AU2006316620B2 - Beta-secretase modulators and methods of use - Google Patents

Description

WO 2007/061670 PCT/US2006/044058 BETA-SECRETASE MODULATORS AND METHODS OF USE This application claims the benefit of U.S. Provisional Application Nos. 5 60/73 8,765, filed November 21, 2005 and 60/854,824, filed October 27, 2006, each of which is hereby incorporated herein by reference in their entireties. FIELD OF THE INVENTION The invention relates generally to pharmaceutically active compounds, 10 pharmaceutical compositions and methods of use thereof, to treat Beta-Secretase mediated disorders, including Alzheimer's disease, plaque formation on the brain and related conditions. BACKGROUND OF THE INVENTION 15 Alzheimer's disease (AD) is a disease that affects greater than 12 million aging people worldwide. AD accounts for the majority of dementia clinically diagnosed after the age of 60. AD is generally characterized by the progressive decline of memory, reasoning, judgement and orientation. As the disease progresses, motor, sensory, and vocal abilities are affected until there is global impairment of multiple cognitive 20 functions. The loss of cognitive function occurs gradually, typically leading to a diminished cognition of self, family and friends. Patients with severe cognitive impairment and/or diagnosed as end-stage AD are generally bedridden, incontinent, and dependent on custodial care. The AD patient eventually dies in about nine to ten years, on average, after initial diagnosis. Due to the incapacitating, generally humiliating and 25 ultimately fatal effects of AD, there is a need to effectively treat AD upon diagnosis. AD is caused by two major physiological factors in the brain. The first factor, beta amyloid plaque formation, supports the "amyloid cascade hyposthesis" which alleges that AD is caused by the formation of characteristic beta amyloid deposits (commonly referred to as beta amyloid "plaques" or "plaque deposits") in the brain and in 30 cerebral blood vessels (beta amyloid angiopathy). The second factor causing AD is intraneuronal tangles, consisting of an aggregate form of the protein tau. Amyloid plaques are thought to be specific for AD, while intraneuronal tangles are also found in other dementia-inducing disorders. Joachim et al., Alz. Dis. Assoc. Dis., 6:7-34 (1992). Several lines of evidence indicate that progressive cerebral deposition of beta 35 amyloid peptide (A-beta) plays a seminal role in the pathogenisis of AD and can precede WO 2007/061670 PCT/US2006/044058 -2 cognitive symptoms by years or even decades. Selkoe, Neuron, 6:487 (1991). Release of A-beta from neuronal cells grown in culture and the presence of A-beta in cerebrospinal fluid (CSF) of both normal individuals and AD patients has been demonstrated. Seubert et al., Nature, 359:325-327 (1992). Autopsies of AD patients have revealed large numbers 5 of lesions comprising these 2 factors in areas of the human brain believed to be important for memory and cognition. Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD. Amyloid containing plaques and vascular amyloid angiopathy were also found in the brains of 10 individuals with Down's Syndrome, Herditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. It has been hypothesized that A-Beta formation is a causative precursor or factor in the development of AD. Deposition of A-beta in areas of the brain responsible for cognitive factors is a major factor in the development of AD. Beta amyloid plaques are 15 primarily composed of amyloid beta peptide (A-beta peptide). A-beta peptide is derived from the proteolytic cleavage of a large transmembrane amyloid precursor protein (APP), and is a peptide ranging in about 39-42 amino acids. A-beta 42 (42 amino acids long) is thought to be the major component of these plaque deposits. Citron, Trends in Pharmacological Sciences, 25(2):92-97 (2004). 20 Several aspartyl proteases are thought to be involved in the processing or cleavage of APP, resulting in the formation of A-beta peptide. Beta secretase (BACE, also commonly referred to as memapsin) is thought to first cleave APP to generate two fragments of the A-beta peptide: (1) a first N-terminus fragment and (2) a second C-99 fragment, which is subsequently cleaved by gamma secretase to generate the C-terminus 25 fragment of the A-beta peptide. APP has also found to be cleaved by alpha-secretase to produce alpha-sAPP, a secreted form of APP that does not result in beta-amyloid plaque formation. This alternate pathway precludes the formation of A-beta peptide. A decription of the proteolytic processing fragments of APP is found, for example, in U.S. Patent Nos. 5,441,870, 5,712,130 and 5,942,400. 30 BACE is an aspartyl protease enzyme comprising 501 amino acids and responsible for processing APP at the beta-secretase specific cleavage site. BACE is present in two forms, BACE 1 and BACE 2, designated as such depending upon the specific cleavage site of APP. Beta secretase is described in Sinha et al., Nature, 402:537 554 (1999) (p510) and PCT application WO 2000/17369. It has been proposed that A- WO 2007/061670 PCT/US2006/044058 -3 beta peptide accumulates as a result of APP processing by BACE. Moreoevr, in vivo processing of APP at the beta secretase cleavage site is thought to be a rate-limiting step in A-beta production. Sabbagh, M. et al., Alz. Dis. Rev. 3:1-19 (1997). Thus, inhibition of the BACE enzyme activity is desirable for the treatment of AD. 5 Studies have shown that the inhibition of BACE may be linked to the treatment of AD. BACE 1 knockout mice fail to produce A-beta, and present a normal phenotype. When crossed with transgenic mice that over express APP, the progeny show reduced amounts of A-beta in brain extracts as compares with control animals (Luo et al., Nature Neuroscience, 4:231-232 (2001)). This evidence further supports the concept that 10 inhibition of beta secretase activity and a corresponding reduction of A-beta in the brain should provide a therapeutic method for treating AD and other beta amyloid or plaque related disorders. Several approaches have been taken to treat AD and plaque-related disorders. One approach has been to reduce the formation of plaque on the brain. Particularly, a 15 common approach has been to inhibit the activity of beta secretase. For example, each of the following PCT publications: WO 03/045913, WO 04/043916, WO 03/002122, WO 03/006021, WO 03/002518, WO 04/024081, WO 03/040096, WO 04/050619, WO 04/080376, 20 WO 04/099376, WO 05/004802, WO 04/080459, WO 04/062625, WO 04/042910, WO 05/004803, WO 05/005374, WO 03/106405, WO 03/062209, WO 03/030886, WO 02/002505, WO 01/070671, WO 03/057721, WO 03/006013, WO 03/037325, 25 Wo 04/0943 84, Wo 04/094413, WO 03/006423, WO 03/050073, WO 03/029169 and WO 04/000821, describe inhibitors of beta secretase, useful for treating AD and other beta-secretase mediated disorders. BRIEF DESCRIPTION OF THE INVENTION 30 The present invention provides a new class of compounds useful for the modulation of beta secretase and, to that end, useful for the regulation or reduction of the formation of A-beta peptide and consequently, the reduction of beta amyloid plaque formation on the brain. Accordingly, the compounds of the invention are useful for the treatment of Alzheimer's disease and other beta secretase mediated disorders.

WO 2007/061670 PCT/US2006/044058 -4 The compounds provided by the invention, including stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, are defined by general Formula I H OH R4 I | AN N N R 5 B

R

3

R

3 5 1 wherein A, B, W, R 3 , R 4 , Ri, i and j are as described below. The invention also provides procedures for making compounds of Formula I, as well as intermediates useful in such procedures. The compounds provided by the invention are capable of modulating beta 10 secretase. To this end, the invention further provides for the use of these compounds for therapeutic, prophylactic, acute and/or chronic treatment of beta secretase mediated diseases, such as those described herein. For example, the compounds are useful for the prophylaxis and treatment of AD and other diseases or conditions involving amyloid plaque formation on the brain. 15 The invention also provides pharmaceutical compositions, which comprise one or more compounds of the invention, methods for the treatment of beta secretase mediated diseases, such as AD, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention. The invention also provides the preparation of a a pharmaceutical composition 20 or of a medicament, containing one or more of the compounds, useful to attenuate, alleviate, or treat disorders through inhibition of beta secretase. For example, and in one embodiment, the invention provides a pharmaceutical composition comprising an effective dosage amount of a compound of Formula I in association with at least one pharmaceutically acceptable carrier. 25 The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and other publications recited herein are hereby incorporated by reference in their entirety.

WO 2007/061670 PCT/US2006/044058 -5 DETAILED DESCRIPTION OF THE INVENTION In one embodiment of the invention, the compounds, including stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, are defined by H OH R4 I | A N N R 5 B R 3

R

3 wherein A is C-o 10 -alkyl, C 2 -o-alkenyl, C 2

-

1 0 -alkynyl, R'-C..

1 o-alkyl-, R-C 2

-

0 alkenyl- or R'-C 2 -o-alkynyl-, wherein 1, 2 or 3 carbon atoms of (1) said C-Cio alkyl, C 1

-C

10 alkenyl, CI-Cio 10 alkynyl or (2) said C 1 ..o-alkyl, C 2

-

1 o-alkenyl, C 2

-

1 0 -alkynyl of R-Ci-io-alkyl-, R'

C

2

-

10 -alkenyl- or R'-C 2 -io-alkynyl-, is optionally replaced with a heteroatom selected from 0, S, S(O), S(0)2 and N, and optionally substituted independently with one or more substituents of 19; and 15 R1 is a fully saturated or a partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms and optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, wherein said ring system is 20 substituted independently with one or more substituents of oxo, R, R, RW,

NR

7

R

7 , NR 7 R!, OR 7 , SR 7 , OR", SR 8 , C(O)R 7 , OC(O)R 7 , COOR 7 , C(O)R, OC(O)R, COOR, C(O)NRR 7 , C(S)NRR 7 , NR 7 C(O)R, NRC(S)R 7 ,

NR

7

C(O)NRR

7 , NR 7

C(S)NR

7

R

7 , NR 7

(COOR

7 ), OC(O)NR 7

R

7 , C(O)NR 7

R

8 , C(S)NRR, NR 7 C(O)R, NRC(S)R 8 , NR 7

C(O)NR

7

R

8 , NR 7

C(S)NR

7

R

8 , 25 NR'(COOR"), OC(O)NR 7

R

8 , S(O) 2 NR7R 7 , NR 7

S(O)

2

NR

7

R

7 , NRS(O) 2

R

7 ,

S(O)

2 R, S(O) 2

NR

7 R", NRS(O) 2 NRR or NRS(O) 2 R; W is -C(=0)-, -OC(=O)-, -NHC(=0)-, -S(=O)b- or -NHS(=O)b-, wherein b is 1 or 2; B is R 2

-(CR

2 aR 2 a)h-, R 2

-O(CR

2 aR 2 a)h-, 2

-S-(CR

2 aR 2 a)- or R 2

-N(R

2 a)-(CR 2 aRa)h-, 30 wherein WO 2007/061670 PCT/US2006/044058 -6

R

2 is CI-Cio alkyl, CI-Cio haloalkyl, C 1

-C

1 0 alkenyl, CI-Clo alkynyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 5 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, wherein said CI-Cio alkyl, CI-Co alkenyl, C 1 -Co alkynyl is optionally substituted independently with one or more substituents of R!, and said ring system is optionally substituted independently with one or more substituents of oxo, RW, R, R9, NR 7

R

7 , NR R 8 , OR, SR , OR', SR , C(O)R, OC(O)R 7 , 10 COOR', C(O)R, OC(O)R, COOR", C(O)NR 7 R, C(S)NR 7

R

7 , NRC(O)R 7 ,

NR

7

C(S)R

7 , NR 7

C(O)NR

7 R, NRIC(S)NR 7

R

7 , NR(COOR), OC(O)NR 7

R

7 ,

C(O)NR

7 R, C(S)NR 7 R!, NR 7 C(O)R, NR 7

C(S)R

8 , NR 7

C(O)NRR

8 ,

NR

7

C(S)NR

7 R, NRJ(COOR'), OC(O)NR 7

R

8 , S(O) 2 NR7R 7 , NR 7

S(O)

2

NR

7

R

7 ,

NR

7

S(O)

2

R

7 , S(O) 2 R", S(O) 2

NRR

8 , NR 7

S(O)

2

NR

7 R" or NR 7

S(O)

2 R!; 15 each R 2 , independently, is H, OH, NO 2 , CN, NH 2 , C 1

-C

10 alkyl, CI-Co alkoxyl or haloalkyl; and h is 0, 1, 2 or 3; i is 1, 2 or 3; j is 0, 1 or 2; 20 each R3, independently, is H, haloalkyl, CN, C 11 o-alkyl, C 2

.

1 .o-alkenyl, C 2

-

1 0 alkynyl, C 3 o-cycloalkyl or C 41 o-cycloalkenyl, each of the Ci 1 0 -alkyl, C 2

-

1 -alkenyl, C 2

..

1 0 alkynyl, C 3 -io-cycloalkyl and C4.

1 o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of RW or R!; R4 is H, haloalkyl, CN, C 1 .io-alkyl, C 2 -. o-alkenyl, C2-.

1 0 -alkynyl, C 3 10 -cycloalkyl or 25 C 4

.

10 -cycloalkenyl, each of the CI1o-alkyl, C 2

-

1 o-alkenyl, C 2 -io-alkynyl, C 3

.

1 <-cycloalkyl and C 4 .1o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of RW or R!; WO 2007/061670 PCT/US2006/044058 -7

R

5 is R1 R 1 IO RR

R

11 R 11 1 R R12 R R Y2Y

R

1 R1 ( x 2 x x X2)m X 2 ) 3()0 X' R 12 m n R1 X2 R113) Kx Y YY Y Y- 3)2 ' -Y Y2 '2 R1R 10

R

1 R R12 R 11 R 12 R11 N N N Y X X Ym / 3 Y) Y ) '(2 42 Ro R R 2 R I , R R 1 2 R 1 o r( R 1 wherein X 1 is CR", C(=O), 0, S, S(O) 2 or NR'; 5 each X 2 , independently, is CRMR'X; each of Y', Y 2 and Y 3 , independently, is CR' 2 R, 0, S or ND m is 0, 1 or 2; and ois, 1,2, 3,4 or 5; provided that (a) no more than two of YM, Y 2 andY 3 isO, S orNR and (b) when 10 o is0, then each of Yi andY 2 is CR 2

R

2

;

WO 2007/061670 PCT/US2006/044058 -8

R

7 is H, Ci- 1 o-alkyl, C 2

..

1 -alkenyl, C 2 10 -alkynyl, C 3 -o-cycloalkyl or C 4

.

10 cycloalkenyl, each of the CI-io-alkyl, C 2 .. io-alkenyl, C 2 .io-alkynyl, C 3 1 0 -cycloalkyl and C 4 1 o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of NRR 9 , NR!R 9 , OR, SR, OR!, SR 9 , 5 C(O)R, OC(O)R, COOR, C(O)R 9 , OC(O)R!, COOR?, C(O)NRR 9 , C(O)NRR 9 ,

NR

9 C(O)R, NR 9

C(O)R

9 , NR!C(O)NRR, NR 9

C(O)NR

9

R

9 , NR!(COOR), NR 9 (COOR),

OC(O)NR

8

R

9 , OC(O)NR 9

R

9 , S(O)2RW, S(O) 2

NR

8

R

9 , S(0) 2

R

9 , S(O) 2

NR

9

R

9 ,

NR

9

S(O)

2 NReR 9 , NRS(O) 2

N

9

R

9 , N 9 S(0) 2

R

8 , NRS(O) 2

R

9 , R or R?; RW is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 10 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substituents of R?, oxo, NRR, OR 9 ; SR?, C(O)R 9 or a partially or fully saturated or unsaturated 5-6 15 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of R 9 ; R? is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, CI-o-alkyl, C2- 10 -alkenyl, C 2 . to-alkynyl, C 31 o-cycloalkyl, C 4 -o-cycloalkenyl, C 1

.

1 0 -alkylamino-, CI 10 -dialkylamino-, C 1 . 1 0 -alkoxyl, C..I 10 -thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered 20 monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CI-o-alkyl, C 2

-

10 -alkenyl, C 2

-

10 alkynyl, C 3 -lo-cycloalkyl, C 410 -cycloalkenyl, CI- 1 o-alkylamino-, C 1 oo-dialkylamino-, C 10 alkoxyl, CI-io-thioalkoxyl and ring of said ring system is optionally substituted 25 independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, CI- 10 -alkylamino-, CI 1 0 dialkylamino-, Ci..

10 -thioalkoxyl, benzyl or phenyl; 30 R1 0 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, C,..o-alkyl, C 2 -.o-alkenyl, C 2 lo-alkynyl, C 3 ,o-cycloalkyl, C 4 io-cycloalkenyl, C-o-alkylamino-, CI 10 -dialkylamino-, C.. so-alkoxyl, C 1 ..o-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said WO 2007/061670 PCT/US2006/044058 -9 heteroatoms selected from 0, N, or S, wherein each of the C- 10 -alkyl, C 2

-

10 -alkenyl, C 2 10 alkynyl, C 3 .o-cycloalkyl, C 4 -o-cycloalkenyl, CI 10 -alkylamino-, C- 1 1 o-dialkylamino-, C- 10 alkoxyl, Cx.o-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, 5 methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmetboxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, Ci 10 -alkylamino-, CbIo dialkylamino-, CI-o-thioalkoxyl, benzyl or phenyl; R" is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, C 1 io-alkyl, C 2

-

10 -alkenyl, C 2 10 ro-alkynyl, C 3

-

10 -cycloalkyl, C 4 .io-cycloalkenyl, Ci 10 -alkylamino-, C- 10 -dialkylamino-, Cj. jo-alkoxyl, C 1 ..o-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CIoo-alkyl, C 2

-

10 -alkenyl, C 2 -1o 15 alkynyl, C 31 o-cycloalkyl, C 4

.

10 -cycloalkenyl, C 1 10 -alkylamino-, CI 10 -dialkylamino-, CI 1 0 alkoxyl, C 1 oo-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert 20 butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, Co.

1 0 -alkylamino-, C 11 0 dialkylamino-, C 1 oo-thioalkoxyl, benzyl or phenyl; alternatively, R 0 and R" taken together with the carbon or nitrogen atoms to which they are attached form a partially or fully saturated or unsaturated 5-6 membered second ring of carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or 25 S, the second ring optionally substituted independently with 1-5 substituents of R, R", R or R's and optionally fused to a 4-7 membered third ring, the third ring formed of carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of R1 2 , R 13 , R1 4 or R 5 ; R1 2 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, oxo, CIoo-alkyl, C 2

-

10 30 alkenyl, C 2

-

1 -alkynyl, C 3

.

10 -cycloalkyl, C4.lo-cycloalkenyl, Cv.

1 o-alkylamino-, CIjo dialkylamino-, C 10 -alkoxyl, C 1 oo-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the WO 2007/061670 PCT/US2006/044058 - 10 C..o-alkyl, C 2 -10-alkenyl, C 2 ..- alkynyl, C 3 -- cycloalkyl, C 4 o-cycloalkenyl, C.-1 0 alkylamino-, C1.to-dialkylamino-, CI-o-alkoxyl, C,,o-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, 5 isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, see-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C 1

-

0 alkylamino-, C1.io-dialkylamino-, C,.-o-thioalkoxyl, benzyl, phenyl or R,4; R is NR 4

R'

5 , NRisR' 5 , OR 4 , SR 4 , OR 5 , SR' 5 , C(O)R' 4 , OC(O)R 4 , COOR' 4 ,

C(O)R'

5 , OC(O)R' 5 , COOR 5 , C(O)NR' 4

R"

5 , C(O)NR' 5

R'

5 , NR' 4

C(O)R'

4 , NR' "C(O)R' 4 , 10 NR' 4

C(O)R'

5 , NR' 5

C(O)R

5 , NR 15

C(O)NR

4

R'

5 , NR' 5

C(O)NR'

5

R

5 , NR' 5 (COOR1 4 ),

NR(COOR

5 ), OC(O)NR' 4 R's, OC(O)NR 5 R 1, S(O) 2 R1 4 , S(O) 2 R1 5 , S(O) 2 NR1 4 R1 5 ,

S(O)

2

NR

5

R

5 , NIR' 4

S(O)

2

NR'

4

R'

5 , NR'sS(O) 2 NR1 5 R's, NR1 4

S(O)

2

R

4 or NR 5

S(O)

2

R'

5 ;

R'

4 is a saturated or partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of 15 carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substituents of R's; and

R

5 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, methyl, methoxyl, 20 ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, C1.

1 0 alkylamino-, C1..o-dialkylamino-, C1..o-thioalkoxyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring 25 system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, see 30 butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl. In another embodiment, the compounds of Formula I include R'-C(=O)- as A, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R'-OC(=O)- as A, in conjunction with any of the above or below embodiments.

WO 2007/061670 PCT/US2006/044058 - 11 In another embodiment, the compounds of Formula I include R'-NHC(=O)- as A, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R'-S(=O)b- as A wherein b is 0, 1 or 2, in conjunction with any of the above or below embodiments. 5 In another embodiment, the compounds of Formula I include or R'-NHS(=O)b- as A wherein b is 0, 1 or 2,in conjunction with any of the above or below embodiments. In another embodiment, Formula I includes compounds wherein A is Cig-alkyl, C 2

-

6 alkenyl, C 2 g-alkynyl, R'-O-Ci.

6 -alkyl-, R-S-CI 6 -alkyl-, R' S(O)2-CI.6-alkyl-, R'-NH-Ci-6alkyl-, R'-O-Ci-6alkenyl-, R'-S-C2-6alkenyl-, R'-S(O)2-C2 10 6 -alkenyl-, R-NH-C 2 g-alkenyl-, R'-O-C 1 -- alkynyl-, R'-S-CI 6 alkynyl-, R-S(O) 2 -CI-6 alkynyl-, R'-NH4-Ci-6alkynyl-, R'--C-6alkyl-O-CI-6alkyl-, R'--C-6-alkyl-S-CI-6alkyl-, Rl CI-6alkyl-S(O)2-CI-6alkyl-, R'-C1-6-alkyl-NH-C1-6-alkyl-, R'-CI-6alkyl-O-Ci-6alkenyl-,

R'-C

1 -6galkyl-S-C 26 -alkenyl-, R'-Ci- 6 -alkyl-S(O) 2

-C

2 g-alkenyl-, R'-Ci-alkyl-NH-C 26 alkenyl-, .R'-Cs-6-alkyl-O-Ci-6alkynyl-, R'-C1.6-alkyl-S-Cl-6alkynyl-, R'-Ci-6-alkyl 15 S(O) 2

-CI.

6 alkynyl- or R1 -C 1

.

6 -alkyl-NH-C 1 .-- alkynyl-, in conjunction with any of the above or below embodiments. In another embodiment, Formula I includes compounds wherein A is Cig-alkyl, C 2

-

6 alkenyl, C 2 g-alkynyl, Cisalkyl-O-C 3 -alkyl-, Cig-alkyl-S-Cl 3-alkyl-, CI-6alkyl-S(O)2-CI-3-alkyl-, Ci-6alkyl-NH-CI-3-alkyl, di-(CI-6alkyl)-N-CI 20 alkyl, C 2 g-alkeny-O-C.

3 -alkyl-, C 2

-

6 -alkenyl-S-C 3 -alkyl-, C 2

.

6 -alkenyl-S(O) 2

-C.

3 -alkyl , C 2 g-alkenyl-NH-C 3 -alkyl- or C 2 g-alkynyl-NH-CI- 3 -alkyl-, wherein the alkyl, alkenyl or alkynyl moiety of each is optionally substituted with 1-5 substituents of R 9 , in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I 25 include as R', phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, 30 benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a ring system of WO 2007/061670 PCT/US2006/044058 - 12 RaRia 0 0 o N Rid 0Ria-, Ricd RI, (R N (Rlb)k-]- lbk (Rib)k-- (Rlbk-- R18 0 (Rib N Ri Ri (RRia 0N 0N0 N RRibi 0 FD(RIkN 1 N i0 bA~~ (Rib(k \ (R 0 Rib NN I <N C Rib R 2

R

1

R

18 Ri R i 2 Z ' )- ( R b ) k " ( R j ( R i b k7 ) - R 1 ) lbb~ N RR1 N b~ N I I R== 0- 0 Rib Rl R / / iNrR 2 whri ~ s (,RB, () 7 a )RCON 7 7

C()R

7

RC()R

7

C(S~R

7 Ra S()NR 7 lSO 2 8 ar

()N

7 8 5 eachRibcan Rid,~ ineednly sRR~ I? (RR 7 RI OR 7 , SR 7

(R

8 ,~ NR 8

G(OR

7

,CO

7

()

8

OO

8

()RRCS)RRN

7 () whern RR 8 iNR 7 ,(R9,NC()R, N(ORC(O)NR 7 R, NRC(S)NR 7 , ON 7

CO

8 ,

C()NR

7 R, S() 2

NR

7 R, NS(O) 2

NR

7 Ror S()NR 7

SO

2 7 502(,S()N 10 " NRSR",) 2 N7R or NR 7

(O)R

8 and ,CON7RCSN ,N7()7 k is 0, 1, 2 or 3, in conjunction with any of the above or below embodiments.

WO 2007/061670 PCT/US2006/044058 - 13 In the immediately preceeding embodiment, the compounds of Formula I include R7, R7 or Re, independently, as each of Ra, Rib, RI" and Rid, independently, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R 2

-(CR

2 aR 2 a)h- as B 5 wherein each R 2 a, independently, is H, OH, NO 2 , CN, NH 2 , C 1

-C

1 o alkyl, C-Co alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R 2 -0-(CR 2 aR 2 a)h- as B wherein each R 2 a, independently, is H, OH, NO 2 , CN, NH 2 , C 1 -Cio alkyl, C-Cio alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments. 10 In another embodiment, the compounds of Formula I include R 2

-S-(CR

2 aR 2 a)h- as B wherein each R 2 , independently, is H, OH, NO 2 , CN, NI-I 2 , C-Clo alkyl, C-Cio alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R 2

-NR

2 a-(CR 2 aR 2 a),_ as B wherein each R 2 , independently, is H, OH, NO 2 , CN, NH 2 , C-Clo alkyl, C 1 -Co 15 alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R 2

-(CHR

2 a)h- as B wherein R 2 " is OH, NO 2 , CN, NH 2 , C-Clo alkyl, C 1 -Clo alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R 2

-(CH

2 )h- as B, in 20 conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R 2

-O-(CH

2 )h- as B, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R 2

-S-(CH

2 )h- as B, in conjunction with any of the above or below embodiments. 25 In another embodiment, the compounds of Formula I include R 2

-NH-(CH

2 )h- as B, in conjunction with any of the above or below embodiments. In another embodiment, Formula I includes compounds wherein R 2 is a C

C

4 alkyl, Cr-C 4 alkenyl, C-C 4 alkynyl, C-Co haloalkyl or an optionally substituted ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, 30 triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, WO 2007/061670 PCT/US2006/044058 - 14 pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include an optionally 5 substituted ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl and benzimidazoly as R2, in conjunction with any of the above or below embodiments. 10 In another embodiment, the compounds of Formula I include C 1

-C

1 0 alkyl, CI-Clo alkenyl or Cr-Clo alkynyl as R2, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include CI-Cio haloalkyl as R2, in conjunction with any of the above or below embodiments. 15 In another embodiment, the compounds of Formula I include H, haloalkyl, CN, Ci- 1 O-alkyl, C 2

.

1 o-alkenyl or C 2 -o-alkynyl as R3, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include H as R3, in conjunction with any of the above or below embodiments. 20 In another embodiment, the compounds of Formula I include C 1

..

1 0 -alkyl as RW, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include H, haloalkyl, CN,

C

1 ..o-alkyl, C 2 -to-alkenyl or C 2 -o-alkynyl as R 4 , in conjunction with any of the above or below embodiments. 25 In another embodiment, the compounds of Formula I include H as R 4 , in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include haloalkyl or C 1 0 alkyl as R 4 , in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include h as 0, 1, 2 or 3, in 30 conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include h as 1 or 2, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include i as 1, 2 or 3, in conjunction with any of the above or below embodiments.

WO 2007/061670 PCT/US2006/044058 - 15 In another embodiment, the compounds of Formula I include i as 1, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include j as 0, 1 or 2, in conjunction with any of the above or below embodiments. 5 In another embodiment, the compounds of Formula I include j as 0, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include as (R12) , (R 2)P R12()p R 2 1)2)P R 2 / 12 / 1 Z2 (R o X2 /(a) (R -), 10 wherein m, o, R', X', X 2 , Y', Y 2 and Y 3 are as defined hereinabove;

Z

2 taken together with the carbon atoms to which it is attached is a partially or fully unsaturated 5-8 membered monocyclic ring, said ring formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 15 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, provided that (a) no more than two of Y, Y 2 and Y 3 is 0, S or NR 1 and (b) when o is 0, then each of Y' and

Y

2 is CR(RR; and p is 0, 1, 2, 3, 4 or 5, in conjunction with any of the above or below embodiments. 20 In the immediately proceeding embodiment, the compounds of Formula I include

CR'

2

R

2 as X, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include CHR" as X in conjunction with any of the above or below embodiments.

WO 2007/061670 PCT/US2006/044058 - 16 In the immediately preceeding embodiment, the compounds of Formula I include C(=O) as X', in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include CH 2 as X1, in conjunction with any of the above or below embodiments. 5 In the preceeding embodiment, the compounds of Formula I include 0 as X', in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include S as X', in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include S(O) 2 as X1, 10 in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include NR1 2 as X1, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include NH as X 1 , in conjunction with any of the above or below embodiments. 15 In the preceeding embodiment, the compounds of Formula I include CR 2 R1 2 as each X 2 , independently, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include CHR1 2 as each X 2 , independently, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include CH 2 as each 20 X 2 , independently, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include CR1 2

R

12 as each of Yl, Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include CHR' 2 as 25 each of Y', Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include CH 2 as each of Y', Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments. 30 In the preceeding embodiment, the compounds of Formula I include 0 as any one or two of Y', Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments.

WO 2007/061670 PCT/US2006/044058 - 17 In the preceeding embodiment, the compounds of Formula I include S as any one or two of Y', Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include NR1 2 as any 5 one or two of Y', Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include 0 as Y 2 and

CH

2 as each of Y' and Y 3 , in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include S as Y 2 and 10 CH 2 as each of Y' and Y 3 , in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include NR1 2 as y2 and CH 2 as each of Y' and Y 3 , in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include an optionally 15 substituted benzene, pyridine, pyrimidine, triazine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene, thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole or isoxazole ring as Z 2 , in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include compounds 20 wherein R 5 is

(R

12 )p

A

3 / R12 A2 X A (x) Al

(R

1 2 )p wherein m is 0 or 1; o is I or 2; 25 pis 0, 1,2or3; A' is CH, C(=O), 0 or NR1 2 ; each of A' and A 2 , independently, is CR" or N, provided WO 2007/061670 PCT/US2006/044058 - 18 that no more than one of A' and A 2 is N;

X

2 is CH;

Y

3 is CR1 2 or 0; and each R", independently, is H, halo, haloalkyl, CN, OH, 5 NO 2 , NH 2 , acetyl, oxo, CI.,o-alkyl, C 2 -lo-alkenyl, C 2 ,o-alkynyl, C 3 -lo-cycloalkyl,

C

41 o-cycloalkenyl, C,..o-alkylamino-, C 1 ..o-dialkylamino-, C..o-alkoxyl, Cio-thioalkoxyl or a ring selected from phenyl, pyridyl, pyrimidinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, oxazolinyl, 10 isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein each of the.Cio-alkyl, C 2 -o-alkenyl, C 2 .,o-alkynyl, C 3 -o-cycloalkyl,

C

4 -o-cycloalkenyl, C,.,o-alkylamino-, C,..o-dialkylamino-, C. 10 -alkoxyl, CIao-thioalkoxyl and ring is optionally substituted independently with 1-5 substituents of halo, haloalkyl, 15 CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl,.butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopently, hexyl, cyclohexyl, Cl-,o alkylamino-, C,-lo-dialkylamino-, C1.o-thioalkoxyl, benzyl or phenyl, in conjunction with any of the above or below embodiments. 20 In another embodiment, the compounds of Formula I include as R

R

1 o R 1 R1o R 10 12 12RYR 11 R1

R

1 6

R

1 8

R

16

R

1 9

R

16 Ri 6 R11 R1 1 R 1 RI,

R

1 R RR R16 (A X XK X1 X2 X1 m2 X R/ Ri R, 2 R0 1

R

1 R or RIG

R

12 wherein X1 is C(=O), 0, S, S(O) 2 or NR12 WO 2007/061670 PCT/US2006/044058 - 19 each X 2 , independently, is CR'R; mis0,l or2; and each R' 6 , independently, is haloalkyl, methyl, methoxyl, ethyl, ethoxyl, alkoxy alkyl, alkylamino-alkyl, dialkylamino-alkyl, propyl, propoxyl, isopropyl, isopropoxyl, 5 cyclopropyl, butyl, isobutyl, sec-butyl or tert-butyl, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include as R 5 R11 R11 RRO 1 RRo 1 X1 2 ) X) X1 i X~X 3

SR

1 0

R

10

R

10 R 2 RR R11 R N 1 R12 N R1 (X , xx 2 X2)mJ 3)xX 2 3

XK

2

R

1 1 / R 1

R

1 2 NM/ 1 Y Y3 Y3 N/ R 1o Ro R o r re R12 R2R 2 R12o wherein XN is C(=0), , S, S(R) 2 or NRR; 10 each X 2 , independently, is CR 2

R'

2 ; each of Y', Y 2 and Y 3 , independently, is CR 12 R', 0, S or NE m is 0, 1 or 2; and ois , , 2,R3.,.4or5; WO 2007/061670 PCT/US2006/044058 - 20 provided that (a) no more than two of Y', Y 2 and Y 3 is 0, S or NR" 2 and (b) when o is 0, then each of Y' and Y 2 is CR1 2

R'

2 , in conjunction with any of the above or below embodiments. In another embodiment, the invention provides compounds of Formula I, wherein 5 h is 1 or 2; i is 1; jis0; A is C-alkyl, C 2 .6-alkenyl, R'-O-C-alkyl-, R'-S-C 1

.

6 alkyl, R'-S(0) 2

-C

1 ..-alkyl-, R'-NH-C 1 .6-alkyl-, R'-0-C 1

.

6 -alkenyl-, R'-S-C 2

-

6 -alkenyl-, Rl 10 S(0) 2

-C

2

.

6 -alkenyl-, R'-NH-C 2 -6-alkenyl-, R'-C 1 .-- alkyl-O-C 1 .-- alkyl-, R'-CI-6-alkyl-S-C.. 6 -alkyl-, RI-C 1

-

6 -alkyl-S(O) 2 -Cv- 6 -alkyl- or R I-C-alkyl-NH-Ci- 6 -alkyl-, wherein R' is phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, 15 isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl, 20 cyclohexyl or cycloheptyl, each of which is optionally substituted as defined in claim 1;

R

2 is an optionally substituted ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, 25 isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl and benzimidazolyl; each R3, independently, is H, haloalkyl, CN, C 110 -alkyl, C 2

-

1 -alkenyl or C 2 0 alkynyl; R( is H, CN or Ciio-alkyl; WO 2007/061670 PCT/US2006/044058 - 21 Rais R12 2 (R 1 2 )p R 12 (R12)p R 12

(R

1 2)p R12 (R12)p /)R (x X 1 X 2 X (X ) X 1 ) X 2

N'

1

(R

12 )p (R 12 )p

(R

12 )p Y 2

(R

12 ) 2 R12 z2 R12)pN' 1 2(1) (R2) N) ,or (R12) YX Y Y YY wherein m, o, R' 2 , X 2 , i 1

Y

2 and Y 3 are as defined in claim 1; 5 X' is C(=0), 0, S, S(O) 2 or NR 2 ;

Z

2 is an optionally substituted phenyl, pyridine, pyrimidine, triazine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene, thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole or isoxazole ring; and pis0, 1, 2,3,4or. 10 R 7 is H, C 1 .. o-alkyl or C 2 -2 0 -alkenyl, each of the C 11 o-alkyl, or C 2

.

10 -alkenyl optionally substituted with 1-3 substituents of R(';

R

8 is a ring system selected from phenyl, pyridyl, pyrimnidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinol inyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuiranyl, pyrrolyl, pyrazolyl, thieno 15 pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2 ,3-dihydroindolyl, isoindolyl, indazolyl, benzofuiranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperaziny1, pyranyl, 20 dioxozinyl, 2,3-dihydro- 1,4-benzoxazinyl, 1 ,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl and cycloheptyl, said ring system optionally substituted independently with 1-3 substituents of R 9 , oxo, NR 9

R

9 , OR 9 , SR 9 , C(O)R 9 or a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally WO 2007/061670 PCT/US2006/044058 - 22 including 1-3 heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of R9; R? is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, C 1 io-alkyl, C 2

-

10 -alkenyl, C 2 10 -alkynyl, C 3

.

7 -cycloalkyl, C 4

.

7 -cycloalkenyl, C 1

I

10 -alkylamino-, C.

1 0-dialkylamino-, C 1 . 5 10 -alkoxyl, C 1 .. 10-thioalkoxyl; and R1 2 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, CI-io-alkyl, C 2

-

1 0 -alkenyl, C 2 jo-alkynyl, C 3 ..o-cycloalkyl, C 4 .io-cycloalkenyl, C 1

..

1 -alkylamino-, Cl-.o-dialkylamino-, C 1 . 10 -alkoxyl, C 1 ..- thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms 10 optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the C 1 ..- alkyl, C 2 .- lo-alkenyl, C 2

-

1 0 alkynyl, C 3

.

10 -cycloalkyl, C 4

.

10 -cycloalkenyl, CI1io-alkylamino-, C 1 ..- dialkylamino-, C 1

.

1 0 alkoxyl, C 1

..

10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, 15 methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pentyl, cyclopently, hexyl, cyclohexyl, Cl.lo-alkylamino-, C 1

.

10 dialkylamino-, C 1 -.o-thioalkoxyl, benzyl or phenyl. In another embodiment, the invention provides compounds of Formula II, H OH R 4 W R5

R

3 V 20 R 2 II or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative or prodrug thereof, wherein A is CI.

6 -alkyl, C 2

-

6 -alkenyl, C 2

-

6 alkynyl, R'-CI- 6 -alkyl-, R'-C 2

-

6 -alkenyl- or R'-C 2 25 6 -alkynyl-, wherein 1, 2 or 3 carbon atoms of (1) said C-C 6 alkyl, C-C 6 alkenyl, C-C 6 alkynyl or (2) said CI.

6 -alkyl, C 2

-

6 alkenyl, C 2 .- alkynyl of R'-CI.-alkyl-, R'-C 2

-

6 -alkenyl- or R'-C2-6 alkynyl-, is optionally replaced with a heteroatom selected from 0, S, S(O), S(O) 2 and NH, and optionally substituted independently with 1-3 substituents of R; and WO 2007/061670 PCT/US2006/044058 - 23 R1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, 5 benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted 1-3 substituents 10 of oxo, R 8 , R?, NRR 7 , NR 7 R, OR 7 , SR 7 , OR, SR 8 , C(O)R 7 , OC(O)R 7 , COOR 7 , C(O)R, OC(O)R, COOR!, C(O)NRR, NR 7

C(O)R

7 , NR 7

C(O)NRR

7 ,

NR

7

(COOR

7 ), OC(O)NRR 7 , C(O)NRR, NR 7 C(O)R, NR 7

C(O)NR

7 R',

NR

7 (COOR), OC(O)NR 7 R, S(O) 2

NR

7

R

7 , NR 7

S(O)

2

NR

7

R

7 , NRIS(O) 2

R

7 ,

S(O)

2 R, S(O) 2

NR

7 R!, NR!S(O) 2

NR

7

R

8 or NR 7

S(O)

2

R

8 ; 15 W is -C(=O)-, -OC(=O)-, -NHC(=O)-, -S(=O)b- or -NHS(=O)b-, wherein b is 1 or 2; V is -(CR 2 aR 2 a)h-, -O-(CR 2 aR 2 a)-, -S-(CRaR2a)h- or -NR 2

"-(CR

2 aR 2 a)b-, wherein each R 2 a, independently, is H, C 1

-C

10 alkyl or haloalkyl, and h is 0, 1 or 2; R2 is a CI-Cloalkyl, C 1 Ciohaloalkyl, C-Cioalkenyl, CI-Co alkynyl or a partially 20 or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, wherein said ring system is optionally substituted independently with one or more substituents of oxo, R, R 8 , R, 25 NR 7 R, NR 7

R

8 , OR 7 , SR 7 , OR 8 , SR, C(O)R 7 , OC(O)R 7 , COOR7, C(O)R, OC(O)R, COOR", C(O)NR 7

R

7 , C(S)Nk 7

R

7 , NR 7 C(O)R, NR 7 C(S)R, NR 7

C(O)NRR

7 ,

NR

7

C(S)NR

7

R

7 , NR(COOR), OC(O)NR 7

R

7 , C(O)NR 7 R!, C(S)NRR", NR 7 C(O)R",

NR

7 C(S)R, NR 7

C(O)N

7

R

8 , NR 7

C(S)NR

7 R, NR 7 (COOR), OC(O)NR 7 R, S(0) 2

NR

7

R

7 ,

NR

7

S(O)

2

NR

7

R

7 , NR'S(O) 2

R

7 , S(0)2R(, S(0) 2

NRR

8 , NR 7

S(O)

2 NRR or NR 7 S(0) 2 R; 30 R 3 is H, haloalkyl, CN, Ci-.o-alkyl, C 2 io-alkenyl or C 2 -o-alkynyl; R4 is H, haloalkyl, CN, C 1 .. Io-alkyl, C 2 -lo-alkenyl, C 2 -o-alkynyl, C 3 -jo-cycloalkyl or

C

4 10 -cycloalkenyl, each of the Ci 10 -alkyl, C 2 -,o-alkenyl, C 2 -o-alkynyl, C 3 10 -cycloalkyl and C 410 -cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of R 8 or R9; WO 2007/061670 PCT/US2006/044058 - 24 R is

R

10

R

10 R1R Ri

R

12 R1 R11

R

12 R R1 x Xm(X)

R

16 X

R

16 MX1m

R

1 6 R 1 6 , R 16

R

1 B R 1

R

1 R1 R1 R 10

R

10 RIB

R

1 R R 1 R 1 R 1 6 R xl 7Mx1 X 2 1X;_j X X X m R 12

R

12 X m R16 0 1 1 / R 1 2 RiRI RX2

R

16 or R

R

12 wherein X 1 is C(=O), 0, S, S(0)2 or NR 2 ; each X 2 , independently, is CR1 2 R1 2 ; and 5 m is 0, l or 2; R' is H, C 1

.

1 0 -alkyl, C 2

-

1 0 -alkenyl, C 2

-

10 -alkynyl, C 3

.

1 o-cycloalkyl or C4.10 cycloalkenyl, each of the C 1 ..o-alkyl, C 2

-

1 0 -alkenyl, C 2

-

1 o-alkynyl, C 3 - o-cycloalkyl and C 4 1o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of NRR 9 , NR 9 R?, OR, SR, OR 9 , SR 9 , 10 C(O)R, OC(O)R, COOR, C(O)R 9 , OC(O)R 9 , COOR 9 , C(O)NRR 9 , C(O)NR 9

R

9 ,

NR

9 C(O)R, NR 9

C(O)R

9 , NR 9

C(O)NRR

9 , N 9

C(O)NR

9

R

9 , N 9

(COOR

8 ), NR(COOR),

OC(O)NRR

9 , OC(O)NR 9

R

9 , S(O) 2 R, S(O) 2

NRR

9 , S(O) 2

R

9 , S(O) 2

NRR

9 ,

NR

9

S(O)

2

NR

8

R

9 , NR 9

S(O)

2

NR

9

R

9 , NRS(O) 2

R

8 , NRS(O) 2

R

9 , R or R 9 ;

R

8 is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 15 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substituents of

R

9 , oxo, NR 9

R

9 , OR?; SR!, C(O)R 9 or a partially or fully saturated or unsaturated 5-6 WO 2007/061670 PCT/US2006/044058 - 25 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of R; R? is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, CI1io-alkyl, C 2 -1o-alkenyl, C 2 io-alkynyl, C 3 .io-cycloalkyl, C 4

.

10 -cycloalkenyl, Cl-io-alkylamino-, C 1 .- 1o-dialkylamino-, C. 5 10 -alkoxyl, C 1

.

0 o-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the C2.io-alkyl, C 2 -1o-alkenyl, C 2

-

1 0 alkynyl, C 3

.

1 0 -cycloalkyl, C 4

.

10 -cycloalkenyl, C 1 ..o-alkylamino-, C 1 ..o-dialkylamino-, C 1

.

40 10 alkoxyl, C1.io-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pently, cyclopently, hexyl, cyclohexyl, C1.io-alkylamino-, C .10 15 dialkylamino-, C1io-thioalkoxyl, benzyl or phenyl; R1 0 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, CI.io-alkyl, C 2 -io-alkenyl, C 2 . io-alkynyl, C 3

-

1 o-cycloalkyl, C 4

..

10 -cycloalkenyl, C 1 .o-alkylamino-, C1..io-dialkylamino-, C 1 . io-alkoxyl, C 1 .io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms 20 optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the C 1

.

1 0 -alkyl, C 2

-

10 -alkenyl, C 2

-

1 0 alkynyl, C 3

.

1 o-cycloalkyl, C 4 .io-cycloalkenyl, C 1 -alkylamino-, Ci..o-dialkylamino-, C 11

O

alkoxyl, C 1

.

1 o-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, 25 methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pently, cyclopently, hexyl, cyclohexyl, C 1 .o-alkylamino-, C 1

.

1 0 dialkylamino-, C..I 1 0 -thioalkoxyl, benzyl or phenyl; R" is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, CI.o-alkyl, C 2 -io-alkenyl, C2 30 o-alkynyl, C 3

-

1 0 -cycloalkyl, C 4

.

1 o-cycloalkenyl, C.

10 -alkylamino-, C 1 .io-dialkylamino-, C 1 . o-alkoxyl, Cl..o-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CI.Io-alkyl, C 2 -10-alkenyl, C 2

.-

1 0

-

WO 2007/061670 PCT/US2006/044058 - 26 alkynyl, C 3 -1 0 -cycloalkyl, C 4 .,o-cycloalkenyl, C..i 0 -alkylamino-, C,1o-dialkylamino-, C.

0 alkoxyl, C,1o-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, 5 cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pently, cyclopently, hexyl, cyclohexyl, C,..

0 -alkylamino-, Ci 0 dialkylamino-, Ci.o-thioalkoxyl, benzyl or phenyl; alternatively, R' 0 and R" taken together with the carbon atoms to which they are attached form a partially or fully saturated or unsaturated 5-6 membered ring of carbon 10 atoms optionally including 1-3 heteroatoms selected from 0, N, or S, and the ring optionally substituted independently with 1-5 substituents of R1 2 , R1 3 , R1 4 or R' 5 ; R1 2 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, oxo, CI 1 o-alkyl, C 2

-.

0 alkenyl, C 2 -1-alkynyl, C 3 -1-cycloalkyl, C 4 -o-cycloalkenyl, Ci-o-alkylamino-, C..1 0 dialkylamino-, Ci..o-alkoxyl, CI 1 -thioalkoxyl or a saturated or partially or fully 15 unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the Ci..o-alkyl, C 2 ..o-alkenyl, C 2 ..- alkynyl, C 3 ..o-cycloalkyl, C 4 ,o-cycloalkenyl, Ci-.o alkylanino-, CI-o-dialkylamino-, C,..o-alkoxyl, CI-o-thioalkoxyl and ring of said ring 20 system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pently, cyclopently, hexyl, cyclohexyl, C.1, 0 alkylamino-, CI-.o-dialkylamino-, Ci-.,o-thioalkoxyl, benzyl or phenyl; 25 R1 3 is NR 4

R

5 , NRsR 15 , OR 4 ; SR14, OR 5 ; SR 5 , C(O)R1 4 , OC(O)R 4 , COOR 4 , C(O)R", OC(O)R' 5 , COOR 5 , C(O)NR 4 R 5, C(O)NR1 5

R

5 , NR 4

C(O)R

14 , NR1 5 C(O)R1 4 , NR"C(O)R", NR' 5 C(O)R", NR 5

C(O)NRI

4

R'

5 , NR 5

C(O)NR

5

R'

5 , NR" (COOR1 4 ),

NR

5

(COOR'

5 ), OC(O)NR 4 R's, OC(O)NRisR 5 , S(O) 2

R

4 , S(O) 2 R", S(O) 2 NR1 4 R',

S(O)

2 NR1 5 R1 5 , NR 4

S(O)

2

NR'

4 R1 5 , NR' 5

S(O)

2 NR' 5

R'

5 , NR14S(O) 2 R1 4 or NR 15S(O) 2 R"; 30 R1 4 is a saturated or partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic,,or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and WO 2007/061670 PCT/US2006/044058 - 27 wherein said ring system is optionally substituted independently with 1-5 substituents of

R

1 5 ; R" is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, 5 cyclobutyl, C1io-alkylamino-, C 110 -dialkylamino-, C 1 io-thioalkoxyl, benzyl, phenyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of halo, 10 haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, tert-butyl, cyclobutyl, Ciio-alkylamino-, Ciro-dialkylamino-, C 1

.

1 0 thioalkoxyl, benzyl or phenyl; each R1 6 , independently, is haloalkyl, methyl, methoxyl, ethyl, ethoxyl, alkoxy 15 alkyl, alkylamino-alkyl, dialkylamino-alkyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, butyl, isobutyl, sec-butyl or tert-butyl; h is 0, 1 or 2; and i is 1, 2 or 3. In another embodiment, the compounds of Formula II include 0 as X 1 , in 20 conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula 11 include S as X 1 , in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula II include NR 2 as X', in conjunction with any of the above or below embodiments. 25 In another embodiment, the compounds of Formula I include methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl as R 16 , independently, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula 11 include each independent embodiment, as described herein for variables A, B, R', R'", Rlb, R'c, Rid, R2,R 3 , RW, R 5 , 30 R 6 , R 7 , R!, R?, R'", R", R 1 2 , R1 3 , R 4 , R 5 , W, V, Xi, X 2 , y', y 2 , y 3 , ZI and Z 2 for compounds of Formula I, independently, in conjunction with any of the above or below embodiments for compounds of Formula Il. In another embodiment, the compounds of Formula I or II include compounds wherein R is WO 2007/061670 PCT/US2006/044058 - 28 (R12)p _A3 / R12 |A ' A 2 X A1

R

1 6

R

1 r wherein m is 0 or 1; p is 0, 1, 2 or 3; 5 A' is CH, C(=O), 0 or NR12 each of A' and A 2 , independently, is CR1 2 or N, provided that no more than one of A' and A 2 is N;

X

2 is CH; y3 is CR1 2 or 0; and 10 each R', independently, is H, halo, haloalkyl, CN, OH,

NO

2 , NH 2 , acetyl, oxo,'C,. o-alkyl, C 2 ..lo-alkenyl, C 2 -io-alkynyl, C 3 -,o-cycloalkyl,

C

4 .1o-cycloalkenyl, C 1 1 0 -alkylamino-, C1.,o-dialkylamino-, C1.o-alkoxyl, C1io-thioalkoxyl or a ring selected from phenyl, pyridyl, pyrimidinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, 15 thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein each of the C1.o-alkyl, C 2 -- io-alkenyl, C 2 -o-alkynyl, C 3 -lo-cycloalkyl,

C

4 .o-cycloalkenyl, C1.1 0 -alkylamino-, C 1.o-dialkylamino-, C1-io-alkoxyl, C1..Io-thioalkoxyl 20 and ring is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopently, hexyl, cyclohexyl, C,., 0 alkylamino-, C1.io-dialkylamino-, C1..o-thioalkoxyl, benzyl or phenyl, in conjunction with 25 any of the above or below embodiments. In yet another embodiment, the invention provides compounds generally defined by Formula III, WO 2007/061670 PCT/US2006/044058 - 29 R 3

R

3 A W N N R5

R

3

R

3 B OH III or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative or prodrug thereof, wherein 5 A is C 1 10 -alkyl, C 2

-

10 -alkenyl, C 2

-

1 -alkynyl, R'-CI- 10 -alkyl-, R'-C 2

-

1 0 -alkenyl- or

R'-C

2

.

10 -alkynyl-, wherein 1, 2 or 3 carbon atoms of (1) said C 1 -Co alkyl, C-Co alkenyl, C 1 -Co alkynyl or (2) said Cli-o-alkyl, C 2 -io-alkenyl, C 2 -io-alkynyl of R'-Cli-o-alkyl-, R'

C

2 .-o-alkenyl- or R'-C 2

-

10 -alkynyl-, is optionally replaced with a heteroatom 10 selected from 0, S, S(O), S(O) 2 and NH, and optionally substituted independently with one or more substituents of R?; and R' is a fully saturated or a partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms and optionally including 1-3 15 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, wherein said ring system is substituted independently with one or more substituents of oxo, R 7 , Re, R 9 ,

NR

7

R

7 , NRR 8 , OR 7 , SR, OR, SR, C(O)R 7 , OC(O)R 7 , COOR 7 , C(O)R, OC(O)R, COOR, C(O)NRR, C(S)NRR, NR 7

C(O)R

7 , NR 7

C(S)R

7 , 20 NR 7

C(O)NR

7

R

7 , NR 7

C(S)NR

7

R

7 , NR 7 (COOR), OC(O)NRR 7 , C(O)NR 7 R!, C(S)NRR, NR 7 C(O)R, NRZC(S)R, NRC(O)NRR 8 , NR 7

C(S)NR

7 R!, NR(COOR), OC(O)NRR 8 , S(O) 2

NR

7

R

7 , NR 7

S(O)

2

NR

7

R

7 , NRS(O) 2 R,

S(O)

2 R, S(O) 2

NRR

8 , NR 7

S(O)

2

NR

7 R! or NR 7

S(O)

2

R

8 ; W is -C(=O)-, -OC(=O)-, -NHC(=O)-, -S(=O)b- or -NHS(=O)b-, wherein b is 1 25 or 2; B is R 2

-(CR

2 aR 2 a)-, R 2

O-(CR

2 aR 2 a, R 2

-S-(CR

2 aR 2 a)h- or R 2

-NR

2 a-(CR 2

"R

2 a)h, wherein R2 is C-Co alkyl, C-Co haloalkyl, C-Co alkenyl, C-Co alkynyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 30 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system WO 2007/061670 PCT/US2006/044058 - 30 formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, wherein said C 1

-C

10 alkyl, CI-CIo alkenyl, CI-Cio alkynyl is optionally substituted independently with one or more substituents of R 9 , and said 5 ring system is optionally substituted independently with one or more substituents of oxo, R 7 , R 8 , R?, NR 7

R

7 , NR 7 R, OR 7 , SR 7 , OR!, SR", C(O)R 7 , OC(O)R 7 ,

COOR

7 , C(O)R, OC(O)R, COOR, C(O)NR 7

R

7 , C(S)NR 7

R

7 , NR 7

C(O)R

7 ,

NR

7 C(S)R , NR 7

C(O)NR

7

R

7 , NRC(S)NR 7

R

7 , NR 7

(COOR

7 ), OC(O)NR 7 R7,

C(O)NR

7 R!, C(S)NRR , NRC(O)R, NR 7 C(S)R, NR 7 C(O)NRR, 10 NR 7

C(S)NRR

8 , NR 7 (COOR), OC(O)NR 7 R, S(O) 2

NR

7

R

7 , N 7

S(O)

2

NR

7

R

7 ,

NRS(O)

2

R

7 , S(O) 2 R, S(O) 2

NR

7 R', NR 7

S(O)

2

NR

7 R or NR!S(O) 2 R; each R 2 a, independently, is H, OH, NO 2 , CN, NH 2 , CI-Cio alkyl, CI-Cio alkoxyl or haloalkyl; and b is 0, 1, 2 or 3; 15 i is 1, 2 or 3; j is0, 1 or 2; each R, independently, is H, haloalkyl, CN, C 1 Io-alkyl, C 2 -o-alkenyl, C 2

..

1 0 alkynyl, C 3

.

1 0 -cycloalkyl or C 4

.

1 o-cycloalkenyl, each of the C 1 .o-alkyl, C 2

-

1 o-alkenyl, C 2

-

1 0 alkynyl, C 3 10 -cycloalkyl and C 41 o-cycloalkenyl optionally comprising 1-4 heteroatoms 20 selected from N, 0 and S and optionally substituted with 1-5 substituents of R 8 or R1;

R

4 is H, haloalkyl, CN, C 1 .Io-alkyl, C 2 ..o-alkenyl, C 2 -o-alkynyl, C 3 .o-cycloalkyl or C4 10 -cycloalkenyl, each of the CI 10 -alkyl, C 2 -o-alkenyl, C 2

..

1 0 -alkynyl, C 3

.

10 -cycloalkyl and C 4 -.o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of R 8 or R9; WO 2007/061670 PCT/US2006/044058 - 31 Ris R R 1 0 RI R 10

R

1 a R 16

R

1 s R 1 1 R 1 R

R

1 0

R

10 R1 1 RRo I R RD 1 / R16 R 1 R1x Ri R R1 m1 X X R1 R12 10 R1

R

12 m 1 RD R 10 R111 R Y2 2

R

1 0

R

10 R 1 0

R

10

R

12 R11 j R 1 R 1 R 12 N 1 1 1 N R1 I II

X

2 X2)M (X 2 )XJ 0 XY3, X m X Yl Y Y2

R

1

R

12

R

10

R

2 ) (%X 2

Y

2 , R2 Y, y 0 l 2~~ Y 3 )O

Y

2

R

2

R

2 or Ri RioRioRI WO 2007/061670 PCT/US2006/044058 - 32 wherein X1 is C(=O), 0, S, S(O) 2 or NR1; each X 2 , independently, is CRR ; each of Y', Y 2 and Y 3 , independently, is CR"1R 2 , 0, S or NR 2 ; m is 0, 1 or 2; and 5 o is 0, 1, 2,3,4 or 5; provided that (a) no more than two of Y', Y 2 and Y 3 is 0, S or NR 12 and (b) when o is 0, then each of Y' and Y 2 is CR'R; R! is H, CI-.o-alkyl, C 2

-

1 -alkenyl, C 2 1 o-alkynyl, C 3 1 0o-cycloalkyl or C 4 10 cycloalkenyl, each of the CIiao-alkyl, C 2 10 -alkenyl, C 2 ..o-alkynyl, C 3 10 -cycloalkyl and C 4 . 10 10 -cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of NR 8

R

9 , NR 9 R?, OR 8 , SR, OR 9 , SR 9 , C(O)R, OC(O)R", COOR, C(O)R, OC(O)R 9 , COOR 9 , C(O)NR 8 R?, C(O)NR 9

R

9 ,

NR

9 C(O)R, NR 9

C(O)R

9 , NR 9

C(O)NRR

9 , NR 9

C(O)NR

9

R

9 , NR?(COOR 8 ), NR 9

(COOR

9 ),

OC(O)NRR

9 , OC(O)NR 9 , S(O)21e, S(O) 2 NReR 9 , S(O) 2

R

9 , S(O) 2

NR

9

R

9 , 15 NRS(O) 2

NRR

9 , NRS(O) 2

NR

9

R

9 , NRS(O) 2 R, NRS(O) 2

R

9 , R or R ;

R

8 is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and 20 wherein said ring system is optionally substituted independently with 1-5 substituents of

R

9 , oxo, NR 9

R

9 , OR 9 ; SR!, C(O)R 9 or a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of R?; RW is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, Ci 10 -alkyl, C 2 -1-alkenyl, C 2 25 10 -alkynyl, C 31 o-cycloalkyl, C 41 0 -cycloalkenyl, C 11 o-alkylamino-, C 1 .oo-dialkylamino-, C 1 . 1o-alkoxyl, C 1 oo-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CIoo-alkyl, C 2 -1-alkenyl, C 2

-

0 30 alkynyl, C 3 10 -cycloalkyl, C 4

-

1 o-cycloalkenyl, C 1 .o-alkylamino-, C jo-dialkylamino-, C.

1 o alkoxyl, C 10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert- WO 2007/061670 PCT/US2006/044058 - 33 butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C 1 io.

1 -alkylamino-, CIt o dialkylamino-, Cli-o-thioalkoxyl, benzyl or phenyl;

R

1 0 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, CI-ro-alkyl, C 2 -o-alkenyl, C 2 to-alkynyl, C 3 10 -cycloalkyl, C 41 o-cycloalkenyl, C.

10 -alkylamino-, C 110 -dialkylamino-, Cj. 5 1 0 -alkoxyl, Ci-.o-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the C 1

I

1 0 -alkyl, C 220 -alkenyl, C 2 10 alkynyl, C 3 10 -cycloalkyl, C 4 10 -cycloalkenyl, Cl-.o-alkylamino-, CI 1 0 -dialkylamino-, CI 1 0 10 alkoxyl, C 1 ..o-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C 11 o-alkylamino-, Co 10 15 dialkylamino-, C io-thioalkoxyl, benzyl or phenyl; R" is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, CI 10 -alkyl, C 2 10 -alkenyl, C 2 lo-alkynyl, C 3 .o-cycloalkyl, C 4

.

10 -cycloalkenyl, CI 10 -alkylamino-, C 1 1 0 -dialkylamino-, C. io-alkoxyl, C,.

1 o-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms 20 optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CIolo-alkyl, C 2

-

10 -alkenyl, C 2 10 alkynyl, C 3 1 -cycloalkyl, C 4

.

0 -cycloalkenyl, C 1

.

1 -alkylamino-, CI.

10 -dialkylamino-, Co 1 0 alkoxyl, Cp-o-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, 25 methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, Ci-o-alkylamino-, CI.

10 dialkylamino-, C 1 o-thioalkoxyl, benzyl or phenyl; alternatively, R1 0 and R 1 taken together with the carbon or nitrogen atoms to 30 which they are attached form a partially or fully saturated or unsaturated 5-6 membered second ring of carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S, the second ring optionally substituted independently with 1-5 substituents of R", R1 3 , R14 or R1 5 and optionally fused to a 4-7 membered third ring, the third ring formed of WO 2007/061670 PCT/US2006/044058 - 34 carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of R12, R 3 , R1 4 or R1 5 ; R1 2 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, CI.l 0 -alkyl, C 2

-

10 -alkenyl, C 2 ,o-alkynyl, C 3 ..o-cycloalkyl, C 4 ..io-cycloalkenyl, C,.io-alkylamino-, Co 10 -dialkylamino-, CI 5 10-alkoxyl, CI-1o-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CI-o-alkyl, C 2 ,o-alkenyl, C 2 -o alkynyl, C 3 .. 10-cycloalkyl, C 4 -10-cycloalkenyl, Ci-o-alkylamino-, Ci 10 -dialkylamino-, Ci 0 10 alkoxyl, C,.lo-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, CIo-alkylamino-, C- 1 .o 15 dialkylamino-, Cl-ro-thioalkoxyl, benzyl, phenyl or R4;

R

3 is NR 4 R1 5 , NR1 5 R1 5 , OR 4 ; SR14, OR"; SR', C(O)R 4 , OC(O)R 4 , COOR 4 ,

C(O)R'

5 , OC(O)R' 5 , COOR 5 , C(O)NR 4

R'

5 , C(O)NR' 5 Ri s, NR1 4 C(O)R1 4 , N Ri 5

C(O)RI

4 ,

NR"

4 C(O)R1 5 , IR 5

C(O)R

5 , NR 5

C(O)NR

4 R", NR 5

C(O)NR

5

R'

5 , NR15(COORM), NR1 5 (COOR' ), OC(O)NR 4

R'

5 , OC(O)NR 5 Rs, S(O) 2

R

4 , S(O) 2

R

5 , S(O) 2

NR"'R

5 , 20 S(O) 2 NRR1 5 , NR 4

S(O)

2 NR1 4

R

5 , NR1 5

S(O)

2 NRi 5

R

5 , NR 4

S(O)

2 R1 4 or NR! 5

S(O)

2 R 5; R1 4 is a saturated or partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and 25 wherein said ring system is optionally substituted independently with 1-5 substituents of

R

5 ; and R's is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert 30 butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, CaIo alkylamino-, Cl-ro-dialkylamino-, C,..o-thioalkoxyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, and optionally WO 2007/061670 PCT/US2006/044058 -35/1 substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl. 5 In another embodiment, the compounds of Formula Ill include each independent la lb I d embodiment, as described herein for variables R', R , R , R', R'd, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R8, R9, R1, R", R", R1, R'4, R, B, W, V, XI, X 2 , yI, y2 y 3 , Z' and Z 2 for compounds of Formula I, independently, in conjunction with any of the above or below embodiments for compounds of Formula Ill. 10 In another embodiment, the invention provides each of the Examplary compounds, and stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, and related intermediates, described herein. In another embodiment, the invention a compound of Formula 1: H OH R4 A N N R W 15 B R 3

R

3 or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt, thereof, wherein A is C 1

.

6 -alkyl, C .

6 alkenyl, C.s-alkynyl. C 1

.

6 alkyl-O-C 1

.

3 -alkyl CQo--alkyl-S-CI--alkyl-,C-ky-(z- -ak-,C-ky-HC-lydiC 20 alkyl)-N-C 1

.

3 -alkyl, Cq. -alkenyl-O-C 1

.

3 -alkyl-, C .6-alkenyl-S-C 1

.

3 -alkyl-, C .6-alkenyl S(O)a-C 1 3 -alkyl-, C?-alkenyl-NH-C 3 -alkyl- or C2-alkynyl-NH-C.

3 -alkyl-, wherein the alkyl, alkenyl or alkynyl moiety of each is optionally substituted with 1-5 substituents of

R

9 W is -C(=0)-; 25 B is R 2

-(CR

2 a R 2 a), wherein

R

2 is CI-Clo alkyl, CI-Co haloalkyl, C 2

-C

1 o alkenyl, C 2

-C

1 o alkynyl, or a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 30 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, wherein said CI-Cro alkyl, C 2

-C

1 o alkenyl, C 2

-C

1 o alkynyl, is WO 2007/061670 PCT/US2006/044058 -35/2 optionally substituted independently with one or more substituents of R 9 , and said ring system is optionally substituted independently with one or more substituents of oxo, R7, R 8 , R 9 , NR'R, NR 7 R', OR', SR', OR', SR', C(O)R 7 , OC(O)R 7 ,

COOR

7 , C(O)R', OC(O)R, COOR, C(O)NR'R, C(S)NR 7

R

7 , NR 7 C(O)R, 5 NR 7 C(S)R', NR 7

C(O)NR

7

R

7 , NR 7

C(S)NR

7 R, N R 7

(COOR

7 ), OC(O)NR 7 R 7 , C(O)NR'R', C(S)N R 7 R , NR 7 C(O)R , NR 7 C(S)R', N R 7

C(O)NR

7 R',

NR

7

C(S)NR

7

R

8 , NR 7

(COOR

8 ), OC(O)NR 7 R', S(O) 2

NR

7

R

7 , NR'S(O) 2

NR

7

R

7 ,

NR

7

S(O)

2

R

7 , S(O) 2 R', S(O) 2 NR7R, NR 7

S(O)

2

NR

7 R' or NR 7

S(O)

2

R

8 ; each R2a, independently, is H, OH, NO 2 , CN, NH 2 , CI-Clo alkyl, CI-Co 10 alkoxyl or haloalkyl; and h is 1,; i is 1; j is 0; each R 3 , independently, is H, haloalkyl, CN, CI.o-alkyl, C 2 -.o-alkenyl, C 2 -1 0 15 alkynyl, C 3

.

10 -cycloalkyl or C 4 .io-cycloalkenyl, each of the C 1 .o-alkyl, C 2

-

1 o-alkenyl, C 2 .10 alkynyl, C 3 .,o-cycloalkyl and C 4 .io-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of R 8 or R 9 ; R4 is H, haloalkyl, CN, CI.o-alkyl, C 2 .o-alkenyl, C 2 -io-alkynyl, C 3 .,o-cycloalkyl or

C

4

.

1 o-cycloalkenyl, each of the C,.io-alkyl, C 2 .o-alkenyl, C 2 -io-alkynyl, C 3 .io-cycloalkyl 20 and C 4

.

1 o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of R 8 or R 9 ;

R

5 is R2 Z (R12)P R12 Z (R12)p 12 z 2 z x ) 1 X 2 X

(R

12 )p Y 2 or (R 1 2 )P Y 2 25 wherein X' is CR 2 , C(=0), 0, S, S(0) 2 , or NR 2 ; each X 2 , independently, is CR1 2 R1 2 ; each of Y', Y 2 and Y 3 , independently, is CR 2 R", 0, S or NR 12; WO 2007/061670 PCT/US2006/044058 -35/3

Z

2 taken together with the carbon atoms to which it is attached is a partially or fully unsaturated 5-8 membered monocyclic ring, said ring formed of carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S, provided that (a) no more than two of Y', Y 2 and Y 3 is 0, S or NR1 2 and (b) when o is 0, then each of Y' and Y 2 is 5 CR 2

R

12 ; and m is 0, 1 or 2; and o is 0, 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; provided that (a) no more than two of Y1, Y 2 and Y 3 is 0, S or NR1 2 and (b) when 10 o is 0, then each of Y' and Y 2 is CR 2 R1; each R 7 , independently, is H, CI.o-alkyl, C 2

.

10 -alkenyl, C 2

-

10 -alkynyl, C 3

.

1 0 cycloalkyl or C 4

.

10 -cycloalkenyl, each of the C,- 1 o-alkyl, C 2

-

1 0 -alkenyl, C 2

.

1 -alkynyl, C 3

.

1 0 cycloalkyl and C 4

.

10 -cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-5 substituents of NR R', NR R', OR', SR', 15 OR 9 , SR 9 , C(O)R', OC(O)R', COOR', C(O)R 9 , OC(O)R 9 , COOR 9 , C(O)NRR 9 ,

C(O)NR

9

R

9 , NR 9 C(O)R', NR 9

C(O)R

9 , NR 9

C(O)NRR

9 , NR 9

C(O)NR

9

R

9 , NR 9 (COOR'),

NR

9 (COOR'), OC(O)NR R9, OC(O)NR9R', S(O) 2 R', S(O) 2

NRR

9 , S(O) 2

R

9 , S(O) 2 NR9R9,

NR

9

S(O)

2

NRR

9 , NR 9 S(0) 2 NR9R , NR'S(O) 2 R', NR 9

S(O)

2

R

9 , R' or R9; each R 8 , independently, is a partially or fully saturated or unsaturated 3-8 20 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substituents of R9, oxo, NR 9

R

9 , OR 9 ; SR 9 , C(O)R 9 or a partially or 25 fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1 3 heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of R 9 ; each R 9 ' independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, C.o 10 alkyl, C 2

-

10 -alkenyl, C 2

-

1 0 -alkynyl, C 3

.

10 -cycloalkyl, C 4

.

10 -cycloalkenyl, C,.,o-alkylamino-, 30 C.

10 -dialkylamino-, C 1 -alkoxyl, C 1 io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the

C

1

.

10 -alkyl, C 2 -.o-alkenyl, C 2

.

1 o-alkynyl, C 3

.

1 o-cycloalkyl, C 4 .o-cycloalkenyl, CI.

1 0

-

WO 2007/061670 PCT/US2006/044058 -35/4 alkylamino-, CI- 1 o-dialkylamino-, C 1 i 10 -alkoxyl, CI- 1 o-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, 5 isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C 1

.

1 o alkylamino-, C 1 .io-dialkylamino-, CI.

10 -thioalkoxyl, benzyl or phenyl; each R' 2 independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, oxo, Ci.o-alkyl, C 2 .lo-alkenyl, C 2 .io-alkynyl, C 3 .o-cycloalkyl, C 4

.

1 0 -cycloalkenyl, CIo 10 alkylamino-, CI 10 -dialkylamino-, CI.

10 -alkoxyl, C 1 .- thioalkoxyl or a saturated or 10 partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CI 1 0 -alkyl, C 2

.

1 0 -alkenyl, C 2 -io-alkynyl, C 3

.

1 o-cycloalkyl, C 4

.

1 0 cycloalkenyl, CI.

10 -alkylamino-, C 1 o-dialkylamino-, CI.

10 -alkoxyl, C- 1 1 o-thioalkoxyl and 15 ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C 1

.

0 o-alkylamino-, C 1

.

1 -dialkylamino-, C1.io-thioalkoxyl, benzyl, 20 phenyl or R'4;

R

14 is a saturated or partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and 25 wherein said ring system is optionally substituted independently with 1-5 substituents of R"; and

R

5 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert 30 butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, CI-jo alkylamino-, C 1

.

1 -dialkylamino-, CI 10 -thioalkoxyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, and optionally WO 2007/061670 PCTIUS2006/044058 -35/5 substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl. 5 In another embodiment of the invention there is provided a method of making a compound according to the invention, the method comprising the step of reacting a compound 20 OH

R

4

H

2 N N B

R

3

R

3 20 10 ,wherein i, j, B, R 3 , R 4 and R' are as defined in claim 1, with a compound having the structure R 1 -W-X, wherein R' and W are as defined in claim I and X is a leaving group, to make a compound according to the invention. 15 DEFINITIONS The following definitions should assist in understanding the invention described herein. The term "comprising" is meant to be open ended, including the indicated component(s), but not excluding other elements. 20 The term "H" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical. The term "Cpalkyl", when used either alone or within other terms such as "haloalkyl" and "alkylamino", embraces linear or branched radicals having a to p number of carbon atoms (such as CI-C 10 ). One or more carbon atoms of the "alkyl" radical may be 25 substituted, such as with a cycloalkyl moeity. Examples of "alkyl" radicals include methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, ethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, n-propyl, isopropyl, n-butyl, cyclopropylbutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The term "alkylenyl" embraces bridging divalent alkyl radicals such as methylenyl and 30 ethylenyl.

WO 2007/061670 PCT/US2006/044058 - 36 The term "alkenyl", when used alone or in combination, embraces linear or branched radicals having at least one carbon-carbon double bond in a moiety having between two and ten carbon atoms. Included within alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms and, for example, those radicals having two 5 to about four carbon atoms. Examples of alkenyl radicals include, without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations, as appreciated by those of ordinary skill in the art. The term "alkynyl", when used alone or in combination, denotes linear or 10 branched radicals having at least one carbon-carbon triple bond and having two to ten carbon atoms. Examples of alkynyl radicals include "lower alkynyl" radicals having two to about six carbon atoms and, for example, lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include, without limitation, ethynyl, propynyl (propargyl), butynyl, and the like. 15 The term "Capalkoxyl" when used alone or in combination, embraces linear or branched oxygen-containing alkyl radicals each having c to P number of carbon atoms (such as C 1

-C

10 ). The terms "alkoxy" and "alkoxyl", when used alone or in combination, embraces linear or branched oxygen-containing radicals each having alkyl and substituted alkyl portions of one or more carbon atoms. Examples of such radicals include methoxy, 20 ethoxy, propoxy, butoxy and tert-butoxy. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals or with other substitution. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, fluoropropoxy and cyclopropylmethoxy. 25 The term "aryl", when used alone or in combination, means a carbocyclic aromatic moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner. Every ring of an "aryl" multi-ring system need not be aromatic, and the ring(s) fused to the aromatic ring may be partially or fully unsaturated and include one or more heteroatoms selected from nitrogen, oxygen and 30 sulfur. Thus, the term "aryl" embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl, benzodioxazinyl, and the like. The "aryl" group may be substituted, such as with 1 to 5 substituents including lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower WO 2007/061670 PCT/US2006/044058 - 37 alkylamino, and the like. Phenyl substituted with -O-CH 2 -0- or -O-CH 2

-CH

2 -O- forms an aryl benzodioxolyl substituent. The term "carbocyclic", also referred to herein as "cycloalkyl", when used alone or in combination, means a partially or fully saturated ring moiety containing one 5 ("monocyclic"), two ("bicyclic") or even three ("tricyclic") rings wherein such rings may be attached together in a fused manner and formed from carbon atoms. Examples of saturated carbocyclic radicals include saturated 3 to 6-membered monocyclic groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane. The terms "ring" and "ring system" refer to a ring comprising the delineated 10 number of atoms, the atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur. Where the number of atoms is not delineated, such as a "monocyclic ring system" or a "bicyclic ring system", the numbers of atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring. The ring itself, as well as any substitutents thereon, may be attached at any atom that allows a stable compound to be formed. The 15 term "nonaromatic" ring or ring system refers to the fact that at least one, but not necessarily all, rings in a bicyclic or tricyclic ring system is nonaromatic. The term "cycloalkenyl", when used alone or in combination, means a partially or fully saturated cycloalkyl containing one, two or even three rings in a structure having at least one carbon-carbon double bond in the structure. Examples of cycloalkenyl groups 20 include C 3

-C

6 rings, such as compounds including, without limitation, cyclopropene, cyclobutene, cyclopentene and cyclohexene. The term also includes carbocyclic groups having two or more carbon-carbon double bonds such as "cycloalkyldienyl" compounds. Examples of cycloalkyldienyl groups include, without limitation, cyclopentadiene and cycloheptadiene. 25 The term "halo", when used alone or in combination, means halogens such as fluorine, chlorine, bromine or iodine atoms. The term "haloalkyl", when used alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. For example, this term includes monohaloalkyl, dihaloalkyl and polyhaloalkyl 30 radicals such as a perhaloalkyl. A monohaloalkyl radical, for example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, WO 2007/061670 PCT/US2006/044058 - 38 heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl", as used herein, refers to alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl. 5 The term "heteroaryl", as used herein, either alone or in combination, means a fully unsaturated (aromatic) ring moiety formed from carbon atoms and having one or more heteroatoms selected from nitrogen, oxygen and sulfur. The ring moiety or ring system may contain one ("monocyclic"), two ("bicyclic") or even three ("tricyclic") rings wherein such rings are attached together in a fused manner. Every ring of a "heteroaryl" 10 ring system need not be aromatic, and the ring(s) fused thereto (to the heteroaromatic ring) may be partially or fully saturated and optionally include one or more heteroatoms selected from nitrogen, oxygen and sulfur. The term "heteroaryl" does not include rings having ring members of -O-O-, -O-S- or -S-S-. Examples of unsaturated heteroaryl radicals, include unsaturated 5- to 6 15 membered heteromonocyclyl groups containing I to 4 nitrogen atoms, including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, I H-1,2,3-triazolyl, 2H-1,2,3 triazolyl] and tetrazole; unsaturated 7- to 10- membered heterobicyclyl groups containing 1 to 4 nitrogen atoms, including for example, quinolinyl, isoquinolinyl, quinazolinyl, 20 isoquinazolinyl, aza-quinazolinyl, and the like; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3 furyl, benzofuryl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated 5- to 6 membered heteromonocyclic group containing I to 2 oxygen atoms and 1 to 3 nitrogen 25 atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing I to 2 sulfur atoms and I to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. The term "heterocyclic", when used alone or in combination, means a partially or 30 fully saturated ring moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner, formed from carbon atoms and including one or more heteroatoms selected from N, 0 or S. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 WO 2007/061670 PCT/US2006/044058 - 39 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing I to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, 5 dihydrofuryl and dihydrothiazolyl. The term "heterocycle" also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5 10 b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing I to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing I to 2 oxygen or sulfur atoms [e.g. benzofuryl, 15 benzothienyl, 2,3-dihydro-benzo[l,4]dioxinyl and dihydrobenzofuryl]. Examples of heterocyclic radicals include five to ten membered fused or unfused radicals. Examples of partially saturated and fully saturated heterocyclyls include, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro 20 benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4 tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro- IH-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4 triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3 dihydro-IH-l'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and 25 dihydrothiazolyl, and the like. The term "alkylamino" includes "N alkylamino" where amino radicals are independently substituted with one alkyl radical. Preferred alkylamino radicals are "lower alkylamino" radicals having one to six carbon atoms. Even more preferred are lower alkylamino radicals having one to three carbon 30 atoms. Examples of such lower alkylamino radicals include N-methylamino, and N ethylamino, N-propylamino, N-isopropylamino and the like. The term "dialkylamino" includes "N, N dialkylamino" where amino radicals are independently substituted with two alkyl radicals. Preferred alkylamino radicals are "lower alkylamino" radicals having one to six carbon WO 2007/061670 PCT/US2006/044058 - 40 atoms. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Examples of such lower alkylamino radicals include NN-dimethylamino, NN diethylamino, and the like. The terms "carboxy" or "carboxyl", whether used alone or with other terms, such 5 as "carboxyalkyl", denotes -CO 2 H. The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -(C=O)-. "Carbonyl" is also used herein synonymously with the term "oxo". The term "aminocarbonyl" denotes an amide group of the formula -C(=O)NH 2 . 10 The term "alkylthio" or "thioalkoxy" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of "alkylthio" or "thioalkoxy" is methylthio,(CH 3 S-). The term "haloalkylthio" embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of "haloalkylthio" is 15 trifluoromethylthio. The term "alkylaminoalkyl" embraces alkyl radicals substituted with alkylamino radicals. Examples of alkylaminoalkyl radicals include "lower alkylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N-methylaminomethyl, NN-dimethyl-aminoethyl, 20 NN-diethylaminomethyl and the like. The term "alkylaminoalkoxy" embraces alkoxy radicals substituted with alkylamino radicals. Examples of alkylaminoalkoxy radicals include "lower alkylaminoalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N 25 methylaminoethoxy, NN-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like. The term "Formula I" includes any sub formulas, such as Formula II. Similarly, the term "Formula II" includes any sub formulas and "Formula III' includes any sub formulas. The term "pharmaceutically-acceptable" when used with reference to a 30 compound of Formulas I-III is intended to refer to a form of the compound that is safe for administration. For example, a salt form, a solvate, a hydrate or derivative form of a compound of Formula I, II or of Formula III, which has been approved for mammalian use, via oral ingestion or other routes of administration, by a governing body or WO 2007/061670 PCT/US2006/044058 - 41 regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable. Included in the compounds of Formulas I-III are the pharmaceutically acceptable salt forms of the free-base compounds. The term "pharmaceutically-acceptable salts" 5 embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. As appreciated by those of ordinary skill in the art, salts may be formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. 10 Suitable pharmaceutically acceptable acid addition salts of compounds of Formulas I-III may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic 15 classes of organic acids, examples of which include, without limitation, formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, 20 toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic, thiocyanic, undecanoic, stearic, algenic, p-hydroxybutyric, salicylic, galactaric and 25 galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formulas I, II and III include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including, without limitation, primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl 30 piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, disopropylethylamine and trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formulas I-III.

WO 2007/061670 PCT/US2006/044058 - 42 Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl 5 halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids that may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, citric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, 10 stearic and, salicylic acid, pamoic acid, gluconic acid, ethanesulfonic acid, methanesulfonic acid, toluenesulfonic acid, tartaric acid, fumaric acid, medronic acid, napsylic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium, or with organic bases. 15 Additional examples of such salts can be found in Berge et al., J. Pharm. Sci., 66:1 (1977). Conventional methods may be used to form the salts. For example, a phosphate salt of a compound of the invention may be made by combining the desired compound free base in a desired solvent, or combination of solvents, with phosphoric acid in a desired stoichiometric amount, at a desired temperature, typically under heat 20 (depending upon the boiling point of the solvent). The salt can be precipitated upon cooling (slow or fast) and may crystallize (i.e., if crystalline in nature), as appreciated by those of ordinary skill in the art. Further, hemi-, mono-, di, tri- and poly-salt forms of the compounds of the present invention are also contemplated herein. Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of the compounds, salts and derivatives thereof, 25 are also contemplated herein. The term "derivative" is broadly construed herein, and intended to encompass any salt of a compound of this invention, any ester of a compound of this invention, or any other compound, which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, 30 characterized by the ability to the ability to modulate an enzyme. The term "pharmaceutically-acceptable derivative" as used herein, denotes a derivative which is pharmaceutically acceptable. The term "prodrug", as used herein, denotes a compound which upon administration to a subject or patient is capable of providing (directly or indirectly) a WO 2007/061670 PCT/US2006/044058 - 43 compound of this invention. Examples of prodrugs would include esterified or hydroxylated compounds where the ester or hydroxyl groups would cleave in vivo, such as in the gut, to produce a compound according to Formula 1-111. A "pharmaceutically acceptable prodrug" as used herein, denotes a prodrug which is pharmaceutically 5 acceptable. Pharmaceutically acceptable modifications to the compounds of Formula I-1II are readily appreciated by those of ordinary skill in the art. The compound(s) of Formulas I-III may be used to treat a subject by administering the compound(s) as a pharmaceutical composition. To this end, the compound(s) can be combined with one or more carriers, diluents or adjuvants to form a 10 suitable composition, which is described in more detail herein. The term "carrier", as used herein, denotes any pharmaceutically acceptable additive, excipient, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration purposes. "Diluent" and "adjuvant" are defined hereinafter. 15 The terms "treat", "treating," "treatment," and "therapy" as used herein refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy. Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals. 20 The phrase "effective dosage amount" is intended to quantify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. Accordingly, this term is not limited to a single dose, but may comprise multiple dosages required to bring about a therapeutic or 25 prophylactic response in the subject. For example, "effective dosage amount" is not limited to a single capsule or tablet, but may include more than one capsule or tablet, which is the dose prescribed by a qualified physician or medical care giver to the subject. The term "leaving group" (also denoted as "LG") generally refers to groups that are displaceable by a nucleophile. Such leaving groups are known in the art. Examples of 30 leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH 3 ), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like. Nucleophiles are species that are capable of attacking a molecule at the point of attachment of the leaving group causing displacement of the leaving group. Nucleophiles are known in the art. Examples of nucleophilic groups include, but are not WO 2007/061670 PCT/US2006/044058 - 44 limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like. GENERAL SYNTHETIC PROCEDURES 5 The present invention further comprises procedures for the preparation of compounds of Formulas I, II and III. The compounds of Formulas I-III can be synthesized according to the procedures described in the following Schemes 1-5, wherein the substituents are as defined for Formulas I, H and HI above, except where further noted. The synthetic methods described 10 below are merely exemplary, and the compounds of the invention may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. The following list of abbreviations used throughout the specification represent the following and should assist in understanding the invention: 15 ACN, MeCN - acetonitrile Aq. - aqueous BOP - benzotriazol-1-yl-oxy hexafluorophosphate Cs 2

CO

3 - cesium carbonate 20 CHCl 3 - chloroform

CH

2

CI

2 , DCM - dichloromethane, methylene chloride CuI - copper iodide DCC - dicyclohexylcarbodiimide DIC - 1,3-diisopropylcarbodiimide 25 DIEA, DIPEA - diisopropylethylamine DME - dimethoxyethane DMF - dimethylformamide DMAP - 4-dimethylaminopyridine DMS - dimethylsulfide 30 DMSO - dimethylsulfoxide EDC, EDCI - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Et 2 O - diethyl ether EtOAc - ethyl acetate FBS - fetal bovine serum WO 2007/061670 PCT/US2006/044058 - 45 G, gm - gram h, hr - hour

H

2 - hydrogen

H

2 0 - water 5 HATU - O-(7-azabenzotriazol-1-yl)-N,NN',N' tetramethyluroniumhexafluorophosphate HBr - hydrobromic acid HC1 - hydrochloric acid HOBt - 1-hydroxybenzotriazole hydrate 10 HOAc - acetic acid HPLC - high pressure liquid chromatography IPA, IpOH - isopropyl alcohol

K

2 C0 3 - potassium carbonate KI - potassium iodide 15 LG - leaving group LiOH - lithium hydroxide MgSO 4 - magnesium sulfate MS - mass spectrum MeOH - methanol 20 N 2 - nitrogen NaCNBH 3 - sodium cyanoborohydride Na 2

CO

3 - sodium carbonate NaHCO 3 - sodium bicarbonate NaH - sodium hydride 25 NaB1 4 - sodium borohydride NaOH - sodium hydroxide Na 2

SO

4 - sodium sulfate NLCI - ammonium chloride

NH

4 0H - ammonium hydroxide 30 P(t-bu) 3 - tri(tert-butyl)phosphine PBS - phospate buffered saline Pd/C - palladium on carbon Pd(PPh 3

)

4 - palladium(0)triphenylphosphine tetrakis WO 2007/061670 PCT/US2006/044058 - 46 Pd(dppf)Cl 2 - palladium(1,1 bisdiphenylphosphinoferrocene) 11 chloride Pd(PhCN) 2

C

2 - palladium di-yanophenyl dichloride 5 Pd(OAc) 2 - palladium acetate Pd 2 (dba) 3 - tris(dibenzylideneacetone) dipalladium PyBop - benzotriazol-l-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate RT, rt - room temperature 10 RBF, rbf - round bottom flask TLC, tlc - thin layer chromatography TBTU - O-benzotriazol-1 -yl-NNN',N'-tetramethyluronium tetrafluoroborate TEA, Et 3 N - triethylamine 15 TFA - trifluoroacetic acid THF - tetrahydroflran UV - ultraviolet light While the synthetic strategy for preparing the compounds of Formulas 1, II and mI 20 may vary, as appreciated by persons skilled in the art, one strategy for devising a method of making compounds of these formulas is by retro-synthetic disconnection. For example, H OH- R 4 palaiuRd-canphny dchord I II

AR

3 R3 3 2

R

3 B OH

III

WO 2007/061670 PCT/US2006/044058 - 47 as shown in Formulas I-III above, each squiggly line represents a possible point of bond construction, whose order is generally dependent upon the particular compound being synthesized. Such bond construction methods are generally described in synthetic Schemes 1 - 5 below. 5 Scheme 1 0 0 A- Oy R hydrolysis A- OH 2 0 0 0%/p A 0 activation A LG l' 2' X X Rib Rib Ri ,A R R1 LD R R kL .R R e.g., Mitsunobu, L e.g., Pd assisted hydrolysis 1: OH HO-R1a coupling, R 1 iM H Rla Rla Rla 1" 2" 3 4 hydrolysis x 0 wherein, R K R is CI-C4 alkyl, e.g., CH 3 , C 2

H

5 , etc. L _OH and e.g., X = Br, 1, Ci, etc.: Rib = RlbB(OH) 2 , RIbSnBus, etc. H 5 10 Scheme 1 describes a few methods for preparing A-W acids, useful for preparing compounds of Formulas I-III (see scheme 2) wherein W is -C(O)- or -S(0) 2 - and A is C 10 -alkyl, C 2

-

1 o-alkenyl, C 2

-

10 -alkynyl, R'-C 1

.

10 -alkyl-, R'-C 2

..

10 -alkenyl- or R-C 2 ..o-alkynyl ("L" in scheme I corresponds to the Caio-alkyl, C 2 -10-alkenyl or C 21 o-alkynyl of A 15 defined in A-W above). Desired A-W groups may be commercially available and WO 2007/061670 PCT/US2006/044058 - 48 purchased, or may be made by known, conventional methods. As shown, esters 1 can be hydrolyzed to their corresponding acids 2 using known bases, such as NaOH or LiOH. Acids 2 can then be coupled to an amine (not shown) to prepare compounds of Formula I IIL. Similarly, sulfonic acids 1' can be converted to an activated sulfonate 2' by reaction 5 with oxalyl chloride, for example, to prepare the corresponding sulfonyl chloride 2'. The sulfonyl chloride 2' can be reacted with an amine to prepare compounds of Formula I-IL. In a similar manner, a desired ring R1 of compounds 1", where A is a spacer "L" between the R' ring and W, may first be functionalized prior to coupling to the amino backbone, as shown in scheme 2. An ester-halo (X = halogen such as Br or I) substituted 10 R ring acid 4 or 5, both of which include a substitutable nitrogen in the ring, and which are generally referred to herein as the left-hand portion of the compounds of Formulas I, II and 111, can be prepared according to the method generally described in the second half of Scheme 1. As shown, a methyl ester-halo substituted compound 1" can be reacted in a Mitsunobu-type reaction with a desired hydroxyl-substituted R' compound under suitable 15 conditions, such as in the presence of tri-phenyl phosphine and diethylazodicarboxylate (commonly referred to as DEAD) for a suitable time period to form the ring N-Ra substituted adduct 2". Intermediate 2" may also be formed using a suitable reductive amination method as well utilizing an aldehyde, for example (not shown in scheme 1). Compound 2" can be reacted in a palladium-catalyzed coupling reaction, such as a 20 suzuki-type reaction, in the presence of suitable solvents and accompanying reagents, such as a base, to form the R1-Rlb substituted compound 3. Formation of compound 3 may require heat, up to and including reflux temperatures depending on the particular substrate, solvent and reagent(s) concentration, as appreciated by those skilled in the art. Compound 3 can then be hydrolyzed in the presence of a suitable base and solvent to 25 form the corresponding acid-adduct 4. Acid 4 is then utilized as an intermediate to couple, as described in scheme 2 below, with desired intermediates or other building blocks to make compounds of Formulas 1-111.

WO 2007/061670 PCT/US2006/044058 - 49 Alternatively, compound 1" can be hydrolyzed directly to the corresponding acid 5. Ester-Halo-substituted compound 5 is a useful intermediate for coupling the backbone core compounds with desired B, R 3 and R 4 substitutions already in place. Compound 5 can then be modified to include desirable R' substitutions, including R", R 7 , R 8 and R? 5 groups. In this fashion, analogs of a variety of desired left-hand pieces of compounds of Formulas I -III may be readily synthesized (see scheme 3). By known methods, the acids 1', 2, 4 and 5, may be converted to the corresponding isocycanates and then reacted with an amine (not shown) to make a urea "W" linker or an R'-urea linked A group (where W = -NHC(O)-). 10 Scheme 2

(R

7 , or 9)n (R 7 , 8 or 9) + H 2 N N(R 4

)(C

2

)R

5 (P N(R 4

)(CH

2 )jR 5 (O)MC(O)X B (o)mC(O) B 7 8 o r 9 )n N R ) C 2 R 5/ R 7 , o r 9 ) n N (N R ) C ~

(R

7 a r )

(R

7 8cor 9) 2. / ( + H 2 N HN(R4)(C2)iR5 N C(0)X B B

(R

7 , or9

(R

7 .ar ) 4.1+ H 2 N(R4)(CH2)jR5 (R A n N(R4)(CH2)R ~s() 2 X B (0)2 Desires A-W groups, which may be substituted with various substitutions 15 including one or more R 7 , R 8 or R groups, can be coupled to the core hydroxyl-propyl, WO 2007/061670 PCT/US2006/044058 - 50 hydroxyl-butyl or hydroxyl-pentyl backbone structure, generally designated in Scheme 2 as "Pr" group, by various coupling methods as described in Scheme 2. In each of the 4 sub-schemes, X refers generally to a "LG" or a "leaving group" such as a halide (bromine, chlorine, iodine or fluorine), alkylsulfonate and other known groups (also see 5 definitions herein) which generally forms an electrophilic species (E*) and m is an integer from 0-1. The NH 2 group (primary amine) is a nucleophilic species (Nu~), as is secondary amines, hydroxides, alkoxides, an anionic carbon species and the like, which should be sufficiently strong to the attack the E+ species and displace the leaving group X thereby effecting a coupling of A-W to the Pr backbone. Examples of suitable electrophilic 10 carbonyl species include, without limitation, acid halides, mixed anhydrides, aldehydes, carbamoyl-chlorides, sulfonyl chlorides, acids activated by coupling with activating reagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP and carbodiimides (DCC, EDC and the like), and other electrophilic species including halides, isocyanates, daizonium ions and the like. 15 The coupled adduct of A-W and Pr, shown as products in sub-schemes 1-4, can be brought about using various conventional methods. For example, an amide or a sulfonamide linkage, as shown in sub-schemes 2 and 4, can be made utilizing an amine on the Pr intermediate and an activated electrophilic species, on the A-W group such as the acid chloride or sulfonyl chloride as shown. The reaction proceeds generally in the 20 presence of a suitable solvent and/or base. Suitable solvents include, without limitation, generally non-nucleophilic, anhydrous solvents such as toluene, CH 2 Cl 2 , THF, DMF, DMSO, NN-dimethylacetamide and the like, including solvent combinations thereof. The solvent may range in polarity, as appreciated by those skilled in the art. Suitable bases include, for example, tertiary amine bases such as DIEA, TEA, carbonate bases such as 25 Na 2

CO

3 , K 2 C0 3 , Cs 2

CO

3 , hydrides such as NaH, KH, borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH 3 , and the like. The base itself may also serve as a solvent. The reaction may optionally be run neat, i.e., without any base and/or solvent. These coupling reactions are generally fast and conversion occurs typically in ambient WO 2007/061670 PCT/US2006/044058 - 51 conditions. However, depending upon the particular substrate, such reactions may require heat, as appreciated by those skilled in the art. Similarly, carbamates as illustrated in sub-scheme 1 and ureas as illustrated in sub-scheme 3 may be made as shown, wherein X has the same definition as above, using 5 the same coupling methods described above for sub-schemes 2 and 4. While the above methods are so described, they are not exhaustive, and other methods for linking A-W groups and desired Pr groups together may be utilized as appreciated by those skilled in the art. The coupling methods described in sub-schemes 1-4 of scheme 2 are also 10 applicable for coupling desired A-W intermediates to desired Pr intermediates not containing desired R 5 groups, although sub-schemes 1-4 as illustrated do contain R 5 groups.

WO 2007/061670 PCT/US2006/044058 - 52 Scheme 3 Rio

H

2 N R11

(R

5 ) YX1

Y

2 9 reductive Annation R1o R1O RIO R1O 0 R1 HO, R1

N

3 , RI, H 2 N-R1 . R( ) (R 5 ) (R 5 1) . (R 5 ) O R11 reduction (X X 1 e.g., OPPA, base R11 reduction (xH2 XR 6 7 a mine formation YR11 HN T( y R11 H12N R11

(R

5 ) reduction () hydrolysis (R 5 ) (N X1 ( X1 (X X1 Y1 Y1 Y 1\ Y -Y2 Y2 Y2 10 11 9 Amine intermediate 9 (j= 0) can be prepared according to the method generally 5 described in Scheme 3. As shown, spiro-substituted- or gem-dialky-substituted (not shown) oxo-R 5 ring intermediates 6 can be converted directly to the amino-intermediate 9 using known reductive amination methods, such as in the presence of sodium cyanoborohydride and ammonium acetate. Alternatively, the carbonyl of R 5 may be reduced to the corresponding alcohol using conventional reducing reagents, and then 10 displaced to form the corresponding azido-intermediate 8 using known reagents, such as DPPA, in the presence of a suitable base as shown. Intermediate 8 may be reduced with a suitable reducing agent or by known methods, including triphenylphosphene, WO 2007/061670 PCT/US2006/044058 - 53 trimethylphosphene or lithium aluminum hydride (LAH), to produce the desired amino adduct 9. Yet another method of forming the amine adduct 9, can be via an imine formation to form compound 10. The imine double bond of compound 10 may then be successively 5 reduced and hydrolyzed to yield the primary amine product 9. Such steps may be conducted using known, convention methods, as appreciated by those skilled in the art. Scheme 4

R

1 OH R 4

R

10 HG (R 4 )H-N H 2 N- N1 I 1 P N O R 1) . heat (eg.) H2NB E (R) R11 1. B + 2. deprotection B ( X1 Y1I PG = protecting group yI 12' 9 14' Y 2 H OH0 R 4 Rio 2

(R

4 )HN R1 WR N . (R) - RI W + B(X , B (x><c 12 Y2V 1 \/) 9 14 2 10 WO 2007/061670 PCT/US2006/044058 -54 OSiR3 Rio OH R4 Ro H O~iR 3

(R

4 )HN HN PG N ON R , 1. e.gN reductive R11 (R0X amination (R5) 3.B + 2. deprotections B X1 PG = protecting group Y1 13'9 14' OR1o R4 R1o 0(R 4 )HN ROH

I

4 R, PG N (R') R 1. e.g., ductive H 2 N R11 4. B 2. deprotections B X1 PG = protecting group 1 \ 13 9 14' Scheme 4 describes, generally, multiple different methods for constructing the bond between the Pr starting material or intermediate 12' (sub-scheme 1) or 12 (sub scheme 2) and an R ring intermediate 9, thereby synthesizing a desired intermediate 14' 5 or a final compound 14 of Formulas I-I1. One method to make this bond is to react an epoxide intermediate 12 or 12' (Note: the epoxide 12 or 12' may be purchased commercially or made via known, published methods such as from the olefin precursor), with an amino-R5 intermediate 9, as shown. The reaction may proceed in the presence of a polar solvent, such as an alcohol or dioxanes, and may require additional reagents, as 10 appreciated by those skilled in the art. Additionally, the reaction may require heat for a period of time. Note that while the scheme described the addition o heat, this is by way of example, and not every reaction would require heat as appreciated by those of ordinary skill in the art. The protecting group may be removed using an acid, such as HCI, such that the bonded adduct 14' is recovered as an HCI salt. 15 Alternatively, desired intermediates 14' may be synthesized starting with an amine-protected aldehyde intermediate 13' (sub-scheme 3) or 13 (sub-scheme 4) and condensing the aldehyde with a primary or secondary amine 9 to form an imine (not WO 2007/061670 PCT/US2006/044058 - 55 shown, generally formed in-situ and not isolated). The imine can then be reduced using a known reducing agent, such as a hydride or borohydride, the reduced intermediate may be deprotected to provide an intermediate 14' having an amine useful to prepare compounds 14 of Formulas I-III. 5 Scheme 5 Method A: PG PGNNH R 3 1. e.g., HATU, EtaN. HN R3 N R3 HO N-methoxymethylamine B 1. e.g., PhMe 2 RiH, TF, Ra R, 2. BMX, e.g., BMgBr O R3 R 3 2. e.g., dimethoxypropane B Ra 0 R3. e.g., Os0 4 , NaO 4 15 16 17 PG = protecting group Rio R 3 R3 R4 R 10

(R

4 )HN 1 1 1. e.g., reductive H 2 N NR11 (R5 amination O

.(R

5 Y 17 + 2. deprotection B OH Y Y g 18' Method B: RRio R 4 Rio P0 R11 1. e.g., reductive H 2 N N N~ R 3 I.(OY mnto A NHR 4

R

3 x <x B R3 R 3 4 f 1 2. deprotection B OH Y Y2

Y

2 6 . 18 Scheme 5 describes, generally, two different methods (Methods A and B) for constructing intermediates 18' (Method A) or 18 (Method B) which are useful for making 10 compounds of Formula III. As shown in Method A, the acid group of an olefinic amino acid compound 15 may be modified with a desired B group to form a compound 16, by first activating the acid of 15 with a known activating agent, such as HATU in the presence of a suitable base, and treating activated 15 with a B-substituted grignard WO 2007/061670 PCT/US2006/044058 - 56 reagent or B-ligand metal reagent, which delivers the desired B group to displace the carbonyl activating group and form compound 16. Compound 16 may be oxidized to the corresponding ketone 17 by known methods, such as with sodium periodiate and osmium tetroxide. Ketone 17 may then be reacted with amine 9, via a reductive amination step, to 5 form an amino protected intermediate, which can be deprotected to yield intermediate 18', as shown. Alternatively, intermediate 18 may be made using a reductive amination step with an amine-protected diamine compound 19 and a ketone 6. Such reductive amination step may be employed with conventional conditions using known reducing reagents in suitable 10 solvents, at suitable temperatures, as appreciated by one of ordinary skill in the art. Amine compounds 18 and 18' can then be coupled to acids and sulfonic acid compounds 2, 2', 4 and 5, described in scheme 1, to make amides and sulfonamide compounds ("W" groups) of Formulas I-III by methods described in scheme 2. To enhance the understanding and appreciation of the present invention, the 15 following specific examples (starting reagents, intermediates and compounds of Formulas I-III) are set forth. The following analytical methods were used to purify and/or characterize the compounds, and intermediates, described in the examples below. Analytical HPLC and LC-MS Methods: 20 Unless otherwise indicated, all analytical HPLC analyses were run on an Agilent Model 1100 series system LC/MSD SL using one of the two following Columns: (a) Phenomenex Sernegi (4 micron, Cl 8, 50x2 mm) or (b) a Gemini column (5 micron, C18, 100x2 mm). A typical run through the instrument included: eluting at 1 ml/min with an linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 10 25 minutes; conditions may be varied to achieve optimal separation. Preparative HPLC Method: Unless otherwise indicated, the compounds described herein were purified via reverse phase HPLC using one of the following instruments: Shimadzu, varian, Gilson; WO 2007/061670 PCT/US2006/044058 - 57 utilizing one of the following two HPLC columns: (a) a Phenomenex Luna or (b) a Gemini column (5 micron or 10 micron, C18, 150x50 mm) A typical run through the instrument included: eluting at 45 ml/min with a linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 10 5 minutes; conditions can be varied to achieve optimal separations. Proton NMR Spectra: Unless otherwise indicated, all 'H NMR spectra were run on a Bruker series 300 MHz instrument or a Bruker series 400 MHz instrument. Where so characterized, all 10 observed protons are reported as parts-per-million (ppm) downfield from tetramethylsilane (TMS) or other internal reference in the appropriate solvent indicated. Mass Spectra (MS) Unless otherwise indicated, all mass spectral data for starting materials, 15 intermediates and/or exemplary compounds are reported as mass/charge (m/z), having an (M+H) molecular ion. The molecular ion reported was obtained by electrospray detection method (commonly referred to as an ESI MS) utilizing a PE SCIEX API 150EX MS instrument. Compounds having an isotopic atom, such as bromine and the like, are generally reported 20 according to the detected isotopic pattern, as appreciated by those skilled in the art. NamingZ Convention The compounds disclosed and described herein have been named using the naming convention provided with Chem-Draw Ultra 8.0 software, available in Chem 25 Office. In some instances, compounds were named with the term "spirocarbocycle" inserted where appropriate. For example, where the chroman is substituted with 2,2 spirocyclobutyl, "2,2-spirocyclobutyl" is added to the Chem-Draw nomenclature in the appropriate place. Chem-Draw utilizes the ISIS Draw software compound naming convention, as appreciated by those skilled in the art.

WO 2007/061670 PCT/US2006/044058 - 58 Examples The Examples, described herein below, represent various exemplary starting materials, intermediates and compounds of Formulas 1-III, which should assist in a better 5 understanding and appreciation of the scope of the present invention and of the various methods which may be used to synthesize compounds of Formulas 1, 11 and III. It should be appreciated that the general methods above and specific examples below are illustrative only, for purpose of assistance, and should not be construed as limiting the scope of the present invention in any manner. 10 Example 1 N-((2S,3R)-4-((S)-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1 phenylbutan-2-yl)acetamide 15 Step 1. 2,2-spirocyclobutvilchroman-4-one 1-(2-hydroxyphenyl)ethanone (3.2 ml, 26.6 mmol), cyclobutanone (4 ml, 53.3 mmol), pyrrolidine (2.6 ml, 32 mmol), and diisopropylethyl amine (4.5 ml, 26.6 mmol) were dissolved in 30 ml toluene and refluxed under a Dean Stark trap for 3.5 h. The reaction 20 was terminated (although a large amount of starting material was still present). The cooled reaction mixture was diluted with 100 ml ether, washed with 30 ml HCl (aq., SM), dried over MgSO 4 and evaporated. Column chromatography (3% EtOAc in Hexanes) gave the title compound as a yellow oil 760mg (4.04 mmol, 15%). MS m/z: 189 (M+1). Step 2. (R)-2,2-spirocyclobutylchroman-4-ol 25 A solution of (S)-2 Methyl-CBS-oxazaborolidin (1 M, 200 ul, 0.2 mmol) and borane DMS complex (0.5 ml, 5.25 mmol) in 10 ml toluene was cooled to -20 *C and a solution of 2,2-spirocyclobutylchroman-4-one (17 a, 0.76 g, 4.04 mmol) in 5 ml TH4F was added slowly over a period of 2.5 h. The reaction mixture was stirred for 0.5 h at the same temperature and was than carefully hydrolyzed with MeOH. The mixture was washed WO 2007/061670 PCT/US2006/044058 - 59 with HCl (1 M, aq.) and NaHCO 3 (sat., aq.) and the organic phase was dried over MgSO 4 and evaporated. The crude material was used without further purification in the next step. Step 3. (S)-4-azido-2,2-spirocyclobutylchroman The crude material from Step 2 was dissolved in 10 ml toluene and dppa (1.17 ml, 5.2 5 mmol) and dbu (0.776 ml, 5.2 mmol) was added and the mixture was stirred for 12 h. Two phases were observed and the less heavy layer was diluted with ether and washed with HCl (1 M, aq.) and NaHCO 3 (sat., aq.), dried over MgSO 4 and evaporated. Column chromatography (3% EtOAc in hexanes) gave 0.32 g (1.48 mmol, 35% (over 2 steps)) of the title compound as a yellow oil. MS n/z: 188(40%, M-N 2 ); 173(17%, M-N 3 ). 10 Step 4.(S)-2,2-spirocyclobutylchroman-4-amine (S)-4-azido-2,2-spirocyclobutylchroman (0.32 g, 1.48 mmol) was dissolved in 10 ml TI-F and cooled to 3 'C. LAH (IM in THF, 4.5 ml, 4.5 mmol) was added and stirring was continued for 2.5 h. The reaction mixture was allowed to warm up to room temperature during this period of time and 10 ml THF and 10 ml CH 2 Cl 2 were added. 5 g 15 NaSO 4 1H20 was added carefully, the mixture was stirred 15 min and was filtered. The filtrate was dried over MgSO4 and evaporated and the crude product (MS m/z: 173(100%,

M-NH

2 )) was used without further purification in the next step (240 mg, 1.26 mmol, 86% crude). Step 5. tert-Butyl (2S,3R)-4-((S)-2,2-spirocyclobutylchroman -4-ylamino)-3-hydroxy-1 20 phenylbutan-2-ylcarbamate (S)-2,2-spirocyclobutylchroman-4-amine (240 mg, 1.26 mmol) was mixed with I ml of IPA and tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (396 mg, 1.5 mmol) and heated in the microwave to 125 *C for 15 min. The mixture was diluted wit 2 ml DMF and purified on the prep HPLC (Gilson) to give the title compound. Yield (white 25 TFA salt): 400 mg (0.88 mmol, 70% over 2 steps, MS m/z: 453(100%, M+1)). Step 6. (2R,3S)-3-amino-1-((S)-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan 2-ol WO 2007/061670 PCT/US2006/044058 - 60 tert-Butyl (2S,3R)-4-((S)-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1 phenylbutan-2-ylcarbamate was dissolved in 2 ml dioxane and 4 ml HCI (4M in dioxane) was added and stirring was continued for 2 h. The reaction mixture was evaporated and the crude product used without further purification in the next step: white HCl salt, MS 5 m/z: 353(100%, M+1). Step 7. N-((2S,3R)-4-((S)-2,2-spirocyclobutvlchroman-4-ylamino)-3-hydroxy-1 phenylbutan-2-l)acetamide (2R,3 S)-3-amino- 1 -((S)-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-ol (34 mg, 0.08 mmol) was dissolved in 1 ml DMF and acetic acid (4.5 ul, 0.08 mmol), hatu (30 10 mg, 0.08 mmol) and diisopropyl-ethyl amine (40 ul, 0.24 mmol) were added. The mixture was stirred for 2 h and 5 drops from a Pasteur pipette of HCI (5 M, aq.) was added. The mixture was purified without further work up procedure on the prep HPLC (Gilson) to give the title compound as its white TFA salt. MS m/z: 395(100%, M+l). 15 Example 2 N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1 20 phenylbutan-2-yl)acetamide.TFA salt. To a solution of (2S,3R)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4 ylamino)-4-phenylbutan-2-ol (25 mg, 0.06 mmol, synthesized using analogous procedures as in Example 1), triethylamine (0.02 mL, 0.14 mmol, Aldrich), and CH 2 Cl 2 25 (1 mL) was added N-acetylimidazole (9 mg, 0.08 mmol, Fluka). Stir at room temperature. After 2 h, more N-acetylimidazole (5 mg) was added. After 3 days, the solution was purified by reverse-phase preparative HPLC on a Phenomenex Synergi column (4 micron, MAX-RP, 80 A, 150x30 mm) eluting at 45 ml/min with an linear gradient of 1 0%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 10 30 minutes to give 3.7 mg of the desired product as a colorless solid. MS m/z: 437.4(M+1).

WO 2007/061670 PCT/US2006/044058 - 61 Example 3 N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1 5 phenylbutan-2-yl)-2-(pyridin-4-yl)acetamide.TFA salt The title compound was synthesized by a method analogous to that described in Example 1, using(2S,3R)-3-amino- 1 -((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-4-phenylbutan-2-ol dihydrochloride salt and 2-(pyridin-4-yl)acetic acid 10 hydrochloride (Aldrich) in the presence of DIPEA to obtain the title compound as a colorless solid. MS n/z: 500.3(M+l). Example 4 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' 15 pyrano[2,3-blpyridin]-4'-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-(5-methyl 1H-pyrazol-1-yl)acetamide The title compound was prepared via an intermediate obtained by a method analogous to that described in Example 171 of co-pending patent application serial No. 20 60/738,767. The intermediate was finally coupled by a method analogous to that described in Example 1 above using 2-(5-methyl-1H-pyrazol-1-yl)acetic acid to provide the title compound. MS n/z: 546.3 (M+1). 25 Example 5 Methyl (2S,3R)-3-hydroxy-4-((S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H pyrano[2,3-blpyridin-4-ylamino)-1-phenylbutan-2-ylcarbamate WO 2007/061670 PCT/US2006/044058 - 62 The title compound was prepared via an intermediate obtained by a method analogous to that described in Example 171 of co-pending patent application serial No. 60/738,767. The intermediate was finally coupled by a method analogous to that described in Example 3 above using methyl chloroformate to provide the title compound. 5 MS m/z: 482.3 (M+l). Example 6 Ethyl (2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-chroman-4-ylamino)-3-hydroxy-1 phenylbutan-2-ylcarbamate 10 A mixture of di-succinimidyl carbonate (2.56 g, 1.0 eq), DIPEA (1.29 g, 1.0 eq), and anhydrous EtOH (1.16 mL, 2.0 eq) in dry CH 2

CI

2 and CH 3 CN was stirred at rt overnight. The solvents were removed and the residue was used directly in the next step. TA portion of the crude residue was mixed with (2R,3 S)-3 -amino-I -((S)-6-ethyl-2,2 15 spirocyclobutyl-chroman-4-ylamino)-4-phenylbutan-2-ol hydrochloric acid salt in the presence of 3 drops of DIPEA in anhydrous and the resulting mixture was stirred at rt until the complete consumption of the amine. The title product was obtained as a TFA salt after purification by HPLC. MS m/z: 453 (M+1). The following examples were prepared by a method analogous to that described 20 in Examples 1-6 above. Ex. STRUCTURE Mass MW No. found 7 461 460.614 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1 -phenylbutan-2-yl)pent-4-ynamide 8 505 504.711 3-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2 spirocyclobutylchroman-4-ylamino)-3-hydroxy- 1 phenylbutan-2-yl)propanamide WO 2007/061670 PCT/US2006/044058 -63 9 437 436.592 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1-phenylbutan-2-yl)propionamide 10 453 452.591 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2 methoxyacetamide 11 531,533 531.487 N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1-phenylbutan-2-yI)-2 isopropoxyacetamide 12 503,505 503.434 N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy- -phenylbutan-2-yl)-2 methoxyacetamide 13 529,531 529.472 2-(allyloxy)-N-((2S,3R)-4-((S)-6-bromo-2,2 spirocyclobutylchroman-4-ylamino)-3-hydroxy-1 phenylbutan-2-yl)acetamide 14 517,519 517.461 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2, 1'-cyclobutan]-4-yl)amino)-2-hydroxy- 1-(phenylmethyl) propyl)-3-(methyloxy)propanamide 15 517,519 517.461 N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(ethyloxy)acetamide 16 543,545 543.498 N-((] S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((cyclopropylmethyl) oxyacetamide 17 571,573 571.431 N-((I S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-((2,2,2-trifluoroethyl)oxy) acetamide 18 493 492.656 2-((cyclopropylmethyl)oxy)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 64 19 535 534.736 2-((cyclopropylmethyl)oxy)-N-((1 S,2R)-3-(((4S)-6-(2,2 dimethylpropyl)-3,4-dihydrospiro[chromene-2, 1 -cyclobutan] 4-yl)amino)-2-hydroxy-l1-(phenylmethyl) propyl)acetamide 20 397 793.056 N-((] S,2R)-3-(((5R)-3,3-dimethyl- 1,3 ,4,5-tetrahydro-2 benzoxepin-5-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide 21 427 853.107 N-(( I S,2R)-3-(((5R)-3 ,3-dimethyl- I ,3,4,5-tetrahydro-2 benzoxepin-5-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl) 2-(methyloxy)acetamide 22 425 424.581 N-((1 S,2R)-3-(((5S)-7-ethyl-3,3-dimethyl- 1 ,3,4,5-tetrahydro 2-benzoxepin-5-yl)amino)-2-hydroxy- 1 (phenylmethyl)propyi)acetamide 23 455 454.607 N-((l S,2R)-3-(((5S)-7-ethyl-3,3-dimethyl- I,3,4,5-tetraliydro 2-benzoxepin-5-yI)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(methyloxy)acetainide 24 622,624 622.581 2-(1 ,3-benzothiazol-2-yloxy)-N-((l1S,2R)-3 -(((4S)-6-bromo 3,4-dihydrospiro [chromene-2, 1'-cyclobutan]-4-yI)amino)-2 hydiroxy- I -(phenylmethyl)propyl)acetamide 25 572 571.738 -(1 ,3-benzothiazol-2-yloxy)-N-((I S,2R)-3-(((4S)-6-ethyl-3,4 hydroxy-1 -{phenylmethyl)propyl)acetamide 26 508 507.627 N-((] S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, F' cyclobutan]-4-yI)amino)-2-hydroxy-lI-(phenylmethyl) propyl)-2-(2-oxo- 1,3-oxazolidin 3-yl)acetamide WO 2007/061670 PCT/US2006/044058 -65 27 558,560 558.47 N-((] S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(2-oxo-1,3-oxazolidin-3-yl)acetamide 28 572 571.738 2-(1,3-benzoxazol-2-ylthio)-N-((I S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)acetamide 29 588 587.805 2-(1,3-benzothiazol-2-ylthio)-N-((1 S,2R)-3-(((4S)-6-ethyl 3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)acetamide 30 539 538.688 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, l' cyclobutan}-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)acetamide 31 520 519.638 N-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan] -4-yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl) 2-((5-methyl-3-isoxazolyl)oxy)acetamide 32 556 555.671 2-(1,3-benzoxazol-2-yloxy)-N-((I S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy-1 -(phenylmethyl)propyl)acetamide 33 489 488.628 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(1 H-pyrazol- 1 -yl)acetamide 34 586 585.765 2-((1,3-benzothiazol-2-ylmethyl)oxy)-N-((1 S,2R)-3-(((4S)-6 ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4 yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)acetamide WO 2007/061670 PCT/US2006/044058 -66 35 509 508.655 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-((3R)-tetrahydro-3-furanyloxy)acetamide 36 520 519.638 N-((] S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-((1,3-oxazol-2-ylmethyl)oxy) acetamide 37 509 508.655 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-2-((3S)-tetrahydro-3-furanyloxy)acetamide 38 533 532.6374 N-((1 S,2R)- 1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(2-oxo- 1,3-oxazolidin-3-yl)acetamide 39 534 533.6651 N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-((3S)-tetrahydro-3-furanyloxy)acetamide 40 545 544.6484 N-((1 S,2R)-1 -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-((5-methyl-3-isoxazolyl) oxy)acetamide 41 564 563.6983 N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(1 H-pyrrolo[2,3-b]pyridin-1-yl)acetamide 42 551 550.6958 N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2-oxo-1,3 oxazolidin-3-yl) acetamide WO 2007/061670 PCT/US2006/044058 - 67 43 552 551.7235 N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((3S) tetrahydro-3-furanyloxy) acetamide 44 582 581.7567 N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1H pyrrolo[2,3-b]pyridin-1 -yl)acetamide 45 563 562.7068 N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1-(phenylmethyl) propyl)-2-((5-methyl 3-isoxazolyl)oxy) acetamide 46 533 532.7246 N-(( S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)-3 (2-(I-methylethyl)-1H-imidazol-1-yl)propanamide 47 545 544.7356 (2E)-N-((1S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro 2H-chromen-4-yl)amino)-2-hydroxy- 1-(phenylmethyl) propyl)-3-(1-(2-methylpropyl)-IH-imidazol-4-yl)-2 propenamide 48 502 501.462 N-((IS,2R)-1-((3-bromophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)acetamide 49 420 419.522 N-((I S,2R)-3-(((4S)-6-cyano-3,4-dihydrospiro[chromene-2, ' cyclobutan]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)acetamide 50 499 498.663 N-((2S,3R)-4-((S)-6-ethyl-2,2'-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1-(4-phenyl-phenyl)-butan-2-yl) acetamide WO 2007/061670 PCT/US2006/044058 -68 51 441 440.556 N-((2S,3R)-4-((S)-6-etbyl-2,2'-spirocyclobutylchroman-4 ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl) acetamide 52 471 470.582 N-((2S,3R)-4-((S)-6-ethyl-2,2'-spirocyclobutylchroman-4 ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)-2 methoxyacetamide 53 439 438.565 N-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro [chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1 -phenylpropyl)-2 (methyloxy)acetamide 54 409 408.539 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro [chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- I -phenylpropyl) acetamide 55 532 531.487 N-((1 S,2R)- 1 -((3-bromophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(methyloxy)acetamide 56 478 477.602 N-((1 S,2R)- I -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(methyloxy)acetamide 57 575 574.463 N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-1 -((3,5-difluorophenyl)methyl)-2 hydroxypropyl)-2-(3-pyridinyl)acetamide 58 448 447.576 N-((l S,2R)- I -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)acetamide 59 524 523.673 N-((1 S,2R)-1 -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-phenylacetamide WO 2007/061670 PCT/US2006/044058 -69 60 540 539.672 N-((1 S,2R)- 1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(phenyloxy)acetamide 61 530 529.701 N-((I S,2R)- 1 -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(3-thienyl)acetamide 62 504 503.639 N-((1 S,2R)- 1 -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)tetrahydro-2-furancarboxamide 63 571 570.73 (3S)-N-((IS,2R)-1-((3-cyanophenyl) methyl)-3-(((4S)-6-ethyl 3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-1-cyclobutyl-5-oxo-3-pyrrolidinecarboxamide 64 462 461.603 N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)propanamide 65 518 517.666 N-((1 S,2R)- I -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-((cyclopropylmethyl)oxy) acetamide 66 542 541.4052 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1 -((3 (trifluoromethyl)phenyl)methyl)propyl)acetamide 67 572 571.431 N-((] S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2, 1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-((3 (trifluoromethyl)phenyl)methyl)propyl)-2 (methyloxy)acetamide 68 582.3 581.753 (S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-(1 oxoisoindolin-2-yl)propanamide WO 2007/061670 PCT/US2006/044058 -70 69 575.3 574.733 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4 ylamino)-3-hydroxy- I -phenylbutan-2-yl)-3-(5-fluoro-2 methoxyphenyl)propanamide 70 506.3 505.655 (S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy-1 -phenylbutan-2-yI)-5-oxopyrrolidine 2-carboxamide 71 573.3 572.717 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(5-fluoro-2 methoxyphenyl)acrylamide 72 447.2 446.535 N-((IS,2R)-1-((3,5-difluorophenyl)methyl)-3-((6-ethyl-2,2 dimethyl-3,4-dihydro-2H-chromen-4-yl)amino)-2 hydroxypropyl)acetamide 73 459.2 458.546 N-((lS,2R)-1-((3,5-difluorophenyl) methyl)-3-(((4S)-6-ethyl 3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxypropyl) acetamide 74 489.2 488.572 N-((IS,2R)-1-((3,5-difluorophenyl) methyl)-3-(((4S)-6-ethyl 3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(methyloxy)acetamide 75 416.2 415.599 N-((IS,2R)-3-(((7S)-2-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro 1,3-benzothiazol-7-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide 76 367.2 366.502 N-((1S,2R)-3-(((IS)-3,3-dimethyl-2,3-dihydro-1H-inden-1 yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide 77 397.2 396.528 N-((1 S,2R)-3-(((I S)-3,3-dimethyl-2,3-dihydro- 1 H-inden- 1 yl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)-2 (methyloxy)acetamide 78 494.2 987.201 N-((1 S,2R)- I -((3-cyanophenyl)methyl)-3-(((2S,4S)-6-ethyl 3,4,4',5'-tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2 hydroxypropyl)-2-(methyloxy) acetamide WO 2007/061670 PCT/US2006/044058 -71 79 475.2 949.0896 N-((1 S,2R)-1-((3,5-difluorophenyl) methyl)-3-(((2S,4S)-6 ethyl-3,4,4',5'-tetrahydrospiro[chromene-2,3'-furan]-4 yl)amino)-2-hydroxypropyl)acetamide 80 506.2 1011.231 N-((1 S,2R)-3-(((2R,4S)-6-ethyl-3,4,4',5' tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy 1-(phenylmethyl) propyl)-2-(1H-1,2,4-triazol-1-yI) acetamide 81 491.3 490.6442 N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide 82 542 541.7317 N-((1S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-2 phenylacetamide 83 551 550.7394 N'-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-NN dimethylbutanediamide 84 560 559.7069 N-((l S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2 pyrimidinyloxy)acetamide 85 511 510.6312 2-(((1S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- 1 (phenylmethyl)propyl)amino)-2-oxoethyl dimethylcarbamate 86 548 547.7599 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2 thienyl)acetamide WO 2007/061670 PCT/US2006/044058 -72 87 504 503.6829 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl propyl)-4-pentynamide 88 425 849.0756 N-((IS,2R)-3-((( IR)-3,3-dimethyl-7-(methyloxy)-4-oxo 1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide 89 592 591.7049 2-(((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6 (4-morpholinyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan] 4-yI)amino)propyl)amino)-2-oxoethyl dimethylcarbamate 90 587 586.7532 N-((1 S,2R)-1 -((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6 (4-morpholinyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan] 4-yl)amino)propyl)-2-(2-thienyl)acetamide 91 576 575.705 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydro-2H-chromen-4 yl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)-2-(9-oxo 10(9H)-acridinyl)acetamide 92 509 508.655 N-((IS,2R)-3-(((4S)-6-ethyl-3,4-dihydro-2H-chromen-4 yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2-((2 fluorophenyl)thio)acetamide 93 616 615.77 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-2-(9-oxo-10(9H)-acridinyl)acetamide 94 632 630.579 (2Z)-2-(6-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-N ((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)ethanamide 95 579 579.201 2-((3-chloro-2-methylphenyl)thio)-N-((1 S,2R)-3-(((4S)-6 ethyl-3,4-dihydrospiro[chromene-2, 1-cyclobutan]-4 yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)acetamide WO 2007/061670 PCT/US2006/044058 -73 96 568 567.726 (2S)-N-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(I-oxo-1,3-dihydro-2H-isoindol-2-yl)propanamide 97 557 556.699 2-((2-acetylphenyl)oxy)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)acetamide 98 579 578.7092 N-((1 S,2R)- 1-((3-cyanophenyl)methy])-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(1-oxo- 1,3-dihydro-2H-isoindol-2 yl)acetamide 99 606 604.5416 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-I -(phenylmethyl) propyl)-2-(1 -oxo- 1,3-dihydro-2H-isoindol-2-yl)acetamide 100 555 554.6872 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro 2H-pyrano [2,3-b]pyridin-4-ylamino)-3-hydroxy-1 phenylbutan-2-yl)-2-(1 -oxoisoindolin-2-yl)acetamide 101 597 596.7676 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-2-(] -oxo- 1,3 dihydro-2H-isoindol-2-yl)acetamide 102 613 612.7666 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl) amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(I -oxo- 1,3 dihydro-2H-isoindol-2-yl)acetamide 103 482 963.2662 N-((l S,2R)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 tetrahydrospiro[furan-3,2'-pyrano[2,3-b] pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 -74 104 512 1023.318 N-((1S,2R)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl) amino)-2-hydroxy- I -(phenylmethyl)propyl)-2 (methyloxy)acetamide 105 549 1097.368 N-((1 S,2R)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl) amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1H-1,2,4 triazol-1-yl) acetamide 106 549 1097.368 N-((1 S,2R)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl) amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2H-1,2,3 triazol-2-yl) acetamide 107 429 428.957 N-((IS,2R)-3-(((4S)-6-chloro-3,4-dihydrospiro[chromene 2,1'-cyclobutan] 4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)acetamide 108 459 458.983 N-((1S,2R)-3-(((4S)-6-chloro-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(methyloxy)aeetamide 109 469 938.833 N-((1S)-I -((1 R)-2-(((4S)-6-bromo-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-l hydroxyethyl)-3-methylbutyl)-2-(methyloxy)acetamide 110 439 878.782 N-((IS)-1-((1R)-2-(((4S)-6-bromo-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1 hydroxyethyl)-3-methylbutyl)acetamide 111 473 945.251 N-((1 S,2S)-3-(((4S)-6-ethyl-3,4-dihydrospirotchromene-2, ' cyclobutan] 4-yl)amino)-2-hydroxy- 1 -(1 naphthalenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 -75 112 503 1005.3 N-((1 S,2S)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan] 4-yl)amino)-2-hydroxy-1 -(1-naphthalenylmethyl)propyl)-2 (methyloxy acetamide 113 511 1022.91 N-((1 S,2S)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(1-naphthalenylmethyl) propyl) acetamide 114 467 934.889 N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)- 1 -(cyclohexylmethyl)-2-hydroxypropyl) acetamide 115 467 934.851 N-((l S,2S)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino) 2-hydroxy- 1 -(3-thienylmethyl) propyl) acetamide 116 497 994.902 N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1 -(3-thienylmethyl)propyl) 2-(methyloxy)acetamide 117 466 465.5658 N-(( IS,2R)-I-((3-cyano-5-fluorophenyl) methyl)-3-(((4S)-6 ethyl-3,4-dihydrospiro[chromene-2, 1'-cyclobutan]-4 yl)amino)-2-bydroxypropyl)acetamide 118 538 538.483 N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dibydro-2H chromen-4-yl)amino)-2-hydroxy-1-((3-(3-pyridinyl)phenyl) methyl)propyl)acetamide 119 453 453.2966 N-((3S,4S)-5-((S)-6-bromo-2,2-dimethylchroman-4-ylamino) 1,1, 1-trifluoro-4-hydroxypentan-3-yl)acetamide 120 485 485.4191 N-((I S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-1 ((3-ethynylphenyl)methyl)-2-hydroxypropyl)acetamide 121 488 487.5594 N-((1 S)- 1-((l1R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1-hydroxyethyl)-3,3,3-trifluoropropyl)-2 (methyloxy)acetamide WO 2007/061670 PCT/US2006/044058 -76 122 459 458.6196 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl- 1,1 -dioxido-3,4 dihydro-2H-1-benzothiopyran-4-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide 123 430 429.5819 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- 1-(1,3-thiazol-4 ylmethyl)propyl)acetamide 124 423 422.566 N-((] S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)acetamide 125 487 486.652 N-((IS,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 phenylacetamide 126 499 498.663 N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yI)amino)-2-hydroxy-1-(phenylmethyl)propyl) 2-phenylacetamide 127 529 528.664 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(3 fluorophenyl)acrylamide 128 385 384.517 N-((IS,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-2,6,6 trimethyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl)amino) propyl)acetamide 129 402 400.584 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-2,6,6 trimethyl-4,5,6,7-tetrahydro- I -benzothien-4 yl)amino)propyl)acetamide 130 432 430.61 N-((1 S,2R)-2-hydroxy- 1-(phenylmethyl)-3-(((4S)-2,6,6 imethyl-4,5,6,7-tetrahydro- I -benzothien-4-yl)amino)propyl) 2-(methyloxy)acetamide 131 445 444.636 N-((] S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro 1 -benzothien-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(methyloxy)acetamide WO 2007/061670 PCT/US2006/044058 -77 132 467 466.5898 N-((1S,2R)-1-((3,5-difluorophenyl) methyl)-2-hydroxy-3 (((4S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- 1 -benzothien-4 yl)amino) propyl)-2-(methyloxy)acetamide 133 437 436.564 N-((1 S,2R)- I -((3,5-difluorophenyl) methyl)-2-hydroxy-3 (((4S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- I -benzothien-4 yl)amino)propyl)acetamide 134 426 425.5939 N-((1 S,2R)- 1 -((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S) 2,6,6-trimethyl-4,5,6,7-tetrahydro- 1 -benzothien-4-yl)amino) propyl)acetamide 135 456 455.6197 N-((1 S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S) 2,6,6-trimethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)amino) propyl)-2-(methyloxy)acetamide 136 498 497.7001 N-((1 S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro 1 -benzothien-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(2-oxo-1 -pyrrolidinyl)acetamide 137 547 546.7078 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(3-methyl 5-isoxazolyl) acetamide 138 508 507.6709 N-((1 S,2R)-3-(((4S)-6-((2R,6S)-2,6-dimethyl-4-morpholinyl) 3,4-dihydrospiro [chromene-2,1'-cyclobutan}-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)acetamide 139 494 493.6441 N-((lS,2R)-2-hydroxy-3-(((4S)-6-((3S)-3-methyl-4 morpholinyl)-3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4 yl)amino)-1 -(phenylmethyl)propyl)acetamide 140 476 474.3962 N-((1 S,2R)-3-(((4'R)-6'-bromo-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 -78 141 476 474.3962 N-((IS,2R)-3-(((4'S)-6'-bromo-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide 142 N-((1 S,2R)- I -((3,5-difluorophenyl) methyl)-2-hydroxy-3- 517 516.5856 (((4'S)-6'-(4-morpholinyl)-3',4'-dihydrospiro [cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide 143 517 516.5856 N-((1S,2R)-1-((3,5-difluorophenyl) methyl)-2-hydroxy-3 (((4'R)-6'-(4-morpholinyl)-3',4'-dibydrospiro [cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide 144 509 508.534 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyI [chromene-2,1'-cyclobutan]-4-yl)amino)propyl)-2 (methyloxy)acetamide 145 493 492.535 N-((1 S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2, 1'-cyclobutan]-4-yl)amino)propyl)propanamide 146 479 478.508 N-((1 S,2R)-2-hydroxy-1 -(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)propyl)acetamide 147 561 560.634 N-((1 S,2R)-2-hydroxy-1 -(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl) amino)propyl)-2-(3 thienyl)acetamide 148 555 554.606 N-((1 S,2R)-2-hydroxy- I -(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2,I'-cyclobutan]-4-yl) amino)propyl)-2 phenylacetamide 149 560 559.582 N-((l S,2R)-2-hydroxy- I-(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino) propyl)-2-(3-methyl 5-isoxazolyl) acetamide WO 2007/061670 PCT/US2006/044058 -79 150 441 440.556 N-((l S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)acetamide 151 455 454.582 N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl) propanamide 152 471 470.582 N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)-2-(methyloxy)acetamide 153 522 521.629 N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2, I '-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)-2-(3-methyl-5 isoxazolyl)acetamide 154 517 516.653 N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutanj-4-y)amino)-2 hydroxy- I -(phenylmethyl)propyl)-2-phenylacetamide 155 524 523.645 N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)-2-(2-oxo- 1 pyrrolidinyl)acetamide 156 526 525.617 N-((I S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2, '-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)-2-(2-oxo-1,3-oxazolidin-3 yl)acetamide 157 564 563.57 N-((1 S,2R)-2-hydroxy- 1-(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2, I'-cyclobutan]-4-yl)amino) propyl)-2-(2-oxo- 1,3 oxazolidin-3-yl) acetamide WO 2007/061670 PCT/US2006/044058 -80 158 562 561.598 N-((1S,2R)-2-hydroxy-1-(phenylmetbyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2, 1' -cyclobutan]-4-yl)amino) propyl)-2-(2-oxo- 1 pyrrolidinyl)acetamide 159 517 516.6384 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)-2-(2 pyrazinyloxy)acetamide 160 508 507.6709 N'-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)-N,N dimethylbutanediamide 161 505 504.6274 N-((I S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 (2-pyrimidinyloxy)acetamide 162 496 495.6599 N'-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl) amino)-2-hydroxy-1-(phenylmethyl)propyl) N,N-dimethylbutanediamide 163 526 525.661 N'-((1S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)-N,N dimethylbutanediamide 164 564 563.6134 N'-((1 S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2, 1'-cyclobutanl-4-yl) amino)propyl)-NN dimethylbutanediamide 165 437 436.5488 N-((1 S,2R)-3-(((4S)-6-acetyl-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)acetamide 166 517 516.6384 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)-2-(2 pyrimidinyloxy)acetamide WO 2007/061670 PCT/US2006/044058 -81 167 542 541.6485 N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro-2,2-spirocyclobuty1 [chromene-2,1 '-cyclobutan] 4-yl)amino)-2-hydroxypropyl)-2-(2 pyrimidinyloxy)acetamide 168 535 534.6285 N-((I S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2 spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)-2-(2 pyrimidinyloxy)acetamide 169 573 572.5809 N-((1 S,2R)-2-hydroxy- 1-(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobuty [chromene-2,1'-cyclobutan]-4-yI) amino) propyl)-2-(2 pyrimidinyloxy) acetamide 170 533 532.681 N'-((IS,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro-2,2-spirocyclobutyl[chromene-2,1'-cyclobutan] 4-yl)amino)-2-hydroxypropyl)-N,N-dimethylbutanediamide 171 542 541.6485 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6 ((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl) amino) propyl)-2-(2 pyrazinyloxy)acetamide 172 508 1014.844 N-((1 S,2R)-3-(((3R,4S)-6-bromo-3-hydroxy-2,2-dimethyl 3,4-dihydro-2H-chromen-4-yl) amino)-2-hydroxy- 1 (phenylmethyl)propyl)-2-(methyloxy)acetamide 173 535 534.6532 N-((I S,2R)-1 -((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6 (4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2, 1'-cyclobutan]-4-yI)amino) propyl)-2 (methyloxy)acetamide 174 505 504.6274 N-((1 S,2R)-1 -((3-cyanopbenyl)methyl)-2-hydroxy-3-(((4S)-6 (4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino) propyl)acetamide 175 652 651.93 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclopentan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-((5R)-2-(3-methylbutyl)-2,3,4,5-tetrahydro- 1 H-2 benzazepin-5-yl) acetamide WO 2007/061670 PCT/US2006/044058 - 82 176 467 466.618 N-((1 S,2R)-3-(((4S)-6-ethyl-3 ,4-dihydrospiro[chromene-2, 1' cyclobutanl-4-yI)amino)-2-hydroxy-I -((3 -methylphenyl) niethyl)propyl)-2-(methyloxy)acetamide 177 444 443.491 N-(( 1 S,2R)-3-(((4S)-6-cyano-2,2-dimethyl-3 ,4-dihydro-2H chromen-4-yl)amino)-1 -((3 ,5-difluorophenyl)methyl)-2 hydroxypropyl)acetamide 178 525 525.868 N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)- I -((2-chlorophenyl)methyl)-2 hydroxypropyl)-2-(methyloxy)acetamide 179 495 495.842 N-(( 1 S,2S)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-21 chromen-4-yl)amino)- 1 -((2-chlorophenyl)methyl)-2 hydroxypropyl) acetamide 180 525 525 .868 N-(( IS,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)- I -((3-chlorophenyl)methyl)-2 hydroxypropyl)-2-(methyloxy)acetamide 181 495 495.842 N-(( 1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H cbromen-4-yl)amino)- I -((2-chlorophenyl)methyl)-2 hydroxypropyl) acetamide 182 496 495.842 N-((l1S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)- I -((3-chlorophenyl)methyl)-2 hydroxypropyl) acetamide 183 439 439.347 N-{(IS)-1 -(( 1R)-2-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro 2H-chromen-4-yl)amino)- I-hydroxyethyl)-3-butyn- l-yl)-2 (methyloxy)acetamide 184 409 409.322 N-((1 S)-1 -((] R)-2-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro 2H-chromen-4-yl) amino)- 1 -hydroxyethyl)-3-butyn- Il-yl) acetamide 185 534 533.669 N-((1 S,2R)-3-(((4S)-6-ethyl-3 ,4-dihydrospiro[chromene-2, P' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(( 1-(phenylmethyl)- 11H-1 1 ,2,3-triazol-4-yl)methyl)propyl)-2-(methyloxy)acetamide WO 2007/061670 PCT/US2006/044058 -83 186 504 503.643 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro~chromene-2, 1' cyclobutan)-4-yl)amino)-2-hydroxy- 1 -((1 -(phenylmethyl)- I H 1,2,3-triazol-4-yl)methyl)propyl) acetamide 187 401 400.516 N-((1S)-1-((1R)-2-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-1-hydroxyethyl)-3-butyn-1 -yl) 2-(nethyloxy)acetamide 188 506 505.45 N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1 -(2-phenylethyl)propyl)-2 (methyloxy)acetamide 189 475 475.424 N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- 1 -(2 phenylethyl)propyl)acetamide 190 491 491.4229 N-((I S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-((3-(methyloxy)phenyl) methyl) propyl)acetamide 191 521 521.4487 N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-((3 (methyloxy)phenyl)methyl) propyl)-2-(methyloxy)acetamide 192 411 411.3373 N-((1 S)- 1 -((1 R)-2-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro 2H-chromen-4-yl) amino)- 1-hydroxyethyl)-3-buten- I-yl) acetamide 193 474 473.5171 N-((1S,2R)-3-(((4S)-6-cyano-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)- 1 -((3,5-difluorophenyl)methyl)-2 hydroxypropyl)-2-(methyloxy)acetamide 194 497 497.4301 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-3-butynamide WO 2007/061670 PCT/US2006/044058 -84 195 630 630.5834 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2, 1'-cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(1 -(pbenylmethyl)- I H-1,2,3-triazol-5-yl)acetamide 196 540 540.459 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2, 1'-cyclobutan]-4-yl)amino)-2-hydroxy- 1-(phenylmethyl) propyl)-2-(1H-1,2,3-triazol-4-yl) acetamide 197 546 545.7237 2-(4-(1, 1-dimethylethyl)- 1H-1,2,3-triazol- 1-yl)-N-((1 S,2R)-3 (((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4 yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide 198 532 531.6969 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, ' cyclobutan}-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(4-propyl- 1 H-1,2,3-triazol- 1 -yl)acetamide 199 600 599.694 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(3 (trifluoromethyl)- 1 H-pyrazol- I -yl)acetamide 200 580 580.1688 2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-N-((1S,2R)-3-(((4'S) 6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1 (phenylmethyl) propyl)acetamide 201 594 594.1956 2-(4-chloro-3,5-dimethyl-IH-pyrazol-1-yl)-N-((1S,2R)-3 (((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxy- 1 -(phenylmethyl) propyl)acetamide 202 614 613.7208 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(3-methyl 5-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide WO 2007/061670 PCT/US2006/044058 -85 203 519 518.5538 methyl (4S)-4-(((2R,3S)-4-(3,5-difluorophenyl)-2-hydroxy-3 (((methyloxy) acetyl)amino)butyl)amino)-3,4 dihydrospiro[chromene-2, 1'-cyclobutane]-6-carboxylate 204 561 561.4697 methyl (4S)-4-(((2R,3S)-4-(3-bromopheny)-2-hydroxy-3 (((methyloxy) acetyl)amino)butyl)amino)-3,4 dihydrospiro[chromene-2,1'-cyclobutane]-6-carboxylate 205 505 504.527 (4S)-4-(((2R,3S)-4-(3,5-difluoropheny)-2-hydroxy-3 (((methyloxy)acetyl)amino) butyl)amino)-3,4 dihydrospiro[chromene-2,1'-cyclobutane]-6-carboxylic acid 206 601.3 600.771 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocycloheptylchroman 4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(5-fluoro-2 methoxyphenyl)acrylamide 207 587.3 586.744 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclohexylchroman-4 ylamino)-3-hydroxy-1 -phenylbutan-2-yl)-3-(5-fluoro-2 methoxyphenyl)acrylamide 208 559.2 558.69 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy- I -phenylbutan-2-yl)-3-(5-fluoro-2 methoxyphenyl)acrylamide 209 629.2 628.659 (E)-N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6 (trifluoromethoxy) chroman-4-ylamino)-3-hydroxy-1 phenylbutan-2-yl)-3-(5-fluoro-2-methoxyphenyl)acrylamide 210 587.2 586.744 (E)-3-(5-fluoro-2-methoxyphenyl)-N-((2S,3R)-3-hydroxy-4 ((S)-6-isopropyl-2,2-spirocyclopentylchroman-4-ylamino)-I phenylbutan-2-yl)acrylamide 211 587.3 2346.97 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-(2-methyl) spirocyclopentylchroman-4-ylamino)-3-hydroxy- 1 phenylbutan-2-yl)-3-(5-fluoro-2-methoxyphenyl)acrylamide WO 2007/061670 PCT/US2006/044058 -86-. 212 437.2 873.185 N-((1 S,2R)-3-(((4R)-6-ethyl-4-methyl-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl) propyl)acetamide 213 473.1; 473.408 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene- 475.1 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)acetamide 214 396.2 395.5 N-((1 S,2R)-3-((4'S)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin)-4'-ylamino)-2-hydroxy- 1 (phenylmethyl)propyl)acetamide 215 396.2 395.5 N-((1S,2R)-3-((4'R)-3',4'-dihydrospiro [cyclobutane-1,2' pyrano[2,3-c]pyridin]-4'-ylamino)-2-hydroxy-1 (phenylmethyl) propyl)acetamide 216 396.2 395.5 N-((1S,2R)-3-((4'S)-3',4'-dihydrospiro [cyclobutane-1,2' pyrano[2,3-c]pyridin]-4'-ylamino)-2-hydroxy-1 (phenylmethyl) propyl)acetamide 217 426.2 425.526 N-((1S,2R)-3-((4'S)-3',4'-dihydrospiro [cyclobutane-1,2' pyrano[2,3-c]pyridin]-4'-ylamino)-2-hydroxy-1 (phenylmethyl) propyl)-2-(methyloxy)acetamide 218 464.2 463.497 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4'S)-6' (trifluoromethyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide 219 494.1 493.523 N-((1 S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4'S)-6' (trifluoromethyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)-2 (methyloxy)acetamide 220 430.1 429.945 N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclobutyl-3,4-dihydro 2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1 phenylbutan-2-yl)acetamide 221 460.1 459.971 N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclobutyl-3,4-dihydro 2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1 phenylbutan-2-yl)-2-methoxyacetamide WO 2007/061670 PCT/US2006/044058 -87 222 430.1 429.945 N-((2S,3R)-4-((R)-6-chloro-2,2-spirocyclobutyl-3,4-dihydro 2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1 phenylbutan-2-yl)acetamide 223 449.2 448.564 N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-ethyl-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide 224 454.3 453.579 N-((1 S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)-2-(methyloxy) acetamide 225 NMR only 478.5896 -((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-ethyl-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide 226 496.2 495.6599 N-((1S,2R)-2-hydroxy-3-(((4'S)-6'-(3-methylbutyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)- 1 -(phenylmethyl)propyl)-2-(methyloxy)acetamide 227 563.2 562.7748 N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-2-(2-methyl 1,3-thiazol-4-yl) acetamide 228 561.3 560.7346 2-(3,5-dimethyl-4-isoxazolyl)-N-((1 S,2R)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- 1 (phenylmethyl)propyl)acetamide 229 533.3 532.685 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(lH- 1,2,4 triazol- 1-yl) acetamide 230 533.3 532.685 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2H-1,2,3 triazol-2-yl) acetamide WO 2007/061670 PCT/US2006/044058 -88 231 491.2 490.6046 N-((I S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- 1 (phenylmethyl)propyl)-2-(2H-1,2,3-triazol-2-yl)acetamide 232 491.2 490.6046 N-((1 S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-I (phenylmethyl)propyl)-2-(IH-1,2,4-triazol-1-yl)acetamide 233 606.3 606.2066 2-(4-chloro-3-cyclopropyl-1H-pyrazol-1-yl)-N-((1S,2R)-3 (((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxy-1-(phenylmethyl) propyl)acetamide 234 560.3 559.7505 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(3,5 dimethyl-IH-pyrazol-1-yi) acetamide 235 546.3 545.7237 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(3-methyl 1H-pyrazol-1-yl) acetamide 236 546.3 545.7237 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(4-methyl IH-pyrazol-1-yl) acetamide 237 533.2 532.685 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(4H- 1,2,4 triazol-4-yl) acetamide 238 507.0; 507.8532 N-(( 1S,2R)-3-((8-bromo-6-chloro-3,4- 509.0 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl) propyl)acetamide WO 2007/061670 PCT/US2006/044058 -89 239 543.0; 543.8334 N-((1 S,2R)-3-(((4S)-8-bromo-6-chloro-3,4- 545.0 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- 1 -((3,5 difluorophenyl)methyl)-2-hydroxypropyl)acetamide 240 543.0; 543.8334 -((1 S,2R)-3-(((4R)-8-bromo-6-chloro-3,4- 545.0 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- 1-((3,5 difluorophenyl)methyl)-2-hydroxypropyl)acetamide 241 532.0; 532.8633 N-((] S,2R)-3-(((4S)-8-bromo-6-chloro-3,4- 534.0 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1 -((3 cyanophenyl)methyl)-2-hydroxypropyl)acetamide 242 514.1 514.0624 N-((I S,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)acetamide 243 565.1 564.7226 N-((1 S,2R)-3-(((4S)-6,8-di-4-morpholinyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)acetamide 244 550.1 550.0426 N-((IS,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- 1-((3,5 difluorophenyl)methyl)-2-hydroxypropyl) acetamide 245 539.1 539.0725 N-((1 S,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- 1 -((3 cyanophenyl)methyl)-2-hydroxypropyl) acetamide 246 566.1 1132.083 N-((1 S,2R)-3-(((2S,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5' tetrahydrospiro [chromene-2,3'-furan]-4-yl)amino)-1-((3,5 difluorophenyl)methyl)-2-hydroxypropyl)acetamide 247 523.0; 1047.704 N-((1 S,2R)-3-(((2S,4S)-8-bromo-6-chloro-3,4,4',5'- 525.0 tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy 1 -(phenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 -90 248 523.0; 1047.704 N-((1 S,2R)-3-(((2S,4R)-8-bromo-6-chloro-3,4,4',5'- 523.0 tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy 1-(phenylmethyl)propyl)acetamide 249 559.0; 1119.665 N-((1 S,2R)-3-(((2S,4S)-8-bromo-6-chloro-3,4,4',5'- 561.0 tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)- 1-((3,5 difluorophenyl)methyl)-2-hydroxypropyl) acetamide 250 559.0; 1119.665 N-((1 S,2R)-3-(((2S,4R)-8-bromo-6-chloro-3,4,4',5'- 561.0 tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-1-((3,5 difluorophenyl)methyl)-2-hydroxypropyl) acetamide 251 530.0; 530.0614 N-((1 S,2R)-3-(((2S,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5'- 532.0 tetrahydrospiro [chromene-2,3'-furan]-4-yl)amino)-2-hydroxy I -(phenylmethyl)propyl)acetamide 252 530.0; 530.0614 N-((1 S,2R)-3-(((2R,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5'- 532;0 tetrabydrospiro [chromene-2,3'-furan]-4-yl)amino)-2-hydroxy 1 -(phenylmethyl)propyl)acetamide 253 581 580.643 (E)-N-((2S,3R)-4-((S)-6,8-difluoro-3,4 dihydrospiro[chromen-2, '-cyclopentan]-4-ylamino)-3 hydroxy- 1 -phenylbutan-2-yI)-3-(5-fluoro-2 methoxyphenyl)acrylamide 254 563 562.653 (E)-N-((2S,3R)-4-((S)-6-fluoro-3,4-dibydrospiro[chromen 2,1 '-cyclopentan]-4-ylamino)-3-hydroxy- I -phenylbutan-2-yl) 3-(5-fluoro-2-methoxyphenyl)acrylamide 255 (E)-N-((2S,3R)-4-((S)-6-ethyl-3,4-dihydrospiro[chromen-2,1'- 559 558.69 cyclopentan]-4-ylamino)-3-hydroxy-I -phenylbutan-2-yi)-3 (5-fluoro-2-methoxyphenyl)acrylamide 256 479 478.673 N-((1 S,2R)-3-(((4S)-6-neopentyl-3,4-dihydrospiro[chromene 2, 1'-cyclopentyl]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)acetamide 257 413 412.502 N-((1 S,2R)-3-(((4S)-6-fluoro-3,4-dihydrospiro[chromene-2,

'

cyclobutan] 4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)acetamide WO 2007/061670 PCT/US2006/044058 -91 258 465 464.646 N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro [chromene-2, 1'-cyclobutan]-4-yl)amino)-2-hydroxy- 1 (phenylmethyl)propyl)acetamide 259 495 494.672 N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro [chromene-2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)-2-(methyloxy)acetamide 260 463 462.509 N-((1 S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6 (trifluoromethyl)-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)propyl)acetamide 261 493 492.535 N-((1 S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4S)-6 (trifluoromethyl)-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)propyl)-2-(methyloxy)acetamide 262 480 479.617 N-((l S,2R)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- 1 (phenylmethyl)propyl)acetamide 263 493 492.66 N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(4-methyl-1 -piperazinyl) 3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-1 (phenylmethyl)propyl)acetamide 264 464 463.618 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6-(1 pyrrolidinyl)-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4 yl)amino)propyl)acetamide 265 480 479.661 N-((IS,2R)-3-(((4S)-6-((2,2-dimethylpropyl)amino)-3,4 dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)acetamide 266 466 465.634 N-((1 S,2R)-3-(((4'S)-6-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yI)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)acetamide WO 2007/061670 PCT/US2006/044058 -92 267 496 495.66 N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2 (methyloxy)acetamide 268 N-((IS,2R)-3-(((4S)-6-chloro-7-(4-morpholinylmethyl)-3,4- 559 558.115 dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)-2-(methyloxy)acetamide 269 527 526.6244 2-cyano-N-((l S,2R)-1 -((3,5-difluorophenyl)methyl)-3-(((4'S) 6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide 270 502 501.6143 N-((] S,2R)- 1 -((3,5-difluorophenyl) methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide 271 532 531.6401 N-((1 S,2R)- 1 -((3,5-difluorophenyl) methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxypropyl)-2 methoxyacetamide 272 534 533.6731 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1H tetrazol-5-yl)acetamide 273 545 544.7356 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1-(phenylmethyl) propyl)-2-(1 -methyl 1 H-pyrrol-2-yi) acetamide 274 557 556.1428 N-((1 S,2R)-3-(((4S)-6-chloro-7-(1 -piperidinylmethyl)-3,4 dihydrospiro [chromene-2,1'-cyclobutanl-4-yl)amino)-2 hydroxy- I-(phenylmethyl)propyl)-2-(methyloxy)acetamide 275 521 520.67 N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-blpyridin]-4'-yl)amino)-2-hydroxypropyl)-2 (methyloxy)acetamide WO 2007/061670 PCT/US2006/044058 -93 276 558 557.6951 N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxypropyl)-2-(I H 1,2,4-triazol- 1 -yl)acetamide 277 495 494.6758 N-((] S,2R)-3-(((4S)-6-((2-(dimethylamino) ethyl)(methyl)amino)-3,4-dihydrospiro [chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)acetamide 278 482 481.6331 N-((1S,2R)-2-hydroxy-3-(((4S)-6-(methyl (2 (methyloxy)ethyl)amino)-3,4-dihydrospiro[chromene-2,1' cyclobutan}-4-yl)amino)- I -(phenylmethyl)propyl) acetamide 279 461 460.5748 N-((I S,2R)-2-hydroxy-3-(((4S)-6-(lH-imidazol- 1-yl)-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- 1 (phenylmethyl)propyl)acetamide 280 461 460.5748 N-((1 S,2R)-2-hydroxy- I -(phenylmethyl)-3-(((4S)-6-(1 H pyrazol- 1-yl)-3,4-dihydrospiro[chromene-2, 1'-cyclobutan]-4 yl)amino)propyl)acetamide 281 547 546.679 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4 ylamino)-3-hydroxy-1 -phenylbutan-2-yl)-2-(3 fluorophenoxy)acetamide 282 515 514.662 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy-l-phenylbutan-2-yl)-3-(furan-2 yl)acrylamide 283 587 586.729 (E)-3-(2,4-dimethoxypyrimidin-5-yl)-N-((2S,3R)-4-((S)-6 ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy- 1 phenylbutan-2-yI)acrylamide 284 515 514.662 (E)-N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy-l-phenylbutan-2-yl)-3-(furan-3 yl)acrylamide 285 569 568.71 (E)-3-(benzo[d][1,3]dioxol-5-yl)-N-((2S,3R)-4-((S)-6-ethyl 2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy- 1 phenylbutan-2-yl)acrylamide WO 2007/061670 PCT/US2006/044058 -94 286 531 530.729 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-bydroxy-1-phenylbutan-2-yl)-3-(thiophen-2 yl)acrylamide 287 564 563.738 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(IH-indol-3 yl)acrylamide 288 526 525.689 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(pyridin-4 yl)acrylamide 289 526 525.689 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(pyridin-3 yl)acrylamide 290 526 525.689 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman 4-ylamino)-3-hydroxy- 1-phenylbutan-2-yl)-3-(pyridin-2 yl)acrylamide 291 411 410.555 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- I (phenylmethyl)propyl)acetamide 292 503 502.651 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)-2 (phenyloxy)acetamide 293 441 440.58 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)-2 (methyloxy)acetamide 294 521 520.641 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 ((3-fluorophenyl)oxy)acetamide WO 2007/061670 PCT/US2006/044058 -95 295 535 1069.34 (2S)-N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro 2H-chromen-4-yl) amino)-2-hydroxy- 1 (phenylmethyl)propyl)-2-((3-fluorophenyl)oxy)propanamide and '(2R)-N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4 dihydro-2H-chromen-4-yl) amino)-2-hydroxy- 1 1 (phenylmethyl)propyl)-2-((3-fluorophenyl)oxy)propanamide 296 492 491.628 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 (3-methyl-5-isoxazolyl)acetamide 297 533 532.677 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 ((3-(methyloxy)phenyl)oxy)acetamide 298 501 500.679 N-((1S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)-3 phenylpropanamide 299 455 454.607 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 (ethyloxy)acetamide 300 565 564.806 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 (((IR,2S,5R)-5-methyl-2-(1-methylethyl) cyclohexyl)oxy)acetamide 301 517 516.678 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2 ((2-methylphenyl)oxy)acetamide 302 533 532.677 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H cliromen-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)-2 ((2-(methyloxy)phenyl)oxy)acetamide WO 2007/061670 PCT/US2006/044058 -96 303 483 482.661 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 ((2-methylpropyl)oxy)acetamide 304 504 503.639 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- 1-(phenylmethyl)propyl)-2 (3-pyridinyloxy)acetamide 305 425 424.581 N-((1 S,2R)-3-(((4S)-6-ethy1-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl) propanamide 306 439 438.608 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)-2 methylpropanamide 307 471 941.212 N-((1 S,2R)-3-(((2R,4S)-6-ethyl-2-methyl-2 ((methyloxy)methyl)-3,4-dihydro-2H-chromen-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)-2-(methyloxy) acetamide and 'N-((1 S,2R)-3-(((2S,4S)-6-ethyl-2-methyl-2 ((methyloxy)metbyl)-3,4-dihydro-2H-chromen-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)-2-(methyloxy) acetamide 308 455 909.214 N-((1 S,2R)-3-(((2R,4S)-6-ethyl-2-methyl-2 ((methyloxy)methyl)-3,4-dihydro-2H-chromen-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)propanamide and 'N ((1 S,2R)-3-(((2S,4S)-6-ethyl-2-methyl-2 ((methyloxy)methyl)-3,4-dihydro-2H-chromen-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)propanamide 309 424 423.554 N-((I S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- 1 (phenylnethyl)propyl)acetamide 310 495 494.6718 N-((1S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2 (tetrahydro-2H-pyran-4-yl)acetamide WO 2007/061670 PCT/US2006/044058 -97 311 481 961.29 N-((1S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-bydroxy- 1 -(phenylmethyl)propyl)-2 ((2R)-tetrahydro-2-furanyl)acetamide and 'N-((1 S,2R)-3 (((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-chromen-4 yl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)-2-((2S) tetrahydro-2-furanyl)acetamide 312 511 510.6708 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2 (tetrahydro-2H-pyran-4-yloxy)acetamide 313 511 1021.342 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)-2 ((3R)-tetrahydro-2H-pyran-3-yloxy)acetamide and 'N ((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl) amino)-2-hydroxy-1-(phenylmethyl)propyl)-2 ((3S)-tetrahydro-2H-pyran-3-yloxy) acetamide 314 508.3 507.671 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-2-(4-morpholinyl)acetamide 315 531.3 530.748 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, ' cyclobutan]-4-yl)amino)-2-hydroxy- 1-((3-(2-propen- 1 yl)phenyl)methyl)propyl)-6-heptenamide 316 N-((I S,2R)-3-(((2S,4S)-6-ethyl-3,4,4',5'- 439.3 877.129 tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy 1-(phenylmethyl) propyl)acetamide 317 469.2 937.181 N-((I S,2R)-3-(((2S,4S)-6-ethyl-3,4,4',5' tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy I -(phenylmethyl) propyl)-2-(methyloxy)acetamide 318 412.2 411.543 N-((1 S,2R)-3-(((4S)-2-cyclopropyl-6,6-dimethyl-4,5,6,7 tetrahydro- 1,3-benzoxazol-4-yl)amino)-2-hydroxy- 1 (phenylmethyl)propyl)acetamide 319 442.3 441.569 N-((1 S,2R)-3-(((4S)-2-cyclopropyl-6,6-dimethyl-4,5,6,7 tetrahydro-1,3-benzoxazol-4-yl)amino)-2-hydroxy- 1 (phenylmethyl)propyl)-2-(methyloxy) acetamide 320 522.3 521.698 N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-3-(4-morpholinyl)propanamide WO 2007/061670 PCT/US2006/044058 -98 321 396.2 395.544 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((5S)-3,7,7 trimethyl-5,6,7,8-tetrahydro-5-quinolinyl)amino) propyl)acetamide 322 469.2 468.59 N-((1 S,2R)-3-(((2R,4S)-6-ethyl-3,4,4',5' tetrahydrospiro[chromene-2,3'-fiiran]-4-y)amino)-2-hydroxy 1-(pbenylmethyl) propyl)-2-(methyloxy)acetamide 323 469.2 468.59 N-((1 S,2R)-3-(((2S,4S)-6-ethyl-3,4,4',5' tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy 1 -(phenylmethyl) propyl)-2-(methyloxy)acetanide 324 439.2 438.565 N-((1 S,2R)-3-(((2R,4S)-6-ethyl-3,4,4',5' tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy 1-(phenylmethyl) propyl)acetamide 325 439.2 438.565 N-((] S,2R)-3-(((2S,4S)-6-ethyl-3,4,4',5' tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy 1-(phenylmethyl) propyl)acetamide 326 453.3 452.591 N-((1 S,2R)-3-(((4S)-6-ethyl-2',3,3',4,5',6' exahydrospiro[chromene-2,4'-pyran]-4-yl)amino)-2-hydroxy I -(phenylmethyl)propyl)acetamide 327 483.3 482.617 N-((IS,2R)-3-(((4S)-6-ethyl-2',3,3', 4,5',6' hexahydrospiro[chromene-2,4'-pyran]-4-yl)amino)-2-hydroxy 1-(phenylmethyl)propyl)-2-(methyloxy) acetamide 328 438.3 437.5805 N-((1 S,2R)-2-hydroxy-3-(((5'S)-3'-methyl-5',8'-dihydro-6'H spiro[cyclobutane-1,7'-quinolin]-5'-yl)amino)-1 (phenylmethyl) propyl)-2-(methyloxy)acetamide 329 474.2 473.5607 N-((l S,2R)-1 -((3,5-difluorophenyl) methyl)-2-hydroxy-3 (((5'S)-3'-methyl-5',8'-dihydro-6'H-spiro[cyclobutane- 1,7' quinolin]-5'-yl)amino)propyl)-2-(methyloxy)acetamide 330 475.2 474.6056 N-((1 S,2R)-2-hydroxy-3-(((5'S)-3'-methyl-5',8'-dihydro-6'H spiro[cyclobutane- 1,7'-quinolin]-5'-yl)amino)-1I (phenylmethyl) propyl)-2-(1H-1,2,4-triazol-1-yl) acetamide 331 511.2 510.5858 N-((1 S,2R)-1I-((3,5-difluorophenyl) methyl)-2-hydroxy-3 (((5'S)-3'-methyl-5',8'-dihydro-6'H-spiro[cyclobutane-1,7' quinolin]-5'-yl)amino)propyl)-2-(H-1,2,4-triazol-1 yl)acetamide WO 2007/061670 PCT/US2006/044058 -'99 332 475.3 474.6412 N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy- 1-((3-(2-propen- 1 yl)phenyl)methyl)propyl)-2-propenamide 333 489.3 488.668 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1-((3-(2-propen-1 yl)phenyl)methyl)propyl)-3-butenamide 334 503.3 502.6948 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutanl-4-yl)amino)-2-hydroxy- 1 -((3-(2-propen- 1 yl)phenyl)methyl)propyl)-4-pentenamide 335 517.3 516.7216 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1-((3-(2-propen-1 yl)phenyl)methyl)propyl)-5-hexenamide 336 686, 688 686.7268 1,1-dimethylethyl (7-(((1S,2R)-1-((3-bromophenyl)methyl)-3 (((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4 yl)amino)-2-hydroxypropyl)amino)-7-oxoheptyl)carbamate 337 720, 722 720.744 phenylmethyl (7-(((1 S,2R)- 1 -((3-bromophenyl)methyl)-3 (((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, '-cyclobutan]-4 yl)amino)-2-hydroxypropyl)amino)-7-oxoheptyl)carbamate 338 465.2 464.646 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy- I -phenylbutan-2-yl)pentanamide 339 465.2 464.646 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-methylbutanamide 340 465.2 929.292 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy- 1 -phenylbutan-2-yl)-2-methylbutanamide 341 466.1 465.634 2-(dimethylamino)-N-((2S,3R)-4-((S)-6-ethyl-2,2 spirocyclobutylchroman-4-ylamino)-3-hydroxy- 1 phenylbutan-2-yl) acetamide 342 500.2 499.651 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy- 1 -phenylbutan-2-yI)-2-(pyridin-2 yl)acetamide 343 463.1 462.63 2-cyclopropyl-N-((2S,3R)-4-((S)-6-ethyl-2,2 spirocyclobutylchroman-4-ylamino)-3-hydroxy- 1 phenylbutan-2-yl)acetamide WO 2007/061670 PCT/US2006/044058 - 100 344 505.1 504.691 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1 -phenylbutan-2-yl)-2-(thiophen-2 yl)acetamide 345 504.2 503.639 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-(3 methylisoxazol-5-yl)acetamide 346 493.2 492.7 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4 ylamino)-3-hydroxy-1 -phenylbutan-2-yl)heptanamide 347 491.2 490.684 2-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2 spirocyclobutylchroman-4-ylamino)-3-hydroxy-1 phenylbutan-2-yl)acetamide 348 505.1 504.691 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro(chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(3-thienyl)acetamide 349 555.1 555.534 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(3-thienyl)acetamide 350 605.1 605.594 2-(1 -benzothien-3-yl)-N-((1 S,2R)-3-(((4S)-6-bromo-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)acetamide 351 569.1 569.561 N-((IS,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-I-(phenylmethyl) propyl)-2-(2-methyl-3-thienyl)acetamide 352 584.1 584.576 N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- 1-(phenylmethyl) propyl)-2-(2,5-dimethyl-1,3-thiazol-4-yi) acetamide 353 553.2 553.498 N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1-methyl-1H-imidazol-4-yl) acetamide 354 539.1 539.471 N-((IS,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1H-imidazol- I -yl)acetamide 355 503.3 502.655 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, ' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1-methyl-IH-imidazol-4-yl) acetamide WO 2007/061670 PCT/US2006/044058 - 101 356 489.3 488.628 N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1H-imidazol-1-yl)acetamide 357 472.2 471.638 N-((1S,2R)-1-((1-acetyl-3-piperidinyl) methyl)-3-(((4S)-6 ethyl-3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4 yl)amino)-2-hydroxypropyl)acetamide 358 506.2 505.655 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2-oxo- 1 -pyrrolidinyl)acetamide 359 556.1 556.498 N-((I S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(2-oxo- 1 -pyrrolidinyl)acetamide 360 554.2 553.699 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)acetamide 361 520.3 1039.36 (2R)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2-oxo- I-pyrrolidinyl) propanamide 362 520.3 519.682 (2R)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2-oxo- 1 -pyrrolidinyl) propanamide 363 520.3 519.682 (2S)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-2-(2-oxo- 1 -pyrrolidinyl) propanamide 364 480.2 479.617 N~2~-acetyl-N~1~--((I1S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospirolchromene-2, 1'-cyclobutanj-4-yl)amino)-2 hydroxy-1-(phenylmethyl)propyl)glycinamide 365 505.3 1009.33 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((1R)-2-oxocyclopentyl) acetamide 366 520.3 1039.36 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, ' cyclobutan]-4-yl)amino)-2-bydroxy- I -(phenylmethyl) propyl)-2-((3R)-3-methyl-2-oxo- 1 -pyrrolidinyl)acetamide 367 520.3 519.682 N-((IS,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((3R)-3-methyl-2-oxo-1-pyrrolidinyl)acetamide WO 2007/061670 PCT/US2006/044058 -102 368 520.3 519.682 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((3S)-3-methyl-2-oxo-1-pyrrolidinyl)acetamide 369 513.3 512.65 2-(2-cyano-1H-pyrrol-1-yl)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)acetamide 370 494.2 493.644 N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- 1-(phenylmethyl)propyl)-2 (2-oxo-1-pyrrolidinyl)acetamide 371 436.1 435.565 2-cyano-N-((l S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4 dihydro-2H-chromen-4-yl) amino)-2-hydroxy-1 (phenylmethyl) propyl) acetamide 372 442.1 883.137 N-((1 S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((8R)-2,6,6 trimethyl-3-oxo-2,3,5,6,7,8-hexahydro-8 isoquinolinyl)amino)propyl)-2-methoxyacetamide 373 412.1 823.0854 N-((] S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((8R)-2,6,6 trimethyl-3-oxo-2,3,5,6,7,8-hexahydro-8-isoquinolinyl)amino) propyl) acetamide 374 531.2 530.6652 N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(2-oxo- 1 -pyrrolidinyl)acetamide 375 545.2 544.692 N-((1 S,2R)- 1 -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(3-methyl-2-oxo- 1-pyrrolidinyl)acetamide 376 529.2 528.6494 N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)-2-(3-methyl-5-isoxazoly) acetamide 377 549.3 548.7236 N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(2-oxo- 1 pyrrolidinyl)acetamide 378 563.3 562.7504 N-((1S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(3-methyl 2-oxo- I -pyrrolidinyl) acetamide WO 2007/061670 PCT/US2006/044058 - 103 379 547.3 546.7078 N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(3-methyl 5-isoxazolyl) acetamide 380 548.3 1095.471 N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-((1 R)-2 oxocyclopentyl) acetamide 381 559.3 558.7188 N-((1 S,2S)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(pbenylmethyl) propyl)-2-(2-oxo 1(2H)-pyridinyl) acetamide 382 577.3 1153.554 N-((I S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridinl-4' yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((1S,2E)-2 ((methyloxy) imino)cyclopentyl)acetamide 383 481.1 480.6054 N-((1S,2R)-2-hydroxy-3-(((4'S)-6'-(4-norpholinyl)-3',4' dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)- 1 -(phenylmethyl)propyl) acetamide 384 466.1 931.181 N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(tetrahydrofuran-2-yl) 3',4'-dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1-(phenylmethyl)propyl) acetamide 385 397.3 793.064 N-((2S,3R)-3-hydroxy- 1-phenyl-4-((R)-2,7,7-trimethyl 5,6,7,8-tetrahydroquinazolin-5-ylamino)butan 2-yl)acetamide 386 411.3 821.022 N-((1 S,2R)-2-hydroxy-I -(phenylmethyl)-3-((2S,4S)-3,4,4',5' tetrabydrospiro [chromene-2,3'-furan]-4-ylamino)propyl) acetamide 387 489.1 978.8142 N-((1 S,2R)-3-(((2R?,48)-6-bromo-3,4,4',5' tetrahydrospiro[chromene-2,3'-furan] 4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)acetamide 388 492.3 491.6283 N-((1 S,2R)-2-hydroxy-3-(((4S)-6-((1 S,4S)-2-oxa-5 azabicyclo[2.2.1 ]hept-5-yl)-3,4-dihydrospiro[chromene-2, 1' cyclobutan] 4-yl)amino)-1-(phenylmethyl)propyl) acetamide WO 2007/061670 PCT/US2006/044058 - 104 389 507.9 1015.342 N-((1 S,2R)-3-(((4S)-6-((2R,6S)-2,6-dimethyl-4-morpholinyl) 3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)acetamide 390 508.3 507.6709 N-((1 S,2R)-3-(((4S)-6-((2S,5S)-2,5-dimethyl-4-morpholinyl) 3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)acetamide 391 509 508.655 (3S)-tetrahydro-3-furanyl ((I S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclopentan]-4-yl)amino)-2 hydroxy-1 -(phenylmethyl)propyl)carbamate 392 495 494.628 (3S)-tetrahydro-3-furanyl ((1 S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)carbamate 393 463 462.534 methyl ((1 S,2R)- 1 -((3,5-difluorophenyl) methyl)-3-(((4S)-6 ethyl-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl)amino)-2 hydroxypropyl)carbamate 394 439 438.565 methyl (2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-chroman 4-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate 395 483 482.617 2-(methyloxy)ethyl((1 S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)carbamate 396 415 414.611 N-((l S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro 1-benzothien-4-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide 397 512 511.6623 (2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-3-(3-pyridinyl)-2-propenamide 398 545 544.6633 (2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-3-(3-fluoro-4-hydroxyphenyl)-2-propenamide 399 567 566.7418 3-(lH-benzimidazol-1 -yl)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)-2-methylpropanamide 400 579 579.5315 (2E)-3-(4-bromo-2-furanyl)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy-I -(phenylmethyl)propyl)-2-propenamide WO 2007/061670 PCT/US2006/044058 - 105 401 583 582.7652 N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(4-quinazolinylthio)acetamide 402 590 590.5584 (2E)-3-(5-bromo-3-pyridinyl)-N-((I S,2R)-3-(((4S)-6-ethyl 3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)-2-propenamide 403 597 596.6614 (2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-3-(5-fluoro-2-(trifluoromethyl) phenyl)-2 propenamide 404 514 513.6781 N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-3-(3-pyridinyl)propanamide 405 517 516.682 N-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, ' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-3-(1 H-imidazol-1 -yl)butanamide 406 519 518.7182 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-3-(2-thienyl)propanamide 407 532 531.7173 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-y)amino)-2-hydroxy- 1-(phenylmethyl) propyl)-2-(4-pyridinylthio)acetamide 408 552 551.7723 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- 1-(phenylmethyl) propyl)-2-((4-methyl-1,3-thiazol-2-yl) thio)acetamide 409 556 555.6902 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(5-fluoro- I H-indol-3-yl) acetamide 410 562 561.7221 (2E)-N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-3-(3-quinolinyl)-2-propenamide 411 565 564.6445 (2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2, l'-cyclobutan]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl) propyl)-3-(3,4,5-trifluorophenyl)-2-propenamide WO 2007/061670 PCT/US2006/044058 - 106 412 573 572.7169 N-((IS,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-4-(3-fluoro-4-methylphenyl)-4-oxobutanamide 413 576 575.7489 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2-(3-pyridinyl)phenyl) acetamide 414 583 582.7652 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1-phthalazinylthio)acetamide 415 591 590.6634 (2E)-3-(2,2-difluoro-1,3-benzodioxol-4-yl)-N-((1S,2R)-3 (((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4 yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2 propenamide 416 610 609.759 N-1--((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-I-(phenylmethyl) propyl)-N-2--(2-fluorophenyl)-N-2- (methylsulfonyl)glycinamide 417 568 567.7299 (3R)-3-(1H-l,2,3-benzotriazol-1-yl)-N-((I S,2R)-3-(((4S)-6 ethyl-3,4-dihydrospiro[chromene-2, 1'-cyclobutan]-4 yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)butanamide 418 551 550.7842 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(2-thienylthio)propanamide 5 The following compounds in Tables 1 and 2 are additional representative examples of Formulas I-II, as provided by the present invention. Table 1 WO 2007/061670 PCT/US2006/044058 - 107 H OH R R, N s o B R 3

R

3

C

2

H

5 Ex. Wand No. RlB w 1S 419 1-morpholinyl-CH 2 - benzyl-O- H NH cyclobutyl 420 1-piperazinyl-CH 2 - benzyl-S- H S cyclobutyl 421 I-piperidinyl-CH 2 - benzy]-NH- H 0 cyclobutyl 422 3-oxo-l-pyrrolidinyl-CH 2 - benzyl-0- H NH cyclopentyl 423 1-morpholinyl-CH=CH- benzyl-S- H S cyclopentyl [424 1 -piperaziriyl-CH=CH- benzyl-NH- H 0 cyclopentyl 425 oxo-pyrrolidinyl-CH=CH- Benzyl-CH 2 - H S02 cyclopropyl 426 oxazolidinyl-CH=GH- benzyl-0- H NH cyclopropyl 427 isoxazolidinyl-CH 2 - benzyl-S- H S cyclopropyl 428 indolinyl-CH- 2 - benzyl-N-H- H 0 cyclohexyl 429 1-morpholinyl-CH 2 - benzyl-CH 2 - H SO 2 cyclohexyl 430 1 -piperazinyl-CH 2 - benzyl-O- H NH cyclohexyl 431 1-piperidinyl-GH 2 - benzyl-S- H S cyclobutyl 432 3-oxo-I -pyrrolidinyl-CH 2 - benzyl-NH- H 0 clobuftyl 433 1-morpholinyl-CH=CH- benzy]-CH 2 - H S02 cyclobutyl 434 I-piperazinyl-CH=CH- benzyl-O- H Nil cyclopentyl 435 oxo-pyrrolidinyl-CH=CH- benzyl-S- H S cyclopentyl 436 oxazolidinyl-CH=CH- benzyl-NH- H 0 cyclopentyl 437 isoxazolidinyl-CH 2 - benzyl-CH 2 - H S0 2 cyclohexyl 438 indolinyl-CH 2 - 4-CH 3 -phenyl H NH cyclohexyl 439 CH 3 -. phenyl H S cyclohexyl Table 2 5 H R 0 R 3

R

3 B COH

-

r

C

2

H

5 WO 2007/061670 PCT/US2006/044058 - 108 Ex. and No. R' B R4 X1 S 440 1 -morpholinyl-CH 2 - 4-CH 3 -phenyl H NH cyclobutyl 441 1-piperazinyl-CH 2 - 4-CH 3 -phenyl H S cyclobutyl 442 1-piperidinyl-CH 2 - 4-CH 3 -pyridyl H 0 cyclobutyl 443 3-oxo-1-pyrrolidinyl-CH 2 - 4-CH 3 -phenyl H NH cyclopentyl 444 1-morpholinyl-CH=CH- 3-CH 3 -phenyl H S cyclopentyl 445 1-piperazinyl-CH=CH- 3-CH 3 -phenyl H 0 cyclopentyl 446 oxo-pyrrolidinyl-CH=CH- 3-CH 3 -phenyl H SO 2 cyclopropyl 447 oxazolidinyl-CH=CH- 3-CH 3 -phenyl H NH cyclopropyl 448 isoxazolidinyl-CH 2 - phenyl H S cyclopropyl 449 indolinyl-CH 2 - phenyl H 0 cyclohexyl 450 1-morpholinyl-CH 2 - phenyl H SO 2 cyclohexyl 451 1-piperazinyl-CH 2 - phenyl H NH cyclohexyl 452 1-piperidinyl-CH 2 - pyridyl H S cyclobutyl 453 3-oxo-1-pyrrolidiny-CH 2 - phenyl H 0 cyclobutyl 454 1-morpholinyl-CH=CH- 3-F-phenyl H SO 2 cyclobutyl 455 1-piperazinyl-CH=CH- 3-Cl-phenyl H NH cyclopentyl 456 oxo-pyrrolidinyl-CH=CH- 3-CN-phenyl H S cyclopentyl 457 oxazolidinyl-CH=CH- 3-NH 2 -phenyl H 0 cyclopentyl 458 isoxazolidinyl-CH 2 - 2-F-phenyl H SO2 cyclohexyl 459 indolinyl-CH 2 - 4-CH 3 -phenyl H NH cyclohexyl 460 CH 3 - phenyl H S cyclohexyl The following examples provide a further understanding and appreciation of compounds of the present invention. 5 Example 461 N-((1S,2R)-3-(((4S)-6-(2-fluoro-2-methylpropyl)-3,4-dihydrospiro[chromene-2,1' cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide 10 Step 1: (S)-tert-butvl 6-(2-oxopropyl)-2,2-spiroeyclobutvl-3,4-dihyd ro-2H-chromen 4-ylearbamate Pd 2 (dba) 3 (15 mg, 0.017 mmol), (S)-tert-butyl 6-bromo-2,2-spirocyclobutyl-3,4 dihydro-2H-chromen-4-ylcarbamate (15 mg, 0.041 mmol), 2-(dicyclohexylphosphino) 2'-methylbiphenyl (80 mg, 0.170 mmol), potassium phosphate (179 mg, 0.845 mmol), 15 and acetone (2.5 ml, 33.8 mmol) were dissolved in 1 ml THF in a sealed tube. The tube was sealed and heated to 70 OC for 8 hours. The cooled reaction mixture was diluted with DCM (10 mL) and poured into saturated sodium bicarbonate (25 mL). The layers were separated and the aqueous layer was extracted with DCM 2 x 25 mL.

WO 2007/061670 PCT/US2006/044058 - 109 The combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated to provide the title compound as a yellow oil (75 mg; 0.166 mmol, 99%). MS m/z: 368.2 (M+Na). Step 2: (S)-6-(2-fluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4 5 amine To pulverized cerium chloride (428 mg, 1.74 mmol) suspended in 10 mL of THF at 0 0 C was added methylmagnesium bromide (3.0 M in diethyl ether, 0.60 mL, 1.79 mmol). After stirring for 20 min a solution of (S)-tert-butyl 6-(2-oxopropyl)-2,2-spirocyclobutyl chroman-4-ylcarbamate (200 mg, 0.579 mmol) in 3 mL of THF was added and the resulting 10 mixture was stirred at 0 OC for 30 minutes. The reaction was quenched with saturated ammonium chloride (10 mL) and the aqueous layer was extracted with EtOAc 3 x 20 mL. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to provide the corresponding alcohol (209 mg, 99%) as a yellow oil. The derived alcohol (209 mg, 0.578 mmol) was taken up in 1 mL of DCM cooled to -78 0 C and 15 treated with DAST (0.153 mL, 1.16 mmol). After stirring for 45 minutes the reaction was warmed to 0 0 C and quenched with saturated potassium carbonate (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane 3 x 10 mL. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (0-25% EtOAc in 20 hexanes) to provide the amine as a yellow oil. The derived amine was taken up in 5 mL of DCM and treated with 2 mL of TFA. After stirring for 1 hour, the reaction was diluted with 25 mL of DCM and poured into 10% aqueous potassium carbonate (50 mL). The layers were separated and the aqueous layer was extracted with DCM 3 x 20 mL. The combined organic layers were washed with water and brine, dried over sodium sulfate and 25 concentrated to provide the title compound as a yellow oil (113 mg, 74%). MS n/z: 386.2 (M+Na). Step 3: N-((IS,2R)-3-(((4S)-6-(2-fluoro-2-methylpropyl)-3,4-dihydrospiro[chromene-2,1' cyclobutanl-4-yl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)acetamide The amine from step 2 was carried on by methods analogous to those described in Example 30 464, Steps 8-10 herein to afford the title compound. MS found: m/z: 469 (M+1).

WO 2007/061670 PCT/US2006/044058 - 110 Example 462 N-((1S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-blpyridin]-4'-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide 5 Step 1: (S)-tert-butyl 6-(2-oxopropyl)-2,2-spirocyclobutyl-3.4-dihydro-2H-pyranof2,3 blpyridin-4-ylcarbamate Pd 2 (dba) 3 (409 mg, 0.447 mmol) and 2-(dicyclohexylphosphino)-2'-methylbiphenyl (391 mg, 1.07 mmol) were combined in a 250 mL sealable tube. THF (15 mL) was added and 10 the mixture was purged with nitrogen for 5 minutes before the introduction of (S)-tert-butyl 6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (3.30 mg, 8.94 mmol, potassium phosphate(4.74 g, 22.3 mmol), and acetone (51.9 g, 894 mmol). The tube was sealed and heated to 70 0 C for 8 hours. The cooled reaction mixture was concentrated and purified by silica gel chromatography (0-100% ethyl acetate in hexanes) 15 to provide the title compound as a yellow oil (2.15 g, 69%). MS m/z: 347.2 (M+1). Step 2: (S)-6-(2-fluoro-2-methylpropvl)-2.,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3 blpyridin-4-amine To pulverized cerium chloride (12.0 g, 51 mmol) suspended in 25 mL of THF at 0 OC was added methylmagnesium bromide (3.0 M in diethyl ether, 17.0 mL, 51 mmol). After 20 stirring for twenty minutes a solution of (S)-tert-butyl-6-(2-oxopropyl)-2,2-spirocyclobutyl 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (3.50 g, 10 mmol) in 50 mL of THF was added over the course of thirty minutes. After stirring at 0 0 C for 30 minutes the reaction was quenched with saturated ammonium chloride (100 mL) and the aqueous layer was extracted with ethyl acetate 3 x 100 mL. The combined organic layers were washed 25 with brine, dried over sodium sulfate and concentrated to provide the corresponding alcohol as a yellow oil. The derived alcohol was taken up in 100 mL of DCM and cooled to -78 0 C at which point DAST (7.0 mL, 51 mmol) was added. After stirring for 45 minutes the reaction was quenched with saturated sodium bicarbonate (150 mL). The layers were separated and the aqueous layer was extracted with DCM 3 x 100 mL. The combined 30 organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (0-35% EtOAc in bexanes) to provide the fluoride as a yellow foam. The derived amine was taken up in 50 mL of DCM and treated with 20 mL of TFA. After stirring for 1 hour, the reaction was concentrated, taken up in 50 mL of DCM and poured into 10% aqueous potassium carbonate (200 mL). The WO 2007/061670 PCT/US2006/044058 - 111 layers were separated and the aqueous layer was extracted with DCM 3 x 100 mL. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated to provide the title compound as a brown oil (1.15 g, 43%). MS m/z: 365.2 (M+1). 5 Step 3: N-(( S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-dihydrospirocyclobutane 1,2'-pyrano[2,3-blpyridin14-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide The amine from step 2 was carried on by methods analogous to those described in Example 464, Steps 8-10 herein to afford the title compound. MS found m/z: 470 (M+1). Example 463 10 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclopent-3-ene-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide 15 Step 1: 4-(2,2-dimethoxyethyl)hepta-1,6-dien-4-ol In a 2 liter round bottom flask equipped with a stir bar, methyl 3,3-dimethoxypropanoate (24 g, 162 mmol) was dissolved in THF (1L). Under nitrogen, the solution was chilled to 78 "C. Allyl Magnesium bromide, 1.0 M solution in diethyl ether (405 mL, 405 mmol) was added dropwise in such a way that the internal temperature remained lower than -75*C. 20 After addition, the reaction was allowed to stir for 3 hours at -78'C before being quenched with saturated ammonium chloride solution (300 mL). The ice bath was removed and the reaction allowed to come to RT. Water was added (200 mL) and the reaction was concentrated on a rotary evaporator to remove as much THF as possible. The product was extracted from the resulting aqueous with diethyl ether (3x200 mL). The organics were 25 then washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to afford the product. Step 2: 1-(2,2-dimethoxyethyl)cyclopent-3-enol A solution of 4-(2,2-dimethoxyethyl)hepta-1,6-dien-4-ol (28g, 140mmol) in DCM (2L) was charged to a 3 L RB flask. Dry argon was bubbled through the solution for ~ 30 minutes. 30 Grubbs second generation catalyst (5.9g, 7.Ommol) was added and the reaction was allowed to stir under argon for 15 hours. The reaction was quenched with a solution of tetrakis (hydroxymethyl)phosphonium chloride (27g, 140mmol) in isopropanol (200 mL) and 10 N NaOH (14 mL), and stirred for 15 hours. The reaction was diluted with water (1 L) and poured into a seperatory funnel. The DCM layer was separated and the aqueous was WO 2007/061670 PCT/US2006/044058 - 112 extracted with DCM (3x100 mL). The combined organics were concentrated to a dark oil which was purified by flash chromatography on a 330g ISCO column eluting by gradient hexanes to 20% EtOAc/ hexanes over a 50 minute period. Product fractions were combined to afford the title compound. 5 Step 3: 2-(1-(tert-butyldimethylsilyloxy)cyclopent-3-enyl) acetaldehyde 1-(2,2-dimethoxyethyl)cyclopent-3-enol (13.5g, 78mmol) was dissolved in DCM (250mL). This was chilled to 0"C under nitrogen and 2,4,6-trimethylpyridine (42mL, 314mmol) was added dropwise over 10 minutes. Tert-butyldimethylsilyl trifluoromethanesulfonate (18 mL, 78mmol) was added dropwise via syringe very slowly over 20 minutes keeping the 10 internal temperature below 5*C. The reaction was allowed to come to RT. By TLC (20% EtOAc/hexanes; KMnO4 stain), the starting material was completely consumed (-2 hours). The reaction was then chilled back to 0*C and triethylsilyl trifluoromethanesulfonate (35mL, 157mmol) was added in dropwise over a 10 minute period. This was allowed to stir at 0 0 C for 1 hour before adding water (250 mL). The ice bath was removed and this 15 mixture was stirred vigorously for -18 hours. The reaction was poured into a seperatory funnel and the DCM layer was separated. The organic was washed with dilute aqueous HCl, brine, dried over sodium sulfate, filtered and concentrated to afford a yellow oil which was flashed on silica by gradient eluting with hexanes to 20% EtOAc/hexanes over a 40 minute period. Product fractions were combined to afford the title compound. 20 Step 4: (Z)-N-(2-(1 -(tert-butyldimethylsilyloxy)cyclopent-3 -enyl)ethylidene-2 methylpropane-2-sulfinamide 2-(1-(tert-butyldimethylsilyloxy)cyclopent-3-enyl) acetaldehyde (22g, 92mmol) was dissolved in DCM (500 mL). To this was added 2(R)-methylpropane-2-sulfinamide (13g, 1 10mmol), followed by anhydrous cupric sulfate (128 mmol). This was allowed to stir at 25 RT for 72 hours. The reaction was filtered and the resulting mother liquor was concentrated to a yellow oil which was purified by flash chromatography eluting with hexanes to 20% EtOAc/hexanes over a 40 minute period. Product fractions were combined and concentrated to afford the product as a colorless oil. Step 5: (2S)-N-(2-(I-(tertbutyldimethylsilyloxy)cyclopent-3-enyl)-1-(2-fluoro-5 30 neopentvlpyridi-3-vl)ethyl)-2-methylpropane-2-sulfinamide In a flame dried flask, 2,2,6,6-tetramethyl piperidine(6.3mL, 3 7.1mmol) was added to THF (20mL). Chilled to -78"C under nitrogen. To this was added dropwise n-butyllithium (1.6M in hexanes, 12 mL, 30.3mmol). After stirring an additional 5 minutes at -78 0 C, the reaction was removed from the ice bath and allowed to warm to 0"C and then recooled to - WO 2007/061670 PCT/US2006/044058 - 113 78*C. 2-fluoro-5-neopentyl pyridine (4.5g, 27mmol) was added dropwise over a 5 minute period. This was allowed to stir for 30 minutes before adding dropwise (Z)-N-(2-(1-(tert butyldimethylsilyloxy) cyclopent-3-enyl)ethylidene-2-methylpropane-2-sulfinamide (1 l.6g, 33.7mmol) over a 5 minute period. This was allowed to stir for 3 hours before being 5 quenched with saturated bicarbonate solution (100 mL) and the ice bath was removed. Product was extracted with EtOAc (3x75 mL), washed with brine, and concentrated to give a yellow oil which was purified by column chromatography (20% EtOAc/hexanes). The desired compound is the faster running spot at Rf= 0.2, which is UV active. These product fractions were combined and concentrated to afford the product. 10 Step 6: 3',4'-dihydrospirorcyclopent-3-ene-1,2'-pyrano[2,3-blpyridinl-4'-yl)amine 2(S)-N-(2-(1-(tertbutyldimethylsilyloxy)cyclopent-3-enyl)-1-(2-fluoro-5-neopentylpyridi-3 yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.2mmol) was dissolved in DMSO (10 mL) under nitrogen. To this was added granulated cesium fluoride (535mg, 3.5mmol). The mixture was heated at 130"C under nitrogen for 8 hours, then cooled to Rt and poured onto 15 200 mL of saturated sodium bicarbonate. The product was extracted with EtOAc (3x75 mL). Washed with brine, dried over sodium sulfate, filtered and concentrated to give a yellow oil which was dissolved in methanol (10 mL). To this was added 4N HCI in dioxane (20mL). This was allowed to stir at RT for 1 hour, and concentrated to a yellowish residue. The crude salt was free based with 10% sodium carbonate, dried and concentrated to afford 20 the free amine product. MS n/z: 273.2 (M+1) Step 7: N-(( S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospirorcyclopent-3-ene 1,2'-pyrano[2,3-blpyridinl-4'-yl)amino)-I-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide 25 The title compound was obtained using 3',4'-dihydrospiro[cyclopent-3-ene-1,2' pyrano[2,3-b]pyridin]-4'-yl)amine in a method analogous to that described in Example 464 below, Steps 8-10. MS found: m/z: 496 (M+1). Example 464 30 N-((1S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6'-ethyl-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridinj-4'-yl)amino)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 114 Step 1. (S)-2,3-bis(tert-butyldimethylsilyloxyl)ropyl 4-methoxvbenzoate To a 1.0 L RB flask containing (R)-2,3-dihydroxypropyl 4-methoxybenzoate (4.800 g, 21.2 mmol; according to the procedure described in Corey, E.J.; Guzman-Perez, A.; and Noe, M.C. J. Am. Chem. Soc. 1995, 117, 10805-10816) was added DCM (100 mL ) and 5 the mixture was allowed to stir at 0 0 C for 5 minutes. At this time, TEA (8.87 ml, 63.7 mmol) was added and the reaction was allowed to stir for 5 min before the dropwise addition of tert-butyldimethylsilyl triflate (10.2 ml, 44.6 mmol) via syringe. The reaction was allowed to stir for 1 h and then quenched by pouring into HCI (0.1 N, 100 mL). The aqueous layer was extracted with DCM (2 x 75 mL). The combined organics were 10 washed with HC (0.1 N, 2 x 150 mL), sodium bicarbonate (1 x 150 mL, sat), brine, dried sodium sulfate. The concentrated solution was passed through a plug of silica gel to and concentrated to give the title compound as a colorless oil. Step 2: (S)-2,3-bis(tert-butyldimethylsilyloxy)propan-1-ol To a 1.0 L RB flask containing (S)-2,3-bis(tert-butyldimethylsilyloxy)propyl 4-methoxybenzoate (9.200 g, 20 15 mmol) was added DCM (100 mL ) and the mixture was allowed to stir at -78 0 C for 5 minutes. At this time, DIBAL-H (1.0 M, hexanes) (61 ml, 61 mmol) was added via a syringe. The reaction was allowed to stir for 30 min and then quenched with MeOH (4.1 ml, 101 mmol). Sodium patassium tartate (sat, 200 mL) and DCM (100 mL) was added and the solution was allowed to warm to 230 C and stirred for 3 h. The aq. layer was 20 extracted with DCM (3 100 mL). The combined organics were washed with brine and dried with sodium sulfate and concentrated to give a residue. Step 3: (R)- 2

,

3 -bis(tert-butyldimethylsilvloxylpropanaldehyde To a 500 mL RB flask containing (S)- 2 ,3-bis(tert-butyldimethylsilyloxy)propan-1-ol (4.70 g, 14.7 mmol) was added DCM (100 mL ) and the mixture was allowed to stir at 25 23 0 C for 2 minutes. At this time, SODIUM BICARBONATE (3.69 g, 44.0 mmol) and Dess-MartinPeriodinane (7.46 g, 17.6 mmol) were added in one portion and the reaction was allowed to stir for 1.5 h. The reaction was quenched by the addition of SODIUM THIOSULFATE (6.95 g, 44.0 mmol) in one portion followd by sodium bicarbonate (sat,250 mL) and diethyl ether (250 mL). The quenched reaction was allowed to stir for 30 45 min and then the clear layers were separated. The organic layer was washed with sodium bicarbonate (2 x 250 mL), water (1 x 250 mL) and brine (1 x 100 mL). The organic layer was dried with magnesium sulfate, filtered and concentrated to give 5.00 g of a colorless oil. Rf= 0.80 in 20% EtOac in hexanes, not UV, stains pink/orange to WO 2007/061670 PCT/US2006/044058 - 115 anisaldehyde. The aq. layers were back extracted with ether (2 x 125 mL). The combined back extractions were washed with brine, dried with magnesium sulfate, filtered and concentrated to give less than 200 mg of oil. Step 4: (S.E)-N-((S)-2,3-bis(tert-butvdimethylsilyloxy)propylidene)-2-methylpropane-2 5 sulfinamide To a 500 mL RB flask containing (R)-2,3-bis(tert-butyldimethylsilyloxy)propana (4.670 g, 14.7 mmol) was added DCM (100 mL ) and the mixture was allowed to stir at 23 0 C for 2 minutes. At this time, (S)-2-methylpropane-2-sulfinamide (2.13 g, 17.6 mmol) and COPPER(II)SULFATE (5.85 g, 36.6 mmol) (100 g Fluka bottle) were added and the 10 reaction was allowed to stir for 3 days. At this time tic showed that all of the aldehyde was consumed. The crude reaction mixture was filtered through a plug of celite in order to remove the solid copper salt. The organic layer was concentrated to give 7.50g of oil, which was subjected to a 330g Isco column 10-35%EtOAc in hexanes to give the title compound as a white solid. rf= 0.50 in 20% EtOAc in hexanes, UV active and stains 15 yellow to anisaldehyde. Step 5: (S)-N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3-chloro-5 fluorophenvl)butan-2-yl)-2-methylpropane-2-sulfinamide A 500 mL RB flask containing (3-chloro-5-fluorobenzyl)magnesium chloride, 0.25 M in diethyl ether (13040 pl, 3260 pmol) was allowed to stir at -78 0 C for 5 minutes. At this 20 time, TMEDA (492 p1, 3260 imol) was added via a syringe and then THF (10 mL) was added via a syringe and the mixture was allowed to stir for 15 min before the addition of (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2 sulfinamide (550.00 mg, 1304 pmol) (14 mL THF) via a syringe. The reaction was allowed to stir for 30 min and then quenched with ammonium chloride (sat, 100 mL). 25 The aq. layer was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine and dried with sodium sulfate. The dried solution was filtered and concentrated to give 1.30 g of a crude oil that was purified on a 120g ISCO column to give the title compound. Rf= 0.40 in 20 % EtOAc in hexanes. Step 6: (S)-N-((2S,3S)-3-(tert-butvildimethylsilyloxy)-1-(3-chloro-5-fluorophenyl)-4 30 hydroxybutan-2-vl)-2-methylpropane-2-sulfinamide To a 50 mL polypropylene bottle containing (S)-N-((2S,3S)-3,4-bis(tert butyldimethylsilyloxy)-1-(3-chloro-5-fluorophenyl)butan-2-yl)-2-methylpropane-2 sulfinamide (350.00 mg, 618 limol) was added THF (10 mL ) and the mixture was WO 2007/061670 PCT/US2006/044058 - 116 allowed to stir at 0 0 C for 5 minutes. At this time, PYRIDINE (2699 il, 33371 pimol) was added via syringe before the addition of HF-Pyridine, 70% HF 30% pyr (1782 pl, 19775 pmol) via a syringe. The reaction was allowed to stir at this temp for 2h and then quenched by pouring into sodium bicarbonate (sat 150 ml). The aq. layer was extracted 5 with EtOAc 94 x 75 mL). The combined organics were washed with HCl (0.1 N, 3 x- 100 mL), bicarbonate (sat, 100 mL), brine and dried with sodium sulfate. The dried solution was filtered and concentrated to give a yellow oil which was purified on a 40 g ISCO column to give the title compound. Step 7: (S)-N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-I-(3-chloro-5-fluorophenyl)-4 10 oxobutan-2-yl)-2-methylpropane-2-sulfinamide To a 250 ml rbf was added (S)-N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-chloro-5 fluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (160.00 mg) and DCM (10 ml) followed by SODIUM BICARBONATE (148.7 mg, 5 eq) and Dess MartinPeriodinane (195.1 mg, 1.30 eq). The reaction was allowed to stir for 2 h and then 15 quenched with sodium bicarbonate (sat, 100 mL) and added SODIUM THIOSULFATE (391.7 mg, 2477 pmol) along with diethyl ether (100 ml). The quenched reaction was allowed to stir for 2 h and then the aq. layer was extracted with ether (3 x 75 mL). The combined organics were washed with brine and dried with magnesium sulfate, filtered and concentrated to give 1280 mg of a solid/oil mixture, which was purified on a silica 20 gel column (20% EtOAc in hexanes) to give the title compound as a colorless oil. Step 8: (S)-N-((2S,3R)-3-(tert-butyldimethylsilyloxy)-1-(3-chloro-5-fluorophenyl)-4-((S) 6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-blpyridin-4-ylamino)butan-2-yl) 2-methylpropane-2-sulfinamide To a 150 mL rbf containing (S)-N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-chloro-5 25 fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (75.00 mg, 167 pimol) was added DCE (3mL) and the mixture was allowed to stir at 23 0 C for 2 minutes. At this time, 6 -ethyl-2,2-spirocyclobutyl-8-azachromanyl-4-amine (36 mg, 167 pmol) was added in DCE (5mL) and TRIMETHYL ORTHOFORMATE (276 d, 2500 pmol) was added via a syringe. The reaction was allowed to stir for 20 min when FIA/MS indicated that 30 imine had formed. At this time, SODIUM TRIACETOXYBOROHYDRIDE (141 mg, 667 ttmol) was added in one portion and the reaction was allowed to stir for 12 h. The reaction was quenched by the addition of sodium carbonate (10%, 30 mL) and diluted with DCM (50 mL). The aq. layer was extracted with DCM (3 x 50 mL). The combined WO 2007/061670 PCT/US2006/044058 - 117 organics were washed with brine and dried with sodium sulfate. The dried solution was passed through a plug of silica gel and eluted with EtOAc, concentrated and placed on a high vacuum to give the title compound as a colorless oil. Step 9: (2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-1-((S)-6-ethyl-2,2-spirocyclobutyl 5 3,4-dihvdro-2H-pyranof2,3-blpyridin-4-ylamino)butan-2-ol To a 100 mL rbf was added MeOH (1OmL) and the mixture was allowed to stir at 0 0 C for 5 minutes. At this time, ACETYL CHLORIDE (2518 sl, 35409 gmol) was added via syringe and the reaction was allowed to stir for 20 min before it was added to a flask containing Reactant 1 (105.00 mg, 161 ptmol). The reaction was allowed to stir at 23*C 10 for 24 h and checked by LC/MS. The reaction was allowed to stir an additional 2 days and then the solvents were removed by rotary evaporator. The residue was placed on a high vacuum for 3 h. Note that acetyl chloride reacts with anhydrous MeOH, generating methylacetate and HCL. In the described procedure above, HCl is the reactive reagent for the removal of sulfinyl or other protecting groups involved in the synthesis of this 15 compound or analogs. Alternatively, commercially available reagent HCI (e.g., 4.0 M in dioxane) can be used directly. Step 10: N-((1S,2R)- I-((3-chloro-5-fluorophenvl)methyl)-3-(((4'S)-6'-ethyl-3',4' dihydrospirofcyclobutane-1,2'-pyrano2,3-blpyridinl-4'-yl)amino)-2 hydroxypropyl)acetamide 20 The title compound was prepared using 1-(1H-imidazol-1-yl)ethanone (18 mg, 159 gmol) and (2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-1-((S)-6-ethyl-2,2-spirocyclobutyl-3,4 dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2-ol in DMF. The crude reaction was injected into a reverse phase HPLC and the clean fractions were collected and extracted after adding sodium carbonate (3 x EtOAc). The combined organics were washed with 25 brine, dried with sodium sulfate and concentrated to give the title compound as a white solid. MS Found: m/z: 476 (M+1). Example 465 30 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-blpyridin-4'-yl)amino)--((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 118 Step 1: (S)-N-((2S,3S)-3,4-bis(tert-butyldimethylsily1oxy)-1-(3-fluorophenyl)butan-2-l) 2-methylpropane-2-sulfinamide The title compound was prepared by the method described in Example 464, Step 5 using 3-fluorobenzyl)magnesium chloride (0.25 M in diethyl ether) (139 ml, 35 mmol), TMEDA (5.2 ml, 35 mmol) and (S,E)-N-((S)-2,3 5 bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (4.890 g, 12 mmol). Step 2: tert-Butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)-4 hydroxybutan-2-ylcarbamate To a 500 mL RBF containing (S)-N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3 10 fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (2.600 g, 4.9mmol) was added EtOH (25 ml) and the mixture was allowed to stir at 0 0 C for 15 min. At this time, HCI (4N in dioxane) (3.7 ml, 15mmol) was added via syringe. The reaction was monitored at lh by LC/MS 76877-2-1 and tlc (100% EtOAC amino bis TBS; Rf= 0.80 UV active stains orange to anisaldehyde amine with primary alcohol deprotected Rf= 0.45 to 0.1 15 streak, UV active and stains white to anisaldehyde). The reaction was allowed to stir for 3 h at 0*C and then TEA (4.1 ml, 29 mmol) was added fast dropwise and a white solid formed. An LC/Ms was obtained to confirm that the secondary TBS ether was not removed during the TEA neutralization process. Approximately 15 mL of EtOH were removed by rotary evaporator and then DCM (10 mL) was added and the solid went into 20 solution. At this time, (BOC) 2 0 (2.3 ml, 9.8 mmol) was added in one portion and the reaction was allowed to stir for 1 h and then poured into diethyl ether (300 ml). The organic layer was washed with ammonium chloride (3 x 150 mL, sat) and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated to give a colorless crude oil. The desired product has an Rf= 0.40 in 35% EtOAc in hexanes, UV 25 active, stains white to anisaldehyde and purple to moly stain. The crude oil was purified on a 120g Isco column (10 to 35% EtOAc in hexanes) to give the title compound as a colorless oil. Step 3: Tert-Butyl (2S,3S).-3-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)-4-oxobutan 2-ylcarbamate 30 To a 150 mL RBF containing tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3 fluorophenyl)-4-hydroxybutan-2-ylcarbamate (170.00 mg, 411 Imol) was added DCM (10 mL) and the mixture was allowed to stir at 23 0 C for 2 minutes. At this time, pyridine (299 pl, 3699 pmol) was added via syringe before the addition of Dess- WO 2007/061670 PCT/US2006/044058 - 119 MartinPeriodinane (262 mg, 617 itmol) in one portion. The reaction stayed a clear solution and was allowed to stir 1 h before loading directly to a silica gel column (20% EtOAc). The purified product was concentrated to give the title compound as a colorless oil. 5 Step 4: N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3'.4'-dihydrospirorcvclobutane-1,2' pyrano2.3-blpyridinl-4'-vl)amino)-1-((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide The title compound was prepared using the methods described in Example 464, steps 8 10 herein. The final product was purified by reverse phase HPLC and the pure fraction 10 was lyophilized to give the title compound as a white solid. MS Found m/z: 484(M+1). Example 466 N-((2S,3R)-4-((S)-2,2-spirocyclopropyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3 15 bJpyridin-4-ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)acetamide Step 1: 1-(2,2-dimethoxyethyl)cyclopropanol To a 1.0 L RBF containing methyl 3,3-dimethoxypropanoate (17.6500 g, 119 mmol) was added THF (150 ml) and diethyl ether (150 ml), and the mixture was allowed to stir at 0 0 C for 15 min. At this time, tetra-isopropoxy titanium (6.98 ml, 23.8 mmol) was added 20 in one portion before the dropwise addition of ethylmagnesium bromide (99.3 ml, 298 mmol) via syringe. The reaction was allowed to warm to 23 0 C and stir for 14 hours before being re-chilled to 0*C. After 5 min at this temp, water (15 ml) was added and a solid formed. Diethyl ether (200 ml) was added and the quenched reaction was stirred for 10 min before filtering through a plug of magnesium sulfate. The filtrate was dried with 25 additional magnesium sulfate, filtered and concentrated to give a colorless oil. The crude material was used directly in the next reaction. Step 2: 2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)acetadehyde To a 2.0 L RBF containing 1-(2,2-dimethoxyethyl)cyclopropanol (17.400g, 119 mmol) was added DCM (550 ml) and the mixture was allowed to stir at 0 0 C for 15 min. 2,4,6 30 Collidine (63.1 ml, 476 mmol) was added and the reaction was allowed to chill for 5 min before the addition of tert-butyldimethylsilyl triflate (27.3 ml, 119 mmol) over 10 min. The reaction was allowed to stir for 20 min and then analyzed by tic which showed that all of the tertiary alcohol had been protected as its TBS ether. So, triethylsilyl WO 2007/061670 PCT/US2006/044058 - 120 trifluoromethanesulfonate (53.8 ml, 238 mmol) was added via syringe over 10 min. After 20 min, tlc showed all of the material was converted to a baseline Rf material (mixed acetal) and then water (300 mL) was added and the reaction was allowed to stir overnight. The layers were separated. The DCM was washed with dilute HCI to remove the 2,4,6 5 collidine. The aq. layer was back extracted with DCM. The combined organics were washed with sodium bicarbonate, brine, dried with sodium sulfate and filtered though a plug of silica gel. Desired fractions were collected to give the product. Step 3: (R.E)-N-(2-(I-(tert-butyldimethylsilyloxy)cyclopropyl)ethylidene)-2 methylpropane-2-sulfinamide 10 To a 1.0 L round bottom flask containing 2-(1 -(tert butyldimethylsilyloxy)cyclopropyl)acetaldehyde (5.00 g, 23.3 mmol) (crude 10.5 g with TESOH, 1H NMR showed about 50/50 sm to impurity) was added DCM (200 mL) and the mixture was allowed to stir at 23 0 C for 5 min. At this time, (R)-2-methylpropane-2 sulfinamide (2.83 g, 23.3 mmol) and cupric sulfate anhydrous (2.58 ml, 58.3 mmol) were 15 added and the reaction was allowed to stir for 40h. The copper salts were removed by celite filtration. The filtrate was concentrated to give a yellow oil that was purified on a 330g Isco column (5 to 20% EtOAc in hexanes)to afford the title compound as a colorless oil. Step 4: (26R)-N-(2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-I -(2-fluoro-5 20 neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide Prepared following the procedure described for Example 272, Step 7 utilizing 2,2,6,6-tetramethylpiperidine (2.21 ml, 13.0 mmol), butyllithium (4.62 ml, 11.6 mmol), 2-fluoro-5-neopentylpyridine (1.610 g, 9.63 mmol), and (R,E)-N-(2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)ethylidene)-2 methylpropane-2-sulfinamide (3.97 g, 12.5 mmol). The desired product is the 25 stereoisomer with higher Rf (approx 3:1 ratio) (Rf= 0.45 in 35% EtOAc in hexanes). Step 5: (S)-1-(2-amino-2-(2-fluoro-5-neopentvlpyridin-3-yl)ethyl)cyclopropano To a 500 mL RBF containing (26R)-N-(2-(1 -(tert-butyldimethylsilyloxy)cyclopropyl)- 1 (2-fluoro-5-neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.03 g, 2.12 mmol) was added THF (13 ml) and the mixture was allowed to stir at 23 0 C for 5 min. At 30 this time, TBAF (1.00 M in THF) (2.12 ml, 2.12 mmol) was added and tlc showed that the TBS group was removed in the first 5 min. After 30 min, tlc showed that a rearrangement started to occur at 23 *C (higher Rf spot= 0.80 in 35% EtOAc in hexanes, UV active, stains pink to anisaldehyse). So, EtOH (5 ml) and HCI (4 N in dioxane, 5 ml) WO 2007/061670 PCT/US2006/044058 - 121 were added and the reaction was allowed to stir for 1h. The solution was poured into sodium bicarbonate and extracted with EtOAc. The combined organics were washed with brine, dried with sodium sulfate, filtered and concentrated to give the title compound as a crude, colorless oil. 5 Step 6: (S)-2,2-spirocyclopropyl-6-neopentyl-3,4-dihvdro-2H-pyranor2,3-blpyridin-4 amine To a 500 mL RBF containing 1-(2-amino-2-(2-fluoro-5-neopentylpyridin-3 yl)ethyl)cyclopropanol (crude) (750.00 mg, 2816 Rmol) was added THF (200 mL) and the mixture was allowed to stir at 23 0 C for 5 min. At this time, KIHMDS (0.5 M in 10 toluene) (5632 pl, 2816 pmol) was added via syringe over 2 min. TLC at 10 min showed all of the starting material was consumed and converted to slightly lower Rf compound. The reaction was poured into sodium carbonate (10%, 100 ml) and extracted with EtOac (2 x 100 ml). The combined EtOAc were washed with brine, dried with sodium sulfate, filtered and concentrated. The aq. layers were combined and then back extracted with 15 DCM. The combined organics was concentrated and the resulting residue purified through a short silica gel column (EtOAc to 10% MeOH (2 M in NH3) in EtOAc to give the title compound as a yellow oil. Step 7: N-((2S.3R)-4-((S)-2,2-spirocyclopropyl-6-neopentyl-3,4-dihydro-2H1-pyrano[2,3 blpyridin-4-ylamino)-1 -(4-fluorophenyl)-3-hydroxybutan-2-yllacetamide 20 The title compound was prepared by a method analogous to that described in Example 464, steps 8-10, and the title compound was purified by reverse phase HPLC and isolated as a white solid. MS Found: m/z: 470 (M+l). Example 467

H

2 N O N CI 25 Synthesis of (S)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H pyrano[2,3-clpyridin-4-amine Step 1: 2-bromo-5-(methoxymethoxy)pyridine WO 2007/061670 PCT/US2006/044058 - 122 To a solution of 6-bromopyridin-3-ol (25 g, 144 mmol) in DMF (300 mL) at 0"C under

N

2 is added portionwise NaH (5.7 g, 144 mmol) over 5 min. The reaction was stirred I h, then chloro(methoxy)methane (12 g, 144 mmol) was added and the reaction stirred an additional 1 h at 0*C. Saturated sodium bicarbonate (500 mL) was added slowly and the 5 suspension stirred 30 min and warmed to rt. The solution was extracted with EtOAc (3 x 400 mL), the combined organic layers washed with H20 (500 mL), saturated NaCI (500 mL), dried (Na 2

SO

4 ), and concentrated in vacuo to give the title compound as a brown oil. Step 2: 5-(methoxymethoxy)-2-neopentylpyridine To a solution of 2-bromo-5-(methoxymethoxy)pyridine (30.5 g, 140 mmol) in THF (5 10 mL) at 0*C under N 2 is added dichloro-((bis-diphenylphosphino)ferrocenyl) palladium(II)(4.88 g, 5.5 mmol) followed by dropwise addition of neopentylmagnesium chloride (155 mL, 155 mmol) over 2 min. After addition, the cooling bath was removed and the reaction stirred 3 h at rt. The reaction was cooled to 0*C and saturated NH 4 CI (500 mL) was added, and the aqueous layers extracted with EtOAc (3 x 200 mL). The 15 combined organic layers were washed with saturated NaCl, dried (Na 2

SO

4 ) and concentrated to give a red oil. Purification by vacuum filtration through a silica plug (9 x 7 cm, dry load, 10-20%% EtOAc/Hexanes) gives 5-(methoxymethoxy)-2 neopentylpyridine as a light yellow oil. Step 3: 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol 20 To a solution of 5-(methoxymethoxy)-2-neopentylpyridine (16.5 g, 79 mmol) and in THF (200 mL) -78*C is added tert-butyllithium (46 ml, 79 mmol) (1.7 M in pentane ) over 2 min via cannula. The reaction was stirred at -78*C 30 min, and acetaldehyde (11 ml, 197 mmol) was added. The reaction was stirred at -78*C 10 min, then the reaction was warmed to rt and stirred 3 h. The reaction was quenched by addition of saturated aqueous 25 NH 4 CI (400 mL), extracted with EtOAc (3 x 200 mL), the combined organic layers washed with saturated NaCI (10 mL), dried (Na 2

SO

4 ), and concentrated to give a orange oil, which was purified by chromatography on an ISCO (330 g SiO 2 , 10%-50% EtOAc/Hexane) gives 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol as a clear, light yellow oil. 30 Step 4: 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-vlethanone To a solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethano (24.4 g, 96.3 mmol) and sodium bicarbonate (32.4 g, 385 mmol) in CHCl 3 (500 mL) at 0 *C was added Dess-Martin Periodinane (53.1 g, 125 mmol). The reaction was stirred 5 h, quenched with saturated aqueous Na 2

SO

3 (300 mL), extracted with CH 2

CI

2 (3 x 250 niL), the WO 2007/061670 PCT/US2006/044058 - 123 combined organic layers washed with saturated NaCl (300 mL), dried (Na 2

SO

4 ), and concentrated to give a yellow oil. Purification by ISCO (330 g SiO 2 , 20% EtOAc/Hexane) gives 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone as a clear, colorless oil. 5 Step 5: 1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone A solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone (21.6 g, 86 mmol) in (2:1:1) 5 M HCI : i-PrOH: THF (800 mL) was stirred 4 h at rt. The mixture was concentrated to remove the THF and i-PrOH. The resulting solution consisting of the product in aqueous HCI was quenched by slow addition to a solution of saturated aqueous 10 NaHCO 3 (500 mL) containing excess solid NaHCO 3 (50 g). The aqueous layer was extracted with CH 2 Cl 2 (3 x 250 mL), the organic layers combined and washed with saturated aqueous NaCl (250 mL), dried (MgSO 4 ), and concentrated to give 1-(5 hyd-roxy-2-neopentylpyridin-4-yl)ethanone as a brown oil. Sten 6: 2,2-spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-clpyridin-4-one 15 A mixture of 1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone (14.8 g, 71 mmol) (76894 11), H~nig's base (12 ml, 71 mmol) ,pyrrolidine (8.9 ml, 107 mmol), and cyclobutanone (13 ml, 179 mmol) in toluene (300 mL) with a Dean-Stark trap was heated in a 140 *C oil bath for 2 h. The mixture was cooled to i, then diluted with EtOAc (25 mL), washed with H 2 0, saturated aqueous NH4Cl, saturated aqueous NaCI, dried (MgSO 4 ), and 20 concentrated. Purification by ISCO (120 g SiO 2 , 10-20% EtOAc/Hexane) gives the title compound as a yellow solid. Step 7: 2,2-spirocyclobutyl-6-neopentyl-7-oxo-2,3-dihydropyrano [2,3-clpvridin-4-one 2

,

2 -spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-c]pyridin-4-one (5.00 g, 19 mmol) was dissolved in 100 ml CHC 3 and cooled to 0*C, mCPBA (10.0 g, 58 mmol) 25 was added portionwise and the reaction was stirred under N 2 and allowed to warm slowly to rt; stirring was continued for 17 h. The mixture was then cooled to 0*C, IM NaOH (100 mL) was added, and stirring was continued vigorously for 10 min. The mixture was extracted with CH 2 Cl 2 (3 x 100 mL), the combined organic layers washed with saturated sodium chloride (100 mL), dried (Na 2

SO

4 ) and evaporated to give the title compound as a 30 white solid. Step 8: 8-chloro-22-sirocyclobutyl-6-neopentvl-2,3-dihydro pyranoF2,3-clpyridin-4-one 2,2-spirocyclobutyl- 6 -neopentyl-7-oxo-2,3-dihydropyrano[2,3-c]pyridin-4-one. (5.3 g, 19 mmol) was taken up in phosphoryl trichloride (20 mL, 218 mmol) and the mixture was heated to 80 0 C for 2 h under N 2 . The reaction mixture was quenched by slow addition to WO 2007/061670 PCT/US2006/044058 - 124 vigorously stirred cold 10% aqueous NaCO 3 (300 mL), extracted with EtOAc (3 x 200 mL), the combined organic layers were washed with saturated NaCl (200 mL), dried (Na 2

SO

4 ), and concentrated to give a brown oil. Purification by ISCO (120 g SiO 2 , 10% EtOAc/Hexane) gives the title compound as a light yellow solid. 5 Step 9: (R)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3 clpyridin-4-ol To a stirred solution of (s)-2-methyl-cbs-oxazaborolidine (1.7 ml, 1.7 mmol) in THF (20 mL) at 0 0 C is added borane-methyl sulfide complex (14 ml, 28 mmol) followed by a solution of 8-chloro-2,2-spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-c]pyridin-4 10 one (4.90 g, 17 mmol) in THF (40 mL) dropwise via syringe pump over 2.8 h. The reaction was stirred an additional 30 min, then was quenched by dropwise addition (1 drop/10 sec) of 5 M HCI (25 mL) at 0 *C, after 15 mL HCI was added, bubbling had ceased and the addition rate was increased as the ice bath was removed. The reaction was stirred an additional 2 h at rt. The reaction was recooled to 0*C and neutralized with 5 M 15 NaOH (27 mL). The mixture was then extracted with EtOAc (2 x 150 mL), washed with saturated aqueous NaCl (200 mL), dried (MgSO 4 ), and concentrated in vacuo. Purification by ISCO (120 g SiO 2 , 20% EtOAc/Hexane) gives the title compound as a white foam. Step 10: (S)-4-azido-8-chloro-2,2-spirocyclobutyl-6-neopentvl-3,4-dihydro-2H 20 pyranor2,3-clpyridine To a solution of (R)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H pyrano[2,3-c]pyridin-4-ol (2.33 g, 7.9 mmol) in toluene (43 mL) is added diphenylphosphoryl azide (2.4 ml, I 1 mmol) then 1,8-diazabicyclo(5.4.0)-7-undecene (1.6 ml, 11 mmol). The reaction was stirred under N 2 at rt 4 days. The clear, light yellow 25 solution first turned into a yellow cloudy/opaque solution after 10 min. Water (100 mL) was added and the reaction mixture extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaCl (150 mL), dried (MgSO 4 ), and concentrated to give the title compound as a brown oil which was used in the next step without purification. 30 Step 11: (S)-8-chloro-2.2-spirocyclobutyl-6-neopentvl-3.4-dihydro-2H-pyrano2,3 clpyridin-4-amine To a solution of (S)- 4 -azido-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H pyrano[2,3-c]pyridine (2.21 g, 6.9 mmol) in 10:1 THF/H 2 0 (44 mL) at 0*C is added NaOH (3.0 ml, 15 mmol) (5 N). After 5 min, trimethylphosphine (2.4 ml, 28 mmol) was WO 2007/061670 PCT/US2006/044058 - 125 added dropwise over 4 min. The reaction went from brown to pink to purple as N 2 evolution occurred. The ice bath was allowed to melt as the reaction warmed to rt and stirred a total of 15 h. The mixture was re-cooled to 0*C and 5 N HCI (25 mL) was added. The resulting mixture was extracted with EtOAc (3 x 50 mL), the combined 5 organic layers were washed with 2.5 N HCI (2 x 25 mL). The combined aqueous layers were cooled to 0"C and basified to pH 14 with 5 N NaOH (100 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL) the combined organic layers dried (Na 2

SO

4 ), and concentrated to give the crude product as a viscous yellow oil. The combined organic layers were combined with the crude product from above and concentrated to give a crude 10 yellow oil. Purification of the crude oil by flash chromatography (5 x 15 cm SiO 2 , 0-10% MeOH/CH 2

CI

2 gradient elution) gave the title compound as a yellow oil. Example 468 15 N-((1S,2R)-3-(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide The title compound was synthesized in manner analogous to that of Example 466, using (S)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4 20 amine and N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-I -(3-fluorophenyl)-4-oxobutan-2 yl)acetamide to obtain the title compound as a colorless solid. MS m/z: 518.2(M+1). Example 469 25 N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-8-(methylamino)-6-neopentyl-3,4-dihydro-2H pyrano[2,3-c]pyridin-4-ylamino)--(3-fluorophenyl)-3-hydroxybutan-2-yl)acetamide To a flame-dried microwave vial under argon is added N-((l S,2R)-3-(((4'S)-8'-cbloro-6' (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4' yl)amino)-I-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide(60 mg, 95 pLmol), 30 Pd2dba3 (17 mg, 19 ptmol), and DavePhos (16 mg, 42 smol). The vial was purged with

N

2 5 x, then methanamine (949 pl, 1898 gmol) and LiHMDS (475 jil, 475 tmol, 1.0 M in THF) were added. The vial was sealed and heated in a microwave at 1 10*C for 10 min. The reaction mixture was directly purified by reverse phase HPLC on a Phenomenex Synergi column (5 micron, MAX-RP, 80 A, 150x30 mm) eluting at 45 ml/min with an WO 2007/061670 PCT/US2006/044058 - 126 linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 30 minutes to give to give the title compound as a white amorphous solid. MS r/z: 513.2(M+1). 5 Example 470 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(methyloxy)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide 10 To a 2 mL microwave vial is added cesium carbonate (283 mg, 869 jimol), di-tert butyl(2-(2-isopropylnaphthalen-1-yl)-3,4,5,6-tetramethylphenyl)phosphine (71 mg, 159 pimol), palladium(II) acetate (33 mg, 145 stmol), and N-((IS,2R)-3-(((4'S)-8'-chloro-6' (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4' yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide(75 mg, 145 jimol) 15 were added and the vial was flushed with N 2 5x, then methanol (160 sl, 3619 pmol) and toluene (1 mL) were added simultaneously. The reaction was heated in the microwave at 110*C for 30 min. LCMS shows 100% conversion. The reaction mixture was filtered through a small plug of silica gel, and the residue purified by reverse phase HPLC on a Phenomenex Synergi column (5 micron, MAX-RP, 80 A, 150x30 mm) eluting at 45 20 ml/min with an linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 30 minutes to give the title compound as a tan amorphous solid. MS n/z: 514.2(M+1). Example 471 25 General procedure for the synthesis of Examples 634-650 and 652, various B and V-R 2 groups of Formulas I and II Me Me O YN O H 0 (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine 3-carboxylate WO 2007/061670 PCT/US2006/044058 - 127 This compound was prepared according to a method described in Example 472, from (S)-2 (tert-butoxycarbonyl)-3-(thiazol-4-yl)propanoic acid. Example 472 Me Me 0 O N -; OH 0 S N 5 Me Synthesis of (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((2-methylthiazol 4-yl)methyl)oxazolidine-3-carboxylate Step 1: (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol 4-ylmethyl)oxazolidine-3-carboxylate 10 (4S,5S)-Tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3 carboxylate (0.096 g, 0.29 mmol) was dissolved in DMF (1 mL) with IH-imidazole (0.026 g, 0.38 mmol) and tert-butylchlorodimethylsilane (0.053 g, 0.35 mmol). The reaction was stirred 2 hrs, diluted with diethyl ether and washed twice with water and once with brine. The organic layer was dried over magnesium sulfate and concentrated to 15 furnish the title compound, which was used for the next step without purification. Step 2: (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2 methylthiazol-4-yl)methyl)oxazolidine-3-carboxylate (4S,5S)-Tert-butyl 5-((tert-butyld imethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4 ylmethyl)oxazolidine-3-carboxylate (0.100 g, 0.23 mmol) was dissolved in THF (2.5 mL) 20 and cooled to -78* C. n-Butyllithium (0.12 ml, 0.29 mmol) was added and the reaction was stirred at -50*C for 40 minutes followed by the addition of iodomethane (0.018 ml, 0.29 mmol). After stirring 40 minutes the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over sodium sulfate to afford the title compound. MS 25 m/z: 457.3 (M+]). Step 3: (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((2-methylthiazol-4 yl)methyl)oxazolidine-3-carboxylate (4S,5S)-Tert-butyl 5-((tert butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylthiazol-4-yl)methyl)oxazolidine- WO 2007/061670 PCT/US2006/044058 - 128 3-carboxylate (0.100 g, 0.219 mmol) was dissolved in THF (4mL) and cooled to 0"C. Next, TBAF (0.547 ml, 0.547mmol) was added dropwise and the reaction was stirred I hr. and then quenched with saturated ammonium chloride and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic 5 layers were washed with water, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (2.5:1 Hexanes/EtOAc) afforded the title compound. Example 473 Me Me o N, A, OH O 0 S N 10 (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((2-propylthiazol-4 yl)methyl)oxazolidine-3-carboxylate The title compound was prepared in a manner analogous to that described in Example 472. MS mn/z: 371.3 (M+1). Example 474 Me Me 0 o N -.. OH 0 15 S N (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((5-propylthiazol-4 yl)methyl)oxazolidine-3-carboxylate Step 1: (4S,5S)-tert-butVl 4-((2-(tert-butyldimethylsilyl)thiazol-4-y1)methyl)-5-((tert butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate 20 (4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4 ylmethyl)oxazolidine-3-carboxylate (0.148 g, 0.334mmol) in THF (3mL) was cooled to 78*C when n-butyllithium (2.5 M in hexanes)(0.160 ml, 0.401mmol) was added dropwise. The solution was warmed to -50 0 C for 40 minutes and then cooled to -78*C.

WO 2007/061670 PCT/US2006/044058 - 129 TBS-Cl (0.0605 g, 0.40 Immol) in THF (2mL) was added dropwise and the solution was allowed to slowly warm to 0*C when it was quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over sodium sulfate to 5 afford the title compound, which was used without further purification. Step 2: (4S,5S)-tert-butyl 4-((2-(tert-butldimethylsilyl)-5-propylthiazol-4-yl)methyl)-5 ((tert-butvldimethylsilvloxy)methyl)-2.2-dimethyloxazolidine-3-carboxylate (4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)thiazol-4-yl)methyl)-5-((tert butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.150 g, 0.269 10 mmol) in THF (3 mL) was cooled to -78"C when N-BUTYLLITHIUM (2.5 M in hexanes)(0. 119 ml, 0.296 mmol) was added dropwise. The solution was warmed to -50*C for 40 minutes and then cooled to -78*C. 1-Iodopropane (0.0549 g, 0.323 mmol) was added dropwise and the solution was allowed to slowly warm to -50 "C and stirred for 1 hr. The reaction was quenched with saturated ammonium chloride. The layers were 15 separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound, which was used without further purification for the next step. Step 3: (4S,5S)-tert-butyl 5-(hydroxymethyl)-2.2-dimethyl-4-((5-propylthiazol-4 yl)methyl)oxazolidine-3-carboxylate (4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)-5 20 propylthiazol-4-yl)methyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2 dimethyloxazolidine-3-carboxylate was dissolved in THF (3mL) and cooled to 0 0 C when TBAF (0.808 ml, 0.808mmol) was added. The reaction was stirred one hour before being quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, 25 brine and dried over sodium sulfate to afford the title compound. Example 475 O 0 F 3 C Step 1: (S)-methyl 2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoate WO 2007/061670 PCT/US2006/044058 -130 Iodine (0.0140 g, 0.0553 mmol) was added to zinc (0.542 g, 8.29mmol) and the solid mixture was heated under vacuum for 10 minutes. The flask was flushed with nitrogen three times and allowed to cool. DMF (0.5mL, degassed with nitrogen) was added and the suspension was cooled to O"C and stirred while (R)-methyl 2-(tert-butoxycarbonyl)-3 5 iodopropanoate (1.82 g, 5.53 mmol) in DMF (2.8 mL) was added dropwise. The mixture was stirred for 30 minutes at 0 0 C and then allowed to come to RT for 30 minutes. 1-Iodo-4 (trifluoromethyl)benzene (1.50 g, 5.53 mmol), tris(dibenzylideneacetone)dipalladium (0.101 g, 0.111 mmol), and dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-Phos) (0.182 g, 0.442 mmol) were added. The flask was purged with nitrogen and heated at 40*C. 10 After 3 hours the reaction was allowed to cool and partitioned between EtOAc and an aqueous solution of- 9:1 saturated ammonium chloride/ammonium hydroxide. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, and dried over sodium sulfate. Concentration and purification by silica gel chromatography (6:1 Hexanes/EtOAc) afforded (S)-methyl 2-(tert-butoxycarbonyl)-3 15 (4-(trifluoromethyl)phenyl)propanoate. Step 2: (S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoic acid (S)-Mthyl 2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoate (6.20 g, 17.9 mmol) was dissolved in THF (180 mL) and cooled to 0*C. A 0.2 M of aq. LiOH (89.3 ml, 17.9 mmol) was added dropwise and stirred 20 minutes before TLC analysis (2:1 20 Hexanes/EtOAc) showed no starting material. The PH of the reaction was carefully adjusted to PH = 8 with I N HCI. The aqueous layer was washed with diethyl ether and the organics were back extracted with 1% aqueous sodium bicarbonate and the combined aqueous layers were carefully brought to a PH = 4 and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and 25 concentrated to afford (S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoic acid, which was used without further purification. Example 476 WO 2007/061670 PCT/US2006/044058 - 131 Me Me- O O N -OH 0

F

3 C (4S,5S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-5-(hydroxymethyl)-2,2 dimethyloxazolidine-3-carboxylate The title compound was prepared according to the procedures described herein in Example 5 472. Example 477 Me Me o N ,, OH N 10 (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine 3-carboxylate The title compound was prepared according to the procedures described herein in Example 472. 15 Example 478 Me Me $ o N _ OH Me Me

N

WO 2007/061670 PCT/US2006/044058 - 132 (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((2-methylpyridin-4 yl)methyl)oxazolidine-3-carboxylate Step 1: (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxv)methyl)-2,2-dimethyl-4-(pyridin-4 ylmethyl)oxazolidine-3-carboxylate 5 The title compound was synthesized in manner analogous to that described in Example 472, using (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4 ylmethyl)oxazolidine-3-carboxylate in the presence of TBSCI and imidazole, and was used without further purification. Step 2: (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methl)-2,2-dimethyl-4-((2 10 methylpyridin-4-yl)methyl)oxazolidine-3-carboxylate (4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(pyridin-4 ylmethyl)oxazolidine-3-carboxylate (0.150 g, 0.344mmol) was dissolved in THF (3.5mL) and cooled to 0* C. Acetyl chloride (0.0256 ml, 0.361mmol) was added and the reaction was stirred 30 minutes before METHYLMAGNESIUM BROMIDE (0.294 ml, 0.412mmol) 15 was added. The reaction was stirred 1 hr. at 0*C and then warmed to RT and quenched with saturated ammonium chloride and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a 9:1 aqueous solution of saturated ammonium chloride/ammonium hydroxide, water, brine, and dried over sodium sulfate. The crude product was dissolved in 20 isopropylacetate (4mL) and heated to 50"C before DDQ (0.117 g, 0.515 mmol) was added. After 30 minutes the reaction was cooled and diluted with ethyl acetate and washed twice with saturated sodium bicarbonate, once with water, brine, and dried over sodium sulfate. The mixture was passed through a plug of silica gel with 2:1 Hexanes/EtOAc and concentrated to afford the title compound, MS m/z: 451.3(100%, M+1)). 25 Step 3: (4S,5S)-tert-butyl 5-(hydroxymethyl)-2.2-dimethvl-4-((2-methylpyridin-4 yl)methyl)oxazolidine-3-carboxylate (4S,5S)-Tert-butyl 5-((tert butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylpyridin-4-y)methyl)oxazolidine 3-carboxylate (0.083 g, 0.18mmol) was dissolved in THF (2mL) and cooled to 0 0 C. Next, TBAF (0.28 ml, 0.28mmol) was added dropwise and the reaction was stirred 1 hr. and then 30 quenched with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (19:1 DCM/MeOH) afforded the title compound, MS m/z: 337.2 (100%, M+1).

WO 2007/061670 PCT/US2006/044058 - 133 Example 479 Me Me 0 N- OH CI / C'-N (4S,5S)-tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2 5 dimethyloxazolidine-3-carboxylate. The title compound was prepared according to the procedures described herein in Example 478, from (S)-2-(tert-butoxycarbonyl)-3-(2-chloropyridin-4-yl)propanoic acid. Example 480 Me Me O N ,,-OH 0 ~ Cl N 10 Me Step 1:(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4 yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate. The title compound was synthesized in a manner analogous to Example 475, step I via (4S,5S)-tert-butyl 4-((2-chloropyridin-4 yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate in the presence of 15 TBSCI and imidazole and was used without further purification. Step 2: (4S,5S)-tert-butyl 5-((tert-butvidimethylsilyloxy)methyl)-4-((2-chloro-6 methylpyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate Dimethylethanolamine (0.128 ml, 1.27mmol) was added to anhydrous hexanes (1.4 L) and cooled to 0*C. N-BUTYLLITI1UM (2.5 M in hexanes)(1.02 ml, 2.55mmol) was added 20 dropwise and stirred for 30 minutes before being cooled to -78 0 C. (4S,5S)-Tert-butyl 5 ((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4-yl)methyl)-2,2 dimethyloxazolidine-3-carboxylate (0.200 g, 0.425mmol) in hexanes (lmL) was added dropwise and the solution was stirred for 1 hour at -78*C to give a dark orange solution. Mel (0.106 ml, 1.70 mmol) in THF (3.2mL) was added dropwise and the reaction was WO 2007/061670 PCT/US2006/044058 - 134 allowed to slowly warm to 0*C and was quenched with saturated aqueous ammonium chloride. The reaction was diluted with ethyl acetate and water and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated to give the titled compound which 5 was used directly for the next step without purification. Step 3: (4S,5S)-tert-butyl 4-((2-chloro-6-methylpyridin-4-yl)methyl)-5-(hydroxymethyl) 2,2-dimethyloxazolidine-3-carboxylate (4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloro-6-methylpyridin 4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.206 g, 0.425 mmol) was dissolved 10 in THF (4mL) and cooled to 0 0 C. TBAF (0.637 ml, 0.637 mmol) was added to the mixture dropwise and the reaction was stirred 1 hr and then quenched with saturated ammonium chloride and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated. The crude material was purified by 15 silica column chromatography (19:1 DCM/MeOH) and then reverse phase HPLC to give the title compound. MS n/z: 371.3 (100%, M+1). Example 481 Me Me 0 N- OH MeO 20 (4S,5S)-tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2 dimethyloxazolidine-3-carboxylate (4S,5S)-Tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2 dimethyloxazolidine-3-carboxylate (0.200 g, 0.560 mmol) was dissolved in a 25% solution of SODIUM METHOXIDE (12.8 ml, 56.0 mmol) in methanol and refluxed for 12 hrs and 25 cooled. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give (4S,5S)-tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2 dimethyloxazolidine-3-carboxylate, MS mz: 353.3 (100%, M+l).

WO 2007/061670 PCT/US2006/044058 - 135 Example 482 Me Me o N -K OH + O=N Me (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((1-methyl-2-oxo-1,2 dihydropyridin-4-yl)methyl)oxazolidine-3-carboxylate 5 (4S,5S)-Tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2 dimethyloxazolidine-3-carboxylate (0.281 g, 0.797 mmol) was refluxed in methanol (17 mL) with Mel (0.0798 ml, 1.28 mmol) for 48 hrs. Concentration and purification by silica gel chromotography (20:1 DCM/MeOH) afforded the titled compound along with recovered starting material. 10 Example 483 Me Me 0 0 N- OH

F

3 CO 0N (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((2-(2,2,2 trifluoroethoxy)pyridin-4-yl)methy)oxazolidine-3-carboxylate 15 NaH (60% by weight in mineral oil) (0.672 g, 16.8mmol) was added carefully to trifluoroethanol (20.0 ml, 276mmol) cooled at 0*C and then stirred at RT for 30 minutes. The resulting solution is added to (4S,5S)-tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5 (hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (0.400 g, 1.1 2 mmol) dissolved in 10mL of NMP and the resulting solution was microwaved for 30 minutes fixed at 180 0 C. 20 The reaction was diluted with EtOAc and washed repeatedly with water. The combined aqueous layers were back extracted with EtOAc and the combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The product was purified by silica gel chromatography (2:1 to 1:1 Hexanes/EtOAc) to afford the title compound. MS m/z: 421.3 (100%, M+1).

WO 2007/061670 PCT/US2006/044058 - 136 Example 484 0 O KOH XOO S N CI (S)-methyl 2-(tert-butoxycarbonyl)-3-(4-chlorothiazol-2-YI)propanoate 5 The title compound was synthesized in a manner analogous to that described Example 475, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 2,4-dichlorothiazole (prepared according to Reynaud, Pierre; Robba, Max; Moreau, Robert C; New synthesis of the thiazole ring; Bulletin de la Societe Chimique de France (1962), 1735-8). MS m/z: 321 (23%, M+1), 265.0 (100%, M-55.1). 10 Example 485 O O-J N H OH (S)-methyl 3-(benzofuran-2-yl)-2-(tert-butoxycarbonyl)propanoate The title compound was synthesized in a manner analogous to that described Example 475, 15 using(R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 2-bromobenzofuran. (MS m/z: 220.1 (100%, M-99). Example 486 0 SN O0 N %OH N N CF3 20 (S)-methyl 2 -(tert-butoxycarbonyl)-3-(2-(trifluoromethyl)pyrimidin-4-yl)propanoate WO 2007/061670 PCT/US2006/044058 - 137 The title compound was synthesized in a manner analogous to that described Example 475, using(R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 4-chloro-2 (trifluoromethyl)pyrimidine. 5 Example 487 0 O- NHO S ,-TIPS N (S)-methyl 2-(tert-butoxycarbonyl)-3-(2-(triisopropylsilyl)thiazol-5-yl)propanoate The title compound was synthesized in a manner analogous to that described Example 475, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 5-bromo-2 10 (triisopropylsilyl)thiazole (prepared according to Stangeland, Eric L.; Sammakia, Tarek, Use of Thiazoles in the Halogen Dance Reaction: Application to the Total Synthesis of WS75624 B, Journal of Organic Chemistry (2004), 69(7), 2381-2385.). MS m/z: 443.3 (100%, M+Il). 15 Example 488 N-((1R,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospirolcyelobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1-(4-pyridinylmethyl)propyl)acetamide This compound was isolated as a minor diastereomer by product following the final step in the synthesis of N-((1 S,2R)-3-(((4'S)-6-(2,2-dimethylpropyl)-3',4' 20 dihydrospiro[cyclobutane-1,2'-pyrano[2,3 -b]pyridin]-4'-yl)amino)-2-hydroxy- 1 -(4 pyridinylmethyl)propyl)acetamide. Example 489 25 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1-((2-oxo-1,2-dihydro-4 pyridinyl)methyl)propyl)acetamide N-((l S,2R)-3-(((4'S)-6'-(2,2-Dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1-((2-(methyloxy)-4 30 pyridinyl)methyl)propyl)acetamide (0.150 g, 0.302mmol) and Nal (0.679 g, 4.53mmol) WO 2007/061670 PCT/US2006/044058 - 138 were refluxed in HOAc (3mL). After three hours the reaction was concentrated and dissolved in chloroform. The organic layers were washed with IN NaOH, aqueous sodium thiolsulfate, and brine. The organic layer was concentrated and purified directly by reverse phase HPLC to afford the title product as a TFA salt. MS m/z: 483.3 (100%, M-1). 5 Example 490 N-((1S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2-cyano-2-methylpropyl)-3',4' dihydrospirocyclobutane-1,2'-pyrano[2,3-blpyridinl-4'-yl)amino)-2 hydroxypropyl)acetamide 10 Step 1: (S)-tert-butyl 6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-blpyridin 4-ylcarbamate Triethylamine (3.74 ml, 26.8 mmol) and BOC-Anhydride (5.07 g, 23.2 mmol) were added to (S)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine 15 (4.81 g, 17.9 mmol) in DCM (50mL) and the reaction was allowed to stir at RT until TLC analysis (20:1 DCM/MeOH) demonstrated the reaction to be complete (12 hrs). The reaction mixture was concentrated and the crude material was taken up in EtOAc, washed twice with saturated ammonium chloride, water, brine, and concentrated. The product was purified by a short column of silica gel (10:1 hexanes/EtOAC to 4:1 Hexanes/EtOAC) to 20 afford the titled product. Step 2: (S)-tert-butyl allyl(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyranor2,3 blpyridin-4-yl)carbamate (S)-Tert-butyl 6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4 ylcarbamate was dissolved in DMF (60 mL) and cooled to 0"C. NaH (60% by weight in 25 mineral oil)(0.858g, 21.4mmol) was carefully added and the solution was allowed to stir for 40 minutes. ALLYL BROMIDE (1.62 ml, 18.8mmol) was added and the reaction was stirred 45 minutes and then diluted with saturated ammonium chloride. Water was added and the solution was extracted with diethyl ether. The combined organic layers were washed with water, brine, dried over magnesium sulfate, and concentrated. The crude 30 product was used without further purification. MS n/z: 409.1(100%, M). Step 3: (S)-tert-butyl allyl(6-(hydroxymethyl)-2,2-spirocyclobutyl-3.4-dihydro-2H pyranof2,3-blpyridin-4-yl)carbamate (S)-Tert-butyl ally](6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano(2,3-blpyridin-4 yl)carbamate (7.02 g, 17.2 mmol) was dissolved in THF (IOOmL) and cooled to -78'C. n- WO 2007/061670 PCT/US2006/044058 - 139 Butyllithium (2.5 M in hexanes) (8.23 ml, 20.6 mmol) was added dropwise to give a dark orange solution. After 30 minutes, DMF (14.5 ml, 189mmol) was added and the solution was stirred 45 minutes before being quenched by addition of saturated ammonium chloride and water. The aqueous solution was extracted with EtOAc and the combined 5 organic layers were washed with water, brine, dried over sodium sulfate and concentrated to afford (S)-tert-butyl allyl(6-formyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3 b]pyridin-4-yl)carbamate as the product which was used in the next step without further purification. MS m/z: 359.2 (100%, M+1). The crude material was dissolved in 80 mL of methanol and cooled to 0*C when 10 sodium tetrahydroborate (1.62 g, 42.9 mmol) was added. After stirring 40 minutes the reaction was quenched by addition of saturated ammonium chloride and water. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The product was purified by column chromatography (1:1 Hex/EtOAc to EtOAc) to give the titled 15 compound. Step 4: (S)-tert-butyl allyl(6-(2-cyano-2-methylpropyl)-2,2-spirocyclobutyl--3,4-dihydro 2H-pyranor2,3-blpyridin-4-yl)carbamate (S)-Tert-butyl allyl(6-(hydroxymethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3 b]pyridin-4-yl)carbamate (1.45 g, 4.02 mmol) in DCM (4OmL) was added to a solution of 20 dibromotriphenylphosphorane (1.87g, 4.43 mmol) in DCM (40 mL) at ambient temperature. After stirring 45 minutes the reaction was concentrated and the crude product, (S)-tert-butyl allyl(6-(bromomethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H pyrano[2,3-b]pyridin-4-yl)carbamate taken up in THF (40 mL). In a separate flask, diisopropylamine (3.58 ml, 25.3 mmol) was added to THF (100 mL) and the solution was 25 cooled to -78*C. n-Butyllithium (2.5 M in hexanes)(9.65 ml, 24.1 mmol) was added and the solution was stirred 20 minutes at 0 *C. Isobutyronitrile (2.17 ml, 24.1 mmol) was added and the yellow solution was stirred 30 minutes at 0*C before the intermediate (S) tert-butyl ally1(6-(bromomethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3 b]pyridin-4-yl)carbamate in THF (4OmL) was added dropwise. The reaction was stirred at 30 0*C and after 1 hour 30mL of a stock solution of isobutyronitrile enolate (prepared in the identical manner from the same amounts of diisopropylamine, n-butyllithium, isobutyronitrile as above in THF (70mL)) was added to the reaction. After ten minutes, the reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The combined organic layers were washed with water, brine, and dried over sodium WO 2007/061670 PCT/US2006/044058 - 140 sulfate. Concentration and purification by silica gel column (1.5:1 Hex/EtOAc) afforded the titled compound. MS m/z: 412.3 (100%, M+1). Step 5: (S)-3-(4-amino-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-blpyridin-6-yl)-2,2 dimethylpropanenitrile 5 (S)-Tert-butyl allyl(6-(2-cyano-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H pyrano[2,3-b]pyridin-4-yl)carbamate (0.1 00g, 0.24 mmol) was stirred in DCM (2mL) with TFA (1.0 ml, 13mmol). After 3 hrs the reaction was concentrated. The crude product was taken up in DCM and 10% aqueous sodium carbonate and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with 10 brine, dried over sodium sulfate and concentrated to afford (S)-3-(4-(allylamino)-2,2 spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)-2,2-dimethylpropanenitrile. The crude product was used without further purification. MS n/z: 312.2 (100%, M+1). The crude product was dissolved in degassed (N 2 ) DCM (2 mL) and 1,3 dimethylbarbituric acid (0.11 g, 0.73 mmol) was added. After two minutes, 15 tetrakis(triphenylphosphine)palladium(0) (0.014 g, 0.012 mmol) was added and the reaction was stirred at 35*C for 3 hours. The reaction was diluted with DCM and 10% aqueous sodium carbonate and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel 20 chromatography (20:1 DCM/MeOH) to afford the titled compound. n/z: 272.2 (M+1). Step 6: N-((1 S,2R)-1 -((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2-cyano-2-methylpropyl) 3',4'-dihydrospirorcyclobutane- 1.2'-pyrano2,3 -blpyridinl-4'-yl)amino)-2 hydroxypropyl)acetamide The title compound was prepared by a method analogous to that described in Example 25 464, steps 8-10. MS Found m/z: 511.2 (M+1) Example 491 N-((1S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(3,3-difluoro-2,2-dimethylpropyl) 30 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin-4'-yl)amino)-2 hydroxypropyl)acetamide Step 1: (S)-tert-butyl allyl(6-(2.2-spirocyclobutyl-3-oxopropyl)-2,2-dimethyl-3,4-dihydro 2H-pyrano[2,3-blpyridin-4-yl)carbamate WO 2007/061670 PCT/US2006/044058 - 141 (S)-tert-butyl allyl(6-(2-cyano-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H pyrano[2,3-b]pyridin-4-yl)carbamate (0.708 g, 1.72 mmol) was dissolved in toluene (12 mL) and cooled to 0*C. DIBAL, 1.0 M solution in hexanes (5.08 ml, 5.08 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction was quenched with 1 5 N HCI and diluted with a saturated aqueous sodium potassium tartrate solution and vigorously stirred for 3 hours. The layers were separated and the aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, and dried over sodium sulfate. The crude product was purified by silica gel chromatography (2:1 Hexanes/EtOAc) to afford the titled compound. 10 Step 2: (S)-tert-butyl allyl(6-(3,3-difluoro-2,2-dimethylpropyl)-2,2-spirocyclobutyl-3.,4 dihydro-2H-pyrano[2,3-blpyridin-4-yllcarbamate (S)-Tert-butyl allyl(6-(2,2-spirocyclobutyl-3-oxopropyl)-2,2-dimethyl-3,4-diydro-2H pyrano[2,3-b]pyridin-4-yl)carbamate (0.196 g, 0.473 mmol) was dissolved in DCM (1.5mL) and cooled to -78"C. DAST (0.150 ml, 1.13 mmol) was added and the reaction was 15 slowly warmed to RT and stirred for 12 hrs. The reaction was carefully quenched with 10% aqueous sodium carbonate and diluted with DCM. The aqueous layer was extracted with DCM and the combined organic layers were washed with water, brine, and dried over sodium sulfate. The crude product was used directly for the next step without further purification. 20 Step 3: N-((I S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(3,3-difluoro-2,2 dimethylpropyl)-3',4'-dihydrospirofcyclobutane-1,2'-pyranof2,3-blpvridinl-4'-yl)amino) 2-hydroxNypropyl)acetamide The title compound was prepared in a manner analogous to that described in Example 490 Step 5 and Step 6. MS Found m/z: 536.2 (M+I1). 25 Example 492 30 N-((1S,2R)-1-((4-chloropbenyl)methyl)-3-(((4'S)-6'-(2,2-dimethyl-3-butyn-1-yl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bpyridinl-4'-yl)amino)-2 hydroxypropyl)acetamide Step 1: (S)-tert-butyl allyl(6-(2,2-dimethylbut-3-ynyl)-2,2-spirocyclobutyl-3,4-dihydro 2H-pyranof2,3-blpyridin-4-yl)carbamate WO 2007/061670 PCT/US2006/044058 - 142 Potassium carbonate (0.155 g, 1.12 mmol) was added to a solution of (S)-tert-butyl allyl( 6 -(2,2-spirocyclobutyl-3-oxopropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3 blpyridin-4-yl)carbamate (0.233 g, 0.562 mmol) and Ohira's Reagent (0.130 g, 0.674 mmol) in MeOH (6 mL). After stirring 15 hrs, the reaction was diluted with 10% sodium 5 carbonate and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated. The product obtained was taken on without further purification. MS m/z: 411.3 (M+1). Step 2: N-((I S,2R)-I-((4-chlorophenvl)methyl)-3-(((4'S)-6'-(2,2-dimethyl-3-butyn-I -yl) 3',4'-dihydrospirofcyclobutane-1,2'-pyranof2,3-blpyridinl-4'-yllamino)-2 10 hydroxypropyl)acetamide The title compound was synthesized in analogous manner according to procedures described for Example 491, Step 3 and purified by column chromatography (20:1 DCM/MeOH). MS Found m/z: 510.2 (M+1). 15 Example 493 N-((18,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylbutyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bIpyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide 20 The compound of Example 492 (0.100 g, 0.196 mmol) was dissolved in MeOH (2 mL) and diazenedicarboxylic acid, dipotassium salt (0.762 g, 3.92 mmol) was added. HOAc (0.673 ml, 11.8 mmol) in MeOH (2 mL) was slowly added to the heterogeneous solution and the reaction was stirred. After all the acetic acid was added and the solution went from yellow to clear and upon complete reduction, the reaction was concentrated and partitioned 25 between 1 N NaOH and DCM. The aqueous was layer was extracted with DCM and the combined organics were washed with brine and concentrated. The crude material was dissolved in a minimal amount of MeOH and directly purified by reverse phase HPLC to afford the title compound. MS m/z: 514.2 (M+1). 30 Example 494 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4'-dihydrospiro[cyclobutane 1, 2 '-pyrano[ 2

,

3 -blpyridin-4'-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide Step 1: 2

,

6 -difluoro-3-neopentylpyridine WO 2007/061670 PCT/US2006/044058 - 143 To a 500 mL RBF was added neopentylmagnesium chloride, 1.OM in ether (28.0 ml, 28 mmol) and an ice bath. After cooling, zinc(H) chloride, 0.5M in THF (56.0 ml, 28 mmol) was added dropwise. The cooling bath was removed and after stirring for 45 minutes, Reactant 1 (0.26 g, 0.32 mmol) was added followed by 2,6-difluoro-3-iodopyridine (2.74 g, 5 8.0 mmol) in TI-F (10 mL), which was added dropwise. The yellow solution was then heated to 60*C. After stirring overnight the reaction was allowed to cool and sat'd. NH 4 Cl was added cautiously. The reaction mixture was partitioned between EtOAc/Water. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers washed with brine and concentrated in vacuo. The crude product was adsorbed onto a plug of silica 10 gel and chromatographed through a Redi-Sep@ pre-packed silica gel column (40 g), eluting with 1% EtOAc in hexane, to provide 2,6-difluoro-3-neopentylpyridine as a colorless oil. MS m/z: 186 (M+I). Step 2: N-((S)-2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2,6-difluoro-5 neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide 15 To a three-necked RBF was added 2,2,6,6-tetramethylpiperidine (0.34 ml, 2 mmol), THEF (10mL), and an ethanol/N 2 bath. After cooling to -78*C, butyllithium (0.70 ml, 2 mmol) was added dropwise. After stirring for several minutes, the solution was cooled to -100'C of 2,6-difluoro-3-neopentylpyridine (0.230 g, I mmol) in THF (2mL) was added dropwise. The solution was then treated with (R,E)-N-(2-(1 -(tert 20 butyldimethylsilyloxy)cyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide (0.71 g, 2 mmol) in THF (3mL). After the addition was complete the reaction was allowed to warm to 0*C as the liquid N 2 boiled off. The reaction was then quenched with water (1OmL) and extracted with EtOAc (3 X 20mL). The combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep@ 25 pre-packed silica gel column (12 g), eluting with 1% to 20% EtOAc in hexane, to provide N-((S)-2-(I-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2,6-difluoro-5-neopentylpyridin-3 yl)ethyl)-2-methylpropane-2-sulfinamide (0.07 g, 11% yield). This material was used without further purification in the next step. MS n/z: 517 (M+1). Step 3: N-((S)-7-fluoro-2,2-dimethyl-6-neopentyl-3,4-dihydro-2H-pyranor2,3-blpyridin-4 30 yl)-2-methylpropane-2-sulfinamide To a 150 mL RBF was added N-((S)-2-(l -(tert butyldimethylsilyloxy)cyclobutyl)-I-(2,6-difluoro-5-neopentylpyridin-3-yl)ethyl)-2 methylpropane-2-sulfinamide (0.070 g, 0.14mmol), THF (3mL), and TBAF, 1M in THF (0.14 ml, 0.14mmol). The reaction was stirred at RT. After 20 minutes, the reaction was eluted through a plug of silica gel with THE. The resulting filtrate was concentrated in WO 2007/061670 PCT/US2006/044058 - 144 vacuo and taken up in THF (2OmL) and treated with NaH (0.035 g, 0.88 mmol, 60% in mineral oil). The reaction was stirred at 40*C for 16 hours. The reaction was allowed to cool to RT and quenched with sat'd NHCl, and extracted with EtOAc (25 mL). The combined organic layers were concentrated in vacuo to give N-((S)-7-fluoro-2,2-dimethyl 5 6 -neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-sulfinamide. This material was carried forward without further purification. MS m/z: 383 (M+1). Step 4: (S)-7-fluoro-2,2-spirocyclobutane-6-neopenyl-3.4-dibydro-2H-pyrano2,3 blpyridin-4-amine To a 500 mL RBF was added N-((S)-7-fluoro-2,2-dimethyl-6-neopentyl-3,4-dihydro-2H 10 pyrano[2,3-blpyridin-4-yl)-2-methylpropane-2-sulfinamide (1.71 g, 4.5mmol), dichloromethane (20mL), and hydrogen chloride, 4.OM in dioxane (2.00 ml, 8.Ommol). The reaction was stirred at RT. After 15 hours, the reaction was washed with sat'd NaHCO 3 and the organic layer concentrated in vacuo. The resulting crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep@ pre-packed silica gel 15 column (12g), eluting with 0% to 50% EtOAc in DCM to provide (S)-7-fluoro-2,2 spirocyclobutane-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine as a light yellow oil. Step 5: N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropl)-7'-fluoro-3',4' dihydrospiro[cyclobutane-1,2'-pyranor2,3-blpvridinl-4'-yl)amino)-2-hydrox- 1 20 (phenylmethyl)propyl)acetamide The amine from Step 4 was used in a mthod analogous to that described in Example 464, steps 8-10 to give 'N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide as a colorless solid. MS m/z: 484 (M+1). 25 Example 495 N-((1S, 2 R)-3-((( 4

'S)-

6 '-(-fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane 30 1,2 t -pyrano[2,3-bpyridin-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide Step 1: N-al lyl-N-t-butylcarbamate-(4'S)-6'-(1 -hydroxy-2,2-dimethylpropyl)-3',4' dihydrospirorcyclobutane-1,2'-pyranof2 3-blpyridinl-4-amine WO 2007/061670 PCT/US2006/044058 - 145 A solution of N-allyl-N-t-butylcarbamate-(4'S)-6'-(bromo)-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-amine (4.12 g, 10.1 mmol) in ether (80mL) was cooled to 78*C and then t-butyllithium (12.5 ml, 21.3 mmol) was added and stirred for 15 minutes before the pivalaldehyde (3.80 ml, 35.0 mmol) (Note: freshly distilled) was added. After 5 5 minutes, LC-MS shows the starting material has been consumed. The reaction was quenched with sat'd NH 4 CI and the organic layer separated. The organic layer was combined with previous trial reactions and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep@ pre-packed silica gel column (120 g), eluting with 0% to 30% EtOAc in hexane, to provide N-allyl-N-t-butylcarbamate-(4'S)-6'-(1 -hydroxy 10 2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-amine as a yellow oil. MS n/z: 417 (M+1). Step 2: N-allyl-(4'S)-6'-(1-fluoro-2,2-dimethylpropyl)-3',4'-dihvdrospiro[cyclobutane- 1,2' pyranor2,3-blpyridinl-4'-amine To a 250mL RBF was added N-allyl-N-t-butylcarbamate (4'S)-6'-(1 -hydroxy-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3 15 b]pyridin]-4'-amine (4.01 g, 9.6mmol), toluene (1OOmL), a dry ice bath, and after cooling for 20 minutes DAST (1.81 ml, 14mmol) was added. After 1 hour, LC-MS shows Reactant 1 consumed. The reaction was quenched with sat'd NH 4 CI (20mL). The layers were separated and the aqueous layer extracted with EtOAc (20 mL). The combined organic layers were concentrated in vacuo to give a golden oil. The oil was taken up in MeOH 20 (50mL) and treated with HCI, 4M in dioxane (5.0 ml, 20mmol). After 1.5 hours, no changes were seen by LC-MS. The reaction was treated with an additional HCI (5 mL) and heated to 60*C. After stirring for 5 hours, the solution was allowed to cool to RT. After a further 16 hours, the reaction was concentrated in vacuo to give a brown oil, which was taken up in DCM and washed with sat'd NaHCO 3 , brine and concentrated in vacuo to give 25 N-allyl-(4'S)-6'-(1-fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-amine (3.15 g) as a brown oil. MS m/z: 319 (M+1). The crude material was used without further purification in the next step. Step 3: (4'S)-6'-(] -fluoro-2,2-dimethylpropyl)-3',4'-dihydrospirorcyclobutane-1,2' pyranor2,3-b~pyridinl-4'-amine To a 250 mL RBF was added N-allyl-(4'S)-6'-(1-fluoro 30 2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-amine (3.10 g, 9.7 mmol), degassed DCM (80 mL), and 1,3-dimethylbarbituric acid (4.58 g, 29 mmol). After stirring for 5 minutes, Palladium Tetrakis (0.56 g, 0.48 mmol) was added and the solution heated to 40*C. After 4 hours, the solution was poured into a separator funnel containing 10% Na 2

CO

3 (50mL) and the layers separated. The organic layer was again WO 2007/061670 PCT/US2006/044058 - 146 extracted with 10% Na 2

CO

3 (5OmL). The combined aqueous layers were back extracted with DCM (50 mL). The combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep@ pre-packed silica gel column (80 g), eluting with 50% to 80% EtOAc in hexane, to provide a mixture of 5 product and triphenyl-phosphine oxide. The material was taken up in EtOAc and extracted with HCl (IN, 2 X 20 mL). The aqueous layer was then neutralized and extracted with EtOAc (2 X 20 mL). The combined EtOAc layers were concentrated in vacuo to give (4'S) 6'-(1-fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin] 4'-amine (1.81 g 69% for step 2 and 3) as a colorless oil. MS n/z: 279 (M+1). 10 Step 4: N-(I S,2R)-3-(((4'S)-6'-(1 -fluoro-2,2-dimethylpropyl)-3',4' dihydrospirofcyclobutane-1,2

'

-pyranof2,3-blpyridinl-4'-yl)amino)- -((4 fluorophenvl)methyl)-2-hvdroxvpropvl)acetamide The amine from step 3 was reacted in a manner analogous to that described in Example 464, steps 8-10, to give the title compound as a white solid. MS m/z: 502 (M+1). 15 Example 496 N-((lS, 2

R)-

3

-(((

4 'S)-6'-(cyclopropylmethyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-bpyridin]-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2 20 hydroxypropyl)acetamide Step 1: (S)-tert-butyl 6 -allyl- 2 ,2-spiroyclobutl-3,4-dihydro-2H-pyranor2,3-blpridin-4 ylcarbamate A mixture of Pd 2 (dba) 3 (186 mg, 0.203 mmol) tri-t-butylphosphonium tetrafluoroborate (354 mg, 1.22 mmol), cesium fluoride (3.08 g, 4.06 mmol) and (S)-tert-butyl 6-bromo-2,2 25 spirocyclobutyl- 3

,

4 -dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate in 12mL of dioxane was purged with nitrogen for 30 minutes before being treated with allyltributylstannane (6.23mL, 20.3mmol). The mixture was heated to 100 4C for 10 hours at which point the reaction was allowed to cool to room temperature. The mixture was diluted with ethyl acetate (50mL) and successively washed with saturated potassium fluoride (5OmL), water 30 and brine. Drying over sodium sulfate and concentration provided a residue that was purified by silica gel chromatography (0-25% EtOAc in hexanes) to provide the title compound as light yellow solid. MS nz: 331.2 (M+1). Step 2: (S)- 6 -(cyclopropylmethyll-2,2-spirocyclobutv1-3,4-dihydro-2H-pyrano[23 blpyridin-4-amine WO 2007/061670 PCT/US2006/044058 - 147 A solution of diethylzino (1.0 M in hexanes, 9.00 mL, 9.00 mmol) was cooled to -10*C and treated with TFA (0.70 ml, 9.0 mmol) dropwise over 5 minutes. After an additional 5 minutes diiodomethane (0.70 ml, 9.0 mmol) was added, and the reaction mixture was allowed to stir for 10 minutes. The resulting suspension was treated with a solution of (S) 5 tert-butyl 6-allyl- 2

,

2 -spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (0.580 g, 2.00 mmol) in 10 mL dichloromethane. The reaction mixture was allowed to stir at -10*C for 30 minutes before being allowed to warm to RT. The suspension was quenched with MeOH and saturated sodium bicarbonate (5 mL) and was allowed to stir for an additional hour. The reaction mixture was then diluted with EtOAc (50 mL) and filtered 10 through a short plug of silica. The filtrate was concentrated and the crude residue was resubmitted to the reaction conditions and allowed to stir at RT overnight. The reaction mixture was quenched with methanol (5 mL) and saturated sodium bicarbonate (5 mL). 6N NaOH (15 mL) was added and the reaction mixture was allowed to stir for one hour before being diluted with DCM (50 mL). The aqueous was extracted with DCM 3 x 50 mL and the 15 combined organics were washed with brine, dried over magnesium sulfate and concentrated. Purification of the crude residue by reverse phase HPLC provided the title compound as a yellow oil. MS r/z: 245 (M+1). Step 3: N-((I S, 2 R)-3-((( 4

'S)-

6 '-(cvclopropylmethyl)-3',4'-dihydrospirofcyclobutane-1,2' pyranof2,3-blpyridinl-4'-vl)amino)-I-(( 4 -fluorophenyl)methyl)-2-hydroxypropyl)acetamide 20 The title compounds made by a method analogous to that described in Example 464, steps 8-10. MS Found m/z: 468 (M+1). Example 497 25 N-((1S,2R)-1-((4-Fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-((1 methylcyclopropyl)methyl)-3', 4 '-dihydrospirofcyclobutane-1,2'-pyrano[2,3 bJpyridinl- 4 '-yl)amino)propyl)acetamide Step 1: (S)-tert-butyl 6

-(

2 -methylaly)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyranof2,3 blpyridin-4-ylcarbamate 30 A mixture of Pd 2 (dba) 3 (133 mg, 0.145 mmol) tri-t-butylphosphonium tetrafluoroborate (252 mg, 0.869 mmol), cesium fluoride (1.32 g, 8.69 mmol) and (S)-tert-butyl 6-bromo-2,2 spirocyclobutyl- 3

,

4 -dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate in 3 mL of dioxane was purged with nitrogen for 30 minutes before being treated with tributyl(2 methylallyl)stannane (2.50 g, 7.24 mmol). The mixture was heated to 90 0 C for 10 hours at WO 2007/061670 PCT/US2006/044058 - 148 which point the reaction was allowed to cool to RT and diluted with EtOAc (50 mL) and successively washed with saturated potassium fluoride (50 mL), water and brine. Drying over sodium sulfate and concentration provided a residue that was purified by silica gel chromatography (0-25% EtOAc in hexanes) to provide the title compound as light yellow 5 solid. MS m/z: 345 (M+1). Step 2: (S)-tert-butyl 6-((1-methylcyclopropyl)methyl)-2,2-spirocyclobutyl-3,4-dihydro 2H-pyrano[2,3-blpyridin-4-ylcarbamate A solution of diethyl zinc (1.0 M, 35.0 mL, 35 mmol)in 20mL hexanes was cooled to -10 0 C and treated with chloroiodomethane (5.00 mL, 65mmol). After stirring for 30 minutes at 10 this temperature a solution of (S)-tert-butyl 6-(2-methylallyl)-2,2-spirocyclobutyl-3,4 dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate in 20 mL of dichloromethane was added and the reaction was allowed to warm to room temperature where it was maintained for an additional 10 hours. The reaction was quenched with methanol (10 mL) and saturated sodium bicarbonate (3 mL). The slurry was then treated with DIEA (0.80 mL, 4.00 mmol) 15 and di-tert-butyl dicarbonate (1.0 mL, 4.0 mmol) and allowed to stir for 3 hours. The reaction was then diluted with EtOAc (25 mL) and washed successively with saturated sodium bicarbonate (30 mL), water and brine before being dried over magnesium sulfate. Concentration provided a residue that was taken up in 20 mL of DCM and added a solution of diethyl zinc (1.0 M, 35.0 mL, 35 mmol) and chloroiodomethane (5.00 mL, 65 mmol) in 20 20 mL hexanes at -10 0 C. The reaction was allowed to warm to RT where it was maintained for an additional 10 hours. The reaction was quenched with methanol (10 mL) and saturated sodium bicarbonate (3 mL). The slurry was then treated with DIEA (0.80 mL, 4.00 mmol) and di-tert-butyl dicarbonate (1.0 mL, 4.0 mmol) and allowed to stir for 3 hours. The reaction was then diluted with EtOAc (50 mL) and washed successively with 25 saturated sodium bicarbonate (50 mL), water and brine before being dried over magnesium sulfate. Concentration and purification by silica gel chromatography (0-50% ethyl acetate in hexanes) provided the title compound as a yellow oil. MS m/z: 359 (M+1). Step 3: (S)-6-((1-methylcyclopropyl)methyl)-2,2-spirocyclobutyl-3,4-dihydro-2H pVyranor2,3-blpvridin-4-amine 30 A solution of (S)-tert-butyl 6-((1-methylcyclopropyl)methyl)-2,2-spirocyclobutyl- 3

,

4 dihydro-2H-pyrano(2,3-b]pyridin-4-ylcarbamate (0.860 g, 2.4 mmol) and 2,6-lutidine (2.80 ml, 24.0 mmol) in 10 mL of DCM was cooled to 0*C and treated with trimethylsilyl triflate (2.30 ml, 12.0 mmol). The reaction mixture was allowed to warm to RT and stir for 10 hours before being diluted with ethyl acetate (50 mL) and washed with saturated sodium WO 2007/061670 PCT/US2006/044058 - 149 bicarbonate (50 mL) and brine. The combined organics were dried over magnesium sulfate, concentrated and purified reverse phase HPLC to provide the title compound as a yellow oil. MS m/z: 259 (M+I). Step 4: N-((I S.2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3 -((4'S)-6'-(( 1 5 methylcyclopropyl)methyl)-3',4'-dihydrospirorcvclobutane-1,2'-pyranof2,3-blpyridinl-4' yl)amino)propyl)acetamide The title compound was made by a method analogous to that described in Example 464, steps 8-10. MS Found m/z: 482 (M+I). 10 Example 498 N-((1S,2R)-3-(((4'S)-6'-(3,3-difluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bpyridinl-4'-yl)amino)-1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide 15 Sten 1: Tert-butyl (S)- 6

-(

2 -methvl-3-oxopropyl)-2,2-spirocyclobuyl-3,4-dihydro-2H pyrano[2,3-blpyridin-4-ylcarbamate A solution of (S)-tert-butyl 6 -bromo- 2

,

2 -spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3 b]pyridin-4-ylcarbamate (1.500 g, 4.06 mmol), Pd 2 (dba) 3 (0.186 g, 0.203 mmol), tri-t 20 butylphosphonium tetrafluoroborate (0.354 g, 1.22 mmol), 2 -methylprop-2-en- I -ol (1.38 ml, 16.2 mmol), cesium fluoride (0.617 g, 4.06 mmol), and N-cyclohexyl-N methylcyclohexanamine (5.17 ml, 24.4 mmol) in 8 mL of dioxane was purged with nitrogen for 30 minutes. The reaction vessel was then sealed and heated to 80 'C for 10 hours. The cooled reaction mixture was quenched with saturated sodium bicarbonate (50 mL), and the 25 aqueous layer was extracted with EtOAc 3 x 50 mL. The combined organics were washed with brine, dried over sodium sulfate and concentrated. Purification of the crude residue by column chromatography (0-50% EtOAc in hexanes) provided the title compound as a colorless oil. MS m/z: 361 (M+1). Step 2: Tert-butyl (S)- 6

-(

3

,

3 -difluoro-2-methvlpropvl)-2,2-spirocyclobutyl-3,4-dihydro-2H 30 pyranof2,3-blpyridin-4-ylcarbamate A solution of tert-butyl (S)- 6

-(

2 -methyl-3-oxopropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H pyrano[2,3-b]pyridin-4-ylcarbamate (0.270 g, 0.749 mmol) in 1.5 mL of DCM was cooled to -78 0 C and treated with DAST (0.218 ml, 1.65 mmol). The reaction mixture was allowed to warm to RT and stir for 8 hours. An additional equivalent of DAST was added, and the WO 2007/061670 PCT/US2006/044058 - 150 reaction mixture was allowed to stir for 2 hours before being diluted with EtOAc (25 mL) and washed with saturated sodium bicarbonate and brine. The organics were dried over magnesium sulfate, concentrated and purified by silica gel chromatography (0-30% EtOAc in hexanes) to furnish the title compound as a yellow oil. MS nz: 383 (M+1). 5 Step 3: (4S)-6-(3,3-difluoro-2-methylpropyl)-2,2-spirocyclobutyl-3.4-dihydro-2H pyranof2,3-blpyridin-4-amine A solution of tert-butyl (S)-6-(3,3-difluoro-2-methylpropyl) 2,2-spirocyclobutyl-3,4-dihydro-21-pyrano[2,3-b]pyridin-4-ylcarbamate (0.110 g, 0.3 mmol) in 2mL of DCM was treated with HCl (4.0 M in dioxane, 1.50 ml, 6.00 mmol) and was allowed to stir at RT for 10 hours. The reaction mixture was diluted with EtOAc (50 10 mL) and was washed with 2N NaOH (50 mL) and brine. The organics were dried over magnesium sulfate and concentrated to provide the title compound as a yellow solid. MS m/z: 283 (M+1). Step 4: N-((IS,2R)-3-(((4'S)-6'-(3,3-difluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano12,3-blpyridinl-4'-yl)amino)-1-((4 15 fluorophenyl)methyl)-2-hydroxypropyl)acetamide The title compound was made by a method analogous to that described in Example 464, steps 8-10. MS Found m/z: 506 (M+1). Example 499 20 N-((1S,2R)-3-(((4'S)-6'-((2S)-3-fluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-blpyridin]-4'-yl)amino)-1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; and N ((1S,2R)-3-(((4'S)-6'-((2R)-3-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane 25 1,2'-pyrano[2,3-bpyridinl-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide Step 1: Tert-butyl (S)-6-(3-(tert-butyldimethylsiyloxy)-2-methylpropyl)-2,2 spirocyclobutyl-3,4-dihvdro-2H-pvranof2,3-blpyridin-4-vlcarbamate Tert-butyldimethyl(2-methylallyloxy)silane was treated with 9-BBN (0.5 M in diethyl 30 ether, 53.0 ml, 26.0 mmol) and the resulting solution was purged with nitrogen for 15 minutes before being allowed to stir at RT for 10 hours. In a separate flask a solution of palladium acetate (100 mg, 0.500 mmol) and SPhos (700 mg, 2.00 mmol) in 2 mL of toluene and 2 mL of THF was purged with nitrogen for 30 minutes and allowed to stir at RT for one hour. The resulting solution was added to the organoborane, followed by potassium WO 2007/061670 PCT/US2006/044058 - 151 phosphate (4.00 g, 21.0 mmol) and a solution of (S)-tert-butyl 6-bromo-2,2-spirocyclobutyl 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (1.95 g, 5.00 mmol) in 15 mL of DMF. The reaction mixture was purged with nitrogen for 15 minutes and heated to 90*C for 3 hours at which point it was cooled to RT, diluted with EtOAc (50 mL) and filtered 5 through a plug of celite. The filtrate was washed with water, brine, and the organics were dried over sodium sulfate and concentrated. Purification of the crude residue by column chromatography (0-25% EtOAc in hexanes) provided the title compound, contaminated with starting olefin, as a colorless oil. Step 2: Tert-butvl (S)-6-(3-hydroxy-2-methylpropyl)-2,2-spirocyclobutl-3,4-dihydro-2H 10 pyrano[2,3-blpyridin-4-ylcarbamate A solution of tert-butyl (S)-6-(3-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2,2 spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (2.80 g, 6 mmol) in 20 mL of DCM was treated with tetrabutyl ammonium fluoride (TBAF; 1.0 M in THF, 29.0 ml, 29.0 mmol) and allowed to stir at RT for 3 hours. The reaction mixture was 15 concentrated to reduce the volume by half and it was allowed to stir for an additional hour at which point it was concentrated and the crude residue was purified by column chromatography to furnish the title compound as a white solid. MS n/z: 363 (M+I1). Step 3: 3-((S)-4-(tert-butoxycarbonyl)-2,2-spirocyclobutl-34-dihydro-2H-pyrano f2,3 blpyridin-6-vl)-2-methylpropyl methanesulfonate 20 A solution of tert-butyl (S)-6-(3-hydroxy-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro 2H-pyrano[2,3-b]pyridin-4-ylcarbamate (0.350 g, 0.97 mmol) in 5mL of DCM was treated with DIEA (0.340 ml, 1.90 mmol) cooled to 0*C and exposed to methane sulfonyl chloride (0.082 ml, 1.10 mmol). The reaction mixture was allowed to warm to RT and was maintained at this temperature for one hour before being diluted with EtOAc (50 mL), 25 washed with water and brine and dried over sodium sulfate. Concentration provided the title compound as a white solid. MS m/z: 441 (M+1). Step 4: (4S)-6-(3-fluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3 blpyridin-4-amine A solution of 3-((S)-4-(tert-butoxycarbonyl)-2,2-spirocyclobutyl-3,4-dihydro-2H 30 pyrano[2,3-b]pyridin-6-yl)-2-methylpropyl methanesulfonate (1.200 g, 3.00 mmol) in THF (5 mL) was treated with TBAF (1.0 M in THF, 14.0 ml, 14.0 mmol) and heated to 80"C for 10 hours. The cooled reaction mixture was diluted with EtOAc (50 mL) and was washed successively with 2N NaOH (25 mL) and brine. The organics were dried over sodium WO 2007/061670 PCT/US2006/044058 - 152 sulfate, filtered and concentrated to provide a residue that was purified by reverse phase HPLC to provide the title compound a yellow oil. MS m/z: 265 (M+1). Step 5: N-((IS,2R)-3-(((4'S)-6'-((2S)-3-fluoro-2-methylpropyl)-3',4' dihydrospirorcyclobutane-1,2'-pyranoF2,3-blpyridinl-4'-yl)amino)-l -((4 5 fluorophenyl)methvl)-2-hydroxypropyl)acetamide; and N-((IS,2R)-3-(((4'S)-6'-((2R)-3-fluoro-2-methylpropyl-3',4'-dihydrospirorcyclobutane-1,2' pyrano[2,3-blpyridinl-4'-yl)amino)-I-((4-fluorophenyl)methyl)-2-hydroxvpropyl)acetamide The title compounds were made by a method analogous to that described in Example 464, steps 8-10. MS Found m/z: 488 (M+1). 10 Example 500 N-((1S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4 quinolinyl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide 15 Step 1: 4-bromo-N-(2-methylbut-3-yn-2-yl)benzenamine To a solution of 4-bromobenzenamine (4.0 g, 23 mmol), TEA (4.3 ml, 31 mmol), 2.0 ml of water, copper (0.058 g, 0.91 mmol) and copper(I) chloride (0.058 g, 0.59 mmol) in diethyl ether (9.8 ml, 20 mmol) was added 3-chloro-3-methylbut-1-yne (2.0 g, 20 mmol), dropwise. After stirring overnight, the reaction mixture was transferred to a seperatory 20 funnel containing water and diethyl ether. The aqueous layer was washed 3X with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated. The crude oil was purified with by MPLC (100% DCM to 10% (91/1 0/1 DCM:MeOH:NH4OH)) to provide the product as an oil. MS m/z: 240 (M+2). Step 2: 6-bromo-2,2-dimethyl-1,2-dihydroquinoline 25 To a solution of 4-bromo-N-(2-methylbut-3-yn-2-yl)benzenamine (3.30 g, 14 mmol) in toluene (14 ml, 14 mmol) was added copper(I) chloride (0.300 g, 3.0 mmol) in one portion. The reaction vessel was sealed and the resulting mixture was heated to 90 deg C. After stirring overnight, the mixture was transferred to a separatory funnel containing water and EtOAc. The aqueous layer was washed IX with EtOAc and 3X with DCM. 30 The organic layers were combined, dried with MgSO4, filtered and concentrated. The crude oil was purified with an MPLC (100% DCM to 10% (9 1/10/1 DCM:MeOH:NH40H)) to provide the product. MS m/z: 238. Step 3: 6-bromo-2,2-dimethyl-1,2,3,4-tetrahvdroquinolin-4-ol WO 2007/061670 PCT/US2006/044058 - 153 To a solution of 6-bromo-2,2-dimethyl-1,2-dihydroquinoline (4.50 g, 18.9 mmol) in tetrahydrofuran (37.8 ml, 18.9 mmol) was added BH3DMS (3.58 ml, 37.8 mmol) dropwise at 0 deg C. The resulting solution was allowed to warm to RT and stirred for 1 hour. The temperature was returned to 0 deg C and sodium hydroxide (6N) (30.0 ml, 18.9 5 mmol) followed by Hydrogen peroxide (30.0 ml, 18.9 mmol) was slowly added to the reaction mixture. The resulting solution was stirred for 45 minutes and then transferred to a sep. funnel containing water and EtOAc. The layer were separated and the aqueous layer was subsequently washed 3X with DCM. The organic layers were dried with MgSO4, filtered and concentrated. The crude mixture was then purified with the MPLC 10 (100% DCM to 10% 90: 10:1 DCM:MeOH:NH40H) to provide the desired product. MS m/z: 257 (M+1). Step 4 and 5: 6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine To a solution 6-bromo-2,2-dimethyl- 1,2,3,4-tetrahydroquinolin-4-ol (3.16 g, 12.3 mmol) and DPPA (1.76 ml, 8.14 mmol) in THF (41.1 ml, 12.3 mmol) at 0"C was added DBU 15 (1.22 ml, 8.14 mmol) dropwise. The resulting mixture was warmed to RT and stirred for 18 hours. The crude mixture was poured into a sep. funnel containing water. The aqueous layer was washed 3X with EtOAc. The organic layers were combined, dried with MgSO4 and concentrated to an oil. The crude product (2.29 g, MS m/z: 240 (M N3)) was taken to the next step in the reaction sequence. 20 To a solution of 4-azido-6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinoline (2.29g, 8.15mmol), water (6.50ml, 361 mmol), and THF (20.4ml, 8.15mmol) was added triphenylphosphine (2.35 g, 8.96mmol) in one portion. The resulting mixture was heated to 40 deg C and stirred overnight. The crude mixture was dissolved with EtOAc and transferred to a sep. funnel containing 0.5MHCI. The aqueous layer was washed 5X 25 DCM. The aqueous layer was then neutralized with 6N NaOH and washed 3X with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to provide the desired product. MS m/z: 239 (M-NH2). Step 6: 2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-amine To neopentylmagnesium chloride (1.65 ml, 1.65 mmol) was added zinc(II) chloride (2.19 30 ml, 1.10 mmol) dropwise - strong exotherm was observed. The resulting mixture stirred for 10 minutes. A solution of 6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine (0.0700 g, 0.274 mmol) in tetrahydrofuran (1.37 ml, 0.274 mmol) was then added followed by palladium tetrakistriphenylphosphine (0.0317 g, 0.0274 mmol). The reaction vessel was sealed and heated to 65 deg C. The reaction mixture was stirred for 6 hours.

WO 2007/061670 PCT/US2006/044058 - 154 The crude mixture was filtered through a plug of celite with EtOAc and concentrated in the presence of silica gel. The crude mixture was purified with the MPLC (100% DCM to 100% 90:10:1 DCM:MeOH:NH40H) to provide the desired product. MS m/z: 230 (M-NH2). 5 Step 7: Tert-butyl (2S,3R)-3-(tert-butyldimethylsilyloxy)-4-((S)-2,2-dimethl-6 neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-1-(3-fluorophenyl)butan-2-ylcarbamate To a solution of tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)-4 oxobutan-2-ylcarbamate (0.148 g, 0.360 mmol) and (S)-2,2-dimethyl-6-neopentyl 1,2,3,4-tetrabydroquinolin-4-amine (0.0886 g, 0.360 mmol) in DCM (7.19 ml, 0.360 10 mmol) was added trimethoxymethane (0.394 ml, 3.60 mmol). The resulting solution was stirred for 1 hour at which time, sodium triacetoxyborohydride (0.229 g, 1.08 mmol) was added. The solution was then stirred for 30 minutes, quenched with saturated Rochelle's salt and stirred for an additional 20 minutes. The mixture was transferred to a sep. funnel containing DCM and H20. The aqueous layer was washed 4X with DCM. The organic 15 layers were combined, washed IX with brine, dried with MgSO4, filtered and concentrated to afford the title compound. MS m/z: 642 (M+1). Step 8: Tert-butyl (2S,3R)-4-((S)-2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahvdroquinolin-4 ylamino)-1 -(3-fluorophenyl)-3-hydroxybutan-2-ylcarbamate To a solution of tert-butyl (2S,3R)-3-(tert-butyldimethylsilyloxy)-4-((S)-2,2-dimethyl-6 20 neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-I -(3-fluorophenyl)butan-2-ylcarbamate (0.231 g, 0.360 mmol) in DCM (1.20 ml, 0.360 mmol) was added tetrabutylammonium fluoride (1.44 ml, 1.44 mmol). The resulting solution was stirred overnight. The mixture was transferred to a sep. funnel containing EtOAc and H20. The aqueous layer was washed 4X with EtOAc. The proganic layers were combined, dried over MgSO4, filtered 25 and concentrated. The crude mixture was purified by the MPLC. MS n/z: 528 (M+1). Steps 9 and 10: N-((2S,3R)-4-((S)-2,2-dimethyl-6-neopentyl- 1,2,3,4-tetrahydroquinolin 4-ylamino)-1 -(3-fluorophenyl)-3-hydroxybutan-2-yl)acetamide 4N HCI in MeOH (15.0 ml, 0.379 mmol) was added to tert-butyl (2S,3R)-4-((S)-2,2 dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-1-(3-fluorophenyl)-3 30 hydroxybutan-2-ylcarbamate (0.200 g, 0.379 mmol) in a RBF and the resulting solution was stirred overnight. The solution was then concentrated and the solid product was taken on to the next step. To a solution of (2R,3 S)-3-amino- 1 -((S)-2,2-dimethyl-6-neopentyl-1,2,3,4 tetrahydroquinolin-4-ylamino)-4-(3-fluorophenyl)butan-2-ol dihydrochloride (0.104 g, WO 2007/061670 PCT/US2006/044058 - 155 0.379 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.396 ml, 2.27 mmol) in DCM (1.52 ml, 0.379 mmol) was added 1-(IH-imidazol-1-yl)ethanone (0.0396 g, 0.360 mmol) in one portion. The resulting solution was stirred over the weekend. The crude mixture was concentrated and purified with the HPLC. Due to insufficient purity, the title 5 compound was free based and purified with the ISCO MPLC. MS n/z: 470 (M+1). Example 501 N-((lS,2R)-3-(((4'S)-6'-butyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3 10 bjpyridinl-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamide To a solution of N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H pyrano[2,3-b]pyridin-4-ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)acetamide (0.100 g, 0.203 mmol), tri-t-butylphosphonium tetrafluoroborate (0.0118 g, 0.0406 mmol) and butylzinc(II) bromide (2.03 ml, 1.02 mmol) in tetrahydrofuran (2.03 ml, 0.203 mmol) 15 was added Pd(OAc)2 (0.00456 g, 0.0203 mmol) in one portion at RT. The reaction mixture was stirred for 2.5 hours. The reaction mixture was then quenched with water and the resulting mixture was transferred to a sep. funnel. The aqueous layer was washed 3X with EtOAc. The organic layer were combined and concentrated. The crude mixture was purified with the Gilson HPLC to provide the title compound. MS m/z: 470 (M+1). 20 Example 502 N-((2S,3R)-1-(allyloxy)-3-hydroxy-4-(2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro 2H-pyrano[2,3-b]pyridin-5-ylamino)butan-2-yl)acetamide 25 Step 1: tert-butyl (S)-2-(allyloxy)-l-((S)-oxiran-2-yl)ethylcarbamate To a solution of tert-butyl (S)-2-hydroxy-1-((S)-oxiran-2-yl)ethylcarbamate (0.125 g, 0.6 mmol; see: Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49, 6195) in toluene (6 mL), was added allyliodide 0.3 mL, 3 mmol) followed by silver(I) oxide (0.7 g, 3 mmol). The solution was stirred at 65 0 C in a darkened hood for a period of 15 h. The mixture was then 30 cooled to ambient temperature, filtered through Celite, washed with CH 2

CI

2 , and conc. in vacuo. Purification on SiO 2 (10-20% EtoAc/Hexanes) gave the title compound as a yellow oil. Step 2: (2S,3S)-4-(allyloxy)-3-(tert-butoxycarbonvl)-2-hydroxvbutl acetate WO 2007/061670 PCT/US2006/044058 - 156 To a solution of lithium carbonate (0.10 g, 1.4 mmol) in DMF (2.5 mL), was added AcOH (0.078 mL, 1.4 mmol) and the solution stirred for a period of 5 min. To this mixture was added a solution of tert-butyl (S)-2-(allyloxy)-1 -((S)-oxiran-2-yl)ethylcarbamate (0.11 g, 0.45 mmol) in DMF (2.5 mL). The mixture was heated to 110 OC overnight then cooled to 5 ambient temperature. The cooled mixture was poured onto H20 and 1 N citric acid (20 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL) and the organic extracts were dried (Na 2

SO

4 ), filtered, and conc. in vacuo to afford the title compound as a yellow oil. The crude material was used without further purification. MS mn/z: 326 (M+23) Step 3: (2S,3S)-4-(allyloxy)-3-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiyloxy)butyl 10 acetate The crude material from Step 2 (0.090 g) was dissolved in CH 2 Cl 2 (3 mL) and cooled to 0 oC. To the cooled solution, was added 2,6-lutidine (0.10 mL, 0.90 mmol) followed by TBSOTf (0.10 mL, 0.4 mmol). The mixture was stirred at 0 oC for 2h then diluted with H20 and sat'd NaHCO 3 . The aqueous phase was extracted with CH 2 C1 2 (3 x 20 mL) and the 15 organic extracts dried (Na 2

SO

4 ), filtered, and conc in vacuo. Purification on Si0 2 (5-20% EtOAc/Hexanes) gave the title compound as a yellow oil. Step 4: Tert-butyl (2S.3S)-1-(allyloxy)-3-(tert-butyldimethylsilyloxy)-4-hydroxybutan-2 ylcarbamate To a solution of (2S,3S)-4-(allyloxy)-3-(tert-butoxycarbonyl)-2-(tert 20 butyldimethylsilyloxy)butyl acetate (0.060 g, 0.1 mmol) in MeOH (2 mL), was added

K

2

CO

3 (0.10 g, 0.7 mmol) and the mixture stirred at ambient temperature overnight. The mixture was then conc in vacuo and diluted with EtOAc (25 mL). The organic layer was washed with H20, brine, then dried (Na 2

SO

4 ), filtered, and conc in vacuo. The crude material was used without further purification. 25 Step 5: Tert-butyl (2S,3S)-1-(allyloxy)-3-(tert-butyldimethylsilyloxy)-4-oxobutan-2 ylcarbamate The crude material from Step 4 (0.040 g) was dissolved in CH 2 Cl 2 (3 mL) and treated with Dess-Martin periodinane (0.07 g, 0.2 mmol). The mixture was stirred at ambient temperature for 4 h then diluted with EtOAc (10 mL), sat'd NaHCO 3 (5 mL), and aqueous 30 Na 2

S

2 0 3 (5 mL). The biphasic mixture was stirred until it was colorless. The organic layer was washed with brine, dried (Na 2

SO

4 ), filtered, and conc in vacuo. The crude aldehyde was used without further purification.

WO 2007/061670 PCT/US2006/044058 - 157 Step 6: Tert-butyl (2S,3R)-1-(allyloxy)-3-(tert-butyldimethylsilyloxy)-4-(2,2 spirocyclobutvl-6-neopentyl-3,4-dihydro-2H-pyrano[2.3-blpyridin-5-ylamino)butan-2 ylcarbamate To a solution of tert-butyl (2S,3S)-1-(allyloxy)-3-(tert-butyldimethylsilyloxy)-4-oxobutan 5 2-ylcarbamate (0.033 g) in 1,2-dichloroethane (1.0 mL), was added 2,2-spirocyclobutyl-6 neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-amine (0.03 g, 0.1 mmol) followed by sodium triacetoxy(borohydride) (0.03 g, 0.1 mmol). The mixture was stirred overnight at ambient temperature then diluted with sat'd NaHCO 3 (10 mL). The mixture was extracted with EtOAc (3 x 25 ml), and the combined organic layers were dried (Na 2

SO

4 ), filtered, and 10 conc in vacuo. Purification on SiO 2 (1.25 to 2.5% MeOH*/CH 2

CI

2 ;*2.0 M NH 3 in MeOH) gave the title compound as a light yellow solid. MS n/z: 517 (M-Boc). Step 7: N-((2S,3R)-I-(allyloxy)-3-hydroxy-4-(2,2-spirocyclobutyl-6-neopentyl-3,4 dihydro-2H-pyranof2,3-blpyridin-5-ylamino)butan-2-yl)acetamide To a solution of tert-butyl (2S,3R)-1-(allyloxy)-3-(tert-butyldimethylsilyloxy)-4-(2,2 15 spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-bjpyridin-5-ylamino)butan-2 ylcarbamate (0.033 g, 0.05 mmol) in 1,4-dioxane (1.0 mL), was added a solution of HCl (0.6 mL, 4 M in 1,4-dioxane). The mixture was stirred at ambient temperature for a period of 24 h then conc. in vacuo. The crude residue obtained was diluted with EtOAc (20 mL) and sat'd NaHCO 3 (10 mL). The resulting aqueous layer was extracted with EtOAc (2 x 25 20 mL) and the combined organic extracts were washed with brine, dried (Na 2

SO

4 ), filtered, and conc in vacuo. The crude amino alcohol obtained was immediately dissolved in

CH

2 Cl 2 (1.0 mL) and treated with NN-diisopropylethylamine (0.05 mL, 0.3 mmol) followed by N-acetyl-imidazole (0.006 g, 0.06 mmol). The mixture was stirred at ambient temperature for 15 h then conc in vacuo. Purification on SiO 2 (2.5% MeOH*/CH 2 Cl 2 ;*2.0 25 M NH 3 in MeOH) gave the title compound as a white solid. MS m/z: 446 (M+1). Example 503 N-((1S,2R)-3-(((1S)-3,3-dimethyl-7-((3S)-tetrahydro-3-furanyloxy)-1,2,3,4 30 tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide Step 1. Diethyl 2-(1-(4-methoxyphenyl)-2-methylpropan-2-yl)malonate Diethylisopropylidenemalonate (6.686 ml, 34.09 mmol) was dissolved in 300 ml Et2O and cooled to -78 0 C. 4-Methoxybenzylmagnesium chloride (150.000 ml, 37.50 mmol) was added and stirring was continued for 5h. The temperature was warmed up to 0*C.

WO 2007/061670 PCT/US2006/044058 - 158 The reaction was hydrolyzed with 0.5 M HCI and extracted 3 x EtOAc. Glass col. Chromatography (10-50 %EtOAc in Hex.) provided diethyl 2-(1-(4-methoxyphenyl)-2 methylpropan-2-yl)malonate. MS m/z: 323.1 (M+1). Step 2: 7-Methoxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one contaminated with 2 5 chloro-7-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one Diethyl 2-(1-(4-methoxyphenyl)-2-methylpropan-2-yl)malonate (6.841 g, 21.22 mmol) was dissolved in 30 ml MeOH and 100 ml of 50% NaOH (aq.) was added. The mixture was refluxed for 4h. The cooled slurry was acidified (conc. HCl) and extracted 4 x EtOAc (400 ml each). The combined organic extracts were dried over MgSO4 and evaporated. 10 The crude oil was next heated to 180*C for 1h (decarboxylation). The reaction mixture was dissolved in 150 ml benzene and phosphorus pentachloride (6.000 g, 28.81 mmol) was added. The mixture was refluxed for 45 min and cooled to 0 *C. Stannic chloride (2.483 ml, 21.22 mmol) was added and the mixture was refluxed for lh. The mixture was cooled to 0 *C and washed with 2.5M HCI (aq.). The organic phase was evaporated. 15 LCMS analysis showed the formation of 2 products approx. 1:1. The products almost co elute on silica. The product mixture was obtained by glass col. chrom. (5-25% EtOAc in Hex.): 3g of a yellow oil. The chlorinated product was characterized by IH NMR of a pure fraction, as was the desired title compound (MS m/z: 205.1 (M+1)). 20 Step 3: 7-Methoxy-3,3-dimethyl-3,4-dihydronaphthalen-1 (2H)-one The product mixture from the previous reaction was dissolved in 30 ml THF and cooled to 0*C. 30 ml Rieke Zn (5g in 100 ml THF) was added and the mixture was stirred for 2.5 h at 0 'C. The reaction was hydrolyzed with 20 ml H20 and evaporated. The mixture was dissolved in 100 ml DCM and dried over MgSO4, evaporated. Glass col. Chrom. 25 afforded 7-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-1 (2H)-one as a yellow oil. Step 4: 7-Hydroxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one 7-Methoxy-3,3-dimethyl-3,4-dihydronaphthalen- I (2H)-one (2.25 g, 11.0 mmol)was dissolved in 30 ml CH2CI2 and cooled to -78 *C. Boron tribromide (25.000 ml, 25.0 mmol) was added and the reaction was stirred for 6h. The temperature was elevated to 30 0*C during this time. The mixture was pored into ice and extracted 3 x EtOAc (300 ml each). The combined organic extracts were dried over MgSO4 and evaporated. Glass col. Chrom. gave 7-hydroxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one as a yellow solid. MS m/z: 191.1 (M+1). Step 5: (S)-3,3-Dimethyl-7-(tetrahydrofuran-3-vloxv)-3.4-dihydronaphthalen-1(2H)-one WO 2007/061670 PCT/US2006/044058 - 159 7-Hydroxy-3,3-dimethyl-3,4-dihydronaphthalen- I (2H)-one (0.95 g, 4.99 mmol) was dissolved in 30 ml DCMand triphenylphosphine (1.96 g, 7.49 mmol) and diisopropyl azodicarboxylate (1.23 ml, 6.24 mmol) and (r)-(-)-3-hydroxytetrahydrofuran (0.600 ml, 7.49 mmol) was added. The mixture was stirred over night. 0.5M HCI (aq.) was added 5 and the mixture was extracted 3 times with EtOAc. Glass col. Chrom. (5-30% EtOAc in Hex.) provided (S)-3,3-dimethy1-7-(tetrahydrofuran-3-yloxy)- 3 ,4-dihydronaphthalen 1(2H)-one as a yellow oil. MS m/z: 261.1 (M+1). Step 6: N-((1 S.,2R)-3-(((1 S)-3,3-dimethyl-7-((3S)-tetrahydro-3-furanyloxy)-1,2,3,4 tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenylmethyl)pronvl)acetamide 10 The title compound was made from the product from step 5 by a method analogous to that described in Example 464, steps 8-10. MS Found m/z: 467.3 (M+1). Example 504 15 N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((5'S)-3'-(2,2-dimethylpropyl)-5',6' dihydrospiro[cyclobutane-1,7'-pyrano[ 2

,

3 -cIpyridazin]-5'-yl)amino)-2 hydroxypropyl)acetamide. Step 1. N-(2-(I-(tert-butvldimethylsilylox)cyclobutyl)-1-(3-chloro-6 neopenlovridazin-4-vllethyl)-2-methyloropane-2-sulfinamide 20 2,2,6,6-Tetramethylpiperidine (0.68 ml, 4.0 mnol) was dissolved in 120ml THF and 1 butyllithium (1.5 ml, 3.8 mmol) was added at -78oC drop wise. The mixture was allowed to warm to 0*C (over a period of 5 min) and kept there for 5 min. The mixture was cooled back to -78"C and a solution of 3-chloro-6-neopentylpyridazine (0.45 g, 2.4 mmol) in 10 ml of THF was added drop wise. Stirring was continued for 20 min and a solution of(E) 25 N-(2-(l -(tert-butyldimethylsilyloxy)cyclobutyl)ethylidene)-2-methylpropane- 2 sulfinamide (1.450 g, 4.4 mmol) in 5 ml THF was added drop wise. Stirring was continued for 10 min and the mixture was hydrolyzed with H20. The mixture was extracted with EtOAc (3x 300 ml) dried over MgSO4 and evaporated. The crude product was used in the next step without further purification. 30 Step 2: (S)-7,7-Spirocyclobutyl-3-neo amine N-(2-(1-(tert-Butyldimethylsilyloxy)cyclobutyl)-1-(3-chloro-6-neopentylpyridazin-4 yl)ethyl)-2-methylpropane-2-sulfinamide (0.870 g, 2 mmol) was dissolved in 20 ml of THF and tetrabutylammonium fluoride, 1.0m in THF (0.5 ml, 2 mmol) was added at RT.

WO 2007/061670 PCT/US2006/044058 - 160 The mixture was stirred for 10 min and filtered through a plug of silica (wash with THF). The mixture was died over MgSO4 and evaporated and re-dissolved in 200 ml of THF. NaH (60%) (0.3 g, 7mmol) was added and the mixture was heated to 66 for 3h. The mixture was hydrolyzed with water and extracted 3 times with EtOAc (200 ml each). The 5 crude product (MS m/z: 366.2 (M+1)) was re-dissoolved in 5 ml MeOH and 15 ml 4M HCI in dioxane was added. The mixture was stirred for Ilh and evaporated and purified on the HPLC. The Product was obtained as a brown solid. Step 3: N-( 1S,2R)-1 -((3,5-difluorophenyl)methyl)-3-(((5S)- 3 '-(2,2-dimethylpropyl) 5',6'-dihydrospiro[cyclobutane-1.7'-pyranor2,3-clpyridazinl-5'-yl)amino)-2 10 hydroxypropyl)acetamide The title compound was made from the product from step 5 by a method analogous to that described in Example 464, steps 8-10. MS Found m/z: 503.2 (M+1). Example 505 15 N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4' dihydrospirolcyclobutane-1,2'-pyrano[ 2 ,3-bpyridin]-4'-yl)amino)-i-(( 4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; and N-((1S,2R)-3-(((1s,3R,4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4' 20 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bipyridin1-4'-yl)amino)-1-(( 4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide Step 1: 1,3-Ditosyloxy-2-methyl-propane . 2-Methylpropane-1,3-diol (50 g, 555 mmol) was dissolved in 555 ml pyridine and cooled to 0*C. p-Toluenesulfonyl chloride (212 g, 1110 mmol) was added and stirring was 25 continued over night. 200 ml H20 was added and the reaction was extracted with DCM (2 x IL). The combined organic extracts were dried over MgSO4 and evaporated. The product was recrystallized from EtOH/Hex and the product was obtained as a white solid. MS m/z: 399.0 (M+1). Step 2: 3-Methyl- 1 -(methylsulfinyl)- 1 -(methylthio)cyclobutane 30 Methylsulfinyl(methylthio)methane (29.927 g, 240.91 mmol) was dissolved in 500 ml THF and cooled to -10*C. Butyllithium (96.363 ml, 240.91 mmol) was added slowly and stirring was continued for 2h. 1,3-Ditosyloxy-2-methyl-propane (48.000 g, 120.45mmol) was added at -10*C and the mixture was allowed to warm up to RT. Stirring was continued over night. 150 ml H20 was added and the mixture was extracted with DCM, WO 2007/061670 PCT/US2006/044058 - 161 dried over MgSO4 and evaporated. The crude material was filtered through a silica plug and used without further purification in the next step. Step 3: 3-Methylcyclobutanone Crude 3-Methyl-1-(methylsulfinyl)-1-(methylthio)cyclobutane (11.300 g, 63.371 5 mmol)from the previous step was dissolved in 50 ml Et2O and 20 ml conc. HCI was added. The mixture was distilled at 1 atm and 80*C: ether comes over. Temperature was increased to 110-120 0 C where the product (along with some water) was collected. This fraction was diluted with 100 ml ether, dried over MgSO4 and evaporated (carefully) to give 3-methylcyclobutanone. 10 Step 4: 1-Allvl-3-methylcyclobutanol Methylcyclobutanone (3.200 g, 38.043 mmol) was dissolved in 200 ml THF and allylmagnesium bromide (190.21 ml, 190.21 mmol) was added in one portion. The mixture was stirred for 4h at RT, hydrolyzed with water and extracted. The combined organic extracts were dried over MgSO4 and evaporated and purified via glass col. 15 Chrom. (25-75% hex. in EtOAc). 1-Allyl-3-methylcyclobutanol (2.250 g, 46.9% yield) was obtained as a mixture of cis-trans isomers approx 4:1 (where the major compound is the one Me-cis to OH) based on NMR. Step 5: (1 -Allvl-3-methylcyclobutox)(tert-butl)dimethylsilane 1-Allyl-3-methylcyclobutanol (2.25000 g, 17.8 mmol) (the 4:1 mixture of cis/trans 20 isomers) was dissolved in 50 ml of CH2Cl2 and DIEA (5.59 ml, 32.1 mmol) and tert butyldimethylsilyl triflate (5.73 ml, 25.0 mmol) were added. The mixture was stirred for 2h and hydrolyzed with water, extracted with 200 ml Et2O (3x each), dried over MgSO4 and evaporated. Glass col. chrom. (10-30% EtOAc in Hex.) provided (1-allyl-3 methylcyclobutoxy)(tert-butyl)dimethylsilane as a yellow oil. Mixture of cis/trans at the 25 cyclobutylring (4:1) Step 6: (E)-N-(2-(1-(tert-butyldimethylsilvloxy)-3-methylcyclobutyl)ethylidene)- 2 methylpropane-2-sulfinamide (1-Allyl-3-methylcyclobutoxy)(tert-butyl)dimethylsilane (4.1000 g, 17.05 mmol) was dissolved in 150 ml of t-BuOH/H20/THF (2/2/1) and osmium tetroxide (10.84 ml, 30 0.8525 mmol, 2.5 wt%) and 4-methylmorpholine oxide (2.996 g, 25.58 mmol) were added. The mixture was stirred for 6h and the mixture was diluted with 250 ml water and extracted with EtOAc. The combined organic extracts were evaporated and re-dissolved in 150 ml of t-BuOH/H20/THF (2/2/1). Sodium periodate (4.741 g, 22.17 mmol) was added and stirring was continued for 6h. The mixture was filtered and diluted with 250 ml WO 2007/061670 PCT/US2006/044058 - 162 of water. The mixture was extracted with Et2O and the combined organic extracts were dried over MgSO4, evaporated and re-dissolved in 100 ml CH2CI2. Cupric sulfate anhydrous (8.164 g, 51.15 mmol), and(r)-(+)-2-methyl-2-propanesulfinamide (4.133 g, 34.10 mmol) were added at RT and stirring was continued over night. The reaction was 5 filtered and hydrolyzed with 30 ml water. The mixture was extracted 3 x EtOAc (3x 150 ml) and the combined organic extracts were dried over MgSO4 and evaporated. Glass col. chrom. (20-50% EtOAc in Hex) provided (E)-N-(2-(1-(tert-butyldimethylsilyloxy)-3 methylcyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide. Mixture of cis/trans at the cyclobutylring (4:1). 10 Step 7: N-((S)-2-(1-(tert-butvldimethylsilyloxy)-3-methylcyclobutl)-1-(2-fluoro-5 neopentylpyridin-3 -yl)ethyl)-2-methylpropane-2-sulfinamide 2,2,6,6-Tetramethylpiperidine (2.47 ml, 14.7 mmol) was dissolved in 100 ml THF and cooled to -78'C. 1-Butyllithium (5.23 ml, 13.1 mmol, 2.5M) was added and the reaction was allowed to warm up to 0*C for 5 min before it was cooled back to -78*C again. At 15 this point, a solution of 2-fluoro-5-neopentylpyridine (1.75000 g, 10.5 mmol) was added dropwise and the reaction was stirred for 1 h. Next, a solution of (E)-N-(2-(1 -(tert butyldimethylsilyloxy)-3-methylcyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide (3.98 g, 11.5 mmol) in THF was added dropwise and stirring was continued for lh. The mixture was hydrolyzed with NH4CI in the cold, warmed up to RT extracted with EtOAc 20 (3x 150 ml), dried over MgSO4 and evaporated. N-((S)-2-(1-(tert Butyldimethylsilyloxy)-3-methylcyclobutyl)-1 -(2-fluoro-5-neopentylpyridin-3-yl)ethyl) 2-methylpropane-2-sulfinamide (3.30 g, 61.5% yield) was obtained after glass col. Chrom. (20-70% EtOAc in Hex.). Low yield due to the formation of a minor diastereomer at the N-H center (approx 30%). Mixture of cis/trans at the cyclobutylring (4:1). 25 Step 8: N-((1 S,2R)-3-(((4'S)-6'-(2,2-Dimethylpropyl)-3-methyl-3',4' dihydrospirofcyclobutane-1,2'-pyrano12,3-blpyridinl-4'-yl amino)-1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide: and N-((1S,2R)-3-((f(s,3R,4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4' dihydrospirorcyclobutane-1,2'-pyranor2.3-blpyridinl-4'-yl)amino)-1 -((4 30 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((S)-2-(1-(Tert-butyldimethylsilyloxy)-3-methylcyclobutyl)-1 -(2-fluoro-5 neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (3.30 g, 6.435 mmol) was dissolved in 60 ml THF and tetrabutylammonium fluoride, (1.0 M in THF; 6.435 ml, 6.43 5 mmol) was added. The mixture was stirred for 30 min and filtered through a plug of WO 2007/061670 PCT/US2006/044058 - 163 silica (wash with THF). The solution was evaporated and redissolved in 600 ml THF. NaH (0.74 g, 32.17 mmol, 60% in mineral oil) was added and the reaction was heated up to 65 *C for 3h. The mixture was hydrolyzed carefully with water and extracted 3 times with EtOAc (3x 200 ml). The combined organic extracts were dried over MgSO4 and 5 evaporated. The crude product was dissolved in 20 ml MeOH and 20 ml 4M HCl in dioxane was added. The reaction was stirred for I h, basified with NaOH (5M aq.) and extracted 4 times with 200 ml EtOAC (each). Glass col. Chrom. gave the 2 products which were submitted for separation of the diastereomers. The major isomer was identified to be the one where the 0 and the Me group are cis to each other (NOE). 10 Prior to separation, the title compound, a 4:1 mixture, was made by the method described in Example 464, steps 8-10. MS Found m/z: 498.2 (M+1). Example 506 15 N-((lS,2R)-3-(((1s,3S,4'S)-6'-(2,2-dimethylpropyl)-3-hydroxy-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bpyridin]-4'-yl)amino)-1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide. Step 1: 1-((1,3-Dibromopropan-2-yloxy)methyl)benzene 2-Benzyloxy-1,3-propanediol (15.000 g, 82.32 mmol) was dissolved in CH2CI2 (500ml) 20 and carbon tetrabromide (81.90 g, 247.0 mmol) and triphenylphosphine (64.77 g, 247.0 mmol) were added. The mixture was stirred overnight and concentrated. The reaction was suspended in hexanes and filtered and evaporated to afford the title compound. Step 2: 3-(Benzyloxy)cvclobutanone Methylsulfinyl(methylthio)methane (13 ml, 125 mmol) was dissolved in 250 ml THF and cooled to -20*C. n-Butyllithium (50 ml, 125 25 mmol) was added and the mixture was stirred for 3h at -20*C. The mixture was cooled down to -78*C and a solution of 1-((1,3-dibromopropan-2-yloxy)methyl)benzene (16.000 g, 52 mmol) was added. The reaction was stirred over night and allowed to warm up to RT. It was stirred for an additional 6h at RT, hydrolyzed with water and extracted with EtOAc. The combined organic extracts were evaporated, dissolved in ether (50 ml) and 30 treated with conc. HCl (10 ml) for 30 min at reflux. The mixture was neutralized with NaOH (1 OM) and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and evaporated. Glass col. Chrom. (10-50 % EtOAc in Hex) gave 3 (benzyloxy)cyclobutanone as a yellow oil.

WO 2007/061670 PCT/US2006/044058 - 164 Step 3: N-((IS,2R)-3-(((1s,3S.,4'S)-6'-(2,2-dimethylpropyl-3-hydroxy-3',4' dihydrospiro[cyclobutane-1,2'-pyranof2.3-blpvridinl-4'-vl)amino)-1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide The title compound was prepared in a manner analogous that described in Example 505. 5 MS Found m/z: 500 (M+1). Example 507 N-((1S,2R)-2-hydroxy--(phenylmethyl)-3-(((4'S)-6'-((2S)-tetrahydro-2 furanylmethyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridinj-4' 10 yl)amino)propyl)acetamide; and N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4'S)-6'-((2R)-tetrahydro-2 furanylmethyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bpyridin]-4' yl)amino)propyl)acetamide Step 1: (4S,5R)-tert-butyl 4 -benzyl-2,2-dimethyl-5-(((S)-6-((tetrahydrofuran-2-yl)methyl) 15 2

,

2 -spirocyclobutyl-3,4-dihydro-2H--pyrano2,3-blpyridin -4.lamino)methylloxzol idine-3 carboxylate A solution of sodium tert-butoxide (74 mg, 769 Itmol), Pd 2 (dba) 3 (16 mg, 17 pmol) and 1 (diphenylphosphino)-2-(2-(diphenylphosphino)phenoxy)benzene (19 mg, 35 pmol) in 5mL of THF was purged with nitrogen for 15 minutes at which point (4S,5R)-tert-butyl 4 20 benzyl-5-(((S)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4 ylamino)methyl)-2,2-dimethyloxazolidine-3-carboxylate (200 mg, 349 Imol) and pent-4 en-1-ol (36 p1, 349 pmol) were added. The resulting slurry was then heated at 70 0 C for 8 hours. The cooled reaction mixture was diluted with EtOAc (15 mL) and poured into 10% sodium bicarbonate (25 mL). The layers were separated and the aqueous layer was 25 extracted with ethyl acetate 3 x 15 mL. The combined organic layers were washed with water then brine and dried over sodium sulfate. After filtration and concentration the residue was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to provide the title compound as a yellow oil. MS m/z: 578.2 (M+1). Step 2: N-((I S,2R)-2-hydroxy- 1 -(phenvlmethvl)-3 -(((4'S)-6'-((2S)-tetrahydro-2 30 furanylmethyl)-3',4'-dihydrospirorcyclobutane-1 2'-pyranor2,3-blpyridinl-4' yl)amino)propyllacetamide: and N-((1 S,2R)-2-hydroxy-1 -(phenvlmethyl)-3-(((4'S)-6'-((2R)-tetrahvdro-2-furanylmethyl) 3'.4'-dihydrospirorcyclobutane-1,2'-pyranof2,3-blpyridinl-4'-yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 165 The title compounds were prepared in a manner analogous that described in Example 464, steps 8-10. MS Found m/z: 480 (M+1). Example 508 5 N-((1S,2R)-2-hydroxy-3-(((4'S)-6'-(((2S)-2-methyltetrahydro-2-furanyl)methyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bipyridin]-4'-yl)amino)-1 (phenylmethyl)propyl)acetamide; and N-((1S,2R)-2-hydroxy-3-(((4'S)-6'-(((2R)-2-methyltetrahydro-2-furanyl)methyl) 10 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bpyridin]-4'-yl)amino)-1 (phenylmethyl)propyl)acetamide. Step 1: (4S,5R)-tert-butyl 4-benzyl-2,2-dimethyl-5-(((S)-6-((2-methyl-tetrahydrofuran-2 vl)methyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyranof2.3-blpyridin-4 ylamino)methyl)oxazolidine-3-carboxylate 15 1-(diphenylphosphino)-2-(2-(diphenylphosphino)phenoxy)benzene (29 mg, 0.054 mmol) and Pd 2 (dba) 3 (25 mg, 0.027 mmol) were combined in a sealed tube and ImL of THF was introduced. After stirring for 5 minutes, sodium tert-butoxide (130 mg, 1.35mmol) was added followed by a solution of (4S,5R)-tert-butyl 4-benzyl-5-(((S)-6-bromo-2,2 spirocyclobutyl-3,4-dibydro-2H-pyrano[2,3-b]pyridin-4-ylamino)methyl)-2,2 20 dimethyloxazolidine-3-carboxylate (310 mg, 0.541 mmol) and 4-methylpent-4-en- 1 -ol (81 mg, 0.812mmol) in 3mL of THF. The tube was sealed and heated at 70 0 C for 8 hours. The cooled reaction mixture was diluted with EtOAc (5mL) and poured into 10% sodium bicarbonate (25mL). The layers were separated and the aqueous layer was extracted with ethyl acetate 3 x 25mL. The combined organic layers were washed with water and brine 25 and dried over sodium sulfate. After filtration and concentration the residue was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to provide the title compound as a yellow oil. MS m/z: 592.2 (M+1). Step 2: N-(( S,2R)-2-hydroxy-3-(((4'S)-6'-(((2S)-2-methyltetrahydro-2-furanyl)methy1) 3'.4'-dihydrospirorcyclobutane-1,2'-pyranor2,3-blpyridinl-4'-yl)amino)- 1 30 (phenylmethyl)propyl)acetamide; and N-((] S,2R)-2-hydroxy-3-(((4'S)-6'-(((2R)-2 methyltetrahydro-2-furanyl)methyl)-3',4'-dihydrospirorcyclobutane-1,2'-pyranof2,3 blpyridinl-4'-yl)amino)-1-(phenylmethvl)propyl)acetamide The title compounds were prepared in a manner analogous that described in Example 464, steps 8-10. MS Found m/z: 494 (M+1).

WO 2007/061670 PCT/US2006/044058 - 166 Example 509 N-((1S,2R)-3-(((2R,4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H 5 chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide; and N-((1S,2R)-3-(((2S,4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide Step 1: (Z)-2-(1-(benzylimino)ethyl)-4-bromophenol A mixture of 5"-bromo-2"-hydroxyacetophenone (15.0 g, 69.8 mmol) and benzylamine 10 (7.62 ml, 69.8 mmol) in ethanol was stirred at RT for 3 h. The resulting suspension was filtered and rinsed with hexane. The crystalline solid was dried in vacuum to afford (Z)-2 (1-(benzylimino)ethyl)-4-bromophenol as a bright yellow solid. MS m/z: 304. Step 2: (Z)-4-(benzylamino)-4-(5-bromo-2-hydroxyphenyl)-l 1,1 -trifluorobut-3-en-2-one To a solution of (Z)-2-(1-(benzylimino)ethyl)-4-bromophenol (18.0 g, 59.2 mmol) in 15 anhydrous THF was added lithium hydride (1.65 g, 207 mmol) portion wise at room temperature. The resulting mixture was heated in a oil bath (60*C) to initialize the reaction (cool down the mixture with a ice bath). Once the reaction is slowing down, the mixture was heated at 70-75'C for 24 h (reaction was monitored by using TLC and LCMS). At this point, there was still trace amount of SM left (MS+ = 304). The mixture was concentrated 20 to dryness under vacuum. The residue was treated with 120 ml of 7% AcOH/ H20. The precipitate that formed was filtered and rinsed with water. The solid was dried in vacuum to give (Z)-4-(benzylamino)-4-(5-bromo-2-hydroxyphenyl)-1,1,1 -trifluorobut-3-en-2-one as a orange color solid. MS m/z: 400. The crude material was used without further purification in the next step. 25 Step 3: (Z)-N-(6-bromo-2-(trifluoromethyl)-4H-chromen-4-ylidene)(phenyl)methanamine To a cooled (ice bath) EtOH (96 ml) was bubbled through hydrogen chloride gas for 30 min. (Z)-4-(benzylamino)-4-(5-bromo-2-hydroxyphenyl)-1,1,1-trifluorobut-3-en-2-one (24.0 g, 60 mmol) was then added in one portion to this solution. The reaction was stirred at RT for 36 h. The resulted mixture was diluted with 900 ml of cool water, 28% aq N13 (96 30 ml) was then added. The precipitate formed was filtered and washed with water to give a brown sticky solid. The solid was dissolved in EtOAc, washed with IN HCI and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was crystallized from hexane to give the title compound as a brown solid. MS m/z: 382. Step 4: 6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-one WO 2007/061670 PCT/US2006/044058 - 167 A mixture of malonic acid (1.2 ml, 19 mmol) and (Z)-N-(6-bromo-2-(trifluoromethyl)-4H chromen-4-ylidine)(phenyl)methanamine (6.63 g, 17 mmol) in dioxane was heated to reflux for 18h until the reaction was completed. The mixture was cooled to RT and treated with 50% EtOH/H20 (20 ml) followed by cone. HCI (5.0 ml). The resulted mixture was left 5 to stand at RT for 40 min, and then diluted with water (500 ml). The product was extracted with hexane (3 x 300 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (2-10% EtOAc/hexane) to afford the title compound as yellow oil. MS m/z: 310 (M+1). Step 5: (4R)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-ol 10 To a cooled (ice bath) solution of (s)-2-methyl-cbs-oxazaborolidine 1.0 M in toluene (100 il, 100 imol) was added borane-dimethyl sulfide 2.0 M in THF (500 1l, 1000 jimol). After stirred 15 min, a solution of 6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-one (309 mg, 1000 pmol) in toluene was added drop wise. The reaction was completed after stirring 9h at 0"C. 2N HCI was added slowly to quench the reaction. The resulted mixture was extracted 15 with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column to afford the title compound. -> Step 6:(4S)-4-azido-6-bromo-2-methyl-2-(trifluoromethyl)chroman To a cooled (ice bath) solution of (4R)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-ol 20 (277 mg, 890 gmol) was added drop wise diphenylphosphoryl azide (249 R1, 1158 pmol). After stirring 20 min, 1,8-diazabicyclo(5.4.0)undec-7-ene (173 pl, 1158 pmol) was added drop wise. The reaction was stirred at the same temperature for 2h, then stirred 15h at ambient temperature. Water was added to quench the reaction. The resulted mixture was extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered 25 and concentrated. The residue was purified on a silica gel column (5-20% EtOAc/hexane) to afford the title compound. MS m/z: 308(M-N2). Step 7: ( 4

S)-

6 -bromo-2-methyl-2-(trifluoromethyl)chroman-4-amine To a solution of ( 4

S)-

4 -azido-6-bromo-2-methyl-2-(trifluoromethyl)chroman (190 mg, 565 gmol) was added triphenylphosphine (222 mg, 848 Rmol). The mixture was stirred at RT 30 for 4h. Water (15 ml) was added and the reaction was heated at refluxing for 24 h. The resulted mixture was concentrated to dryness and extracted with CHCl3. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated and dried in vacuum to afford the title compound. MS m/z: 293, 295(M-NH2).

WO 2007/061670 PCT/US2006/044058 - 168 Step 8: tert-Butyl (2S,3R)-4-((4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H chromen-4-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate A mixture of (4S)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-amine (179 mg, 577 pmol) and tert-butyl (S)-i-((S)-oxiran-2-yl)-2-phenylethylcarbamate (198 mg, 750 Rmol) in 5 ethanol was heated at reflux for 16 h. At this point, there was still the starting amine left. An additional 1.3 eq of epoxide was added to the reaction, and continued to reflux for 6 h. The resulted mixture was concentrated and purified on Shimadzu HPLC to afford the title compound as a TFA salt. MS m/z: 573, 575. Step 9: N-((I S,2R)-3-(((2R,4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H 10 chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide; and N-((1 S, 2 R)-3-(((2S,4S)-6-bromo-2-methyl-2-(trifluoromethyl-3,4-dihydro-2H-chromen-4 yl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)acetamide To a solution of (2R,3 S)-3 -amino-i -((4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4 dihydro-2H-chromen-4-ylamino)-4-phenylbutan-2-ol dihydrochloride (160 mg, 338 gmol) 15 in DMF was added 1-(1H-imidazol-1-yl)ethanone (37.2 mg, 338 pimol) followed by DIPEA (177 sl, 1014 gmol). The reaction was stirred at RT for 30 min, then diluted with MeOH and purified on Shimadzu HPLC to afford 43.0 mg of the title compounds as a mixture. MS m/z: 515, 517. Example 510 20 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6-(2,2,2-trifluoroethyl)-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)propyl)acetamide Step 1: 2,2,2-trifluoro-l -(4-hydroxyphenyl)ethanone To a cooled (-78"C) solution of 2 ,2, 2 -trifluoro-4'-methoxyacetophenone (15 ml, 73 mmol) 25 in DCM was added 1.0 M tribromoborane (73 ml, 73 mmol) drop wise. After the addition was completed, the reaction was slowly warmed to RT and stirred for overnight (15 h). At this point, reaction was completed by TLC. The product mixture was poured into ice water. The organic layer was washed with 10% aq Na2CO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (5-40% 30 EtOAc/hexane) to afford the title compound as a white crystalline solid. The major side product was a colorless oil with MS+ = 379. Step 2: 4-(2,2,2-trifluoro- 1 -hydroxyethyl)phenol To a solution of 2,2,2-trifluoro- I -( 4 -hydroxyphenyl)ethanone (5.0 g, 26 mmol) in dichloroethane was added zinc iodide (2.7 ml, 39 mmol) followed by sodium WO 2007/061670 PCT/US2006/044058 - 169 cyanoborohydride (10 ml, 197 mmol). The reaction was stirred at RT for 18 h. Both TLC and LCMS showed one product was formed. MS+= 175 (desired mass 192 - OH). The mixture was filtered through elite and rinsed with dichloromethane. The filtrate was concentrated and dried in vacuum to afford the title compound as colorless oil. MS m/z: 5 175(M-H20). Step 3: 4-(1-chloro-2,2,2-trifluoroethvl)phenol To a cooled (ice bath) mixture of 4-(2,2,2-trifluoro-1-hydroxyethyl)phenol (4.3 g, 22 mmol) and anhydrous pyridine (1.8 ml, 22 mmol) in toluene was added thionyl chloride (SOC12) (2.3 ml, 31 mmol) drop wise via a syringe. After stirred for 1 h at 0*C, the reaction was 10 heated at 70 0 C for 2h. At this point, reaction did not go completion, indicated by LCMS. Heating was continued for 16 h. Reaction was quenched with ice water. The resulted mixture was diluted with EtOAc. The organic layer was washed with saturated Na2CO3, water and brine. After dried over Na2SO4, the solution was filtered and concentrated. The residue was purified on a silica gel column (5-10% EtOAc/hexane) giving the title 15 compound as a light yellow oil. MS n/z: 211 (M+1). Step 4: 4-(2,2,2-trifluoroethyl)phenol To a solution of 4-(1-chloro-2,2,2-trifluoroethyl)phenol (3.60 g, 17.1 mmol) in THF was added sodium borohydride (0.903 ml, 25.6 mmol) in one portion. The reaction was stirred at RT for 18 h, and then quenched with MeOH. The resulting mixture was concentrated and 20 diluted with EtOAc. After washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dried in vacuum to afford 4-(2,2,2 trifluoroethyl)phenol as a colorless oil. MS m/z: 175(M-1). Step 5: 1-( 2 -hydroxy-5-(2,2.2-trifluoroethyl)phenvl)ethanone To a solution of 4-(2,2,2 trifluoroethyl)phenol (1.00 g, 5.68 mmol) in CH2Cl2 (5.0 ml) was added 25 trifluoromethanesulfonic acid (0.0151 ml, 0.170 mmol) with stirring. A solution of acetic chloride (0.444 ml, 6.25 mmol) in CH2Cl2 (5.0 ml) was added drop wise to the reaction. After stirred 45 min at RT, all the phenol was consumed. The product mixture was diluted with CH2CI2, washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dried in vacuum until no weight loss 30 was observed. To the above residue was added anhydrous aluminum(I11) chloride (0.757 g, 5.68 mmol). The mixture was heated at 150*C for lh until all the starting material was consumed (monitored by TLC). The resulted brown gum was cooled to 0"C, diluted with diethyl ether and IN HCI. Layers-were separated. The aqueous layer was extracted with ether. The organic layers were combined, dried over Na2S04, filtered and concentrated.

WO 2007/061670 PCT/US2006/044058 - 170 The residue was purified on silica gel column (2-15% EtOAc/hexane) to afford the title compound. Step 6: 2,2-spirocyclobutyl-6-(2,2,2-trifluoroethyl)-2,3-dihydrochromen-4-one A solution of 1-(2-hydroxy-5-(2,2,2-trifluoroethyl)phenyl)ethanone (320 mg, 1467 pmol), 5 cyclobutanone (617 mg, 8800 [tmol), N-ethyl-N-isopropylpropan-2-amine (569 mg, 4400 pmol) and pyrrolidine (313 mg, 4400 jmol) in ACN was heated in microwave at 75"C for 2h. The resulted mixture was diluted with EtOAc, washed with IN HCI, saturated Na2CO3 and brine. The organics were dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (2-15% EtOAc/hexane) to afford the title compound. 10 Step 7: (R)-2,2-spirocyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-chromen-4-ol The title compound was prepared according to the methods described in step 5 of Example 509. MS m/z: 255(M+I-H20). Step 8: (S- 4 -azido- 2

,

2 -spirocyclobutvl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-chromene The title compound was prepared according to the methods described in step 6 of 15 Example 509. MS m/z: 270(M+1-N2). Step 9: (S)- 2

,

2 -spirocyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-chromen-4-amine The title compound was prepared according to the methods described in step 7 of Example 509. MS m/z: 255(M-NH2). Step 10: (4R, 5S)-tert-butyl5-benzyl-4-((6-(2,2,2-trifluoroethl)-2,2-spirocyclobutyl-3_4 20 dihydro-2H-chromen-4-ylamino)methyl)-2,2-dimethylpyrrolidine- I -carboxylate To a stirred solution of (S)-2,2-spirocyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H chromen-4-amine (40 mg, 147 smol) in DCM was added (4S,5S)-tert-butyl 4-benzyl-5 formyl-2,2-dimethyloxazolidine-3-carboxylate (71 mg, 221 pmol) followed by tirmethoxymethane (161 pd, 1475 pmol). After stirred for 1/2 h, sodium cyanoborohydride 25 (46 mg, 737 Rmol) was added to the reaction. After stirred 3 h at RT, most of the amine was consumed. The reaction was quenched by the addition of saturated Na2CO3 and diluted with CH2CI2. The resulted mixture was extracted with CH2Cl2 (2x). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column to afford the title compound. MS m/z: 575(M+1). 30 Step 11: N-((I S,2R)-2-hvdroxy-1 -(phenylmethyl)-3 -((( 4 S)-6-(2,2,2-trifluoroethyl)-3,4 dihydrospirorchromene-2,1 '-cyclobutanl-4-yl)amino)oropyl)acetamide. TFA salt The title compound was synthesized in a manner analogous to that described in Example 509, as a white solid. MS m/z: 477.2(M+1).

WO 2007/061670 PCT/US2006/044058 - 171 Example 511 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6-(2-pyridinyl)-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)propyl)acetamide. TFA salt 5 A mixture of (2S,3R)-3-amino- 1 -(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4 ylamino)-4-phenylbutan-2-ol dihydrochloride salt (50 mg, 106 umol), 2-tri-n butylstannylpyridine (58 [il, 158 pmol) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 5 pmol) in dioxane was heated in a sealed tube for 1 5h. The reaction was cooled to RT and filtered. The filtrate was purified on Shimadzu HPLC to afford the title compound as a 10 colorless oil. MS n/z: 472.2(M+1). Example 512 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4'S)-6'-(2,2,2-trifluoroethyl)-3',4' 15 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-blpyridin]-4'-yl)amino)propyl)acetamide Step 1: 6-bromo-4-(tert-butldimethylsilyloxy)-2,2-spirolyclobutyl-3,4-dihydro-2H pyrano(2,3-b)pyridine To a cooled (ice bath) solution 6-bromo-2,2-spirolcyclobutyl-3,4-dihydro-2H-pyrano(2,3 b)pyridine-4-ol (3.71 g, 13.7 mmol) in DCM was added TEA (3.82 ml, 27.5 mmol) 20 followed by tert-butyldimethylsilyl trifluoromethanesulfonate (3.47 ml, 15.1 mmol). The reaction was stirred at RT for 2h until all the alcohol was consumed. 1N HCI was added to quench the reaction. The resulted mixture was extracted with CH2Cl2. The organic layers were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated. After dried in vacuum, the title compound was obtained as a yellow solid. It 25 was carried on to the next step without further purification. MS m/z: 386.1(M+1). Step 2: 1-(4-(tert-butVldimethylsilyloxy)-2,2-spirolcyclobutyl-3,4-dihydro-2H-pyrano(2,3 b)pyridine-6-yl)-2,2,2-trifluoroethanone To a cooled (-78 0 C) solution of compound 1 from step 1 (4.20 g, 11 mmol) in THF was added slowly butyllithium, 1.6m in hexanes (7.5 ml, 12 mmol) via a syringe. After stirred 30 for 15 min, methyl 2,2,2-trifluoroacetate (1.1 ml, I 1 mmol) was added drop wise. The reaction was stirred for 15min at the same temperature. At this time, all the starting chromen was consumed, determined by LCMS. The reaction was quenched by the addition of saturated NH4Cl (40 mlO and EtOAc (50 ml). The mixture was then warmed to room temperature. The aqueous layer was extracted with EtOAc (50 ml). The organics were WO 2007/061670 PCT/US2006/044058 - 172 combined, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column giving the title compound. MS m/z: 419.8(M+18). Step 3: 1-(4-(tert-butyldimethylsilyloxy)-2,2-spirolcyclobutyl-3,4-dihydro-2H-pyrano( 2

,

3 b)pyridine-6-yl)-2,2,2-trifluoroethanol 5 To a solution of compound from step 2 (3.30 g, 8.22 mmol) in EtOH was added sodium borohydride (0.333 ml, 9.45 mmol). The reaction was stirred 4h at ambient temperature. At this point, all the starting material was consumed. Water was added to quench the reaction. Solvent was removed under reduced pressure. The aqueous residue was extracted with EtOAc (3x). The organic layers were combined, dried over MgSO4, filtered and 10 concentrated. The residue was purified over silica gel column (2-15% EtOAc/hexane) to afford the title compound as a light yellow solid. It contained two fractions. Each had the same MS, but had different retention time on TLC. MS m/z: 404.2(M+1). Step 4: 4-(tert-butyldimethylsilyloxy)-6-(I-chloro-2,2,2-trifluoroethyl)-2,2 spirolcyclobutyl-3,4-dihydro-2H-pyrano(2,3-b)pyridine 15 To a cooled (ice bath) mixture of compound 3 (2.34 g, 5.8 mmol) (from step 3) and pyridine (0.47 ml, 5.8 mmol) in toluene was added drop wise thionyl dichloride (0.59 ml, 8.1 mmol) via a syringe. After the addition was completed, the reaction was stirred at RT for 30 min, and heated at 75*C for 16 h. Reaction was cooled to RT and quenched with water. The resulted mixture was extracted with EtOAc (2x). The organic layers were combined, dried 20 over MgSO4, filtered and concentrated. The residue was dried in vacuum to afford the title compound. It was carried to the next step without further purification. MS m/z: 422.1 (M+l). Step 5: 4-(tert-butldimethylsilyloxy)-6-(2,2,2-trifluoroethyl)-2,2-spirolcyclobutyl- 3

,

4 dihydro-2H-pyrano(2,3-b)pyridine 25 To a solution of compound from step 4 (1.78 g, 4.22 mmol) in THF was added sodium tetrahydroborate (0.239 g, 6.33 mmol) in one portion. The reaction was heated under refluxing for 15 h and all the starting chloride was consumed. After cooled to room temperature, water was added to quench the reaction. The mixture was extracted with EtOAc (3x). The organic layers were dried over MgSO4, filtered and concentrated. The 30 residue was dried in vacuum to afford the title compound. It was carried to the next step without further purification. MS m/z: 388.2 (M+I). Step 6: 6-(2,2,2-trifluoroethyl)-2,2-spirolcyclobutyl-3,4-dihydro-2H-pyrano(2,3-b)pyridine 4-ol WO 2007/061670 PCT/US2006/044058 - 173 To compound 5 (1.21 g, 3 mmol) (crude from step 5) was added 4 N HCl/dioxane. The reaction was stirred at room temperature until all the starting material was consumed. The mixture was concentrated and dried in vacuum to give the title compound. It was carried to the next step without further purification. 5 Step 7: 6-(2,2,2-trifluoroethyl)-2,2-spirolyclobutyl-2,3,-dihydropano(2,3-b)pyridin-4-one To a stirred solution of compound (0.82 g, 3.0 mmol)(crude from step 6) in DCM was added sodium bicarbonate (0.12 ml, 3.0 mmol) in one portion followed by Dess martin Reactant 3 (1.3 g, 3.0 mmol) Stirring was continued for 3h at RT and 1.0 ml MeOH was added. After Stirring for an additional 30 min, the mixture was filtrated. The filtrate was 10 treated with 4 ml of 1M NaOH and stirred for 20 min. The mixture was extracted with 20 ml DCM (2x) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel column to afford the title compound. MS n/z: 272.0 (M+1). Step 8: (R)-2,2-spirolcyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano(2,3 15 b)pyridin-4-ol The title compound was prepared according to the methods described in step 5 of Example 509. MS m/z: 274.1 (M+1). Sten 9: (S)-4-azido-2,2-spirolcyclobutl-6-(2,2,2-trifluoroethyl)-3,4-dihvdro-2H pyrano(2,3-b)pyridine 20 The title compound was prepared according to the methods described in step 6 of Example 509. MS n/z: 299.1 (M+1). Step 10: (S)-2,2-spirolcyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano(2,3 b)pvridine-4-amine To a cooled (ice bath) solution of (S)-4-azido-2,2-spirolcyclobutyl-6-(2,2,2-trifluoroethyl) 25 3,4-dihydro-2H-pyrano(2,3-b)pyridine (196 mg, 657 Rmol) in THF was added lithium aluminum hydride (657 pl, 1314 pimol) drop wise. After stirred 1 h at room temperature, reduction was completed. The reaction mixture was diluted with THF and quenched by the slow addition of Na2SO4 12H20 until no bubble producing. The resulted mixture was filtered and the filtrate was concentrated, and dried in vacuum to afford the title compound 30 as colorless oil. MS m/z: 256 (M-NH2), 273 (M+1). Step 11: N-((1 S,2R)-2-hydroxy- 1-(phenylmethvl)-3-(((4'S)-6'-(2,2.2-trifluoroethyl)-3',4' dihydrospirofcyclobutane-1,2'-pyranof2.3-blpyridinl-4'-yl)aminO)Propyl)acetamide. TFA salt WO 2007/061670 PCT/US2006/044058 - 174 The title compound was prepared according to the methods described in steps 10 and 11 of Example 510. MS m/z: 478.1 (M+1). Example 513 5 N-((1S,2R)-1-((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-((2R)-3,3,3-trifluoro-2 methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide; and N-((1S,2R)-1-((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-((2S)-3,3,3-trifluoro-2 10 methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-blpyridinl-4' yl)amino)propyl)acetamide Step 1: Tert-butyl allvl((S)-2,2-spirolcyclobutyl-6-(3,3,3-trifluoro-l-hydroxy-2 methylpropyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-ylcarbamate To a cooled (-78"C) solution of (S)-tert-butyl allyl(6-bromo-2,2-spirocyclobutyl- 3

,

4 15 dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate (8.70 g, 21 mmol) in diethyletber was added tert-butyllithium (25 ml, 43 mmol) dropwise. After stirred 15 min, the fresh distilled 3,3,3-trifluoro-2-methylpropanal (5.8 ml, 53 mmol) was added. The reaction was stirred 30 min, then quenched with sat. NH4Cl. The resulted mixture was warmed to RT and extracted with EtOAc (3x). The organic layers were combined, dried over Na2SO4, filtered and 20 concentrated. The residue was purified on silica gel column to afford the title compound as light yellow oil. MS nz: 457 (M+1). Step 2: Tert-butyl allyl((S)-2,2-spirolcyclobutyl-6-(3,3,3-trifluoro-1 -chloro-2 methylpropyl)-3.4-dihydro-2H-pyrano(2,3-b)pyridine-4-vl)carbamate To a cooled (ice bath) mixture of compound 1 (1.33 g, 2.9 mmol) (from step 1) and 25 pyridine, anhydrous (0.24 ml, 2.9 mmol) in toluene was added thionyl chloride (SOCI2) (0.30 ml, 4.1 mmol) dropwise. After the addition was completed, the mixture was warmed to RT and then heated at 45*C for 2 h. At this point, all the Reactant 1 was consumed and the desired product was formed, determined by LCMS. The reaction was cooled to RT and quenched with water (25 ml). The layers were separated. The aqueous layer was extracted 30 with EtOAc (2x). The organic layers were combined, washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated and purified on silica gel column (5 15% EtOAc/hexane) to provide the title compound as yellow oil. MS m/z: 475 (M+1). Step 3: (4S)-6-(3,3,3-trifluoro-1-chloro-2-methylpropyll-2,2 spirocyclobutyl-3,4-dihydro 2H-pyrano(2,3-b)pyridine-4-amine To compound (1.06 g, 2 mmol) from step 2 was added WO 2007/061670 PCT/US2006/044058 - 175 hydrogen chloride 4.Om in 1,4-dioxane (2.0 ml, 9 mmol). After stirred 15 h (over night), the Boc group was removed. The resulted mixture was diluted with CH2Cl2 and neutralized with saturated Na2HCO3 (25 ml). The aqueous layer was extracted with CH2CI2 (2x). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue 5 was dried in vacuum to provide a yellow oil product. MS m/z: 475.2 (M+1). The yellow oil product from above was dissolved in CH2C12. 1,3-dimethylpyrimidine-2,4,6(1 H,3H,5H) trione (1 g, 7 mmol) was then added. After degassed for 10 min, PalladiumTetrakis (0.1 g, 0.1 mmol) was added and the mixture was heated at 40"C for 1.5 h under N2 atmosphere. At this point, reaction was completed, determined by LCMS. Reaction was then warmed to 10 room temperature and quenched with 1 N HCl. The organic layer was washed with 1 N HCI (2x). The aqueous layers were combined, neutralized with sat. Na2CO3 to PH = 6.5, and then extracted with CH2Cl2 (3x). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was dried in vacuum to provide 845 mg of the title compound as off-white foam. MS n/z: 335 (M+1). 15 Step 4: N-((1 S,2R)- I -((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-((2R)-3,3,3 -trifluoro 2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-blpyridinl-4' yl)amino)propv1)acetamide; and N-((I S,2R)-l -((3-fluorophenyl)methyl)-2-hydrox-3-(((4'S)-6'-((2S)-3,3,3-trifluoro-2 methylpropyl)-3',4'-dihydrospirorcyclobutane-1,2'-pyranof2,3-blpyridinl-4' 20 yl)amino)propyl)acetamide The title compounds were prepared by the method described in co-pending patent application serial no. 60/738,767 Example 170. MS m/z: 524.2 (M+1). Example 514 25 Ethyl 1-(2-(((1S,2R)-3-(((4S)-6-bromo-3,4-dihyd rospiro[chromene-2,1'-cyclobutan] 4-yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)amino)-2-oxoethyl)-1H-1,2,3 triazole-4-carboxylate Step 1: 2 -Azido-N-(( 2

S,

3 R)-4-((S)-6-bromo-2,2-spircyclobutlchroman-4-ylamino)-3 30 hydroxy-1-phenylbutan-2-yl)acetamide The (2R,3 S)-3 -amino-1 -((S)- 6 -bromo-2,2-spirocyclobutylchroman-4-ylamino)-4 phenylbutan-2-ol (0.43 g, 0.99 mmol) and 2-azidoacetic acid (0.100 g, 0.99 mmol) were dissolved in dmf (6.0 mL). Hunig's Base (0.22 ml, 1.2 mmol) was added. HATU (0.38 g, 0.99 mmol) was added, and the mixture was stirred at rt for 12 h. The reaction was WO 2007/061670 PCT/US2006/044058 - 176 concentrated to remove most of the DMF. The residue was taken up in EtOAc (100 mL) and the organic layer was extracted with water (7 mL), half-saturated brine (7 mL), and saturated brine (7 mL), then was dried over sodium sulfate and concentrated. The material was purified through silica gel (70 mL) which had been deactivated with Et 3 N 5 (7.5 mL) eluting with EtOAc, affording the title compound. MS m/z 514/516 (M+1). Step 2: Ethyl 1-(2-(((l S,2R)-3 -(((4S)-6-bromo-3,4-dihydrospiro[chromene-2, 1' cyclobutanl-4-yl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)amino)-2-oxoethyl)-1 H 1,2,3-triazole-4-carboxylate In a sealable vessel, ethyl propiolate (0.0067 ml, 0.066 mmol) and 2-azido-N-((2S,3R)-4 10 ((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy- I -phenylbutan-2 yl)acetamide (0.020 g, 0.039 mmol) were dissolved in dioxane (0.3 mL). The vessel was sealed and placed in an 80 deg oil bath for 12 h. The reaction was cooled, taken up in EtOAc (60 mL) and the organic layer was extracted with dilute NaHCO3 (5 mL), half saturated brine (5 mL) and saturated brine (5 mL), then was dried over sodium sulfate and 15 concentrated. The material was purified through silica gel (15 mL) which had been deactivated with Et 3 N (2 mL), eluting with 3% MeOH-EtOAc, yielding the title compound as a white solid. MS n/z 612/614 (M+1). Example 515 20 N-((1S,2R)-1-((3-Bromo-4-fluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl) 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-blpyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide Step 1: (3-Bromo-4-fluorophenyl)methanol 25 3-Bromo-4-fluorobenzaldehyde (0.300 g, 1.48 mmol) was dissolved in methanol (3 mL). Sodium borohydride (0.0671 g, 1.77 mmol) was added. After 3 h, the reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was taken up in 2:1 EtOAc-hexane (60 mL). The organic layer was extracted with dilute NaHCO 3 (6 mL) then half-saturated brine (6 mL), then was dried over sodium sulfate and 30 concentrated. The material was purified through silica gel (45 mL) using 30% to 40% EtOAc-hexane to afford the title compound. Step 2: 2-Bromo-4-(bromomethyl)- I -fluorobenzene (3-Bromo-4-fluorophenyl)methanol (0.264 g, 1.29 mmol) was dissolved in DCM (3 mL). The solution was cooled to 0 deg, and tribromoborane (1.0 M in DCM, 0.863 ml, 0.863 WO 2007/061670 PCT/US2006/044058 - 177 mmol) was added. The mixture was stirred at 0 deg for 1 h, then rt for I h. The reaction was quenched with water, and- the mixture was transfered to a separatory funnel with half saturated NaHCO 3 (15 mL), and the aqueous phase was extracted with DCM (3 x 20 mL). The organics were combined, washed with half-saturated brine (5 mL), dried over sodium 5 sulfate and concentrated. Purification of the residue through silica gel (40 mL) using 5% EtOAc-hexane afforded the title compound. Step 3: N-((1S,2R)-1-((3-Bromo-4-fluorophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospirorcyclobutane-1.2'-pyranof2,3-blpyridinl-4'-yl)amino) 2-hydroxypropyl)acetamide 10 2-Bromo-4-(bromomethyl)-1-fluorobenzene was converted to the title compound using a method analogous to that described in Examples 509 and 510. Example 516 15 2-(5-(Aminomethyl)-1H-1,2,3-triazol-1-yl)-N-((18,2R)-3-(((4S)-6-bromo-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide; and 2-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)-N-((S,2R)-3-(((4S)- 6-bromo-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1 20 (phenylmethyl)propyl)acetamide In a microwave vessel, 2 -azido-N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutylchroman 4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)acetamide (0.020 g, 0.039 mmol) was taken up in prop-2-yn-1-amine (0.49 ml, 7.2 mmol). The vessel was sealed and placed in a 100 deg oil bath. After 12 h, the reaction was concentrated on the rotovap. The residue was 25 purified through silica gel (15 mL) which had been deactivated with Et 3 N (2.0 mL) using 5% MeOH-dichloromethane to afford the title compounds as an equal mixture of isomers. MS m/z 569/571 (M+1) Example 517 30 N-((1S,2R)-1-((3-Cyano-4-fluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl) 3

',

4 '-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 178 Step 1: (S)-N-((2S,3S)-I-(3-Bromo-4-fluorophenyl)-3,4-bis(tert butyldimethylsilyloxy)butan-2-yl)-2-methylpropane-2-sulfinamide The title compound was prepared from (S,E)-N-((S)-2,3-bis(tert butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide and 2-bromo-4 5 (bromomethyl)- 1 -fluorobenzene using a method analogous to that described in Examples 509 and 510. Step 2: (S)-N-((2S,3S)-3,4-Bis(tert-butyldimethylsilyloxy)-1-(3-cyano-4 fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide The (S)-N-((2S,3S)-1-(3-bromo-4-fluorophenyl)-3,4-bis(tert 10 butyldimethylsilyloxy)butan-2-yl)-2-methylpropane-2-sulfinamide (0.247 g, 0.404 mmol), Pd 2 (dba) 3 -CHCl 3 (0.209 g, 0.202 mmol) dppf (0.224 g, 0.404 mmol) and zinc cyanide (0.0522 g, 0.445 mmol) were suspended in dmf (10 mL). A condenser was affixed and the flask was placed in a 120 deg oil bath. After 14 h, flask was concentrated. The residue was taken up in EtOAc (100 mL) and water (10 mL), and the mixture was 15 filtered through Celite. The aqueous layer was separated and the organic layer was extracted with saturated brine (10 mL), dried over sodium sulfate and concentrated. Purification of the black residue through silica gel (40 mL) using 10% to 15% EtOAc hexane afforded the title compound. MS m/z 557 (M+1). Step 3: N-((1 S,2R)- 1 -((3-Cyano-4-fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 20 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1.2'-pyranof2,3-blpyridinl-4'-yl)amino) 2-hydroxypropvl)acetamide (S)-N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3-cyano-4-fluorophenyl)butan-2 yl)-2-methylpropane-2-sulfinamide was converted to the title compound using a method analogous to that described in Examples 509 and 510. MS n/z 509 (M+1). 25 Example 518 N-((1S,2R)-1-((3-Chloro-2,4-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridinj-4' 30 yl)amino)-2-hydroxypropyl)acetamide Step 1: (3-Chloro-2,4-difluorophenyl)methanol 3-Chloro-2,4-difluorobenzoic acid (5.37 g, 27.9 mmol) was dissolved in THF (20 mL) and the solution was cooled to 0 deg. Borane methylsulfide (2.0 M in THF, 55.8 ml, 112 mmol) was added. The resulting solution was warmed to rt and stirred for 14 h. The WO 2007/061670 PCT/US2006/044058 - 179 solution was cooled in an ice bath, and 10% aqueous Na 2

CO

3 (7 mL) was added slowly. The material was concentrated on the rotovap to a white solid. The residue was acidified with 3M aqueous HCI (30 mL), diluted with dichloromethane (50 mL), and the mixture was filtered through Celite. The layers were separated, and the organic layer was dried 5 over sodium sulfate and concentrated. The residue was purified through silica gel (500 mL) using 30% EtOAc-hexane, to afford the title compound. Step 2: 1-(Bromomethyl)-3-chloro-2,4-difluorobenzene (3-chloro-2,4-difluorophenyl)methanol was converted to the title compound using the procedure described in Example 461, Step 2. 'H NMR in CDC 3 0: 7.29 (in, 1H), 6.98 10 (td, 1H, J= 8.4, 1.6), 4.48 (s, 2H). Step 3: N-((1 S,2R)-1 -((3-Chloro-2,4-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihvdrospiro[cyclobutane- 1,2'-pyrano[2,3-blpyridinl-4'-yl)amino) 2-hydroxypropyl)acetamide I -(Bromomethyl)-3-chloro-2,4-difluorobenzene was converted to the title compound 15 using a method analogous to that described in Examples 509 and 510. MS m/z 536 (M+1). Example 519 N-((1S, 2 R)-1-((4-Chlorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-((-methylethyl)oxy) 20 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-blpyridin]-4' yl)amino)propyl)acetamide Step 1: (S)-tert-Butyl 6-bromo-2,2-spirocyclobutvl-3,4-dihydro-2H-pyranor2,3-blpvridin 4-ylcarbamate

(S)-

6 -bromo- 2

,

2 -spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine (968 mg, 25 3.6 mmol), Hunig's base (0.94 mL, 5.4 mmol), and Boc anhydride (0.98 g, 4.5 mmol) were dissolved in dichloromethane (15 mL), and the mixture was stirred at rt for 14 h. The reaction was quenched with ethanolamine (0.13 mL, 2.2 mmol), diluted with 10% aqueous sodium carbonate (9 mL), and the aqueous layerwas extracted with DCM (3 x 20 mL). The organics were combined, washed with dilute brine, dried over sodium 30 sulfate and concentrated. The product was purified through silica gel (200 mL) using 28% EtOAc-hexane to afford the title compound. MS m/z 369/371 (M+1). Step 2: (S)-tert-Butyl allyl(6-bromo-2.2-spiroyclohntvl-3,4-dihydro-2H-pyranof2,3 blpyridin-4-yl)carbamate WO 2007/061670 PCT/US2006/044058 - 180 (S)-tert-Butyl 6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-bpyridin-4 ylcarbamate (1.27 g, 3.45 mmol) was dissolved in DMF (10 mL) and NaH (60%, 165 mg, 4.14 mmol) was added. The suspension was cooled to 0 deg, and allyl bromide (0.418 mL, 4.83 mmol) was added. The mixture was stirred at 0 deg for 5 h. The mixture was 5 concentrated, diluted with 90% ether-hexane (60 mL), and the organic layer was washed with water (2 x 5 mL) and saturated brine (5 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified through silica gel (150 mL) using 20% EtOAc-hexane to afford the title compound. MS m/z 409/411 (M+I1). 10 Step 3: (S)-tert-Butyl allvl( 6 -hydroxy-2.2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3 blpyridin-4-vl)carbamate (S)-tert-Butyl allyl( 6 -bromo- 2

,

2 -spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4 yl)carbamate (1.16 g, 2.8 mmol) and triisopropylborate (3.3 mL, 14 mmol) were dissolved in THF (25 mL). The solution was cooled to -78 deg. A solution of n 15 butyllithium in hexane (2.5 M, 2.1 mL, 5.2 mmol) was added. The solution was stirred at -78 deg for 30 min, then warmed to 0 deg. An aqueous solution of hydrogen peroxide (30% w/w, 2.9 mL, 28 mmol) and 2.5 M aqueous NaOH (6.5 mL) was added, and the mixture were stirred for 30 min. The aqueous layer was extracted with EtOAc (3 x 25 mL). The organics were combined, washed with saturated brine (2 x 5 mL), dried over 20 sodium sulfate and concentrated. The material was purified through silica gel (125 mL) using 50% EtOAc-hexane to afford the title compound. MS m/z 347 (M+1). Step 4: (S)-tert-Butyl allyl( 6 -isopropoxy-2,2-spiroyclobutl-3,4-dihydro-2H-pyranof2,3 blpyridin-4-yl)carbamate In a sealable vessel, (S)-tert-butyl allyl(6-hydroxy-2,2-spirocyclobutyl-3,4-dihydro-2H 25 pyrano[2,3-b]pyridin-4-yl)carbamate (180 mg, 0.52 mmol) and cetyltrimethylammonium bromide (19 mg, 0.052 mmol) were dissolved in dioxane (0.42 mL) and 3.0 M aqueous potassium hydroxide (0.866 mL, 2.6 mmol) was added. Isopropyl bromide (0.098 mL, 1.04 mmol) was added. The vessel was sealed and the reaction mixture was heated at 100 deg for 3 h. The vessel was cooled, to rt, the mixture was diluted with ether (60 mL), and 30 the organic layer was washed with water (2 x 6 mL) and saturated brine (6 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified through silica gel (40 mL) using 30% EtOAc-hexane to afford the title compound. MS n/z 389 (M+I).

WO 2007/061670 PCT/US2006/044058 - 181 Step 5: (S)-N-Allyl-6-isopropoxy-2,2-spirocyclobutyl-3.4-dihvdro-2H-pyrano[2,3 blpyridin-4-amine In a sealable vessel,(S)-tert-butyl allyl(6-isopropoxy-2,2-spirocyclobutyl-3,4-dihydro-2H pyrano[2,3-b]pyridin-4-yl)carbamate (246 mg, 0.63 mmol) was dissolved in 5 dichloromethane (3.5 mL). TFA (0.488 mL, 6.3 mmol) was added. The vessel was sealed and heated at 50 deg for 6 h. The mixture was concentrated, and the residue was neutralized with 10% aqueous sodium carbonate (8 mL). The aqueous phase was extracted with 5% MeOH-dichloromethane (60 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound. MS m/z 289 (M+1). 10 Step 6: (S)-6-Isopropoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pvrano[2,3-blpyridin-4 amine (S)-N-Allyl- 6 -isopropoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4 amine (181 mg, 0.63 mmol), 1,3-dimethylpyrimidine,2,4,6(lH,3H,5H)-trione (0.294 g, 1.88 mmol), Pd(PPh 3

)

4 (36.3 mg, 0.031 mmol) were dissolved in dichloromethane (4 15 mL). The mixture was heated at 35 deg for 1.5 h. The mixture was diluted with 0.5 M aqueous sodium carbonate (8 mL) and the aqueous phase was extracted with 5% MeOH dichloromethane (3 x 20 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate, and concentrated. The residue was purified through silica gel (25 mL) which had been deactivated with triethylamine (2.5 mL), eluting with 20 0.5% MeOH-dichloromethane to afford the title compound. MS m/z 249 (M+1). Step 7: N-((1 S,2R)- 1 -((4-Chlorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-(( 1 methylethyl)oxy)-3',4'-dihydrospirorcyclobutane-1,2'-pyrano[2,3-blpyridinl-4' yl)amino)propyl)acetamide

(S)-

6 -Isopropoxy- 2

,

2 -spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine was 25 converted to the title compound using a method analogous to that described in Examples 509 and 510. MS m/z 488 (M+1). The following compounds are further examples of the present invention, and were made by methods described hereinabove. Table 4 Ex. No. Compound Name Mass Found Cell Assay WO 2007/061670 PCT/US2006/044058 - 182 N-((1 S,2R)-I-((3,5-difluorophenyl)methyl)-2-hydroxy-3 520 (((4S)-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4- 512 2.158087 dihydrospiro[chromene-2,1 '-cyclobutan]-4 yl)amino)propyl)acetamide N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(1-methyl-i H- 1,2,3 521 triazol-4-yl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 476 10 yl)amino)- 1-(phenylmethyl)propyl)acetamide N-((1S,2R)-3-(((4S)-6-((2R)-2-fluoropropyl)-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 522 hydroxy-l-(phenylmethyl)propyl)acetamide 455 0.010493 N-((1 S,2R)-3-(((4S)-6-((2S)-2-fluoropropyl)-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxy- 1 -(phenylmethyl)propyl)acetamide N-((l S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4' 523 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 452 0.004092 yl)amino)-1 -(phenylmethyl)propyl)acetamide N-((1 S,2R)-1 -((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2 524 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 495 0.002424 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4 525 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488 0.003945 yl)amino)- 1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H 526 chromen-4-yl)amino)-1-((3-cyanophenyl)metbyl)-2- 486,488 0.116235 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 183 N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H 527 chromen-4-yl)amino)- 1 -((3-cyanophenyl)methyl)-2- 516, 518 0.12029 hydroxypropyl)-2-(methyloxy)acetamide N~1~-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro 528 2H-chromen-4-yl)amino)-1-((3-cyanophenyl)methyl)-2- 529, 531 1.122924 hydroxypropyl)-N-2-,N-2--dimethylglycinamide N-((l S,2R)-3-(((4S)-8-bromo-6-ethyl-2,2-dimethyl-3,4 529 dihydro-2H-chromen-4-yl)amino)-1-((3- 514, 516 0.033865 cyanophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-1 -((3-cyanophenyl)methyl)-3-(((1 S)-3,3 dimethyl-7-(methyloxy)-4-oxo-1,2,3,4-tetrahydro-1 naphthalenyl)amino)-2-hydroxypropyl)-2 530 (methyloxy)acetamide N-((1S,2R)-1-((3- 480 0.220964 cyanophenyl)methyl)-3-(((1 R)-3,3-dimethyl-7-(methyloxy) 4-oxo- 1,2,3,4-tetrahydro- 1-naphtbalenyl)amino)-2 hydroxypropyl)-2-(methyloxy)acetamide N-((1 S,2R)-1 -((3-cyanophenyl)methyl)-3-(((l S)-3,3 dimethyl-7-(methyloxy)-4-oxo-1,2,3,4-tetrahydro- 1 531 naphthalenyl)amino)-2-hydroxypropyl)acetamide 450 0.135497 N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((lR)-3,3 dimethyl-7-(methyloxy)-4-oxo- 1,2,3,4-tetrahydro-1 naphthalenyl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)- 1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-2,2 532 dimethyl-8-(4-morpholinyl)-3,4-dihydro-2H-chromen-4- 521 0.011199 yl)amino)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 184 N-((I S,2R)-3-(((4R)-6-ethyl-2,2-dimethyl-8-(1-pyrrolidinyl) 3,4-dihydro-2H-chromen-4-yl)amino)-2-hydroxy- 1 533 (phenylmethyl)propyl)acetamide N-((1S,2R)-3- 480 0.064408 (((4S)-6-ethyl-2,2-dimethyl-8-(I-pyrrolidinyl)-3,4-dihydro 2H-chromen-4-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide N-((IS,2R)-3-(((4S)-8-(dimethylamino)-6-ethyl-2,2 dimethyl-3,4-dihydro-2H-chromen-4-yl)amino)-2-hydroxy 534 1-(phenylmethyl)propyl)acetamide N-((1 S,2R)- 0.022928 3-(((4R)-8-(dimethylamino)-6-ethyl-2,2-dimethyl-3,4 dihydro-2H-chromen-4-yl)amino)-2-hydroxy-

I

(phenylmethyl)propyl)acetamide N-((IS,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-8-(methylamino) 535 3,4-dihydro-2H-chromen-4-yi)amino)-2-hydroxy-1 - 440 0.923788 (phenylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-8-(4 536 morpholinyl)-3,4-dihydrospiro[chromene-2, 1'-cyclobutan]-4- 568 2.090331 yl)amino)- 1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-8-(4 537 morpholinyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 550 1.96531 yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide N-((1 S)- 1 -((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 538 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 432 0.176659 yl)amino)-1-hydroxyethyl)-3-methylbutyl)acetamide WO 2007/061670 PCT/US2006/044058 -- 18 5 N-((1 S)- 1 -((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 539 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 430 0.050267 yl)amino)- 1 -hydroxyethyl)-3-inethyl-3-buten- I -yl)acetamide N-((1 S,2R)- 1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2,2 540 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 0.002035 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-2-hydroxy-3-(((5'S)-3'-methyl-5',8'-dihydro-6'H 541 spiro[cyclobutane-1,7'-quinolin]-5'-yl)amino)-1- 408 0.650675 (phenylmethyl)propyl)acetamide N-((1 S,2R)- 1 -((3-cyanophenyl)methyl)-2-hydroxy-3-(((5'S) 542 3'-methyl-5',8'-dihydro-6'H-spiro[cyclobutane-1,7'-quinolin]- 433 0.064592 5'-yl)amino)propyl)acetamide N-((1 S,2R)- 1 -((3-cyanophenyl)methyl)-2-hydroxy-3 -(((5S) 543, 3,7,7-trimethyl-5,6,7,8-tetrahydro-5- 421 0.123613 quinolinyl)amino)propyl)acetamide N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3 544 (((4S)-6-(1,3-oxazol-2-yI)-3,4-dihydrospiro[chromene-2,1'- 498 0.631397 cyclobutan]-4-yl)amino)propyl)acetamide N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl 545 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)amino)-2- 454 0.004607 hydroxy-1-(phenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 186 N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl 546 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)amino)- 1 -((3- 472 0.001669 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 547 dihydrospiro[cyclopentane- 1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.034798 yl)amino)-1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 548 dimethylpropyl)-3',4'-dihydrospiro[cyclopentane-1,2'- 516 0.002832 pyrano[2,3-blpyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 549 dihydrospiro[cyclopentane- 1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.006927 yl)amino)- 1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 550 dihydrospiro[cyclopropane-1,2'-pyrano[2,3-b]pyridin]-4'- 442 0.020321 yl)amino)-1-((4-fluoro-3-methylphenyl)methyl)-2 bydroxypropyl)acetamide N-((I S,2R)-3-(((4'S)-6'-((1 S)- 1-fluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1-((4-fluorophenyl)methyl)-2 551 hydroxypropyl)acetamide

N

((1 S,2R)-3-(((4'S)-6'-((1R)- 1-fluoro-2-methylpropyl)-3',4- 488 1.647171 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 187 N-((1 S,2R)-3-(((4'S)-6'-((1 R)- I -fluoro-2-methylpropyl)-3',4' 552 dihydrospiro[cyclobutane-1 ,2'-pyrano[2,3-b]pyridinl-4'- 488 1.260258 yI)amino)- I -((4-fluorophenyl)rnethyl)-2 hydroxypropyl)acetamide N-(( I S,2R)-3-(((4'S)-6'-((1 S)- I1-fluoro-2-methylpropyl)-3',4' 553 dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'- 488 0210 yl)amino)- 1 -((4-fluorophenyl)methyl)-2- 0210 hydroxypropyl)acetamide N-(( 1 S,2R)-3-(((4'S)-6'-((1 S)- 1-loo2mtypoy)3,' 554 dibydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin] -4'- 488 2.581944 yI)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-((1 S)- I -fluoro-2-methylpropyl)-3',4' 55 diihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'- 488 1.429449 yI)amino)-l -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide (methyloxy)ethyl)amino)-4-oxo- 1,2,3,4-tetrahydro- 1 naphthalenyl)amino)-2-hydroxy- 1 556 (phenylmethyl)propyl)acetamide N-((1 S,2R)- 468 10 3-((( 1R)-3,3 -dimethyl-7-((2-(methyloxy)ethyl)amino)-4-oxo 1 ,2,3,4-tetrahydro- I -naphthalenyl)amino)-2-hydroxy- I1 (phenylmethyl)propyl)acetamide N-(( I S,2R)-3-((( 1 R)-7-(cyclopentylamino)-3,3-dimethyl-4 oxo- I ,2,3,4-tetrahydro- 1 -naphthalenyl)amino)-2-bydroxy- 1 557 (phenylmethyl)propyl)acetamide N-(( I S,2R)-3- 478 0.03 8437 (((I S)-7-(cyclopentylamino)-3,3-dimethyl-4-oxo- 1,2,3,4 tetrahydro- 1 -naphthalenyl)amino)-2-hydroxy- I1 (phenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 188 N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((1S)-7-(2,2 dimethylpropyl)-3,3-dimetbyl-4-oxo-1,2,3,4-tetrahydro-1 558 naphthalenyl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-I-((3,5-difluorophenyl)methyl)-3-(((1R)-7-(2,2- 501 0.038226 dimethylpropyl)-3,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-1 naphthalenyl)amino)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydro 559 1'H-spiro[cyclobutane-1,2'-quinolin]-4'-yl)amino)-1-((4- 482 0.104975 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-I-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 560 dimethylpropyl)-3',4'-dihydro- 1'H-spiro~cyclobutane- 1,2'- 500 0.011735 quinolin]-4'-yl)amino)-2-hydroxypropyl)acetamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydro 561 1'H-spiro[cyclobutane- 1,2'-quinolin]-4'-yl)amino)- 1-((3- 482 0.029368 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((l S,2R)- 1-((3-bromo-4-fluorophenyl)methyl)-3-(((4'S) 562 6'-(2,2-dimethylpropyl)-3',4'-dihydro- l'H-spiro[cyclobutane- 561 0.14112 1, 2 '-quinolin]-4'-yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)- 1'-oxo-3',4' 563 dihydro- 'H-spiro [cyclopentane- 1,2'-naphthalen]-4'- 509 10 yl)amino)- 1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 189 N-((1 S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)- I '-oxo-3',4' 564 dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-4'- 509 0.569059 yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((3 S,4'S)-6'-chloro-3',4,4',5 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4' 565 yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide 446 10 N-((1 S,2R)-3-(((3R,4'S)-6'-chloro-3',4,4',5 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane 566 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)- 1 -((3- 442 0.029044 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)- 1-((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6' 567 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 518 0.003274 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 568 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 484 0.008126 yl)amino)-1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 569 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'- 484 0.005216 yl)amino)-1-((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 570 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 484 0.022073 yl)amino)-1 -((4-fluoropbenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 190 N-((1S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4' 571 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1-((4-fluoropbenyl)methyl)-2- 488 0.080924 hydroxypropyl)acetamide N-((I S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl 572 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)amino)-1 -((4- 472 0.013847 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-I-((3,5-difluorophenyl)methyl)-3-(((4S)-6-(2,2 573 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 490 0.003117 b]pyridin-4-yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2S)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4' 574 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488 0.10607 yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 575 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.004641 yl)amino)- 1 -((4-fluoro-3-methylphenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 576 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.002151 yl)amino)- I -((3-fluoro-4-methylphenyl)methyl)-2 hydroxypropyl)acetamide methyl ((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 577 dihydrospiro[cyclobutane- l,2'-pyrano[2,3-b]pyridin]-4'- 500 0.060048 yl)amino)- 1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)carbamate WO 2007/061670 PCT/US2006/044058 - 191 N-((IS,2R)-1-((4-fluoro-3-methylphenyl)methyl)-3-(((4'S) 578 6'-(2-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 502 0.028506 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 579 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 496 0.00461 yl)amino)-2-hydroxy- 1 -((3 (methyloxy)phenyl)methyl)propyl)acetamide N-((1 S,2R)-1 -((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2 580 dimethylpropyl)-3',4'-dihydrospiro[cyclopropane-1,2'- 486 0.119905 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethyl-3-(methyloxy)propyl) 581 3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 514 0.137018 yl)amino)-1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2 582 dimethylpropyI)-3',4'-dibydrospiro[cyclobutane- 1,2'- 509 0.031787 pyrano[2,3-c]pyridin]-4'-yl)amino)-2-hydroxy- I (phenylmethyl)propyl)acetamide N-((I S,2R)-3-(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4' 583 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'- 518 0.112144 yl)amino)- 1 -((4-fluorophenyl)metbyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-((( 4 'S)-6'-(2,2-dimethylpropyl)-8' 584 (ethylamino)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3- 527 0.005288 c]pyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2 bydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 192 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((1 585 methylethyl)amino)-3',4'-dihydrospiro[cyclobutane- 1,2'- 541 0.022345 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-8'-(cyclopropylamino)-6'-(2,2 586 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 0.014049 pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4 fluorophenyl)methyl)-2-bydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(tetrahydro 587 2 H-pyran-4-ylamino)-3',4'-dihydrospiro[cyclobutane- 1,2'- 583 0.008485 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((l S,2R)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2 588 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 527 0.052264 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-8'-((1, 1 -dimethylethyl)amino)-6'-(2,2 589 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 0.615121 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8' 590 (methylamino)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((3- 513 0.001406 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8' 591 (ethylamino)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3- 527 0.002976 c]pyridin]-4'-yl)amino)- 1-((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 193 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(tetrahydro 592 2H-pyran-4-ylamino)-3',4'-dihydrospiro[cyclobutane-1,2'- 0.003238 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2 593 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 527 0.023623 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-oxo 594 3',4',7',8'-tetrahydrospiro[cyclobutane-1,2'-pyrano[2,3- 500 0.023364 c]pyridin]-4'-yl)amino)-1-((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((] S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-(( 1 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-clpyridin]-4'-yl)amino)-1 -((4 595 fluorophenyl)methyl)-2-hydroxypropyl)acetamide 542 0.607192 N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(( 1 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-((1 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-c]pyridin]-4'-yl)amino)-1 -((3 596 fluorophenyl)methyl)-2-hydroxypropyl)acetamide 542 0.036426 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((1-5 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 194 N-((1 S,2R)-1 -((3,5-difluorophenyl)methyl)-3-(((4'R)-6'-(2,2 dimethylpropyl)-8'-((1-methylethyl)oxy)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4' 597 yl)amino)-2-hydroxypropyl)acetamide 560 0.050591 N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-8'-((1-methylethyl)oxy)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide N-((l S,2R)- 1-((3,5-difluorophenyl)methyl)-3-(((4'S)-8' 598 (dimethylamino)-6'-(2,2-dimethylpropyl)-3',4'- 545 0.026836 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide N-((l S,2R)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2 599 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 552 0.167357 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1-((4 (dimethylamino)phenyl)methyl)-2-hydroxypropyl)acetamide N-((I S,2R)-I-((4-chlorophenyl)methyl)-3-(((4'S)-8' 600 (dimethylamino)-6'-(2,2-dimethylpropyl)-3',4'- 543 0.633888 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-1-((2,3-difluorophenyl)methyl)-3-(((4'S)-8' 601 (dimethylamino)-6'-(2,2-dimethylpropyl)-3',4'- 545 0.226574 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4'S)-8'-(cyclopropylamino)-6'-(2,2 602 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 539 0.002887 pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 195 1,1-dimethylethyl (2-((( 4 'S)-4'-(((2R,3S)-3-(acetylamino)-4 603 (3-fluorophenyl)-2-hydroxybutyl)amino)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 642 0.012859 pyrano[ 2 ,3-c]pyridin]-8'-yl)amino)ethyl)carbamate N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(3 604 (methyloxy)-l-azetidinyl)-3',4'-dihydrospiro[cyclobutane- 569 0.00579 1, 2 '-pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((l S,2R)-3-(((4'S)-8'-amino-6'-(2,2-dimethylpropyl)-3',4' 605 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 499 0.001558 yl)amino)- 1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3 -(((4'S)-8'-((2-aminoethyl)amino)-6'-(2,2 606 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 542 0.004432 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetanide N-((1 S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-((1 607 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane- 1,2'- 542 0.080297 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((] S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((1 608 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'- 542 0.064326 pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-((( 4 'R)-6'-(2,2-dimethylpropyl)-8'-((1 609 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'- 542 0.06672 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 196 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((.

610 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'- 542 0.17223 pyrano[2,3-c]pyridin]-4'-yl)amino)- 1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)- 1-((3,5-difluorophenyl)methyl)-3-(((4'R)-6'-(2,2 611 dimethylpropyl)-8'-((1 -methylethyl)oxy)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'- 560 0.161326 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)- 1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 612 dimethylpropyl)-8'-((1-methylethyl)oxy)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'- 560 0.024218 yl)amino)-2-hydroxypropyl)acetamide N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8' 613 (methyloxy)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 514 0.103038 c]pyridin]-4'-yl)amino)- 1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(3 614 (methyloxy)-1 -azetidinyl)-3',4'-dihydrospiro[cyclobutane- 569 0.059045 1, 2 '-pyrano[2,3-c]pyridin]-4'-yl)amino)- 1-((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3 615 (((1 s, 3 R,4'S)-3-methyl-6'-(2-methylpropyl)-3',4'- 484 0.024809 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide N-((] S,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3 616 (((1r,3S,4'S)-3-methyl-6'-(2-methylpropyl)-3',4'- 484 0.062677 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 197 N-((1S,2R)-1-((3-fluorophenyl)methyl)-2-hydroxy-3 617 (((1s,3R,4'S)-3-methyl-6'-(2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 484 0.002985 yl)amino)propyl)acetamide N-((1S,2R)-1-((4-chlorophenyl)methyl)-2-hydroxy-3 618 (((1s,3R,4'S)-3-methyl-6'-(2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 500 0.072183 yl)amino)propyl)acetamide N-((1 S,2R)-3-(((1 S,2S,4'S)-6'-(2,2-dimethylpropyl)-2 619 methyl-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3- 498 0.032589 b]pyridin]-4'-yl)amino)- 1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)- I -((4-cblorophenyl)methyl)-3-(((1 S,2S,4'S)-6' 620 (2,2-dimethylpropyl)-2-methyl-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514 0.062047 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3 -(((1 R,2R,4'S)-6'-(2,2-dimethylpropyl)-2 621 methyl-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3 b]pyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2- 498 10 hydroxypropyl)acetamide N-((1 S,2R)- 1-((4-chlorophenyl)methyl)-3-(((1 R,2R,4'S)-6' 622 (2,2-dimethylpropyl)-2-methyl-3',4'-5 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514 10 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((1 S,2R,4'S)-6'-(2,2-dimethylpropyl)-2 623 methyl-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3- 498 0.038235 b]pyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 198 N-((] S,2R)- I -((4-chlorophenyl)methyl)-3-(((1 S,2R,4'S)-6' 624 (2,2-dimethylpropyl)-2-methyl-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514 0.061497 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((1R,2S,4'S)-6'-(2,2-dimethylpropyl)-2 625 methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3 b]pyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2- 498 10 hydroxypropyl)acetamide N-((1 S,2R)-1 -((4-chlorophenyl)methyl)-3-(((1 R,2S,4'S)-6' 626 (2,2-dimethylpropyl)-2-methyl-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 514 10 yl)amino)-2-hydroxypropyl)acetamide methyl ((1 S,2R)- 1-((4-chlorophenyl)methyl)-3-(((4'S)-6' 627 ( 2 ,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 516 0.936069 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)carbamate N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 628 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1 -((4-fluorophenyl)methyl)-2-hydroxypropyl)-2- 514 0.010499 (methyloxy)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 629 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1 -((4-fluorophenyl)methyl)-2-hydroxypropyl)-2- 502 0.012573 fluoroacetamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 630 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.036373 yl)amino)- 1-(( 4 -fluorophenyl)methyl)-2-hydroxypropyl)-2,2- 5. difluoroacetamide WO 2007/061670 PCT/US2006/044058 - 199 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 631 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 538 yl)amino)- I -((4-fluorophenyl)methyl)-2-hydroxypropyl)- 0.05701 2,2,2-trifluoroacetamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimetylpropyl)-3',4' 632 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 552 0.30775 yl)amino)- 1 -((4-fluorophenyl)methyl)-2-hydroxypropyl) 3,3,3-trifluoropropanamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 633 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 528 0.017117 yl)amino)-1 -((4-fluorophenyl)methyl)-2-hydroxypropyl)-3 (methyloxy)propanamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 634 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 473.3 0.014226 yl)amino)-2-hydroxy-1 -(1,3-thiazol-4 ylmethyl)propyl)acetamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 635 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 467.3 0.003044 yl)amino)-2-hydroxy- 1 -(4-pyridinylmethyl)propyl)acetamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 636 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 5153 yl)amino)-2-hydroxy- 1 -((2-propyl-1,3-thiazol-4- 0.01464 yl)metbyl)propyl)acetamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 637 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 515.3 0.92]516 yl)amino)-2-hydroxy- 1 -((5-propyl- 1,3-tbiazol-4 yl)methyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 200 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 638 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 473.3 0.002316 yl)amino)-2-hydroxy-1-(1,3-thiazol-5 ylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 639 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin}-4'- 487.3 0.023717 yl)amino)-2-bydroxy-1-((2-methyl-1,3-thiazol-4 yl)methyl)propyl)acetamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 640 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 481.3 0.009886 yl)amino)-2-bydroxy-1-((2-methyl-4 pyridinyl)methyl)propyl)acetamide N-((1 S,2R)- 1-((4-chloro-1,3-thiazol-2-yl)methyl)-3-(((4'S) 641 6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 507.3 0.00682 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((l S,2R)-1 -((2-chloro-4-pyridinyl)methyl)-3-(((4'S)-6' 642 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 501.3 0.003369 pyrano[2,3-b~pyridin]-4'-yl)amino)-2hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 643 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 497.4 0.006793 yl)amino)-2-hydroxy- 1-((2-(methyloxy)-4 pyridinyl)methyl)propyl)acetamide N-((I S,2R)- 1-((2-chloro-6-methyl-4-pyridinyl)methyl)-3 644 (((4'S)-6'-(2,2-dimethylpropyl)-3',4'- 515.3 0.006321 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 201 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 645 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxy- 1 -((2-((2,2,2-trifluoroethyl)oxy)-4- 565.3 0.005164 pyridinyl)methyl)propyl)acetamide N-((1S,2R)-1-(1-benzofuran-2-ylmethyl)-3-(((4'S)-6'-(2,2 646 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 506.3 0.052887 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 647 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 536.3 0.152163 yl)amino)-2-hydroxy- 1 -((2-(trifluoromethyl)-4 pyrimidinyl)metbyl)propyl)acetamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 648 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 534.3 0.189329 . yl)amino)-2-hydroxy- 1-((4 (trifluoromethyl)phenyl)methyl)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 649 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin-4'- 497.3 0.030021 yl)amino)-2-hydroxy- 1 -((1-methyl-2-oxo- 1,2-dihydro-4 pyridinyl)methyl)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2-cyano-2-methylpropyl)-3',4' 650 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 495.3 0.020206 yl)amino)- 1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)- 3

-(((

4 'S)-6'-(2-cyano-2-methylpropyl)-3',4' 651 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 495.2 0.004239 yl)amino)-1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 202 N-((I S,2R)-3-(((4'S)-6'-(3,3-difluoro-2,2-dimethylpropyl) 652 3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 502.2 0.00784 yl)amino)-2-hydroxy- 1-(phenylmethyl)propyl)acetamide N-((I S,2R)-3-(((4S)-2-ethyl-4,7-dihydro-5H-spiro[ 1 653 benzothiophene-6, 1'-cyclobutan]-4-yl)amino)-2-hydroxy- I - 427.2 0.126989 (phenylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4S)-2-(2,2-dimethylpropyl)-6,6-dimethyl 654 4,5,6,7-tetrahydro- I -benzothien-4-yl)amino)-2-hydroxy- 1- 457.2 0.01385 (phenylmethyl)propyl)acetamide methyl ((I S,2R)-3-(((4S)-2-(2,2-dimethylpropyl)-6,6 655 dimethyl-4,5,6,7-tetrahydro- I -benzothien-4-yl)amino)-2- 473.2 0.104522 hydroxy- 1 -(phenylmethyl)propyl)carbamate N-((I S,2R)- 1-((3,5-difluorophenyl)methyl)-3-(((3 S,4'R)-6' (2,2-dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 656 hydroxypropyl)acetamide N-((1S,2R)-1-((3,5- 518.2 0.041264 difluorophenyl)methyl)-3-(((3R,4'R)-6'-(2,2 dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1 -((3,5-difluorophenyl)methyl)-3-(((3S,4'S)-6'

(

2

,

2 -dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 657 hydroxypropyl)acetamide N-((IS,2R)-1-((3,5- 518.2 0.002512 difluorophenyl)methyl)-3-(((3R,4'S)-6'-(2,2 dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 203 N-((1 S,2R)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl)-3'4,4',5 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1-((4-fluorophenyl)methyl)-2 658 hydroxypropyl)acetamide N-((1 S,2R)-3- 500.2 0.020173 (((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4,5 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-1 -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 659 dimethylpropyl)-7'-fluoro-3',4'-dihydrospiro[cyclobutane- 520.2 0.006422 1,2'-pyrano[2,3-blpyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 tetrahydrospiro[firan-3,2'-pyrano[2,3-b]pyridin]-4' yl)amino)- 1 -((3-fluorophenyl)methyl)-2 660 hydroxypropyl)acetamide N-((1S,2R)-3- 500.2 0.003621 (((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4' 661 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2 0.010152 yl)amino)-1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4' 662 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2 0.094665 yl)amino)- 1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 204 N-((1S,2R)-1-((4-chlorophenyl)methyl)-3-(((3S,4'S)-6-(2,2 dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 663 hydroxypropyl)acetamide N-((I S,2R)- 1 -((4- 516.2 0.099545 chlorophenyl)methyl)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl) 3',4,4',5-tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)- 1 -((4-chlorophenyl)methyl)-3-(((3 S,4'R)-6'-(2,2 dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2 664 hydroxypropyl)acetamide N-((l S,2R)- 1-((4- 516.2 TBD chlorophenyl)methyl)-3-(((3R,4'R)-6'-(2,2-dimethylpropyl) 3',4,4',5-tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 665 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514.2 0.00853 yl)amino)-1 -((3-fluoro-4-(methyloxy)phenyl)metbyl)-2 hydroxypropyl)acetamide N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 666 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514.2 0.16163 yl)amino)-I-((3-fluoro-4-(methyloxy)phenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1 -((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2 667 dimethylpropyl)-7'-fluoro-3',4'-dihydrospiro[cyclobutane- 518.2 0.384736 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 205 N-((1R,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane-l,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-1-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2 668 hydroxypropyl)acetamide N-((1S,2R)- 552.2 0.156196 3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)- 1 -((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2 hydroxypropyl)acetamide N-((l S,2R)- I -((4-chlorophenyl)methyl)-3-(((3S,4'S)-6'-(2,2 669 dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2'- 516.2 10 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- I -((4-chlorophenyl)methyl)-3-(((3R,4'S)-6'-(2,2 670 dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2'- 516.2 0.051785 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 671 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'- 500.2 0.020468 yl)amino)-1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5 672 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'- 500.2 0.023752 yl)am ino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 206 N-((IS,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-((1R)-1 fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 673 hydroxypropyl)acetamide N ((1 S,2R)- 1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-((1 S)- 1- 518.2 0.05856 fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-((1 S)- 1-fluoro-2,2-dimethylpropyl) 674 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2 1.081474 yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-((1 R)- 1-fluoro-2,2-dimethylpropyl) 675 3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 502.2 0.012112 yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 676 dihydrospiro[cyclobutane- t,2'-pyrano[2,3-b]pyridin]-4'- 552.2 0.018142 yl)amino)- 1-((4-fluoro-3-(trifluoromethyl)phenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-1-((2,3-difluorophenyl)methyl)-3-(((4'S)-6' 677 ((1 R)- 1-fluoro-2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 520.2 0.008608 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-((1 R)- 1-fluoro-2,2-dimethylpropyl) 678 3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 502.2 0.002069 yl)amino)-1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 207 N-((1 S,2R)-3-(((4'S)-6'-((IR)- 1-fluoro-2,2-dimethylpropyl) 679 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 484.3 0.006045 yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-((1R)- 1 680 fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 518.2 0.023122 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1S,2R)-1 -((3,5-difluorophenyl)methyl)-3-(((4'S)-6' 681 ((1R)- 1-fluoro-2,2-dimethylpropyl)-3',4'- 520.3 0.003463 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide N-((] S,2R)-3-(((4'S)-6'-(cyclobutylmethyl)-3',4' 682 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 482.2 yl)amino)- I -((4-fluorophenyl)methyl)-2- 0.066452 hydroxypropyl)acetamide N-((1 S,2R)-3-(((5R,5aS)-3-(2,2-dimethylpropyl)-5a,6,7,8 683 tetrahydro-5H-pyrrolo[1',2':1,5]pyrrolo[2,3-b]pyridin-5- 469 0.523798 yl)amino)- 1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((I S,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S) 684 6'-(1 -hydroxypentyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 522 2.86427 pyrano[ 2 ,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 685 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.009279 yl)amino)-2-hydroxy- 1 -((2,4,5 trifluorophenyl)methyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 208 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 686 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.007068 yI)amino)-2-hydroxy- 1 -((3,4,5 trifluorophenyl)methyl)propyl)acetamide N-((l S,2R)-3-(((4'S)-6'-(cyclopropylmethyl).3',4' 687 dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridinj-4'- 486 0.007837 yl)amino)- 1-((3 ,5-difluorophenyl)methyl).2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4R)-6-bromo-2,2-dimethyl. 1,2,3,4 tetrahydro-4-quinolinyl)amino)-2-hydroxy 1 688 (phenylmethyl)propyl)acetamide N-(( 1S,2R)-3-(((4S)-6- 461 0.230897 bromo-2,2-dimethyl-1 ,2,3,4-tetrahydro-4-quinolinyl)amino) 2-hydroxy. 1 -(phenylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4R)-6-(2,2-dimethylpropyl)-2,2-dimethyl. 1 , 2 ,3,4-tetrahydro-4-quinolinyl)amino)-2hydroxy- 1 689 (phenylmethyl)propyl)acetamide N-((I S,2R)-3-(((4S)-6- 452 0.072801 (2,2-dimethylpropyl)-2,2-dimethyl. I,2,3,4-tetrahydro-4 quinolinyl)amino)-2-hydroxy- I (phenymethyl)propyl)acetamide N-((1 S,2R)-3-(((4R)- 1-acetyl-6-bromo-2,2-dimethyl- 1,2,3,4 tetrabydro-4-quinolinyl)amino)-2-hydroxy- 690 (phenylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4S)- - 503 0.873045 acetyl-6-bromo-2,2-dimethyl- 1,2,3,4-tetrahydro-4 quinolinyl)amino)-2-hydroxy- 1 (phenylmethyl)propyl)acetamide N-(( I S,2R)- 1 -((3,5-difluorophenyl)niethyl)-3-((Q4'S)-6'-(2 691 ethylbutyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 516 0.095804 blpyridin]- 41 -yI)amino)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 209 692 1 ,2,3,4-tetrahydro-4-quinolinyI)amino)-2-hydroxy-. - 452 0.03 0558 (phenylmethyl)propyl)acetamide N-((1 S,2R)-lI-((3,5-difluorophenyI)methyI)-3-(((4S)-6-(2,2 693 dimethylpropyl)-2,2-dimethyl- I ,2,3,4-tetrahydro-4- 488 0.005491 quinolinyl)amino)-2-hydroxypropyI)acetamide N-((1 S,2R)- I-((4-fluorophenyI)nethyl)-2.hydroxy.3.(((4'S). 694 6'-propyl-3 ,4'-dihydrospiro[cyclobutane- l,2'-pyrano[2,3 - 456 0.03 7222 blpyridin]-4'-yI)amino)propyl)acetamide N-((1 S,2R)- I-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S.. 695 ' 6

-((

2 S)-2-methylbutyl)-3',4'-dihydrospiro[cycobutane.1,2' 484 0.043378 pyrano[ 2 ,3-b]pyridiri]-4'-yl)amino)propyl)acetamide N-(( IS,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S). 696 6'-(2-methyl- I-propen- I -yI)-3',4'-dihydrospiro[cyclobutane- 468 0.253945 I , 2 '-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((l 1 R--(4S-6-22dmtyprpny)3,' 697 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.276687 yI)amino)- I -((4-fluorophenyl)i-netl)-2 hydroxypropyl)acetamide 2-azido-N-((1S,2R)-3-(((4S)6.bromo3,4 698 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)-2- 514.7 2.377589 hydroxy- 1 -(phenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 210 N-((l S,2R)- 1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4'S) 699 6'-(trifluoromethyl)-3 ',4'-dihydrospiro[cyclobutane- 1,21- 488.8 0.848676 pyrano[2,3-b]pyridin]-4'-ylamino)propyl)acetamide N-((1 S,2R)- I-((3,5-difluorophenyl)methyl)-2-hydroxy-3 700 ((( 4 1 S)-6'-(trifluorometbyl)-3',4'-dihydrospiro[cyclobutane. 499.8 1.199997 I , 2 '-pyrano[ 2 ,3-bljpyridinl-4'-yl)amino)propyl)acetamide N-((1 S,2R)- I-((3,4-difluorophenyl)methyl)-3 -(((4'S)-6-(2,2-. 701 dimethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- 1,2'- 501.9 0.0023 56 pyrano[2,3-b]pyridin]-4'-y)amino).2 hydroxypropyl)acetamide N-((1 S,2R)- I -((3-chloropbenyl)methyl)-3-(((4'S)-6'.(2,2 702 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 4990.001238 pyrano[2,3 -b]pyridin]-4'-yl)amino)-2 hydraxypropyl)acetamide N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethypropyl)-3',4'. 703 dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'- 483.9 0.005085 yI)amino)- 1 -((2-fluorophenyl)metbyl)-2 hydroxypropyl)acetamide N-(( I S,2R)- I -((2,4-difluorophenyl)methyl)-3-(((4'S).6'-(2,2.. 704 d imethylpropyl)-3',4'-dihydrospiro[cyclobutane-.1,2'- 502.2 0.018443 pyrano[2,3-b]pyridin..4'.yl)amino)-2 hydroxypropyl)acetamide N-((1 S)- 1 -((1 R)-2-(((4'S)-6-(2,2-dimethylpropyl)-3',4'. 705 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 428.2 0.432865 yI)amino)-1I -hydroxyethyl)-3-pentyn- I -yl)acetamide WO 2007/061670 PCT/US2006/044058 - 211 N-((1S,2R)-1-((3-chloro-4-fluorophenyl)methyl)-3-(((4'S)-6' 706 ( 2

,

2 -dimethylpropyl)-3',4'-dihydrospiro[cyclobutane.12'- 517.8 0.003113 pyrano[2,3-b]pyridin]-4'-yl)amino)-2-50 hydroxypropyl)acetamide N-((1S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2 707 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 0.012555 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((IS,2R)-I-((2-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2 708 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 0.023419 pyrano[2,3-b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide N-((IS,2R)-1-((3-(dimethylamino)-4-fluorophenyl)methyl) 709 3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'- 526.9 0.008013 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 710 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 526.9 0.004251 yl)amino)- I -((3-(ethylamino)-4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-1 -((3,4-dichlorophenyl)mnethyl)-3-(((4'S)-6'-(2,2 711 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 533.8 0.029584 pyrano[2,3-blpyridin]-4'-yl)amino)-2-5 hydroxypropyl)acetamide N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 712 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 549.8 0.064957 yl)amino)-2-hydroxy- 1 -((4 ((trifluoromethyl)oxy)phenyl)methyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 212 N-((1 S,2R)-1-((3-chloro-4-fluorophenyl)methyl)-3 713 (((1 s,3R,4'S)-6'-(2,2-dimethylpropyl)-3 -methyl-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4- 532.2 0.015499 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-1 -((4-chlorophenyl)methyl)-3-(((1s,3R,4'S)-6' 714 (2,2-dimethylpropyl)-3-methyl-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514.2 0.026711 yl)amino)-2-hydroxypropyl)acetamide N-((1 S)-1-((IR)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 715 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 429.9 0.040837 yl)amino)-1-hydroxyethyl)-4-penten-1 -yl)acetamide N-((1 S,2R)- 1-(( 4 -chloro-3-(trifluoromethyl)phenyl)methyl) 716 3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane-I,2'-pyrano[2,3-b]pyridin]-4'- 567.8 0.023342 yl)amino)-2-hydroxypropyl)acetamide N-((1 S)- 1-((1 R)-2-(((1 s,3R,4'S)-6'-(2,2-dimethylpropyl)-3 ,7 , methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3 b]pyridin]-4'-yl)amino)-1-hydroxyethyl)-4-penten- 1- 0.052462 yl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 718 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3 -b]pyridin]-4'- 533.9 0.003985 yl)amino)-2-hydroxy- 1 -((3 (trifluoromethyl)phenyl)methyl)propyl)acetamide N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4' 719 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 519.9 0.009351 yl)amino)-I-((3 (trifluoromethyl)phenyl)methyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 213 N-((IS,2R)-1-((4-chloro-3-fluorophenyl)methyl)-3-(((4'S)-6' 720 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 517.8 0.008567 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1S,2R)-1-((4-chloro-3-(methyloxy)phenyl)methyl)-3 721 (((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 530.2 0.021395 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)- 1 -(cyclopropylmethyl)-3-(((4'S)-6'-(2,2 722 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 430.2 0.046453 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 723 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 4443 0.194643 yl)amino)-2-hydroxy- 1 -((2 methylcyclopropyl)methyl)propyl)acetamide N-((l S,2R)- 1-(cyclopropylmethyl)-3-(((4'S)-6'-(4,4-difluoro 724 2,2-dimethylbutyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 480.2 0.183543 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((I S,2R)- 1 -(cyclopropyimethyl)-3-(((1 s,3R,4'S)-6'-(2,2 725 dimethylpropyl)-3-methyl-3',4'-dihydrospiro[cyclobutane- 444.2 0.068761 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1 -((2-((difluoromethyl)oxy)-4 726 pyridinyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'- 533.2 0.009724 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 214 N-I -((1 S,2R)-3-(((4S)-6-bromo-3,4 727 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1-((3- 541 0.300311 cyanophenyl)methyl)-2-hydroxypropyl)-N~2~,N~2~-5 dimethylglycinamide methyl (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-3-((N,N 728 dimethylglycyl)amino)-2-hydroxybutyl)amino)-3,4- 521 0.043943 dihydrospiro[chromene-2, 1'-cyclobutane]-6-carboxylate methyl (4S)-4-(((2R,3S)-3-(acetylamino)-4-(3-cyanophenyl) 729 2 -hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2, 1'- 478 1.449592 cyclobutane]-6-carboxylate methyl (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-2-hydroxy-3 730 (((methyloxy)acetyl)amino)butyl)amino)-3,4- 508 1.018648 dihydrospiro[chromene-2, 1'-cyclobutane]-6-carboxylate N-((1S, 2 R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 731 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1- 377 2.52388 ((methyloxy)methyl)propyl)acetamide N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 732 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1- 405 3.263952 ((propyloxy)methyl)propyl)acetamide N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene 733 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- 1- 453 10 (((phenylmethyl)oxy)methyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 215 N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospirofchromene. 734 2,1 '-cyclobutan]-4-yI)amino)-2-hydroxy- 1-(lH-pyrazol-1- 413 5.365972 ylmethyl)propyl)acetamide 735 dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-bjpyridin] -4- 478 10 yl)amino)-2-hydroxy-1-(IH-pyrazol- I1 ylmethyl)propyl)acetamide N-((1 S)- 1-((lI R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 736 dibydrospiro[cyclobutane- I ,2'-pyrano[2,3-bjpyridin]-4'- 416 0.03402 yl)amino)- I -hydroxyethyl)-3-buten- 1 -yl)acetamide N-((] S)- I -((1 S)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 737 dihydrospirolcyclobutane- 1 ,2'-pyrano[2,3-b]pyridin]-4'- 416 10 yl)arnino)- 1 -hydroxyethyl)-3-buten-1 -yI)acetamide N-((1 S)- I -((1R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'. 738 dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridinj-4'- 472 1.420952 yJ)amino)- I -hydroxyethyl).4,4,4-trifluorobutyl)acetamide N-((1 S,3E)- 1 -((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)..3',4'. 739 dihydrospiro[cyclobutane-1,2'-pyrano[2,3.b~pyridiDI-4' 430 0.298128 yI)amino)- 1-hydroxyethyl)-3-penten- I -yl)acetamide N-((1 S)- 1 -((I R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3,4'. 740 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-bjpyridin]-4'- 402 3.33333 yI)amino)- I -hydroxyethyl)-2-propen- I -yl)acetamide WO 2007/061670 PCT/US2006/044058 - 216 N-((1S)-1-((lR)-2-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4' 741 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 420 0.193221 yl)amino)-1-hydroxyethyl)-3-buten-1-yl)acetamide N-((1S)-1-((1R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 742 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 442 0.285911 yl)amino)-1-hydroxyethyl)-3-hexyn-1-yl)acetamide N-((1 S,2R)-3-(((2S,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5' tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)- 1 -((3,5 743 difluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((2R,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5'- 566.1 0.302172 tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-1 -((3,5 difluorophenyl)methyl)-2-hydroxypropyl)acetamide 744 N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4- 546.3 0.005722 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2 hydroxy- I -(phenylmethyl)propyl)-2-(IH-2-methyl-imidazol 1-yl) acetamide N-((1 S,2R)-3-(((4'S)-6'-bromo-3',4' 745 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 510.0; 512.0 0.033121 yl)amino)-I-((3,5-difluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((I S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 746 (((4'S)-6'-(1 H-pyrazol- I -yl)-3', 4 '-dihydrospiro[cyclobutane- 498.1 0.214725 1, 2 '-pyrano[ 2

,

3 -b]pyridin]-4'-yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 217 N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 747 (((4'S)-6'-(1H-imidazol-1-yl)-3',4'-dihydrospiro[cyclobutane- 498.2 0.497891 1, 2 '-pyrano[2,3-b]pyridin]-4'-yl)amino)propyI)acetamide N-((IS,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 748 (((4'S)-6'-(1,3-thiazol-2-yl)-3',4'-dihydrospiro[cyclobutane- 515.1 1.051834 1, 2 '-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 749 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 466.2 0.013955 yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide N-((1 S,2R)- 1 -((3 -chloro-5-fluorophenyl)methyl)-3-(((4'S)-6' 750 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 518.2 0.020286 pyrano[2,3-c]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-2-hydroxy 751 3-(((4'S)-6'-(2-hydroxy-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 520.2 0.038775 yl)amino)propyl)acetamide N-((1S,2R)-3-(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4' 752 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 552.1 0.042155 yl)amino)- 1 -((3 -chloro-5-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((IS,2R)-3-(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4' 753 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-clpyridin]-4'- 500.2 0.01375 yl)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 218 N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(4 754 morpholinyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 551.3 0.052212 c]pyridin]-4'-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(1 755 pyrrolidinyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 535.3 0.006495 c]pyridin]-4'-yl)amino)-2-hydroxy-1 (phenylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4S)-8-(dimethylamino)-6-(2,2 756 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3 c]pyridin-4-yl)amino)-1 -((3-(dimethylamino)-5- 0.199655 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((l S,2R)-1 -((3-chloro-5-fluorophenyl)methyl)-3-(((4S)-8 757 (dimethylamino)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4- 549.2 0.068949 dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-1 -((3,4-difluorophenyl)methyl)-3-(((4S)-6-(2,2 758 dimethylpropyl)-2,2-dimethyl-8-(1-pyrrolidinyl)-3,4 dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2- 559.3 0.040129 hydroxypropyl)acetamide N-((1 S,2R)- 1-((3-(dimethylamino)-5-fluoropbenyl)methyl) 759 3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 527.3 0.017872 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)- 1-((3,4-difluorophenyl)methyl)-3-(((4S)-6-(2,2 760 dimethylpropyl)-2,2-dimethyl-8-(methylamino)-3,4-dihydro- 519.2 0.011255 2H-pyrano[2,3-c]pyridin-4-yl)amino)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 219 N-((1S,2R)-3-(((4S)-8-chloro-6-(2,2-dimethylpropyl)-2,2 761 dimethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)- 506.2 0.126221 1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4S)-8-(dimethylamino)-6-(2,2 762 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 515.3 0.165675 c]pyridin-4-yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1S,2R)-I-((3-bromo-5-fluorophenyl)methyl)-3-(((4'S) 763 6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 562.1; 564.1 0.006487 pyrano[2,3-b]pyridinJ-4'-yl)amino)-2 hydroxypropyl)acetamide N-((IS,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 764 dimethylpropyl)-3-methyl-3',4'-dihydrospiro[cyclobutane- 516.2 0.001554 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((IS,2R)-1-((3,5-difluorophenyl)methyl)-3-(((1s,3R,4'S) 765 6'-(2,2-dimethylpropyl)-3-methyl-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 516.2 0.001138 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4' 766 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 498.2 0.015805 yl)amino)-1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((I S,2R)-3-(((1s,3R,4'S)-6'-(2,2-dimethylpropyl)-3 767 methyl-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3- 498.2 0.005703 b]pyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 220 N-(( IS,2R)-I-((2,3-difluorophenyl)methyl)-3-(((1r,3S,4'S) 768 6'-(2,2-dimethylpropyl)-3-methyl-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-blpyridin]-4'- 516 0.03889 yl)amino)-2-hydroxypropyl)acetamide N-((l S,2R)- 1 -((2,3-difluoropheny1)methyl)-3 -(((1 s,3R,4'S) 769 6'-(2,2-dimethylpropyl)-3-methyl-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 516 0.033758 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((1 s,3R,4'S)-6'-(2,2-dimnethylpropyl)-3 770 methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 498.2 0.002464 b]pyridin]-4'-yl)amino)-I-((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4S)-6-(cyclopentylamino)-3,4 771 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2- 478.3 0.165691 hydroxy- 1 -(phenylmethyl)propyl)acetamide N-((I S,2R)-3-(((4S)-6-((1,1-dimethylethyl)amino)-3,4 772 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2- 466.3 0.980967 hydroxy- 1-(phenylmethyl)propyl)acetamide N-((1 S,2R)-3-(((4S)-6-chloro-8-(1 H-imidazol- 1-yl)-3,4 773 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)- 1- 532.2 0.021949 ((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene 774 2,1 '-cyclobutan]-4-yl)amino)- 1-((3,5- 510.2 0.088192 difluorophenyl)methyl)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 221 N-((l S,2R)-3-(((4S)-8-(1 H-benzimidazol- 1 -yl)-6-chloro-3,4 775 dihydrospiro[chromene-2,1'-cyclobutan]-4-y1)amino)-1- 582.2 0.212243 ((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4S)-6-chloro-8-(11-pyrazol-1-yl)-3,4 776 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1- 532.2 0.124289 ((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3 777 (((4S)-6-(l H-pyrazol- 1 -yI)-3,4-dihydrospirochromene-2, 1'- 497.2 0.041157 cyclobutan]-4-yl)amino)propyl)acetamide N-((I S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4S)-6-(2 778 thienyl)-3,4-dihydrospiro[chromene-2, '-cyclobutan]-4- 477.2 0.083329 yl)amino)propyl)acetamide N-((1S,2R)-2-hydroxy-3-(((4S)-6-(1-(2-methylpropyl)-1

H

779 pyrazol-3-yl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 517.3 0.190194 yl)amino)- 1 -(phenylmethyl)propyl)acetamide N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3 780 (((4S)-6-(1-(2-methylpropyl)- IH-pyrazol-3-yl)-3,4- 553.3 1.652355 dihydrospiro[chromene-2, 1'-cyclobutan]-4 yl)amino)propyl)acetamide N-((1 S,2S)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3 781 (((4S)-6-(1H-pyrazol- 1 -yl)-3,4-dihydrospiro[chromene-2, '- 497.2 1.158731 cyclobutan]-4-yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 222 N-((1S,2R)- 1-((3 ,5-difluorophenyl)methyl)-2-hydroxy-3 782 (((4S)-6-(1 H-iniidazol-1-y])-3,4-dihydrospiro[chromene-2, 1'- 497.2 0.081605 cyclobutan]-4-yl)amino)propyl)acetamide N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(1 -methyl-i H-pyrazol-3 783 yl)-3,4-dihydrospirotchromene-2, 1'-cyclobutan] -4- 475.3 3.244922 yl)amino)-l -(phenylmethyi)propyl)acetamide N-((] S,2R}. 1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 784 (((4S)-6-(1-methyl- 1 H-pyrazol-3-yi)-3,4- 5131642 dihydrospiro[chromene-2, I'-cyclobutan]-4- 5131642 yl)amino)propyl)acetamide N-(( 1 S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3 785 (((4S)-6-(2-thienyl)-3,4-dihydrospiro[chromene-2, V~- 513.3 2.967655 cyclobutan]-4-yI)amino)propyl)acetamide N-(( I S,2S)-3-(((4S)-6-chloro-8-(l H-pyrazol- l-yl)-3, 4 786 dihydrospirotchromene-2, 1'-cyclobutan]-4-yI)amino)- 1 - 532.2 1.367329 ((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4S)-7-bromo-3,4-dihydrospiro[chomene. 787 2,1 '-cyclobutan]-4-yI)amino)- 1 -((3,5- 510.1 10 difluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-1 -((3 ,5-difluorophenyl)metliyl)-2-hydroxy-3 788 (((4S)-7-(1 H-imidazol- I -yl)-3,4-dihydrospiro[chromene-2, 1V- 497.2 cyclobutan]-4-yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 223 N-((4S)-4-(((2R,3S)-3-(acetylamino)-4-(3,5-difluorophenyl) 789 2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2, 1'- 488.2 0.017688 cyclobutan]-6-yl)acetamide N-((1 S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3 790 (((4S)-6-((3R)-tetrahydro-3-furanylamino)-3,4- 516.3 0.05852 dihydrospiro[chromene-2, I-cyclobutan]-4 yl)amino)propyl)acetamide N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3 791 (((4S)-6-(2H- 1,2,3-triazol-2-yl)-3,4-dihydrospiro[chromene- 498.3 0.803182 2,1 '-cyclobutan]-4-yl)amino)propyl)acetamide N-((1 S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3 792 (((4S)-6-(1 H- 1,2,4-triazol- I -yl)-3,4-dihydrospiro[chromene- 498.3 0.137058 2,1 '-cyclobutan]-4-yl)amino)propyl)acetamide N-((I S,2R)- 1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 793 (((4S)-6-(2-oxo-I-pyrrolidinyl)-3,4-dihydrospiro[chromene- 514.2 0.358885 2,1 '-cyclobutan]-4-yl)amino)propyl)acetamide N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl 794 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2- 454.3 0.034817 hydroxy- I -(phenylmethyl)propyl)acetamide N-((I S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 795 (((4S)-6-(2-oxo- I -azetidinyl)-3,4-dihydrospiro[chromene- 500.2 0.255326 2, 1'-cyclobutan]-4-yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 224 N-((1S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-3-(((4S)-6 796 (2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H- 507.3 0.008388 pyrano[2,3-c]pyridin-4-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-3-(((4S)-6 797 (2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H- 521.3 0.01127 pyrano[2,3-c]pyridin-4-yl)amino)-2 hydroxypropyl)propanamide N-((1S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl 798 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)--1 -((3- 472.3 0.006725 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl 799 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-1 -((4- 472.3 0.045368 fluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4S)-6-(2,2 800 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 490.3 0.003558 c]pyridin-4-yl)amino)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4S)-6-bromo-7-fluoro-3,4 801 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1- 528.1 0.570646 ((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide N-((I S,2R)-3-(((4S)-6-bromo-7-fluoro-2,2-dimethyl-3,4. 802 dihydro-2H-chromen-4-yl)amino)- 1-((3,5- 516.1 0.525381 difluorophenyl)methyl)-2-hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 225 N-((1 S,2R)- 1 -((3,5-difluorophenyl)methyl)-3-(((4S)-7 803 fluoro-6-((3R)-tetrahydro-3-furanylamino)-3,4 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2- 0.115798 hydroxypropyl)acetamide N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4S)-7 804 fluoro-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4- 449.2 2.952856 yl)amino)-2-hydroxypropyl)acetamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 805 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 583.4 0.005137 yl)amino)- 1-((3-fluoro-5-(tetrahydro-2H-pyran-4 ylamino)phenyl)methyl)-2-hydroxypropyl)acetamide N-((I S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4S)-7 806 fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-3,4-5 dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2- 548.3 0.451865 hydroxypropyl)acetamide N-((1S,2R)-1-((3-fluorophenyl)methyl)-3-(((4S)-7-fluoro-6 807 (IH-pyrazol-1-yl)-3,4-dihydrospiro[chromene-2,1'- 497.2 0.48859 cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)- I -((4-fluorophenyl)methyl)-3-(((4S)-7-fluoro-6 808 (1 H-pyrazol- 1 -yI)-3,4-dihydrospiro[chromene-2, 1'- 497.2 1.94044 cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide N-((I S,2R)- 1 -(cyclobutylmethyI)-3-(((4'S)-6'-(2,2 809 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 0.078673 pyrano[2,3-blpyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 226 N-((I S,2R)- I -((2-bromophenyl)methyl)-3-(((4'S)-6'-(2,2 810 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 545.2 0.197405 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((IS,2R)-I-((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6' 811 ((1 R)- 1-fluoro-2,2-dimethylpropyl)-3',4'- 5372 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-5 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((2R,4S)-1'-acetyl-6-ethyl-3,4 dihydrospiro[chromene-2,3'-pyrrolidin]-4-yl)amino)-2 812 hydroxy-1-(phenylmethyl)propyl)acetamide N- 1.948759 ((1 S,2R)-3-(((2S,4S)-1'-acetyl-6-ethyl-3,4 dihydrospiro[chromene-2,3'-pyrrolidin]-4-yl)amino)-2 hydroxy- 1 -(phenylmetbyl)propyl)acetamide N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 813 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin-4'- 520 0.100123 yl)amino)-2-hydroxy- 1 -((2,4,6 trifluorophenyl)methyl)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 814 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.056329 yl)amino)-2-hydroxy- 1 -((2,3,4 trifluorophenyl)methyl)propyl)acetamide N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4' 815 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 506 0.224171 yl)amino)- I -((2,4,6-trifluorophenyl)methyl)propyl)acetamide N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4' 816 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 506 0.137486 yl)amino)-1 -((2,3,4-trifluorophenyl)methyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 -227 N-((1 S,2R)-1-((4-chlorophenyl)methy1)-3-(((4'S)-6'-(2,2 817 dimethypropyl)-3',4'-dihydrospiro[cyclopentane-1,2'- 515 0.131569 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1S,2R)-1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S) 818 6'-(phenylmethyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 504 1.80048 pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((I S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4S)-6-((2R) tetrahydro-2-furanyl)-3,4-dihydrospiro[chromene-2, 1' 819 cyclobutan]-4-yl)amino)propyl)acetamide 465 0.160704 N-((l S,2R)-2-hydroxy-1 -(phenylmethyl)-3-(((4S)-6-((2S) tetrahydro-2-furanyl)-3,4-dihydrospiro[chromene-2,

'

cyclobutan]-4-yl)amino)propyl)acetamide N-((1S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4'S)-6'-((2R) tetrahydro-2-furanylmethyl)-3',4'-dihydrospiro[cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)- 2 820 (methyloxy)acetamide N-((l S,2R)-2- 510 0.098566 hydroxy- 1 -(phenylmethyl)-3 -(((4'S)-6'-((2S)-tetrahydro-2 furanylmethyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)-2 (methyloxy)acetamide N-((1 S,2R)-2-hydroxy-1 -(phenylmethyl)-3-(((4S)-6-((2S) tetrahydro-2-furanylmethyl)-3,4-dihydrospiro[chromene 821 2,1 '-cyclobutan)-4-yl)amino)propyl)acetamide 479 0.104947 N-((1 S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4S)-6-((2R) tetrahydro-2-furanylnethyl)-3,4-dihydrospiro[chromene 2,1'-cyclobutan]-4-yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 228 N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(5-hydroxypentyl)-3,4 822 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1- 481 0.066235 (phenylmethyl)propyl)acetamide N-((2S,3R)-3-hydroxy-4-((S)-6-isopropoxy-2,2 823 spirocyclobutyl-chroman-4-ylamino)- 1 -phenylbutan-2- 453 0.310061 yl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 824 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 467 0.002325 yl)amino)-2-hydroxy- 1 -(3-pyridinylmethyl)propyl)acetamide N-((1 S,2R)-1 -((2,3-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 825 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 502 0.004339 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- I -((2,6-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 826 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 502 0.006934 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4' 827 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'- 488 0.025843 yl)amino)-1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2 828 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 504 0.07843 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 229 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 829 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 487 2.629707 yl)amino)-2-hydroxy-1-((1 -methyl-3 piperidinyl)methyl)propyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 830 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)- 1-((5-fluoro-3-pyridinyl)methyl)-2- 485 0.001825 hydroxypropyl)acetamide N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 831 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)- 1-((5-fluoro-3-pyridinyl)methyl)-2- 485 0.166762 hydroxypropyl)acetamide N-((1 S,2R)-l -((3,4-bis(methyloxy)phenyl)methyl)-3-(((4'S) 832 6 '-(2, 2 -dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 526 0.009283 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1-((2,3-difluorophenyl)methyl)-3-(((4'S)-6'-(2 833 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 506 0.031005 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-1 -((3-bromo-4-fluorophenyl)methyl)-3-(((4'S) 834 6

'-(

2 -fluoro- 2 -methylpropyl)-3',4'-dihydrospiro[cyclobutane- 566 0.009305 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2 835 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 506 0.002048 pyrano[2,3-b]pyridin]-4'-yl)amino)-2-5 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 230 N-((1S,2R)-1-((3-chloro-4-fluorophenyl)methyl)-3-(((4'S)-6' 836 (2-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 522 0.01471 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6' 837 (2-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 522 0.003578 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4' 838 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 538 0.013298 yl)amino)-2-hydroxy- 1 -((3 (trifluoromethyl)phenyl)methyl)propyl)acetamide N-((1 S,2R)- 1 -(1,3-benzodioxol-5-ylmethyl)-3-(((4'S)-6'-(2,2 839 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 510 0.005492 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1 -(1,3-benzodioxol-5-ylmethyl)-3-(((4'S)-6'-(2 840 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 514 0.027663 pyrano[2,3-blpyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((l S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4'S)-6'-(2,2,2 841 trifluoroethyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 478.2 0.084821 pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((1S,2R)-1-((3,4-difluorophenyl)methyl)-2-hydroxy-3 842 (((4'S)-6'-(2,2,2-trifluoroethyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 514.2 0.106066 yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 231 N-((1 S,2R)-3-(((4'S)-6'-bromo-3',4' 843 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 512.2 0.503441 yl)amino)- 1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1 -((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S) 844 6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 470.2 0.003627 pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((1 S,2R)- I -((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S) 845 6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 470.2 0.011411 pyrano[ 2 ,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((l S,2R)- 1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 846 (((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 488.2 0.001722 1, 2 '-pyrano[2,3-b]pyridin}-4'-yl)amino)propyl)acetamide N-((1 S,2R)- 1-((3-chloro-5-fluorophenyl)methyl)-2-hydroxy 847 3-(((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 504.2 0.004272 1, 2 '-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide 3-((2S,3R)-2-(acetylamino)-3-hydroxy-4-(((4'S)-6'-(2 848 methylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'- 495.2 0.012834 pyrano[2,3-b]pyridin]-4'-yl)amino)butyl)benzamide N-((1 S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4'S) 849 6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 477.2 0.001259 pyrano[ 2 ,3-b]pyridin]-4'-yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 232 N-((I S,2R)- 1-((2,3-difluorophenyl)methyl)-2-hydroxy-3 850 (((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 488.2 0.008683 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((1 S,2R)- 1 -((3,4-difluorophenyl)methyl)-2-hydroxy-3 851 (((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 488.2 0.003236 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((1 S,2R)-3-(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3',4' 852 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-bjpyridin]-4'- 470.2 0.051988 yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide N-((I S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-7' 853 fluoro-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 506.2 0.011208 1,2'-pyrano[2,3-blpyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3',4' 854 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 488.2 0.151206 yl)amino)- 1-((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3',4' 855 dihydrospiro[cyclobutane- I,2'-pyrano[2,3-b]pyridin]-4'- 488.2 0.025226 yl)amino)- I -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide N-((I S,2R)-1 -((2,3-difluorophenyl)methyl)-3-(((4'S)-7' 856 fluoro-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 506.2 0.205783 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide WO 2007/061670 PCT/US2006/044058 - 233 N-((1 S,2R)- 1-((4-chloro-3-fluorophenyl)methyl)-2-hydroxy 857 3-(((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 504.2 0.026204 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((1 S,2R)- 1-((4-chlorophenyl)methyl)-2-hydroxy-3-(((4'S) 858 6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 486.2 0.052694 pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide N-((1 S,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S) 859 6'-(1,3,3,3-tetrafluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 542.2 0.148464 yl)amino)propyl)acetamide N-((I S,2R)- 1-((4-chlorophenyl)methyl)-2-hydroxy-3-(((4'S) 860 6'-(1,3,3,3-tetrafluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 558.2 0.452497 yl)amino)propyl)acetamide N-((1 S,2R)- 1 -((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S) 861 6'-(1,3,3,3-tetrafluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 542.2 0.026399 yl)amino)propyl)acetamide N-((1 S,2R)-2-hydroxy- I -(phenylmethyl)-3 -(((4'S)-6' 862 (1,3,3,3-tetrafluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 524.2 0.074055 yl)amino)propyl)acetamide N-((1 S,2R)-1 -((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S) 863 6'-(3,3,3-trifluoro-l-hydroxy-2-methylpropyl)-3',4'- 540.2 1.82816 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 234 N-((IS,2R)-1-((4-chlorophenyl)methyl)-2-hydroxy-3-(((4'S) 864 6'-(3,3,3-trifluoro-1-hydroxy-2-methylpropyl)-3',4'- 556 10 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- .510 yl)amino)propyl)acetamide N-((1 S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4'S)-6'-(3,3,3 865 trifluoro-1-hydroxy-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bpyridin]-4'- 522.2 1.93998 yl)amino)propyl)acetamide N-((1 R,2R)- 1-((3-chloro-2-fluorophenyl)methyl)-3-(((4'S) 866 6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 10 pyrano[2,3-b]pyridin}-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1-((5-chloro-2-fluorophenyl)methyl)-3-(((4'S)-6' 867 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 0.002326 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1 S,2R)- 1-((3-chloro-2-fluorophenyl)methyl)-3-(((4'S)-6' 868 (2,2-dinethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 0.006256 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide N-((1S,2R)-1-((3-chloro-4,5-difluorophenyl)methyl)-3 869 (((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 536 0.017919 yl)amino)-2-hydroxypropyl)acetamide N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 870 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.035578 yl)amino)-2-hydroxy-1-((2,3,6 trifluorophenyl)methyl)propyl)acetamide WO 2007/061670 PCT/US2006/044058 - 235 N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 871 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.002026 yl)amino)-2-hydroxy-1-((2,3,5 trifluorophenyl)methyl)propyl)acetamide N-((1 S,2R)- 1-((4-bromophenyl)methyl)-3-(((4'S)-6'-(2,2 872 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 544/546 0.034468 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide methyl ((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 873 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 482 0.020588 yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)carbamate N-((1 S,2R)- 1 -((3,5-difluorophenyl)methyl)-3-(((4'S)-6' 874 ethyl-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3- 460 0.012128 b]pyridin]-4'-yl)amino)-2-hydroxypropyl)acetamide methyl ((1 S,2R)-1-((3,5-difluorophenyl)metbyl)-3-(((4'S)-6' 875 ethyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 476 0.325018 blpyridin]-4'-yl)amino)-2-hydroxypropyl)carbamate methyl ((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6' 876 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 0.010815 pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)carbamate N-((] S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' 877 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'- 480 0.064123 yl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)propanamide WO 2007/061670 PCT/US2006/044058 - 236 N-((IS,2R)-1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S) 878 6'-(3-hydroxy-2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 500 0.235839 yl)amino)propyl)acetamide The present invention also provides methods for making compounds of Formulas 5 1-111. In another embodiment of the invention, there is provided a method of making a compound of Formula I or II, the method comprising the step of reacting a compound 20 OH

R

4

H

2 N N R 5 B RaRa 20 ,wherein i, j, A, B, R 3 , R 4 and R are as defined herein, with a compound having the structure A-W-X, wherein A and W are as defined herein and X is a leaving group, to make a compound of Formulas I or II. 10 In another embodiment of the invention, there is provided a method of making a compound of Formula III, the method comprising the step of reacting a compound 30

R

3

R

3

H

2 N N R5

R

3

R

3 B OH 30 ,wherein i, j, B, R 3 , R4 and R are as defined herein, with a compound having the structure 15 A-W-X, wherein A and W are as defined herein with respect to Formula III and X is a leaving group, to make a compound of Formula III. As can be appreciated by the skilled artisan, the above synthetic schemes and representative examples are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. 20 Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.

WO 2007/061670 PCT/US2006/044058 - 237 For example, in these procedures, the steps may be preceded, or followed, by additional protection/deprotection steps as necessary. Particularly, if one or more functional groups, for example carboxy, hydroxy, amino, or mercapto groups, are or need to be protected in preparing the compounds of the invention, because they are not 5 intended to take part in a specific reaction or chemical transformation, various known conventional protecting groups may be used. For example, protecting groups typically utilized in the synthesis of natural and synthetic compounds, including peptides, nucleic acids, derivatives thereof and sugars, having multiple reactive centers, chiral centers and other sites potentially susceptible to the reaction reagents and/or conditions, may be used. 10 The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they readily lend themselves, i.e. without undesired secondary reactions, to removal, typically accomplished by solvolysis, 15 reduction, photolysis or other methods of removal such as by enzyme activity, under conditions analogous to physiological conditions. It should also be appreciated that the protecting groups should not be present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions described herein. Synthetic chemistry transformations and protecting group methodologies (protection and 20 deprotection) useful in synthesizing the inhibitor compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and 25 Sons (1994); A. Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2 nd edition (2001); M. Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductions by the Alumino and Borohydrides in Organic Synthesis, 2 nd edition, Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). 30 Salts of a compound of the invention having a salt-forming group may be prepared in a conventional manner or manner known to persons skilled in the art. For example, acid addition salts of compounds of the invention may be obtained by treatment with an acid or with a suitable anion exchange reagent. A salt with two acid molecules (for example a dihalogenide) may also be converted into a salt with one acid molecule per WO 2007/061670 PCT/US2006/044058 - 238 compound (for example a monohalogenide); this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from 50 *C to 170 "C, one molecule of the acid being expelled per molecule of the compound. 5 Acid salts can usually be converted to free-base compounds, e.g. by treating the salt with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide. Exemplary salt forms and their preparation are described herein in the Definition section of the application. 10 All synthetic procedures described herein can be carried out under known reaction conditions, advantageously under those described herein, either in the absence or in the presence (usually) of solvents or diluents. As appreciated by those of ordinary skill in the art, the solvents should be inert with respect to, and should be able to dissolve, the starting materials and other reagents used. Solvents should be able to partially or wholly 15 solubilize the reactants in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically cation exchangers for example in the H* form. The ability of the solvent to allow and/or influence the progress or rate of the reaction is generally dependant on the type and properties of the solvent(s), the reaction conditions including temperature, pressure, atmospheric conditions such as in an 20 inert atmosphere under argon or nitrogen, and concentration, and of the reactants themselves. Suitable solvents for conducting reactions to synthesize compounds of the invention include, without limitation, water; esters, including lower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphatic ethers, e.g., Et 2 O and ethylene glycol 25 dimethylether or cyclic ethers, e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- and t-butanol; nitriles including CH 3 CN; halogenated hydrocarbons, including CH 2

C

2 , CHC13 and CC1 4 ; acid amides including DMF; sulfoxides, including DMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine; carboxylic acids, including lower 30 alkanecarboxylic acids, e.g., AcOH; inorganic acids including HCI, HBr, HF, H 2

SO

4 and the like; carboxylic acid anhydrides, including lower alkane acid anhydrides, e.g., acetic anhydride; cyclic, linear, or branched hydrocarbons, including cyclohexane, hexane, pentane, isopentane and the like, and mixtures of these solvents, such as purely organic solvent combinations, or water-containing solvent combinations e.g., aqueous solutions.

WO 2007/061670 PCT/US2006/044058 - 239 These solvents and solvent mixtures may also be used in "working-up" the reaction as well as in processing the reaction and/or isolating the reaction product(s), such as in chromatography. Purification methods are known in the art and include, for example, 5 crystallization, chromatography (liquid and gas phase, and the like), extraction, distillation, trituration, reverse phase HPLC and the like. Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction. The invention further encompasses "intermediate" compounds, including 10 structures produced from the synthetic procedures described, whether isolated or not, prior to obtaining the finally desired compound. Structures resulting from carrying out steps from a transient starting material, structures resulting from divergence from the described method(s) at any stage, and structures forming starting materials under the reaction conditions are all "intermediates" included in the invention. Further, structures 15 produced by using starting materials in the form of a reactive derivative or salt, or produced by a compound obtainable by means of the process according to the invention and structures resulting from processing the compounds of the invention in situ are also within the scope of the invention. New starting materials and/or intermediates, as well as processes for the 20 preparation thereof, are likewise the subject of this invention. In select embodiments, such starting materials are used and reaction conditions so selected as to obtain the desired compound(s). Starting materials of the invention, are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many 25 starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the examples. In synthesizing starting materials, functional groups may be protected with suitable protecting groups when necessary. Protecting groups, their introduction and removal are described above. Compounds of the present invention can possess, in general, one or more 30 asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, WO 2007/061670 PCT/US2006/044058 - 240 dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the 5 separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the 10 enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. All such isomeric forms of such compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric 15 forms. The compounds may also occur in cis- or trans- or E- or Z- double bond isomeric forms. The invention expressly includes all tautomeric forms of the compounds described herein. All crystal forms of the compounds described herein are expressly included in the present invention. 20 Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom, whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen). For example, the R1 2 substituent is drawn unattached to any specific atom of ring Z 2 , and therefore each of 25 the n number of R 2 substituents may be attached to any atom of Z 2 . The compounds of the invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral 30 availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. By way of example, a compound of the invention may be modified to incorporate a hydrophobic group or "greasy" moiety in an attempt to enhance the passage of the compound through a hydrophobic membrane, such as a cell wall.

WO 2007/061670 PCT/US2006/044058 - 241 Although the pharmacological properties of the compounds of the invention (Formulas I-III) vary with structural change, in general, activity possessed by compounds of Formulas I, II and 111 may be demonstrated both in vitro as well as in vivo. Particularly, the pharmacological properties of the compounds of this invention may be 5 confirmed by a number of pharmacological in vitro assays. The following exemplified pharmacological assays have been carried out with the compounds according to the invention. Compounds of the invention were found to modulate BACE activity. BIOLOGICAL EVALUATION 10 The following biological assays were used to characterize the ability of compounds of the invention to regulate the cleavage of amyloid beta precursor protein, thereby reducing or inhibiting the production of amyloid beta. In vitro enzymatic RACE FRET (fluorescence resonance energy transfer) assay 15 Assay buffer is 0.05 M acetate, pH 4.2, 10% DMSO final, 100 uM genapol (which is a nonionic detergent, below it's Critical Micelle Concentration). Enzyme (0.2nM) is pre-incubated for one hour with inhibitors added in luL of DMSO. Then the assay is started by the addition of FRET substrate (50nM) and incubated for one hour. The FRET assay is terminated with by addition of Tris buffer, which raises the pH to 20 neutrality, and the fluorescence is determined. The FRET substrate is a peptide with commercially available fluorophore and quencher, on opposite sides of the BACE cleavage site. Proteolytic cleavage of the FRET substrate releases quenching of fluorescence (excitation 488 nm and emission 425 nm). The compounds of Examples 1-19, 24-52, 54-74, 78-91, 93-108, 111-113, 115 25 137, 139, 141-142, 144-171, 173-178, 180, 182, 185-187, 190-204,206-213,218-247, 249-262, 264,266-276, 278-287, 289-314, 320-327, 329-384, 386, 388, 393-418, 461 466, 468-470, 488-501, 503-510, 512 and 514-520, 522-527, 529-534, 537-562, 564-608, 610, 612-620, 623-624, 627-655, 657-663, 665-689, 691-727, 729-730, 732-734, 736, 738-739, 741-441, 443-448, 781-782, 784-787, 789-828, 830-863 and 865-878 exhibited 30 IC 50 values of 5 jpM or less in the FRET in vitro enzyme assay. RACE cell-based assay: The cell-based assay measures inhibition or reduction of Ap40in conditioned medium of test compound treated cells expressing amyloid precursor protein.

WO 2007/061670 PCT/US2006/044058 - 242 Cells stably expressing Amyloid Precursor Protein (APP) were plated at a density of 40K cells/well in 96 well plates (Costar). The cells were cultivated for 24 hours at 37 *C and 5% CO 2 in DMEM supplemented with 10% FBS. The test compounds were then added to cells in 10-point dose response concentrations with the starting concentration 5 being either 100 gM or 10 gM. The compounds were diluted from stock solutions in DMSO and the final DMSO concentration of the test compounds on cells was 0.1%. After 24 h of incubation with the test compounds the supernatant conditioned media was collected and the Ap 40 levels were determined using a sandwich ELISA. The IC 50 of the compound was calculated from the percent of control or percent inhibition of A3 40 as a 10 function of the concentration of the test compound. The sandwich ELISA to detect AD 40 was performed in 96 well microtiter plates, which were pre-treated with goat anti-rabbit IgG (Pierce). The capture and detecting antibody pair that were used to detect A3 40 from cell supernatants were affinity purified pAb40 (Biosource) and biotinylated 6E10 (Signet Labs Inc.), respectively. The optimal 15 concentration for the pAb40 antibody was 3 gg/ml in Superblock/TBS (Pierce) that was supplemented with 0.05%Tween 20 (Sigma). Optimal concentration for the detection antibody 6E1 0-biotinylated was 0.5 pg/ml in Superblock/TBS (Pierce) that had been supplemented with 2% normal goat serum and 2 % normal mouse serum. Cellular supernatants were incubated with the capture antibody for 3 h at 4 *C, 20 followed by 3 wash steps in TBS-tween (0.05%). The detecting antibody incubation was for 2 h at 4 oC, again followed by the wash steps as described previously. The final readout of the ELISA is Time-Resolved Fluorescence (counts per minute) using Delfia reagents Streptavidin-Europium and Enhancement solutions (Perkin Elmer) and the Victor 2 multilabel counter (Perkin Elmer). 25 Of the compounds tested, Examples 1-3, 5-7, 9-10, 16, 18-19, 24-35, 38-44, 46 52, 54-68, 70-74, 76-91, 93-108, 111-124, 126-137, 139, 141-142, 144-145, 152-171, 173-187, 190-204, 207-213, 218-223, 225-247, 249, 251-252, 254-281, 291-294, 296 299, 301-314, 315-317, 320-335, 337, 341-343, 345-349, 352-382, 384, 386, 388, 393 418, 461-466, 468-470, 488-501, 503-510, 512 and 514-519 exhibited activities with IC 50 30 values of 5 pM or less in the cell-based assay. In addition, the cell based assay data for each of Examples 520-876 is provided in Table 4. The majority of those Examples exhibited activities with IC5o values of 5 pM or less in the cell-based assay.

WO 2007/061670 PCT/US2006/044058 - 243 INDICATIONS Accordingly, compounds of the invention are useful for, but not limited to, the prevention or treatment of beta-secretase related diseases, including Alzheimer's disease. The compounds of the invention have the ability to modulate the formation of amyloid 5 beta, and reduce the formation and deposition of plaque on the brain. In one embodiment of the invention, there is provided a method of treating a disorder related to a beta secretase enzyme in a subject, the method comprising administering to the subject an effective dosage amount of a compound of Formulas I, II or III. In another embodiment, there is provided a method of reducing production of amyloid beta, and of reducing 10 plaque formation. In yet another embodiment, there is provided a method of treating Alzheimer's disease. Accordingly, the compounds of the invention would be useful in therapy as CNS agents in treating neurological disorders and related conditions. Besides being useful for human treatment, these compounds are useful for 15 veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided by the invention. FORMULATIONS AND METHOD OF USE 20 Treatment of diseases and disorders herein is intended to also include therapeutic administration of a compound of the invention, or a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject (i.e., an animal, preferably a mammal, most preferably a human) which may be in need of preventative treatment, such as, for example, for pain, inflammation and the like. Treatment also encompasses prophylactic 25 administration of a compound of the invention, or a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject (i.e., an animal, preferably a mammal, most preferably a human). Generally, the subject is initially diagnosed by a licensed physician and/or authorized medical practitioner, and a regimen for prophylactic and/or therapeutic treatment via administration of the compound(s) or compositions of the 30 invention is suggested, recommended or prescribed. The amount of compound(s) which is/are administered and the dosage regimen for treating neurological disorders and beta-secretase mediated diseases with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, WO 2007/061670 PCT/US2006/044058 - 244 the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.01 to 500 mg/kg, advantageously between about 0.01 and about 50 mg/kg, more advantageously about 0.01 5 and about 30 mg/kg, and even more advantageously between about 0.1 and about 10 mg/kg body weight may be appropriate, and should be useful for all methods of use disclosed herein. The daily dose can be administered in one to four doses per day. While it may be possible to administer a compound of the invention alone, in the methods described, the compound administered normally will be present as an active 10 ingredient in a pharmaceutical composition. Thus, in another embodiment of the invention, there is provided a pharmaceutical composition comprising a compound of this invention in combination with a pharmaceutically acceptable carrier, which includes diluents, excipients, adjuvants and the like (collectively referred to herein as "carrier" materials) as described herein, and, if desired, other active ingredients. A pharmaceutical 15 composition of the invention may comprise an effective amount of a compound of the invention or an effective dosage amount of a compound of the invention. An effective dosage amount of a compound of the invention includes an amount less than, equal to or greater than an effective amount of the compound. For example, a pharmaceutical composition in which two or more unit dosages, such as in tablets, capsules and the like, 20 are required to administer an effective amount of the compound, or alternatively, a multi dose pharmaceutical composition, such as powders, liquids and the like, in which an effective amount of the compound is administered by administering a portion of the composition. The compound(s) of the present invention may be administered by any suitable 25 route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonarily such as by inhalation spray, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly intrasternally and 30 infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active WO 2007/061670 PCT/US2006/044058 - 245 ingredient. Examples of such dosage units are tablets or capsules. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about I to 500 mg, and typically from about 5 to 150 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and 5 other factors, but, once again, can be determined using routine methods and practices. For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants or "excipients" appropriate to the indicated route of administration. If orally administered on a per dose basis, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose 10 alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to form the final formulation. For example, the active compound(s) and excipient(s) may be tableted or encapsulated by known and accepted methods for convenient administration. Examples of suitable 15 formulations include, without limitation, pills, tablets, soft and hard-shell gel capsules, troches, orally-dissolvable forms and delayed or controlled-release formulations thereof. Particularly, capsule or tablet formulations may contain one or more controlled-release agents, such as hydroxypropylmethyl cellulose, as a dispersion with the active compound(s). 20 Formulations for parenteral administration may be in the form of aqueous or non aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds 25 may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or 30 with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (ie. Tween 80). The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be WO 2007/061670 PCT/US2006/044058 - 246 employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the 5 preparation of injectables. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water. The daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, and preferably from about 0.1 to about 10 mg/kg. 10 For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler including dry powder aerosol. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. 15 Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents. Accordingly, in yet another embodiment of the present invention, there is provided a method of manufacturing a medicament, the method comprising combining an 20 amount of a compound according to Formulas I, II or III with a pharmaceutically acceptable carrier to manufacture the medicament. In yet another embodiment, there is provided a method of manufacturing a medicament for the treatment of Alzheimer's disease, the method comprising combining an amount of a compound according to Formulas I, II or III with a pharmaceutically 25 acceptable carrier to manufacture the medicament. COMBINATIONS While the compounds of the invention can be dosed or administered as the sole active pharmaceutical agent, they can also be used in combination with one or more 30 compounds of the invention or in conjunction with other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered simultaneously or sequentially at different times, or the therapeutic agents can be given as a single composition.

WO 2007/061670 PCT/US2006/044058 -247/1 The phrase "co-therapy" (or "combination-therapy"), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co 5 administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or 10 treatment of beta-secretase, gamma-secretase and/or other reagents known in influence the formation and/or deposition of amyloid beta, otherwise responsible for the formation of plaque on the brain. If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of Formulas I, II and III 15 may also be administered sequentially with known anti-inflammatory agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, simultaneous with or after administration of the known anti-inflammatory agent. The foregoing description is merely illustrative of the invention and is not 20 intended to limit the invention to the disclosed compounds, compositions and methods. Variations and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, as defined in the appended claims. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, 25 can make various changes and modifications of the invention to adapt it to various usages and conditions. All patents and other publications recited herein are hereby incorporated by reference in their entireties. Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply 30 the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Each document, reference, patent application or patent cited in this text is expressly incorporated herein in their entirely by reference, which means that it should be read and WO 2007/061670 PCT/US2006/044058 -247/2 considered by the reader as part of this text. That the document, reference, patent application, or patent cited in this text is not repeated in this text is merely for reasons of conciseness. Reference to cited material or information contained in the text should not be understood as a concession that the material or information was part of the common general 5 knowledge or was known in Australia or any other country.

Claims (12)

1. A compound of Formula I: H OH R4 I | AN~yN N R 5 BR 3 R 3 5 or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt, thereof, wherein A is C 1 o-alkyl. Calkenyl C 2 6 -alkynyl. Cualkyl-O-C 3 -alkyl CI--alkyl-S-CI--alkyl-, CI--alkyl-S(0)Z-C,-alkyl-, CI-alkyl-N H-CI--alkldi-(Cg alkyl)-N-C 1 . 3 -alkyl, C,. -alkenyl-O-C. 3 -alkyl-, C,.-alkenyl-S-C 1 3 -alkyl-, C. 6 -alkenyl 10 S(O),-CI-alkyl-, C- 6 -alkenyl-NH-C 1 . 3 -alkyl- or C,.4-alkynyl-NH--C. 3 -alkyl- wherein the alkyl, alkenyl or alkynyl moiety of each is optionally substituted with 1-5 substituents of R 9 W is -C(=0)-; B is R 2 -(CR 2 aR 2 a)h-, wherein 15 R 2 is CI-Cro alkyl, CI-Clo haloalkyl, C 2 -Cj 0 alkenyl, C 2 -Cj 0 alkynyl, or a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected 20 from 0, N, or S, wherein said Ci-Cio alkyl, C 2 -Cj 0 alkenyl, C 2 -C 0 alkynyl, is optionally substituted independently with one or more substituents of R 9 , and said ring system is optionally substituted independently with one or more substituents of oxo, R 7 , R 8 , R 9 , NR R 7 , N R R, OR , SR , OR , SR , C(O)R , OC(O)R , COOR , C(O)R , OC(O)R', COOR', C(O)NR R , C(S)NR R, NR'C(O)R , 25 NR'C(S)R 7 , NR 7 C(O)NR 7 R , NR 7 C(S)NR 7 R', NR 7 (COOR'), OC(O)NR'R 7 , C(O)NR ' R', C(S)NR ' R', NR 7 C(O)R', NR 7 C(S)R 8 , NR 7 C(O)NR 7 R', NR 7 C(S)NR 7 R', NR 7 (COOR'), OC(O)NR7R', S(O) 2 NR 7 R , NR 7 S(O) 2 NR 7 R', NR 7 S(O) 2 R , S(O) 2 R', S(O) 2 NR R, NR S(O) 2 NR R or NR S(O) 2 R; each R 2 ,, independently, is H, OH, NO 2 , CN, NH 2 , CI-Cro alkyl, CI-Cro 30 alkoxyl or haloalkyl; and h is 1,; WO 2007/061670 PCTIUS2006/044058 - 249 i is 1; j is 0; each R 3 , independently, is H, haloalkyl, CN, CI.o-alkyl, C 2 - 1 0 -alkenyl, C 2 10 alkynyl, C 3 .io-cycloalkyl or C 4 . 1 o-cycloalkenyl, each of the C,.o-alkyl, C 2 - 10 -alkenyl, C 2 -1 0 5 alkynyl, C 3 .o-cycloalkyl and C 4 .,o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of R 8 or R 9 ; R 4 is H, haloalkyl, CN, CI.o-alkyl, C2-.o-alkenyl, C 2 - 1 0 -alkynyl, C 3 . 10 -cycloalkyl or C 4 . 1 o-cycloalkenyl, each of the CI-jo-alkyl, C 2 -,o-alkenyl, C 2 - 10 -alkynyl, C 3 .io-cycloalkyl and C 4 . 1 0 -cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S 10 and optionally substituted with 1-5 substituents of R 8 or R 9 ; R' is 12 Z2 2 R12 2' (R12)p R12 2 (1) (X X 1 X2 X Yo Y Y1 Y) (R 1 2 )p Y 2 or (R 1 2 )p Y 2 wherein 15 X' is CR 2 , C(=0), 0, S, S(0)2, or NR 2 ; each X 2 , independently, is CR1 2 R1 2 ; each of Y', Y 2 and Y 3 , independently, is CR" 2 R, 0, S or NR2; Z 2 taken together with the carbon atoms to which it is attached is a partially or fully unsaturated 5-8 membered monocyclic ring, said ring formed of carbon atoms 20 optionally including 1-3 heteroatoms selected from 0, N, or S, provided that (a) no more than two of Y', Y 2 and Y 3 is O, S orNR 2 and (b) when o is 0, then each of Y' and Y 2 is CR1 2 R 2 ; and m is 0, 1 or 2; and o is 0, l, 2, 3, 4 or 5; 25 p is 0, 1, 2, 3, 4 or 5; provided that (a) no more than two of Y', Y 2 and Y 3 is 0, S or NR 2 and (b) when o is 0, then each of Y' and Y 2 is CR1 2 R1 2 ; WO 2007/061670 PCT/US2006/044058 - 250 each R', independently, is H, C 1 I 1 0 -alkyl, C 2 - 10 -alkenyl, C 2 - 10 -alkynyl, C 3 . 10 cycloalkyl or C 4 . 10 -cycloalkenyl, each of the CIo 1 0 -alkyl, C 2 - 1 0 -alkenyl, C 2 - 10 -alkynyl, C 3 . 10 cycloalkyl and C 4 . 1 o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-5 substituents of NRR', NR 9 R 9 , OR', SR , 5 OR 9 , SR 9 , C(O)R 8 , OC(O)R', COOR', C(O)R 9 , OC(O)R 9 , COOR', C(O)NRR 9 , C(O)NR 9 R 9 , NR 9 C(O)R 8 , NR 9 C(O)R 9 , NR 9 C(O)NR 8 R 9 , NR 9 C(O)NR 9 R 9 , NR 9 (COOR'), NR 9 (COOR 9 ), OC(O)NR 8 R', OC(O)NR 9 R 9 , S(O) 2 R', S(O)2NR 8 R 9 , S(O) 2 R 9 , S(0) 2 NR 9 R 9 , NR 9 S(O) 2 NRR 9 , NR 9 S(O) 2 NR 9 R 9 , NR 9 S(O) 2 R 8 , NR 9 S(O) 2 R 9 , R' or R 9 ; each R 8 , independently, is a partially or fully saturated or unsaturated 3-8 10 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substituents of R9, oxo, NR 9 R 9 , OR 9 ; SR', C(O)R 9 or a partially or 15 fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including I 3 heteroatoms selected from 0, N, or S, and optionally substituted independently with 1-5 substituents of R 9 ; each R 9 ' independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, C 1 . 1 0 alkyl, C 2 - 10 -alkenyl, C 2 - 1 -alkynyl, C 3 . 1 0 -cycloalkyl, C 4 . 10 -cycloalkenyl, CI.-alkylamino-, 20 CI. 10 -dialkylamino-, CI. 1 o-alkoxyl, Ci.-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CI- o-alkyl, C2-lo-alkenyl, C 2 1 o-alkynyl, C 3 . 10 -cycloalkyl, C 4 . 10 -cycloalkenyl, C.o 10 25 alkylamino-, C 1 . 0 o-dialkylamino-, CI- 1 o-alkoxyl, CI 10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C 1 . 0 30 alkylamino-, CI.-dialkylamino-, CI. 10 -thioalkoxyl, benzyl or phenyl; each R' 2 independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, oxo, CI. 10 -alkyl, C 2 . 1 o-alkenyl, C 2 . 1 o-alkynyl, C 3 . 10 -cycloalkyl, C 4 . 1 0 -cycloalkenyl, CI. 1 0 alkylamino-, CI. 10 -dialkylamino-, CI. 1 0 -alkoxyl, CI 10 -thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, WO 2007/061670 PCTIUS2006/044058 - 251 said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein each of the CI1io-alkyl, C 2 -io-alkenyl, C 2 -io-alkynyl, C 3 .o-cycloalkyl, C 4 . 1 0 cycloalkenyl, Ci.io-alkylamino-, Ci.io-dialkylamino-, C 1 .io-alkoxyl, CI. 1 0 -thioalkoxyl and 5 ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C 1 . 1 o-alkylamino-, CI. 10 -dialkylamino-, CI 10 -thioalkoxyl, benzyl, 10 phenyl or R 4; R' 4 is a saturated or partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, and 15 wherein said ring system is optionally substituted independently with 1-5 substituents of R 15 ; and R 1 5 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert 20 butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, CI-o alkylamino-, C 1 . 1 o-dialkylamino-, C. 1 0 -thioalkoxyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, and optionally 25 substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl. 30 2. The compound of claim I wherein R 2 is a CI-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, CI-CIO haloalkyl or a substituted ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, WO 2007/061670 PCT/US2006/044058 - 252 oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, 5 cyclopentyl, cyclohexyl and cycloheptyl.

3. The compound of claim I wherein each R 3 , independently, is H, haloalkyl, CN, CI 1 1 oalkyl, C 2 -io-alkenyl or C 2 - 1 0 -alkynyl; 10 R 4 is H or C 1 . 10 -alkyl; h is 1; i is 1; and j is 0. 15 4. The compound of claim I wherein X 1 is CR", 0 orNR Z 2 is a phenyl, pyridine, pyrimidine, triazine, pyridazine, pyrazine, pyridone, pyrrole, imidazole, pyrazole, triazole, thiophene, thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole or isoxazole ring. 20

5. The compound of claim I wherein A is C 1 .- alkyl, C 2 . 6 alkenyl, C 2 - 6 -alkynyl, C 1 . 6 alkyl-O-CI. 3 -alkyl-, CI.6-alkyl-S-CI.3-alkyl-, CI.6-alkyl-S(O)2-C1.3-alkyl-, CI.6-alkyl-N H-CI.3-alkyl, di-(CI. alkyl)-N-C 1 . 3 -alkyl, C 2 . 6 -alkenyl-O-Ci. 3 -alkyl-, C 2 .6-alkenyl-S-CI. 3 -alkyl-, C 2 - 6 -alkenyl 25 S(O) 2 -C 1 . 3 -alkyl-, C 2 -6-alkenyl-NH-C 1 . 3 -alkyl- or C 2 - 4 -alkynyl-NH-C 1 . 3 -alkyl-, wherein the alkyl, alkenyl or alkynyl moiety of each is optionally substituted with 1-5 substituents of R9 W is -C(=0)-; B is R 2 -(CR 2 aR 2 a)h-, wherein h is I and R 2 is a CI-C 4 alkyl, CI-C 4 alkenyl, C 1 30 C 4 alkynyl, CI-CIO haloalkyl or a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, WO 2007/061670 PCTIUS2006/044058 - 253 benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, the ring optionally substituted with 1-5 substituents of R 9 ; 5 each R 3 , independently, is H, haloalkyl, CN, CI.o-alkyl, C 2 -1o-alkenyl or C 2 10 alkynyl; R 4 is H, CN or CI.o-alkyl; R is R1 2 Z 2 (R12)p R12 Z 2 (R 12 )p (X X, X 2 x)m Y Y) Y Y$ 10 (R 12 )p Y 2 or (R 12 )p Y 2 wherein m, o, R' 2 , X 2 , yI, y 2 and Y 3 are as defined in claim 1; X' is CR1 2 or 0, ; Z 2 is a phenyl, pyridine, pyrimidine, triazine, pyridazine, pyrazine, 15 pyridine, pyrrole, imidazole, pyrazole, triazole, thiophene, thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole or isoxazole ring; and p is 0, 1, 2, 3, 4 or 5, each R 7 , independently, is H, Ci.o-alkyl or C 2 -1o-alkenyl, each of the C,.o-alkyl, or C 2 -10-alkenyl optionally substituted with 1-3 substituents of R 9 ; 20 each R , independently, is a ring system selected from phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, 25 benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, WO 2007/061670 PCT/US2006/044058 - 254 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl and cycloheptyl, said ring system optionally substituted independently with 1-3 substituents of R 9 , oxo, NR 9 R 9 , OR 9 , SR9, C(O)R 9 or a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from 0, N, 5 or S, and optionally substituted independently with 1-5 substituents of R 9 ; each R 9 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, C 1 . 1 0 alkyl, C 2 - 10 -alkenyl, C 2 . 1 -alkynyl, C 3 . 7 -cycloalkyl, C 4 . 7 -cycloalkenyl, C- 1 1 o-alkylamino-, C 1 . 10 -dialkylamino-, C 1 .io-alkoxyl, CI 10 -thioalkoxyl; and each R 2 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, oxo, 10 C 1 io-alkyl, C 2 . 10 -alkenyl, C 2 . 1 o-alkynyl, C 3 . 10 -cycloalkyl, C 4 . 1 0 -cycloalkenyl, CI.o alkylamino-, C 1 Io-dialkylamino-, CI 10 -alkoxyl, C 1 . 1 0 -thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, 15 wherein each of the CI 10 -alkyl, C 2 . 1 o-alkenyl, C 2 - 10 -alkynyl, C 3 . 10 -cycloalkyl, C 4 .10 cycloalkenyl, C,- 1 o-alkylamino-, CI 10 -dialkylamino-, CI. 10 -alkoxyl, C 1 . 1 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, 20 isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopently, hexyl, cyclohexyl, C 1 .o-alkylamino-, C. 10 -dialkylamino-, C 1 . 1 -thioalkoxyl, benzyl or phenyl.

6. The compound of claim 5 wherein R 5 is (Rj 2 )P -A3 IA 2 X) A1 (x)0 25 (R1)' wherein m is 0 or 1; WO 2007/061670 PCT/US2006/044058 - 255 o is I or 2; p is 0, 1, 2 or 3; A' is CH, C(=O), O or NR 2 ; each of A 3 and A 2 , independently, is CR' or N, provided 5 that no more than one of A 3 and A 2 is N; X 2 is CH; Y 3 is CHR1 2 or 0; and each R , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, oxo, CI-,o-alkyl, C 2 -.o-alkenyl, C 2 -1o-alkynyl, C 3 .1o-cycloalkyl, C 4 .1 0 10 cycloalkenyl, C,.io-alkylamino-, CI.o-dialkylamino-, C,.o-alkoxyl, C,.io-thioalkoxyl or a ring selected from phenyl, pyridyl, pyrimidinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, 15 pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein each of the CI.o-alkyl, C 2 -1o-alkenyl, C 2 -1o-alkynyl, C 3 .io-cycloalkyl, C 4 .o-cycloalkenyl, CI-,o-alkylamino-, C,.1o-dialkylamino-, CI-,o-alkoxyl, Cl.,o-thioalkoxyl and ring is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, 20 isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopently, hexyl, cyclohexyl, C1., 0 alkylamino-, C,.o-dialkylamino-, CI-io-thioalkoxyl, benzyl or phenyl.

7. A compound or a pharmaceutically acceptable salt thereof, selected from: 25 N-((] S,2R)-2-hydroxy- I -(phenylmethyl)-3-(((4S)-2,6,6-trimethyl-4,5,6,7 tetrahydro- 1 -benzofuran-4-yl)amino) propyl)acetamide; N-((I S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-I -benzothien-4 yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(2-oxo- 1 -pyrrolidinyl)acetamide; 'N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-chromen-4 30 yl)amino)- 1 -((3-cyanophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-chromen-4 yl)amino)- I -((3-cyanophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide; WO 2007/06 1670 PCTJUS2006/044058 - 256 'N-I -- ((I S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3 ,4-dihydro-2H-chromen-4 yI)amimo)- 1 -((3 -cyanophenyl)methyl)-2-hydroxypropyl)-N-2-,N-2- dimethyiglycinamide; 'N-(( 1 S,2R)-3-(((4S)-8-bromo-6-ethyl-2,2-d imethyl-3 ,4-d ihydro-2H-chromen-4 5 yI)amino)- I -((3-cyanophenyl)methyl)-2-hydroxypropy)acetam ide; 'N-((]I S,2R)- I -((3-cyanophenyl)methyl)-3-((( 1 S)-3 ,3-d imethyl-7-(methyloxy)-4 oxo- I ,2,3 ,4-tetrahydro- I -naphthalenyl)amino)-2-hydroxypropyl)-2 (methyloxy)acetamide; N-((]I S,2R)- I -((3-cyanophenyl)methyl)-3 -(((1 R)-3,3 -dimethyl-7-(methyloxy)-4 10 oxo- 1,2,3 ,4-tetrahydro- I -naphthalenyl)amino)-2-hydroxypropyl)-2 (methyloxy)acetam ide; 'N-(( I S,2R)- I -((3-cyanophenyl)methyl)-3 -(((I S)-3 ,3 -dimethyl-7-(methyloxy)-4 oxo- 1,2,3 ,4-tetraliydro- I -naphthalenyl)am ino)-2-hydroxypropyl)acetamide; N-((]I S,2R)- 1 -((3 -cyanophenyl)methyl)-3 -(((I R)-3,3 -dimethyl-7-(methyloxy)-4 15 oxo- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)amino)-2-hydroxypropyl)acetamide; 'N-((]I S,2R)- I -((3-cyanophenyl)methyl)-3 -(((4S)-6-ethyl-2,2-d imethyl-8-(4 morphol inyl)-3 ,4-dihydro-2 H-chromen-4-yl)amino)-2-hydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((4R)-6-ethyl-2,2-d imethyl-8-( I -pyrrolidinyl)-3 ,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 20 N-((]I S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-8-( I -pyrrolidinyl)-3,4-dihydro-2H ch romen-4-yI)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)acetamide; 'N-((]I S,2R)-3 -(((4S)-8-(dimethylamino)-6-ethyl-2,2-d imethyl-3 ,4-dihydro-2H chromen-4-yI)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetam ide; N-((]I S,2R)-3-(((4R)-8-(dimethylamino)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H 25 chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4S)-6-ethyl-2,2-dimethyl-8-(methylamino)-3 ,4-d ihydro-2H chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetam ide; 'N-(( I S,2R)- 1 -((3-cyanophenyl)methyl)-2-hydroxy-3-(((5 S)-3 ,7,7-trimethyl 5,6,7,8-tetrahydro-5 -quinol inyl)am ino)propyl)acetamide; 30 'N-(( I S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H pyrano[2,3-b] pyrid in-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H pyrano[2,3-b]pyridin-4-yl)amino)- 1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetam ide; WO 2007/061670 PCT/US2006/044058 - 257 'N-((1 S,2R)-3-(((1 S)-3,3-dimethyl-7-((2-(methyloxy)ethyl)amino)-4-oxo-1,2,3,4 tetrahydro-l-naphthalenyl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide; N-((] S,2R)-3-(((1 R)-3,3-dimethyl-7-((2-(methyloxy)ethyl)amino)-4-oxo-1,2,3,4 tetrahydro-I -naphthalenyl)amino)-2-hydroxy-I-(phenylmethyl)propyl)acetamide; 5 'N-((1 S,2R)-3-(((I R)-7-(cyclopentylamino)-3,3-dimethyl-4-oxo-1,2,3,4 tetrahydro-I -naphthalenyl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide; N-((] S,2R)-3-(((l S)-7-(cyclopentylamino)-3,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-I naphthalenyl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide; 'N-((l S,2R)-1 -((3,5-difluorophenyl)methyl)-3-(((I S)-7-(2,2-dimethylpropyl)-3,3 10 dimethyl-4-oxo-1,2,3,4-tetrahydro-1 -naphthalenyl)am ino)-2-hydroxypropyl)acetamide; N-((l S,2R)- l-((3,5-difluorophenyl)methyl)-3-(((l R)-7-(2,2-dimethylpropyl)-3,3 dimethyl-4-oxo-I,2,3,4-tetrahydro-I -naphthalenyl)amino)-2-hydroxypropyl)acetamide; 'N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H pyrano[2,3-b]pyridin-4-yl)amino)- I -((4-fluorophenyl)methyl)-2 15 hydroxypropyl)acetamide; 'N-((] S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2 dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)amino)-2-hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((4S)-2-(2,2-dimethylpropyl)-6,6-dimethyl-4,5,6,7-tetrahydro- 1 benzothien-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 20 'methyl ((1 S,2R)-3-(((4S)-2-(2,2-dimethylpropyl)-6,6-dimethyl-4,5,6,7 tetrahydro- I -benzothien-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)carbamate; 'N-((l S,2R)-3-(((4R)-6-bromo-2,2-dimethyl- l,2,3,4-tetrahydro-4 quinolinyl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide N-((] S,2R)-3-(((4S)-6 bromo-2,2-dimethyl-1,2,3,4-tetrahydro-4-quinolinyl)amino)-2-hydroxy- 1 25 (phenylmethyl)propyl)acetamide; 'N-((I S,2R)-3-(((4R)-6-(2,2-dimethylpropyl)-2,2-dimethyl- 1,2,3,4-tetrahydro-4 quinolinyl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide; N-((l S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4 quinolinyl)amino)-2-hydroxy-I -(phenymethyl)propyl)acetamide; 30 'N-((1 S,2R)-3-(((4R)-l -acetyl-6-bromo-2,2-dimethyl- 1,2,3,4-tetrahydro-4 quinolinyl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide; N-((] S,2R)-3-(((4S)-l -acetyl-6-bromo-2,2-dimethyl- 1,2,3,4-tetrahydro-4 quinolinyl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide; WO 2007/061670 PCT/US2006/044058 - 258 N-((] S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4 quinolinyl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide; 'N-((l S,2R)-1 -((3,5-difluorophenyl)methyl)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2 dimethyl-1,2,3,4-tetrahydro-4-quinolinyl)amino)-2-hydroxypropyl)acetamide; 5 'N-((] S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4 quinolinyl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4 quinolinyl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((1 S)-3,3-dimethyl-7-((3S)-tetrahydro-3-furanyloxy)-1,2,3,4 10 tetrahydro- 1 -naphthalenyl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-((] S,2R)-3-(((4S)-8-(dimethylamino)-6-(2,2-dimethylpropyl)-2,2-dimethyl 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-1 -((3-(dimethylamino)-5 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((] S,2R)-l -((3-chloro-5-fluorophenyl)methyl)-3-(((4S)-8-(dimethylamino)-6 15 (2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yi)amino)-2 hydroxypropyl)acetamide; 'N-((I S,2R)-1 -((3,4-difluorophenyl)methyl)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2 dimethyl-8-(] -pyrrolidinyl)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2 hydroxypropyl)acetamide; 20 'N-((l S,2R)- I -((3,4-difluorophenyl)methyl)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2 dimethyl-8-(methylamino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2 hydroxypropyl)acetamide; 'N-((] S,2R)-3-(((4S)-8-chloro-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro 2H-pyrano[2,3-c]pyridin-4-yl)amino)-I -((4-fluorophenyl)methyl)-2 25 hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((4S)-8-(dimethylamino)-6-(2,2-dimethylpropyl)-2,2-dimethyl 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-((] S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H 30 pyrano[2,3-c]pyridin-4-yl)amino)-2-hydroxy-I -(phenylmethyl)propyl)acetamide; 'N-((I S,2R)-1 -((3-chloro-5-fluorophenyl)methyl)-3-(((4S)-6-(2,2 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2 hydroxypropyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 259 'N-((l S,2R)- 1 -((3-chloro-5-fluorophenyl)methyl)-3-(((4S)-6-(2,2 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2 hydroxypropyl)propanamide; 'N-((l S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H 5 pyrano[2,3-c]pyridin-4-yl)amino)- I -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H pyrano[2,3-c]pyridin-4-yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 10 'N-((I S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2 dimethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2-hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((4S)-6-bromo-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4 yl)amino)- I -((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide; N-((2S,3R)-3-hydroxy-4-((S)-6-isopropoxy-2,2-spirocyclobutyl-chroman-4 15 ylamino)- I -phenylbutan-2-yl)acetamide; 'N-((] S,2R)-3-(((2R,4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; and N-((] S,2R)-3-(((2S,4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide. 20

8. A compound or a pharmaceutically acceptable salt thereof, selected from: N-((2S,3 R)-4-((S)-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy- I phenylbutan-2-yl)acetamide; N-((2 S,3 R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylam ino)-3 -hydroxy- I 25 phenylbutan-2-yl)acetamide.TFA salt; N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-I phenylbutan-2-yl)-2-(pyridin-4-yl)acetamide.TFA salt; N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-(5-methyl-i H 30 pyrazol-1-yl)acetamide; Methyl (2S,3R)-3-hydroxy-4-((S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro 2H-pyrano[2,3-b]pyridin-4-ylamino)-I -phenylbutan-2-ylcarbamate; Ethyl (2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-chroman-4-ylamino)-3 hydroxy- I -phenylbutan-2-ylcarbamate; WO 2007/061670 PCTJUS2006/044058 - 260 N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylam ino)-3 -hydroxy- 1 phenylbutan-2-yI)pent-4-ynamide; 3-cyclopentyl-N-((2S,3 R)-4-((S)-6-ethyl-2,2-spi rocyclobutylcbroman-4 ylamino)-3 -hydroxy- I -phenylbutan-2-yI)propanam ide; 5 N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylam ino)-3 -hydroxy- I phenylbutan-2-yi)propionamide; N-((2 S,3 R)-4-((S)-6-ethyl-2,2-spi rocyc lobutylIchroman-4-y lam ino)-3 -hydroxy- I1 phenylbutan-2-yi)-2-methoxyacetamide; 2-( 1,3 -benzothiazol-2-yloxy)-N-(( I S,2R)-3 -(((4S)-6-ethyl-3 ,4-dihydrospiro 10 [chromene-2, I '-cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; N-(( I S,2R)-3 -(((4S)-6-ethyl-3 ,4-d ihydrospiro[chromene-2, I '-cyclobutan]-4 yI)am ino)-2-hydroxy- I-(phenylmethyl) propyl)-2-(2-oxo- 1,3 -oxazolid in-3 -yI)acetam ide; N-(( 1 S,2R)-3 -(((4S)-6-ethyl-3 ,4-d ihydrospiro[chromene-2, I '-cyclobutan]-4 yI)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-( I H-pyrrolo[2,3-blpyridin- 1 15 yI)acetamide; N-(( 1 S,2R)- 1 -((3-cyanophenyl)methyt)-3 -(((4S)-6-ethyl-3 ,4 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)-2-hydroxypropyl)-2-(2-oxo- 1,3 oxazol idin-3-yI)acetamide; N-(( I S,2R)- I -((3-cyanophenyl)methyl)-3 -(((4S)-6-ethyl-3 ,4 20 dihydrospiro[chromene-2, 1 '-cyclobutan]-4-yl)amino)-2-bydroxypropyl)-2 (methyloxy)acetamide; N-(( I S,2R)- 1 -((3-cyanophenyl)methyl)-3 -(((4S)-6-ethyl-3 ,4 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)-2-hydroxypropyl)acetam ide; N-(( 1 S,2R)- 1 -((3-cyanophenyl)methyl)-3 -(((4S)-6-ethyl-3 ,4 25 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)-2-hydroxypropyl)-2 (phenyloxy)acetam ide; (3 S)-N-(( IS,2R)- 1-((3 -cyanophenyl) methyl)-3 -(((4S)-6-ethyl-3 ,4-d ihydrospiro [chromene-2, I '-cyclobutan]-4-yI)amino)-2-hydroxypropyl)- I -cyclobutyl-5 -oxo-3 pyrrol idinecarboxam ide; 30 N-((]I S,2R)- I -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3 ,4 dihydrospi ro[chromene-2, I '-cyclobutan]-4-yI)am ino)-2-hydroxypropyl)propanam ide; N-((]I S,2R)- I -((3-cyanophenyl)methyl)-3 -(((4S)-6-ethyl-3 ,4 dihydrospiro[chromene-2, I '-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-2 ((cyclopropylmethyl)oxy) acetamide; WO 2007/061670 PCTIUS2006/044058 - 261 N-((]1 S,2R)- I -((3-cyanophenyl)methyl)-3 -(((2S,4S)-6-ethyl-3 ,4,4',5' tetrahydrospiro[chromene-2,3'-furan]-4-yI)amino)-2-hydroxypropyl)-2-(methyloxy) acetam ide; N-(( 1S,2R)- 1-((3 ,5-difluorophenyl) methyl)-3 -(((2S,4S)-6-ethyl-3 ,4,4',5' 5 tetrahydrospiro[chromene-2,3'-furan]-4-yI)amino)-2-hydroxypropyl)acetamide; N-(( 1 S,2R)- 1 -((3-cyanophenyl)methyl)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3',4' d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)am ino)-2 hydroxypropyl)acetam ide; 2-((3 -chloro-2-methylphenyl)thio)-N-(( I S,2 R)-3 -(((4S)-6-ethyl-3,4 10 d ihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)-2-hydroxy- I-(phenylmethyl) propyl)acetam ide; N-(( IS,2R)-3-(((4'S)-6'-(2,2-d imethyl propyl)-3 ',4'-d ihydrospiro [cyclobutane I ,2'-pyrano[2,3 -b] pyridin]-4'-yI)amino)-2-hydroxy- I-(phenylmethyl) propyl)-2-( I-oxo I ,3-dihydro-2H-isoindol-2-yI)acetamide; 15 N-((]I S,2 R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3',4,4',5 -tetrahydrospiro [furan-3 ,2' pyrano[2,3 -b] pyridin]-4'-yI) am ino)-2-hydroxy- I-(phenylmethyl) propyl)-2-( 1-oxo- 1,3 dihydro-2H-isoindol-2-yI)acetamide; N-(( IS,2R)-3 -(((3 S,4'S)-6'-(2,2-d imethylpropyl)-3 ',4,4',5-tetrabydrospiro [furan 3 ,2'-pyrano[2,3 -bjpyridin]-4'-yI) amino)-2-hydroxy- 1-(phenylmethyl)propyl)-2 20 (methyloxy)acetamide; N-((]I S,2R)-3 -(((4'S)-6'-(2,2-dimetbylpropyl)-3 ',4'-d ihydrospiro [cyclobutane I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)-2-hydroxy-lI-(phenylmethyl) propyl)-2-(3 methyl-5-isoxazolyl) acetamide; N-(( I S,2R)-3 -(((4S)-6-ethyl-7-fluoro-3 ,4-d ihydrospiro-2,2-spirocyclobutyl 25 [chromene-2, I '-cyclobutan]-4-yI)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2-(2-oxo- I pyrrol id inyl)acetamide; N-((]I S,2R)-3 -(((4S)-6-ethyl-3 ,4-dihydrospiro-2,2-spirocyclobutyl [chromene 2,1 '-cyclobutan]-4-yI)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2-(2 pyrazinyloxy)acetamide; 30 N-((]I S,2 R)- 1 -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3 ,4-d ihydrospiro-2,2 spirocyclobutyl [chromene-2, I '-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-2-(2 pyrimid inyloxy)acetamide; WO 2007/061670 PCTIUS2006/044058 - 262 N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, I'-cyclopentan]-4 yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((5R)-2-(3-methylbutyl)-2,3,4,5 tetrahydro- I H-2-benzazepin-5-yi) acetamide; N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4 5 yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(l H-1,2,3-triazol-4-yl) acetamide; N-((IS,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4 yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(4-propyl- IH-1,2,3-triazol-I yl)acetamide; N-((1 S,2R)- I -((3-cyanophenyl)methyl)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro 10 [cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxypropyl)-2 (methyloxy)acetamide; N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(3-methylbutyl)-3',4'-dihydrospiro [cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-I -(phenylmethyl)propyl)-2 (methyloxy)acetamide; 15 N-((] S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane I,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(2 methyl-1,3-thiazol-4-yi) acetamide; 2-(3,5-dimethyl-4-isoxazolyl)-N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- I,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- I 20 (phenylmethyl)propyl)acetamide; N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(I H 1,2,4-triazol- I-yl) acetamide; N-((] S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane 25 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(2H I,2,3-triazol-2-yl) acetamide; N-((I S,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4-dihydrospiro[chromene-2, ' cyclobutan]-4-yl)amino)- 1 -((3-cyanophenyl)methyl)-2-hydroxypropyl) acetamide; (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3 30 hydroxy-I -phenylbutan-2-yi)-3 -(pyridin-2-yl)acrylamide; N-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4 yl)amino)-2-hydroxy- 1 -((3-(2-propen- I -yl)phenyl)methyl)propyl)-6-heptenamide; N-((I S,2R)-l -((1 -acetyl-3-piperidinyl) methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro [chromene-2, l'-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 263 N-(( I S,2R)-3 -(((4S)-6-ethyl-3 ,4-dihydrospiro[chromene-2, I '-cyclobutan]-4 yI)amino)-2-hydroxy- I-(phenylmethyl) propyl)-2-( I-oxo- 1,3 -d ihydro-2H-isoindol-2 yl)acetamide; 3-( I H-benzimidazol- I -yi)-N-(( I S,2R)-3-(((4S)-6-ethyl-3,4 5 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)-2-hydroxy- 1 (phenylmethyl)propyl)-2-methylpropanam ide; (2E)-3 -(4-bromo-2-furanyl)-N-(( I S,2 R)-3 -(((4S)-6-ethyl-3 ,4 dihydrospirorchromene-2,1I'-cyclobutan]-4-yI)amino)-2-hydroxy- 1 (phenylmethyl)propyl)-2-propenamide; 10 N-(( I S,2R)-3-(((4S)-6-ethyl-3 ,4-dihydrospiro[chromene-2, I '-cyclobutan]-4 yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-( I -phthalazinylthio)acetam ide; N-(( I S,2R)-3 -(((4S)-6-ethyl-3 ,4-dihydrospiro[chromene-2, I '-cyclobutan]-4 yI)am ino)-2-hydroxy-1I-(phenylmethyl) propyl)-2-(2-thienylthio)propanamide; 'N-(( I S,2R)- 1 -((3 ,5-difluorophenyl)methyl)-2-hydroxy-3 -(((4S)-6-( 1-methyl- I H 15 1,2,3 -triazol-4-yI)-3,4-dihydrospiro[chromene-2, I '-cyclobutan]-4 yI)amino)propyl)acetam ide; 'N-((]I S,2R)-2-hydroxy-3-(((4S)-6-( I-methyl-I H-I ,2,3-triazol-4-yl)-3,4 dihydrospirorchromene-2, I t -cyclobutan]-4-yl)amino)- I -(phenylmethyl)propyl)acetamide; 'N-((]I S,2R)-3 -(((4S)-6-(2-fluoro-2-methylpropyl)-3 ,4-dihydrospiro[chromene 20 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-(( I S,2 R)-3-(((4S)-6-((2R)-2-fluoropropyl)-3,4-d ihydrospiro[chromene-2, IV cyclobutan]-4-yI)am ino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2-fluoro-2-methylpropyl)-3 '4'. d ihydrospirolcyclobutane-1I,2'-pyrano[2,3-b] pyrid in]-4'-yI)amino)-2-hydroxy- 1 25 (phenylmethyl)propyl)acetamide; 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2-fluoro-2-methylpropyl)-3 ,4' d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-bjpyridin]-4'-yI)am ino)-2-hydroxy- I (phenylmethyl)propyl)acetamide; 'N-(( I S,2R)-2-hydroxy-3 -(((4'S)-6'-(2-metbylpropyl)-3 1,4' 30 dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-blpyridin]-4'-yI)amino)- I1 (phenylmethyl)propyl)acetamide; 'N-(( I S,2R)- 1 -((3 -cyanophenyl)methyl)-3 -(((4'S)-6'-(2-fluoro-2-methylpropyl) 3',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetam ide; WO 2007/061670 PCT/US2006/044058 - 264 'N-(( I S,2 R)-3 -(((4'S)-6'-(2-lluoro-2-methylpropyl)-3 ',4' d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4'-yI)amimo)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4S)-6-(2,2-dimethylpropyl)-8-(4-morpholinyl)-3 ,4 5 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)- I -((4-fluoropbenyl)methyl)-2 hydroxypropyl)acetamide; 'N-(( 1 S,2R)-3 -(((4S)-6-(2,2-d imethylpropyl)-8-(4-morpholinyl)-3 ,4 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)-2-hydroxy- I (phenylmethyl)propyl)acetam ide; 10 'N-((]I S)- 1 -((1 R)-2-(((4'S)-6'-(2,2-d imethylpropyl)-3',4' dihydrospirolcyclobutane- I ,2'-pyrano[2,3 -b] pyridin]-4'-yI)amino)- I -hydroxyethyl)-3 methylbutyl)acetamide; 'N-((]I S)- 1 -((] R)-2-(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4' dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)-l1-hydroxyethyl)-3 15 methyl-3-buten-1I-yI)acetamide; 'N-((]I S,2R)- 1 -((3 -cyanophenyl)methyl)-3 -(((4'S)-6'-(2,2-dimethyipropy)-3 149.. d ihydrospiro[cyclobutane-1I,2'-pyranolj2,3-b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-(( 1 S,2R)-2-hydroxy-3 -(((5'S)-3'-methyl-5',8'-dihydro-6'H-spiro~cyclobutane 20 1 ,7'-quinolin]-5'-yl)amino)- I -(phenylmethyl)propyl)acetamide; 'N-(( 1 S,2R)- 1 -((3 -cyanophenyl)methyl)-2-hydroxy-3 -(((5'S)-3'-methyl-5 ',8' dihydro-6'H-spiro[cyclobutane-1I,7'-quinolin]-5'-yI)amino)propyl)acetamide; 'N-((]I S,2R)- 1 -((3,5 -di fluorophenyl)methyl)-2-hydroxy-3 -(((4S)-6-( I,3 -oxazol-2 yI)-3 ,4-dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)propyl)acetamide; 25 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospiro[cyclopentane I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetam ide; 'N-(( 1 S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl) 3 ,4'-d ihydrospiro~cyclopentane- I ,2'-pyrano[2,3-b] pyrid in]-4'-yI)amino)-2 30 hydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospirolcyclopentane I ,2 t -pyranoj[2,3-bjpyridin]-4'-yI)amino)- 1 -((3-fluorophenyl)methyl)-2 bydroxypropyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 265 'N-(( I S,2 R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospiro[cyclopropane I ,2'-pyrano[2,3-b] pyridin]-4'-yl)amino)- I -((4-fluoro-3-methylphenyl)methyl)-2 hydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-dihydrospiro[cyclopent-3 -ene 5 1 ,2'-pyrano[2,3-bjpyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetam ide; 'N-(( I S,2 R)-3 -(((4'S)-6'-(( I S)- I -fluoro-2-metbylpropyl)-3 ',4' d ihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3 -blpyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 10 N-(( I S,2R)-3-(((4'S)-6'-(( I R)- I -fluoro-2-methylpropyl)-3',4' d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)-3 -(((4'S)-6'-(( I R)- I -fluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -blpyridin]-4'-yI)amino)- 1 -((4 15 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)-3 -(((4'S)-6'-(( I S)- I -fluoro-2-methylpropyl)-3 14g.. dihydrospirolcyclobutane- I ,2'-pyrano[2,3 -blpyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(( I S)- I -fluoro-2-methylpropyl)-3',4' 20 dihydrospirolcyclobutane- 1 ,2'-pyrano[2,3 -b]pyrid in]-4'-yI)amino)-2-hydroxy- I1 (phenyl methyl)propyl)acetamide; 'N-((]I S,2R)-3-(((4'S)-6'-(( IS)-]I -fluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- I -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 25 'N-(( I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydro- I 'H spiro~cyclobutane- 1 ,2'-quinol in]-4'-yI)amimo)- I -((4-fl uorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-(( I S,2R)- 1 -((3,5-difluorophenyl)methyl)-3 -(((4'S)-6'-(2,2-d imethyipropyl) 3',4'-dihydro- I 'H-spiro[cyclobutane- I ,2'-quinolin]-4'-yl)amino)-2 30 hydroxypropyl)acetamide; 'N-((]I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydro- I 'H spiro[cyclobutane- I ,2'-quinol in]-4'-yI)amino)- I -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 266 'N-((]I S,2R)- 1 -((3 -bromo-4-fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 dimethylpropyl)-3 ',4'-d ihydro- I 'H-spiro[cyclobutane- I ,2'-qu inol in]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-(( 1 S,2 R)-3 -(((4'S)-6'-(2,2-d imethyipropyl)- I t -oxo-3 ',4'-d ihydro- I H 5 spiro~cyclopentane- I ,2'-naphthalen]-4'-yi)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'R)-6'-(2,2-dimethylpropyl)- I t -oxo-3 ',4'-d ihydro- P H spiro[cyclopentane- I ,2'-naphthalen]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 10 'N-(( I S,2R)-3 -(((3 S,4'S)-6'-ch Ioro-3 ',4,4',5 -tetrahydrospiro[furan-3 ,2'-pyrano[2,3 b]pyridin]-4'-yI)am ino)-2-hydroxy- I -(phenylmethyl)propyl)acetam ide; N-(( 1 S,2R)-3 -(((3 R,4'S)-6'-chloro-3',4,4',5 -tetrahydrospiro[furan-3 ,2'-pyrano[2,3 b] pyridin]-4'-yI)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-ethyl-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 15 b] pyridin]-4'-yI)amino)- I -((3-fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( 1 S,2R)- 1 -((3 -chloro-5-fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino) 2-hydroxypropyl)acetamide; 'N-(( 1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' 20 pyrano[2,3-b] pyrid in]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetam ide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3',4'-d ihydrospiro[cyclobutane- I ,2' pyrano[2,3-c]pyridin]-4'-yI)amino)- I -((3 -fluorophenyl)methyl)-2 hydroxypropyl)acetam ide; 25 'N-((]I S,2R)-3-(((4'S)-6'-(2,2-dimetbylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3 -c] pyridin]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetam ide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2-fluoro-2-methylpropyl)-3 ',4' d ihydrospiro~cyclobutane-1I,2'-pyrano[2,3-b] pyrid in]-4'-yI)amimo)- 1 -((4 30 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2S)-3 -(((4'S)-6'-(2-fluoro-2-methylpropyl)-3 '4'. d ihydrospiro~cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 267 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yI)amino)- I -((4-fluoro-3 -methylphenyl)methyl)-2 hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' 5 pyrano[2,3 -b]pyridin]-4'-yI )amino)- I -((3-fluoro-4-methylphenyl)methyl)-2 hydroxypropyl)acetam ide; 'methyl ((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b] pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)carbamate; 10 'N-(( 1 S,2 R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4'-d ihydrospiro[cyclopropane I ,2'-pyranoll2,3-b]pyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-(( I S,2R)- I -((4-fluoro-3 -methylphenyl)methyl)-3 -(((4'S)-6'-(2-fluoro-2 methylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)-2 15 hydroxypropyl)acetamide; 'N-(( I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yI)am ino)-2-hydroxy- 1 -((3 (methyloxy)phenyl)methyl)propyl)acetamide; 'N-(( I S,2R)- I -((4-chlorophenyl)methyl)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4' 20 dihydrospiro~cyclopropane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-(( I S,2 R)-3 -(((4'S)-6'-(2,2-d imethyl-3 -(methyloxy)propyl)-3 I4'.. d ihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-b] pyrid in]-4'-yI)amino)- I -((4 fluorophenyl)metbyl)-2-hydroxypropyl)acetamide; 25 'N-((]I S,2R)-3 -(((4'S)-8'-(dimethylam ino)-6'-(2,2-d imethylpropyl)-3 ',4' d ihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-c]pyrid in]-4'-yI)am ino)-2-hydroxy- I (phenylmethyl)propyl)acetamide; 'N-(( I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(methylamino)-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- 1 -((4 30 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; N-(( I S,2R)-3-(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro~cyclobutane- I ,2'-pyrano[2,3 -c] pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide-, WO 2007/06 1670 PCTJUS2006/044058 - 268 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-(ethylam ino)-3 141.. dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3 -c] pyrid in]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-(( I -methylethyl)am ino)-3 ,4' 5 dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( 1 S,2R)-3 -(((4'S)-8'-(cyclopropylamino)-6'-(2,2-d imethylpropyl)-3',41.. dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 10 'N-(( I S,2 R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-8'-(tetrahydro-2H-pyran-4 ylamino)-3 ',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-c] pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-8'-chloro-6'-(2,2-d imethylpropyl)-3 '4'. dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-clpyridin]-4'-yI)amino)- 1 -((3 15 fluorophenyl)metbyl)-2-hydroxypropyl)acetam ide; 'N-(( 1 S,2R)-3 -(((4'S)-8'-(d imethylam ino)-6'-(2,2-dimethylpropyl)-3 '4'.. d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -c] pyrid in]-4'-yI)amino)- 1 -((4 fi uorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)-3-(((4'S)-8'-((, I, -dimethylethyl)amino)-6'-(2,2-dimethylpropyl)-3',4' 20 dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -c] pyrid in]-4'-yl)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-(methylam ino)-3 ',4' dihydrospiro~cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 25 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-8'-(ethylam ino)-3',4' dihydrospiro~cyclobutane- 1 ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( 1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(tetrahydro-2H-pyran-4 ylam ino)-3',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c] pyridin]-4'-yI)amino)- 1 -((3 30 fi uorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-8'-(d imethylamino)-6'-(2,2-d imethylpropyl)-3',41.. dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; WO 2007/061670 PCT/US2006/044058 - 269 'N-(( I S,2 R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-oxo-3',4', 7', 8' tetrahydrospiro[cyclobutane-1I,2'-pyrano[2,3-c~pyridin]-4'-yI)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2 R)-3 -(((4'R)-6'-(2,2-di methylpropyl)-8'-(( 1 -methylethyl)oxy)-3 ',4' 5 dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 -c]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; N-(( 1 S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-(( I-methylethyl)oxy)-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-cjpyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 10 'N-(( 1 S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-(( I -methylethyl)oxy)-3 ',4' dihydrospiro[cyclobutane-] ,2'-pyranoL2,3 -c] pyridin]-4'-yI)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; N-((]I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-8'-(( I -methylethyl)oxy)-3 ',4' di hydrospiro[cyclobutane- I ,2'-pyrano[2,3-c] pyridin]-4'-yI)amino)- 1 -((3 15 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)- 1 -((3 ,5-difluorophenyl)methyl)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8' ((1 -methylethyl)oxy)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4' yI)amino)-2-hydroxypropyl)acetamide; N-((I S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8' 20 ((1 -methylethyl)oxy)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c] pyridin]-4' yI)am ino)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2 dimethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -cipyrid in]-4'-yI)amimo) 2-hydroxypropyl)acetamide; 25 'N-(( I S,2R)-3 -(((4'S)-8'-(dimethylam ino)-6'-(2,2-d imethylpropyl)-3 ',4' d ihydrospi ro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- 1 -((4 (d imethy lam ino)phenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)- I -((4-chlorophenyl)methyl)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2 dimethylpropyl)-3 ',4'-dihydrospiro~cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amimo) 30 2-hydroxypropyl)acetamide; 'N-(( I S,2R)- I -((2,3-difluoraphenyl)methyl)-3-(((4'S)-8-(dimethylamino)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino) 2-hydroxypropyl)acetam ide; WO 2007/061670 PCT/US2006/044058 - 270 'N-((] S,2R)-3-(((4'S)-8'-(cyclopropylamino)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; '1,1-dimethylethyl (2-(((4'S)-4'-(((2R,3 S)-3 -(acetylam ino)-4-(3 -fluorophenyl)-2 5 hydroxybutyl)amino)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-c]pyridin]-8'-yl)amino)ethyl)carbamate; 'N-(( IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(3-(methyloxy)-1-azetidinyl) 3',4'-dihydrospiro[cyclobutane-l,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 10 'N-((l S,2R)-3-(((4'S)-8'-amino-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-l-((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((] S,2R)-3-(((4'S)-8'-((2-aminoethyl)amino)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- l,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-1 -((3 15 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(methyloxy)-3',4' dihydrospiro[cyclobutane-l,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((] S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-((I -methylethyl)oxy)-3',4' 20 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((I -methylethyl)oxy)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 25 'N-((] S,2R)-3-(((4'R)-6'-(2,2-d imethylpropyl)-8'-((I -methylethyl)oxy)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((] S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((I -methylethyl)oxy)-3',4' dihydrospiro[cyclobutane- l,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-1 -((3 30 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((I S,2R)- 1 -((3,5-difluorophenyl)methyl)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8' ((1 -methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane- l,2'-pyrano[2,3-c]pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide; WO 2007/061670 PCT1US2006/044058 - 271 'N-((]I S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8' ((I -methylethyl)oxy)-3 ',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-c]pyridin]-4' yI)amino)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-(methyloxy)-3 ',4' 5 dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3 -c]pyridin]-4'-yI)amimo)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-(3 -(methyloxy)- I -azetid inyl) 3',4'-di hydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 10 'N-(( 1 S,2R)- 1 -((4-fluorophenyl)methyl)-2-hydroxy-3 -(((1 s,3 R,4'S)-3-methyl-6' (2-methylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4' yl)amino)propyl)acetamide; 'N-((]I S,2R)- I -((4-fl uorophenyl)methyl)-2-hydroxy-3 -(((I r,3 S,4'S)-3 -methyl-6' (2-methylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4' 15 yI)amino)propyl)acetamide; 'N-(( I S,2R)- 1 -((3 -fluorophenyl)methyl)-2-hydroxy-3 -(((1 s,3R,4'S)-3-methyl-6' (2-methylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3 -b]pyridin]-4' yI)amino)propyl)acetam ide; 'N-(( I S,2R)- I -((4-chlorophenyl)methyl)-2-hydroxy-3 -(((1 s,3 R,4'S)-3 -methyl-6' 20 (2-methylpropyl)-3',4'-dihydrospi ro[cyc lobutane- I ,2'-pyrano[2,3-b] pyridin]-4' yI)am ino)propyl)acetam ide; 'N-(( I S,2R)-3-((( I S,2S,4'S)-6'-(2,2-dimethylpropyl)-2-methyl-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4 fi uorophenyl)methyl)-2-hydroxypropyl)acetam ide; 25 'N-(( 1 S,2R)- I -((4-chlorophenyl)methyl)-3-((( I S,2S,4'S)-6'-(2,2-dimethylpropyl) 2-methyl-3 ',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)am ino)-2 hydroxypropyl)acetam ide; 'N-(( I S,2 R)-3 -(((I R,2R,4'S)-6'-(2,2-dimethylpropyl)-2-methyl-3 ,4t d ihydrospiro~cyclobutane-1I,2'-pyrano[2,3-bjpyrid in]-4'-yI)amino)- 1 -((4 30 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)- I -((4-ch Iorophenyl)methyl)-3 -(((1 R,2 R,4'S)-6'-(2,2-d imethyipropyl) 2-methyl-3 ',4'-d ihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b] pyrid in]-4'-yI)am ino)-2 hydroxypropyl)acetamide; WO 2007/06 1670 PCTIUS2006/044058 - 272 'N-(( I S,2R)-3-((( I S,2R,4'S)-6'-(2,2-d imethylpropyl)-2-methyl-3 ',4' dihydrospiro~cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-((]I S,2R)- I -((4-ch Iorophenyl)methyl)-3-((( I S,2R,4'S)-6'-(2,2-dimethylpropyl) 5 2-methyl-3 ',4'-dihydrospirorcyclobutane-1I,2'-pyrano[2,3 -b] pyrid in]-4'-yI)am ino)-2 hydroxypropyl)acetamide; 'N-((I S,2R)-3-(((I R,2S,4'S)-6'-(2,2-dimethylpropyl)-2-methyl-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 10 'N-(( I S,2 R)- I -((4-ch Iorophenyl)methyl)-3-((( 1 R,2S,4'S)-6'-(2,2-dimethylpropyl) 2-methyl-3',4'-d ihydrospirolcyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4'-yI)am ino)-2 hydroxypropyl)acetamide; 'methyl ((I S,2R)-1I-((4-chlorophenyl)methyl)-3 -(((4'S)-6'-(2,2-d imethyipropyl) 3',4'-d ihydrospi ro~cyclobutane- I ,2'-pyrano[2,3 -b] pyridin]-4'-yl)amino)-2 15 hydroxypropyl)carbamate; 'N-((]I S,2 R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-d ihydrospiro[cyclobutane- 1,2' pyrano[2,3-blpyrid in]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2-hydroxypropyl)-2 (methyloxy)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-di methylpropyl)-3',4'-d ihydrospiro[cyclobutane- 1,2' 20 pyrano[2,3 -bipyrid in]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2-hydroxypropyl)-2 fluoroacetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' pyranoll2,3-blpyridinl-4'-yI)amino)- I -((4-fl uorophenyl)methyl)-2-hydroxypropyl)-2,2 difluoroacetamide; 25 'N-(( I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-blpyrid inl-4'-yI)amino)- I -((4-fl uorophenyl)methyl)-2-hydroxypropyl)-2,2,2 trifluoroacetamide; 'N-((]I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b] pyridin]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2-hydroxypropyl)-3 ,3,3 30 trifluoropropanamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' pyrano[2,3 -b] pyridin]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2-hydroxypropyl)-3 (methyloxy)propanamide; WO 2007/06 1670 PCT/US2006/044058 - 273 'N-(( I S,2R)-3-(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-dihydrospiro[cyclobutane-1I,2' pyrano[2,3-bjpyridin]-4'-yI)amino)-2-hydroxy- I -(I ,3 -thiazol-4 ylmethyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane-1I,2' 5 pyrano[2,3 -b]pyridin]-4'-yI)amino)-2-hydroxy- I -(4-pyridinylmethyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- I -((2-propyl- 1,3 -thiazol-4 yI)methyl)propyl)acetam ide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- 1,2' 10 pyrano[2,3-b] pyridin]-4'-yI)am ino)-2-hydroxy- 1 -((5-propyl- 1,3 -th iazol-4 yI)methyl)propyl)acetamide; 'N-(( I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- 1 -(1 ,3-thiazol-5 ylmethyl)propyl)acetamide; 15 'N-(( I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b] pyridin]-4'-yl)am ino)-2-hydroxy- I -((2-methyl- 1,3 -thiazol-4 yl)metbyl)propyl)acetamide; 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2' pyrano[2,3-b] pyridin]-4'-yI)amino)-2-hydroxy- I -((2-methyl-4 20 pyridinyl)methyl)propyl)acetamide; 'N-((]I S,2R)- I -((4-ch loro- 1 ,3-thiazol-2-yI)methyl)-3 -(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yl)amino) 2-hydroxypropyl)acetam ide; 'N-(( I S,2R)- I -((2-ch Ioro-4-pyrid inyl)methyl)-3 -(((4'S)-6'-(2,2-d imethyipropyl) 25 3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetam ide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2' pyrano[2,3-b] pyridin]-4'-yI)amino)-2-hydroxy- I -((2-(methyloxy)-4 pyrid inyl)methyl)propyl)acetamide; 30 'N-(( I S,2R)- I -((2-chloro-6-methyl-4-pyridinyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3 ',4'-dihyd rospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino) 2-hydroxypropyl)acetam ide; WO 2007/061670 PCTJUS2006/044058 - 274 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b] pyrid in]-4'-yI)amino)-2-hydroxy- 1 -((2-((2,2,2-trifluoroethyl)oxy)-4 pyrid inyl)methyl)propyl)acetainide;, 'N-(( I R,2S)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' 5 pyrano[2,3-b] pyridin]-4'-yI)amino)-2-hydroxy- I -(4-pyridinylmethyl)propyl)acetam ide; 'N-(( 1 S,2R)- 1 -(1 -benzofuran-2-yI methyl)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 1,4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetam ide; 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1I,2' 10 pyrano[2,3 -b] pyridin]-4'-yI)amino)-2-hydroxy- I -((2-oxo- I ,2-dihydro-4 pyridinyl)methyl)propyl)acetamide; 'N-(( I S,2R)-3-(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-blpyridin]-4'-yI)amino)-2-hydroxy- 1 -((2-(trifluoromethyl)-4 pyrimid inyl)methyl)propyl)acetamide; 1 5 'N-(( 1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b] pyridin]-4'-yI)amino)-2-hydroxy- 1 -((4 (trifluoromethyl)phenyl)methyl)propyl)acetam ide; 'N-(( 1 S,2R)- 1 -((4-ch Iorophenyl)methyl)-3 -(((4'S)-6'-(2-cyano-2-methylpropyl) 3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)-2 20 hydroxypropyl)acetamide; 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2,2-d imethyipropyl)-3 ',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- 1 -((I -methyl-2-oxo- 1 ,2-dihydro-4 pyrid inyl)methyl)propyl)acetamide; 'N-((]I S,2R)- I -((4-ch Iorophenyl)methyl)-3 -(((4'S)-6'-(3 ,3-d ifiuoro-2,2 25 dimethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4'-yI)amino) 2-hydroxypropyl)acetam ide; 'N-((]I S,2R)- I -((4-ch Iorophenyl)methyl)-3 -(((4'S)-6'-(2,2-d imethyl-3 -butyn- I -yI) 3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetam ide; 30 'N-(( I S,2 R)- I -((4-chlorophenyl)methyl)-3 -(((4'S)-6'-(2,2-dimetlhylbutyl)-3 ',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide; WO 2007/06 1670 PCTJUS2006/044058 - 275 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2-cyano-2-methylpropyl)-3 ',4' dihydrospiro~cyclobutane- I,2'-pyrano[2,3 -blpyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N -((1 S,2R)-3-(((4'S)-6'-(2-cyano-2-methylpropyl)-3',4' 5 dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 -bjpyridin]-4'-yI)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-((]I S,2R)-3 -(((4'S)-6'-(3 ,3-difluoro-2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b] pyridin]-4'-yI)am ino)-2-hydroxy- I1 (phenylmethyl)propyl)acetamide; 10 'N-(( I S,2R)-3 -(((4S)-2-ethyl-4,7-dihydro-5 H-spiro[ I -benzothiophene-6, V cyclobutan]-4-yI)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4' dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 -b]pyrid in]-4'-yI)amino)-2-hydroxy- I (phenylmethyl)propyl)acetam ide; 15 'N-((]I S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((3 S,4'R)-6'-(2,2-dimethylpropyl) 3',4,4',5 -tetrahydrospiro[furan-3 ,2'-pyrano[2,3-b] pyrid in]-4'-yI)am ino)-2 bydroxypropyl)acetamide; N-(( I S,2R)- I -((3 ,5-d ifluorophenyl)methyl)-3 -(((3 R,4'R)-6'-(2,2-dimetbylpropyl) 3',4,4',5-tetrahydrospiro[furan-3 ,2'-pyrano[2,3 -b] pyrid in]-4'-yI)amino)-2 20 bydroxypropyl)acetamide; -N-((]I S,2R)- 1 -((3 ,5-difluorophenyl)methyl)-3 -(((3 S,4'S)-6'-(2,2-d imethyipropyl) 3 ',4,4',5-tetrahydrospiro[furan-3 ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetam ide; N-(( I S,2R)- 1 -((3,5-difluorophenyl)methyl)-3-(((3 R,4'S)-6'-(2,2-dimethylpropyl) 25 3 ,4,4',5-tetrahydrospiro[furan-3 ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((3 S,4'S)-6'-(2,2-d imethylpropyl)-3 ',4,4',5-tetrahydrospiro[furan 3,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 30 N-(( I S,2R)-3-(((3 R,4'S)-6'-(2,2-d imethylpropyl)-3 ',4,4,5-tetrahydrospiro[furan 3,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetam ide; WO 2007/061670 PCT/US2006/044058 - 276 'N-((] S,2R)-l -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7' fluoro-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan 5 3,2'-pyrano[2,3-b]pyridinl-4'-yl)amino)-1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; N-((I S,2 R)-3 -(((3 R,4'S)-6'-(2,2-d imethylpropyl)-3',4,4',5-tetrahydrospiro[furan 3,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-1 -((3-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 10 'N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-1 -((4 15 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((l S,2R)-l -((4-chlorophenyl)methyl)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl) 3',4,4',5-tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; N-((l S,2R)-I-((4-chlorophenyl)methyl)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl) 20 3',4,4',5-tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((] S,2R)-1 -((4-chlorophenyl)methyl)-3-(((3S,4'R)-6'-(2,2-dimethylpropyl) 3',4,4',5-tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide ; 25 N-((IS,2R)-I-((4-chlorophenyl)methyl)-3-(((3R,4'R)-6'-(2,2-dimethylpropyl) 3',4,4',5-tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-I,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-1-((3-fluoro-4-(methyloxy)phenyl)methyl)-2 30 hydroxypropyl)acetamide; 'N-((IS,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-l,2' pyrano[2,3-b]pyridin]-4'-yl)amino)- I -((3-fluoro-4-(methyloxy)phenyl)methyl)-2 hydroxypropyl)acetamide; WO 2007/06 1670 PCT/US2006/044058 - 277 'N-(( 1 S,2R)- I -((4-chlorophenyl)methyl)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-7' fluoro-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -bjpyridin]-4'-yI)amino)-2 hydroxypropyl)acetam ide; 'N-((]I R,2S)-3 -(((4'S)-6'-(2,2-dimetbylpropyl)-3 ',4'-dihydrospiro[cyclobutane-1I,2' 5 pyrano[2,3-b]pyrid in]-4'-yI)amino)- I -((3 -fluoro-4-(trifluoromethyl)phenyl)methyl)-2 hydroxypropyl)acetamide ; N-((]I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-blpyrid in]-4'-yI)amino)- 1-((3 -fluoro-4-(trifluoromethyl)phenyl)methyl)-2 hydroxypropyl)acetam ide; 10 'N-(( IS,2R)-3-(((4'S)-6'-(( 1R)-lI-fluoro-2,2-dimethylpropyl)-3',4' dihydrospiro~cyclobutane- 1,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)- 1-((4 fluoropbenyl)methyl)-2-hydroxypropyl)acetam ide; N-((]I S,2R)-3 -(((4'S)-6'-(( I S)-l1-fluoro-2,2-dimethylpropyl)-3 ',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)-]1-((4 15 fluorophenyl)metbyl)-2-hydroxypropyl)acetam ide; 'N-(( IS,2R)- 1-((4-chlorophenyl)methyl)-3-(((3 S,4'S)-6'-(2,2-dimethylpropyl) 3',4,4',5-tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'-y)amino)-2 hydroxypropyl)acetamide; 'N-(( IS,2R)- 1-((4-chlorophenyl)methyl)-3 -(((3 R,4'S)-6'-(2,2-d imethyipropyl) 20 3',4,4',5-tetrahydrospiro[furan-3 ,2'-pyrano[2,3-b] pyridin]-4'-yI)am ino)-2 hydroxypropyl)acetam ide; 'N-(( 1 S,2R)-3 -(((3 S,4'S)-6'-(2,2-dimethylpropyl)-3 ',4,4',5-tetrahydrospiro[furan 3 ,2'-pyrano[2,3-blpyrid in]-4'-yI)amino)- I -((4-fl uorophenyl)methyl)-2 hydroxypropyl)acetam ide; 25 'N-(( I S,2R)-3 -(((3 R,4'S)-6'-(2,2-dimethylpropyl)-3 ',4,4',5 -tetrahydrospiroffuran 3 ,2'-pyranolj2,3-b]pyridin]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetam ide; 'N-(( I S,2R)- I -((4-chlorophenyl)methyl)-3-(((4'S)-6'-(( I R)- I -fluoro-2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyranoll2,3-b]pyridin]-4'-yI)amino) 30 2-hydroxypropyl)acetamide; N-((]I S,2R)- I -((4-chlorophenyl)methyl)-3 -(((4'S)-6'-(( I S)- I -fluoro-2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino) 2-hydroxypropyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 278 'N-(( I S,2R)-3 -(((4'S)-6'-(( I S)- I -fluoro-2,2-dimethylpropyl)-3 9,4t dihydrospiro~cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yl)amimo)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(( I R)- I -fluoro-2,2-dimethylpropyl)-3 ',4' 5 dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2 R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- I ,2' pyrano[2,3 -b]pyrid in]-4'-yI)amimo)- 1 -((4-fluoro-3 -(trifluoromethyl)phenyl)methyl)-2 hydroxypropyl)acetamide; 10 'N-((]I S,2R)- 1 -((2,3-difluorophenyl)methyl)-3-(((4'S)-6'-(( I R)- I -fluoro-2,2 d imethylpropyl)-3',4'-d ihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-b] pyridin]-4'-yI)amino) 2-hydroxypropyl)acetam ide; t N-(( I S,2R)-3 -(((4'S)-6'-(( I R)- I -fluoro-2,2-dimethylpropyl)-3 ,4t dihydrospirolcyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)- 1 -((3 15 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(( 1 R)- I -fluoro-2,2-dimethylpropyl)-3 ',4' d ihydrospiro[cyclobutane- I ,2 1 -pyrano[2,3-b] pyridin]-4'-yI)am ino)-2-hydroxy- 1 (phenylmethyl)propyl)acetam ide; 'N-(( I S,2R)- 1 -((4-chlorophenyl)methyl)-3-(((4'S)-6'-(( 1 R)- I -fluoro-2,2 20 d imethyl propyl)-3',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4'-yI)amino) 2-hydroxypropyl)acetamide; 'N-(( I S,2R)- 1 -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(( I R)- I -fluoro-2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino) 2-hydroxypropyl)acetamide; 25 'N-((]I S,2 R)-3 -(((4'S)-6'-(cyclobutylmethyl )-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyrid in]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-(( I S,2R)-3-(((5 R,5aS)-3-(2,2-dimethylpropyl)-5a,6,7,8-tetrahydro-5H pyrrolol 1',2': I ,5]pyrrolo[2,3-b]pyridin-5-yI)amino)- I -((4-fluorophenyl)methyl)-2 30 hydroxypropyl)acetamide; 'N-(( I S,2 R)- I -((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-( I hydroxypentyl)-3 ,4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4' yI)amino)propyl)acetamide; WO 2007/06 1670 PCTIUS2006/044058 - 279 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- 1 -((2,4,5 trifluorophenyl)methyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' 5 pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- 1 -((3,4,5 trifluorophenyl)methyl)propyl)acetamide; 'N-(( 1 S,2R)-3 -(((4'S)-6'-(cyclopropylmethyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2' pyrano[2,3 -b] pyridin]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 10 'N-(( 1 S,2R)- I -((4-fluoroplienyl)methyl)-2-hydroxy-3-(((4'S)-6'-(( I methylcyclopropyl)methyl)-3 ',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -blpyridin]-4' yI)am ino)propyl)acetam ide; 'N-((]I S,2R)-3-(((4'S)-6'-(3 ,3 -difluoro-2-methylpropyl)-3 9,4' d ihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3 -b] pyrid in]-4'-yI)amino)- 1 -((4 15 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-(( I S,2 R)-3 -(((4'S)-6'-(cyclopropylmetiyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' pyrano[2,3-blpyridin]-4'-yI)amino)- I -((3,5-difluorophenyl)methyl)-2 hydroxypropyl)acetam ide; 'N-((]I S,2R)-3 -(((4'S)-6'-((2S)-3 -fluoro-2-methylpropyl)-3',4' 20 dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyrid in]-4'-yI)am mno)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; N-(( I S,2R)-3 -(((4'S)-6'-((2 R)-3 -fluoro-2-methylpropyl)-3 ',4' dihydrospirolcyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)amimo)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 25 'N-((]I S,2R)- I -((3 ,5-d ifi uorophenyl)methyl)-3 -(((4'S)-6'-(2-ethylbutyl)-3 14t.. dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3 -b] pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-((]I S,2R)- I -((4-fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-propyl-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyrid in]-4'-yI)am ino)propyl)acetam ide; 30 'N-(( I S,2R)- I -((4-fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-((2S)-2 methylbutyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4' yI)amino)propyl)acetamide; 'N-(( I S,2R)-3-(((4'S)-6'-butyl-3',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 bipyrid in]-4'-yI)amino)- I-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; WO 2007/061670 PCTIUS2006/044058 - 280 'N-((l S,2R)-1 -((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-(2-methyl-I propen-1 -yI)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide; 'N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropanoyl)-3',4'-dihydrospiro[cyclobutane 5 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; '2-azido-N-((l S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2, ' cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-((I S,2R)- 1 -((3-cyanophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-(trifluoromethyl) 10 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide; 'N-((I S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6' (trifluoromethyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide; 'N-((I S,2R)- 1 -((3,4-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl) 15 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((] S,2R)- I -((3-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 20 'N-((] S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-d ihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)- I -((2-fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-((I S,2R)- I -((2,4-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl) 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 25 hydroxypropyl)acetamide; 'N-((l S)- 1 -((I R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)- I -hydroxyethyl)-3 pentyn- I -yl)acetamide; 'N-((I S,2R)-1-((3-chloro-4-fluorophenyl)methyl)-3-(((4'S)-6'-(2,2 30 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- I,2'-pyrano[2,3-b]pyridin]-4'-yl)amino) 2-hydroxypropyl)acetamide; 'N-((l S,2R)- I -((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; WO 2007/061670 PCT[US2006/044058 - 281 'N-(( I S,2R)- I -((2-ch Iorophenyl)methyl)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 '4'. dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-(( I S,2R)- 1 -((3 -(d imethylam ino)-4-fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 5 d imethylpropyl)-3 ',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 -b]pyrid in]-4'-yI)amino) 2-bydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1I,2' pyranor2,3-b] pyridin]-4'-yI)amino)- 1 -((3 -(ethylamino)-4-fluorophenyl)methyl)-2 Iiydroxypropyl)acetamide; 10 'N-(( 1 S,2R)- 1 -((3 ,4-dichlorophenyl)methyl)-3 -(((4'S)-6'-(2,2-dimethylpropyl) 3',4'-d ihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3 -b] pyridin]-4'-yI)am ino)-2-hydroxy- 1 -((4 15 ((trifluoromethyl)oxy)phenyl)methyl)propyl)acetamide; N-((]I S,2R)- I -((3-ch Ioro-4-fluorophenyl)methyl)-3-((( I s,3 R,4'S)-6'-(2,2 dimethylpropyl)-3-methyl-3',4'-dibydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)-2-hydroxypropyl)acetam ide; N-((]I S,2R)- I -((4-ch Iorophenyl)methyl)-3 -(((I s,3 R,4'S)-6'-(2,2-dimethylpropyl) 20 3-methyl-3',4'-dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetam ide; 'N-(( I S)- I -((I R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro~cyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4'-yI)amino)- I -hydroxyethyl)-4 penten- I -yI)acetamide; 25 'N-(( I S,2R)- 1 -((4-cbloro-3 -(trifluoromethyl)phenyl)methyl)-3-(((4'S)-6'-(2,2 d imethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)amino) 2-hydroxypropyl)acetamide; 'N-(( IS)- I -((] R)-2-((( I s,3R,4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4'-yI)amino)- I -hydroxyethyl)-4 30 penten-1I -yI)acetam ide; 'N-(( 1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b] pyridin]-4'-yI)amino)-2-hydroxy- 1 -((3 (trifluoromethyl)phenyl)methyl)propyl)acetam ide; WO 2007/061670 PCT/US2006/044058 - 282 'N-((] S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4' dihydrospiro[cyclobutane- I,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)- 1 -((3 (trifluoromethyl)phenyl)methyl)propyl)acetamide; 'N-((1 S,2R)- 1 -((4-chloro-3-fluorophenyl)methyl)-3-(((4'S)-6'-(2,2 5 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino) 2-hydroxypropyl)acetamide; 'N-((l S,2R)- 1 -((4-chloro-3-(methyloxy)phenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino) 2-hydroxypropyl)acetamide; 10 'N-((l S,2R)- I -(cyclopropylmethyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane-l,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((] S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-bJpyridin]-4'-yl)amino)-2-hydroxy- 1 -((2 15 methylcyclopropyl)methyl)propyl)acetamide; 'N-((I S,2R)- 1 -(cyclopropylmethyl)-3-(((4'S)-6'-(4,4-difluoro-2,2-dimethylbutyl) 3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((] S,2R)- 1 -(cyclopropylmethyl)-3-(((] s,3R,4'S)-6'-(2,2-dimethylpropyl)-3 20 methyl-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((I S,2R)- 1 -((2-((difluoromethyl)oxy)-4-pyridinyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino) 2-hydroxypropyl)acetamide; 25 'N- I -- ((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2, I'-cyclobutan] 4-yl)amino)- I -((3-cyanophenyl)methyl)-2-hydroxypropyl)-N-2-,N-2- dimethylglycinamide; 'methyl (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-3-((N,N-dimethylglycyl)amino)-2 hydroxybutyl)amino)-3,4-d ihydrospiro[chromene-2,l'-cyclobutane]-6-carboxylate; 30 'methyl (4S)-4-(((2R,3S)-3-(acetylamino)-4-(3-cyanophenyl)-2 hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2, I'-cyclobutane]-6-carboxylate; 'methyl (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-2-hydroxy-3 (((methyloxy)acetyl)amino)butyl)amino)-3,4-dihydrospiro[chromene-2, I'-cyclobutane]-6 carboxylate; WO 2007/061670 PCTIUS2006/044058 - 283 'N-(( I S,2R)-3 -(((4S)-6-ethyl-3 ,4-dihydrospiro[chromene-2,1I'-cyclobutan]-4 yI)am ino)-2-hydroxy- I -((methyloxy)methyl)propyl)acetam ide; 'N-(( 1 S,2R)-3 -(((4S)-6-ethyl-3 ,4-dihydrospiro~chromene-2, I '-cyclobutan]-4 yI)am ino)-2-bydroxy- I -((propyloxy)methyl)propyl)acetamide; 5 'N-((]I S,2R)-3 -(((4S)-6-ethyl-3 ,4-d ihydrospiro[chromene-2, I '-cyclobutan]-4 yI)amino)-2-hydroxy- I -(((phenylmethyl)oxy)methyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4S)-6-ethyl-3 ,4-d ihydrospiro[chromene-2, I '-cyclobutan]-4 yI)amino)-2-hydroxy- I -(I H-pyrazol- I -ylmethyl)propyl)acetam ide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' 10 pyrano[2,3 -b] pyrid in]-4'-yI)amino)-2-hydroxy- 1 -(I 1--pyrazol- I ylmethyl)propyl)acetam ide; 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2' pyrano[2,3-b] pyridin]-4'-yI)am ino)-2-hydroxy- I -((2-propen- I1 yloxy)methyl)propyl)acetamide; 15 'N-(( iS)- I -((I R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)- 1 -hydroxyethyl)-3 buten- I -yI)acetamide; 'N-((] IS)-!I -((] S)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)- I -hydroxyethyl)-3 20 buten- I -yI)acetam ide; 'N-(( 1S)- I -((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3,4' dihydrospi ro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)- I -hydroxyethyl)-4,4,4 trifluorobutyl)acetam ide; 'N-(( 1S,3 E)- I -((I R)-2-(((4'S)-6'-(2,2-d imethylpropyl)-3 '4'. 25 dihydrospiro~cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- I -hydroxyethyl)-3 penten- I -yI)acetamide; 'N-(( 1S)- I -(( I R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4'-yI)amino)- I -hydroxyethyl)-2 propen- I -yI)acetamide; 30 'N-(( IS)- 1 -((1 R)-2-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-b]pyridin]-4'-yI)am ino)- 1 -hydroxyethyl)-3 buten- I -yI)acetamide; WO 2007/061670 PCTIUS2006/044058 - 284 'N-((l S)- I -((] R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dibydrospiro[cyclobutane-1I,2'-pyrano[2,3 -bipyrid in]-4'-yI)amino)- I -hydroxyethyl)-3 hexyn- I -yI)acetamide; 'N-((]I S,2R)-3-(((2S,4S)-6-chloro-8-(4-morphol inyl)-3 ,4,4',5' 5 tetrahydrospiro[chromene-2,3'-furan]-4-yI)amino)- 1 -((3 ,5-d ifluorophenyl)methyl)-2 hydroxypropyl)acetam ide; N-(( 1S,2 R)-3 -(((2R,4S)-6-ch Ioro-8-(4-morphol inyl)-3 ,4,4',5' tetrahydrospiro[chromene-2,3'-furan]-4-yI)amino)- 1 -((3 ,5-di fluorophenyl)methyl)-2 hydroxypropyl)acetamide; 10 N-(( 1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro[chromene-2, 1' cyclobutan]-4-yI)amino)-2-hydroxy- 1 -(phenylmethyl)propyl)-2-( 1 H-2-metbyl-imidazol l-yI) acetamide; 'N-(( 1 S,2R)-3 -(((4'S)-6'-bromo-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 bjpyridin]-4'-yl)amino)- 1 -((3 ,5-difluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 15 'N-(( I S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-( I H-pyrazol I -yl)-3',4'-dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3 -b]pyridin]-4' yl)amino)propyl)acetamide; 'N-(( 1 S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-( I H-imidazol I -yI)-3',4'-d ihydrospiro[cyclobutane- I ,2-pyrano[2,3 -b]pyridin]-4' 20 yI)amino)propyl)acetamide; 'N-((]I S,2R)- 1 -((3 ,5-difluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-( 1,3 -th jazol 2-yI)-3 t ,4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 -b]pyridin]-4' yI)amino)propyl)acetam ide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3',4'-d ihydrospiro[cyclobutane- 1,2' 25 pyrano[2,3 -c] pyridin]-4'-yI)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetam ide; -N-((]I S,2R)- I -((3 -chloro-5-fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 d imethylpropyl)-3',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c] pyridin]-4'-yI)amino) 2-hydroxypropyl)acetamide; 'N-((]I S,2R)- 1 -((3 -chloro-5 -fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(2 30 hydroxy-2-methylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyrid in]-4' yI)amino)propyl)acetam ide; 'N-(( I S,2R)-3 -(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3 '4'. dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)- I -((3-chloro-5 fi uorophenyl)methyl)-2-hydroxypropyl)acetamide; WO 2007/06 1670 PCT/US2006/044058 - 285 'N-(( I S,2R)-3 -(((4'S)-8'-ch Ioro-6'-(2,2-d imethylpropyl)-3 ',4' dihydrospiro~cyclobutane- I ,2'-pyrano[2,3 -c]pyrid in]-4'-yI)amino)-2-bydroxy- I1 (phenylmethyl)propyl)acetamide; 'N-(( I S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((5'S)-3'-(2,2-dimethylpropyl) 5 5',6 t -dihydrospiro[cyclobutane- I ,7'-pyrano[2,3-c] pyridazin]-5'-yI)amino)-2 hydroxypropyl)acetamide; 'N-((]I S,2 R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-(4-morpholinyl)-3',4' dihydrospirolcyclobutane- 1 ,2'-pyrano[2,3-c]pyridin]-4'-yI)amino)-2-hydroxy- I (phenylmethyl)propyl)acetamide; 10 'N-((]I S,2R)-3-(((4'S)-6'-(2,2-dimetbylpropyl)-8'-( I -pyrrolidinyl)-3',4' d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-c] pyrid in]-4'-yI)amino)-2-hydroxy- I (phenylmethyl)propyl)acetamide; 'N-(( I S,2R)- I -((3-(dimethylam ino)-5-fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 dimetbylpropyl)-3 t ,4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b] pyrid in]-4'-yI)amino) 15 2-hydroxypropyl)acetamide; 'N-(( I S,2R)- I -((3-bromo-5 -fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 d imethylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyrid in]-4'-yl)amino) 2-hydroxypropyl)acetamide; 'N-(( I S,2 R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4' 20 dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; N-(( I S,2R)-3-((( I s,3R,4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4' d ihydrospirolcyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 25 'N-(( 1 S,2R)- 1 -((3,5 -difluoroplienyl)methyl)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 methyl-3 ',4'-d ihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyrid in]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-(( I S,2R)- I -((3,5-d ifluorophenyl)methyl)-3 -(((1 s,3 R,4'S)-6'-(2,2 d imethylpropyl)-3 -methyl-3 ',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b~pyridin]-4' 30 yI)amino)-2-hydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3-rnethyl-3',4' dihydrospiro~cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; WO 2007/06 1670 PCT/US2006/044058 - 286 'N-(( 1 S,2R)-3-((( 1s,3 R,4'S)-6'-(2,2-dimethylpropyl)-3 -methyl-3 '4'. dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 -b]pyridin]-4'-yl)amino)- 1 -((4 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)- 1 -((2,3 -difluorophenyl)methyl)-3 -(((1 r,3 S,4'S)-6'-(2,2 5 dimethylpropyl)-3 -methyl-3',4'-dihydrospiro[cyclobutane-l1,2'-pyrano[2,3-b] pyridin]-4' yl)amino)-2-hydroxypropyl)acetamide; 'N-(( I S,2R)- 1 -((2,3-difluorophenyl)methyl)-3-((( 1 s,3R,4'S)-6'-(2,2 dimethylpropyl)-3 -methyl-3',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 -b] pyridin]-4' yI)amino)-2-hydroxypropyl)acetamide; 10 'N-(( 1 S,2R)-3 -(((I s,3 R,4'S)-6'-(2,2-dimethylpropyl)-3 -methyl-3 ',4' dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-((]I S,2R)-3 -(((I s,3 S,4'S)-6'-(2,2-dimethylpropyl)-3 -hydroxy-3 '4' dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)- 1-((4 15 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)-3 -(((4S)-6-(cyc lopentylam ino)-3 ,4-dihydrospiro[chromene-2, P' cyclobutan]-4-yl)am ino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; 'N-(( 1 S,2R)-3 -(((4S)-6-(( 1,1 -dimethylethyl)amino)-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenyl methyl)propyl)acetamide; 20 'N-((]I S,2R)-3-(((4S)-6-chloro-8-( I H-imidazol- I -yi)-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yI)amino)- I -((3 ,5-difluorophenyl)methyl)-2 hydroxypropyl)acetam ide; 'N-((]I S,2R)-3 -(((4S)-6-bromo-3 ,4-dihydrospiro[chromene-2, 1 '-cyclobutan]-4 yl)am ino)-!I -((3,5 -difi uorophenyl)methyl)-2-hydroxypropyl)acetam ide; 25 'N-(( 1 S,2R)-3-(((4S)-8-( I H-benzimidazol- I -yi)-6-chloro-3,4 dihydrospiro[chromene-2, I '-cyclobutan]-4-yl)amino)- 1 -((3,5 -difluorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-(( I S,2 R)-3 -(((4S)-6-chloro-8-( 1 H-pyrazol- I1-yi)-3 ,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yI)amino)- 1 -((3 ,5-d ifluorophenyl)methyl)-2 30 hydroxypropyl)acetamide; 'N-(( 1 S,2R)- I -((3,S-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-( I H-pyrazol- I yI)-3,4-dihydrospiro[chromene-2, 1 '-cyclobutan]-4-yI)am ino)propyl)acetam ide; 'N-(( 1 S,2 R)-2-bydroxy- 1 -(phenylmethyl)-3 -(((4S)-6-(2-thienyl)-3 ,4 dihydrospiro[chromene-2, 1 '-cyclobutan]-4-yl)amino)propyl)acetamide; WO 2007/061670 PCT/US2006/044058 - 287 'N-((] S,2R)-2-hydroxy-3-(((4S)-6-(I-(2-methylpropyl)- 1 H-pyrazol-3-yl)-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- 1 -(phenylmethyl)propyl)acetamide; 'N-((] S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-(1-(2 methylpropyl)- I H-pyrazol-3-yI)-3,4-dihydrospiro[chromene-2, 1'-cyclobutan]-4 5 yl)amino)propyl)acetamide; 'N-((I S,2S)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-(l H-pyrazol- I yI)-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; 'N-((l S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-(I H-imidazol I -yI)-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; 10 'N-((1 S,2R)-2-hydroxy-3-(((4S)-6-( 1-methyl-I H-pyrazol-3-yI)-3,4 dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- I -(phenylmethyl)propyl)acetamide; 'N-((I S,2R)-l -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-( 1-methyl-i H pyrazol-3-yI)-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; 'N-((l S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-(2-thienyl) 15 3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; 'N-((l S,2S)-3-(((4S)-6-chloro-8-(l H-pyrazol- I-yl)-3,4-dihydrospiro[chromene 2,1 '-cyclobutan]-4-yl)amino)- I -((3,5-difluorophenyl)methyl)-2 hydroxypropyl)acetamide; 'N-((l S,2R)-3-(((4S)-7-bromo-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4 20 yl)amino)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((] S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-7-(I H-imidazol I-yl)-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; 'N-((4S)-4-(((2R,3S)-3-(acetylamino)-4-(3,5-difluorophenyl)-2 hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-6-yl)acetamide; 25 'N-((l S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-((3R) tetrahydro-3-furanylamino)-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4 yl)amino)propyl)acetamide; 'N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-(2H- 1,2,3 triazol-2-yI)-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; 30 'N-((l S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-(1 H- 1,2,4 triazol- 1-yl)-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; 'N-((1 S,2R)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-(2-oxo- I pyrrolidinyl)-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; WO 2007/061670 PCT/US2006/044058 - 288 'N-((l S,2R)-1 -((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4S)-6-(2-oxo- 1 azetidinyl)-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)propyl)acetamide; 'N-((l S,2R)-3-(((4S)-6-bromo-7-fluoro-3,4-dihydrospiro[chromene-2, ' cyclobutan]-4-yl)amino)- 1 -((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide; 5 'N-((I S,2R)- I -((3,5-difluorophenyl)methyl)-3-(((4S)-7-fluoro-6-((3R)-tetrahydro 3-furanylamino)-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 hydroxypropyl)acetamide; 'N-((l S,2R)-l -((3,5-difluorophenyl)methyl)-3-(((4S)-7-fluoro-3,4 dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide; 10 'N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-1 -((3-fluoro-5-(tetrahydro-2H-pyran-4 ylamino)phenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((l S,2R)-1 -((3,5-difluorophenyl)methyl)-3-(((4S)-7-fluoro-6-(tetrahydro-2H pyran-4-ylamino)-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2 15 hydroxypropyl)acetamide; 'N-((1 S,2R)- 1 -((3-fluorophenyl)methyl)-3-(((4S)-7-fluoro-6-(I H-pyrazol- 1-yl) 3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide; 'N-((] S,2R)- I -((4-fluorophenyl)methyl)-3-(((4S)-7-fluoro-6-(I H-pyrazol- I-yl) 3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide; 20 'N-((] S,2R)- 1 -(cyclobutylmethyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((1 S,2R)- 1 -((2-bromophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4' dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 25 hydroxypropyl)acetamide; 'N-((l S,2R)- 1 -((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6'-((I R)- I -fluoro-2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino) 2-hydroxypropyl)acetamide; 'N-((] S,2R)-3-(I -azatricyclo[6.2.2.0-2,7-]dodeca-2,4,6-trien-8-ylamino)-2 30 hydroxy- 1 -(phenylmethyl)propyl)acetamide; 'N-((I S,2R)-3-(((2R,4S)- l'-acetyl-6-ethyl-3,4-dihydrospiro[chromene-2,3' pyrrol idin]-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; N-((l S,2R)-3-(((2S,4S)- l'-acetyl-6-ethyl-3,4-dihydrospiro[chromene-2,3' pyrrolidin]-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide; WO 2007/06 1670 PCTIUS2006/044058 - 289 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4-dihydrospiro[cyclobutane-1I,2' pyrano[2,3 -b]pyridin]-4 t -yI)am ino)-2-hydroxy- 1 -((2,4,6 trifluorophenyl)methyl)propyl)acetam ide; 'N-(( 1 S,2R)-3 -(((4'S)-6'-(2,2-d imethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1,2' 5 pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- 1 -((2,3,4 trifluorophenyl)methyl)propyl)acetamide; 'N-(( 1 S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3 ',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((2,4,6 trifluorophenyl)methyl)propyl)acetam ide; 10 'N-(( I S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3 ',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)- 1 -((2,3,4 trifluorophenyl)methyl)propyl)acetamide; 'N-(( 1 S,2R)- I -((4-chlorophenyl)methyl)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 '4'. d ihydrospiro[cyclopentane-1I,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)-2 15 hydroxypropyl)acetamide; 'N-(( 1 S,2R)- 1 -((4-fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(phenylmethyl) 3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)propyl)acetamide; 'N-(( 1 S,2R)-2-hydroxy- I -(phenylmethyl)-3 -(((4S)-6-((2R)-tetrahydro-2-furanyl) 3 ,4-dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)am ino)propyl)acetam ide; 20 N-(( 1 S,2R)-2-hydroxy- 1 -(phenylmethyl)-3 -(((4S)-6-((2S)-tetrahydro-2-furanyl) 3 ,4-dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)am ino)propyl)acetamide; 'N-((]I S,2R)-2-hydroxy- I -(phenylmethyl)-3 -(((4'S)-6'-((2S)-tetrahydro-2 furanylmethyl)-3',4'-d ihydrospirolcyclobutane- I ,2'-pyrano[2,3-bjpyrid in]-4' yI)amino)propyl)acetamide; 25 N-(( 1 S,2R)-2-hydroxy- I -(phenylmethyl)-3 -(((4'S)-6'-((2R)-tetrahydro-2 furanylmethyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4' yI)amino)propyl)acetamide; 'N-(( 1 S,2R)-2-hydroxy- I -(phenylmethyl)-3 -(((4'S)-6'-((2R)-tetrahydro-2 furanylmethyl)-3 ',4'-di hydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4' 30 yI)amino)propyl)-2-(methyloxy)acetamide; N-(( I S,2R)-2-hydroxy- I -(phenylmethyl)-3 -(((4'S)-6'-((2S)-tetrahydro-2 furanylmethyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4' yI)amino)propyl)-2-(methyloxy)acetamide; WO 2007/061670 PCT/US2006/044058 - 290 'N-((l S,2R)-2-hydroxy- I -(phenylmethyl)-3-(((4S)-6-((2S)-tetrahydro-2 furanylmethyl)-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4 yl)amino)propyl)acetamide; N-((] S,2R)-2-hydroxy- I -(phenylmethyl)-3-(((4S)-6-((2R)-tetrahydro-2 5 furanylmethyl)-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4 yl)amino)propyl)acetamide; 'N-((I S,2R)-2-hydroxy-3-(((4S)-6-(5-hydroxypentyl)-3,4 dihydrospiro[chromene-2, '-cyclobutan]-4-yI)amino)-1 -(phenylmethyl)propyl)acetamide; 'N-((] S,2R)-2-hydroxy-3-(((4'S)-6'-(((2S)-2-methyltetrahydro-2-furanyl)methyl) 10 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)- 1 (phenylmethyl)propyl)acetamide; N-((l S,2R)-2-hydroxy-3-(((4'S)-6'-(((2R)-2-methyltetrahydro-2-furanyl)methyl) 3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)- I (phenylmethyl)propyl)acetamide; 15 'N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- 1 -(3-pyridinylmethyl)propyl)acetamide; 'N-((] S,2R)- 1 -((2,3-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl) 3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 20 'N-((l S,2R)- 1 -((2,6-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl) 3',4'-dihydrospiro[cyclobutane- I,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((] S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)-1 -((3 25 fluorophenyl)methyl)-2-hydroxypropyl)acetamide; 'N-((I S,2R)-1 -((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl) 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' 30 pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-I 1-(( -methyl-3 piperidinyl)methyl)propyl)acetamide; 'N-((] S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)- 1-((5-fluoro-3-pyridinyl)methyl)-2 hydroxypropyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 291 'N-((l S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' pyrano[2,3-b]pyridin]-4'-yl)amino)-1 -((5-fluoro-3-pyridinyl)methyl)-2 hydroxypropyl)acetamide; 'N-((I S,2R)-1 -((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6' 5 ((trimethylsilyl)methyl)-3',4'-dihydrospiro[cyclobutane-I,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide; 'N-((] S,2R)-l -((3,4-bis(methyloxy)phenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino) 2-hydroxypropyl)acetamide; 10 'N-((l S,2R)- I -((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6' ((trimethylsi lyl)methyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide; 'N-((] S,2R)- I -((2,3-difluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6' ((trimethylsi lyl)methyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4' 15 yl)amino)propyl)acetamide; 'N-((I S,2R)- 1 -((2,3-difluorophenyl)methyl)-3-(((4'S)-6'-(2-fluoro-2 methylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-bjpyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((l S,2R)- 1 -((3-bromo-4-fluorophenyl)methyl)-3-(((4'S)-6'-(2-fluoro-2 20 methylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((] S,2R)- 1 -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2-fluoro-2 methylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 25 'N-((] S,2R)- I -((3-chloro-4-fluorophenyl)methyl)-3-(((4'S)-6'-(2-fluoro-2 methylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-((1 S,2R)- 1 -((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6'-(2-fluoro-2 methylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-blpyridin]-4'-yl)amino)-2 30 hydroxypropyl)acetamide; 'N-((] S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4' dihydrospiro[cyclobutane-I,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-1 -((3 (trifluoromethyl)phenyl)methyl)propyl)acetamide; WO 2007/061670 PCT1US20061044058 - 292 -N-(( I S,2 R)- I -(1,3 -benzodioxol-5-ylmethyl)-3 -(((4'S)-6'-(2,2-d imethyipropyl) 3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4'-yI)amino)-2 hydroxypropyl)acetam ide; 'N-(( i S,2R)- I -(1,3 -benzodioxol-5-ylmethyl)-3 -(((4'S)-6'-(2-fluoro-2 5 methylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)-2 hydroxypropyl)acetamide; 'N-((]I S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4S)-6-(2,2,2-trifluoroethyl)-3 ,4 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)propyl)acetam ide; 'N-(( I S,2R)-2-hydroxy- 1 -(phenylmethyl)-3 -(((4S)-6-(2-pyridinyl)-3 ,4 10 dihydrospiro[chromene-2, I '-cyclobutan]-4-yI)amino)propyl)acetamide; 'N-(( I S,2R)-2-hydroxy- 1 -(phenylmethyl)-3 -(((4'S)-6'-(2,2,2-trifluoroethyl)-3 ,4t dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4'-yI)am ino)propyl)acetam ide; 'N-(( I S,2R)- I -((3 ,4-difluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(2,2,2 trifluoroethyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4' 1 5 yI)amino)propyl)acetamide; 'N-((]I S,2R)- I -((3-fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(2,2,2 trifluoroethyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4' yI)amino)propyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-bromo-3 ',4'-dihydrospi rolicyclobutane- I ,2'-pyrano[2,3 20 b]pyridin]-4'-yI)amino)- I -((4-fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)- 1 -((3 -fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(2-methylpropyl) 3',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)propyl)acetamide; 'N-(( 1 S,2R)- I -((4-fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(2-methylpropyl) 3',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide; 25 'N-(( 1 S,2R)- 1 -((3,5 -difluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(2 methylpropyl)-3 ',4'-dihydrospiro[cyclobutane- 1 ,2-pyrario[2,3-b] pyrid in]-4' yI)amino)propyl)acetamide; 'N(( S,2R)- 1 -((3 -cbloro-5 -fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(2 methylpropyl)-3 ,4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4' 30 yI)amino)propyl)acetamide; '3 -((2 S,3 R)-2-(acetylam ino)-3-hydroxy-4-(((4'S)-6'-(2-methylpropyl)-3 ',4' d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4'-yI)ami no)butyl)benzam ide; 'N-(( I S,2R)- 1 -((3 -cyanophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl) 3 ',4'-dihydrospiro[cyclobutarie- 1 ,2'-pyrano[2,3 -b] pyrid in]-4'-yi)am ino)propyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 293 'N-(( I S,2R)- 1 -((2,3 -difluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-(2 methylpropyl)-3 ',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4' yI)am ino)propyl)acetamide; 'N-((]I S,2R)- 1 -((3 ,4-difluorophenyl)metbyl)-2-hydroxy-3 -(((4'S)-6'-(2 5 methylpropyl)-3',4'-d ihydrospiro[cyclobutane- 1,2'-pyrano[2,3 -b]pyridin]-4' yI)amino)propyl)acetamide; 'N-(( 1 S,2R)-3 -(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3 ',4' dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- I (phenylmethyl)propyl)acetamide; 10 'N-((]I S,2R)- 1 -((3,5 -difluorophenyl)methyl)-3 -(((4'S)-7'-fluoro-6'-(2 methylpropyl)-3 ',4'-dihydrospiro[cyclobutane-I ,2'-pyrano[2,3-b] pyridin]-4'-yI)am ino)-2 hydroxypropyl)acetam ide; 'N-(( 1 S,2R)-3 -(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- I -((4 15 fluorophenyl)methy!)-2-hydroxypropyl)acetam ide; 'N-(( I S,2 R)-3 -(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3 ',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yI)amino)- 1 -((3 fluorophenyl)methyl)-2-hydroxypropyl)acetam ide; 'N-(( I S,2R)- I -((2,3 -difluorophenyl)methyl)-3 -(((4'S)-7'-fluoro-6'-(2 20 methylpropyl)-3 ',4'-d ihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b] pyridin]-4'-yI)amino)-2 hydroxypropyl)acetam ide; 'N-(( I S,2R)- I -((4-chloro-3 -fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(2 methylpropyl)-3',4'-d ihydrospiro[cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4' yI)am ino)propyl)acetamide; 25 'N-(( I S,2R)- I -((4-chlorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-(2 methylpropyl)-3',4'-dihydrospiro[cyclobutane-1I,2 t -pyrano[2,3-b]pyrid in]-4' yI)am ino)propyl)acetam ide; 'N-(( I S,2R)- I -((4-fl uorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-( I,3 ,3,3 tetrafluoro-2-methylpropyl)-3 ',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-bjpyridin]-4' 30 yI)amino)propyl)acetamide; 'N-(( I S,2R)- I -((4-chlorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-( I,3 ,3,3 tetrafluoro-2-methylpropyl)-3 ',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3-blpyridin]-4' yI)amino)propyl)acetamide; WO 2007/061670 PCTIUS2006/044058 - 294 'N-((]I S,2R)- 1 -((3 -fluoropbenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-( 1,3,3,3 tetrafluoro-2-methylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b] pyrid in]-4' yI)amino)propyl)acetamide; 'N-(( I S,2 R)-2-hydroxy- I -(pbenylmethyl)-3 -(((4'S)-6'-( 1,3,3,3 -tetrafluoro-2 5 methylpropyl)-3',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4' yI)am ino)propyl)acetamide; 'N-((]I S,2R)- I -((3 -fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(3 ,3 ,3-trifluoro- 1 hydroxy-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b] pyridin]-4' yI)amino)propyl)acetamide; 10 'N-((]I S,2R)- I -((4-chlorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(3 ,3,3 -trifluoro- 1 hydroxy-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4' yl)amino)propyl)acetamide; 'N-(( 1 S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4'S)-6'-(3,3 ,3-trifluoro- I -hydroxy 2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-bjpyrid in]-4' 15 yI)amino)propyl)acetamide; 'N-(( I S,2R)- 1 -((3 -fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-((2R)-3 ,3,3 tri fluoro-2-methylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- I ,2'-pyranoll2,3-b]pyrid in]-4' yI)amino)propyl)acetam ide; N-(( I S,2R)- 1 -((3 -fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-((2S)-3 ,3 ,3 20 trifluoro-2-methylpropyl)-3 ',4'-d ihydrospiro~cyclobutane- I ,2'-pyrano[2,3-b] pyrid in]-4' yI)amino)propyl)acetamide; 'ethyl I -(2-(((]I S,2R)-3 -(((4S)-6-bromo-3 ,4-d ihydrospiro[chromene-2, 1' cyclobutan]-4-yl)am ino)-2-hydroxy- I -(phenylmethyl)propyl)amino)-2-oxoethyl)- I H I ,2,3-triazole-4-carboxylate; 25 'N-((] S,2R)- I -((3-bromo-4-fluorophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b] pyridin]-4'-yI)amino) 2-hydroxypropyl)acetamide; '2-(5-(aminomethyl)- I H-I ,2,3-triazol- I -yi)-N-(( I S,2R)-3-(((4S)-6-bromo-3,4 d ihydrospiro[chromene-2, I '-cyclobutan]-4-yI)am ino)-2-hydroxy- I1 30 (phenylmethyl)propyl)acetamide; 'N-(( 1 R,2R)- 1 -((3 -chloro-2-fI uorophenyl)methyl)-3 -(((4'S)-6'-(2,2 dimethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b] pyridin]-4'-yI)amino) 2-hydroxypropyl)acetam ide; WO 2007/061670 PCTIUS2006/044058 - 295 'N-(( I S,2 R)- 1 -((5-chloro-2-fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1I,2'-pyrano[2,3 -b] pyrid in]-4'-yI)amino) 2-hydroxypropyl)acetam ide; 'N-(( I S,2R)- 1 -((3 -chloro-2-fluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 5 dimethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b] pyrid in]-4'-yl)amino) 2-hydroxypropyl)acetamide; 'N-(( I S,2R)- 1 -((3 -chloro-2,4-difl uorophenyl)methyl)-3 -(((4'S)-6'-(2,2 dimethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-bjpyrid in]-4'-yI)amino) 2-hydroxypropyl)acetamide; 10 'N-(( 1 S,2R)- I -((3-ch Ioro-4,5-difluorophenyl)methyl)-3 -(((4'S)-6'-(2,2 d imethylpropyl)-3 ',4'-d ihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-b] pyrid in]-4'-yl)amino) 2-hydroxypropyl)acetamide; 'N-((]I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- 1 -((2,3,6 15 trifluorophenyl)methyl)propyl)acetamide; 'N-(( I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1,2' pyrano[2,3-b]pyridin]-4'-yI)amino)-2-hydroxy- I -((2,3,5 trifluorophenyl)methyl)propyl)acetamide; 'N-(( I S,2R)- 1 -((4-bromophenyl)methyl)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 '4'. 20 dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)acetamide; 'N-(( I S,2R)- I -((4-chlorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-(( I methylethyl)oxy)-3 ',4'-dihydrospiro[cyclobutane- I ,2'-pyrano[2,3-b]pyrid in]-4' yI)amino)propyl)acetam ide; 25 'methyl ((I S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3 ',4' dihydrospiro[cyclobutane- I ,2'-pyrano[2,3 -b]pyridin]-4'-yl)amino)-2-bydroxy- I (phenylmethyl)propyl)carbamate; 'N-(( I S,2R)- I -((3 ,5-d ifluorophenyl)methyl)-3 -(((4'S)-6'-ethyl-3',41.. d ihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3 -b]pyridin]-4'-yI)amino)-2 30 hydroxypropyl)acetamide; 'methyl ((1 S,2R)- 1-((3 ,5-d ifluorophenyl)methyl)-3 -(((4'S)-6'-ethyl-3 ',4' dihydrospiro~cyclobutane-1I,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2 hydroxypropyl)carbamate; WO 2007/061670 PCT/US2006/044058 - 296 'methyl ((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino) 2-hydroxypropyl)carbamate; 'N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2' 5 pyrano[2,3-c]pyridin]-4'-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)propanamide; and 'N-((1 S,2R)-1 -((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-(3-hydroxy-2,2 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-I,2'-pyrano[2,3-b]pyridin]-4' yl)amino)propyl)acetamide. 10 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as defined in any one of claims 1-8.

10. Use of the compound as defined in any one of claims 1-8 for the preparation of a medicament for the treatment of a disorder related to the activity of beta-secretase in a 15 subject. ]1. Use of the compound as defined in any one of claims 1-8 for the preparation of a medicament for the treatment of Alzheimer's disease in a subject. 20 12. Use of the compound as defined in any of claims 1-8 for the preparation of a medicament for the reduction of plaque on the brain of a subject.

13. Use of the compound as defined in any of claims 1-8 for the preparation of a medicament for the treatment of mild cognitive impairment, Down's syndrome, 25 Hereditary cerebral hemorrhage with dutch-type amyloidosis, cerebral amyloid angiopathy, degenerative dementia, dementia associated with Parkinson's disease, dementia associated with supranuclear palsy, dementia associated with cortical basal degeneration, diffuse lewy body type of Alzheimer's disease or a combination thereof in a subject. 30

14. A method of making a compound of claim 1, the method comprising the step of reacting a compound 20 WO 2007/061670 PCT/US2006/044058 - 297 OH R 4 H 2 N N R 5 B R 3 R 3 20 ,wherein i, j, B, R 3 , R 4 and R 5 are as defined in claim 1, with a compound having the structure R'-W-X, wherein R' and W are as defined in claim I and X is a leaving group, to make a compound of claim 1. 5

15. A compound according to any one of claims 1, 7, and 8, substantially as herein described with reference to the Examples.

16. A pharmaceutical composition according to claim 9 substantially as herein described 10 with reference to the Examples.

17. Use according to any one of claims 10 to 13, substantially as herein described with reference to the Examples. 15 18. A method according to claim 14 substantially as herein described with reference to the Examples.