodiment of the compounds of Formula I, R' is -C(O)-O-CI.6 alkyl, for example -C(O)-O-CH 3 or -C(O)-O-CH 2

CH

3 . 10 In yet another embodiment of the compounds of Formula 1, R' is -C 1

.

6 alkylene-C(O)-C 1 .6 alkyl, for example -CH 2

-C(O)-CH

3 . In yet another embodiment of the compounds of Formula I, R 1 is -C1.s alkylene-C(O)-O-C1.6 alkyl, for example -CH 2

-C(O)O-CH

3 or

-CH

2

-C(O)O-CH

2

CH

3 . 15 In yet another embodiment of the compounds of Formula I, R 1 is -C1.6 alkylene-C(O)-NH 2 , -C1.6 alkylene-C(O)-NH(C 1

.

6 alkyl), -C1.6 alkylene-C(O)-N(C1.6 alkyl)2, -C1.., alkylene-C(O)-NH(C.1o aryl),-C 1

.

6 alkylene-C(O)-N(C.1o aryl)2, or -C1.6 alkylene-C(O)-N(C1.E alkyl)(C 6

.

1 o aryl), for-example -CH 2

C(O)-NH(CH

2

CH

3 ) or -CH 2

C(O)-NH

2 . 20 In yet another embodiment of the compounds of Formula l,*R is one of: O, O , O0 0, O0 OH

OCH

3 0

/H

2 N -- N NH -- NH ~'N N \ -- N N N NH -- 8 PN N N -N NH YNH N H r NH O 0 0 O - CH 3 HN N-=N /N=N / N N -- N IH N .- N NH /--N CH 3 --NI N H HN \ -N OH 3 00 0 0 0 U -N N ,orO In yet another embodiment of the compounds of Formula 1, R 2 is H. In yet another embodiment of the compounds of Formula 1, R 2 is a C1.6 5 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl. In yet another embodiment of the compounds of Formula I, R 2 is a C1.6 haloalkyl, for example -CH 2 CI, -CH 2 F, -CHCl 2 , -CHF 2 , -CF 3 . In yet another embodiment of the compounds of Formula I, R 2 is a C2.6 10 alkynyl, for example -CaC-H, -CeC-CH 3 , -CaC-CH 2

CH

3 , etc. In yet another embodiment of the compounds of Formula 1, R 2 is a C1.6 alkyl substituted with one or more hydroxy groups, for example -CH 2 OH,

-CH

2

CH

2 OH, -CH 2

CH(OH)CH

3 , or -CH 2

C(OH)(CH

3

)

2 . In yet another embodiment of the compounds of Formula I, R 2 is -CN 15 or -C 1

.

6 alkylene-CN, for example -CH 2 CN or -C(CH 3

)

2 CN. In yet another embodiment of the compounds of Formula 1, R 2 is -C3-6 S-C-CN cycloalkylene-CN, for example /A In yet another embodiment of the compounds of Formula 1, R 2 is -NH 2 . In yet another embodiment of the compounds of Formula I, R 2 is 20 NH-S(0 2

)-C

1

.

6 alkyl, -N(C1.

6 alkyl)-S(0 2

)-C

1

.

6 alkyl or -N(C 6

.

1 0 aryl)-S(0 2

)-C

1 .e alkyl for example -NH-S(0 2

)-CH

3 . In yet another embodiment of the compounds of Formula I, R 2 is

-NH-C(O)-NH

2 . -9- In yet another embodiment of the compounds of Formula 1, R 2 is -C1.6 alkylene-O-C1.e alkyl, for example -CH 2 0CH 3 . In yet another embodiment of the compounds of Formula 1, R 2 is -C(O)-C1.6 alkyl, for example -C(O)-CH 3 or -C(O)-CH 2

CH

3 . 5 In yet another embodiment of the compounds of Formula I, R 2 is

-C(=N-OH)-C

1

.

6 ,alkyl or -C(=N-O-CI- 6 alkyl)-CIe alkyl, for example

-C(=N-OH)-CH

3 , -C(=N-OH)-CH 2

CH

3 , or -C(=N-OCH 3

)-CH

3 . In yet another embodiment of the compounds of Formula 1, R 2 is -C(O)-NH(C1.6 alkyl), -C(O)-N(C1.e alkyl)2, -C(O)-NH(C6.10 aryl), -C(O)-N(Ce..10 10 aryl) 2 , -C(O)-N(CI-e alkyl)( C5.

10 aryl), or -C(O)-NH 2 , for example -C(O)-NH 2 or -C(O)-NH(CH 3 ). In yet another embodiment of the compounds of Formula I, R 2 is -C(O)-O-C1..6 alkyl, for example -C(O)-O-CH 3 or -C(O)-O-CH 2

CH

3 . In yet another embodiment of the compounds of Formula 1, R 2 is -C 1

.

6 15 alkylene-C(O)-C1.6 alkyl, for example -CH 2

-C(O)-CH

3 . In yet another embodiment of the compounds of Formula 1, R 2 is -C1.6 alkylene-C(O)-O-Ct.6 alkyl, for example -CH 2

-C(O)O-CH

3 or

-CH

2

-C(O)O-CH

2

CH

3 . In yet another embodiment of the compounds of Formula I, R 2 is -C1.6 20 alkylene-C(O)-NH 2 , -C1.6 alkylene-C(O)-NH(Cle 6 alkyl), -C6 alkylene-C(O)-N(C1.6 alkyl) 2 , -C1.6 alkylene-C(O)-NH(Cr.10o aryl),-Ce 6 alkylene-C(O)-N(C 6 .1o aryl) 2 , or -C6 alkylene-C(O)-N(Cl.6 alkyl)(C 6 .1o aryl), for example -CH 2

C(O)-NH(CH

2

CH

3 ) or -CH 2

C(O)-NH

2 . In yet another embodiment of the compounds of Formula 1, R 2 is one 25 of: 0, 0 , O OH

OCH

3 0

H

2 N O N -N -N HN-N -- N NH --N NH -N NH --N NH NH O , O , O , O , O , -10- 0 OSICH 3 0// HN -N N=N /N N N N -- N OH 3 --N

OH

3 00 0 , 0 , 0 HN N HN o ,--N NJor0 In yet another embodiment of the compounds of Formula I, R 3 is a C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, 5 n-pentyl, or n-hexyl. In yet another embodiment of the compounds of Formula 1, R 4 is H. In yet another embodiment of the compounds of Formula I, R 4 is C1.6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl. 10 In yet another embodiment of the compounds of Formula 1, R 4 is C3-6 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In yet another embodiment of the compounds of Formula I, R 4 is C3_6 heterocycloalkyl, for example pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahyd ropyranyl, azetidinyl, morpholinyl, piperazinyl, or 15 piperidinyl. In yet another embodiment of the compounds of Formula 1, R 4 is C5-12 heteroaryl, for example benzimidazolyl, benzofuranyl, benzothiophenyl, fD-ra ThliidalylVIisogUitilyl,~pyrazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, quinoxalinyl, quinazolinyl, thiophenyl, isoxazolyl, triazolyl, thiazolyl, or 20 thiadiazolyl. In yet another embodiment of the compounds of Formula 1, R 4 is C aryl, for example phenyl or naphthyl. In yet another embodiment of the compounds of Formula I, R 4 is C1.6 acyl, for example -C(O)CH 3 , -C(O)CH 2

CH

3 , -C(O)CH 2

CH

2

CH

3 , 25 -C(O)CH(CH 3

)

2 , -C(O)C(CH 3

)

3 , or -C(0)CH 2

CH(CH

3

)

2 . - 11 - In yet another embodiment of the compounds of Formula 1, R 4 is C6o1 aroyl, for example benzoyl or naphthoyl. In yet another embodiment of the compounds of Formula I, R 4 is C1.3 alkylsulfonyl, for example -S(0 2

)CH

3 or -S(0 2

)CH

2

CH

3 . 5 In yet another embodiment of the compounds of Formula I, R 4 is C6.1o arylsulfonyl, for example -S(0 2 )-phenyl or -S(0 2 )-naphthyl. In yet another embodiment of the compounds of Formula 1, R 5 is H. In yet another embodiment of the compounds of Formula I, R" is C1.6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, 10 n-pentyl, or n-hexyl. In yet another embodiment of the compounds of Formula I, R 6 is H. In yet another embodiment of the compounds of Formula 1, R 6 is C1.e alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl. 15 In yet another embodiment of the compounds of Formula I, R 6 is C 3 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In yet another embodiment of the compounds of Formula I, R 6 is C6.10 aryl, for example phenyl or naphthyl. In yet another embodiment of the compounds of Formula I, R 7 is H. 20 In yet another embodiment of the compounds of Formula I, R 7 is C 1

.

6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl. In yet another embodiment of the compounds of Formula 1, each R , together with the carbon atom to which they are shown attached, form a C 3

-

6 25 cycloalkyl ring, for example , I Ud , or 0 In yet another embodiment of the compounds of Formula 1, R 8 is H. In yet another embodiment of the compounds of Formula 1, Ra is C1.6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl. -12- In yet another embodiment of the compounds of Formula I, R 8 is -NH-S(0 2

)-C

1

-

6 alkyl, -N(C 1

.

6 alkyl)-S(0 2

)-C

1

.

6 alkyl or -N(C 6

.

1 0 aryl)-S(0 2

)-C

1

.

alkyl for example -NH-S(0 2

)-CH

3 . In yet another embodiment of the compounds of Formula 1, R 8 is 5 -NH-S(0 2

)-C

6

.

1 0 aryl, -N(C 1

.

6 alkyl)-S(0 2

)-C.

1 0 aryl or

-N(C

6

.

10 aryl)-S(0 2

)-C.

1 0 aryl, for example -NH-S(0 2 )-phenyl or -NH-S(0 2 )-4 methylphenyl. In yet another embodiment of the compounds of Formula 1, R 8 is

-NH-C(O)-C

1

.

6 alkyl, -N(C 1

.

6 alkyl)-C(O)-C 1 .- alkyl or -N(C 6

.

1 0 aryl)-C(O)-C 6 10 alkyl for example -NH-S(O 2

)-CH

3 . In yet another embodiment of the compounds of Formula I, R 8 is

-NH-C(O)-C.

10 aryl, -N(C 1 .e alkyl)-C(O)-C 6 .10 aryl or

-N(C

6

.

1 0 aryl)-C(O)-C 6

.

1 0 aryl, for example -NH-C(O)-phenyl or -NH-C(O)-4 methylphenyl. 15 In yet another embodiment of the compounds of Formula 1, R" is -C1.6 alkylene-O-C 1

..

6 alkyl , for example -CH 2 0CH 3 . In yet another embodiment of the compounds of Formula I, R 8 is a C1-6 alkyl substituted with one or more hydroxy groups, for example -CH 2 OH,

-CH

2

CH

2 OH, -CH 2

CH(OH)CH

3 , or -CH 2

C(OH)(CH

3

)

2 . 20 In yet another embodiment of the compounds of Formula I, R 8 is -CN. In yet another embodiment of the compounds of Formula I, R" is -NH 2 ,

-N(C

1

.

6 alkyl) 2 , -NH(C 1

..

6 alkyl), -N(C 6

.

1 o aryl) 2 , -NH(C 6

-

10 aryl), -N(C3.

6 cycloalkyl) 2 , -NH(C 3

-

6 cycloalkyl), -N(C 1

.

6 alkyl)(C 6

..

1 o aryl), -N(C 1

.

6 cycloalkyl)(C.Io aryl), or -N(C 1

.

6 cycloalkyl)(C1.

6 alkyl). 25 In yet another embodiment of the compounds of Formula I, R 9 is H. Jn-y.eLan.othe.r-embo.iment of-thecompounds-of Formula I, R 9 is C1.6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl. In yet another embodiment of the compounds of Formula I, R 9 is C6.1o 30 aryl, for example phenyl or naphthyl. In yet another embodiment of the compounds of Formula I, each R 9 together with the nitrogen atom to which they are shown attached, form a C1.6 -13heterocycloalkyl ring. For example -N(R 9

)

2 forms one of

--

Nj -- N ,or In yet another embodiment of the compounds of Formula 1, X is -C(O)-. In yet another embodiment of the compounds of Formula I, X is 5 -S(0 2 )-. In yet another embodiment of the compounds of Formula I, Y is -CH 2 -. In yet another embodiment of the compounds of Formula 1, Y is -0-. In yet another embodiment of the compounds of Formula 1, Y is -N(H)-C(O)-, -N(C 1

.

6 alkyl)-C(O)-, or -N(C 6

.

10 aryl)-C(O)-, for example 10 -N(H)-C(O)-, -N(CH 3 )-C(O)-, or -N(phenyl)-C(O)-. In yet another embodiment of the compounds of Formula 1, Z is -CH 2 -. In yet another embodiment of the compounds of Formula 1, Z is -C(C1 6 alkyl) 2 or -CH(C 1

.

6 alkyl), for example -C(CH 3

)

2 - or -CH(CH 3 )-. In yet another embodiment of the compounds of Formula I, Z is -NH-. 15 In yet another embodiment of the compounds of Formula I, Z is -N(C 1 .6 alkyl)-, for example -N(CH 3 )- or -N(CH 2

CH

3 )-. In yet another embodiment of the compounds of Formula 1, Z is -N(C 6 . 10 aryl)-, for example -N(phenyl)- or -N(naphthyl)-. In yet another embodiment of the compounds of Formula I, Z is -0-. 20 In yet another embodiment of the compounds of Formula I, n is 0. In yet another embodiment of the compounds of Formula I, n is 1. In yet another embodiment of the compounds of Formula 1, n is 2. In still yet another embodiment, the compounds of Formula I have the following structure IB:

D

1

D

2 R R2

CF

3 HN O YCF 3 25

CH

3 (IB); wherein each of R' and R 2 are as shown in the following Table 1: - 14- Compound R R2 1 5-N -CN O-O 0 2 -- N O -ON N O C CH 3 y NH 4,c H 3 O

H

2 N OH 4 g-N NH c CH3 O H 2 5 ~ -N 5 1-

-CH

2 CN 6O N 7 -CN N 8 -C(O)-O-CH 3 N 9 N -CN 0 N 10 -C(O)-NH 2

--

-- N 11NH

-CH

2

C(OH)(CH

3

)

2 N 12 -CH20H -N I - 15- CompoundR /~N 13 N 1-CH 2

OCH

3 14

-CH

2 0CH 3

L

NN 15 NH -CH 2 -- NH-S(0 2

)-CH

3 /-- N 16 -N NH -CH 2

C(O)-NH(CH

2

CH

3 ) /N 17 LIZ- \I NH -CH 2

-C(O)O-CH

2

CH

3 ZZN/-- N 18 NH -C(=N-OH)-CH 2

CH

3 /N 19 \1 H-C(O)-CH 2

CH

3 20 LkZ-N \frNH -CH 2 0CH 3 -N 21 L\NH -0(O)-N H(CH 3 ) /~N 22 -C(O)-NH(CH 3 ) N NN 23 y H-CH 2 OH 0 6 Compound Rl R2 /-- N 24 NH-CH 2 C H 2 OH /-- N 25 y2- NH -OH 2

CH

2

OH

3 /~N 26 LI-Ny NH -CH 2 0CH 3 /~N 27 -CH 2 00H 3 'Y NH 0 28 O H 3 H O H 0 /--z N 29 )-N NH -CH 2

C(O)-NH

2 0 /~N 30 NH -CH 2 -C(0)-CH 3 /-- N 31. -0H 2 -C(O)O-0H 3 0 33 _-C-N 0 - 17- Compound Rl R 34 -CN 0 N 35 -CN NH 36 -NH-S(0 2

)-CH

3 -CN 37 -CN -NH-S(0 2

)-CH

3 N 38 - NH -CH 2 CN 39 -CN -NH 2 40 -NH 2 -CN 41 -NH-C(0)-NH 2 -CN N 42 --N NH -CN 43 --N H OH -N OHH 44 / N H -- N N H 0

OCH

3 45 -N H NH -18- Compound R R

OCH

3 46 H ~- NH 00 OCH3 HN 47 -N H 00

O::-S/-H

3 HN 48 H >NH -NZN 49H

HH

2 N >-NN 50 H2 NHN NN 51 NH-0(0)-N.H 2 N/-- N 52 NH -C(=N-O0H 3

)-CH

3 -19- Compound R1 R 2 /- N 53 .-N NH -C(O)-CH 3 0 /- N 54 NH -C(=N-OH)-CH 3 O N 55 .-N NH -C(O)OCH 3 O /-- N N 56 .- N NH -CH 2 CI 0 , N N 57 '.--N NH -CH 3 0 /- N 58 -- N NH -C(=N-OCH 3

)-CH

2

CH

3 O N 59 -NHC(O)CH 3 0 / N-N 60 H - --N(NH SNN 61 N H H In still an additional embodiment, the present invention is directed to a method of treating a disease (or disorder or condition) in a patient in need of - 20 such treatment, wherein the disease is selected from the group consisting of: (1) respiratory diseases (e.g., chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), (2) inflammatory diseases (e.g., arthritis and psoriasis), (3) skin disorders (e.g., atopic dermatitis and contact 5 dermatitis), (4) ophthalmalogical disorders (e.g., retinitis, ocular hypertension and cataracts), (5) 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, (6) addictions (e.g., alcohol dependence and psychoactive substance abuse), 10 (7) epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11) Alzheimer's disease, (12) AIDS related dementia, (13) Towne's disease, (14) stress related disorders (e.g., post traumatic stress disorder), (15) obsessive/compulsive disorders, (16) eating disorders (e.g., bulimia, anorexia nervosa and binge eating), (17) sleep disorders, (18) mania, (19) 15 premenstrual syndrome, (20) gastrointestinal disorders (e.g., irritable bowel syndrome, Crohn's disease, colitis, and emesis), (21) atherosclerosis, (22) fibrosing disorders (e.g., pulmonary fibrosis), (23) obesity, (24) Type i diabetes, (25) pain related disorders (e.g., headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), (26) 20 bladder and genitourinary disorders (e.g., interstitial cystitis and urinary incontinence), (27) emesis (e.g., chemotherapy-induced (e.g., induced by cisplatin, doxorubicin, and taxane), radiation-induced, motion sickness, ethanol-induced, and post operative nausea and vomiting), and (28) nausea, comprising administering to the patient an effective amount of at least one 25 (e.g., one) compound of Formula I or a pharmaceutically acceptable salt and/or-solyate thereof. In still an additional embodiment, the present invention is directed to a method of treating a disease (or disorder or condition) in a patient in need of such treatment, wherein the disease is selected from the group consisting of: 30 respiratory diseases (e.g., cough), depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorders, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain related -21disorders (e.g., headaches, such as migraines, neuropathic pain, post operative pain, and chronic pain syndromes), bladder disorders, genitourinary disorders, emesis and nausea, comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically 5 acceptable salt and/or solvate thereof. In still an additional embodiment, the present invention also is directed to a method of treating a disease (or disorder or condition) wherein there is microvascular leakage and mucus secretion in a patient in need of such treatment, comprising administering to the patient an effective amount of at 10 least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof. In still an additional embodiment, the present invention also is directed to a method of treating asthma, emesis, nausea, depressions, anxieties, cough and pain related disorders in a patient in need of such treatment 15 comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof. In still an additional embodiment, the present invention also is directed to a method of treating emesis, depression, anxiety and cough in a patient in 20 need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof. In still an additional embodiment, the present invention also is directed to a method for antagonizing an effect of a Substance P at a neurokinin-1 25 receptor site in a patient in need of such treatment, comprising administering to the patient at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof. In still an additional embodiment, the present invention also is directed to a method for the blockade of NK 1 receptors in a patient in need of such 30 treatment, comprising administering to the patient at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof. In still an additional embodiment, the present invention also is directed to a method for treating depression and/or anxiety in a patient in need of such treatment comprising administering to the patient an effective amount of one -22or more compounds of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of one or more anti depressant agents and/or one or more anti-anxiety agents. In still an additional embodiment, the present invention also is directed 5 to a method of treating an NK 1 receptor mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of one or more selective serotonin reuptake inhibitors 10 ("SSRIs"). In still an additional embodiment, the present invention also is directed to a method of treating depression and/or anxiety in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt and/or 15 solvate thereof, in combination with an effective amount of one or more selective serotonin reuptake inhibitors. In yet an additional embodiment, the present invention also is directed to a method of treating an NK 1 receptor mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to 20 the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with at least one therapeutic agent selected from the group consisting of: other types of NK 1 receptor antagonists (e.g., NK1 receptor antagonists other than those according to Formula I of the present invention), prostanoids, H 1 receptor 25 antagonists, x-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-HT 3 receptor antagonists (e.g., 30 ondansetron), serotonin 5-HT 2 , receptor agonists, nociceptin receptor agonists, glucocorticoids (e.g., dexamethasone), rho kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance protein 5. -23- In yet an additional embodiment, the invention also is directed to a method for treating an NK 1 mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically 5 acceptable salt and/or solvate thereof, in combination with at least one therapeutic agent selected from the group consisting of: prostanoids, such as prostaglandin El; a-adrenergic agonists, such as phentolamine mesylate; dopamine receptor agonists, such as apomorphine; angiotensin 11 antagonists, such as losartan, irbesartan, valsartan and candesartan; ETA 10 antagonists, such as bosentan and ABT-627; serotonin 5-HT 3 receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone. In yet an additional embodiment, the invention also is directed to a method for treating an NK 1 mediated disease (or disorder or condition) in a 15 patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of at least one therapeutic agent selected from the group consisting of: other types of NK, receptor antagonists, SSRIs, dopamine receptor 20 agonists, serotonin 5-HT 3 receptor antagonists, serotonin 5-HT 2 0 receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multi drug resistance protein 5. In yet an additional embodiment, the invention also is directed to a method for treating emesis, nausea and/or vomiting in a patient in need of 25 such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically-acceptable salt and/or solvate thereof, in combination with an effective amount of at least one serotonin 5-HT 3 receptor antagonist (e.g., ondansetron) and/or at least one glucocorticoid (e.g., dexamethasone). 30 In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat an NK 1 receptor mediated disease (or disorder or condition), wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound -24of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising another therapeutic agent in a pharmaceutically acceptable carrier, the therapeutic agent being 5 selected from the group consisting of: SSRIs, other types of NK 1 receptor antagonists, prostanoids, H 1 receptor antagonists, a-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin 11 receptor antagonists, angiotensin converting enzyme inhibitors, 10 neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT 3 receptor antagonists, serotonin 5-HT 2 , receptor agonists, nociceptin receptor agonists, glucocorticoids, rho kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance protein 5. In still yet an additional embodiment, the present invention also is 15- directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and/or anxiety, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically 20 acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an antidepressant agent in a pharmaceutically acceptable carrier, and/or wherein a separate container comprises a pharmaceutical composition comprising an antianxiety agent in a pharmaceutically acceptable carrier. 25 In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat an NK 1 receptor mediated disease, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a 30 pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier. -25- In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and/or anxiety, wherein one container comprises a pharmaceutical 5 composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier. 10 In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and/or nausea, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a 15 pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising a serotonin 5-HT 3 receptor antagonist in a pharmaceutically acceptable carrier, and/or wherein a separate container comprises a pharmaceutical composition comprising a glucocorticoid in a 20 pharmaceutically acceptable carrier. In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and/or nausea, wherein one container comprises a pharmaceutical composition 25 comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein a separate container comprises ondansetron, and/or wherein a separate container comprises dexamethasone. Another aspect of the invention is to provide a kit comprising, in 30 separate containers in a single package, pharmaceutical compositions for use in combination to treat an NK 1 receptor mediated disease, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition -26 comprising a therapeutic agent in a pharmaceutically acceptable carrier, the therapeutic agent being selected from the group consisting of: other types of

NK

1 receptor antagonists, SSRIs, dopamine receptor agonists, serotonin 5

HT

3 receptor antagonists, serotonin 5-HT 2 c receptor agonists, nociceptin 5 receptor agonists, glucocorticoids and inhibitors of multi-drug resistance protein 5. Except where stated otherwise, the following definitions apply throughout the specification and claims. When any variable occurs more than one time in any moiety, its definition on each occurrence is independent of its 10 definition at every other occurrence. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. 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 15 "hydroxyalkyl," "haloalkyl," "alkoxy," etc. Ac means acetyL. AcOH (or HOAc) means acetic acid. Boc means t-butoxycarbonyl. Bu means butyl. 20 t-Bu or But means tertiary-butyl. Bn means benzyl. Cbz means carbobenzoxy (i.e., Ph-CH 2 -0-C(O)-). DCM means dichloromethane. DIEA means diisopropylethyl amine. 25 DMF means dimethylformamide. DMAP means dimethylaminopyridine. DMPU means N,N H -dimethyl propylene urea. DMSO means dimethylsulfoxide. DPPA means diphenylphosphorazide. 30 Et means ethyl. EDC means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. FAB means fast atom bombardment. HOTs means p-toluene sulfonic acid. - 27 - HATU means O-(7-azabenzotriazol-1-yl)-N,N,N',N' tetramethyluroniumhexafluorophosphate. HPLC means High Performance Liquid Chromatography. HRMS means high resolution mass spectroscopy. 5 LCMS means liquid chromatography/mass spectroscopy LiHMDS means lithium hexamethyldisilazide. Me means methyl. MeOH means methanol. MS means mass spectroscopy. 10 Ms or mesyl means methane sulfonyl. Ni (Ra) means Raney Ni. OD means optical density. Ph means phenyl i-PA (or IPA or iPA) means iso-propyl. 15 PPTS means pyridinium p-toluenesulfonic acid. PTSA means p-toluene sulfonic acid. PYBOP means (benzotriazol-1-yloxy)tripyrrolidino phosphonium hexafluorophosphate. RT or rt means room temperature. 20 TBAF means tetrabutylammonium fluoride. TBAI means tetrabutylammonium iodide. TFA means trifluoroacetic acid. THF means tetrahydrofuran. TLC means Thin Layer Chromatography. 25 TMS means trimethylsilyl. TMSCI means trimethylsilyl chloride. "Tosyl" means toluene sulfonyl. "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. 30 Portions of chemical formulae enclosed in parentheses and/or brackets denote pendant groups. For example, -C(O)- refers to a carbonyl group (i.e., - 28 - 0 C), -N(alkyl)- refers to a divalent amine group with a pendant alkyl group

,OCH

3 alkyl N (i.e., -N-) and -C(=NOCH 3

)-CH

3 refers to -C-CH 3 "Alkyl" means an aliphatic hydrocarbon group, which may be straight or branched and comprising about I to about 20 carbon atoms in the chain. 5 Preferred alkyl groups contain about I to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain that may be 10 straight or branched. The term "substituted alkyl" means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , carboxy and -C(0)0-alkyl. Non 15 limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkylene" means a divalent aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkylene groups contain about 1 to about 12 carbon atoms in 20 the chain. More preferred alkyl groups contain about I to about 6 carbon atoms in the chain. Non-limiting examples of an alkylene group include methylene (i.e., -CH 2 -) and ethylidene (-CH 2

CH

2 - or -CH(CH 3 )-). "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and 25 comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon 30 atoms in the chain, which may be straight or branched. The term "alkenyl" includes substituted alkenyl which means that the alkenyl group may be -29 substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl (i.e., vinyl), propenyl, n-butenyl, 3 5 methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more 10 preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain that may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3 15 methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means an aromatic monocyclic or multicyclic ring system 20 comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. 25 "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising-about.5-to-aboutiA4ing-atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" 30 can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non - 30 limiting examples ot suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, 5 oxindolyl, imidazo[1,2-a]pyridinyl, imidazo(2,1-blthiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrim idyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl, tetrazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl 10 moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2 15 phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. A non-limiting example of a suitable alkylaryl group is tolyl. The bond to the 20 parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring 25 system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include I-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for 30 example, indanyl, tetrahydronaphthyl and the like. "Cycloalkylene" means a divalent cycloalkyl ring system, comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkylene rings contain about 5 to about 7 ring atoms. The cycloalkylene can be optionally substituted with one or more "ring system -31substituents" which may be the same or different, and are as defined above. Non-limiting example of suitable monocyclic cycloalkylenes includes cyclopropylene (i.e., or ). "Halogen" means fluorine, chlorine, bromine, or iodine. Preferred 5 halogens are fluorine, chlorine and bromine. "Halogen" or "halo" substituted groups (e.g., haloalkyl groups) refers to groups substituted with one or more fluorine, chlorine, bromine, and/or iodine atoms. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system, which, for example, replaces an available 10 hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl; halo, nitro, cyano, carboxy, 15 alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocycloalkyl, -C(=N-CN)-NH 2 , -C(=NH)-NH 2 , -C(=NH)-NH(alkyl), Y 1

Y

2 N-, Y 1

Y

2 N-alkyl-, Y1Y 2 NC(O)-, Y 1

Y

2

NSO

2 - and

-SO

2

NY

1

Y

2 , wherein Y 1 and Y 2 can be the same or different and are 20 independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3

)

2 - and the like which 2-5 form moieties such as, for example: (0 \[b 0 ) ' and "Heterocycloalkyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring 30 system is an element other than carbon, for example nitrogen, oxygen or - 32 sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkyl root name means that at least a nitrogen, oxygen or sulfur atom respectively 5 is present as a ring atom. Any -NH in a heterocycloalkyl ring may be present in protected form such as, for example, an -N(Boc), -N(CBz), -N(Tos) group and the like; such protected functional groups are also considered part of this invention. The heterocycloalkyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as 10 defined herein. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non limiting examples of suitable monocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the 15 like. It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, 0 or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: 41 2 5 20 H there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that tautomeric forms such as, for example, the moieties: NO0 H and N OH 25 are considered equivalent in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety.is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include 30 propargylmethyl. -33- "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is 5 through the alkyl. "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. The "alkyl" portion of the hydroxyalkyl is preferably a lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. 10 "Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C(O)- group in which the aryl group is as 15. previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent 20 moiety is through the ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen. 25 "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as pre.io-usLy-de.s-cribecLNon-Jimiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen. "Alkylthio" means an alkyl-S- group in which the alkyl group is as 30 previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups - 34 include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is 5 benzylthio. The bond to the parent moiety is through the sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples 10 of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl. 15 "Alkylsulfonyl" means an alkyl-S(0 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl. "Arylsulfonyl" means an aryl-S(0 2 )- group. The bond to the parent. moiety is through the sulfonyl. 20 The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible 25 only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation.to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term "optionally substituted" means optional substitution with the 30 specified groups, radicals or moieties. The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after -35being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. 5 It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have one or more hydrogen atoms to satisfy the valences. When a ring system (e.g., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) is substituted with a number of substituents varying within an 10 expressly defined range, it is understood that the total number of substituents does not exceed the normal available valencies under the existing conditions. Thus, for example, a phenyl ring substituted with "n" substituents (where "n" ranges from 0 to 5) can have 0 to 5 substituents, whereas it is understood that a pyridinyl ring substituted with "n" substituents has a number of substituents 15 ranging from 0 to 4. When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as 20 well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York, herein incorporated by reference. When any variable (e.g., aryl, heterocycloalkyl, R 2 , etc.) occurs more than one time in any constituent or in Formula 1, its definition on each 25 occurrence is independent of its definition at every other occurrence. As-us-ed-herein,.heiterm "c~omposition"Iis.intendad-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. 30 "Alkylheteroaryl" means an alkyl group attached to a parent moiety via a heteroaryl group. "Alkylsulfinyl" means an alkyl-S(O)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl. -36- "Aralkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2 phenethenyl and 2-naphthylethenyl. The bond to the parent moiety is through 5 the alkenyl. . "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples 10 of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Arylsulfinyl" means an aryl-S(O)- group. Non-limiting examples of suitable arylsulfinyl groups include phenylsulfinyl and naphthylsulfinyl. The bond to the parent moiety is through the sulfinyl. 15 A carbamate group means a -O-C(O)-N(alkyl or aryl)- group, and a urea group means a -N(alkyl or aryl)-C(O)-N(alkyl or aryl)- group. Representative carbamate and urea groups may include the following: H O N H NYN H 3 C N N/

H

3 C O ~NyN OyN< H 3 C OyNg H HH 3 C 0 20 "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system 25 substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. - 37 - "Cycloalkylamino" means a cycloalkyl group as defined herein attached to the parent moiety through a nitrogen atom. "Cycloalkylaminocarbonyl" means a cyclic alkyl group attached to a nitrogen atom, which is attached to a carbonyl group; the whole may be 5 referred to as a substituted amide. "Heteroalkyl" means an alkyl as defined herein, in which at least one the atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. "Heteroaralkenyl" means a heteroaryl-alkenyl- group in which the 10 heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3 yl)ethenyl. The bond to the parent moiety is through the alkenyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl 15 and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl. "Heteroaralkylthio" means a heteroaryl-alkyl-S group wherein the group 20 is attached to the parent moiety through the sulfur. "Heteroarylsulfinyl" means a heteroaryl-S(O)- group wherein the heteroaryl is as defined herein and the heteroarylsulfinyl group is attached to the parent moiety through the sulfinyl. "Heteroarylsulfonyl" means a heteroaryl-S(0 2 ) - group wherein the 25 heteroaryl is as defined herein and the heteroarylsulfonyl group is attached to the parent moiety through the sulfonyl. "Heteroarylthio" means a heteroaryl-S- group wherein the heteroaryl is as defined herein and the heteroarylsulfinyl group is attached to the parent moiety through the sulfur. 30 "Heterocycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon -38 double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkenyl root name means that at least a nitrogen, oxygen or 5 sulfur atom respectively is present as a ring atom. The heterocycloalkenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic 10 azaheterocycloalkenyl groups include 1,2,3,4- tetrahydropyridine, 1,2 dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6 tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocycloalkenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the 15 like. Non-limiting example of a suitable multicyclic oxaheterocycloalkenyl group is 7-oxabicyclo[2,2.1}heptenyl. Non-limiting examples of suitable monocyclic thiaheterocycloalkenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclic" means, in addition to the heteroaryl groups defined 20 below, saturated and unsaturated cyclic organic groups having at least one 0, S and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 5-, 6- or 7-membered and may or may not have double bonds that lack delocalized pi electrons, which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms, e.g., 2- or 25 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3 thim-orpholinyl "Sulfonamide" means a sulfonyl group attached to a parent moiety through an amide. As is well known in the art, a bond drawn from a particular atom 30 wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom. For example: - 39 pzN/N N C H 3 C H 0 represents 0 It should also be noted that throughout the specification and Claims appended hereto, that any formula, compound, moiety or chemical illustration with unsatisfied valences is assumed to have the hydrogen atom to satisfy the 5 valences unless the context indicates a bond. With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is 10 well within the knowledge of those skilled in the art. The wavy line nrv as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry. For example, OH OH O means containing both and N N N 15 H H H When the stereochemistry in a structure is not expressly indicated, the structure can have a mixture of, or any of the individual possible stereoisomers. Thus, when the stereochemistry is not explicitly indicated in a structure, the structure inclUdes all stereochemical configurations having the 20 indicated connectivity (e.g., all possible enantiomers or diastereomers), as well as mixtures of such stereoisomers (e.g., racemic mixtures). For example, -40- NN OH

CF

3 O 0CF 3

CH

3 means N ] NN N N \ OH

CF

3 N OH

CF

3 O CF 3 HN

CF

3

CH

3

CH

3 N OOH F /N H CF 3 N/5 OH CF3 CF3

CF

3

CF

3

OH

3 OH 3 N N H- OH CF 3 O H CF 3 HN )IHN

CF

3 0 CF 3

OH

3

CH

3 N N z N,OH OF 3 O H CF 3 HN H N 0"-. CF 3 N. CF 3 5

,H

3 and/or /H 3 Lines drawn into the ring systems, such as, for example: -41indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms. Prodrugs and solvates of the compounds of the invention are also 5 contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery 10 Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto. "Solvate" means a physical association of a compound of this invention 15 with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable 20 solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is H 2 0. "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention 25 effective in antagonizing the neurokinin-1 receptor and thus producing the desired therapeutic effect in a suitable patient. The compounds of Formula I form salts that are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term 30 salts(s), as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or -42 organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. 5 Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium 10 followed by lyophilization. Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, 15 fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, 20 propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as 25 calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, 30 choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl -.43 and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. 5 Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of 10 Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331, each of which is incorporated herein by reference. All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts 15 are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Compounds of Formula I and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present 20 invention. Polymorphic forms of the compounds of Formula I, and of the salts, solvates, and/or prodrugs thereof, are intended to be included in the present invention. All stereoisomers (for example, geometric isomers, optical isomers and 25 the like) of the present compounds (including those of the salts, solvates and prodrugs-of-the-compounds-as well as-the-salts-and solvates-of.the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and 30 diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined -44 by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. "At least one", examples include 1-3, 5 1-2 or 1. Compounds of Formula I are effective antagonists of the NK 1 receptor, and have an effect on its endogenous agonist, Substance P, at the NK, receptor site, and therefore, can be useful in treating diseases, disorders, or conditions caused or aggravated by the activity of the receptor. 10 The in vitro and in vivo NK 1 , NK 2 and NK 3 activities of the compounds of 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 NK 1 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 15 MSB is defined by the following equation, wherein "dpm" represents "disintegrations per minute": % MSB = (dpm of unknown) - (dpm of nonspecific binding) 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 20 equation. In vivo activity may be measured by inhibition of an agonist-induced foot tapping in a gerbil, as described in Science, 281, 1640-1695 (1998), which is herein incorporated by reference in its. entirety. It will be recognized that compounds of Formula I can exhibit NK 1 antagonist activities of varying 25- -degsre--~Firist rrvc-cwrtaircimp unds carrexhibit stronger NK 1 antagonist activities than others. The compounds of the present invention exhibit potent affinities for the

NK

1 receptor as measured by Ki values (in nM). The activities (potencies) for the compounds of the invention are determined by measuring their Ki values. 30 The smaller the Ki value, the more active is a compound for antagonizing the

NK

1 receptor. Compounds of the invention exhibit a wide range of activities. The NK 1 average Ki values for compounds of Formula I generally range from -45 - 0.01 nM to about 1000 nM, preferably, from about 0.1 nM to about 100 nM, with values of from about 0.1 nM to about 10 nM being more preferred. Even more preferred are compounds having average Ki values of from 0.1 nM to about 5 nM for the NK 1 receptor. Especially preferred compounds have NK 1 5 average Ki values of from 0.1 nM to about I nM. Even more especially preferred compounds have NK 1 average Ki values of from 0.1 nM to about 0.3 nM. Compounds 2, 9, 10,12,14,16, 19, 20, 23, 29, 30, 42, and 54 (see Table I above) have Ki values, respectively, of 0.12, 0.18, 0.1, 0.05, 0.1, 0.13, 0.1, 0.11, 0.12 0.11, 0.54, 0.28, and 0.12 nM. 10 Compounds of the Formula I have a number of utilities. For instance, the inventive compounds can be useful as antagonists of neurokinin receptors, particularly, NK 1 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 (physiological disorders, 15 symptoms and diseases) in a patient in need of such treatment, wherein the disease states are selected from the group consisting of: (1) respiratory diseases (e.g., chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), (2) inflammatory diseases (e.g., arthritis and psoriasis), (3) skin disorders (e.g., atopic dermatitis and contact dermatitis), 20 (4) ophthalmologic disorders (e.g., retinitis, ocular hypertension and cataracts), (5) 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, (6) addictions (e.g., alcohol dependence and psychoactive substance abuse), (7) 25 epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11) Alzheimer's disease, (12) AIDs related dementia, (13) Towne's disease, (14) stress related disorders (e.g., post traumatic stress disorder), (15) obsessive/compulsive disorders, (16) eating disorders (e.g., bulimia, anorexia nervosa and binge eating), (17) sleep disorders, (18) mania, (19) 30 premenstrual syndrome, (20) gastrointestinal disorders (e.g., irritable bowel syndrome, Crohn's disease, colitis, and emesis), (21) atherosclerosis, (22) fibrosing disorders (e.g., pulmonary fibrosis), (23) obesity, (24) Type 1I diabetes, (25) pain related disorders (e.g., headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), (26) -46 bladder and genitourinary disorders (e.g., interstitial cystitis and urinary incontinence), (27) emesis (e.g., chemotherapy-induced (e.g., induced by cisplatin, doxorubicin, and taxane), radiation-induced, motion sickness, ethanol-induced, and post operative nausea and vomiting), and (28) nausea. 5 Preferably, the inventive compounds can be useful in treating and preventing one of the following mammalian (e.g., human) disease states in a patient in need of such treatment: respiratory diseases (e.g., cough), depression, anxiety, phobia, and bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related 10 disorders, obsessive/compulsive disorder, bulimia, anorexia nervosa and binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain related disorders, bladder disorders, genitourinary disorders, emesis and nausea. In particular, the compounds according to Formula I are useful for treating disease states related to microvascular 15 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, more especially, emesis, depression, anxiety and cough. In another aspect, the invention relates to pharmaceutical compositions 20 comprising at least one compound (e.g., one to three compounds, preferably, one compound) represented by Formula I and at least one pharmaceutically acceptable excipient or carrier. The invention also relates to the use of such pharmaceutical compositions in the treatment of mammalian (e.g., human) disease states, such as those listed above. 25 In still another aspect of the invention, a method is provided for antagonizing-th-e-effects-of-a-Subs.tan-celPat anrieurJkinin-1 receptor site or for the blockade of one or more neurokinin-1 receptors in a mammal (i.e., a patient, e.g., a human) in need of such treatment, comprising administering to the mammal an effective amount of at least one (e.g., one) compound 30 according to Formula I. In another aspect of the invention, an effective amount of one or more of the inventive NK 1 receptor antagonists may be combined with an effective amount of one or more anti-depressant agents and/or one or more anti anxiety agents (e.g., gepirone, gepirone hydrochloride, nefazodone, and -47netazoaone nyarocnionae (e.g., Serzone*)) to treat depression and/or anxiety. U.S. 6,117,855 (2000), the disclosure of which is incorporated herein by reference, discloses a method for treating or preventing depression or anxiety with a combination therapy of a specific NK 1 receptor antagonist 5 together with an anti-depressant and/or anti-anxiety agent. Thus, anti depressant and/or anti-anxiety agents, such as those disclosed in U.S. 6,117,855 (2000), can be combined with one or more (e.g., one) compounds of the Formula I to treat depression and/or anxiety disease states in a mammal, preferably, a human. 10 In still another aspect of the invention, an effective amount of one or more (e.g., one) of the inventive NK 1 receptor antagonists may be combined with an effective amount of one or more (e.g., one) selective serotonin reuptake inhibitors ("SSRIs") to treat a variety of mammalian disease states, such as those described above. SSRIs alter the synaptic availability of 15 serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin.- U.S. 6,162,805 (2000), the disclosure of which is incorporated herein by reference, discloses a method for treating obesity with a combination therapy of a NK 1 receptor antagonist and an SSRI. One or more inventive compound(s) of the Formula I can be combined together with 20 an SSRI(s) in a single pharmaceutical composition, or it can be administered simultaneously, concurrently or sequentially with an SSRI. This combination may be useful in the treatment and prevention of obesity or another of the above-identified human and animal disease states. In particular, an effective amount of at least one (e.g., one) compound having the Formula 1, alone or 25 together with an effective amount of at least one (e.g., one) selective serotonin reuptake inhibitor, can be useful intthe treatmentadi prevention of depression, and/or anxiety. Numerous chemical substances are known to alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation 30 of neuronally released serotonin. Representative SSRIs include, without limitation, the following: fluoxetine, fluoxetine hydrochloride (e.g., Prozac*), fluvoxamine, fluvoxamine maleate (e.g. Luvox*), paroxetine, paroxetine hydrochloride (e.g., Paxil*), sertraline, sertraline hydrochloride (e.g., Zoloft*), citalopram, citalopram hydrobromide (e.g., Celexa

TM

), duloxetine, duloxetine -48hydrochloride, venlafaxine, and venlafaxine hydrochloride (e.g., Effexor*). Further SSRIs include those disclosed in U.S. 6,162,805 (2000). Other compounds can readily be evaluated to determine their ability to selectively inhibit serotonin reuptake. Thus, one aspect of the invention relates to a 5 pharmaceutical composition comprising at least one (e.g., one) NK 1 receptor antagonist having the Formula 1, at least one (e.g., one) SSRI, and at least one pharmaceutically acceptable excipient or carrier. Another aspect of the invention relates to a method of treating the above identified mammalian (e.g., human) disease states, the method comprising administering to a patient in 10 need of such treatment an effective amount of a pharmaceutical composition comprising at least one (e.g., one) NK1 receptor antagonist having the Formula I in combination with at least one (e.g., one) SSRI, such as one of those recited above, and at least one pharmaceutically acceptable excipient or carrier. 15 In a preferred aspect, the invention relates to a method of treating depression and anxiety, the method comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) NK 1 receptor antagonist having the Formula I in combination with at least one (e.g., one) SSRI, such as one of those described above. When an inventive 20 NK 1 receptor antagonist is combined with an SSRI for administration to a patient in need of such treatment, the two 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). In general, when the two active ingredients are 25 administered consecutively or sequentially, the inventive NK 1 receptor antagonist is ,prerablyi.adrniniteredtbeforetbhe-administration of the SSRI. It is another embodiment of the invention to treat a patient suffering from multiple ailments with a combination therapy, the therapy.comprising administering to a patient (e.g., a mammal, preferably a human) in need of 30 such treatment at least one compound of Formula 1, and at least one other active ingredient (i.e., drug) used for treating one or more of the ailments being suffered by the patient. The compounds of Formula I and the other active ingredients can be administered sequentially, concurrently and/or simultaneously. The compounds of Formula I and the other active ingredients -49can be administered separately in any suitable dosage form. Preferably, administration is accomplished using an oral dosage forms or using a transdermal patches. The compounds of Formula I and the other active ingredients can be formulated together and administered in one combined 5 dosage form. Thus, the compounds of the invention may be employed alone or in combination with other active agents. Combination therapy includes the administration of two or more active ingredients to a patient in need of treatment. In addition to the above described NK 1 receptor antagonist/SSRI 10 combination therapy, the compounds having the Formula I may be combined with one or more other active agents, such as the following: other types of

NK

1 receptor antagonists (e.g., those that are disclosed in neurokinin receptor antagonist patents cited above), prostanoids, H 1 receptor antagonists, a adrenergic receptor agonists, dopamine receptor agonists, melanocortin 15 receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin I receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT 3 receptor antagonists (e.g., ondansetron, ondansetron hydrochloride (e.g., Zolfran*), palonosetron, granisetron, and 20 granisetron hydrochloride (e.g., Kytril*), serotonin 5-HT 2 c receptor agonists, nociceptin receptor agonists, glucocorticoids (e.g., dexamethasone), rho kinase inhibitors, potassium channel modulators and/or inhibitors of multi-drug resistance protein 5. Particularly useful therapeutic agents for combination therapy with 25 compounds of the invention are the following: prostanoids, such as prostaglandin-E1;-ca-adrenergic-agonists;isuch as phentolamine mesylate; dopamine receptor agonists, such as apomorphine; angiotensin I antagonists, such as losartan, irbesartan, valsartan and candesartan; ETA antagonists, such as bosentan and ABT-627; serotonin 5-HT 3 receptor 30 antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone. In preferred embodiments of the invention, the inventive compounds can be combined with: other types of NK 1 receptor antagonists, SSRIs, dopamine receptor agonists, serotonin 5-HT 3 receptor antagonists, -50serotonin 5-HT 2 c receptor agonists, nociceptin receptor agonists, glucocorticoids and/or inhibitors of multi-drug resistance protein 5. Another embodiment of this invention is directed to a method for treating a physiological disorder, symptom or disease in a patient in need of 5 such treatment, comprising administering to the patient an effective amount of at least one compound of Formula I, and an effective amount of at least one active ingredient selected from the group consisting of: other NK 1 receptor antagonists, selective serotonin reuptake inhibitors, dopamine receptor agonists, serotonin 5-HT 3 receptor antagonists, serotonin 5-HT 2 c receptor 10 agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multidrug resistance protein 5, wherein the physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress 15 related disorder, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, cough, emesis and nausea. 20 Pharmaceutical compositions may contain from about 0.1 to about 99.9 weight percent, or from about 5 to about 95 weight percent, or from about 20 to about 80 weight percent of active ingredient (compound of the Formula I). For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid 25 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 30 be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 2 0 th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD, herein incorporated by reference. - 51 - Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene'glycoi 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 5 administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations, which are intended to be 10 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 15 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 20 containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units, in any of the forms described herein, comprised of more than one (e.g., two) pharmaceutically 25 active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid "more than one pharmaceutically active agents". The term "bulk 30 composition" means material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present -52invention is also intenaea to encompass the administration of the aforesaid bulk composition and individual dosage units. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 4000 mg, preferably from 5 about 0.02 mg to about 1000 mg, more preferably from about 0.3 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. 10 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 15 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. 20 The pharmaceutical compositions of the invention may be administered from about 1 to about 5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The quantity of NK 1 receptor antagonist in combination with a selective serotonin reuptake inhibitor ("SSRI") in a unit dose of preparation may be from 25 about 10 to about 300 mg of NK 1 receptor antagonist combined with from about 10 to about 100 mg of SSRI. In another combination the quantity of

NK

1 receptor antagonist in combination with a SSRI in a unit dose of preparation may be from about 50 to about 300 mg of NK 1 receptor antagonist combined with from about 10 to about 100 mg of SSRI. In another 30 combination the quantity of NK 1 receptor antagonist in combination with SSRI in a unit dose of preparation may be from about 50 to about 300 mg of NK, receptor antagonist combined with from about 20 to about 50 mg of SSRI. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. - 53 - Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. Upon improvement of a patient's condition, a maintenance dose of a compound, composition or 5 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 10 intermittent treatment on a long-term basis upon any recurrence of disease symptoms. Specific dosage and treatment regimens for any particular patient may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, 15 sex and diet of the patient, the time of administration, the rate of excretion, the specific drug combination, the severity and course of the symptoms being treated, the patient's disposition to the condition being treated and the judgment of the treating physician. Determination of the proper dosage regimen for a particular situation is within the skill of the art. 20 EXAMPLES The invention disclosed herein is exemplified by the following preparations and examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures 25 may be apparent to those skilled in the art. PREPARATIVE-EXAMRLE -1 N N. HNCF 30 Step 1: -54- CI 0 CbzN u. O EtN, CHCI CbzN .. C 42b / a in a 25 mL round-bottomed flask, Compound 42b (0.253 g, 0.42 mmol, 1.0 equiv) was taken up in 5 mL of CH 2 C1 2 , and the resulting reaction mixture was cooled to 0*C in an ice bath. Et 3 N (0.088 mL, 0.63 mmol, 1.5 5 equiv) followed by 4-chlorobutyryl chloride (0.065 mL, 0.5 mmol, 1.2 equiv) was then added to the reaction mixture, which was subsequently slowly warmed to room temperature and was stirred for 14 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane) and MS. Upon completion, the reaction mixture was diluted with CH 2

CI

2 , quenched with 10 saturated aqueous NaHCO 3 , followed by brine. The organic layer was dried over Na 2 SO4 and concentrated to give crude Compound Ia (0.3 g), which was used in the next step without further purification. Electrospray MS [M+1] 724.4. 15 Step 2: H N FCN N ~CN GF, 60%NaH, o THF CbN C bz N -,, C F , \ / In a flame-dried 25 mL round-bottomed flask, Compound 1a (0.3 g, 0.4 mmol, 1.0 equiv) was taken up in' dry THF. To this reaction mixture, 60% 20 NaH (0.025 g, 0.62 mmol, 1.5 equiv) was added, and reaction mixture was stirred at 6bit empehratufe6f5f2his~~The pidrsf lie rssoioii'was monitored by TLC (60:40 EtOAclhexane) and MS. Upon completion, the reaction mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO 3 .The organic layer was dried over Na 2

SO

4 and 25 concentrated to give Compound I b (0.25 g), which was used in the next step without further purification. Step 3: - 55 - C CN CF CN C -. ,CN GAeO H, 3 ( , ) CbzN G F CFg CF, 1b1 Compound lb (0.25 g, 0.37 mmol, 1.0 equiv) was dissolved in dry MeOH (2.0 mL) and was treated with 20% Pd(OH) 2 (60% wt.) under an inert 5 atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and was monitored by TLC (60:40 EtOAc/hexane). The reaction was completed in 45 min, and the reaction mixture was then filtered through CELITE (diatomaceous earth), washed with EtOAc, and concentrated to give a crude product. Purification was carried out using preparative plate 10 chromatography (60/40 EtOAc/hexane) to give Compound 1 (0.10 g, 49%). Electrospray MS [M+1] 554.3. HRMS (FAB) calculated for C 2 sH 2 9

F

6

N

3 0 2 (M+1) 554.2242, found 554.2249. 15 PREPARATIVE EXAMPLE 2 _N K CN CP 3 HN CF, Example 2 20 Step 1: 0 H -H2N ,CN CF 3 c0 o N ,CN CF 3 CbzN C EtaN. CH2C12 CbzN ,,0 . CF Y CF 3 NCF, 42b2 2a 25 In a 25 ml round-bottomed flask, Compound 42b (0.3264 g, 0.44 mmol, 1.0 equiv) was taken up in 5 mL of THF, and the reaction mixture was cooled to O 0 C in an ice bath. Et 3 N (0.073 mL, 0.44 mmol, 1.2 equiv) followed -56by 2-chloroethiyl chlorotormate (0.054 mL, 0.44 mmol, 1.2 equiv) was then added to the reaction mixture, which was slowly warmed to room temperature and stirred for 14 hrs. The progress of the reaction was monitored by TLC (40:60 EtOAc/hexane) and MS. The reaction did not go to completion, and 5 hence was diluted with EtOAc and quenched with saturated NaHCO 3 followed by brine. The organic layer was dried over Na 2

SO

4 and concentrated to give (0.3 g) crude product, which was subjected to BIOTAGE chromatography (40:60 EtOAc/hexane) to give Compound 2a (0.125 g). Electrospray MS [M+1] 712.4. 10 Step 2: C1 N N CF N 3 ,CN CF, 06f% NaH, C CbzN .CF, .H CbzN - CF 2a 2b 15 In a flame-dried 25 ml round-bottomed flask, Compound 2a (0.125 g, 0.175 mmol, 1.0 equiv) was taken up in dry THF. To this reaction mixture, 60% NaH (0.10 g, 0.26 mmol, 1.5 equiv) was added and reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (40:60 EtOAc/hexane) and MS. Upon completion of the 20 reaction, the reaction mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO 3 . The organic layer was dried over Na 2

SO

4 and concentrated to give Compound 2b -(0.11 g), which was used in the next step without further purification. Electrospray MS [M+1] 676.2. 25 Step 3: N CN CF, 2/ PdOH- NN CF, MeOH, H,(9)7 CbzN .0 ~HN ObN OA CF, ' H CF3 2b Compound 2 30 - 57 - Compound 2b (0.11 g, 0.16 mmol, 1.0 equiv) was dissolved in dry MeOH (2.0 mL) and was treated with 20% Pd(OH) 2 (60% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60 5 EtOAc/hexane). The reaction was completed in 45 min, filtered through CELITE, washed with EtOAc, and concentrated to give a crude product. The crude product was purified using preparative plate chromatography (45/55 EtOAc/ hexane) to give Compound 2 (0.04 g, 45%). Electrospray MS [M+1] 542.3. 10 HRMS (FAB) calculated for C 2 6

H

2 6

F

6

N

3 0 3 (M+1) 542.1897, found 542.1878. PREPARATIVE Example 3 and Example 4

H

0 H OH CF * N O pH CF, HN. CF F 15 Example 3 Example 4 N ON OH ' O OH \ N ,,,o CF 3 N ., CF N\\.-N CF, NaBHEF, +F 30 3 4 NaBH 4 (60 mg, 1.53 mmol, 8 equiv.) was added in portions to a 20 solution of Compound 30 (109 mg, -0.19 mmol, I equiv.) in absolute ethanol (2 mL) at 0*C. After stirring at 00C for 30 minutes, TLC (MeOH/CH 2

CI

2 =10%) analysis of the reaction mixture showed only product. The product was purified by BIOTAGE chromatography (2-10% MeOH in CH 2 Cl 2 ), to provide a pure mixture of two diastereomers. The two diastereomers were separated 25 using Chiral HPLC (ChialCel OD, IPA/Hexane=10%) to give Example 3, MS [M+1]* 573.1; and Example 4, MS [M+1]* 573.1. PREPARATIVE EXAMPLE 5 -58- N N HN ..,OCF3 Compound 5 HO - NHBoc CF, a. MsCl. NEt NC NHBoc CF 3 b. KCN, DMF 0 CF 3 CF, C bzN -.,O N C, -- CbzN Y C F Compound 26a Compound 5b 5 MsCI (0.102 mL, 1.32 mmol) was added to a solution of Compound 26a (0.375 g, 0.528 mmol) and Et 3 N (0.368 mL, 2.64 mmol) in CH 2 Cl2 (5.0 mL) at 0*C. The reaction mixture was quenched with water (15.0 mL) after 30 minutes and then diluted with CH 2

CI

2 (50 mL). The resulting aqueous phase 10 was extracted with CH 2

CI

2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude mesylate was taken up in DMF (3.0 mL) and treated with KCN (0.344 g, 5.28 mmol). The resulting mixture was heated at 100*C for 12 hours before it was cooled to room temperature. The reaction 15 mixture was diluted with EtOAc (100 mL) and washed with water (3 x 15 mL). The organic layer was then washed with brine (25 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified by BIOTAGE chromatography (hexane/EtOAc, v/v = 7/1) to give Compound 5b (0.14 g, 37% for 2 steps). 20 Step B: NC- NHBoc CFN a. TFA NC CF 3 CbzN b. HC(O)NHNHC(O)H, TMSC, EtN, Py *,_1_&

CF

3 CbzN -O CF3 Compound Sb Compound Sc A solution of Compound 5b (0.14 g, 0.195 mmol) in TFA (2.5 mL) was 25 stirred at room temperature for 20 minutes before the solvent was removed under reduced pressure. The residue was taken up in EtOAc (50 mL) and - 59 washed with a NaOH solution (4.0 N, 15 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and then dried over MgSO 4 . After filtration and concentration, the crude product was passed through a short pad of silica 5 gel with EtOAc/MeOH (v/v = 10/1) as eluent, to provide an amine (90 mg) after solvent removal. The amine was taken up in pyridine (1.0 mL) and treated with HC(O)NHNHC(O)H (38.3 mg, 0.435 mmol), TMSCI (0.276 mL, 2.175 mmol) and Et 3 N (0.152 mL, 1.088 mmol) at room temperature in a sealed tube. The reaction mixture was then heated at 100*C for 2.5 hours 10 before it was cooled down to room temperature. The mixture was then diluted with EtOAc (40 mL) and washed with HC (10 mL, 2.0 N). The resulting aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (25 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using 15 BIOTAGE chromatography (EtOAc/MeOH, v/v = 10/1) to give Compound 5c (40 mg, 31% for 2 steps). Step C: N, N NC N CF' NNNN

H

2 , Pd(OH) 2 /C, EtOHN CF NC -Y CF 3 Cb .

CF, HN .o N CF, HN .,,, N CF3 Compound So Compound 5 Compound Sd 20 Compound 5c (40 mg, 0.0595 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH) 2 /C (8 mg, 10 wt%) and was hydrogenated using a H 2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent 25 was removed under reduced pressure, and the crude product was purified using preparative TLC (EtOAc/MeOH, v/v = 40/1) to give Compound 5 (18 mg, 56%, Electrospray MS [M+1]* 538.1.) and Compound 5d (6 mg, 19%, Electrospray MS [M+1]* 538.1.). -60- PREPARATIVE EXAMPLE 6 N N N CRa CP. HN .,,. Compound 6 5 Step A: ON OH CF 3

.

N CHa CF . a. MsCI, NE% 3 2~ b. NaBH 4 , DMSO Cbz CF3 CbzN ,CF Compound 23d Compound Sa MsCI (75 mL, 0.969 mmol) was added to a solution of Compound 23d (0.248 g, 0.388 mmol) and Et 3 N (0.27 mL, 1.94 mmol) in CH 2

CI

2 (3.0 mL) at 10 room temperature. The reaction was quenched with water (10.0 mL) after 30 minutes and diluted with CH 2

C

2 (30 mL). The aqueous phase was extracted with CH 2

CI

2 (3 x 10 mL). The combined organic layers were washed with. water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude mesylate was taken up in anhydrous DMSO (3.0 mL) 15 and treated with NaBH 4 (59.0 mg, 1.552 mmol). The reaction mixture was heated at 85*C for 48 hours before it was cooled down to room temperature. The mixture was then diluted with EtOAc (50 mL) and washed with aqueous HCI (10 mL, 1.0 M). The resulting aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (3 x 15 20 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexanelEtOAc, v/v = 5/1) to give Compound Ga (0.11 g, 45% for 2 steps). StepB N 0 2 N, CHC CF, N CF, a. Zn, HOAC CbzN CF b. HC(O)NHNHC(O)H, TMSCI, EtaN, Py CbzN , CF CFA - .. Ob F, Compound 6a Compound 6b A mixture of Compound 6a (0.11 g, 0.176 mmol) and Zn dust (0.114 g, 1.76 mmol) in HOAc (1.5 mL) was heated at 60'C for 2 hours. The reaction 5 mixture was cooled down and filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the residue was taken up in EtOAc (25 mL) and washed with a NaOH solution (4.0 N, 10 mL). The resulting aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with 10 water (15 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude amine (67.1 mg, 0.113 mmol) was taken up in pyridine (1.0 mL) and treated with HC(O)NHNHC(O)H (29.8 mg, 0.339 mmol), TMSCI (0.214 mL, 1.69 mmol) and Et 3 N (0.118 mL, 0.847 mmol) at room temperature in a sealed tube. The mixture was then heated at 100*C for 2.5 15 hours before it was cooled down to room temperature. The mixture was then diluted with EtOAc (40 mL) and washed with HCI (10 mL, 2.0 N) The resulting aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using 20 BIOTAGE chromatography (EtOAc/MeOH, v/v = 20/1) to give Compound 6b (37 mg, 33% for 2 steps). Step C: N' N' H' z 4.N1 CH, CFa ',N ,C CF H,. Pd(OH)2/C, EtOH ' O3 CbzN

.

CF, HN ..,o & CF' Compound 6b Compound 6 25 -62t.,ompouna OD t0.5 mg, 0.0565 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH) 2 /C (7.3 mg, 10 wt%) and was hydrogenated using a H 2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent 5 was removed under reduced pressure and the crude product was purified using preparative TLC (EtOAc/MeOH/Et 3 N, v/v/v = 40/1/0.1) to give Compound 6 (20 mg, 69%). Electrospray MS [M+1] 513.1. PREPARATIVE EXAMPLE 7 10 N NC HN O Compound 7 Step A: <N N HO a. Dess-Man Fedinane CF, b.HONH2.HCI, NaCAc, EtCH F c. 1,1'-oxaydiimidazole, PhH CbZN a bzN O . CF, '/ OCF, Compound 12a Compound 7a 15 Dess-Martin Periodinane (0.114 g, 0.268 mmol) was added to a mixture of Compound 12a (70.5 mg, 0.107 mmol) and NaHCO 3 (0.112 g, 1.34 mmol) in CH 2 Cl 2 (3.0 mL) at room temperature. The reaction was stirred for 1 hour before it was diluted with the addition of EtOAc (30 mL) and water 20 (10 mL). The organic phase was washed with saturated Na 2 S20 3 solution (3 x 10 mL). The combined aqueous phases were extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with a NaOH solution (10 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude aldehyde (70.5 mg, 0.107 mmol) was 25 dissolved in EtOH (3.0 mL) and treated with HONH 2 -HCI (74.4 mg, 1.07 mmol) and NaOAc (43.9 mg, 0.535 mmol) at room temperature. The reaction mixture was stirred for 12 hours before it was diluted with EtOAc (20 mL) and - 63 washed with aqueous NaHCO 3 (10 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude oxime was obtained (63 mg, 0.093 mmol) which was 5 taken up in benzene (2.0 mL) and treated with 1,1'-oxalyldiimidazole (35.4 mg, 0.186 mmol). The reaction mixture was heated at 80 0 C for 3 hours before it was cooled down to room temperature and diluted with EtOAc (20 mL) and washed with aqueous HCl (0.5 N, 5 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with 10 water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography (EtOAc) to give Compound 7a (39 mg, 55% for 3 steps). Step B: (N N 'NN ObNC CFH 2 , Pd(OH) 2 /C, EtOH NC CF, CbzN HN CF 15 Compound 7a Compound 7 Compound 7a (39 mg, 0.059 mmol) in EtOH (2.5 mL) was treated at room temperature with Pd(OH) 2 /C (7.8 mg, 10 wt%) and was hydrogenated using a H 2 balloon for 30 minutes. The reaction solution was filtered through a 20 short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using preparative TLC (EtOAc/Et 3 N, v/v = 100/0.1) to give Compound 7 (12.2 mg, 40%). Electrospray MS [M+1I] 524.3. 25 PREPARATIVE EXAMPLE 8 - 64 - ON SH3CO C N HN **, N H ACF 3 Compound 8 Step A: 'N a. Dess-Martin Periodinane a ' H 2-methyl-2-buteneN, NCF HCO N CF, NO OF, b. NaHP0 4 , tert-butano)CF c. TMSCHN 2 , MeO, PhH C b z N . O C b z N , C .'0A CF, Tb CF3 Compound 12a Compound 8a 5 Dess-Martin Periodinane (0.325 g, 0,767 mmol) was added to a mixture of Compound 12a (0.202 g, 0.306 mmol) and NaHCO3 (0.322 g, 3.83 mmol) in CH 2 Cl 2 (5.0 mL) at room temperature. The reaction was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic 10 phase was washed with saturated Na 2

S

2

O

3 solution (3 x 15 mL). The combined aqueous phases were extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude aldehyde (0.202 g) was taken up in tert-butanol (4.0 15 mL) and water (1.0 mL) and treated with NaH 2

PO

4

-H

2 0.(84.4 mg, 0.612 mmol), NaCIO 2 (96.8 mg, 1.07 mmol) and 2-methyl-2-butene (0.227 mL, 2.14 mmol) successively. The reaction mixture was stirred for 2 hours and then diluted with EtOAc (30 mL) and washed with aqueous NH 4 CL. The resulting aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic 20 layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude acid was dissolved in benzene (4.0 mL) and MeOH (1.0 mL). The resulting solution was treated with

TMSCHN

2 (0.306 mL, 0.612 mmol) at room temperature and stirred for 20 minutes. Solvent was removed under reduced pressure and the crude product 25 was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 5/1 to 1/3) to give Compound 8a (62 mg, 29% for 3 steps). -65 - Step B: (,C , F o0Jj 2 H,, Pd(OH)/C, EtOH HCO N CF, CbzN F, HN F, Compound Sa Compound 8 Compound 8a (62 mg, 0.090 mmol) in EtOH (3.0 mL) was treated at 5 room temperature with Pd(OH) 2 /C (12.4 mg, 10 wt%) and was hydrogenated using a H 2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (EtOAc/MeOH, v/v = 6/1) to give 10 Compound 8 (42 mg, 84%). Electrospray MS [M+1]* 557.3. PREPARATIVE EXAMPLE 9 0 eCN CF, HN .F, 15 Step 1: HzN *CN CF, CI C CN CF, CF, RTemp-80'C CFC a9a In a 25 ml round-bottomed flask, Compound 42b (0.21 g, 0.35 mmol, 20 1.0 equiv) was taken up in 2 mL of toluene. 3-chloropropionyl chloride (0.037 mL, 0.38 mmol, 1.1 equiv) was then added to the reaction mixture, which was stirred at room temperature for five hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane) and MS, which showed some starting material was still present. The reaction mixture was thus heated to -66- 800C. Upon completion of the reaction after a further hour of heating, the mixture was concentrated to give crude product Compound 9a (0.2 g), which was used in the next step without further purification. 5 Step 2: N CN CFCN _g 50NaHin Q C b z -C CC F C b zC C "1 CF, (411) Cz ",A CF 3 9a 9b in a flame-dried 25 ml round-bottomed flask, Compound 9a (0.2 g, 10 0.287 mmol, 1.0 equiv) was taken up in a 0.5 M solution of dry CH 2

CI

2 /DMF (4/1) ratio (4.59 mL/1.15 mL). To this mixture a 0.5 M solution of 60% NaH (0.012 g, 0.316 mmol, 1.1 equiv) in dry CH 2

CI

2 /DMF (411 ratio; 5.06 mL/1.26 mL) was very slowly added using a syringe pump over a period of 3.5 hrs and the reaction mixture was stirred at room temperature overnight. The progress 15 of the reaction was monitored by TLC (40:60 EtOAc/hexane) and MS. The reaction went to 60% completion, and was then diluted with CH 2

CI

2 and quenched with saturated aqueous NH 4 CI. The organic layer was dried over Na 2

SO

4 and concentrated to give crude product (0.18 g), which was purified using BIOTAGE chromatography (30/70 EtOAc/ hexane) to give Compound 20 9b (0.125 g). Electrospray MS [M+1] 660.2. Step 3: -o 0 ,CN CF 3 20%dH, N 0CN CF MeOH. Hg) CbzN .,.O CF HN CF, CF, 25 9b Compound 9b (0.125 g, 0.189 mmol, 1.0 equiv) was dissolved in dry MeOH (1.0 mL) and was treated with 20% Pd(OH) 2 (60% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric -67 pressure and the progress of the reaction was monitored by TLC (60:40 EtOAc/hexane). The reaction was completed in 20 min, and the reaction mixture was filtered through CELITE, washed using EtOAc, and concentrated to give crude product. Purification was carried out using prep plate 5 chromatography (45/55 EtOAc/ hexane) to give Compound 9 (0.071g, 71%). Electrospray MS [M+1] 526.3. HRMS (FAB) calculated for C 26

H

2 6

F

6

N

3 0 2 (M+1) 526.1932, found 526.1929. 10 PREPARATIVE EXAMPLE 10 0 NN

H

2 N CF 3 HN o H e CFa Compound 10 Step A: 15 0 N N O N'N HCO yN CF, H2N N CF, HN I NH,, MeOH HN O N -r .O N CF 3 / C, Compound 8 Compound 10 A solution of Compound 8 (35 mg, 0.063 mmol) in ammonia methanol solution (3.0 mL, 7.0 M) in a Parr bomb was heated at 800C for 5 days. The 20 system was cooled to room temperature and solvent was removed under reduced pressure. The crude product was purified using BIOTAGE chromatography (EtOAc/MeOH, v/v = 10/1) to give Compound 10 (26.8 mg, 79%). Electrospray MS [M+1]* 542.1. 25 PREPARATIVE EXAMPLE 11 -68 - H , N OH \ -N CF 3 HN *.O CF, *\ / Example 11 Step 1: H OH O- e CF, MeMgBr,THF ' N CF 3 CbzN . 0 CCbzN . 0 C 'A CF3, CF 3 30b 11a 5 A solution of methylmagnesium bromide in tert-butylether (0.42 mL, I.0M, 0.42 mmol, 6.2 equiv.) was syringed into a solution of Compound 30b (48 mg, 0.068 mmol, 1.0 equiv.) in anhydrous THF (1 mL) at O'C. The reaction mixture was then warmed up to room temperature. After TLC (EtOAc 10 eluent) showed that the reaction was complete, the reaction mixture was diluted with ether and washed with saturated aqueous NH 4 CI solution. The combined organic layers were dried over MgSO 4 , filtered and concentrated to give crude product, Compound 11a, which was used in the next step without purification. 15 Step 2: N' O OH H'T OH N'..N /C Pd(OH) 2 /C, H, N CF,

CF

3 . CF, / (3%framsob) 11Ia 11 Using the same procedure as that of Example 31, Step 6, the crude 20 Compound 11a was hydrogenated to give pure Example 30b (yield 52.6% from Compound 11). MS [M+1]* 587.1. PREPARATIVE EXAMPLE 12 -69- N, N HO CF, HN O CF, HN Compound 12 Step A: HO NH 2 HON CbzN O( CF3 OHONHNHCHO, TMSCI, Et 2 N, Py CbzN oCF 5 Compound 23d Compound 12a HC(O)NHNHC(O)H (0.28 g, 3.18 mmol), TMSC (2.0 mL, 15.9 mmol) and Et 3 N (1.1 mL, 7.95 mmol) were added successively to a solution of Compound 23d (0.647 g, 1.06 mmol) in pyridine (5.0 mL) at room 10 temperature in a sealed tube. The mixture was then heated at 100'C for 2.5 hours before it was cooled down to room temperature. The mixture was then diluted with EtOAc (100 mL) and washed with HCI (35 mL, 2.0 N). The aqueous phase was extracted with EtOAc (3 x 25 mL), and the combined organic layers were washed with water (15 mL), brine (25 mL), and dried over 15 MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography (EtOAc/MeOH, v/v 5/1) to give Compound 12a (0.48 g, 68%). Step b: 20 N 'N N HO ?N CF 2

H

2 , Pd(OH) 2 /C, EtOH HO NF 2 bzNCF CF Compound 12a Compound 12 - 70 - Compound 12a (32.6 mg, 0.049 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH) 2 /C (6.5 mg, 10 wt%) and was hydrogenated using a H 2 balloon for 30 minutes. The reaction mixture was then filtered through a short pad of CELITE and the residue was washed with EtOH (15 5 mL). The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography.(EtOAc/MeOH eluent, v/v = 6/1) to give Compound 12 (17.2 mg, 66%). Electrospray MS [M+1]* 529.1. PREPARATIVE EXAMPLE 13 and 14 10 HaC -N CF HCO ? CF H -,, O . H C F

F

3 /\/ Compound 13 Compound 14 Step A: N' N HCO NH 2 CF HCO N- CF HC(O)NHNHC(O)H, TMSCI, Et 3 N, Py CbzN CF, CbzN

CF

3 Compound 26a Compound 14a 15 HC(O)NHNHC(O)H (67.1 mg, 0.762 mmol), TMSCI (0.484 mL, 3.81 mmol) and Et 3 N (0.266 mL, 1.905 mmol) were added successively to a solution of Compound 26a (0.155 g, 0.254 mmol) in pyridine (2.0 mL) at room temperature in a sealed tube. The mixture was then heated at 1 00'C for 20 2.5 hours before it was cooled down to room temperature. The mixture was diluted with EtOAc (40 mL) and washed with HCI (15 mL, 2.0 N). The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (25 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using 25 BIOTAGE chromatography (EtOAc/MeOH, v/v = 10/1) eluent to give Compound 14a (0.129 g, 75%). -71- Step B: N, N NN NN H,CO 4j CF HCO H2, Pd(OH) 2 C, EtOH HCO'. N CF H 3 CO -CF CbzN -, O t i

CF

3 HN ., N CF HN O N CF, Compound 14a Compound 13 Compound 14 5 Compound 14a (129 mg, 0.19 mmol) in EtOH (4.0 mL) was treated at room temperature with Pd(OH) 2 C (25.8 mg, 10 wt%) and hydrogenated using a H 2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using 10 preparative TLC (EtOAc/Et 3 N, v/v = 100/0.1) to give Compound 13 (36 mg, 35%, Electrospray MS [M+11f 543.1.) and Compound 14 (30 mg, 29%, Electrospray MS [M+1]* 543.1.). 15 PREPARATIVE EXAMPLE 15 O,, ('NH HaC .Nd Cj N - ,10OACF 3 Compound 16 Step A: N'NH N'NH HO'. CF a. Dess-Martin periodinane H 3 CO - a CF 3 b.p-MeOBnNH2, NaBH(OAc)a CbzN .,,O CF CICH2CHaCI CbzN ,,CFO 20 Compound 23 g Compound 1Sa Dess-Martin Periodinane (57.7 mg, 0.136 mmol) was added to a mixture of Compound 23g (46 mg, 0.0678 mmol) and NaHCO 3 (57 mg, 0.678 mmol) in CH 2

CI

2 (2.5 mL) at room temperature. The reaction mixture was - 72stirred for 1 hour before it was diluted with EtOAc (20 mL) and water (10 mL). The organic phase was washed with saturated Na 2

S

2

O

3 solution (3x10 mL). The combined aqueous phases were extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with NaOH solution (10 mL, 1.0 N), 5 water (10 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude aldehyde (46 mg, 0.0679 mmol) was taken up in

CICH

2

CH

2 CI (1.0 mL) and treated with 4A molecular sieves (15 mg) and para methoxybenzyl amine (26.7 [d, 0.204 mmol), followed with addition of NaBH(OAc) 3 (86 .4 mg, 0.408 mmol). The resulting reaction mixture was 10 stirred at room temperature for 12 hours. The system was then diluted with EtOAc (20 mL) and washed with aqueous NaHCO 3 (10 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE 15 chromatography (hexane/EtOAc, v/v = 2/3) to give Compound 15a (38 mg, 70% for 2 steps). Step B: (N 'NH N ,NH

H

3 CO H O CFH NH4CO 2 H, Pd/C, MeOH . N CF, CbzN . HF HN 0 F Compound 15a Compound 15b 20 A mixture of Compound 15a (46.6 mg, 0.0584 mmol), Pd/C (46.6 mg, 10 wt%), and NH 4

CO

2 H (36.8 mg, 0.584 mmol) in MeOH (2.0 mL) was heated at reflux for 5 hours. The mixture was cooled to room temperature and filtered through a short pad of CELITE, and the residue was washed with EtOH (15 25 mL). Solvent was removed under reduced pressure to give a crude product, which was taken up with EtOAc (20 mL) and washed with aqueous NaHCO 3 (10 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was -73 purified using preparative TLC (MeOH/EtOAc, v/v = 1/10) to give Compound 15b (18 mg, 57%). Step C: 5 N, N, NNH 00 N'NH N4 CF 0 F H 3 C' N1W 40 MsC, N~t 3 , CH2C 2 H N HN CF, HN CF 3 Compound 15b Compound 15 MsCl (2.5 pL, 0.0324 mmol) was added to a solution of Compound 15b (8.8 mg, 0.0162 mmol) and Et 3 N (5.4 1 4L, 0.0388 mmol) in CH 2 Cl 2 (1.0 10 mL) at 0*C. The reaction was quenched with water (5.0 mL) in 30 minutes and diluted with EtOAc (15 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v 1/5) 15 to give Compound 15 (7.2 mg, 72%). Electrospray MS [M+1]* 622.3. PREPARATIVE EXAMPLE 16 H N'N(' HNN N\-N 75 CF 3 0 HN .CF, 20 compound 15 Step 1: H O HN N\\ -N -C O 2 H CF 3 N'\\- N - CF\ CbzN o HATU, EtNH2 ChzN CF DMF 'CF 3 31h 16a -74- Using the same procedure as that of Example 30, Step 1, Compound 16a was prepared using ethylamine in the place of NN-dimethylamine hydrochloride salt, and without using diisopropyl ethyl amine. The crude 5 product was used in the next step without purification. Step 2: N. CH a H ON ~ (71% from CW8) C \C / 16a compound 16 10 Using the same procedure as that of Example 31, Step 6, the crude Compound 16a was hydrogenated to give pure Example 16 (yield 70.5% from Compound 16). MS [M+1]* 600.1. 15 PREPARATIVE EXAMPLE 17 H \ -N CF 3 N *N r HN 0 CF 3 Example 17 Step 1: H N\-N CO2H CFa \\- CF, 0 CbzN 0 D. MAP, EObz

CF

3 EtOH. GHCj 3 .",. CF 3 20 31h1 1a A solution of Compound 31h (46.3 mg, 0.066 mmol, 1.0 equiv.) in anhydrous dichloromethane (1 mL) was cooled to 0*C. To this solution was added sequentially DMAP (8 mg, 0.066 mmol, 1.0 equiv.), and ethanol (36 -75 gL). The reaction mixture was allowed to warm up to room temperature, and then concentrated to dryness. The residue was taken up into EtOAc and washed with saturated aqueous NaHCO 3 solution. The organic layer was dried over Na 2

SO

4 , filtered and concentrated to give the crude product, 5 Compound 17a, which was used in the next step without purification. Step 2: HF 0 CF, NCF Pd(OH)1C, H 2 0 CbN CF, HN (46% from 31h) 0A CF 3 17a 17 10 Using the same procedure as that of Example 31, Step 6, the crude Compound 17a was hydrogenated to give pure 17 (yield 46% from Compound 31h). MS [M+1]* 601.1. PREPARATIVE EXAMPLE 18 15 HO, N CNH H N . ., O C F Compound 18 Step A: N, - NH N O N CF, HO,N N NH CF

NH

2 OH, EtOH -O'N, ON 0

CF

3 CF, HN C, 0 Compound 19 Compound iS 20 Compound 19 (10 mg, 0.0175 mmol) in EtOH (1.5 mL) was treated with HONH 2 -HCI (12.2 mg, 0.175 mmol) and NaOAc (7.2 mg, 0.0876 mmol) at room temperature. The reaction mixture was then stirred at 60'C for 12 -76 hours. The mixture was diluted with EtOAc (20 mL) and washed with aqueous NaHCO 3 . The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was 5 purified by preparative TLC (hexane/EtOAc, v/v = 2/3) to give Compound 18 (10 mg, 98%). Electrospray MS [M+1]4 586.1. PREPARATIVE EXAMPLE 19 NNH OA..'N CF, H N CF, 10 Compound19 Step) A: NH N HO 0. N CFa. Dess-Marin penodinane 0 N4 b. VinyI~gBr, THF 0 F CbzN .I CFa c. Dess-Martin peiodinane CbzN .

CF3 Compound 23h Compound 19a 15 Dess-Martin Periodinane (0.252 g, 0.595 mmol) was added to a mixture of Compound 23h .(0.202 g, 0.297 mmol) and NaHCO 3 (0.25 g, 2.97 mmol) in CH 2

CI

2 (4.0 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic phase was washed with a saturated Na 2

S

2 0 3 solution (3x15 mL). 20 The combined aqueous phases were extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude aldehyde (0.202 g) was taken up in anhydrous THF (4.0 mL) and was treated with CH 3 MgBr (1.19 mL, 1.19 mmol, 1.0 M in THF) 25 at -78*C. The reaction temperature was slowly increased to room temperature and the reaction was quenched in 2 hours by the slow addition of saturated -77aqueous NH 4 CI solution (10 mL). The reaction mixture was then diluted with EtOAc (50 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly acidic. The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and 5 dried over MgSO 4 . After filtration and concentration, the crude secondary alcohol (0.21 g),was taken up in CH 2 CI2.(5.0 rnL) and treated with Dess-Martin Periodinane (0.379 g, 0.894 mmol) and NaHCO 3 (0.375 g, 4.47 mmol) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic phase was 10 washed with saturated Na 2 S20 3 solution (3x15 mL). The combined aqueous phases were extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with aqueous NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude produce was purified using BIOTAGE chromatography (hexane/EtOAc, 15 v/v = 1/1) to give Compound 19a (90 mg, 43% for 3 steps). Step B: N CF H, Pd(OH)/C, EOH N CF0 CbzN ,, 0 CF HNCF Cr 3 H ... oCF, Compound 19a Compound 19 20 Compound 19a (57.4 mg, 0.0816 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH) 2 /C,(11.5 mg, 10 wt%) and was hydrogenated using a H 2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product 25 was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 2/3) to give Compound 19 (41 mg, 88%). Electrospray MS [M+1]* 571.1. PREPARATIVE EXAMPLE 20 - 78 - 0 ( NH

H

3 CO'. N, CF HNCF Compound 20 Step A: 0 O H aC O N H 2 C F a a . C H O CO E , N a B H (O A c ), H a OH (NHN H CICHCHC] H 2 O -C Cf, HC F CbzN -F,,,O b. TMSN=C=0,

CICH

2

CH

2 C ' CbzN -,,, o CF, + CbzN CFa Compound 26b Compound 20a Compound 20b 5 NaBH(OAc) 3 (81.4 mg, 0.384 mmol) was added at room temperature to a solution of Compound 26b (79.9 mg, 0.128 mmol), CHOCO 2 Et (37.8 pil, 0.192 mmol, 45-50% in toluene), and 4 A molecular sieves (30 mg) in 10 CICH 2

CH

2 CI (1.0 mL). The reaction mixture was stirred for 12 hours before it was diluted with EtOAc (20 mL) and washed with aqueous NaHCO 3 (10 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product (91 mg, 0.128 15 mmol) was taken up in CICH 2

CH

2 C1 (0.5 mL) and treated with TMSN=C=O (2.5 mL). The reaction mixture was heated at 70*C for 72 hours before the solvent was removed under reduced pressure. The crude product was purified using BIOTAGE chromatography (hexane/EtOAc, vv = 1/1) to give a mixture of Compound 20a and 20b, which was further purified by OD chiral HPLC to 20 give pure Compound 20a (30 mg, 33%) and Compound 20b (25 mg, 28%). Step B: - 79 - U 0 NH NH HC - . N CF' H 2 , Pd(OH)2/C. EtOH H ICO - N 4 GF 3 CbzN CF0 HN CFo CF, CF Compound 20a Compound 20 Compound 20a (23 mg, 0.0325 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH) 2 /C (4.6 mg, 10 wt%) and was hydrogenated 5 using a H 2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/3 to 1/9) to give Compound 20 (14.3 mg, 77%). Electrospray MS [M+11 574.3 10 PREPARATIVE EXAMPLE 21 and 22 HN'N 0 HN' O b-N NH' CF N, NH CF. 0 0 HN *I HN H OA CFO C 21 22 BocN OH CF, BOC-N N CF 3 H CbzN PYBOP, DJEAO CF, ~ ~ ~'CF 3 MeNH 2 , CH2CI, A F 15 21a 21b Compound 21a (1.0 g, 1.4 mmol, 1.0 equiv) was dissolved in CH 2

C

2 (16 mL) and the solution was cooled to OC. Diisopropylamine (0.54 g, 4.2 mmol, 3.0 equiv,) was added to the reaction mixture, followed by PYBOP (0.88 g, 1.7 mmol, 1.2 equiv.), and the reaction mixture was stirred at 0"C for 20 5 min., then warmed to room temperature. After 20 min., excess methyl amine (7.0 mL, 14 mmol, 10.0 equiv.) was added as a 2.OM solution in THF. The flask became slightly warm, and was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (95/5 EtOAc/MeOH eluent). Upon completion of the reaction, the reaction mixture -80was diluted with H 2 0 and EtOAc, the organic and aqueous layers were separated, and the organic layer was washed with brine, dried with Na 2

SO

4 , and concentrated to give a crude product (1.9 g) as white solid. Purification was carried out using BIOTAGE chromatography (1:1 to 2:1 EtOAc/hexane) 5 to give Compound 21b as a white solid (0.72 g, 72%). Electrospray MS [M+1] 738.2. BocN NN CF, HN N c~ CF, TFA , H 2 C1 2 C C-b N _________CbzN N .0NCF, .. ,,ANCF 3 21b 21c 10 Compound 21c (0.7 g, 0.95 mmol, 1.0 equiv) was dissolved in CH 2 Cl2 (10 mL) under a N 2 atmosphere, To the reaction was added excess TFA (2.0 g, 19.4 mmol, 20.0 equiv.), and the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC 15 (1/1 EtOAc/MeOH eluent), which indicated that some starting material was still present. Accordingly, 10.0 equiv. of TFA was added and the reaction mixture was allowed to stir for 3 h. Upon completion of the reaction, the reaction mixture was cooled to 0*C, quenched with saturated NaHCO 3 , and diluted with EtOAc. The organic and aqueous layers were separated, and the 20 organic layer was washed with brine, dried with Na 2

SO

4 , and concentrated to give Compound 21d (0.6 g, 99%) as a white foam. BocH 0

H

2 N N CF H HN \N CF, H BocNHNH 2 , ImCOlm CbzN THF CbzN CFa CF 3 21c 21d Compound 21c (0.24 g, 0.38 mmol, 1.0 equiv) was dissolved in 5 mL 25 of anhydrous THF under a nitrogen atmosphere. The solution was cooled to 00C. In a separate round-bottomed flask was combined carbonyldiimidazole (0.15 g, 0.90 mmol, 2.4 equiv) and tert-butyl carbazate (0.1 g, 0.76 mmol, 2.0 equiv) in anhydrous THF (2 mL). The solution was allowed to stir for 30 min - 81 and added via cannula to the solution of Compound 21c over I min. The cannula was rinsed with anhydrous THF (1 x 0.8 mL). The reaction mixture was heated to reflux until the starting material was consumed. The reaction mixture was then cooled to room temperature and concentrated under 5 vacuum to afford a colorless foam. The crude mixture was purified using BIOTAGE chromatography (2%-5% MeOH/CH 2

CI

2 ) to give Compound 21d (0.22 g, 74%) as a white solid. 10 Bac N HN 0 N-- 0 / NH CF, HCl in Dioxane NH CF, CbzN CH21 2 CbZ CF N ~ ~ OF N* F, 21e 21d Compound 21d (0.22 g, 0.28 mmol, 1 equiv) was dissolved in 15 mL of anhydrous CH 2

CI

2 under a nitrogen atmosphere. The solution was cooled to 0*C. HCI (1.4 mL, 5.6 mmol, 20 equiv, 4 M solution in dioxane) was added 15 and the solution was allowed to warm to room temperature and stirred overnight. The solution was cooled to 0*C and quenched with saturated NaHCO 3 (5 mL) solution and diluted with EtOAc. The organic and aqueous layers were separated and the organic layer was washed with brine (10 mL), and dried over Na 2

SO

4 . The organic layer was filtered and concentrated under 20 vacuum to give a white solid. The crude mixture was purified using BIOTAGE chromatography (5%-8% MeOH/CH 2

CI

2 ) to give Compound 21e (0.15 g, 79%) as a white solid. 11N, 0N*, HN'N 0 HN H H -H CF, NHCHNH 2 -N \NH CF, CbzN ACOH, DMF CbzN N -~ CF, " CF, 25 21e 21f Compound 21e (0.15 g, 0.22 mmol, 1.0 equiv) was dissolved in anhydrous DMF (1 mL). Foramidine acetate (0.126g, 1.2 mmol, 5.5 equiv.) followed by acetic acid (0.69 mL, 1.2 mmol, 5.5 equiv.) was added, and the - 82reaction mixture was heated to 80*C for 30 min. Residual starting material was found by TLC analysis, and accordingly the reaction mixture was refluxed for an additional 6 h. The progress of the reaction was monitored by TLC (9/1

CH

2 Cl 2 /MeOH eluent). Upon completion of the reaction, the reaction mixture 5 was cooled to room temperature, quenched with H 2 0, and diluted with EtOAc. The organic and aqueous layers were separated and the organic layer was washed with brine, dried with Na 2

SO

4 , and concentrated to give a crude product (0.131 g) as white foam. Purification was carried out using BIOTAGE chromatography (gradient of 100% CH 2 Cl 2 to (95:5) MeOH) to give 10 Compound 21f as a white solid (0.11g, 72%). Electrospray MS [M+1] 706.4. N HN1N HN'N o IHN'" 0 />,-N NH OF N HO MeOH NH,~, N 0 N 10%Pd/C, NH0,CH N HN CbzN MeF, N *"' O *N "'-'CF, 21 22 2if Compound 21f (0.02 g, 0.028 mmol, 1.0 equiv.) was dissolved in dry 15 MeOH (1.0 mL) and was treated with 10% Pd/C (40% wt.) followed by ammonium formate (0.09 g, 0.14 mmol, 5.0 equiv.) under an inert atmosphere. The reaction mixture was heated to reflux and was monitored by TLC (9/1 CH 2

CI

2 /MeOH eluent). The reaction was completed in 1 hr. The reaction mixture was filtered through CELITE, washed using EtOAc, and 20 concentrated under vacuum. The resulting residue was taken up in EtOAc, and washed with saturated NaHCO 3 , followed by brine and H 2 0 to give a crude product (0.019 g) as solid film. Purification was carried out by BIOTAGE chromatography (gradient of 2% to 6% MeOH/CH 2

C

2 ). The de aired product was converted to the HCI salt to give a mixture of Compounds 25 21 and 22 (0.014 g) as a white solid. HRMS (FAB) calculated for C 2 cH 28

F

6

N

3 0 2 (M+1)572.2096, found 572.2103, PREPARATIVE EXAMPLE 23 30 - 83 - NNH HO . N CF 3 H -,,, OCF, Compound 23 Step A:

O

2 N CF, 0 2 N CF NaBH, MeOH, 0 *C 1bz a CF, CbzN *F 5 Compound 23a Compound 23b NaBH 4 (2.42 g, 64.1 mmol) was added in 4 portions to a solution of Compound 23a in MeOH (160 mL) at 00C. The reaction mixture was stirred for 4 hours and the reaction temperature was slowly increased to rt. The 10 reaction was quenched by the slow addition of saturated aqueous NH 4 CI solution (50 mL). The reaction mixture was then diluted with EtOAc (400 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly acidic. The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried 15 over MgSO 4 . After filtration and concentration, the crude product was passed through a short pad of silica gel (hexane/EtOAc, v/v = 7/1). Solvent was removed under reduced pressure to give Compound 23b, 17.4 g (89%) as a light yellow syrup. 20 Step B: 0NCF, H0'Il. NO, F 02N, OH

O

2 N CF, paraformaldehyde, TBAF CF2 CbzN C,,F THF, 0 *C CbzN C + CbzN . " 0 1 CF 3 N. s CF, Compound 23b Compound 23c Compound 23d -84- TBAF (2.23 mL, 2.23 mmol, 1.0 M in THF) was added dropwise to a mixture of Compound 23b (9.1 g, 14.89 mmol) and paraformaldehyde (3.85 g) in THF (100 mL) at 0*C. The reaction mixture was stirred at 0*C for 8 hours before it was quenched with addition of saturated aqueous NH 4 CI solution (50 5 mL). The reaction mixture was then diluted with EtOAc (250 mL) and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE (CH 2

CI

2 /EtOAc, v/v = 100/0.5) to give Compound 23c (6.0 g, 63%) 10 and 23d (2.34 g, 24%). Step C: HO-', NO CF 3 HO-' NH 2 CF, CbzN O CF, Zn, HOAc, 60 *0 CbzN CFa Compound 23c Compound 23e 15 A mixture of Compound 23c (7.54 g, 11.76 mmol) and Zn dust (7.68 g, 117.6 mmol) in HOAc (120 mL) was heated at 60"C for 2 hours. The reaction mixture was cooled down and filtered through a short pad of CELITE and the residue was washed with EtOH (50 mL). Solvent was removed under reduced 20 pressure and the residue was taken up in EtOAc (250 mL) and washed with NaOH solution (50 mL, 4.0 N). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, 25 v/v = 1/3 and EtOAcIMeOH, v/v = 10/1) to give Compound 23e (6.4 g, 89%). Step D HO-''. NH, CFE Bno". NH 2

CF

3 CbzN .

Bn~r, (NH,),HSO 4 , NaOH, THF CbzN . N CF, 0-&CF, Compound 23e Compound 23f - 85 - BnBr (0.668 mL, 5.58 mmol) was added at rt to a vigorously stirring mixture of Compound 23e (3.1 g, 5.07 mmol) and Bu 4

NHSO

4 (0.334 g, 1.014 mmol) in THF (20 mL) and aqueous NaOH solution (20 mL, 50 wt%). The 5 reaction mixture was stirred at room temperature for 12 hours before it was diluted with EtOAc (250 mL) and washed with water (100 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE 10 chromatography (hexane/EtOAc, v/v = 113 to 117) to give Compound 23f (2.8 g, 79%). Step E: Ha EtO=N-NHCO 2

CH

3 , 'NH BnO'. N2 CF 3 a, 31 EtOH BnO O'Ca CbzN b. NaOCH,, MeOH, 80 *C CF, CbzN CF, Compound 23f 15 Compound 23g A solution of Compound 23f (2.72 g, 3.88 mmol) and reagent 31c (i.e., N-ethoxymethylene-hydrazine carboxylic acid methyl ester) (2.83 g, 19.4 mmol) in EtOH (15 mL) was heated at 60oC for 18 hours. The reaction mixture 20 was diluted with MeOH (15 mL) and then treated with NaOCH 3 (7.0 mL, 38.8 mmol, 30% in MeOH). The resulting reaction mixture was heated at 80 0 C for 4 hours before it was cooled to room temperature. The reaction mixture was diluted with EtOAc (200 mL) and aqueous NH 4 CI solution (75 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic 25 layers were washed with water (50 mL), brine (100 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 2.5/1 to 1/1) to give Compound 23g (2.54 g, 85%). 30 Step F: -86- N'NH N'NH BnO-'. NA CF3 HO'. N, CF BC1, CH 2 01 2 -78 '0 C b z N . N C C b z N . C F ""0--CF3 _OaF, Compound 239 Compound 23h

BC

3 (3.26 mL, 3.26 mmol, 1.0 M in hexane) was added dropwise to a 5 stirring solution of Compound 23g (0.502 g, 0.653 mmol) in CH 2

CI

2 (45 mL) at -78*C. The reaction was quenched in 1 hour by the addition of aqueous NaHCO3 solution (50 mL) at -78*C. The mixture was diluted with EtOAc (100 mL) and vigorously stirred at room temperature for 2 hours. The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers 10 were washed with water (50 mL), brine (50 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/3 to 1/9) to give Compound 23h (0.39 g, 91%). 15 Step G: -NH N'NH HO''A N C0 a H21 Pd(OH)/C, EtOH HO N 0 CF CbzN O \ HN CFN CF, CF, Compound 23h Compound 23 ConpRt-nd 23h (100Tg,~0:152-mrnol) in EtOH'(5.0 mL) was treated 20 at room temperature with Pd(OH) 2 /C (20 mg, 10 wt%) and was hydrogenated using a H 2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/7) to give 25 Compound 23 (68 mg, 82%). Electrospray MS [M+1]* 545.1. -87- PREPARATIVE EXAMPLE 24

H

0 W OH H N ., O CF HN / 5 Example 24 HJ H ,' N OH 2) EtOH, NaBH, CbzN O CF 3) Pd(OH) 2 /C, H 2 HN , \ / (63%) / 319 Example 24 A solution of Compound 31g (83.3 mg, 0.12 mmol, 1.0 equiv.) in anhydrous dichloromethane (4 mL) was cooled to -78*C. Then 03 was 10 bubbled through the solution until the solution turned blue. The solution was then purged with N 2 to remove excess 03, and the reaction mixture was concentrated to dryness. The resulting residue was then taken up in ethanol (2 mL), and treated with sodiurn borohydride (46 mg, 1.2 mmol, 10'equiv.). The reaction mixture was stirred at room temperature until TLC (50% 15 EtOAc/hexanes) showed that the starting material was completely consumed. The reaction mixture was then concentrated to dryness. The residue was dissolved in absolute ethanol (4 mL) and treated with Pd(OH) 2 /C (80 mg, 20 wt%, 0.11 mmol, 0.88 equiv.) before hydrogenating with a hydrogen balloon. The reaction mixture was stirred at room temperature until TLC (5% 20 MeOH/CH 2

CI

2 ) showed that the starting material was completely consumed. The reaction mixture was again concentrated to dryness. The residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and the aqueous and organic layers separated. The aqueous layer was further extracted with ethyl acetate. The combined 25 organic layers were dried over anhydrous Na 2

SO

4 , filtered, concentrated to give the crude product, which was purified using Prep-TLC (MeOH/CH 2

CI

2 =5%) to give pure Compound 24 (42 mg, yield 63%). MS [M+1]* 559.1. -88- PREPARATIVE EXAMPLE 25 H 0 HN .,,o 'A OF compound 25 5 N'N (/N' { N OCF2, CF', Pd(OH) 2 C, H, CbzN .0 N F EtOH HN *A CF \ / (84%) 31g compound 25 To a solution of Compound 31g (83.3 mg, 0.12 mmol, 1.0 equiv.) in absolute ethanol (3 mL) was added Pd(OH) 2 /C (20 mg, 20 wt%, 0.028 mmol, 10 0.88 equiv.) before hydrogenating with a hydrogen balloon. The reaction mixture was stirred at room temperature until TLC (50% EtOAc/hexanes) showed that starting material was completely consumed. The reaction mixture was.then concentrated to dryness. The resulting residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous 15 solution, and the aqueous and organic layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2

SO

4 , filtered, and concentrated to give the crude product, which was purified using Prep-TLC (50% EtOAc/hexanes) to give pure Compound 25 (15 mg, yield 84%). MS [M+1]* 557.1. 20 PREPARATIVE EXAMPLE 26 'NH o CFa H e CF, Compound 26 - 89 - Step A: HO NH, CF, HO NHBoc Boc2O, NEta, dioxane CbzN F* ObzN .,_,a - 0 - '- - & CF Compound 26a Compound 26b 5 Et 3 N (0.129 mL, 0.93 mmol) was added to a solution of Compound 26a (0.472 g, 0.77 mmol) and Boc 2 O (0.168 g, 0.77 mmol) in dioxane (3.0 mL) at room temperature. The resulting solution was stirred for 8 hours before it was diluted with EtOAc (50 mL). The organic phase was washed with 0.5 N HCI (10 mL). The aqueous phase was extracted with EtOAc (3 x 15 mL). The 10 combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v 1/1) to give Compound 26b (0,465 g, 85%). 15 Step B: HO NHBoc CF, H3CO NHBoc CF3 CHal, (NH 4

)

4 H80 4 , NaOH, THF CbzN, CF, CbzN ., o C Compound 26b Compound 26c

CH

3 1 (0.372 mL, 5.98 mmol) was added at rt to a vigorously stirring 20 mixture of Compound 26b (0.425 g, 0.598 mmol) and Bu 4

NHSO

4 (40.6 mg, 012~mrnol)YiTHF (5~:0 mL) and aqueous NaOH solution (5.0 mL, 50 wt%). The reaction mixture was stirred at room temperature for 12 hours before it was diluted with EtOAc (50 mL) and washed with water (15 mL). The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers 25 were washed with water (15 mL), brine (15 mL), and dried over MgSO 4 .After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 5/1) to give Compound 26c (0.345 g, 80%). -90- Step C: a. TFA N EtO NH 'NH HCO NH2 CF, b. ' N-NHCOCH, EtOH HCO-d.. N-- CF, HCO . CF CbzN c. NaOCH,, MeOH, 80 *C CbzN .., O CF, + CbzN CF, Compound 26c Compound Compound 26e 26d 5 A solution of Compound 26c (0.345 g, 0.476 mmol) in TFA (3.0 mL) was stirred at room temperature for 20 minutes before the solvent was removed under reduced pressure. The residue was taken up in EtOAc (50 10 mL) and washed with NaOH solution (4.0 N, 15 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude amine (0.29 g, 0.464 mmol) was dissolved in EtOH (3.0 mL) and treated with reagent 31c (0.4.6 g, 2.78 mmol). The resulting 15 solution was heated at 60*C for 18 hours. The reaction mixture was diluted with MeOH (3.0 mL) and then treated with NaOCH 3 (0.672 mL, 3.712 mmol, 30% in MeOH). The resulting reaction mixture was heated at 80*C for 4 hours before it was cooled to room temperature. The system was diluted with addition of EtOAc (50 mL) and aqueous NH 4 CI solution (15 mL). The aqueous 20 phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/3) to give a mixture of Compounds 26d and 26e (0.275 g, 83% for 3 steps) which were separated with OD chiral 25 HPLC (hexane/isopropanol v/v = 9515) to give pure Compounds 26d and 26e. Step D: - 91 - N 'NH N,-NH

H

3 Co-,.. N-4 Ho- N-4 CF,

H

2 , Pd(OH)/C, EtOH CbzN .,O N CF, HN CF, Compound 26d Compound 26 Compound 26d (38 mg, 0.0548 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH) 2 /C (7.6 mg, 10 wt%) and was hydrogenated 5 using a H 2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexanefEtOAc, v/v = 114) to give Compound 26 (25 mg, 82%). Electrospray MS [M+1]* 559.1. 10 PREPARATIVE EXAMPLE 27 N,-NH (NH

H

3 CO yN CF CbzN , CF Compound 27 15 Step A: IN -NHN 'NH N'NH NH

H

3 CO ~N- CF, H 3 CO pN- CF,, C H 2 , Pd(OH)2/C, EtOH CbzN .CF, CbzN CF, Compound 26o Compound 27 20 Compound 26e (41 mg, 0.0592 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH) 2 /C (8.2 mg, 10 wt%) and was hydrogenated using a H 2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent - 92 was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/4) to give Compound 27 (26 mg, 79%). Electrospray MS [M+1]* 559.1. 5 PREPARATIVE EXAMPLE 28 N N FC HN -,, O CF, Compound 28 Step A: H2N

CF

3 H NHo C Boc-a-methyl alanine / HN CF, HATU, EDC, OIEA HN - 10 Compound 44b Compound 28a In a 25 mL round-bottomed flask, Compound 44b (0.2 g, 0.45 mmol, 1.0 equiv) was dissolved in DMF (5.0 mL). HATU (0.342 g, 0.90 mmol, 2.0 equiv), EDC (0.172 g, 0.90 mmol, 2.0 equiv), and DJEA (0.118 mL, 0,68 15 mmol, 1.5 equiv) were added. The reaction mixture was cooled to 0*C and Boc-a-methyl alanine (0.109 g, 0.54 mmol, 1.2 equiv) was added. The reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with saturated NaHCO 3 (5 mL), diluted with EtOAc (10 mL), and extracted with EtOAc (2 x 5 mL). The organic layer was washed with brine (10 20 mL), dried over MgSO 4 , and concentrated. The resulting residue was purified by preparative TLC (9/1 hexanes/EtOAc) to give 0.12 g (43%) of Compound 28a. Step B: - 93 - H NHBoFC NH, FC / TFA, DCM/ HN CF, HN / CF, Compound 28a Compound 28b Compound 28b was prepared by a method similar to that the compound 45c, described below, in which a DCM solution of Compound 5 28a was reacted- with TFA to remove the Boc protecting group. Step C: Ri 0 H N H F, CNFC / HC(OMe), HN / CHaCO2H HN CF Compound 28b Compound 28 10 In a 10 mL round-bottomed flask, compound 28b (0.050 g, 0.094 mmol, 1.0 equiv) was dissolved in toluene (1 mL), and then trimethylorthoformate (0.012 mL, 0.113 mmol, 1.2 equiv) and I drop of acetic acid were added. The solution was heated at 60'C. The reaction mixture was allowed to stir for over 48 hours. The reaction mixture was then taken up in 15 EtOAc (5 mL) and washed with saturated NaHCO 3 (5 mL). The organic layer was washed with brine (5 mL), dried over MgSO 4 , and concentrated. The crude product was purified by preparative TLC (EtOAc) to yield 0,010 g of Compound 28. HRMS calculated for C 27

H

2 9

F

6

N

3 0 2 (M+H) 542.2242, found 542.2222. 20 PREPARATIVE EXAMPLE 29 - 94- H Ny N-N ,--CONH, CF, HN , CF, Example 29 .0 H 0 N\N -CO2H CF* 1) EtOC(O)Ci, EtN N - O0N -CONH2 CF, NH3, CHPCI Cbz CF, 2) Pd(OH H 2N. ' O CF, 3th (57% for 2 steps) Example 29 A solution of Compound 31h (39 mg, 0.055 mmol, 1.0 equiv.) in 5 anhydrous dichloromethane (1 mL) was cooled to -20*C. Then triethylamine (10 mL, 0.069 mmol, 1.25 equiv.) and ethyl chloroformate (6.5 mL, 0.066 mmol, 1.2 equiv.) were added. The resulting pale green solution was stirred at -1 5 0 C for 30 minutes. Ammonia gas was bubbled through the solution for 20 minutes. TLC (EtOAc) indicated that the reaction was complete. The 10 reaction mixture was diluted with ethyl acetate, washed sequentially with IN HCl (1 mL), saturated sodium carbonate aqueous solution, and brine. The organic layer was dried over Na 2

SO

4 , filtered, and concentrated. The resulting residue was dissolved in absolute ethanol (6 mL), to which was added Pd(OH) 2 /C (17 mg, 20 wt%, 0.024 mmol, 0.43 equiv.) before attaching 15 a hydrogen balloon to the reaction flask. The reaction mixture was stirred at room temperature until TLC (5% MeOH/EtOAc) showed that the starting material was completely consumed. The reaction mixture was concentrated to dryness, and the residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and the organic and aqueous 20 layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2

SO

4 , filtered, and concentrated to give the crude product, which was purified using Prep-TLC (5% MeOH/EtOAc) to give pure Example 29 (18 mg, yield 57%). MS [M+1]* 572.1. 25 PREPARATIVE EXAMPLE 30 - 95 -

H

0 H O -CF, compound 30 Step 1:

H

0

H

0 N-OMe \N -COH CF, \\-N CFa HATU, MeONH 2 MeCl 0 CbzN CbNF,F3 (43.6%) 31h 30a 5 To a solution of Compound 31h (450 mg, 0.64 mmol, 1.0 equiv.) in anhydrous DMF (3.5 mL), was added, sequentially, HATU (290.5 mg, 0.764 mmol, 1.2 equiv.), NN-dimethylamine hydrochloride salt (99 mg, 1.01 mmol, 1.6 equiv.) and diisopropyl ethylamine (0.50 ptL, 2.87 mmol, 4.5 equiv.). The 10 resulting orange solution was stirred at room temperature until TLC (5% MeOH/EtOAc) showed that starting material was completely consumed. The reaction mixture was poured into dichloromethane (200 mL), washed sequentially with half-saturated citric acid aqueous solution, saturated NaHCO 3 , and brine. The organic layer was dried over anhydrous Na 2

SO

4 , 15 filtered, and concentrated to give the crude product, which was purified using BIOTAGE chromatography (EtOAc/Hexane =3:1) to give Compound 30a as a brown solid (208 mg, yield 43.6%). Step 2: N-O ,NH N C-OH - N- 0 C SMeMgBr, THF CbzN O ~ CbzN ..,,o N CF 20 0a 30b Methylmagnesium bromide (1.65 mL, 1.0 M in t-butylether, 1.65 mmol, 6.0 equiv.) was added dropwise to a solution of Compound 30a (206 mg, - 96 - 0.275 mmol, 1.0 equiv.) in anhydrous THF (3 mL). TLC (EtOAc) showed that the starting material was totally gone after the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with ethyl acetate, quenched with a saturated aqueous NH 4 CI solution, and 5 extracted with EtOAc. The combined organic layers were dried over Na 2

SO

4 , filtered and concentrated to give the crude product, Compound 30b. Compound 30b was used in the next step without purification. Step3: O C0 N'C~ Cbz N .'' CF a Pd(OH)gC, H 2 MN CF 3 10 30b (s6% from30a) 30 Using the same procedure as that of Example 31, Step 6, the crude Compound 30b was hydrogenated to give pure Example 30 (150 mg, yield 95.6% from Compound 30a). MS [M+1]+ 571.1. 15 PREPARATIVE EXAMPLE 31 H N\\-N f-C0 2 Me CF 3 HN CF, 31 Step 1: 88'C Eto HNNHC(O)OCH + (EtO) 3 CH ( 5%N-N H 20 Zia Sib (>55%) 31c (0)0C Compound 31b (32 mL) was added to a solution of Compound 31a (1.0 g, 11.1 mmol, 1.0 equiv.) in triethylorthoformate. The solution was heated at 88*C for 36 hours, and then concentrated to dryness under vacuum. 25 The resulting residue was recrystallized from EtOAc, to give Compound.31c (0.94 g, yield 58%). - 97 - Step 2:

O

3 N CFO" O, 0 2 N CFa O2N,. .CF CbzN , O C CbzN + CbzN .,CF, OA CF 3 -Pd(pph 3 )4 GF3 '~' CF 3 2) HPLC separation 23b 31d 31e 5 To a solution of Compound 23b (2.5 g, 4.1 mmol) in THF (20 mL) was added allylmethylcarbonate (0.465 ml, 8.2 mmol), and Pd(PPh 3

)

4 (236 mg, 0.205 mmol). The reaction vessel was purged three times with nitrogen, and then the solution was allowed to stir for 16 hours. The solvent was then 10 removed and the residue was filtered through a short silica column using 20% EtOAC /hexanes as eluent. The filtrate was concentrated and Compounds 31d and 31e were separated using prep-HPLC. MS [M+1]* 651.1 for both compounds. 15 Step 3: 02N .( F, Z/Hc H2N CF CbzN CF Zn/ HOAc bzN CF, (82%) \ / 31d Sif A round-bottomed flask was charged with Compound 31d (3.84 g, 20 5.90 mmol, 1.0 equiv.) and glacial acetic acid (20 mL). To the resulting yellowish solution at 0*C was added as several small portions of Zinc dust (3.86 g, 59.0 mmol, 10 equiv.). The reaction mixture was stirred at room temperature for 6 hours until TLC (30% EtOAc/hexane) showed that the starting material Compound 31d was totally consumed. The reaction mixture 25 was then diluted with ethyl acetate, and passed through a CELITE pad in a funnel. The CELITE pad was thoroughly washed with ethyl acetate, and the combined with the filtrate. The filtrate was concentrated to provide a crude product, which was purified using BIOTAGE chromatography (30% - 98 - EtOAc/hexanes) to give a pure colorless oil product, Compound 31f (3 g, yield 81.9%). H2N *.'N-CF Et NCO2MeCF EtOH CbzN CF i) MeOH, MeONa, 700C CbzN .O a CF, 5 31* (60%) 31g To a solution of Compound 31f (33.4 mg, 0.054 mmol, 1.0 equiv.) in ethanol (0.4 mL) was treated with reagent 31c (67.5 mg, 0.46 mmol, 5 equiv.) and stirred at room temperature overnight. It was then diluted with 10 anhydrous methanol (1 mL) and treated with sodium methoxide, then heated at 88 0 C until TLC (EtOAc) showed only product. It was concentrated to dryness, and then taken up into ethyl acetate, washed with saturated sodium bicarbonate solution and the layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layer was dried 15 over anhydrous Na 2

SO

4 , filtered, and concentrated to get the crude product, which was purified via BIOTAGE chromatography (25-40% EtOAc/hexanes) to get pure compound 31g (22.4 mg, yield >60%). Step 4: 20 CF , 1)O, CH2C t 2 , -CO 2 H CF 0 MeOH, -78C CbzN F3 2) H 2 0, HCO 2 H CbzN .

F, \ / 319 ~ (80.6%)31 Compound 31g (306 mg, 0.44 mmol, 1.0 equiv.) was dissolved in anhydrous dichloromethane (5 mL). The resulting colorless solution was 25 cooled to -78*C, then O was bubbled through until the solution turned purple. The solution was then purged with N 2 to remove excess 03. The solution was - 99 then concentrated to dryness. The resulting white foam was dissolved in formic acid (1.5 mL) and treated with hydrogen peroxide (1.5 mL, 30% aqueous solution) to form a white suspension, which was heated to 800C overnight. LCMS analysis showed only the product peak. The solvent was 5 removed under vacuum, and the residue was dissolved in ethyl acetate and washed with half saturated Na 2

S

2 0 3 aqueous solution. The resulting two layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2

SO

4 , filtered and concentrated to give the Compound 31h (284.2 mg, yield 90.6%). 10 Compound 31 h was used in the next step without purification. Step 5: 0-N '-CO 2 H CF, TN ,,s-CO2Me CF,

TMSCHN

2 CbzN CF Benzene CbzN CF, 3 MeOH 31h31i 15 To a solution of Compound 31h (104 mg, 0.147 mmol, 1.0 equiv.) in benzene (4 mL) and methanol (1 mL), was added dropwise a 2.0M solution of trimethylsilyl diazomethane in hexanes (88 pL, 0.177 mmol, 1.2 equiv.). TLC (10% MeOH/CH 2

CI

2 ) showed that the starting material was gone completely 20 after stirring the reaction mixture at room temperature for 30 minutes. The solvent was removed to give the crude product, which was used in the next step without purification. Step 6: "U .- COMe CF, '1-N O-COzMe CF, Pd(OH)2/C CbzN o HN -,7 F H, EtOH 25 311 (% compound 31 The crude product from Step 5, Compound 311, was dissolved in absolute ethanol (4.5 mL). To this solution was added Pd(OH) 2 /C (46.7 mg, -100 - 20 wt%, 0.067 mmol, 0.45 equiv.), and then the reaction mixture was hydrogenated with a hydrogen balloon. The hydrogenation reaction was stopped when TLC (10% MeOH/CH 2

C

2 ) showed that the starting material was consumed. The diluted reaction mixture was carefully passed through a 5 CELITE packed funnel, and the CELITE pad was washed thoroughly with methanol. The filtrate was concentrated to dryness. The resulting residue was purified by prep-TLC (10% MeOH/CH 2 Cl 2 ) to give the pure Compound 31 (56.2 mg, yield 65% from Compound 31g), MS [M+1]* 587.1. 10 PREPARATIVE EXAMPLE 32 S=O N ,CN CF, HNCF 32 15 Step 1:

H

2 N .CN CF, C S -CN -I - C 0 CbzN .

CF, ENu (CHahCl2 CbzN . A CF 42b 32a In a 25 ml round-bottomed flask, Compound 42b (0.142 g, 0.23 mmol, 20 1.0 equiv) was taken up in 3 mL of dichloroethane under a N 2 atmosphere and the reaction mixture was treated with Et3N (0.0.48 ml, 0.34 mmol, 1.5 equiv) followed by 3-chlorosulfonyl propyl chloride (0.037 ml, 0.3 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane) and 25 MS, which indicated no desired product was formed. Accordingly, the reaction mixture was then heated to reflux. After one hour of heating the reaction was complete. The reaction mixture was then cooled and diluted -101with CH 2

CI

2 , and quenched with 1N HCI. The organic layer was dried over Na 2

SO

4 and concentrated to give crude Compound 32a (0.11 g), which was used in the next step without further purification. 5 Step 2: cl ) 0 CON CF 0,CN CF, O DBUDMF CbzN *,O N CbzN F3 32a 32b In a flame dried 15 ml round-bottomed flask, Compound 32a (0.11 g, 0.23 mmol, 1.0 equiv) was taken up in dry DMF. To this reaction mixture, 10 1,8-diazabicyclo(5.4.0]undec-7ene (0.044 g, 0.29 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (30:70 EtOAc/hexane) and MS. Upon completion of the reaction, the reaction mixture was diluted with EtOAc and quenched with H 2 0. The organic layer was dried over Na 2

SO

4 and 15 concentrated to give crude Compound 32b (0.1g). Purification was carried out using BIOTAGE chromatography (30/70 EtOAc/hexane) to give purified Compound 32b (0.072g). Electrospray MS [M+1] 710.2. 20 Step 3: 0 0 N ,CN CF3 20 PdO CN CF, CbzN 0A N HN H(o CF, 32b 9 32 Compound 32b (0.072 g, 0.1 mmol, 1.0 equiv) was dissolved in dry 25 MeOH (1.5 ml) and was treated with 20% Pd(OH) 2 (60% wt.) under an inert atmosphere. The reaction was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60 EtOAc/hexane). - 102- The reaction was completed in 45 min, and was filtered through CELITE, washed with EtOAc, and concentrated to give a crude product. The crude product was purified using preparative chromatography (60/40 EtOAc/hexane) to give Compound 32 (0.04g, 70%). 5 Electrospray MS [M+1]576.2. HRMS (FAB) calculated for C 26

H

2 8

F

6

N

3 0 2 (M+1) 576.1756, found 576.1764. PREPARATIVE EXAMPLE 33 10 0 ~N F N CF 3 H O f[bCF3 Example 33 Step 1: GI 0 H

H

2 N CN OFa Cl N N CF, 0 C y CF& EtIN,CHCl2 O CF, 15 4233 In a 25 ml round-bottomed flask, Compound 42b (0.322 g, 0.53 mmol, 1.0 equiv) was taken up in 5 ml of CH 2 Cl 2 and the reaction mixture was cooled to O'C in an ice bath. Et 3 N (0.111 mL, 0.79 mmol, 1.5 equiv) followed by 4 chlorobutyryL-chloride (0.072 ml, 0.64 mmol.--.2.equiv)-was-then added-to the 20 reaction mixture, which was slowly warmed to room temperature and stirred for 14 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane eluent) and MS. Upon completion of the reaction, the reaction mixture was diluted with CH 2 Cl 2 and quenched with saturated NaHCO 3 followed by brine. The organic layer was dried over Na 2

SO

4 and concentrated 25 to give crude Compound 33a (0.32 g), which was used in the next step without further purification. -103- Step 2: C1 0 HN ~CN CF, CF: o OC 60%NaH, CbzN CF,, N bzN 01& F 33a 33b In a flame dried 25 ml round-bottomed flask, Compound 33a (0.32 g, 5 0.45 mmol, 1.0 equiv) was taken up in dry THF. To this solution, 60% NaH (0.025 g, 0.68 mmol, 1.5 equiv) was added, and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane) and MS. Upon completion of the reaction, the reaction mixture was diluted with EtOAc and quenched with 10 saturated NaHCO 3 . The organic layer was dried over Na 2

SO

4 and concentrated to give Compound 33b (0.4 g), in the form of a yellow oil, which was used in the next step without further purification. Step 3: C r0 _r0 CN OF, 20%PdOH, CN MeOH, H2(9) CbZN. CF HN _' N-a F 15 33b Compound 33 Compound 33b (0.4 g, 0.59 mmol, 1.0 equiv) was dissolved in dry MeOH (4.0 mL) and was treated with 20% Pd(OH) 2 (60% wt.) under an inert atmosphere. The reaction was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60 EtOAc/hexane 20 eluent). The reaction was completed in 45 min, was filtered through CELITE and washed using EtOAc and concentrated to give a crude product. Purification of the crude product was carried out using BIOTAGE chromatography (60/40 EtOAc/hexane) to give Compound 33 (0.18 g, 59%). HRMS (FAB) calculated for C 2 6

H

28

F

6

N

3 0 2 (M+1) 540.2086, found 25 540.2078. PREPARATIVE EXAMPLE 34 - 104- <Ir, ON O N C~'' F , H ACF3 Example 34 Step 1: 5 CI H2N, C N,, N OF, 0 CbzN CF, EtN,C I, ObzN . C 42c 34a In a 25 ml round-bottomed flask, Compound 42c (0.23 g, 0.38 mmol, 1.0 equiv) was taken up in 3 mL of CH 2

CI

2 , and the reaction mixture was cooled to 0*0 in an ice bath. Et 3 N (0.079 ml, 0.57 mmol, 1.5 equiv) followed 10 by 4-chlorobutyryl chloride (0.051 ml, 0.45 mmol, 1.2 equiv) was then added to the reaction mixture, which was slowly warmed to room temperature and was stirred for 14 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane eluent) and MS. Upon completion of the reaction, the reaction mixture was diluted with CH 2

CI

2 and quenched with saturated 15 NaHCO 3 followed by brine. The organic layer was dried over Na 2

SO

4 and concentrated to give crude Compound 34a (0.23 g), which was used in the next step without further purification. Step 2: 20 Cl H 0 N, ON FC CN CF, SzCF 6 NaH, CbzN . O CF, 34a 34b -105 - In a flame dried 25 ml round-bottomed flask, Compound 34a (0.23 g, 0.38 mmol, 1.0 equiv) was taken up in dry THF (1 mL). To this reaction mixture, 60% NaH (0.022 g, 0.57 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 2 hrs. The progress of 5 the reaction was monitored by TLC (60:40 EtOAc/hexane eluent) and MS. Upon completion of the reaction, the reaction mixture was diluted with EtOAc and quenched with saturated NaHCO 3 . The organic layer was dried over Na 2 SO4 and concentrated to give Compound 34b (0.21 g) in the form of a yellow oil, which was used in the next step without further purification, 10 Electrospray MS [M+1] 674.2. Step 3: 0 _ ON CF 3 20% PdOH, N\. . CC Cbz O1L CF, MeCH, H2(9) CF3 34b 34 15 Compound 34b (0.21 g, 0.31 mmol, 1.0 equiv) was dissolved in dry MeOH (2.0 mL) and was treated with 20% Pd(OH) 2 (40% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and the progress of the hydrogenation was monitored by TLC (40:60 EtOAc/hexane eluent). After 45 min, the reaction mixture was filtered through 20 CELITE, washed with EtOAc, and concentrated to give a crude product. The crude product was purified using BIOTAGE chromatography (60140 EtOAc/ hexane), to give Compound 34 (0.10 g, 59%). HRMS (FAB) calculated for C 26

H

2 8

F

6

N

3 0 2 (M+1)540.2086, found 540.2078. 25 PREPARATIVE EXAMPLE 35 - 106- N,NH NC C F, N Q o 0 A HN .CF, Compound 35 HO INO2 CFHO .NH2 CbzN -,,,O C Zn, HOAc, 60 *C CbzN - 0 CF. ~\ / Compound 23d Compound 35a 5 Compound 35 was prepared using a procedure similar to procedure for preparing Compound 23e in Example 23. HO ?NH CFa BnO ?NH2 CF, CbzN BnBr, (NH 4

)

4 HS0 4 , NaOH, THF CbzN O N --,O CF -F, Compound 35a Compound 35b 10 Likewise, Compound 35b was prepared by a procedure similar to the procedure used to prepare Compound 23f in Example 23. EtO N BnO NH2 OF, a. ~NHCO2CH , EtOH N 'NH - . 31 BnO 4 CF, CbzN F b. NaOCHa, MeOH, 80 'C OF, Cbz N -,,,C O N F, Compound 35b 15 Compound 35c Compound 35c was prepared by a procedure similar to the procedure used to prepare Compound 23g in Example 23. - 107- N- N (NH N'NH Bno--. N-do CF Bn'~. N0 CF, Pd(OH), H, bzNCF MeO HN \e\ / Compound 35c Compound 36d Compound 35d was prepared by a procedure similar to the procedure for preparing Compound 23 in Example 23. 5 N'NH N'NH BnO''.. N-O CF, HO%, N CF 3 BCI, DOM H -,,O N CF, - 78 C HN ..,CF Compound 36d Compound 35e Compound 35e was prepared by a procedure similar to the procedure 10 for preparing Compound 23h in Example 23. N NH H N'NH Ho CF HNO CF, HN Dess-Martin perliodinane HN .C

CF

3 H Compound 35e Compound 35f 15 Compound 35f was preparing by a procedure similar to the procedure for preparing Compound 42e. in Example.42. H (NH N'NH 0 ONe F, HO,N .- CF4 NH2OH.HC, NaOAc N 0 OF HN ..

CF

3 HN , OF, \ / Compound 36f Compound 35g - 108 - Compound 35g was prepared by a procedure similar to the procedure for preparing Compound 42g in Example 42. N-'NH 'NH N CF NC .N CF3 1,1'-oxalyldilmidazole HN ,, CF, Benzene HN . CF 5 Compound 3ag Compound 35 Compound 35 was prepared by a procedure similar to the procedure for preparing Compound 42 in Example 42. HRMS calculated for

C

25

H

23 FaN 5 0 2 (M+H) 540.1834, found 540.1822. 10 PREPARATIVE EXAMPLE 36 NC NHSO 2 Me C

HCF

2 .Compound 36 15 Step A: NC,, NH 2

CF

2 NC , NHSO 2 Me CF, MsCl. TEA CbzN CF, CbzN ..,O N CF Compound 42b Compound 36a Compound 36a was prepared by a procedure similar to the procedure 20 for preparing Compound 47 in Example 47. Step B: - 109- Nnn,, Me CF 3 NC NHSO 2 Me CF,

H

2 , Pd(OH)2 Cbz , CF 3 MeOH NHCF, Compound 36a Compound 36 Compound 36 was prepared by a procedure similar to the procedure for preparing Compound 23 in Example 23. HRMS calculated for 5 C 24

H

2 5

F

6

N

3 0 3 S (M+H) 550.1599, found 550.1603. PREPARATIVE EXAMPLE 37 NC NHSO 2 Me CF, HN .o NCF 10 Compound 37 Step A: NC PNH 2 CF NC ,NHSO2Me CF, MsC, TEA CbzN CbzN CF Compound 42b Compound 37a 15 Compound 37a was prepared by a procedure similar to the procedure for preparing compound 47 in Example 47. StepB. NC ,NHSO 2 Me CF, NC NHSO 2 Me

CCF

3

H

2 , Pd(OH) 2 Cbz CF, MeCH H .

CF, 20 Compound 37a Compound 37 - 110- Compound 37 was prepared using a procedure similar to the procedure for preparing Compound 23 in Example 23. HRMS calculated for

C

24

H

25

F

6

N

3 0 3 S (M+H) 550.1599, found 550.1603. 5 PREPARATIVE EXAMPLE 38 00 HN CFI HN CFa CbN 2) NH 2 0H NaOAc Cbz CF

CF

3 3) (Im),C0 'F 31g 38a 10 Step 1: To a solution of Compound 31g (640 mg, 0.93 mmol) in 10 mL CH 2 Cl2 maintained at -78"C was bubbled 03 gas until the reaction mixture turn blue. The reaction mixture was then purged with nitrogen until it became colorless. TBAI (412 mg, 1.11 mmol) was then added and the reaction mixture was 15 stirred at 20 0 C for 2h. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous Na 2 S2O 3 , water and brine, and the dried and concentrated. The resulting residue was dissolved in EtOH (22 mL) and NaOAc (262.7 mg, 3.2 mmol) and hydroxylamine hydrochloride salt (222 mg, 3.2 mmol) were added, and the mixture was stirred overnight. The reaction 20 mixture was then concentrated and the residue was partitioned between 20 mL EtOAc-and water. The organic layer was dried and concentrated. The crude intermediate was dissolved in toluene (6.8 mL) followed by the addition of 1,1'-oxallyldiimidazole (165 mg, 1.8 mmol) and the mixture was heated at 80 0 C for 2h. After cooling the reaction mixture to 23 0 C, the toluene solution 25 was loaded to a silica gel column and eluted with 20-100% EtOAc/hexanes to give product Compound 38a. MS [M+1)] 688.1. - 111 - 0 0 HN~ 6 HN4 N N N CF, N CF, CbzN CF Pd(OH) 2 /C, H2 C CF, 38a compound 38 Step 2: Using a procedure similar to that of Example 31, Step 6, Compound 38a was hydrogenated to give Compound 38. MS [M+1]-* 554.1. 5 PREPARATIVE EXAMPLE 39 and 40 NC ,H 2 CFa NC, NH 2 C HN C0 N HN 0 N .. O CF, H OA CF, Compound 39 Compound 40 10 Step A: NC,, CF, NC, NH CF, ObzN ..,70 CF HN .,,0Ca - ' CF, g"" CF, Compound 42b H 2 , Pd(OH) 2 Compound 40 + MeOH + NC NH 2

CF

3 NC. NH2 CF, CbzN A CFaHN OA CF, Compound 42c Compound 39 Compounds 39 and 40 were prepared using a procedure similar to the procedure for preparing Compound 38. HRMS calculated for 15 C 23

H

23 FrN 3 0 (M+H) 472.1824, found 472.1820. PREPARATIVE EXAMPLE 41 -112- NC,, NHCONH 2 CF, H N . " F , Compound 4' Step A: NC, NH 2

CF

3 NC,, NHCONH 2 CF, TMSNC CbzN -F3 CE CbzN CF, Compound 42b Compound 41a 5 In a 25 mL round-bottomed flask Compound 42b (0.15 g, 0.248 mmol, 1.0 equiv) was dissolved in 6 mL of DCE. Trimethylsilyl isocyanate (0.51 mL, 3.72 mmol, 15.0 equiv) was added and the reaction mixture was refluxed at 800C overnight. The reaction mixture was cooled and quenched with 10 saturated NaHCO 3 (10 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL). The organic layers were washed with brine (5 mL), dried over MgSO 4 , and concentrated. The crude product was purified by preparative TLC (1:1 EtOAc:hexanes) to yield 0.060 g (37%) of Compound 41a. 15 Step B: NC, NHCONH, CF NC NHCONH 2 CF, .! H 2 , Pd(OH) 2 CbzN NH .,, F CF, MeOH HCF Compound 41a Compound 41 Compound 41 was prep-ared by a procedure similar to procedure for preparing Compound 23 in Example 23. HRMS calculated for C 24

H

24

F

6

N

4 0 2 20 (M+H) 515.1882, found 515.1874. PREPARATIVE EXAMPLE 42 -113- N..NH , N-4. CF, HNCF Compound 42 Step A: CF NC,, NH2 CFa NC NH2 CF 3 CbzN C NaCN, NH4CI, NH 3

.H

2 0 O CF Cb2N .,, N. CFa. - -- ,O CF, 5 Compound 41a 42b Compound 42c Compound 41a (6.87 g, 11.86 mmol) in EtOH (7 mL) was added to a solution of NaCN (0.767 g), NH 4 CI (0.889 g) and NH 3

-H

2 0 (3.84 mL) in EtOH (7.0 mL) and water (7.0 mL) at room temperature in a sealed tube. The sealed 10 tube was then heated at 60*C for 12 hours before it was cooled down to room temperature. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (50 mL). The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was 15 purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 7/2 to 5/2) to give Compound 42b (2.6 g, 36%) and Compound 42c (1.8 g, 25%). Step B: HN-NHCHO NC,,. NH 2 CFa COCI/NaHCO2 O= then NH.NHC(0)HIPy NC,,. N CF CbzN .

N. CF3 CN Or CF 3 20 Compond 42 Compound 42d Phosgene (6.67 mL, 12.4 mmol, 20% in toluene) was added dropwise to a vigorously stirred mixture of Compound 42b (1.5 g, 2.48 Mmol) in CH 2

CI

2 (30 mL) and a saturated NaHCO 3 solution (30 mL) at 0*C. The mixture was -114stirred at 0*C for 3 hours before it was diluted with CH 2

CI

2 (50 mL) and the aqueous phase was separated from the organic phase. The organic phase was washed with a cold aqueous NH 4 CI solution, brine, and dried over MgSO 4 . The solvent was reduced to a volume of about 5 mL under reduced 5 pressure, at room temperature, to remove excess phosgene. The residue was dissolved in CH 2

CI

2 (15 mL) and treated with NH 2 NHC(O)H (0.446 g, 7.44 mmol) and pyridine (1.2 mL, 14.88 mmol) at room temperature. The resulting solution was stirred at room temperature for 12 hours. The reaction mixture was then diluted with EtOAc (200 mL) and washed with HCI (50 mL, 0.5 N). 10 The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using BIOTAGE chromatography eluted with hexane/EtOAc (v/v = 1/2 to 1/7) to give Compound 42d (1.1 g, 64%). 15 Step C: HN-NHCHO N N O CF HMDSITMSClLiI N O CFo CbNCF 3 140'C CNF, Compound 42d Compound 42 20 TMSCI (50 pL) was added to a stirring mixture of Compound 42d (15 mg, 0.0217 mmol) and Lil (2.9 mg, 0.0217 mmol) in HMDS (0.5 mL) at room temp.eratureiTiAe-resulting-reaction- mixture-was-heated-atA40"C-(bath temperature) for 30 hours before it was cooled down to room temperature. The reaction mixture was diluted with EtOAc (25 mL) and washed with HCI (5 25 mL, 1.0 N). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 614) to give Compound 42 (4 mg, 34%). -115- ALTERNATE PROCEDURE FOR EXAMPLE 42 Alternatively, Compound 42 can also be prepared from Compound 23g as follows 5 Step A: NN 'NH HN'N - O CF NA0 CF, CbzN O CF, Dess-Martin periodinane CbzN CFI \ / CF, Compound 23g Compound 42e in a 10 mL round-bottomed flask, Compound 23g (0.02 g, 0.037 mmol, 1.0 equiv) was dissolved in DCM (3 mL) and the reaction mixture was 10 cooled to O C. Dess-Martin periodinane (0.02 g, 0.048 mmol, 1.3 equiv) was added and the reaction mixture was stirred under nitrogen at room temperature for 45 minutes. The progress of the reaction was monitored by TLC (9/1 EtOAC/MeOH eluent), and the reaction was quenched after 1.5 hrs, by pouring the reaction mixture into separatory funnel containing saturated 15 Na 2

S

2 0 3 /NaHCO 3 solution (1:1) (5 mL). The mixture in the separatory funnel was shaken vigorously, and the aqueous layer was extracted with Et 2 O (2 x 5) and dried over MgSO 4 and concentrated to give crude Compound 42e (0.02 g), which was used in the next step without further purification. 20 Step B: N, H N NH N, O CF 3 HO N 0. 0 01 . 0' N NH2OH.HCI. NaOAc N CbzN I Cz CF, EtOH CbzNN CF, Compound 42f Compound 42g In a 25 mL round-bottomed flask, Compound 42f (0.09 g, 0.13 mmol, 25 1.0 equiv) and sodium acetate (0.032 g, 0.39 mmol, 3.0 equiv) were dissolved in EtOH (6 mL), to which hydroxylamine hydrochloride (0.056 g, 0.080 mmol, -116- 6.0 equiv) was added. The reaction mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was then diluted with EtOAc (15 mL), quenched with saturated NaHCO 3 (5 mL), and the organic layer was washed using brine (5 mL) and dried over MgSO 4 to give crude 5 Compound 42g (0.95 g), which was used in the next step without further purification. Step C: S N,NH 'NNH N-Z., N CF NC,, N4 OF 1,1'-oxalyldlmidazole CbzN , C Ben2ene CbzN .,,, O N Compound 42g Compound 42h 10 In a 50 mL round-bottomed flask, Compound 42g (1.1 g, 0.59 mmol, 1.Oequiv) was dissolved in benzene (25 mL). 1, 1'-oxalyldiimidazole (0.302 g, 1.89 mmol, 1.5 equiv) was added to the solution, and the reaction mixture was heated to 75'C under nitrogen for 4 hrs. The reaction mixture was then .15 quenched with water (20 mL), diluted with EtOAc (30 mL), dried over MgSO 4 and concentrated to give a crude product. The crude product was purified using BIOTAGE chromatography (1/1 EtOAc/hexanes) to give Compound 42h (0.7 g, 66% over three steps). 20 Step D: - NNH 'N'NH NC, N-O C NC,, N -TMSI,.CH3CN. CbzN ,I CF HN a, 1 CF, Compound 42i Compound 42 In a 50 mL round-bottomed flask, Compound 421 (0.5 g, 0.742 mmol, 1.0 equiv) was taken up in acetonitrile (9 mL). The reaction mixture was 25 cooled to O'C, and TMSI (0.742 mL, 5.19 mmol, 7.0 equiv) was added dropwise via syringe. The reaction mixture was stirred overnight at room - 117 temperature. The progress of the reaction was monitored by MS, which indicated some starting material was still present. The reaction mixture was quenched using saturated Na 2

S

2

O

3 /NaHCO 3 (1:1) (10 mL) and diluted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over 5 MgSO 4 , and.concentrated to yield a crude product. The crude product was purified using BIOTAGE chromatography (60/40 EtOAc/hexanes) to give Compound 42. (0.4 g). HRMS calculated for C 25

H

23

F

6

N

5 0 2 (M+H) 540.1834, found 540.1813. 10 PREPARATIVE EXAMPLE 43 & N CF 3 HN

CF

3 Compound 43 15 Step A: FC HN CFH .N NHBoc Boc-aminocyclopropyl N C carboxylic acidpropy. CF, CF HATU, EDC, DJEA Compound 44b Compound 43a Compound 43a was prepared by a procedure similar to the procedure for preparing Compound 28a. 20 Step B: HN NHBoc HN NH 2 TFA, DCM HN CF 3 HN -. ,,/ CF, Compound 43a Compound 43b - 118 - Compound 43D was prepared by a procedure similar to the procedure for preparing Compound 45c. Step C: HN NH 2

NCF

3 HN --,/O CF 3 C"3CO2H HN CF, 5 Compound 43a Compound 43 Compound 43 was prepared by a procedure similar to the procedure for preparing Compound 28 (step c). 10 PREPARATIVE EXAMPLE 44 H H I' >=O N HO N O F7 HN -, O ~ CF 3 Compound 44 02N CF 2

H

2 N CF 3 Zn, AcOH H CFH

CF

3 15 Compound 44a Compound 44b In a 50 mL round-bottomed flask, Compound 44a (1.1 g, 2.31 mmol, 1.0 equiv) was dissolved in acetic acid (20 mL), and the resulting reaction mixture was cooled to 0*C. Zn powder (1.51 g, 23.1 mmol, 10.0 equiv) was 20 added and the mixture was refluxed for 2.5 hr. The reaction mixture was then filtered through CELITE, concentrated, diluted with EtOAc (30 mL), and neutralized with saturated NaHCO3 (30 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL), washed with brine (20 mL), dried over -119- MgSO 4 and concentrated. The crude product was purified using a filter column to yield 1.0 g (99%) of Compound 44b. Step B: N NHBoC

H

2 N HN H CF BocNHNH2, CDI HCF, THF CF, 5 Compound 44h Compound 44c Compound 44c was prepared by a procedure similar to the procedure for preparing Compound 45b. 10 Step C: O WNHBocO On HN H C. HN H 0 - 1. TFA, DCM HN . N CF 3 2. pyridine, DCM HN . - CF2 \ I BnDCI \ / Compound 44c Compound 44d Compound 44d was prepared by a procedure similar to the procedure for preparing Compound 45c. 15 Step D: C) H H H -N H -C O B n

NF

3 CFH 2 M NaOH, EtOH FAC HN .F HN o CF. Compound 44d Compound 44e Compound 44e was prepared by a procedure similar to the procedure 20 for preparing Compound 45d. Step E: - 120 - H H N

N

BnO N)=O HO N SnO H F 3 C Pd/C, HCO 2 NH4 F HN . O CF a MeOHIH 2 0 N CF, Compound 44a Compound 44 in a 10 mL round-bottomed flask, Compound 44e (0.34 g, 0.54 mmol, 1.0 equiv) was taken up in 5.5 mL of MeOH/H 2 0 (10:1). The round-bottomed 5 flask was degassed, and Pd/C (10 wt%, 0.18 g) was added followed by

HCO

2

NH

4 (0.174 g, 2.68 mmol, 5.0 equiv). The resulting heterogeneous mixture was refluxed overnight, cooled, filtered through CELITE, concentrated, diluted with EtOAc (10 mL), washed with saturated NaHCO 3 (10 mL), and dried over Na 2

SO

4 . The crude product was purified by BIOTAGE 10 chromatography (9:1 EtOAc:MeOH) to yield 0.11 g (38%) of Compound 44. HRMS calculated for C 25

H

26

F

6

N

4 0 3 (M+H) 545.1987, found 545.1988. PREPARATIVE EXAMPLE 45 and 46 15 H H M I" >=0 #e_)L40 MeO N F 3 C MeO F HN F H C HN O''a C3 g" O) OF 3 Compound 46 Compound 46 Step A: 0 2 N CF, H 2 N CF, CF, Raney NI, H 2 CbzC CF tOH -~ &F Compound 41a Compound 45a 20 Compound 41a (2.8 g, 4.59 mmol, 1.0 equiv) was taken up in ethanol (15 mL). Raney nickel was added to the solution, and the reaction mixture was hydrogenated in a Parr shaker at 60 psi. The progress of the hydrogenation was monitored by TLC (411 EtOAc/hexanes). After 3 hours, - 121 the reaction mixture was then filtered through CELITE, washed with ethanol (30 mL) and concentrated. The crude product was purified by BIOTAGE chromatography (411 EtOAc/hexanes), to give Compound 45a (1.75 g, 65%). 5 Step B: N NHBoc

H

2 N CF HN H CF 3 BocNHNH 2 , CDI CbzN CF THF CbzN ..,,,O CF Compound 45a Compound 45b In a 50 mL round-bottomed flask, Compound 45a (1.0 g, 1.72 mmol, 1.0 equiv) was dissolved in dry THF (20 mL) and cooled to 0*C. A solution of 10 tert-butyl carbazate (0.228 g, 1.72 mmol, 1.0 equiv) and carbonyl diimidazole (0.335 g, 2.06 mmol, 1.2 equiv), which was previously stirred in dry THF (10 mL), was added to the above cooled solution via cannula. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then concentrated and purified by BIOTAGE 15 chromatography (1/1 EtOAc/hexanes) to give Compound 45b (0.85 g, 67%). Step C: NHBoc NN OMe HN H CF 3 HN H C 1. TFA, DCM CbN .,O 2. pyridine, DC CbzN ,CF \ MeOly C) Compound 45b 0 Compound 46c 20 In a 50 mL round-bottomed flask, Compound 45b (0.39 g, 0.53 mmol, 1.0 equiv) was dissolved in CH 2

C

2 (10.0 mL) and cooled to 0*C. Trifluoroacetic acid (1.02 mL, 13.2 mmol, 25.0 equiv) was added to the solution, and the reaction mixture was allowed to stir at room temperature. The progress of the reaction was monitored by MS (i.e., disappearance of 25 starting material). The reaction mixture was concentrated after 7 h, and was - 122 used in the next step without any further purification. The crude intermediate was dissolved in THF (5 mL) and cooled to O*C. A 20 % aqueous solution of NaOH (5.0 mL) was added, followed by methoxyacetyl chloride (0.096 mL, 1.06 mmol, 2.0 equiv). The reaction mixture was allowed to stir at room 5 temperature overnight, and was then diluted with H 2 0 (10 mL), extracted with Et 2 0 (2 x 10 mL), washed with brine (10 mL), dried over MgSO 4 and concentrated to yield crude Compound 45c (0.35 g, 95%), which was used in the next step without any further purification. 10 Step D: o N OMe H NN_ N-N HN H 0 MeO N O 2 M NaOH, EOH S CF CbzN .,, CF Compound 45a Compound 45d In a 25 mL round-bottomed flask, Compound 45c (0.35 g, 0.49 mmol, 1.0 equiv) was dissolved in EtOH (3.0 mL). 3.0 mL of a 6 M solution of NaOH 15 was added and the reaction mixture was refluxed overnight. The reaction mixture was then concentrated and purified by preparative TLC (EtOAc) to give 0.145 g (42%) of Compound 45d. Step E: N H N N NA MeO -- A N ==0 MeO N ==0 MeO N FCH2, Pd(OH), FC CbzN 0MeOH HN H o CF3 CF, CeNN .~ F, , 20Compound 45d Compound 45Copud4 In a 10 mL round-bottomed flask, Compound 45d (0.125 g, 0.18 mmol, 1.0 equiv) was dissolved in 3 mL MeOH. Pd(OH) 2 (0.010 g, 0.072 mmol, 40 wt%) was added, and the heterogeneous mixture was hydrogenated 25 at room temperature. The progress of the hydrogenation was monitored by MS. The reaction mixture was filtered through CELITE, concentrated and -123purified by preparative TLC (EtOAc) affording a mixture of Compounds 45 and 46 (0.008 g, 8%). HRMS calculated for C 26

H

2 aF 6

N

4 0 3 (M+H) 559.2144, found 559.2146. 5 PREPARATIVE EXAMPLE 47 and 48 H H NIN N-N MeO 2 SHN CF MeO 2 SHN CF, HN ,CFH CF Compound 47 Compound 48 10 Step A: H H NH HNN HN NCF 3 MeO2SHN CF 3 H O CF 3 HN CF 3 Compound 49 Compound 47 MsCl, TEA H HN N-N H2N O CF3 MeO 2 SHN =O CF H CF - CF Compound 50 Compound 48 In a 10 mL round-bottomed flask, a mixture of Compounds 49 and 50 (0.025 g, 0.047 mmol, 1.0 equiv) was dissolved in 2 mL of DCM and cooled to 15 0*C. Triethylamine (0.0073 mL, 0.052 mmol, 1.1 equiv) was added, followed by MeSO 2 C] (0.004 mL, 0.052 mmol, 1.1 equiv). The reaction Mixture was allowed to stir overnight. The reaction mixture was then diluted with EtOAc (10 mL) and quenched with saturated NaHCO 3 (5 mL). The aqueous phase was extracted with EtOAc (2 x 5 mL), dried over Na 2

SO

4 , and concentrated. 20 The crude product was purified by preparative TLC (4:1 EtOAc/hexanes) to -124give 0.028 g (100%) of a mixture of Compounds 47 and 48. HRMS calculated for C 2 5

H

27 FcN 5 0 4 S (M+H) 608.1766, found 608.1785. 5 PREPARATIVE EXAMPLE 49 and 50 H H NN N

H

2 N CF 3 H2N CF 3 HN CF 3 HN CF, Compound 49 Compound 60 10 Step A: H

,CF

3 0 2 N CFa CbzN ..,,,O CF3 0 2 N-CbzN o CF3 Compound 49a Compound 49b Compound 49a (0.50 g, 0.77 mmol, 1.0 equiv) was added to a 50 mL 15 round-bottomed flask. Fuming HNO 3 (3 mL) was then added to the flask, and the resulting reaction mixture was allowed to stand for I h. After the reaction was complete, ice (10 g) was added. The reaction mixture was diluted with EtOAc (25 mL) and neutralized with saturated NaOH (3 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL). The organic layers were 20 washed with brine (10 mL), dried over MgSO 4 , and concentrated. The crude product was purified by BIOTAGE Chromatography (7:3 EtOAc:hexanes) to give 0.45 g (79%) of Compound 49b. Step B: - 125 - H H NN NN NN

O

2 N CF H 2 N CF, H2N CF 0 Zn, Ac0H + H 0 2 N-CbzN .0O CF, HN , 'N CF, OCF, Compound 49b Compound 49 Compound 50 Compounds 49 and 50 were prepared by a procedure similar to the procedure for preparing Compound 44b. HRMS calculated for C 24

H

25

F

6

N

5 0 2 5 (M+H) 530.1991, found 530.1977. PREPARATIVE EXAMPLE 51 HN' N~ 0N a N O CF, H NH 2 CF 0 NH 3 /MeOH 0 CbzN CbzN C b z .N 0 C F , 8 0 0 C C z /C F , 10 55 51a Compound 55 (0.078 g, 0.11 mmol, 1.0 equiv) was dissolved in 7 M ammonia in MeOH (3.0 mL) and was added to a small Parr bomb, which was 15 heated to 80*C for 2 days. The progress of the reaction was monitored by TLC (9/1 CH 2

CI

2 /MeOH). Upon completion of the reaction, the reaction mixture was concentrated to give a crude product in the form of a white solid. The crude product was purified using BIOTAGE chromatography (2:1 to 4:1 EtOAc/Hexane) to give Compound Sla as a white solid (0.48 g). 20 Electrospray MS [M+1] 692.2. HN'N' 0 HN' N ' 0 H -~ NH2 CF 0 10%Pd/C, NH 4

O

2 CH H . NH 2

-F

0 CFzNMeOH HN - ' 40 CF, ".,_, 0 'N F, 51a Compound 51 - 126 - Compound 51a (0.045 g, 0.065 mmol, 1.0 equiv.) was dissolved in dry MeOH (2.0 mL) and was treated with 10% Pd/C (40% wt.) followed by ammonium formate (0.02g, 0.03 mmol, 5.0 equiv.) under an inert atmosphere. The reaction mixture was heated to reflux and the progress of the reaction 5 was monitored by TLC (100% EtOAc). The reaction was completed in 1 hr. The reaction mixture was filtered through CELITE, washed with EtOAc and concentrated under vacuum. The resulting residue was taken up in EtOAc, washed with saturated NaHCO 3 , followed by brine and H 2 0 to give the desired product, Compound 51 in the form of a white solid, which was 10 converted to its HCI salt (0.034g, 94%). HRMS (FAB) calculated for C 26

H

2 8

F

6

N

3 0 2 (M+1)558.19242, found 558.19398. PREPARATIVE EXAMPLE 52 15

H

3 CO-J. N'H H N . N OC F H .. ,,.0CF, Compound 52 Step A: N NH N NH O N CF3 NH,0H,H EOH NCON N'N CF, HN O y CF, HN 20 Compound 53 Compound 52 Compound 53 (18.1 mg, 0.0325 mmol) in EtOH (2.5 mL) was treated with MeONH 2 .HCI (24.4 mg, 0.292 mmol) and NaOAc (12.0 mg, 0.146 mmol) at room temperature. The reaction mixture was stirred at 60*C for 12 hr, then 25 diluted with EtOAc (20 mL) and washed with aqueous NaHCO 3 . The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After - 127 fift(ation and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 1/1 to 1/9) to give Compound 52 (16 mg, 84%). Electrospray MS [M+1]* 586.1. 5 PREPARATIVE EXAMPLE 53 N O .. N CF, Compound 63 Step A: 10 N'NH HO '.. NA CF a. Dess-Mrtin periodinane O N CF b. MeMgBr, THF 0 F CbzN . c. Dess-Martin periodinane O CF, .Cbz e . CF Compound 23h Compound 53a Dess-Martin periodinane (0.234 g, 0.553 mmol) was added to a mixture of Compound 23h (0.25 g, 0.369 mmol) and NaHCO 3 (0.232 g; 2.76 mmol) in 15 CH 2 Cl 2 (5.0 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic phase was washed with saturated Na 2

S

2

O

3 solution (3x1 5 mL). The combined aqueous phases were extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 20 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude aldehyde (0.25 g) was taken up in anhydrous THF (4.0 mL) and was treated with MeMgBr (0.49 mL, 1.48 mmol, 3.0 M in Et 2 0) at -78*C. The reaction temperature was slowly increased to room temperature and the reaction was quenched in 2 hours with the slow addition of saturated aqueous 25 NH 4 CI solution (10 mL). The reaction mixture was then diluted with EtOAc (50 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly -128acidic. The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude secondary alcohol (0.26 g) was taken up in CH 2

C

2 (5.0 mL) and treated with Dess-Martin 5 periodinane (0.468 g, 1.11 mmol) and NaHCO 3 (0.466 g, 5.55 mmol) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic phase was washed with saturated Na 2 S20 3 solution (3x15 mL). The combined aqueous phases were extracted with EtOAc (3 x 15 mL). The combined organic layers were washed 10 with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude produce was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/1) to give Compound 53a (0.11 g, 43% for 3 steps). 15 Step B: 0 . N 0 C FH 2 P d ( O H ) / C , E t 0 H . C F CbzN .

' CF 3 HN ,o CF . Compound 53a Compound 53 Compound 53a (107 mg, 0.155 mmol) in EtOH (5.0 mL) was treated 20 at room temperature with Pd(OH)2/C (21.5 mg, 10 wt%) and was hydrogenated with a H 2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v 25 1/3 to 1/9) to give Compound 53 (66 mg, 76%). Electrospray MS [M+1]* 557.3. PREPARATIVE EXAMPLE 54 30 -129- N'NH HO, . N CF, HN CF, \ / Compound 54 ~NH i N 'N O N CF, H CF, NH2OH, EtOH HN HN . CF 3 Com ound 53 Compound 54 5 Compound 53 (14.3 mg, 0.0257 mmol) in EtOH (2.5 mL) was treated with HONH 2 .HCl (10.7 mg, 0.154 mmol) and NaOAc (6.3 mg, 0.077 mmol) at room temperature. The reaction mixture was stirred at 60'C for 12 hr, then diluted with EtOAc (20 mL) and washed with aqueous NaHCO 3 . The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers 10 were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 1/2) to give Compound 54 (11 mg, 75%). Electrospray MS [M+1]* 572.1. 15 PREPARATIVE EXAMPLE 55 O NH H3CO 1. N4O CF 3 HN C N Compound 56 Step A: 20 -130- N -H0fN N H0~.a. Dess-Martin Perlodinane 0# N CNH b.HO N CF3 b 2-methyl-2-butene, NaCIO 2 HCO N- CF NaH 2

PO

4 , tert-butanol CbzN * ' CFn c. TMSCHN,, MeOH, PhH CbzN CF, Compound 23h Compound 55a Dess-Martin Periodinane (0.12 g, 0.284 mmol) was added to a mixture of Compound 23h (96.3 mg, 0.142 mmol) and NaHCO 3 (0.12 g, 1.42 mmol) 5 in CH 2

CI

2 (3.0 mL) at room temperature. The reaction mixture was stirred for I hour before it was diluted with addition of EtOAc (50 mL) and water (10 mL). The organic phase was washed with saturated Na 2

S

2

O

3 solution (3x1 5 mL). The combined aqueous phases were extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), 10 water (10 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude aldehyde (96.3 mg) was taken up in tert-butanol (2.0 mL) and water (0.5 mL) and treated with NaH 2

PO

4

-H

2 0 (39.2 mg, 0.284 mmol), NaCIO 2 (44.9 mg, 0.497 mmol) and 2-methyl-2-butene (0.105 mL, 0.994 mmol) successively. The reaction mixture was stirred for 2 hours and 15 then diluted with EtOAc (20 mL) and washed with aqueous NH 4 CL. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude acid (95 mg) was dissolved in benzene (2.8 mL) and MeOH (0.7 mL). The resulting solution was treated with 20 TMSCHN 2 (82.2 pt]L, 0.164 mmol) at room temperature and stirred for 20 minutes, The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 2/3) to give Compound 55a (70 mg, 35% for 3 steps). 25 Step B: 0 (N'NH 0 NNH HaCO 0. N CF, H 2 1 Pd(OH) 2 /C, EtOH HCO N CF 3 CbzN .

H .,,0 CF, Compound 5Ma Compound 55 -131- Compound 55a (38 mg, 0.0537 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH) 2 /C (7.6 mg, 10 wt%) and was hydrogenated with a H 2 balloon for 30 minutes. The reaction solution was filtered through a 5 short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 2/3) to give Compound 55 (24 mg, 78%). Electrospray MS [M+1]* 573.1. 10 PREPARATIVE EXAMPLE 56 e-NH CI-\ NA CF, 0 CfbCF 3 HN C a Compound 6 Step A N N'NH a. H 2 , Pd(OH) 2 /C, EtOH . CF CbzN b. HCI, EtO HN CF CbN ~ " CF~, NC*F,~. 15 Compound sa Compound 66 Compound 56a (15 mg, 0.0227 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH) 2 1C (3.6 mg, 10 wt%) and was hydrogenated with a H 2 balloon for 30 minutes. The reaction solution was filtered through a 20 short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was taken up in Et 2 O (0.5 mL) and treated with HCI in ether (0.23 mL, 0.23 mmol, 1.0 M in ether). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with EtOAc (20 mL) and washed with aqueous 25 NaOH (5 mL, 0.5 N). The aqueous phase was extracted with EtOAc (3 x 10 mL), The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude - 132 product was purified using preparative TLC (hexane/EtOAc, v/v 1/1) to give Compound 56 (8.5 mg, 67%). Electrospray MS [M+1]* 563.1. 5 PREPARATIVE EXAMPLE 57 N'NH HC, N CF

CF

3 Compound 57 Step A: 10 f -NH N. H0- N' HO'' o N CF 3 a. MsC[, NEt,, CH2C12 H 3 C, N CFN CF b. NaBH 4 , DMF, 90 C - + CbzN CF CbzN .. j.. a CbzN *.,, ~ N ~ CF, Cbz CF, F Compound 23 / Compound 57a Compound 86a MsC[ (11.7 iL, 0.151 mmol) was added to a solution of Compound 23h (42.8 mg, 0.063 mmol) and Et 3 N (26.4 ptL, 0.189 mmol) in CH 2 Cl 2 (1.0 15 mL) at room temperature. The reaction mixture was quenched with water (5.0 mL) after 30 minutes and diluted with CH 2 Cl 2 (15 mL). The aqueous phase was extracted with CH 2

CI

2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (IQ mL), and dried over MgSO 4 . After filtration and concentration, the crude mesylate (44 mg, 0.0582 mmol) was 20 taken up in anhydrous DMF (2.0 mL) and treated with NaBH 4 (11.0 mg, 0.291 mmol). The reaction mixture was heated at 900C for T hour before it was cooled down to room temperature. The reaction mixture-was then diluted with EtOAc (20 mL) and washed with aqueous HCl (5 mL, 1.0 M). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers 25 were washed with water (3x10 mL), brine (10 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using - 133.preparative TLC (hexane/EtOAc, v/v = 3/2) to give Compound 57a (18 mg, 43%) and Compound 56a (15 mg, 36%). Step B: 5 N N'NH N NH

H

3 C, N-1e CF 3

H

2 , Pd(OH) 2 /C, EtOH H 3 C, N CF 3 Cbz C ' HN . CF 3 Compound 57a Compound 67 Compound 57a (18 mg, 0.027 mmol) in EtOH (3.0 mL) Was treated at room temperature with Pd(OH) 2 /C (3.6 mg, 10 wt%) and was hydrogenated 10 with a H 2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 1/1) to give Compound 57 (10 mg, 70%). Electrospray MS [M+1]* 529.1. 15 PREPARATIVE EXAMPLE 58

H

3 CON N CF HN *_ Ya

CF

3 Compound 68 20 N NH NH 0 "x. \ CF, HaCON N'NH C

NH

2 0CH 3 , EtOH O 3 HN CF HN

CF

3 CF, \\ / Compound 19 Compound 58 Compound 19 (10.0 mg, 0.0175 mmol) in EtOH (1.5 mL) was treated with MeONH 2 -HCI (14.6 mg, 0.175 mmol) and NaOAc (7.2 mg, 0.0876 mmol) -134 at room temperature. The reaction mixture was stirred at 60*C for 12 hr, and was then diluted with EtOAc (20 mL) and washed with aqueous NaHCO 3 . The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . 5 After filtration and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 213) to give Compound 58 (10.5 mg, 100%). Electrospray MS [M+1]* 600.1. PREPARATIVE EXAMPLE 59 10 HN CF, Compound 69 Step A: BnO NH CFBnO NHAc CbzN O AcCI, EtN, CH2C2 C F 3 C b z N .'' F Compound 69a 15 Compound 59b To a solution of Compound 59a (0.53 g, 0.76 mmol) in CH 2 C1 2 (4 mL) was added Et 3 N (0.14 mL, 0.98 mmol). The reaction mixture was cooled to -78*C and acetyl chloride (0.065 mL, 0.91 mmol) was added. The reaction 20 mixture was slowly warmed to room temperature and stirred for 72 hours. Additional Et 3 N (0.068 mL) and acetyl chloride (0.033 mL) was- added to the reaction mixture, which was then stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified with BIOTAGE chromatography (hexane/EtOAc, v/v = 3/2) to give Compound 59b (0.5 g). 25 Step B: -135- BnO NHAc CFHO NHAc BC1 3 , CH 2 C6, -78 "C CbzN CF Cb N - bF Compound59b Compound 59c BCl 3 (3.7 mL, 3.7 mmol, 1.0 M in hexane) was added dropwise to a stirring solution of Compound 59b (0.55 g, 0.74 mmol) in CH 2

CI

2 (9 mL) at 5 -78*C, The reaction was quenched in 1 hour by the addition of aqueous NaHCO3 solution (50 mL) at -78*C. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO 3 (100 mL), and dried over Na 2

SO

4 . The mixture was filtered and concentrated to give crude Compound 59c (0.4 g), which was used in the next reaction without further 10 purification. Step C: H HO NHAc CFO NHAc CFa CbzN Dess-Martin, NaHCO,, CHC CbzN CF CF, F Compound 59c Compound 59d 15 Dess-Martin periodinane (0.12 g, 0.28 mmol) was added to a mixture of Compound 59c (0.12 g, 0.18 mmol) and NaHCO 3 (0.17 g, 2.0 mmol) in

CH

2

CI

2 (5.0 mL) at room temperature and stirred for 45 minutes. Additional Dess-Martin periodinane (50 mg) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was then 20 concentrated and purified with BIOTAGE chromatography (hexane/EtOAc, v/v = 1/1) to give Compound 59d (0.1 g). Step D: - 136 - HN HO NHAc CF 3 0 NHAc CF 3 CbzN . CI a TosCHNC, K 3 CO,, MeOH CbzN - OC

CF

3 A CF 3 Compound 59d Compound 59e A mixture of Compound 59d (0.11 g, 0.17 mmol), potassium bicarbonate (26 mg, 0.19 mmol), tosylmethyl isocyanide (36 mg, 0.19 mmol) 5 and methanol (3 mL) was heated at 80 0 C for 48 hours. The reaction mixture was then concentrated and diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO 3 (2 x 100 mL). The organic layer was dried over Na 2

SO

4 , filtered and concentrated. The crude product was purified with BIOTAGE chromatography (hexane/EtOAc, v/v = 2/3 to 0/100) to give 10 Compound 59e (50 mg). Step E: (N N N NHAc CF, NHAc CF 3 CbzN 0 H2, Pd(OHX/C, MeOH H .., , OC CF, CF3 Compound 59d Compound 59 15 Compound 59d (0.31 mg, 0.45 mmol) in MeOH (10.0 mL) was treated at room temperature with Pd(OH) 2 /C (0.2 g, 20 wt%) and was hydrogenated with a H 2 balloon for 2 hours. The reaction solution was filtered through a short pad of CELITE and the residue was washed with MeOH (30 mL). The solvent was removed under reduced pressure and the crude product was 20 purified with BIOTAGE chromatography (EtOAc/MeOH, v/v = 9/1) to give. mixture of two isomers (190 mg), which were further purified by HPLC (chiral OD column).with hexane/IPA (v/v = 9/1) to give Compound 59 (90 mg). PREPARATIVE EXAMPLE 60 25 -137 - HN N 0 4~N CF 3 Compound 60 Step A: HN'N H2CCF a. CICE EtN, CH 2 Cl 2 CbzN b. NaN, Bu 3

NHSO

4

CF

3 c. TMSN 3 , toluene, 110 0 C b . CF, 5 Compound 60a Compoundso0 To a solution of Compound 60a (0.26 g, 0.43 mmol) in CH 2

CI

2 (4 mL) at 0*C was added Et 3 N (0.071 mL, 0.51 mmol) followed by ethylchloroformate (0.052 mL, 0.56 mmol), and the reaction mixture was stirred for 1 hour. To 10 the reaction mixture was then added sodium azide (64 mg, 0.98 mmol) and tetrabutylammonium hydrogen sulfate (43 mg, 0.13 mmol) and stirring was continued for 1 hour. The reaction mixture was then diluted with CH 2

C

2 (100 mi) and washed with water (1 x 100 mL) and brine (1 x 100 mL). The organic layer was dried over Na 2

SO

4 , filtered and concentrated. The residue was 15 dissolved in dry toluene (4 ml) and heated to 80*C for 2 hours and then cooled to room temperature. TMSN 3 (0.13 mL, 0.94 mmol) was added and the reaction mixture was heated to -1 10 C for 18 hours, The reaction mixture was then cooled to room temperature, concentrated and purified by BIOTAGE chromatography (hexane/EtOAc, v/v = 2/1, followed by MeOH/EtOAc, v/v = 20 1/99) to give Compound 60b (0.17 g). Step B: - 138 - HN IN NHN N O CF, cF, H2, Pd(OH),C, MeOH CbzN - CF, HN 1 CF3 Compound 60b Compound 60 Compound 60b (0.17 mg, 0.26 mmol) in MeOH (10.0 mL) was treated at room temperature with Pd(OH) 2 /C (15 mg, 20 wt%) and was hydrogenated 5 with a H2 balloon for 2 hours. The reaction solution was filtered through a short pad of CELITE and the residue was washed with MeOH (30 mL). The solvent was removed under reduced pressure and the crude product was purified by BIOTAGE chromatography (EtOAc/MeOH, v/v = 98/2) to give Compound 60 (20 mg). 10 While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, medications and variations are intended to fall within the spirit and scope of the present invention. - 139 -

Claims (18)

1. A compound of Formula 1: R 1 R 2 Ar 2 R4,N )n 5 Ar 0 R (I) or pharmaceutically acceptable salts andlor solvates thereof, wherein: R1 and R 2 are each independently selected from the group consisting of H, alkyl, haloalkyl, alkyl substituted with one or more hydroxyl groups, -CN, 10 alkynyl, -N(R 6 ) 2 , -N(R 6 )-S(0 2 )-alkyl, -N(R 6 )-C(O)-N(R 9 ) 2 , -alkylene-CN, -cycloalkylene-CN, -alkylene-0-alkyl, -C(O)-alkyl, -C(=N-OR)-alkyl, -C(O)-N(R 9 ) 2 , -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R)2, 0 xY Z N, HN -N N N.'N N N N N lr"and, Y \/ >Q) X )m N 15 with the proviso that at least one of R1 and R 2 is -CN, 0 N -N N Z , HN k \ N N W r , O N N ON 0 OpJr- , or t\"; W is =C(Ra)- or =N-; X is -C(O)- or -S(0 2 )-; Y is selected from the group consisting of -CH 2 -, -0-, and 20 -N(R 6 )-C(O)-, with the proviso that: (a) the nitrogen atom of -N(R)-C(O)- is bonded to X, and - 140- Y N (b) if R 1 and/or R 2 is A and Y is -0-, X is not -S(0 2 )-; Z is -C(R 7 ) 2 -, -N(Rr)-, or -0-; R 3 is selected from the group consisting of H, -CH 2 OR 5 , and alkyl; R 4 is selected from the group consisting of H, alkyl, cycloalkyl, 5 heterocycloalkyl, heteroaryl, aryl, acyl, aroyl, alkylsulfonyl, and arylsulfonyl; R 5 is H or-alky; R 6 is selected from the group consisting of H, alkyl, cycloalkyl, and aryl; each R 7 is independently H or alkyl; or each R , together with the ring carbon to which they are shown 10 attached, form a cycloalkylene ring; RS 8 is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -N(RS 6 ) 2 , -N(R 6 )-S(0 2 )-alkyl, -N(R 6 )-S(0 2 )-aryl, -N(R 6 )-C(O)-alkyl, -N(R 6 )-C(O)-aryl, alkylene-O-alkyl, and -CN; 15 R 9 is selected from the group consisting of H, alkyl; and aryl, or each R9, together with the nitrogen to which they are shown attached, form a heterocycloalkyl ring; Ar' and Ar 2 are each independently selected from the group consisting of unsubstituted aryl and aryl substituted with 0 to 3 substituents selected 20 from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -CN, -OH, and -NO 2 ; n is 0,11, or2; and m is 1, 2, or 3. 25 2.- The compound according to claim 1, wherein the compound of Formula I has the following structure: R 1 R 2 Ar 2 N~> Ar4 0 R 3 . - 141 -

3. The compound according to claim 1, wherein: R 3 is alkyl; R 4 is H; Ar' is substituted or unsubstituted phenyl; 5 Ar 2 is substituted or unsubstituted phenyl; and n is 1.

4. The compound according to claim 2, wherein: R 3 is alkyl; 10 R4 is H; Ar is unsubstituted phenyl; Ar2 is substituted phenyl; and n is 1. 15 5. The compound according to claim 1, wherein: R 3 is alkyl; R4 is H; Ar 1 is monosubstituted phenyl; Ar2 is substituted phenyl; and 20 n is 1.

6. The compound according to claim 4, wherein: Ar 2 is 3,5-bis(trifluoromethyl)phenyl, 3,5-bis(fluoro)phenyl, 3,5 bis(chloro)phenyl, 3,5-bis(methyl)phenyl, or 3,5-bis(methoxy)phenyl. 25

7. The compound according to claim 6, wherein: R 3 is -CH 3 .

8. The compound according to claim 7, wherein: N 30 one of R 1 or R 2 is -142- 9: The coripauna according to claim 7, wherein: -N ~<R8 one of R 1 or R 2 is

10. The compound according to claim 7, wherein: N N N 5 one of R 1 or R 2 is '.

11. The compound according to claim 7, wherein: one of R 1 or R 2 is -CN. 10 12. The compound according to claim 8, wherein: X is -S(02)-; Y is -CH 2 -; and m is 2. 15 13. The compound according to claim 8, wherein: X is -C(O)-; Y is -CH 2 -; and m is 2. 20 14. The compound according to claim 8, wherein: X is -C(O) Y is -CH 2 -; and m is 3. 25 15. The compound according to claim 8, wherein: X is -C(O)-; Y is -0-; and m is 2. - 143 -

16. The compound according to claim 8, wherein: X is -C(0)-; Y is -CH 2 -; and m is 1. 5

17. The compound according to claim 8, wherein: X is -C(0)-; Y is -NH-C(0)-; and m is 1. 10

18. The compound according to claim 9, wherein: Z is -NH-; and R" is H. 15 19. The compound according to claim '9, wherein: Z is -NH-; and R" is -NH-S(0 2 )-CH 3 .

20. The compound according to claim 9, wherein: 20 Z is -NH-; and R" is -CH 2 -OH.

21. The compound according to claim 9, wherein: Z is -NH-; and 25 R' is -CH 2 -0-CH 3 .

22. The compound according to claim 9, wherein: Z is -NH-; and R' is -NH 2 . 30

23. The compound according to claim 9, wherein: Z is ;and - 144 - R" is H.

24. The compound according to claim 9, wherein: Z is -C(CH3) 2 -; and 5 R 8 is H.

25. The compound according to claim 1, having the Formula IB O& CF 3 CH3 (IB) 10 wherein R1 and R 2 are selected from the group consisting of: Compound R' R 2 1 -- NP -CN -O 0 2 \--N O -CN O 3 -- N yNH C CH 3 O H 2 OH 4 -N NHC C O H 3 0 H 2 /- N 5 -- N -CH 2 CN /N 6 -CH 3 --- N - 145 - Compound R 1 R 2 7 -CNN I /~N 8 -C(O)-O-CH3 -N I 9 -ON 0 10 -0(O)-NH 2 I /~ N NH -CH 2 C(OH)(CH 3 ) 2 12 -CH 2 0H L-\ 13 'rN -CH 2 0CH 3 14 -CH 2 0CH 3 N I /~N /N 17 y- N -CH 2 -C(2)-CH 3 18 NHN -C(=N-O)-HCH 2 CH 3 ) -16 Compound R R N 19 - NH -C(O)-CH 2 CH 3 0 O 20 -N NH -CH 2 0CH 3 O /- N 21 N NH -C(O)-NH(CH 3 ) O /-- N fN=N 22 -C(O)-NH(CH 3 ) N NH O N 23 NH -CH 2 OH O N 24 --N NH -CH 2 CH 2 OH ZN 25 --N NH -CH 2 CH 2 CH 3 O /- N 26 --N NH -CH 2 OCH 3 0 / N 27 -CH 2 0CH 3 NH 0 /~N 28 ---N CH 3 H CH 3 -147- Compound R R2f /-, N N 29 NH -CH 2 C(O)-NH 2 - -N 30 -- N NH -CH 2 -C(O)-CH 3 N 31 NH -CH 2 -C(O)O-CH3 32 N -CN 33 .- N -CN 34 -CN 0 /~N 35 -CN - NH 36 -NH-S(0 2 )-CH 3 -CN 37 -CN -NH-S(Q 2 )-CH 3 /~N 38 ~-N NH -CH 2 CN 39 -CN -NH 2 40 -NH 2 -CN 41 -NH-C(O)-NH 2 -CN - 148- Compound R R N 42 -- N NH -CN O 43 -N H 0 OH 44 NN H -N NH 00H ~~~ ~~OCH3 45 N H N NH O OCH 3 -N 46 N (NH 0 0 0 i -SH 3 HN 47 -N H NH 48 H -N HNH 0O - 149/- Compound RR 2 49 NH H 2 N >-N 50 H -N I y NH , N 51 y- NH -C(O)-NH 2 52 yN NH -C(=N-OCH 3 )-CH 3 , N 55 N -C(O)OCH, 3 /-N 56 ~ -N IH -C 2 /-- N

575- NH -OOH 3 -050 Compound R R 2 /-N 58 NH -C(=N-OCH 3 )-CH 2 CH 3 O ;_N 59 -NHC(O)CH3 0 N N NN 61 5-N NH H O 26. A compound represented by the following formula: HN HNCN CF 3 OHN 0CF3 CH 3 5 27. A compound represented by the following formula: N ,N O \ N/. NH 2 CF 3 O CF 3 CH 3 28. A compound represented by the following formula: - 151 - N HN >~N p( CF 3 0 0a HN CF 3 CH 3 29. A compound represented by the following formula: N /OH HN N N) CF3 H HN 0,,O F CH 3 30. A compound represented by the following formula: 0 HN N f~O'CH3 CF 3 0 HN CF 3 5 CH 3 31. A compound represented by the following formula: /N HN N p NH 2 CF 3 O H N ' C F 3 CH 32. A compound represented by the following formula: - 152- CF 3 0 HN O H N %:0 C F 3 CH 3 33. A compound represented by the following formula: HN N N CF 3 0 HN /_no , CF 3 CH3 34. A compound represented by the following formula: N HN H N N N CH3 O HCF 3 5 CH 3 35. A compound represented by the following formula: O CF 3 O CF3 CH3 36. A pharmaceutical composition comprising: at least one compound of claim 1 or a pharmaceutically acceptable salt 10 and/or solvate thereof, and at least one pharmaceutically acceptable carrier. -153- 37. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, at least one serotonin reuptake inhibitor, and at least one compound of claim 1. 5 38. A method of treating a physiological disorder, symptom or disease, comprising: administering to a patient in need thereof an effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt and/or solvate thereof, 10 wherein the physiological disorder, symptom or disease is selected from the group consisting of respiratory diseases, inflammatory diseases, skin disorders, ophthalmalogical disorders, central nervous system conditions, depression, anxiety, phobia, bipolar disorder, addictions, alcohol dependence, psychoactive substance abuse, epilepsy, nociception, psychosis, 15 schizophrenia, Alzheimer's disease, AIDS related dementia, Towne's disease, stress related disorders, obsessive/compulsive disorders, eating disorders, bulimia, anorexia nervosa, binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, atherosclerosis, fibrosing disorders, obesity, Type II diabetes, pain related disorders, headache, neuropathic pain, 20 post-operative pain, chronic pain syndrome, bladder disorders, genitourinary disorders, cough, emesis, and nausea. 39. The method of claim 38, wherein the physiological disorder, symptom or disease is emesis, depression, anxiety or cough. 25 40. The method of claim 39, wherein the physiological disorder, symptom or disease is depression or anxiety. 41. The method of claim 39, wherein the physiological disorder, symptom 30 or disease is emesis and/or nausea. 42. The method of claim 39, wherein the physiological disorder, symptom or disease is cough. - 154- 43. The method of claim 40, further comprising administering to the patient an effective amount of at least one anti-depressant agent and/or at least one anti-anxiety agent. 5 44. The method of claim 40, further comprising: administering to the patient an effective amount of at least one selective serotonin reuptake inhibitor, and wherein the physiological disorder, symptom or disease is depression. 10 45. A method for antagonizing an effect of a Substance P at a neurokinin-1 receptor site or for blocking at least one neurokinin-1 receptor, in a patient in need of such treatment, comprising administering to a patient an effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt and/or solvate thereof. 15 46. The method according to claim 38, further comprising: administering an effective amount of at least one active ingredient selected from the group consisting of other NK 1 receptor antagonists, selective serotonin reuptake inhibitors, dopamine receptor agonists, serotonin 20 5-HT 3 receptor antagonists, serotonin 5-HT 2 , receptor agonists,.nociceptin receptor agonists, glucocorticoids and inhibitors of multidrug resistance protein 5; and wherein the physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, 25 phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorder, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, post-operative pain, chronic pain syndrome, 30 bladder disorder, genitourinary disorder, cough, emesis and nausea. 47. A method of treating emesis and/or nausea in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable - 155- salt and/or solvate thereof in combination with an effective amount of at least one serotonin 5-HT 3 receptor antagonist and/or at least one glucocorticoid. 48. The method of claim 47, wherein the serotonin 5-HT 3 receptor 5 antagonist is ondansetron and the glucocorticoid is dexamethasone. 49. A kit, comprising: two or more separate containers in a single package, wherein each container comprises a pharmaceutical composition; 10 wherein a first container of said package comprises a first pharmaceutical composition comprising an effective amount of a compound of claim 1 and/or a pharmaceutically acceptable salt and/or solvate thereof in a pharmaceutically acceptable carrier, a second container of said package comprises a second 15 pharmaceutical composition comprising another therapeutic agent in a pharmaceutically acceptable carrier, and the other therapeutic agent is selected from the group consisting of SSRIs, other types of NK, receptor antagonists, prostanoids, H, receptor antagonists, ca-adrenergic receptor agonists, dopamine receptor agonists, 20 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-HT 3 receptor antagonists, serotonin 5-HT 2 c receptor agonists, nociceptin receptor agonists, glucocorticoids, rho 25 kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistanee -protein- 5. 50. A purified compound according to claim 1. -156-