AU2006249248A1 - Pharmaceutical compositions having activity as inhibitors of cytochrome P450RAI - Google Patents

Description

Our Ref:20140794 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Address for Service: Invention Title: Allergan, Inc.

2525 Dupont Drive Irvine California 92612 United States of America DAVIES COLLISON CAVE Patent Trade Mark Attorneys 255 Elizabeth Street Sydney, New South Wales, Australia, 2000 Pharmaceutical compositions having activity as inhibitors of cytochrome P450RAI The following statement is a full description of this invention, including the best method of performing it known to me:- 5951

\O

0 PHARMACEUTICAL COMPOSITIONS HAVING ACTIVITY AS SINHIBITORS OF CYTOCHROME P450RAI This application is a divisional of Australian patent application No.

2001286471, the disclosure of which is incorporated herein by reference.

00 BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is directed to pharmaceutical compositions Scomprising compounds which inhibit the enzyme cytochrome P450RAI. More particularly, the compounds generally relate to derivatives of phenylacetic or heteroarylacetic acid, and which inhibit the enzyme cytochrome P450RAI.

Several compounds that have an inhibitory effect on the enzyme cytochrome P450RAI include a cyclopropyl aryl, cyclopropylheteroaryl, cyclopropylaminoaryl, or (1-imidazolyl) methylaryl structure.

BACKGROUND ART Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, WO 02/18361 PCT/US01/25443 02 1 including, premalignant and malignant hyperproliferative diseases such as 2 cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, 0 3 esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, 4 metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. In addition, N 6 retinoid compounds can be used as agents to treat diseases of the eye, 7 including, without limitation, proliferative vitreoretinopathy (PVR), retinal 8 detachment, dry eye and other corneopathies, as well as in the treatment and 9 prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention 11 ofpost-angioplasty restenosis and as an agent to increase the level of 12 circulating tissue plasminogen activator (TPA). Other uses for retinoid 13 compounds include the prevention and treatment of conditions and diseases 14 associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, 16 colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's 17 disease, Parkinson's disease and stroke, improper pituitary function, 18 including insufficient production of growth hormone, modulation of 19 apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination 21 therapies with the present compounds and other agents such as MinoxidilR, 22 diseases associated with the immune system, including use of the present 23 compounds as immunosuppressants and immunostimulants, modulation of 24 organ transplant rejection and facilitation of wound healing, including modulation ofchelosis. Retinoid compounds have relatively recently been 26 also discovered to be useful for treating type II non-insulin dependent 27 diabetes mellitus (NIDDM).

28 Several compounds having retinoid-like activity are actually 7 WO 02/18361 PCT/US01/25443 3 I marketed under appropriate regulatory approvals in the United States of 2 America and elsewhere as medicaments for the treatment of several diseases 3 responsive to treatment with retinoids. Retinoic acid (RA) itself is a natural 4 product, biosynthesized and present in a multitude of human and mammalian tissues and is known to play an important rule in the regulation 6 of gene expression, tissue differentiation and other important biological 7 processes in mammals including humans. Relatively recently it has been 8 discovered that a catabolic pathway in mammals, including humans, of 9 natural retinoic acid includes a step of hydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoic acid inducible).

11 Several inhibitors of CP450RAI have been synthesized or discovered 12 in the prior art, among the most important ones ketoconazole, liarozole and 13 R1 16010 are mentioned. The chemical structures of these prior art 14 compounds are provided below. It has also been noted in the prior art, that administration to mammals, including humans, of certain inhibitors of CP- 16 450RAI results in significant increase in endogeneous RA levels, and 17 further that treatment with CP450RAI inhibitors, for example with liarozole, 18 gives rise to effects similar to treatment by retinoids, for example 19 amelioration of psoriasis.

21 22 23 24 WO 02/18361 PCT/UJS01/25443 4 2 00 3 4 c-I R116010 6

N

7 9 a a

ICETOCONAZOLE

LUAROZOLE

WO 02/18361 WO 0218361PCTIUS01/25443 1 The following publications describe or relate to the above- 2 summarized role of CP450RAI in the natural catabolism of RA, to inhibitors 003 of CP.-450RAI and to in vitro and in vivo experiments which demonstrate 4 that inhibition of CP450RAI activity results in a increases endogeneous RA levels and potential therapeutic benefits.

(716 Ku~jpers, et al., "The effects of oral liarozole on epidermal proliferation and 7 differentiation in severe plaque psoriasis are comparable with those of (718 acitretin", British Journal of Dermatology, (1998) 139: pp 380-389.

9 Kang, et ali., "Liarozole Ihibits Human Epidermal Retinoid Acid 4- Hydroxylase Activity and Differentially Augments Human Skin Responses 11 to Retinoic Acid and Retinol In Vivo", The Journal of Investigative 12 Dermatology, (August 1996) Vol. 107, No. 2: pp 183-187.

13 Van Wauwe, et ali., "Liarozole, an Inhibitor of Retinoic Acid Metabolism, 14 Exerts Retinoid-Mimetic Effects in Vivo", The Journal of Pharmacology and ExpRerimental Therapeutics, (1992) Vol. 261, No 2: pp, 773-779.

16 De Porre, et al., "Second Generation Retinoic Acid Metabolism Blocking 17 Agent (Ramnba) RI 16010: Dose Finding in Healthy Male Volunteers", 18 University of Leuven, Belgium, pp 19 Wauwe, et al., "Ketoconazole Inhibits the in Vitro and in Vivo Metabolism of All-Trans-Retinoic Acid", The Journal of Pharmacology and Experimental 21 Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.

22 White, et al., "eDNA Cloning of Human Retinoic Acid-metabolizing 23 Enzyme (hP45ORAI) Identifies a Novel Family of Cytochromes P450 24 (CYP26)*", The Journal of Biological Chemistr, (1997) Vol. 272, No. Issue of July 25 pp 18538-18541.

26 Hanzlik, et al., "Cyclopropylaines as Suicide Substrates for Cytochromes 27 P45ORAI", Journal of Medicinal Chemistry (1979), Vol. 22, No. 7, pp 759-

O

O6 761.

Ortiz de Montellano, "Topics in Biology The Inactivation of Cytochrome Oo P450RAI", Annual Reports in Medicinal Chemistry, (1984), Chapter 20, pp 201-210.

Hanzlik, et al. "Suicidal Inactivation of Cytochrome P450RAI by \O Cyclopropylamines> Evidence for Cation-Radical Intermediates", J. Am.

SChem. Soc., (1982), Vol. 104, No. 107, pp. 2048-2052.

The present invention provides pharmaceutical compositions comprising several new chemical compounds which act as inhibitors of CP450RAI, and as such potentially provide therapeutic benefit in the treatment or prevention of the diseases and conditions which resppnd to treatment by retinoids and or which in healthy mammals, including humans, are controlled by natural retinoic acid. The perceived mode of action of these compounds is that by inhibiting the enzyme CP450RAI that catabolyzes natural RA, endogenous RA level is elevated to a level where desired therapeutic benefits are attained. The chemical structures of the compounds are summarized by Formulas 1 through 8 which are provided in the Summary Section of this application for patent. Based on the chemical structures the following art is of interest as background to the novel structures.

U.S. Patent Nos. 5,965,606; 6,025,388; 5,773,594; 5,675,024; 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,089,509; 5,616,712; 5,134,159; 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,015,658; 5,130,335; 4,740,519; 4,826,984; 5,037,825; 5,466,861; WO 85/00806; EP 0 130,795; DE 3316932; DE 3708060; Dawson, et al.

"Chemistry and Biology of Synthetic Retinoids", published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 1.

U.S. Patent Nos. 5,965,606; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; WO 02/18361 PCT/US01/25443 7 1 4,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; 2 WO 92/06948;EPO 0 170 105;EP 0 286364;EP 0 514269;EP 0 617020; 0Q 3 EP 0 619 116; DE 3524199; Derwent JP6072866; Dawson, et al.

4 "Chemistry and Biology of Synthetic Retinoids", published by CRC Press Inc., 1990, pages 324-356; are of interest to compounds of Formula 2.

S6 Dawson, et al. "Chemistry and Biology of Synthetic Retinoids", 0 7 published by CRC Press. Inc., (1990), pages 324-356; is of interest to 8 compounds of Formula 3.

9 U.S. Patent Nos. 5,965,606; 5,773,594; 5,675,024; 5,663,347; 5,023,341; 5,264,578; 5,089,509; 5,149,705; 5,130,335; 4,740,519; 11 4,826,969; 4,833,240; 5,037, 825; 5,466,861; 5,559,248; WO 85/00806; 12 WO 92/06948; WO 95/04036; WO 96/05165; EP 0 098 591; EP 0 170 105; 13 EP0 176034;EP0253,302;EP0303915;EP0514269;EP0617020; 14 EP 0 619 116; EP 0661 259; DE 3316932; DE 3602473; DE 3715955; UK application GB 2190378; Eyrolles etal., J. Med Chem.. (1994), 37, 1508- 16 1517; Graupner et al. Biochem. and Biophysical Research 17 Communications, (1991), 1554-1561; Kagechika, et al., J. Med. Chem.

18 (1988), 31, 2182-2192; Dawson, et al. "Chemistry and Biology of Synthetic 19 Retinoids", published by CRC Press. Inc., (1990), pages 324-356; are of interest to compounds of Formula 4.

21 U.S. Patent Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 22 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 23 4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; 24 WO 92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020; EP 0 619 116; DE 3524199; Derwent JP6072866; Dawson, et al.

26 "Chemistry and Biology of Synthetic Retinoids", published by CRC Press 27 Inc., (1990), pages 324-356; are of interest to compounds of Formula 28 U.S. Patent Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; WO 02/18361 WO 0218361PCTIUS01/25443 8 17-- 1 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 2 4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91116051; 00 ~3 WO092/06948; EP 0.170 105; EP 0286 364; EP 0514 269; EP 0617 020; 4 EP 0 619 116; DE 3524199; Derwert YP6072866; Dawson4 et al.

"Chemistry and Biology of Synthetic Retinoids", published by CRC Press 6 Inc, (1990), pages 324-356; is of interest to compounds of Formula 6.

7 U.S. Patent Nos. 6,048,873; 5,663,347; 5,045,551; 5,023,341; (Ni8 5,739,338; 5,264,578; 5,089,509; 5,616,712; 5,399,561; 4,826,984; 9 5,037,825; EP 0 130 795; DE 3316932; Dawson, et al. "Chemistry and Biology of Synthetic Retinoids", published by CRC Press. Inc., (1990), 11 pages 324-356; are of interest to compounds of Formula 7.

12 U.S. Patent Nos. 5,965,606; 5,998,471; 5,773,594; 5,675,024; 13 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,134,159; 5,346,895; 14 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,130,335; 4,326,055; 4,539,154; 4,740,519; 4,826,969; 4,826,984; 4,833,240; 5,037,825; 16 5,466,861; 5,559,248; WO 85/00806; WO 92/06948; WO 95/04036; 17 WO096/05165; EP 0098 591; EPO0 130 795; EPO0 176 034; EP 0253 302; 18 EP 0303 915; EP 0514 269; EP 0617 020; EP 0619 116;EP 0661259; 19 DE 3316932; DE 3602473; DE 3708060; DE 3715955; U.K. application GB 2 19 0 378; Eyrolles et J. Med. Chem., (1994), 37 1508, 1517; 21 Graupner et Biochem. and Bionhysical Research Communications, 22 (1991) 1554-1561; Kagechika, et al., J. Med. Chem.. (1988), 31, 2182- 23 2192; Dawson, et a. "Chemistry and Biology of Synthetic Retinoids", 24 published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 8.

O

ID

O9 SUMMARY OF THE INVENTION The present invention as claimed relates to pharmaceutical 00 compositions comprising one or more compounds of Formulae 1 to 8 depicted Sbelow and as defined in the claims in admixture with a pharmaceutically acceptable excipient. The pharmaceutical compositions can further include Sother active agents.

The present invention as claimed further relates to uses of the cpharmaceutical compositions in therapy and to the manufacture of said pharmaceutical compositions.

The present invention also relates to compounds of Formula 1 R, R

(R

3 )m SY Z-A(R 2 )-(CH2)--COOR 8 (R),p

Y

Formula 1 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I; 9a r-~Z is 0 -(CR,=CR 1 where n' is an integer having the value I 00 -CO-NRm-,

-CO-O-,

-CS-NkR WO 02/18361 PTUO/54 PCTIUS01/25443 1 NRI-CS-, 2 -CO-S-, 00 3 -S-CO-, 4 R, is independently H Or ailkyl of 1 to 6 carbons; 6 p is an integer having the values of 0 to 4; 7 R 2 is independently H, akl of I to 6 carbons, F, Cl, Br, I, CF 3 8 fluoro substituted alkyl of 1 to 6 carbons, alkoxy of I to 6 carbons, or 9 alkylthio of I to 6 carbons;

R

3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, 1, fluoro, 11 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, 12 alkylthio of 1 to 6 carbons or benzyl; 13 m is an integer having the values 0 to 2; 14 R 4 is independently H, alkyl of I to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen; 16 o is an integer having the values of 0 to 2; 17 n is an integer having the values ofO0 to 4, and 18 R. is H, alkyl of i to 6 carbons, -CH 2

O(C

1 -6-alky1), or a cation of a 19 pharmaceutically acceptable base.

The present invention also relates to compounds of Formula 2 21 (R3)M 22 23 1 J 2

COOR

8 24 X-2X

C

26 Rj Formula 2 27 WO 02/18361 WO 0218361PCTIUS01/25443 I wherein A is a phenyl or naphthyl group, or heteroaryl selected from 2 a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, 00 3 pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and N 4 heteroaryl groups being optionally substituted with one or two R 2 groups; X isO0, Sor NRwhere Ris-H, alkyl oflI to 6carbons or benzyl; 6 Z is 7 -(CR 1 where n' is an integer having the value I 8 -CO-NR 1 9 NRI -GO-,

-CO-O-,

11 -0-cO-, 12 -CS-NTI 1 13 NRI-CS-, 14 -CO-S-,

-S-GO-,

16 17 R, is independently H or alkyl of 1 to 6 carbons; 18 p is an integer having the values of 0 to 4; 19 R12 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, 1, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or allcylthio of 1 21 to 6 carbons; 22 R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, 1, fluoro 23 substituted alkyl of 1 to 6 carbons, OH, SI!, alkoxy of 1 to 6 carbons, 24 alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values 0 to 4; 26 R5 is H, ailkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 27 carbons, benzyl, or lower alkyl or halogen substituted benzyl; WO 02/18361 WO 0218361PCTIUS01/25443 12 1 n is an integer having the values of 0 to 4, and 2 R 8 is H, alkyl of 1 to 6 carbons, -CH 2 0(CI-6-alkyl), or a cation of a 0C) 3 pharmaceutically acceptable base.

4 The present invention relates to compounds of Formula 3 R, R, 6

(R

3 8 1 'iWV"VZ-A(R 2

)-(CH

2

)-COOR

8 11 Formula 3 12 13 wherein A is a phenyl or naphthyl group, or heteroaryl selected from 14 a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and 16 heteroaryl groups being optionally substituted with one or two R 2 groups; 17 Y is H, alkyl of I to 10 carbons, benzyl, lower alkyl or halogen 18 substituted benzyl, fluoro-substituted ailkyl of I to 10 carbons, cycloalcyl of 19 3 to 6 carbons, lower alkyl substituted cycloalkyl of 1 to 6 carbons, Cl, Br, orn; 21 Z is -CR=C-, 22 -(CR 1 =CRI)n' where n' is an integer having the value 1 23 -CO-NR 1 24 NR,-.CO-,

-CO-O-,

26 -0-CO-, 27

-CS-NR

1 WO 02/18361 PCT/US01/25443 13 1 NRi-CS-, 2 -CO-S-, 00 3 -S-CO-, 4 R, is independently H or alkyl of 1 to 6 carbons; S6 p is an integer having the values of 0 to 7 R, is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 8 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 9 to 6 carbons;

R

3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 11 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, 12 alkylthio of 1 to 6 carbons or benzyl; 13 m is an integer having the values 0 to 2; 14 R 4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen; 16 o is an integer having the values of 0 to 4; 17 n is an integer having the values of 0 to 4, and 18 R S is H, alkyl of 1 to 6 carbons, -CH20(C 1 6 -alkyl), or a cation of a 19 pharmaceutically acceptable base.

WO 02/18361 PCTIUS01/25443 14 I The present invention also relates to compounds of Formula 4 2 R, R, R) 00(R06 4 7 6 7 X, Y 8 Formula 4 9 wherein A is a phenyl or naphthyl group, or heteroaryl selected from 11 a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, 12 pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and 13 heteroaryl groups being optionally substituted with one or two R 2 groups; 14 X, is I -imidazolyl, or lower alkyl or halogen substituted 1 imidazolyl, OR, SR, NRR 6 where R is H, alkyl of 1 to 6 carbons or benzyl; 16 17 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 18 substituted benzyl, fluoro-substituted ailkyl of I to 10 carbons, cycloalkyl of 19 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, orn; 21 Z is -CE-C-, 22 -(CR 1

=CR

1 where n' is an integer having the value 1 23

-CO-NR

1 24 NR 1

-CO-,

-CO-C-,

26 -0-GO-, 27 -CS-NR 1 WO 02/18361 PCT/US01/25443 1 NRI-CS-, 2 -CO-S-, 00 3 -S-CO-, 4

R

1 is independently H or alkyl of 1 to 6 carbons; S6 R, is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro O 7 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 C 8 to 6 carbons; 9 R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, 11 alkylthio of 1 to 6 carbons or benzyl; 12 m is an integer having the values 0 to 2; 13 R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 14 alkyl of I to 6 carbons, or halogen; o is an integer having the values of 0 to 4; 16 R 6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl 17 substituted cycloalkyl of 3 to 6 carbons; 18 n is an integer having the values of 0 to 4, and 19 R, is H, alkyl of 1 to 6 carbons, -CHO(C 1 .6-alkyl), or a cation of a pharmaceutically acceptable base, with the proviso that when Y is H, A is 21 phenyl and X 1 is OH then n is 1 to 4.

22 The present invention also relates to compounds of Formula WO 02/18361 PCTUS01/25443

U

16 1 (R 3 )m 2 4 003 (CH2)5 COORB 4

Y

C-I 6 7N Formula 7 CI 8 wherein A is a phenyl or naphthyl group, or heteroaryl selected from 9 a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and 11 heteroaryl groups being optionally substituted with one or two R 2 groups; 12 X is 0, S or NR where R is H, alkyl of 1 to 6 carbons, C 1 6 13 trialkylsilyl or benzyl; 14 Y is H, alkyl of I to 10 carbons, beazyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of I to 10 carbons, cycloalkyl of 16 3 to 6 carbons, lower alkyl substituted cycloallcyl of 3 to 6 carbons, Cl, Br, 17 or 1; 18 Zis 19 where n' is an integer having the value 1

-CO-NR

1 21 NR 1

-CO-,

22

-CO-O-,

23

-O-CO-,

24

-CS-NR

1

NR-CS-,

26

-CO-S-,

27

-S-CO-,

28 WO 02/18361 WO 0218361PCTIUS01/25443 17 1 R, is independently H or alkyl of 1 to 6 carbons; 2 R 2 is independently H, alkyl of 1 to 6 carbons, F, CI, Br, I, fluoro 0C) 3 substituted alkyl of 1 to 6 carbons, ailcoxy of 1 to 6 carbons, or allcylthio of I 4 to 6 carbons;

R

3 is independently ailkyl of 1 to 6 carbons, F, Cl, Br, 1, fluoro 6 substituted alkyl of I to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, 7 alkylthio of 1 to 6 carbons or benzyl; 8 m is an integer having the values 0 to 3; 9 R 7 is HI, alkyl of i to 6 carbons, cycloalkyl of 3 to 6 carbons or lower alkyl substituted cycloalkyl of 1 to 6 carbons; I1I n is an integer having the values of I to 4, and 12 R 8 is H, ailkyl of i to 6 carbons, -C11 2 0(C-alkyl), or a cation of a 13 pharmaceutically acceptable base.

14 The present invention also relates to compounds of Formula 6

(R

3

)M

16 17 11 'wZ-A(R 2

(CHY-COOR

8 18 19

Y

21 Formula 6 22 wherein A is a phenyl or naphthyl group, or heteroaryl selected from 23 a group consisting of pyridyl, thienyl, fiiryl, pyridazinyl, pyrimidinyl, 24 pyrazinyl, tbiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; 26 X 2 is I1-imidazolyl, lower alkyl or halogen substituted I1-imidazolyl, 27 OR 1

SR

7 or NRR 7 where R is H, alkyl of 1 to 6 carbons or benzyl; WO 02/18361 W002/8361PCT/USOI/25443 18 1 Y is H, alkyl of 1 to 10 carbons, benzyl, lower aVIcy or halogen 2 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 00 3 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, 4 or Z is 6 -(CR 1 where n' is an integer having the value 1 7 -CO-NR 1 8 NRI-CO-, 9 -CO.O-, -0-GO-, 11 -CS-NR 1 12 NRI-CS-, 13 -CO-S., 14 -S-GO-, 16 R, is independently H or alkyl of i to 6 carbons; 17 R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, 1, fluoro 18 substituted alkyl of I to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 19 to 6 carbons;

R

3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, 1, fluoro 21 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of-I to 6 carbons, 22 alkylthio of 1 to 6 carbons or benzyl; 23 m is an integer having the values 0 to 3; 24 R 7 is H, alkyl of 1 to 6 carbons, cycloakl of 3 to 6 carbons, lower alkyl substituted cycloallcyl of 3 to 6 carbons or C 1 6 -triallcylsilyl.

26 n is an integer having the values of 0 to 4, and 27 N~ is H, alkyl of I to 6 carbons, -CH 2

O(C

1 .g-alkyl), or a cation of a 28 pharmaceutically acceptable base.

WO 02/18361 PCT/US01/25443 U) 19 1 The present invention also relates to compounds of Formula 7 00 3 R Ri (R)m 6 vvZ-A(R2-(CH2)--COORa 7 7 CN 8 Formula 7 9

(R)P

11 wherein A is a phenyl or naphthyl group, or heteroaryl selected from 12 a group consisting ofpyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, 13 pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and 14 heteroaryl groups being optionally substituted with one or two R, groups; Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 16 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 17 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, Cl, 18 Br, or I; 19 Zis -(CRI=CRI)n, where n' is an integer having the value 1 21 -CO-NR 1 22

NR

1

-CO-,

23 -CO-O-, 24 -O-CO-,

-CS-NRI-,

26 NR 1

-CS-,

27 -CO-S-, 28 -S-CO-, WO 02/18361 PCT/US01/25443 020 1 2 R i is independently H or alkyl of 1 to 6 carbons; 00 3 p is an integer having the values of 0 to 4 R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or

N

6 alkylthio of 1 to 6 carbons; 7 R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 fluoro C 8 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, 9 alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values 0 to 2; 11 R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 12 alkyl of 1 to 6 carbons, or halogen; 13 o is an integer having the values of 0 to 4; 14 n is an integer having the values of 0 to 4, and Rg is H, alkyl of 1 to 6 carbons, -CH 2

O(C

1 6 -alkyl), or a cation of a 16 pharmaceutically acceptable base.

17 The present invention also relates to compounds of Formula 8 18 R R,Ri 19 (R)m (R4o)0u^ T 1 6 I Z-A(R2)-(CF2)5COORS 21 X 7 22 23 24 Formula 8 wherein A is a phenyl or naphthyl group, or heteroaryl selected from 26 a group consisting ofpyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, 27 pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and WO 02/18361 WO 0218361PCT/USOI/25443 21 I heteroaryl groups being optionally substituted with one or two R 2 groups; 2 X 3 is S, or 0, C(R 1 2 or CO; 003 Yj is H, lower alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, 4 benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons; Z is 6 -(CR 1 =CRI)n' where n' is an integer having the value 1 8 7 -CO-.NR 1 8 NICO-, 9 -CC-C-, -0-Go-, 11 -CS-NR 1 12 NR,-CS-, 13 -CO-S-, 14 -S-CC-, 16 R, is independently H or alkyl of I to 6 carbons; 17 1R. is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 18 fluoro substituted akl of 1 to 6 carbons, alkoxy of I to 6 carbons, or 19 allylthio ofl1to 6carbons;

R

3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 fluoro 21 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of I to 6 carbons, 22 alkylthio of 1 to 6 carbons or benzyl; 23 m is an integer having the values 0 to 2; 24 R 4 is independently H, alkyl of I to 6 carbons, or F; fluorosubstituted alkyl of I to 6 carbons, or halogen; 26 o is an integer having the values of 0 to 4;) 27 n is an integer having the values of 0 to 4, and 28 R8 is Hi, alkyl of 1 to 6 carbons, -CH 2 0(C 1 6 -alkyl), or a cation of a

IO

O

22 pharmaceutically acceptable base, the compound meeting at least one of the O provisos selected from the group consisting of: YI is cycloalkyl, when YI is not cycloalkyl then X 3 is O or S and n is 1, when Y1 is not cycloalkyl then X 3 is CO, and n is 1, iwhen Y, is not cycloalkyl then X 3 is CO and the moiety A is Ssubstituted with at least one F group.

C This invention further relates to the use of the compounds of Formula 1 through Formula 8 for the prevention or treatment of diseases and conditions in mammals, including humans, which diseases or conditions are prevented, treated, ameliorated, or the onset of which is delayed by administration ofretinoid compounds or by the mammalian organism's naturally occurring retinoic acid. Because the compounds act as inhibitors of the breakdown of retinoic acid, the invention also relates to the use of the compounds of Formula 1 through Formula 8 in conjunction with retinoic acid or other retinoids. In this regard it is noted that retionoids are useful for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The retinoids are also useful for the prevention and treatment of metabolic diseases such as type II non-insulin dependent diabetes mellitus (NIDDM) and for prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon,

O

O

023 r- bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of OO the mucous membranes and in the treatment of Kaposi's sarcoina. Retinoids Scan also be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye Sand other corneopathies, as well as in the treatment and prevention of Svarious cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoids include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.

The pharmaceutical formulations of the invention comprise one or more compounds of Formula 1 through Formula 8 in admixture with a pharmaceutically acceptable excipient, said formulation being adapted for administration to a mammal, including a human being, to treat or alleviate the conditions which were described above as treatable by

IO

024 retinoids, or which are controlled by or responsive to the organism's native O retinoic acid. These formulations can also be co-administered with retinoids to enhance or prolong the effects of medications containing retinoids or of 00 Sthe organism's native retinoic acid.

These and other aspects of the invention are described below and in the C claims which follow.

SBRIEF DESCRIPTION OF THE DRAWING FIGURE cr Figure 1 is a schematic representation of the P450RAI cell based assay utilized to evaluate the ability of the compounds of the invention to inhibit the Cytochrome P450RAI enzyme.

BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION P450RAI-1 Cell-Based Inhibitor Assay: Figure 1 shows a schematic diagram of the P450RAI-1 cell based assay. P450RAI-1 stably transfected HeLa cells are maintained in 100 millimolar tissue culture dishes in Modified Eagle's Medium (MEM) containing 10 Fetal Bovine Serum (FBS) and 100 gg/ml hygromycin.

Exponentially growing cells are harvested by incubating in trypsin. Cells are then washed with IX Phosphate Buffered Saline (PBS) and plated in a 48well plate at 5 X10 5 cells in 0.2 ml MEM medium containing 10 FBS and 0.05 Ci 3 H]-RA in the presence or absence of increasing concentrations of the test compounds. The compounds are diluted in 100% DMSO and then added in triplicate wells at either 10, 1 or 0.1 iM final concentration. As a positive control for RA metabolism inhibition, cells are also incubated with ketoconazole at 100, 10 and 1 jiM. Cell are incubated for 3 hours at 37 0

C.

The retinoids are then extracted using the procedure ofBligh et al. (1959) Canadian Journal of Biochemistry 37, 911-917, modified by using methylenechloride instead of chloroform. The publication Bligh et al (1959) Canadian Journal of Biochemistry 37, 911-917 is specifically incorporated herein by reference. The water soluble radioactivity is WO 02/18361 PCT/US01/25443 1 quantified using a p-scintillation counter. IC 5 0 values represent the 0 2 concentration of inhibitor required to inhibit all-trans-RA metabolism by S3 percent and are derived manually from log-transformed data. The IC 50 4 values obtained in this assay for several preferred compounds of the invention are disclosed in Table 1 below.

6 Assays of Retinoid-like or Retinoid Antagonist and Inverse Agonist- 07 like Biological Activity 8 Assays described below measure the ability of a compound to bind 9 to, and/or activate various retinoid receptor subtypes. When in these assays a compound binds to a given receptor subtype and activates the transcription 11 of a reporter gene through that subtype, then the compound is considered an 12 agonist of that receptor subtype. Conversely, a compound is considered an 13 antagonist of a given receptor subtype if in the below described 14 co-tranfection assays the compound does not cause significant transcriptional activation of the receptor regulated reporter gene, but 16 nevertheless binds to the receptor with a Kd value of less than approximately 17 1 micromolar. In the below described assays the ability of the compounds to 18 bind to RAR, RARe, RAR RXR', RXRf and RXR receptors, and the 19 ability or inability of the compounds to activate transcription of a reporter gene through these receptor subtypes can be tested.

21 As far as specific assays are concerned, a chimeric receptor 22 transactivation assay which tests for agonist-like activity in the RAR, 23 RAR, and RAR, receptor subtypes, and which is based on work published 24 by Feigner P. L. and Holm M (1989) Focus, 112 is described in detail in United States Patent No. 5,455,265. The specification of United States 26 Patent No. 5,455,265 is hereby expressly incorporated by reference. The 27 numeric results obtained with several preferred compounds of this WO 02/18361 PCT/US01/25443 26 1 invention in this assay are shown below in Table 1. These data demonstrate 2 that generally speaking the compounds are not agonists (or only weak 00 3 agonists) ofRAR retinoic receptors, and also that they do not bind, or in 4 some cases bind only weakly to RAR retinoid receptors.

A holoreceptor transactivation assay and a ligand binding assay C 6 which measure the antagonist/agonist like activity of the compounds of the S7 invention, or their ability to bind to the several retinoid receptor subtypes, 8 respectively, are described in published PCT Application No. WO 9 W093/11755 (particularly on pages 30 33 and 37 41) published on June 24, 1993, the specification of which is also incorporated herein by reference.

11 A detailed experimental procedure for holoreceptor transactivations has 12 been described by Heyman et al. Cell 68, 397 406, (1992); Allegretto et 13 al. J. Biol. Chem. 268, 26625 26633, and Mangelsdorfet al. The 14 Retinoids: Biology, Chemistry and Medicine, pp 319 349, Raven Press Ltd., New York, which are expressly incorporated herein by reference. The 16 results obtained in this assay are expressed in ECs 5 numbers, as they are 17 also in the chimeric receptor transactivation assay. The results of ligand 18 binding assay are expressed in Kd numbers. (See Cheng et al. Biochemical 19 Pharmacology Vol. 22 pp 3099-3108, expressly incorporated herein by reference.) 21 The results if the ligand binding assay for several preferred 22 compounds of the invention are included in Table 1. In the holoreceptor 23 transactivation assay, tested for RXRU, RXR 6 and RXR, receptors, the 24 compounds of the present invention are, generally speaking, entirely devoid of activity, demonstrating that the compounds of the invention do not act as 26 RXR agonists.

WO 02/18361 WO 0218361PCT[USOI/25443 TABLE 1RA 2 3 Compound [General I Formula Table #1 ECSO/(EFFICACY)/KdnM (x 1 0 y P450RAI

INHIBITION

DATA

INTACT HELA

IC

50

P.M

110 2 3 NA 74 262 (44) (42) 2058 409 112 2 3 NA 335 NA (37) 5853 704 685 3 4 5 280 4.8 9.8 (28) (54) (52) 3 145 0.8 158 114 2 3 NA NA NA 108 2 3 6.6 283 141 (36) (10) 21K 547 13K 116 2 3 NA WA NA 3269 732 886 77 2 3 NA WA NA 2207 225 16 78 2 3 NA NA NA >10K 1 2 33 1.2 6.8 (207) (126) (140) 1.7 69 1.3 363 42 1 2 NA NA NA 0.19 15K 13636 >10K WO 02/18361 WO 0218361PCTIUSOI/25443 28 8 9 NA NA NA 0.34 21K 4272 2 3 NA NA NA >10K 69 2 3 313 12 52.6 (50) (31) 469 133 501 73 2 3 WA 22.5 91 (39) (24) 486 26 351 74 2 3 NA NA NA IlK 14K 8 9 0.28 14 2.2 84 44 1 2 49 1.7 (138) (100) (116) 0.27 37 1.9 392 82 2 3 NA NA NA >10K 81 2 3 NA 490 183 (67) 846 1058 89 2 3 268 26 12 (50) (46) 980 475 2 3 NA NA NA 0.95 >10K 94 2 3 NA NA NA I>10K WO 02/18361 WO 0218361PCT/US01/25443 93 2 j. 3 4821 20 10 I(114) (39) (55) I I3450 554 358 11 (36) 2815 0.55 9148 4 6 7 8 9 11 12 8 4 5 NA 363 NA (96) 0.4 3781 86 2 3 NA NA NA 1.4 >10K 85 2 3 976 3.5 (77) (65) 1861 240 302 98 2 3 NA NA NA 0.8 13 4 5 NA 3.2 116 3.1 10 8 9 57 0.3 6 (146) (86) (94) 0.7 36 8 9 0.033 13K 4896 492 38 8 9 0.025 5317 2884 34 8 9 0.13 61.5 15 119 6 7 0.4 >10K >10K >10K WO 02/18361 WO 0218361PCT/US01/25443

U

00 121 6 7 0.1 >100K >100K 8 >10K 2.2 8 9>1 18 4 32 8 9 0.18 27K 4225 13K 139 4 0.05 22 3 4 1.6 24 3 4 3 137 4 0.1 26 4 127 6 7 0.4 126 6 7 0.09 48 1 2 0.03 1 2 0.014 52 1 2 54 1 2 00 ___0.022 WO 02/18361 PCT/US01/25443

C

62 56 71- 8 0.13 134 6 7 4 58 1 2 0.18 1 2 1.6 143 0.8 145 0.2 1The "Table refers to the Table provided below where the compound is identified with reference to a corresponding specific formula of Formulas 9 through 16.

WO 02/18361 PCT/US01/25443 U) 32 1 TOPICAL SKIN IRRITATION TESTS S2 As is known the topical retinoid all-trans-retinoic acid (ATRA) and 3 oral retinoids such as 13-cis RA and etretinate are known to induce 0O 4 substantial skin irritation in humans. This irritation is a direct result of activation of the RAR nuclear receptors. Analysis of retinoid topical 6 irritation is also a highly reproducible method of determining in vivo S7 retinoid potency. The SKH1-hrBR or hairless mouse provides a convenient 8 animal model of topical irritation, since retinoid-induced skin flaking and 9 abrasion can be readily scored by eye (Standeven et al., "Specific antagonist of retinoid toxicity in mice." Toxicol. Appl. Pharmacol., 138:169-175, 11 (1996); Thacher, et al., "Receptor specificity of retinoid-induced 12 hyperplasia. Effect of RXR-selective agonists and correlation with topical 13 irritation". J. Pharm. Exp. Ther., 282:528-534, (1997)). As is demonstrated 14 below the topical application of P450RAI inhibitors of the present invention also causes an increase in the endogenous levels of ATRA that results in 16 ATRA-induced irritation in skin of hairless mice. The attached data table 17 discloses the retinoid-mimetic effects of some P450RAI inhibitor 18 compounds of the present invention on the skin of hairless mice.

19 Methods Female hairless mice (Crl:SKH1-hrBR), 5-7 weeks old, were 21 obtained from Charles River Breeding Labs (Wilmington, MA). Animals 22 were about 6 weeks old at the start of the experiments. Food (Purina Rodent 23 Chow 5001) and reverse osmosis water were provided ad libitwn. Mice 24 were housed individually throughout the dosing period. In some experiments, mice that fit within a defined weight range, 21-25g, were 26 selected from the available stock and then randomly assigned to the various 27 treatment groups, using body weight as the randomization variable.

28 The compounds to be tested were dissolved in acetone for application WO 02/18361 PCT/US01/25443 33 1 to the backs of the mice.

2 Mice were treated topically on the back in a volume of 4.0 ml/kg 0 3 (0.07-0.12ml) adjusted daily so as to deliver a fixed dose of test compound S4 per g body weight. Doses are disclosed as Unless indicated otherwise, mice were treated with retinoids once S6 daily on days 1 through 5 and observed on days 2, 3, 4, 5, 6, 7 and 8.

7 The mice were weighed daily and the dorsal skin was graded daily 8 using separate semi-quantitative scales to determine flaking and abrasion.

9 These flaking and abrasion scores were combined with weight change (if any) to create a cutaneous toxicity score (Blackjack score).

11 Cutaneous Toxicity Score 12 A visual grading scale was used for characterizing topical irritation 13 on a daily basis. The grading scale used is as follows: 14 Flaking Abrasions 0 none 0 none 16 1 slight (small flakes, <50% 1 slight (one or two abrasions 17 coverage) with a light pink color) 18 2 mild (small flakes, 50% 2 mild (several abrasions with a 19 coverage) pink color) 3 moderate (small flakes, >50% 3 moderate (one or two deep 21 coverage large flakes, <25% abrasions with red color, 22 coverage) coverage) 23 4 severe (small flakes, >50% 4 severe (multiple deep abrasions 24 coverage large flakes, 25-50% with red color, >25% coverage) coverage) 26 5 very severe (large flakes, 27 coverage) WO 02/18361 PCT/US01/25443 S34 I Topical Toxicity Score 2 The flaking and abrasion observations were combined with body c 3 weight observations to calculate a single, semiquantitative topical or 4 cutaneous "toxicity score" as detailed below. The toxicity score (also known as "blackjack score" since the theoretical maximum is 21) takes into C 6 account the maximal severity, and the time of onset of skin flaking and S7 abrasions and the extent of weight between the first and last days of the 8 experiment. Below are listed the seven numerical components of the 9 toxicity score and an explanation of how those values are combined to calculate the toxicity score.

11 1. Flaking-Maximal Severity: 12 Highest flaking score attained during observation period.

13 2. Flaking-Day of Onset of grade 2 or worse: 14 0 8 days 1 -day 8 16 2 day 6 or 7 17 3 day 4 or 18 4 day 2 or3 19 3. Flaking-Average Severity: Flaking severity scores are summed and divided by the number 21 of observation days.

22 4. Abrasion-Maximal Severity: 23 Highest abrasion score attained during observation period.

24 5. Abrasion-Day of Onset of grade 2 or worse: Same scale as above.

26 6. Abrasion-Average Severity: 27 Abrasion severity scores are summed and divided by the 28 number of observation days.

WO 02/18361 WO 0218361PCTIUS01/25443 1 7. Systemic Toxicity (weight loss): 2 0 -<lg 003 1 Ito2g 4 2 2to 4g 3 -4 to 6g 6 4 ->6g or dead 7 Calculation of Composite Flaking Score 8 Flaking onset score and average severity score are summed 9 and divided by two. The quotient is added to the maximal severity score Composite flaking scores are calculated for each individual animal in a I1I group, averaged, and rounded to the nearest integer. Values can range from 12 0-9.

13 Calculation of Composite Abrasion Score 14 Abrasion onset score and average severity score are summed and divided by two. The quotient is added to the maximal severity score 16 Composite abrasion scores are calculated for each individual animal in a 17 group, averaged and rounded to the nearest integer. Values can range from 18 0-8.

19 Calculation of Toxicity Score Composite flaking score, composite abrasion score, and systemic 21 toxicity score are summed to give the "toxicity score." Toxicity scores are 22 calculated for each individual animal in a group, averaged, and rounded to 23 the nearest integer. Values can range from 0-21 and are expresscd in Table 24 LA below as the mean SD of the values for a group.

Calculation of Percentage Change in Body Weight 26 The body weight at the time of the last weighing (day 8, 11, or 12) 27 was subtracted from the initial body weight. The difference was divided by 28 the initial body weight, multiplied by 100%, and rounded to the nearest WO 02/18361 PCT/US01/25443 integer. Values were calculated for each individual animal and the mean and standard deviation for each group are shown.

TABLE 1A Cutaneous Toxicity Score (Blackjack Score) Compound No. 100 300 1000 nmole nmole nmole 0 613 1± 1 5±2 36 111 1110 38 1±1 10+1 8 5±2 8+3 12± 1 22 010 010 11 137 1±1 11 5 ±2 48 1±1 3 1 7±2 1±0 3±2 8±2 58 0±0 0±0 0±0 131 1±1 0±1 1±1 127 0±0 0±0 0±0 18 0±0 5 2 10 ±2 Modes of Administration The compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations. Thus, in the treatment ofdermatoses, it will WO 02/18361 WO 0218361PCT/US01/25443 37 I generally be preferred to administer the drug topically, though in certain 2 cases such as treatment of severe cystic acne or psoriasis, oral administration 0C) 3 may also be used. Any common topical formulation such as a solution, 4 suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical N 6 formulations as exemplified, for example, by Remington's Pharmaceutical 7 Science, Edition 17, MAck Publishing Company, Easton, Pennsylvania. For 8 topical application, these compounds could also be administered as a 9 powder or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the 11 like or as a syrup or elixir suitable for oral administration. For intravenous 12 or intraperitoneal administration, the compound will be prepared as a 13 solution or suspension capable of being administered by injection. In 14 certain cases, it may be useful to formulate these compounds by injection.

In certain cases, it may be useful to formulate these compounds in 16 suppository form or as extended release formulation for deposit under the 17 skin or intramuscular injection.

18 Other medicaments can be added to such topical formulation for such 19 secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing 21 infection, reducing irritation, inflammation and the like.

22 Treatment of dermatoses or any other indications known or 23 discovered to be susceptible to treatment by retinoic acid-like compounds, 24 or to control by naturally occurring retinoic acid will be effected by administration of the therapeutically effective dose of one or more 26 compounds of the instant invention. A therapeutic concentration will be 27 that concentration which effects reduction of the particular condition, or 28 retards its expansion. In certain instances, the compound potentially may be WO 02/18361 WO 0218361PCTIUSOI/25443 38 1 used in prophylactic manner to prevent onset of a particular condition.

2 A useful therapeutic or prophylactic concentration will vary from 00 3 condition to condition and in certain instances may vary with the severity of 4the condition being treated and the patient's susceptibility to treatment.

Accordingly, no single concentration will be uniformly useful, but will 6 require modification depending on the particularities of the disease being 7 treated. Such concentrations can be arrived at through routine 8 experimentation. However, it is anticipated that in the treatment of, for 9 example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a 11 therapeutically effective concentration for total application. If administered 12 systemically, an amount between 0.0 1 and 5 mg per kg of body weight per 13 day would be expected to effect a therapeutic result in the treatment of many 14 diseases for which these compounds are useful.

In some applications pharmaceutical formulations containing the CP- 16 450RAI inhibitory compounds of the invention may be co-administered 17 with formulations containing retinoids.

18 GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY 19 Definitions The term alkyl refers to and covers any and all groups which are 21 known as normal alkyl and branched-chain alkyl. Unless specified 22 otherwise, lower alkyl means the above-defined broad definition of alkyl 23 groups having 1 to 6 carbons in case of normal lower alkyl, and 3 to 6 24 carbons for lower branch chained alkyl groups. A pharmaceutically acceptable salt may be prepared for any compound in this invention having a 26 functionality capable of forming a salt, for example an acid functionality. A 27 pharmaceutically acceptable salt is any salt which retains the activity of the 28 parent compound and does not impart any deleterious or untoward effect on WO 02/18361 PCT/US01/25443 S39 1 the subject to which it is administered and in the context in which it is 2 administered.

3 Pharmaceutically acceptable salts may be derived from organic or 4 inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium.

6 Organic salts may be made with amines, particularly ammonium salts such O7 as mono-, di- and trialkyl amines or ethanol amines. Salts may also be S8 formed with caffeine, tromethamine and similar molecules. Where there is a 9 nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent 11 such as methyl iodide. Preferred salts are those formed with inorganic acids 12 such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a 13 number of simple organic acids such as mono-, di- or tri- acid may also be 14 used.

Some compounds of the present invention may have trans and cis (E 16 and Z) isomers. Unless specific orientation ofsubstituents relative to a 17 double bond or a ring is indicated in the name of the respective compound, 18 and/or by specifically showing in the structural formula the orientation of 19 the substituents relative to the double bond or ring the invention covers trans as well as cis isomers.

21 Some of the compounds of the present invention may contain one or 22 more chiral centers and therefore may exist in enantiomeric and 23 diastereomeric forms. The scope of the present invention is intended to 24 cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures ofdiastereomers and racemic mixtures ofenantiomers (optical 26 isomers) as well. A bond drawn with a wavy line indicates that the carbon 27 to which the bond is attached can be in any of the applicable possible 28 configurations.

WO 02/18361 PCT/US01/25443 1 General Synthetic Methodology 2 The compounds of the invention are encompassed by the general 3 Formulas 1 through 8 provided above. As it can be seen, in each of these 4 formulas a linker or tethering group designated Z covalently connects an aromatic or heteroaromatic moiety designated A(R 2

)-CH

2 )n-COOR 8 and 6 another cyclic moiety which in accordance with these formulas is a 8 7 substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, c 8 thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety.

9 Generally speaking a compound such as X 4

-A(R

2

)-CH

2 )n-COOR 8 is commercially available, or can be made in accordance with the chemical 11 literature, or with such modification of known chemical processes which are 12 within the skill of the practicing organic chemist. The group X 4 represents a 13 reactive group, which is suitable for coupling the X 4

A(R

2

-CH

2

),-COOR

8 14 compound to a derivative of the substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, 16 tetrahydroquinoline or tetrahydroisoquinoline moiety so that as a result of 17 the coupling the linker or tether moiety Z is formed. In many instances the 18 group X 4 is a leaving group such as halogen, or 19 trifluoromethanesulfonyloxy, or a group capable of participating in a Wittig or Homer Emmons reaction. In some instances the group X 4 is an ethynyl 21 group capable of undergoing a coupling reaction with a leaving group (such 22 as a halogen or a trifluoromethanesulfonyloxy group) attached to the 23 substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, 24 thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety. The group X 4 can also represent an OH or an NH 2 group that forms an ester 26 (COO) or amide (CONH) linker, respectively, when reacted with an 27 activated carboxyl derivative of the substituted phenyl, substituted 28 tetrahydronaphthalene, substituted chroman, thiochroman, WO 02/18361 PCT/US01/25443 S41 1 tetrahydroquinoline or tetrahydroisoquinoline moiety. Examples for the 2 compounds of formula X4A(R 2

)-CH

2 )-COORs are provided in the O 3 specific examples below. Further examples where the X 4 group is halogen 4 are ethyl 4-iodobenzoate, ethyl 6-iodonicotinate, ethyl 5-iodofuran-3carboxylate, ethyl 5-iodothiophen-3-carboxylate, ethyl 5-iodofuran-2- 6 carboxylate, ethyl 5-iodothiophen-2-carboxylate, and analogous halogenated 7 derivatives of the respective pyridazine, pyrazine and other heteroaryl 8 carboxylic acid esters. The analogous aryl and and heteroaryl hydroxyl 9 compounds and amines, wherein the halogen of the above-listed compounds is replaced by OH or NH 2 respectively, also serve as additional examples for 11 the reagents of the formula X 4 -A(R2)-CH2)a-COORs. In these examples 12 X 4 is OH or NH 2 respectively.

13 Still further in accordance with the general synthetic methodology to 14 provide the compounds of the present invention, a derivative of the substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, 16 thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety is 17 synthesized first, having a covalently attached X s group. The Xg group 18 reacts with the X 4 group of the reagent X 4 -A(R2)-CH 2 )n-COOR 8 to form 19 the linker designated Z in Formulas 1 through 8. The X group is one that is capable of participating in a catalyzed coupling reaction, (such as an 21 ethynyl group when X 4 is a leaving group), or a leaving group (such as 22 halogen or trifluoromethanesulfonyloxy when X 4 is an ethynyl group) or 23 an activated carboxylic acid function (when X 4 is OH or NH 2 The X 24 group can also be an OH, SH or NH 2 group when the X 4 group is an activated carboxylic acid function. Specific examples for substituted 26 phenyl, substituted tetrahydronaphthalene, substituted chroman, 27 thiochroman, tetrahydroquinoline or tetrahydroisoquinoline intermediates 28 having an X 5 functionality are provided below, and are also available in the WO 02/18361 PCT/US01/25443 0 42 1 chemical scientific and patent literature. Generally speaking, for reagents 2 and reactions covalently joining a substituted tetrahydronaphthalene, 3 substituted chroman, thiochroman, or tetrahydroquinoline intermediate with

OO

4 a substituted aryl or heteroaryl group, such as X 4

-A(R

2

)-CH

2 )n-COORg, to CA 5 form a compound including the linker designated Z, reference is made to 6 United States Patent Nos. 5,648,503; 5,723,666 and 5,952,345 the S7 specification of each of which are expressly incorporated herein by 8 reference.

9 The substituted phenyl, tetrahydronaphthalene, chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety of the 11 novel compounds of the invention are derivatized in a manner to include the 12 specific substituents (such as for example the cycloalkyl substituents) 13 encompassed within the scope of the invention, either before or after the 14 A(R 2

)-CH

2

)-COOR

8 moiety has been attached and the linker Z has formed, as illustrated by the below described specific examples.

16 The -CHz)n-COOR s moiety of the compounds of the invention can be 17 modified in order to obtain still further compounds of the invention. One 18 such modification is saponification of compounds where the R 8 group is an 19 alkyl or -CH20(Cl.

6 -alkyl) group. Another modification is esterification of the carboxylic acid function when the R 8 group is H or a cation. Such 21 saponification and esterification reactions are well known in the art and 22 within the skill of the practicing organic chemist. Still another modification 23 of the compounds of the invention (or of the intermediates X 4

-A(R

2 24 CH 2 )-COORg, or of precursors to these intermediates) is the homologation of the (CH 2 )n group. The latter can be accomplished, for 26 example, by the well known Arndt-Eistert method of homologation, or other 27 known methods of homologation.

28 WO 02/18361 PCT/US01/25443 0 U43 -I SPECIFIC EMBODIMENTS 2 With reference to the symbol A in Formulas 1 through 8, the O 3 preferred compounds of the invention are those where A is phenyl, naphthyl, 4 pyridyl, thienyl or furyl. Even more preferred are compounds where A is 5 phenyl. As far as substitutions on the A (phenyl) and A (pyridyl) groups f6 are concerned, compounds are preferred where the phenyl group is 1,4 7 (para) substituted and where the pyridine ring is 2,5 substituted.

CI 8 (Substitution in the 2,5 positions in the "pyridine" nomenclature corresponds 9 to substitution in the 6-position in the "nicotinic acid" nomenclature.) In the presently preferred compounds of the invention either there is no R 2 11 substituent on the A group, or the Rz substituent is preferably a fluoro 12 group that is preferably located on the aromatic carbon adjacent (ortho) to 13 the carbon bearing the -(CH2)n-COORs group.

14 As far as the -(CH 2

),-COOR

8 is concerned compounds are preferred where n is 0, 1 or 2, and even more preferred where n is 1. In Formulas 16 and 8 only compounds where n is 1 or 2 are preferred, with n=l being most 17 preferred. For the R s group H, lower alkyl of 1 to 3 carbons, and -CH 2 0(C 1 18 6 -alkyl) groups are preferred, as well as the pharmaceutically acceptable 19 salts of the free acids when R S is H. Among the lower alkyl and -CH20(C 1 6 -alkyl) groups ethyl and OCH 2

CH

3 respectively, are presently most 21 preferred.

22 The linker group Z in all the compounds of the invention is 23 preferably ethynyl 24 ester ethenyl, (-CR 1

=CR

1 or amide (CONRI).

Among these the ethynyl and ester (CO-O) linkers are most 26 preferred. Moreover, in the preferred compounds of the invention the linker 27 Z is attached to the 6 position in Formula 1, to the 4 position in Formula 2, WO 02/18361 PCT/US01/25443 S44 1 to the 6 position in Formula 3, to the 6 position in Formula 4, to the 4 o 2 position in Formula 5, to the 4 position in Formula 6, to the 6 position in 3 Formula 7, and to the 6 position in Formula 8. These positions are 4 indicated by arabic numerals in Formulas 1 through 8.

The R, group substituting the non-aromatic rings in Formulas 1, 3, C 6 4, 7 and 8 is preferably alkyl, more preferably alkyl of 1 to 3 carbons, and S7 most preferably methyl. The R 1 group substituting the cyclopropane ring in

C

1 8 Formulas 1, 2, 3 and 7 is preferably non-existent (p is or is alkyl of 1 to 9 3 carbons, even more preferably methyl.

The X group in Formulas 1 and 5 is preferably 0, and in Formula 2 11 X is preferably O or NR.

12 The X 1 group in Formula 4 is preferably 1-imidazolyl, substituted 1- 13 imidazolyl, or NRR 6 where R, is preferably cyclopropyl or branched-chain 14 alkyl. The X 2 group in Formula 6 is preferably 1-imidazolyl or substituted 1-imidazolyl.

16 The X 3 group in Formula 8 is preferably O or C=O.

17 The Y group is preferably H, lower alkyl of 1 to 3 carbons, 18 cycloalkyl, lower alkyl substituted cycloalkyl, or halogen. Among these, H, 19 Cl, and cyclopropyl are most preferred.

The Y 1 group of Formula 8 is preferably H, lower alkyl of 1 to 3 21 carbons, cycloalkyl, or lower alkyl substituted cycloalkyl. Among these H, 22 ethyl and cyclopropyl are presently most preferred.

23 The most preferred compounds of the invention are disclosed in 24 Tables 2 through 9 with reference to Formulas 9 through 16. The compounds specifically shown in Tables 2 through 9 are carboxylic acids, 26 but it should be understood that the C -3alkyl esters, methoxymethyl 27 (OCH 2

CH

3 esters and pharmaceutically acceptable salts of the acids shown O WO 02/18361 PCT/US01/25443 1 in these tables are also highly preferred.

2 It should also be apparent that the preferred compounds shown in 00 3 Table 2 with reference to the more specific Formula 9 are within the scope 4 of Formula 1.

Similarly, the preferred compounds shown in Table 3 with reference S6 to the more specific Formula 10 are within the scope of Formula 2; 7 the preferred compounds shown in Table 4 with reference to the t C 8 more specific Formula 11 are within the scope of Formula 3; 9 the preferred compounds shown in Table 5 with reference to the more specific Formula 12 are within the scope of Formula 4; 11 the preferred compounds shown in Table 6 with reference to the 12 more specific Formula 13 are within the scope of Formula 13 the preferred compounds shown in Table 7 with reference to the 14 more specific Formula 14 are within the scope of Formula 6; the preferred compounds shown in Table 8 with reference to the 16 more specific Formula 15 are within the scope of Formula 7, and 17 the preferred compounds shown in Table 9 with reference to the 18 more specific Formula 16 are within the scope of Formula 8.

WO 02/18361 WO 0218361PCTIUS01/25443 Formula 9 TABLE 2 Compound X Y Z R, n Position of No.

(CH

2

),,COOH

0 H -CeC- H 0 4 42 0 H. -C H 1 4 44 0 H F 0 4 48 0 cyclopropyl H 1 4 0 cyclopropyl F 1 4 52 0 cyclopropyl H 0 4 54 0 cyclopropyl F 0 4 58 0 cyclopropyl -CO-0- H 1 4 0 cyclopropyl -CO-0- H 1 3 66 C11 3 H -CaC- H 0 4 WO 02/18361 WO 0218361PCT/IJS01/25443 2 )n-COOH Rs-- 00 TABLE 3 Compound No. Rs 1R3 n 110 n-propyl (n-propyl)N H 0 112 benzyl NH H 0 114 benzyl (n-benzyl)N H 0 108 n-propyl NH H 0 116 benzy) methylN H 0 77 benzyl 0 H 0 78 benzyl 0 H 1 methyl 0 H 1 69 methyl 0 H 0 73 isopropyl 0 H 0 74 isopropyl 0 H 1 82 benzyl 0 methyl I 81 benzyl 0 methyl 0 89 (CHA)C-C11 2 0 methyl 0

(CH

3 3

C-CH

2 0 methyl I 94 benzyl 0 ethyl 1 93 benzyl 0 ethyl 0 86 isopropyl 0 methyl I isopropyl 0 methyl 0 105 ethyl 0 t-butyl 0 106 ethyl 0 t-butyl 1 98 isopropyl 0 ethyl WO 02/18361 WO 0218361PCTIUS01/25443 Formula I I TABLE 4 Compound No. R 22 F 24 H WO 02/18361 WO 0218361PCT/US01/25443

COOH

Formula 12 TABLE Compound No. XR 2 n 3 mcthyl,cyclopropyl-N H 0 8 methyl,cyclopropyl-N H 1 13 methyl,cyclopropyl-N F 0 18 methyl,cyclopropyl-N F 1 139 1-imidazolyl H 0 137 1-imidazolyl H 1 26 methyl,isopropyl-N H 0 WO 02/18361 WO 0218361PCT/IJSOI/25443 Formula 13 TABLE 6 Compound No. RR7Y R 3 143 H methyl t-butyl t-butyl 145 F methyl Jt-butyl_ t-butyl WO 02/18361 WO 0218361PCTIIJSOI/25443 Formula 14 TABLE 7 Compound No. XR3n 119 1-imidazolyl methyl 0 121 1-imnidazolyl methyl 1 127 1-imidazolyl iso-propyl 1 126 1 -imidazolyl iso-propyl 0 134 ethyl,cyclopropyl-N iso-propyl 0 130 ethyl,cyclopropyl-N methyl 0 131 ethyl,cyclopropyl-N methyl 1 141 (1-methyl)cyclopropyl-oxy iso-1 I propyl WO 02/18361 WO 0218361PCTIUSOI/25443 00 Formula TABLE 8 Compound No. R n 62 j H H 0 63 j Me H 1 WO 02/18361 WO 0218361PCTIUS01/25443 Formula 16 TABLE 9 Compound X 3 YR3 Z R n No. 28 0 H methyl H 1 0 H methyl -CaC- F 0 CO H H H 1 CO H H F 0 36 0 cyclopropyl methyl H 1 38 0 cyclopropyl methyl F 1 46 0 H methyl -CO-O- H 1 CO H H -CO-O- H 1 32 0 H methyl -CE=C- F 1 56 0 ethyl methyl -C=RC- H 1 34 0 cyclopropyl methyl H 0 CO H H -CF-C- F I WO 02/18361 PCT/US01/25443 54 1 The compounds of the invention can be synthesized by applying the S2 general synthetic methodology described above, and by such modifications 3 of the hereinafter described specific synthetic routes which will become 4 readily apparent to the practicing synthetic organic chemist in light of this disclosure and in view of general knowledge available in the art. The C 6 hereinafter disclosed specific reaction schemes are directed to the synthesis 7 of exemplary and preferred compounds of the invention. Whereas each of c 1 8 the specific and exemplary synthetic routes shown in these schemes may 9 describe specific compounds of the invention only within the scope of one or two of the general Formulas 1 through 8, the synthetic processes and 11 methods used therein are adaptable within the skill of the practicing organic 12 chemist and can be used with such adaptation for the synthesis of 13 compounds of the invention which are not specifically described herein as 14 examples.

Reaction Scheme 1 discloses a presently preferred synthetic route to 16 certain intermediates or reagents having the general formula X 4

-A(R

2 17 CH).-COOR s where the symbol A represents a di-, or tri-substituted 18 phenyl moiety. These intermediates are utilized in the synthesis of the 19 compounds of the invention.

WO 02/18361 WO 0218361PCTILJS01/25443 COHMCOH 1H 2 S0 4 N CnOCc reag et B

C

F FF 1. KOE% E*OI refux reagent C 2. E*OJA H90. heuzw4 Dea*.qW KO~i 0H10 X OONS EtOH H,90, PhH Deol.SW* 1 0 CxOB OV KOH, RDHH203 towae 4 iAwnw&d9 s Tf 2 c, An&t CHEIL 2 1.EII Pd(PAh2CZ ==-TM 7MaFCurf, NM,~ TM. irdemedide 6 2 KCO. MeCH reagent D Hic* o&/ PhCH 3 80 0

C

wi

OO&

reagent E HO cQ HC~ oa/ ho fizCH 3 80 0 C reagent F MFCIIONSCHE1 WO 02/18361 WO 0218361PCTIUS01/25443 C2KMnO 4 'Z2O' My~iA& COO C coOe reagent G MeOg4-1M, FM1 DemSwk cof intenne&de 2 reagent H 6(,kcooH

HOF

btannediiae 4 EkOIa H2SO 4

~OF

reagent I RECTIONSCHEEI CONTINVUED) WO 02/18361 PCT/US01/25443 S57 2 00 3 Reaction Scheme 2 discloses presently preferred synthetic routes to 4 obtain exemplary and preferred tetrahydronaphthalenone compounds of the invention within the scope of Formula 8 where the the symbol X 3 6 represents a C=O group, Z represents an ethynyl moiety or a -COO- (ester) 7 function, and A is a substituted phenyl moiety.

C

N 8 Reaction Scheme 3 discloses presently preferred synthetic routes to 9 obtain exemplary and preferred tetrahydronaphthalene compounds of the invention within the scope of Formula 4 where X 1 represents a dialkyl 11 substituted nitrogen, Z is an ethynyl moiety and A is a substituted phenyl 12 moiety.

13 Reaction Scheme 4 discloses presently preferred synthetic routes to 14 obtain exemplary and preferred isoquinoline compounds of the invention within the scope of Formula 3 where the symbol Y represents hydrogen, Z 16 is an ethynyl moiety and A is a substituted phenyl moiety.

17 Reaction Scheme 5 discloses presently preferred synthetic routes to 18 obtain exemplary and preferred chroman compounds of the invention within 19 the scope of Formula 8 where the symbol Yi represents hydrogen, Z is an ethynyl moiety or an ester (COO) function, and A is a substituted phenyl 21 moiety.

WO 02/18361 WO 0218361PCTIUSOI/25443

JVOH

3 77aMe^Za K U cz 2 fkcnf3 20)3 o oa H0OBH 0 jawtsda 8 intameiffe 9 B&CH2, 014O N43, CAP 7 OTf Pdafh) 2 CZP =-TMA Co4 f, i70 0

C

0 QCN; h intwoneitelO imuedde 11 Kc0 3 MeOH 0 il~dfgto 12 1~Amehe3 X JJOBH0 MOOHRMH 3

O

Rfd7w,kja 2 7YWl, N& 04 reagen A, Bor C x 0 ConqowidS a X=H Corqawsdl15 x I X =F bmdiaw 14 m 0X=H R CHM Compoumd4 n1 X=HR=CB 3 Compowdl4 n-I X=FR= C~H.,H I1MNdOfL E1O. 8d'C Womea~de~ 11 reagentD

COOH

0 Coxfound Compound 9 RE4C7TONSCHFME2 WO 02/18361 WO 0218361PCTIUS01/25443 00 Of 1. Pd(OAC) 2 41pp EDL; NFt 3

CO

bineditle 11 j r

,DM

reagentE Compound 2. CF 3 COOI% cCA RFACMINSCEEME2 CONTINUWD WO 02/18361 WO 0218361PCT/US01/25443

COOR

I"1. NaC7WBM 3

~H

X AcOBXAcCNV 2. MegK 2 C0 3 CMSCOLCi o~0 1hHOMeOR-TI;O, waeit 14x0 H N32corud3 n=OX=H compound 4 a =I X HR -HL ConvcapoundS n-1 X H Componni9 n-OX -FR=W 3 LjHz compound13 a X F Compoand4 X-FR- CWN cempawrdl n X-F TMi I. Nat2/ER 3 A cIAcCV 2. Mel, K 2 C0 3

CEI

3 COCH3 0 3J 2 CO, MeOgi M.*04 boarmadage 12 -1f~ 3 b Coz I FI7H inmedae 29 IM NaO.g MAOI M1 C~moad26 REWDIONSUHME3 WO 02/18361 WO 0218361PCT/U SO1/25443 ba 92 -%CK hemmed"to is Lqe"medatcJ6 IVl V 3 HS0, AHE Cab %,.IOMS LL4LI cab HcOOO EDCHZi (vrifffa 1) hr Lwennefiae is inewmea"17 cHja 2 EkiJTh TUF F~h~v

OH

(u'~fa~uace 2) intwneAid~e 21 (mfffeme 2) bwnitwdale9 beeme& 21 LnuWmda 20 1I D1B4AB CM 2. TA NMHO

CN

2 aC, jntamedge 22 6a COM7-B, ~~2 intmfdtcA4 23

ROV

idwwmedjge 25 ilntea"~t 26 7PAP-dmwwpmfyL o1N1--P-WIk..gt P/MO Nybnmbxouliime N-Ozi& r.,fuwacl Twmkaea,1 I kim Sec.(c), 1969,183-1Z88 refffmmz 2 Aq~Umki c iAnvgcw. Cwom hA d nL, 1996, 35,413-414 RFAC77ONSCREWE4 WO 02118361 WO 0218361PCTIUSOI/25443 62 2 3BL reagen B or C 4 ArN.9, 7THF bdonsmedte 2 7 6 7 LiO~H~ffO, MeOTB1H 2

O

1

>K

x=AF copwd 2X F R HsCH2 cwowi23X-H R=CH3 X=flF C,,oam8d 22 X F CeiMpouud24 X=H M 4CITONSaHME4

CONTNVUFD

WO 02/18361 WO 0218361PCT/USO1/25443 63

POOR

04 regent C orG U. Ftoa No&~ 5, 045,551 mad 5,616,597 x

K::

Copowd 29 X F a R =CH Conqvxnd 31 X =F a-1 R ZfL7r2 Compaumdlo X -P=F0 Com~pound32 X -F x or t B U d~ l H 1 SO CL bu ew 2 .pidw, reugat E iVwae 3.9 0/I('WwFCOOJ cHR 2 Conppwwd46 REA CII'ONSCIFES WO 02/18361 PCT/US01/25443 S64 1 Reaction Scheme 6 discloses presently preferred synthetic routes to O 2 obtain other exemplary and preferred chroman compounds of the invention 3 within the scope of Formula 8 where the symbol

Y

1 represents a 4 cyclopropyl group, Z is an ethynyl moiety and A is a substituted phenyl moiety.

6 Reaction Scheme 7 discloses presently preferred synthetic routes to 7 obtain exemplary and preferred chroman compounds of the invention within 8 the scope of Formula 1 where the symbol X represents oxygen Y 9 represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

11 Reaction Scheme 8 discloses presently preferred synthetic routes to 12 obtain other exemplary and preferred chroman compounds of the invention 13 within the scope of Formula 1 where the symbol X represents oxygen 14 Y represents a cyclopropyl group, Z is an ethynyl moiety and A is a substituted phenyl moiety.

WO 02/18361 WO 0218361PCTIUS01/25443 mi73a, cwTIOGHz hiaedeive 30 Cff 2 n, P4(OAc)b FA-w &flih 2 d) TAIS 04 NRt, TAF, 70 0

C

jtmezraede 31 imtemeA*~e 33 interwdkte 32 K CO.* MeOH Pda1" 3 2 d6 7=1 NAt 3 04g reagent A, B or C inueelgg 34 IMNdalZ F*O1 Cnfwmd33 X =H x= R CHl2 RCHj CnWoud37X F nl R Fl 2

:?C

1 Conmowd34 X-H a-0 Ccnmpowd36 XHn1l Campoumd 38 X =F x RECYONSUOEE6 WO 02/18361 WO 0218361PCTIUS01/25443 66 US Baew No. m,9,6 :--rlC dmae3 wediac 36 Pd4MS) 2 Ca ::T WLJ, ND, THIF 7d C iodome~fate 37 beta~eEe 38 X IM]VaJR FoA; 800C Pd(M 3 3 c4 TH1F1VN43 a4 ,regaA,B or G Nk 5p a Composid 39 X -H as 0 R CZH 3

CUI

Compound 43 X =F tl R =CH Compoud4X=H n 0 Compowud42 X-H n-I Compmd 44X F n =0 RMACTION SCHLEAM7 WO 02/18361 WO 0218361PCTIIJS01/25443 intemediate 36 71ld* a2COWS)

C

2 dC6 TCZH i l Bl C I V cm2N jameedite 41 inte,,nefiu 40

CN

2 N) Pd(OA c)2 Ethero Pd (M .J 2 a) l Iz 04 AM., TB1, 70 0

C

intemeide 43

COOR

x

K

2 003, MeOH killh~ TBF N,0 £14 meaent A,AG or i~umdiate 44 Conoud47X=Hm I R=Cff 3 Conpomwd 49 X F a= R =CHf Compond 51 X -H m=0 R CH307 Congmand 53 X -F n 0 R C% Coonqiomd4g X-H m='1 ConipomdSO XF m-1 ConypwadS52 X =H m=O Compowid S4 X -F n -0 MFCTIONSCHFMT8 WO 02/18361 PCT/USO1/25443 S68 1 Reaction Scheme 9 discloses presently preferred synthetic routes to O 2 obtain exemplary and preferred tetrahydroquinoline compounds of the 3 invention within the scope of Formula 1 where the symbol X represents an 4 alkyl substituted nitrogen (alkyl-N), Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

N 6 Reaction Schemes 10 and 11 disclose presently preferred synthetic S7 routes to obtain exemplary and preferred phenyl compounds of the invention N 8 within the scope of Formula 2 where the symbol X represents oxygen 9 Rs is alkyl or benzyl, Z is an ethynyl moiety and A is a substituted phenyl moiety.

11 Reaction Scheme 12 discloses presently preferred synthetic routes to 12 obtain exemplary and preferred phenyl compounds of the invention within 13 the scope of Formula 2 where the symbol Rs-X represents an alkyl, dialkyl, 14 benzyl or dibenzyl substituted nitrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

16 Reaction Schemes 13 and 14 disclose presently preferred synthetic 17 routes to obtain exemplary and preferred phenyl compounds of the invention 18 within the scope of Formula 6 where the symbol X 2 represents a (1- 19 imidazolyl) moiety, Z is an ethynyl moiety and A is a substituted phenyl moiety.

WO 02/18361 WO O2183~1PCTIUS01/25443 aNr NJvE 3 cH~ 2

I

or 00ep Ala, 140'C4 aa nfl(OR). Etmfr THZF Bh beameda 54 Ip QH4 AEY 3 THE, 7 0

C

intermedp 56 uzffmezuare .33 imwenedte 57 1) K 2 CGO Me OH 2) 4-I-CAH-COOFI, R41Th) 4 Conqmp~d Conqwimd 66 R&4CTIONSCHEA!E9 1MNd.hA FObK TLIF WO 02/18361 WO 0218361PCTIUSOI/25443 £,ffyO, ROM R Me, Et ar ill l Teb~be Reqent jpjmwde 62 R ipopyI bVwame'Ene 67 R=~H R'-beemyl hveavne~d 72 R=Me R'=beqyi bdwmeiE'e 77 R-Me R'i-pvopyl h~~ud~~82 R=Me R'-=neopeidYl bzte,,ne 86 R='Fl R'-beisyl i,.traawdine 91 R=FEt R'-ipwpyl R or CW 2 E*,Zn CHp, R or V'op 1. PIdO" 3 )7c4 -mi 04 761C 2. K2COs, MeOH iuumwmmcoe 53 intannedre 63 hbtamga&te 73 intamedigga 78 immumedide 83 intensedfite 87 intamedde 92 !RH R'=Me R =H R'-i-proyl R=H R'=eawny R =SMe R'-bemyi R-Me Rp-iptopyl R-Me R'-m.patYl R bmizy R=Fd R'=i-pwp iamedEidI59 R='H R'=Me iniamedide 64 R =H i-pmopy1 hWt,Mmedde 69 R-H R'-be^71 intame~de 74 R =Me R'-baryl int ate 79 R =Me R'-'i-popy1 inturitede 84 R-Me R'-neqmatY1 iatamedfiate 88 R=B R'=bmody intawedde 93 R=Et Riprqiyl EcFTINSCZUMIO WO 02/18361 WO 0218361PCT/USOI/25443 reagent A or reavetBNU B ijemediie 61 itrmediate 66 internedfide 71 intermediate 76 interwiedhte 81 ireide 85 inemsedide 90 hafamediate 95 R=H RI=Me R =H ipopl R=-Me R'=benyL R-Me R'i-popyI R-Me R'=eopwiyl R =Ek R'=benyL R -Fi ipopy

R

Compowid69 n0O R=H R'=Mdk1Y1 Compowd 70 n~1 R=H R'=mekyL Conipaimd 74 n=1 R-H R'-4fnpyL Compound 77 n-0 R=H R'=benzyL Conqiowd 78 n1l R=H R'bezoL Compound 81 n=O R=Me JR~bean~i Conqound 82 n-I1R=Me R~benzy1 CompoUmd 85 n=OR=Me R'-iiropyL Conpound 86 n=-i R=Me R'-i-wpyI Compound 89 n -0 R M e R'=neope*l' Conpouxd 90 n1= R=Me neopeimy1 Compoiud 93 oo= 0 R bepayl Conrmd.94 o-1R-FJ R'-emyL Compound97 n=O R=Et R'=ippyL Coapound 98 n-i R=Et R ipopyl RFcToNsGHzhIEJ cON TiN UED WO 02/18361 WO 0218361PCTIUS01/25443 4- oft 1. JVBS, CCL. nfl= 2. B& C92C4 3. gepamge itmem A byoam idffamedde 104 R I OHd 97 RC M ,ip d z ROI-P wqS 2. -Bl" EtAo acoQot -4 7 CH, Tebbe Rageilt R i-propyl mterme aftW7I3B4Eiae 104 R -".t-&idyl it incwemedie 98 R i-propyL bdoemedie 107 R=t-bty1 di.106 R=t.bityl \-o~9t7iX T341, THF

PAH

1. 5-CJ-CEV~-2-NIf 2 NAl 3 CE4LA 2. PdPS.2"4 -MS 04Z NrR, TMI 3. K2COl, MeOH ixtumedde 99 R ivpoPYL jitenedte 108 R =t-badyl imtermeafse 10 R -i-popyL hzeameiffte 112 R =t-bityL iate~mdde 100 R=Ipopyl imtw~medde 109 R-=t-buyL I- PdO"f 3 2 CL, TBFI N9t, 04 reagLJt A or' reaent B 2 NaJH Tf7s= bi4sw-pqylsilyf TBA F= &&o*4kbril wnmmnhllwvide ComptodlOl n 0 Compzmd 102 n= I Conqpouadl 10 m=0 Compound 106 an- *R =i-.py1 i-propyl =t-bulyl R bityL 5-aICAHN-2-Nf 2 I 0

CP

3 R,4 CJYONSCIME 11 WO 02/18361 WO 0218361PCTIUS01/25443 73 Br .1 KOIA OH(Cffz) 2 OJ9 3. 3MHa ha ed te 11l3 inta&iehS o cfpHApnda'e 2. BH,:MeyS inteamedi'Ie 118 igtemmiae 121 hkamediate 124 intemediate 125 cFIfcB cno, NaCNBH3 ,S q e M4 KOO, doe s-YIoy R =-pOpy ipropyl R9 hem jL RbszyKR'=bemyd Orrneie 3 R ar P I= Rw hp04 NF., TB11 2. K 2 Cg MeOH hsteweae 118 R. qIMWpy intameduie 121 R rpy niprryL iiaewdde 124 R=1-A R'=bwjy intemeie 125 R -bm!Ayl bewryl idmufuliue 130 R -sntJ4y R'=benryl Rfk intam~ediatc 120 imtejynedide 123 intwfnediate 127 inteimwdAge 129 bdlamnediate 132 R- IZR'=~ niprpyl R npropyI, R' n-prpyL RJ R'=beqyi R-betoylR'=berzy1 RmetyL R'="hemyL coom Pd(F% 3 )2a2, 77ZF, NF 3 04 4-r-CACOOD N- Rl Compound 108 2. NtOH R Conqroud 110 C,omud 112 Compoand 114 Comipoundll6 FC7ONSCEFM12 of mpyl R -rp~R' 'n-popyL R-H, R'-bearyI R=bercAy R'bwgzy R mtdIRf= benyi WO 02/18361 WO 0218361PCT[USO 1/2544 3 0 74 2 00 EOOCC.4 AW. 70f C ew~ aM m 2. K,c0, MeOH bi~amedA 133 ipgmateMe cooEt M3NS~l~, C92Cl 3 2 11, TBIR 3 K-g OH Comupowd 117

-COOH

I 2. ma Ntt)HM Zitemdii 137 aHComound 119 AMPA.Ca2Cofer,. Nag. DMF imgwdlta 138 intrmefiae 139 iiamegatn 133 1. coom 1. NfIt) 2 d 2 TBI, N,&S a4 NF4, THE '70C

A

Z 2O eHZNaOH CoMond 121 heawmedae 141 RE4CrONSCFME 13 WO 02/18361 WO 0218361PCT/USOI/25443 OH 1. Mk KCO, acIOo Zof 1. R& :H ~c oTRs 14;2. TYgCJ bnidi=Ole 2. MB~ CCd 4 3. t-Bu4- DMF ildeame4&t 143 1. TB, TRF

OV

2. 5-:.CZA-2-NYl M4 CACL 2 3, N~aB 4 03 4. mBSC4 I dazoke DMF iatemedit 150 1. e IM 2

C

2 W Yd

N.

QL4Ck reagent A or reagenit B* 07BS 7B hoodu el 12 uilwm1dm 153 intemeE lef 154 inmedate 146 1. Np7f! 3 2 t24 =-TINS W, 71F 2. K 2 COl, MeOH N. 1. TBA41 THF 2. B.S Cu 2 x-0 Rehyl a =mt1 or.

ildwe~daSS 155 a0 R edhyj jnte~edae56 n1I R-mMa 1. -aQdyLbui4o1e £BcffV, 2 NafJH Compoaund 126 ii 0 Compowad 12 7 n =I 3

H

5 N-2' ccz RE4C7YONSCME14 WO 02/18361 PCT/US01/25443 S76 1 Reaction Scheme 15 disclose presently preferred synthetic routes to 2 obtain exemplary and preferred phenyl compounds of the invention within 0 3 the scope of Formula 6 where X 2 represents an alkyl and cyclopropyl 4 substituted nitrogen (X 2 (alkyl,cycloalkyl)N), Y represents hydrogen,

Z

is an ethynyl moiety and A is a substituted phenyl moiety.

6 Reaction Scheme 16 discloses presently preferred synthetic routes to 7 obtain exemplary and preferred tetrahydronaphthalene compounds of the 8 invention within the scope of Formula 4 where the symbol X 1 represents a 9 (1-imidazolyl) moiety, Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

11 Reaction Scheme 17 discloses presently preferred synthetic routes to 12 obtain exemplary and preferred phenyl compounds of the invention within 13 the scope of Formula 6 where the symbol X 2 represents a 1-methyl- 14 cyclopropoxy moiety, Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

16 Reaction Scheme 18 discloses presently preferred synthetic routes to 17 obtain exemplary and preferred phenyl compounds of the invention within 18 the scope of Formula 5 where the symbol X represents oxygen Y 19 represents a tertiary-butyl group, Z is an ethynyl moiety and A is a substituted phenyl moiety.

21 WO 02/18361 WO 0218361PCT[US01/25443 77 II> SOa 2 ,pnn eydaropyl ane or W, Kzc0 3 H~ 2 BH3:AVe2S iigtermediae 159 1.L4fws 2 z~ Tm1 \d"C NTff 3 )cJ, M~I~ 3 cULL NFI 3 TBI 7tC Ck& reage~w A or reagen~t B 2. K 2 C0 3 MeOH jineditte 161 Copound 128 n -0 R CompowwdlO x =0 Cmomwdl29 m -1 R -Me Compoadl3l a -I cog

N.

N

a.

inteymejgie 155 eyclopiwpjdwne, E*OH WL 1 3 c0 3

LE~OIN

Comod 132 Compound.133 NaJH Conround.134 WO 02/18361 WO 0218361PCT/US01/25443 Rf(FYh 3 2 ciz THz w t Cm creageiseA orB 0 NaMH MeOHMEOH 0 iakjfmedittel3 n=O R=t Coinpotad4 x-J R-Me M0R I. NW'cwmbonvyldIddxo~e, TRF 2. NaJH l rc"0 S= 0,1 n =0 Compoand 135 n1l R-Me Cotpoad 137 n1= Compound 139 n-0 RZEACIONSCLMWfE6 WO 02/18361 WO 0218361PCTIUS01/25443 I OTf Tebbe rearn HOH czl 3 coaZpyi ibe bea,dae 149 irtemedae 162 01? OTf I. Fd(f1%i) 2 a)l -M 2.K2CO3 Me-OH irdgmw4Udel64 b"vwdiae 166 04 reagent B 2. NaJH Cmomud 141 MECTIONSCLUW]dE7 WO 02/18361 WO 0218361PCT[US01125443 Pd(M1)2J~p

-=TM

Cm& NE( 3 TJZl, 2 MA K 2 C0 3 Lz&eOM 3. K2C0 3 MeOH Bi(IT' 3 2 C4 TBiI~ NF1 3 Q4~Z reagent B or reagent H bdtemedi ate 169 R NaGH Compoad 142 R=H Compawdl44 R=F Composnd 143 R =H Composind 145 R F R4CTON SCHOEE18 WO 02/18361 PCT/US01/25443 S81 1 SPECIFIC EXAMPLES 2 4-Hydroxy phenyl acetic acid-t-butyl ester (Reagent E) 00 3 A stirred suspension of 4-hydroxy-phenyl acetic acid (0.152g, 4 Immol) in anhydrous toluene (5mL) was heated at 80 0 C and N,N-dimethyl formamide-di-t-butyl acetal (ImL, 4.17mmol) was added when the solution S6 became homogenous. After 0.5h, the reaction mixture was cooled to 7 ambient temperature and the volatiles were distilled off in vacuo. The C1 8 residue was diluted with water and extracted with diethyl ether The 9 combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil which was subjected to flash 11 column chromatography over silica gel (230-400 mesh) using 16% ethyl 12 acetate in hexane as the eluent to afford the title compound as a solid (0.1 g, 13 56%).

14 'H-NMR (300 MHz, CDC13):6 1.44(s, 9H), 3.45(s, 2H), 6.55(s, 1H), 6.69(d, J= 8.8Hz, 2H), 7.06(d, J= 8.5Hz, 2H).

16 3-Hydroxy phenyl acetic acid-t-butyl ester (Reagent F) 17 A stirred suspension of 3-hydroxy-phenyl acetic acid (1.52g, 18 1 Ommol) in anhydrous toluene (20mL) was heated at 80 0 C and N,N- 19 dimethyl formamide-di-t-butyl acetal (9.6mL, 40mmol) was added when the solution became homogenous. After 0.5h, the reaction mixture was cooled 21 to ambient temperature and the volatiles were distilled off in vacuo. Th 22 residue was diluted with water and extracted with diethyl ether The 23 combined organic extract was dried over anhydrous sodium sulfate, filtered 24 and evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 16% ethyl 26 acetate in hexane as the eluent to afford the title compound as a solid (1.17g, 27 56%).

WO 02/18361 PCT/US01/25443 S82 1 'H-NMR (300 MHz, CDC1 3 1.47(s, 9H), 3.49(s, 2H), 6.30(s, 1H), 6.70- S2 6.79 2H), 6.81(d,J= 7.6Hz, 1H), 7.16(t, J= 7.7Hz, 1H).

3 Methyl-2-fluoro-4-iodo benzoate (Reagent G)

OO

4 A solution of 2-fluoro-4-iodo toluene (5g, 26.6mmol) in pyridine (2mL) and water (20mL) was treated with potassium permanganate (16.6g, 6 105mmol) and heated at 150 0 C overnight. The reaction mixture was then S7 cooled to room temperature and filtered and the filtrate was extracted with C 8 hexane. The aqueous phase was acidified with 10% hydrochloric acid and 9 extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved 11 in 20mL of methanol, treated with concentrated sulfuric acid (ImL) and 12 refluxed overnight. The volatiles were distilled off in vacuo and the residue 13 was dissolved in diethyl ether, washed with brine, dried over anhydrous 14 sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in 16 hexane as the eluent afforded the title compound as an oil (0.26g, 17 'H NMR (300 MHz, CDC1 3 8 7.60 4H), 3.93 3H).

18 Ethyl-2-fluoro-4-hydroxy benzoate (Reagent I) 19 A solution of 2-fluoro-4-hydroxy benzoic acid (Intermediate 4, 3g, 19.2mmol) in ethanol (65mL) and benzene (90mL) was treated with 21 concentrated sulfuric acid (1.5mL) and heated at reflux overnight using' a 22 Dean-Stark water trap. The volatiles were distilled off in vacuo and the 23 residue was diluted with water and diethyl ether. The phases were separated 24 and the organic phase was washed with saturated aqueous sodium bicarbonate water (xl) and brine dried over anhydrous 26 magnesium sulfate, filtered and evaporated in vacuo to afford the title 27 compound as a solid (3.07g, 86%).

WO 02/18361 WO 0218361PCT/US01/25443 83 r- I1 H-NMR (300 MHz, CD 3

COCD

3 5 1.34 J= 7.1lHz, 3H), 4.32 J= 2 7. 1Hz, 2H), 6.66(dd, J 2.6, 10.9Hz, 1 6.76 (dd, J 2.3, 8.5Hz, I H), 00 3 7.83(d, J 8.4H4z, IHM, 9.91 1H).

4 Ety--furo4tiloo (Iufyoy~ezaentermediate 6) A stirred, cooled (ice bath) solution of etbyl-2-fluoro-4-hydroxy- 6 benzoate (Intermediate 5, 0.368g, 2mmol) and 2,6-di-tert-butyl-4-methyl- 7 pyridine (0.81 g, 8mmol) in 8mL of dichioromethane was treated with 8 trifluoromethanesulfonic anhydride (0.l1g, 4mmol). The reaction mixture 9 was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to flash column chromatography over silica 11 gel (23 0-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to 12 afford the title compound (0.53g, 13 'H-NMR (300 MHz, CDCl 3 8 1.41 J= 7.3Hz, 3H), 4.42 7.1lHz, 14 2H), 7.12-7.20(m, 2H), 8.08(t, J= 8.3Hz, LH).

Etl-2-fluoro-4-trimethiylsilgnvlethyny1-benzoate (Intermediate 7) 16 A solution of ethyl-2-fluoro-4- trifluoroniethylsulfonyloxy-benzoate 17 (Intermediate 6, 1.82g, 6mmol) in triethyl amine (Il2mL) and anhydrous 18 tetrahydrofuran (3 OmL) was treated with copper(Diodide 12g, 0.6mmol) 19 and sparged with argon. Dichlorobis(triphenylphosphine)palladium(II) (0.43g, 0.6mmol) was added followed by (lrimethylsilyl)acetylene (3 .6mL, 21 24mxnol) and the resulting reaction mixture was heated at 701C overnight. It 22 was then cooled to ambient temperature, diluted with diethyl ether and 23 filtered over a bed of celite. The filtrate was evaporated in vacuo to an oil 24 which was subjected to flash column chromatography over silica gel (230- 400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title 26 compound as an orange oil (1.5g, quantitative).

27 1 H-NMR (300 M]Rz, GDCI 3 0.011 9H), 1.13(t, J= 7.1Hz, 3H), 4.13 (q, WO 02/18361 WO 0218361PCT[US01/25443 84 I J=7.lHz, 2H),6.93-7.02(m, 21), 7.07 1H),7.61(t,J==7.9HZ, 1H).

2Etl-4-ethvnvl-2-fluoro benzoate (Reagent D) 00 3 A solution of ety--loo4tiehliayehnlbnot 4 (Intermediate 7, 1 .5g, 6mmnol) in ethanol (I 6mL) was treated with potassium carbonate (1 .485g, l0.74mmol) and stirred overnight at room N 6 temperature. The reaction mixture was then diluted with water and extracted 7 with diethyl. ether The combined organic phase was dried over 8 anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an 9 orange oil. Flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent afforded the title compound 11 (1g, 86%).

12 'H-NMR (300 MHz, CDCl 3 1.39 J= 7.1H4z, 3.26 1H), 4.39 (q, 13 J= 7.11Hz, 2H1), 7.22-7.33 (in, 2H1), 7.88(t, J= 7.7Hz, 1H).

14 Methyl-4-iodo-phenyl acetate (Reagent B) A solution of 4-iodo phenyl acetic acid (5g, 19mmol) in methanol was 16 treated with concentrated sulfuric acid (0.SmL) and refluxed overnight. The 17 volatiles were distilled off in vacuo and the residue was dissolved in ethyl 18 acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and 19 evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in 21 hexane as the eluent to afford the title compound as a clear oil (5g, 22 1H NMR (300 MHz, CDCI 3 8 7.63 211I, J= M.Hz), 7.01 211, J 23 8.0Hz), 3.67 311), 3.55 211).

24 2-F1Uoro-4-iodo-phenyl acetonitrile (Intermediate 2) A solution of 2-fluoro-4-iodo-benzyl bromide (Intermediate 1, 26 2.56g, 8.l5mniol) in ethanol (5 5nL and water (IOm1L) was treated with 27 sodium cyanide (2.15g, 43.86inmol) and refluxed for 0.5h. The volatiles WO 02/18361 PCTIUS01/25443 1 were distilled off in vacuo and the residue was diluted with water and S2 extracted with diethyl ether The combined organic extract was washed 3 with water (xl) and brine dried over anhydrous magnesium sulfate, 4 filtered and evaporated in vacuo to afford the title compound as a pale yellow solid (2.05g, 96%).

IN 6 'H-NMR (300 MHz, CDC13): 5 3.71(s, 3H), 7.16(t, J= 8.2Hz, 1H), 7.45(dd, 7 J= 1.7, 9.1Hz, 11), 7.51(dd,J= 1.5, 8.2Hz, 1H).

C

8 2-Fluoro-4-iodo-phenvl acetic acid (Intermediate 3) 9 A solution of2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 2.05g, 7.83mmol) in ethanol (50mL and water (15mL) was treated with 11 potassium hydroxide (3.4g, 60.7mmol) and refluxed for 4h. The volatiles 12 were distilled off in vacuo and the residue was diluted with water and poured 13 into cold, dilute hydrochloric acid and the precipitated solid was filtered.

14 The solid was dissolved in diethyl ether, and the organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to 16 afford the title compound a pale yellow solid (1.75g, 79%).

17 'H-NMR (300 MHz, CDC1 3 3.64 2H), 6.98(t, J= 7.9Hz, 1H), 7.25- 18 7.46 2H), 9.60-10.40(br s, 1H).

19 Ethyl-2-fluoro-4-iodo-phenyl acetate (Reagent C) A solution of 2-fluoro-iodo-phenyl acetic acid (Intermediate 3, 21 1.75g, 6.22mmol) in ethanol (50mL) and benzene (100mL) was treated with 22 concentrated sulfuric acid (1.4mL) and heated at reflux overnight using a 23 Dean-Stark water trap. The volatiles were distilled off in vacuo and the 24 residue was diluted with water and diethyl ether. The phases were separated and the organic phase was washed with saturated aqueous sodium 26 bicarbonate water (xl) and brine dried over anhydrous 27 magnesium sulfate, filtered and evaporated in vacuo to afford an oil which WO 02/18361 PCT/US01/25443 86 1 was subjected to flash column chromatography over silica gel (230-400 2 mesh) using 5%-10% ethyl acetate in hexane as the eluent to afford the title 00 3 compound as a pale yellow solid (1.4g, 73%).

4 'H-NMR (300 MHz, CDC): 8 1.25 J= 7.1Hz, 3H), 3.60 2H), 4.16 (q, J= 7.1Hz, 2H), 6.99(t, J 8.0Hz, 1H), 7.39-7.44(m, 2H).

S6 Methyl-2-fluoro-4-iodo-phenvl acetate (Reagent H) 7 A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 8 3g, 11.45mmol) in methanol (50mL) and benzene (50mL) was treated with 9 p-toluene sulfonic acid (2.5g, 13.15mmol) and heated at reflux overnight using a Dean-Stark water trap. The volatiles were distilled off in vacuo and 11 the residue was diluted with water and diethyl ether. The phases were 12 separated and the organic phase was washed with saturated aqueous sodium 13 bicarbonate water (xl) and brine dried over anhydrous 14 magnesium sulfate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel (230-400 16 mesh) using 6% ethyl acetate in hexane as the eluent to afford the title 17 compound as a colorless oil (2.7g, 18 IH-NMR (300 MHz, CDC13): 8 3.62 2H), 3.70 3H), 6.99(t, J 7.9Hz, 19 1H), 7.39-7.45(m, 2H).

GENERAL PROCEDURE A: 7-Methoxy-1.1-dimethyl-1.2.3.4- 21 tetrahydronaphthalene (Intermediate 8) 22 A stirred, cooled (-40 0 C) solution of titanium tetrachloride in 23 anhydrous dichloromethane (1M, 20mL) under argon, was treated with a 24 solution of dimethyl zinc (2M, 40mL) in toluene. After 0.5h, a solution of 7methoxy-l-tetralone (1.76g, 10mmol) in anhydrous dichloromethane 26 was cannulated into the reaction mixture and the resulting solution was 27 allowed to warm to ambient temperature and stirred overnight. The reaction WO 02/18361 WO 0218361PCT/US01/25443 87 i mixture was then cooled to -40'C and cautiously quenched with methanol 2 (11 mL). it was diluted with dichioromethane and saturated aqueous 00 3 ammonium chloride solution. The phases were separated and the aqueous 4 phase was extracted with dichioromethane (x2mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in 6 vacuc to the title compound (1 .75g, 92%) as an oil.

7 1 H-NMR (300 MHz, CDCl 3 1.33(s, 6H), 1.67-1.71(mn, 2H1), 1.79-1.90(m, 8 2M1, 2.75(t, J1= 6.2Hz, 2H), 3.83(s, 311), 6.72(dd, J 8.3Hz, 1H), 9 6.93 J 2.6H4z, IlH), 7.02(d, J 8.3 Hz, IlH).

GENERAL PROCEDURE B: 6-Methoxy-4,4-dimethvl-l.2.3.4- 11 tetrahvdrongphthalene- 1-one (Intermediate 9) 12 A solution of 7-methoxy- 1 -dimethyl- 1,2,3,4-tetrahydronaphthalene 13 (Intermediate 8, 1.65g, 8.7 mmol) in 7.5mL of glacial acetic acid was 14 cooled to 0 0 C and treated with a solution of chromium trioxide (2g, in 8mL of acetic acid and 7mL of water. The reaction mixture was then 16 allowed to warm to ambient temperature and stirred overnight. It was 17 diluted with water and extracted with diethyl ether The combined 18 organic phase was washed with water saturated aqueous sodium 19 bicarbonate (xl) and brine dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (1 .64g, 93%) as 21 a yellow oil.

22 1 H-NMvR (300 MHz, CDCI 3 1.34(s, 6H1), 1.96(t, J 1Hz, 211), 2.64(t, J 23 7. 1Hz, 2H), 3.83(s, 3H), 6.77(dd, J= 2.6, 8.7Hz, 1 6.83(d, J 2.5H z, 24 111), 7.98(d, J 8.7H1z, 1Wl.

6-Hydr-oxy-4,4-dirnethyl-l .2.3 .4-tetrahydronaphthalene- 1 -one 26 (Intermediate WO 02/18361 WO 0218361PCTIUSOI/25443 88 1A stirred, cooled (78 0 CQ solution of 6-methoxy-4,4-dimethy1-1 ,2,3,4- 2 tetrahydronaphthalefle-lI-onle (Intermediate 9, 0.8, 3nunol) under argon was 00 3 treated with a I M solution of boron tribromide (1lnmL). The reaction c-i4 mixture was allowed to warm to ambient temperature and stirred overnight.

The reaction mixture was cooled to -780C, quenched and diluted with 6 saturated aqueous sodium bicarbonate solution and the aqueous phase was 7 extracted with dichioromethane The combined organic phase was c-I8 dried over anhydrous sodium sulfate, filtered and evaporated in vacua to an 9 oil. Flash column chromatography over silica gel (230-400 mesh) using 30% ethyl acetate in hexane as the eluent afforded the title compound (0.3g, I I. 52%) as a yellow viscous oil.

12 'H-NMR (300 M1z, CDCI 3 1.33(s, 6H1), 1.97(t, J 6.8H1z, 214), 2.71(t, J 13 6.7Hfz, 2fH), 6.81l(dd, J 2.3, 8.5H1z, 1H1), 6.94(d, J =2.3Hz, 1Hi), 7.98(d, 14 J 8.7Hz, 1H), 9.35(s, 111).

GENERAL PROCEDURE C: 4.4-Dimethyl-6-trifluoromethvlsulfonvloxy- 16 1 .2.3.4-tetrahydronaphtalene-1 -one (Intermediate 11) 17 A stirred, cooled (0 0 C) solution of 6.-hydroxy-4,4-dimethyl-l,2,3,4- 18 terahydronaphthalene-l -one (Intermediate 10, 0.3g, 1 .6mniol) in anhydrous 19 dichloromethane (IlOmL) was treated with 4-(diniethylamino)pyridine (0.36g, 3.27mmol) followed by 2-[N,N'-bis(trifluoromethylsulfonyl)amuno]- 21 5-chloropyridine (0.79g, 2mmol). After stirring at ambient temperature for 22 0.75h, the reaction mixture was diluted with dichloromethane and washed 23 with water The organic phase was dried over anhydrous sodium 24 sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 8-10% ethyl acetate in 26 hexane as the eluent afforded the title compound (0.

4 62g, 90%) as an off- 27 white solid.

WO 02/18361 WO 0218361PCT[USOI/25443 89 I t H4-NMR (300 MHz, CDC1 3 S1.36(s, 2.O1(t, J=6.8Hz, 21), 2.70(t, J 2 =6.7Hz, 2H), 7.1 5(dd, J 8.7Hz, 1H), 7.28(d, J =2.411z, 111), 8.06(d, 00 3 J =8.7Hz, IH).

c-i 4 GENERAL PROCEDURE D: 4.4-Dimethy-6trimth 1S-alChyfil 1.2.3.4-tetrahydronaplithalene- 1-one (Intermediate 12) 6 A solution of 4,4-dimethyl-6-trifuoroethy1sulfoloxy-1,2,3,4- 7 tetrahydronaphthalene- I-one (Intermediate 11, 0.46g, 1.43mmol) in triethyl 8 amine (3niL) and anhydrous tetrahydrofuran (8mL) was treated with 9 copper(I)iodide 1 g, 0.5 3 mmol) and sparged with argon for 5 minutes.

Trimethylsilyl acetylene (0.85 mL, 6mrnol) was then added followed by 11 dichlorobis(triphenylphosphine)palladiurn(II) (0.25g, 0.36mmol). The 12 resulting reaction mixture was heated at 70 0 C for 17h. It was then cooled to 13 ambient temperature, diluted with diethyl ether and filtered over a bed of 14 celite. The filtrate was evaporated vacuo to an oil which was subjected to flash column chromatography over silica gel (23 0-400 mesh) using 5% ethyl 16 acetate in hexane as the eluent to afford the title compound (0.28g, 72%).

17 'H-NMIR (300 M&z, CDC1 3 8 0.26(s, 9H1), 1 .36(s, 6117, 1 .99(t, J 6.8H1z, 18 2H), 2.69(t, J =6.711z, 2H), 7.35(dd, J 1.7, 8.2Hz, 11H), 7.49 (unresolved 19 d, 1H), 7.93(d,J 1H1).

GENERAL PROCEDURE E: 6-Ethvnyl-4.4-dinefhl-1.2,3,4- 21 tetrahydronphthalene- 1 -one (Intermediate 13) 22 A solution of 4,4-dimethyl-6-trimethylsilanylethynyl- 1,2,3,4- 23 tetrahydronaphthalene- 1-one (Intermediate 12, 0.28g, 1 .03mmol) in 24 methanol (IlOmL) was treated with potassium carbonate (0.74g, 5.3 and stirred at ambient temperature for 4h. The volatiles were distilled off in 26 vacuo and the residue was diluted with water and extracted with diethyl ether 27 The combined organic extract was dried over anhydrous magnesium WO 02/18361 WO 0218361PCTfUS01/25443 1- sulfate, filtered and evaporated in vacuo to afford the title compoud(. g 0 2 89%) as an oil that solidified on standing.

003 1 H-NMR (300 MHz, CDCI 3 1 .33(s, 611, 1 .96(t, J 6.8Hz, 2H1), 2.67(t, J 4 6.8Hz, 2H1), 3.25(S, 1H), 7.33(dd, J 8.1Hz, 111), 7.49 J= IH), 7.13(d, J =8.Hz, 1H).

6 GENERAL PROCEDURE F: 4-(8.8-JDimethv1-5-oxo-5,6,7,8-tetrahydro- 7 naph)thalene-2-yl-ethvnyl)-benzoic acid etl ester (Intermediate 14) 8 A solution of 6-ethynyl-4,4-dmethyl- 1,2,3 ,4-tetrahydronaphthalene- 9 1 -one (Intermediate 13, 0.23g, 1. 1 mmol) and ethyl-4-iodo benzoate (Reagent A, 0.3 6g, 1 .3mmnol) in triethyl amine (7mL) and anhydrous 11 tetrahydrofuran (3mL) was treated with copper(1)iodide 1 14g, O.6mmol) 12 and sparged with argon for 5 minutes.

13 Dichlorobis(triphenylphosphine)palladium(1I) (0.23g, 0.33mmol) was added 14 and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite. The filtrate was 16 evaporated in vacuo to a brown oil that was subjected to flash column 17 chromatography over silica gel (23 0-400 mesh) using 6-7% ethyl acetate in 18 hexane as the eluent to afford the title compound (0.29g, 72%) as a pale 19 brown solid.

1 HNMR (300 MHz, CDCl 3 8 1.3(t, J =7.111z, 311), 1.37(s, 611), 1.80 J 21 6.8Hz, 2H), 2.69(t, J1 6.8Hz, 2H), 4.35 J 7. 1Hz, 2H), 7.40(dd, J= 22 1.5, 8.2Hz, 111), 7.51 J =1.6Hz, 1H1), 7.57 J =.MHz, 2H), 7.96(d, J 23 8.2H1z, 11H), 7.99(d, J 8.5Hz, 211).

24 GENERAL PROCEDURE (G 4-(5-Cyclo~rgolamino-8.8-dime~tvl-5.6.7.8tetrahydro-na~hthalene-2y1-ethvnyl)-benzoic acid ethyl este (Compound 1, 26 General Formula 4) WO 02/18361 WO 0218361PCTIUSOI/25443 91 I A solution of 4-88dmty--x-,,,- rhdo ~t 2 2-ylethynyl)-belzoic acid ethyl ester (Intermediate 14, 0.14g, 0.4ntmol) in 0C) 3 3mL of dichioromethane and 2inL of acetonitrile was treated with 4 cyclopropyl amine(l mL, 14.45mrnol). After 5 minutes, acetic acid (I mQL was added followed by sodium cyanoborohydride (0.13g, 2mmol). The 6 reaction was stirred overnight at ambient temnperature. It was then diluted 7 with water and saturated aqueous sodium carbonate solution and extracted 8 with dichloromethane The combined organic extract was dried over 9 anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (2 30-400 mesh) using 20% ethyl I11 acetate in hexane as the eluent afforded the title compound 1 g, 62%) as a 12 pale yellow solid.

13 'H-NMR (300 MvHz, CDCI 3 8 0.30-0.60(m, 4H), 1.28(s, 3H1), 1.35 3H), 14 1.30(t,J 7.1Hz, 3H1), 1.55-1.61(m, 1H), 1.83-2.05(m, 3H), 2.25 (quintet, J 3.0 Hz, 111), 3.80 J =4.91-z, 11H), 4.39(q, J= 7.111z, 2H), 7.27-7.36(m, 16 2H), 7.52 1H1), 7.55(d, J 8.311z, 2H), 8.03(d, J 8.Hz, 2H).

17 GENERAL PROCEDURE H 4-[(5-Cyclo~ropl-methyl-amino)-8. 8.

18 dimethyl-5.6.7. 8-tetrahydro-nanhthalene-2-ylethvnyl] -benzoic acid ethyl 19 P =1 (Compound 2, General Formula 4) A solution of 4-(5-cyclopropylamino-8,8-dimethyl-5,6,7,8-tetrahydro- 21 naphthalene-2-ylethynyl)-benzoic acid ethyl ester (Compound 1, 0.064g, 22 0. l6mmol) in acetone (2mL) was treated with potassium carbonate (0.6g, 23 4.34mmol) and methyl iodide (lmL, l6mmol) and stirred overnight at 24 ambient temperature. The volatiles were distilled off in vacuc and the residue was diluted with water and extracted with dichloromethane (x2), 26 The combined organic extract was dried over anhydrous sodium sulfate, 27 filtered and evaporated in vacuo to afford the title compound (0.065g, 99%).

WO 02/18361 WO 0218361PCTIUS01/25443 92 r-I 'H-NMiR (300 MHz, CDCI 3 8 0.28-0.49 (mn, 4H1), 1.(,3H,12(s31) 0 2 1.33 J lHz, 3H), 1.58-1.73 (mn,2H), 1.83-1.89 2H), 2.02-2.08 (in, 00 ~3 11H), 2.06 311), 3.88 J= 8.11Hz, 1H1), 4.32(q,J 7.1 Hz, 2H), 7.20(d, J 't 4 =7.8Hz, 1H), 7.41 1H), 7.46 J 7.8Hz, 1H1), 7.52(d, J =8.4Hz, 211), 8.03(d, J =8.3Hz, 2H1).

6 GENERAL PROCEDURE 1: 4-r(5-!Cyclopropy1-meth1-amiflo)-8,8- 7 diniethyl-5.6.7.8-tetrhdro-nghthaene-2y-ehfll-belzoic acid 8 (Compound 3, General Formula 4) A solution of 9 methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-laphtalele- 2 -yethynyl]F benzoic acid ethyl ester (Compound 2, 0.065g, 0.lS8mmol) in ethanol 11 (1mL) and tetrahydrofuran (iniL) was treated with 1M aqueous sodium 12 hydroxide solution (ImL) and heated at 80 0 C for 1h. The volatiles were 13 distilled off in vacuo and the residue was diluted with saturated aqueous 14 ammnonium chloride solution and extracted with ethyl acetate The combined organic extract was dried over anhydrous sodium sulfate, filtered 16 and evaporated in vacuo to afford a solid that was washed with 17 dichoromethane and dried to afford the title compound (0.029g, 38%) as a 18 white solid.

19 'H-NMR (300 MHz, CD 3

COCD

3 5 0.35-0.5 1(m, 4H), 1.26(s, 3H), 1.29 (s, 3H), 1.60-1.82(m, 2H), 1.88-2.02(mn, 2H), 2.02-2.15 (in, 111), 2.10 3H), 21 3.93 J 8.0Hz, 1H1), 7.26(dd, J 1.5, 8.2Hz, 1H), 7.51 J 22 1H1), 7.52(d, J 8.2Hz, 11H), 7.62(d, J 8.5H1z, 2H), 8.02(d, J =8.2Hz, 211).

23 44[(8.8-Dimethyl-5-oxo-5 .6.7.8-tetrahydro-naphthalene-2-vl-etyl)- 24 phenyll-acetic acid methyl ester (Compound 4, General Formula 8) Following general procedure F and using 6-ethynyl-4,4-dimethyl- 26 1,2,3 ,4-tetrahydronaphthalene- 1 -one (Intermediate 13, 0.31 2g, 1 27 4-iodo phenyl acetic acid methyl ester (Reagent B, 0.50g, 1.8mnaol), iriethyl WO 02/18361 WO 0218361PCT/US01/25443 93 1 amine (7rnL), anhydrous tetrahydrofian (3mL), copper(I)iodide (0.04g, 2 O.2mxnol) and dichlorobis(triphenylphosphile)palladiul3(I) (0.1 0C) 3 0.2 l3mmol) followed by flash column chromatography over silica gel (230- 4 400 mesh) using 16-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow solid (0.42g, 76%).

6 1 H-NtvlR (300 MFz, CDCl 3 1.42(s, 6H1), 2.04(t, J =6.7Hz, 2.74(t, J 7 6.7Hz, 2H), 3.66(s, 211), 3.7 l(s, 3H1), 7.29 J =8.211z, 2H), 7.43(dd, J 8 1.5, 7.9Hz, 111), 7.52 J =8.2Hz, 2M1, 7.57 J 1.5Hz, 11H), 8.'00(d, J 9 =8.2Hz, 1H1).

GENERAL PROCEDURE J: 4-r(8.8-Dimetl-5-oxo-5.6.7.8-tetrahydro- 11 ngphthalene-2-vl-etUDyl-phenyll1-acetic acid (Compound 5, General 12 Formula 8) 13 A solution of 4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene- 14 2-yiethynyl)-phenylj-acetic acid methyl ester (Compound 4, 0.l1g, 0.28mmol) in a mixture of methanol (2mL), tetrahydrofuran (3.5mL) and 16 water (1.5mL) was treated with lithium hydroxide monohydrate 1Ig, 17 2.62mmol) and the resulting reaction mixture was stirred at ambient 18 temperature for 3h. The volatiles were distilled off in vacua and the residue 19 was diluted with water and dilute hydrochloric acid and extracted with ethyl acetate The combined organic phase was dried over anhydrous sodium 21 sulfate, filtered and evaporated in vacua to afford the title compound as a 22 pale yellow solid (0.088g, 92%).

23 'H-NMR (300 MHz, CDCI 3 8 1.41I(s, 611), 2.02(t, J= 6.7Hz, 2H1), 2.74(t, J 24 6.8Hz, 2H1), 3.68(s, 211), 7.28 J 8.2Hz, 211), 7.42(dd, J 8.2Hz, 111), 7.52 J 8.2Hz, 2H), 7.56 J .SHz, 1M1, 7.99(d, J =8.211z, 26 111).

WO 02/18361 WO 0218361PCTIUS01/25443 94 1 4-[(5-(Cy-clopropy1-al~nino)-8.8-diflethyl- 5,6,7,8-tetrah dro-naphhlIe 2 2 yl-ethnI-hnl-~tCai methyl ester (Compound 6, General 00 3 Formula 4) 4 Following general procedure G and using 4-[(8,8-dimethyl-5-oxo- 5,6,7,8-tetrahydro-naphthalene-2-yl-ethylyl)-phel-acetic acid methyl ester 6 (Compound 4, 0.2g, 0.54mmol), dichioromethane (4mL), acetonitrile(2mL), 7 cyclopropyl amnine(lmL, 14.45nmol), acetic acid (lmL)and sodium 8 cyanoborohydride 1 6g, 2.54mmol) followed by flash colun 9 chromatography over silica gel (230-400 mesh) using 30% ethyl acetate in hexane as the eluent the title compound was obtained as a pale yellow oil 11 (0.22g, 99%).

12 'H-NMR (300 MHz, CDC1 3 8 0.38-0.60 4H), 1.26(s, 311), 1.33(s, 3H), 13 1.50-1.59(m, 1H1), 1.79-2.10 (mn, 3H1), 2.25(m, 111), 3.63(s, 2H), 3.69(s, 3H), 14 3.79(t, J =4.8Hz, 111), 7.20-7.32 4H), 7.47(s, I 7.58(d, J =8.2H4z, 2H).

16 4-1 (5-(Cyclopropvl-methvl-arnino)-8.8-dimethvl- 5,6.7.8-tetahdro- 17 naphthalene -2-yI-ethynyl)-,phenvll-acetic acid metyl ester (Compound 7, 18 General Formula 4) 19 Following general procedure H and using 8,8-dimethyl- 5,6,7,8-tetrahydro-naphtbalene-2-ylethynyl)-phenyl] -acetic 21 acid methyl ester (Compound 6, 0.15g, 0.37mmol), acetone 22 potassium carbonate (1.1g, 7.95mrnol) and methyl iodide (lmL, l6mmol), 23 the following work-up was used. The volatiles were distilled off in vacuo 24 and the residue was diluted with water and extracted with dichioromethane The combined organic extract was dried over anhydrous sodium 26 sulfate, filtered and evaporated in vacuo to afford the title compound 27 148g, 97%).

WO 02/18361 WO 0218361PCTIUS01/25443 I '1--NMR (300 Mf-zCDCL 3 80.38-0.58(m, 4H), 1.27(s,311), 131 3H-), 2 1.68-1.81(m, 211), 1.85-1.98(mn, 2H1), 2.08-2.15 (in, 1H1), 2.12 3H1), 3.62(s, 0C) 3 2H), 3.69(s, 311), 3.94 J= 7.9Hz, I 7.24(d, J =8.2Hz, 1H), 7.24 J 4 8.2Hz, 211), 7.44-7.5 1(m, 4H).

S 4[(5(Ccloroyl-metl-amilo)-.-ITehl 5,6,7,8-tetrahydro- 6 nahtlialene-2-vl-etynyl)-phenyll-acetic acid (Compound 8, General 7 Formula 4) 8 Following general procedure J and using 9 amino)-8,8-dimethyl-5 ,6,7,8-tetrahydro-naphthalene-2yIethylyl)-phelIacetic acid methyl ester (Compound 7, 0.148g, O.357mmo1), methanol I1I (2mL), tetrahydrofuran (4mL), water (lmL) and lithium hydroxide 12 monohydrate (0.25g, 5.95mmol) followed by flash column chromatography 13 over silica gel (230-400 mesh) using 30-75% ethyl acetate in hexane as the 14 eiuent, the title compound was obtained as a white solid (0.08g, 56%).

'H-NN4R (300 MHz, CDCl 3 6 0.52-0.54(m, 211), 0.68-0.70(mn, 211), 1.2 7(s, 16 3H1), 1.29(s, 1.63-1.80(m, 1.95-2.17(m, 2H1), 2.19-2.24(mn, 1H), 17 2.24(s, 3H1), 3.60(s, 2H), 4.18(t, J =7.7Hz, 1IM, 7.24(dd, J3= 1.5, 8.Hz, 18 111), 7.26 J 8.2H1z, 2H1), 7.43 J 8.2Hz, 11H1), 7.47(s, 1H), 7.47(d, J 19 8.2Hz, 2H), 10.37(br s, 111).

2-Fluoro-4-r(8.8-dim-tyl-5-oxo-5 .6.7L8-tetrahydro-naphten-2-vl- 21 etkhbenzoic acid thyl ester (Compound 9, General Formula 8) 22 A solution of 4,4-dimethyl-6-trifluromethylsulfonyloxy- 1,2,3,4- 23 tetrahydronaphthalene-1 -one (Intermediate 11, 0.3g, 0.9mmol), 24 copper(I)iodide (0.057g, 0.3nuuol) and ethyl-2-fluoro-4-ethynyl-benzoate (Reagent D, 0.44g, 2.27nimol) in triethyl amine (2mL) and tetrahydrofuran 26 (3mL) was sparged with argon for 5 minutes and treated with 27 dichlorobis(triphenylphosphine)palladium(iL) 13 5g, 0. 1 92rnmol) and WO 02/18361 WO 0218361PCT/IJS01/25443 96 1 stirred at room temperature overnight and then refluxed for 2h. It was then 2 cooled to ambient temperature, diluted with diethyl ether and filtered over a 00 3 bed of celite. The filtrate was evaporated in vacuo to an oil which was 4 subjected to flash column chromatography over silica gel (230-400 mesh) using 10- 15 ethyl acetate in hexane as the eluent to afford the title 6 compound as a yellow solid (0.22g, 67%).

7 'H-NMR (300 M~z, CDCI 3 8 1.38 J= 7.0Hz, 3H), 1.39(s, 6H), 2.01(t, J 8 6.7H-z, 2H), 2.7 1(t, J 6.7Hz, 2H), 4.37(q, J= 7Hz, 2H1), 7.28(dd, J= 0.9, 9 10H-z, 111), 7.34(dd, J 0.9, 8.2Hz, 111), 7.41 (dd, J 8.2H1z, IH), 7.57(d, J 0.9Hz), 7.90(t, J= 7.9Hz, 7.93 J= 7.9H-z, 111).

11 2-Fluoro-4-(8.8-dirnethyl-5-oxo-5,63.78-tetraydro-nphale-2y-eth fll)- 12 benzoic acid (Compound 10, General Formula 8) 13 A solution of 2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro- 14 naphthalen-2-ylethynyl)benzoic acid ethyl ester (Compound 9, 0.1g, 0.274mmo1) in ethanol(4rnL), methanol (2mL) and tetrahydrofuran (2mL) 16 was treatedviwith IM aqueous sodium hydroxide solution and heated at 17 for lh. The volatiles were distilled off in vacuc and the residue was diluted 18 with water and dilute hydrochloric acid and extracted with ethyl acetate (x2).

19 The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid that was recrystallized from 21 hot aqueous acetonitrile to afford the title compound (0.025g, 27%).

22 'H-NlvR (300 MHz, CDCl 3 8 1.43(s, 61-1), 2.05(t, J= 6.9Hz, 2M1, 2.76(t, J 23 6.9Hz, 2H), 7.26-7.47(m, 31-1), 7.60(d, J= 1. 1Hz, 1H), 7.99-8.05(m, 211).

24 4-r5-(cyclopropy1-aino-8.8-dimethyl- 5.6,7,8-tetrahvdr- n Wphha yl-ethynll-2-fluoro-benzoic acid ethyl ester (Compound 11, General 26 Formula 4) 27 Following general procedure G and using 2-fluoro-4-(8,8-dimethyl-5- 28 oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoic acid ethyl ester WO 02/18361 WO 0218361PCTIUS01/25443 97 1 (Compound 9, 0-132g, 0.3mmol), dichioromeihale (4mL), 2 acetonitrile(2inL), cyclopropyl amine(lmL, l4.45nunol), acetic acid 00 3 (1 mLand sodium cyanoborohydride (0.18g, 2.86mmol) followed by flash 4 column chromatography over silica gel (230-400 mesh) using 16-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale 6 yellow oil (0.l1g, 82%).

7 'H-NMR (300 MIHz, CDCI 3 0.36-0.54 (in, 414I), 1.27(s, 311), 1.33(s, 311), 8 1.40(t, J= 7.011lz, 311), 1.54-1.61(m, 1.82-2.05 (in, 2.26(m, 1H1), 9 3.79 J= 4.9H-z, 1H), 4.39(q, J= 7.1Hz, 2M1, 7.26-7.50(m, 4H), 7.87(s, 111), 7.92 J =7.9Hz, I H).

11 4-[5-(Cyclop~ropyl-methyl-amino)-8.8-dimgetl- 5.6.7.8-tetrhydro- 12 naphthalene-2-yl-e thynvl]-2-fluoro benzoic acid ethyl ester (Compound 12, 13 General Formula 4) 14 Following general procedure H and using amnino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro- 16 benzoic acid ethyl ester (Compound 11, 0.lg, 0.246mmo1), acetone (4mL), 17 potassium carbonate (0.917g, 6.63mmol) and methyl iodide (0.8miL, 18 11 inmol), the following work-up was used. The volatiles were distilled off 19 in vaczso and the residue was diluted with water and extracted with dichioromethane The combined organic extract was dried over 21 anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash 22 column chromatography over silica gel (230-400 mesh) using 8-10% ethyl 23 acetate in hexane as the eluent afforded the title compound as a pale yellow 24 oil (0.102g, 98%).

'H-NMiR (3 00 CDCI 3 8 0.39-0.62 (in, 411), 1 .29(s, 311), 1 3 4(s, 3H), 26 1.42(t, J= 6.9H1z, 311), 1.

6 5-1.82(m, 211), 1.85-2.02 (in, 2H1), 2 .0 2 2 WO 02/18361 WO 0218361PCT/US01/25443

U

98 1 1H), 2.15(s, 3W), 3.97(t, J=7.7Hz, 1W), 4.42(q, J=7.0Hz, 2H), 7.28-7.36 2 (in, 3H), 7.59(s, 1W), 7.55(d, J 7.9Hz, 211), 7.92 J= 7.51-z, 1W).

003 4-r5-(Q~clppy1metl-aminol-8.8-dimethyI- 5.6.78-tetrahydro- 4 naphthalene-2-l-ethnll- 2 -fluoTo benzoic acid (Compound 13, General Formula 4) 6 Following general procedure I and using 8 benzoic acid ethyl ester (Compound 12, 0. 102g, 0.23minol), ethanol (4mL) 9 and 1 M aqueous sodium hydroxide solution (2mL) followed by flash column chromatography over silica gel (230-400 mesh) 30% ethyl acetate in 11 hexane as the eluent, the title compound was obtained as an off-white 12 solid(0.015g, 16%).

13 'H-NMR (300 MHz, CDCl 3 8 0.54-0.65 (in, 4H), 1.29 3H), 1.32 3H-), 14 1.68-1.83 (in, 214), 1.97-2.05 (in, 2H1), 2.18-2.25 (in, 2.25 3H), 4.13 J 6.7Hz, I M, 7.26-7.30 (mn, 211), 7.34 (dd, J 1. 5, 7.9Hz, I1H), 7.48 (d, 16 J= 1.8Hz, 1W), 7.60 J= 8.5Hz, 1H), 7.95 J 7.9Hz, 1IM.

17 [2-Fluoro-4-(8,8-dimethyl-5-oxo-5.6.7.8-tetrahydro-naphthalene-2-y- 18 etbynyl)-phenyl1 acetic acid etyl este (Compound 14, General Formula 19 8) Following general procedure F and using 6-ethynyl-4,4-dimethyl- 21 1,2,3,4-tetrahydro-naphthalene-1-one (Intermediate 13, 0.298g, 1 .43mmol), 22 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.44g, 23 1.43mmol), friethyl amine (Intermediate 13, 3mL), anhydrous 24 tetrahydrofuran (7mL), copper(I)iodide (0.04g, 0.2mmol) and dichlorobis(triphenylphosphine)palladium(II) 15g, 0.2l3mmol) followed 26 by flash column chromatography over silica gel (230-400 mesh) using 14- WO 02/18361 WO 0218361PCT/US01/25443 99 1 16% ethyl acetate in hexane as the eluent, the title compound was obtained 2 as an oil (0.43g, 77%).

00 ~3 l'{-fl (3 00 M fz, CDCl 3 6 1.26(t, J =7.2Hz, 3H), 1.4 1(s, 6H), 2.04(t, J 4 6.7H1z, 2H-1), 2.74(t, J1= 6.7Hz, 2H), 3.6 8(s, 211), 4. 18(q, J 1Hz, 2H1), 7.23 -7.5 7(m, 4H1), 7.5 9 J 1. 5Hz, 1 7.99(d, J =7.9Hz, 1IH).

ID6 [2Fur--88dm y--x-..78ttgyr-ahhtn--l 7 eftinyl)phenyll-acetic acid (Compound 15, General Formula 8) 8 Following general procedure J and using [2-fluoro-4-(8,8-diinethyl-5- 9 oxo-5 ,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl] acetic acid methyl ester (Compound 14, 0.18g, O.48mmol), methanol (4mnL, tetrahydrofuran 11 (8mL), water (2m.L) and lithium hydroxide monohydrate (0.2g, 4.76mmol) 12 followed by flash column chromatography over silica gel (23 0-400 mesh) 13 using 50- 100% ethyl acetate in hexane as the eluent, the title compound was 14 obtained as a dirty white solid (0.068g, 41 'H-NMR (300 MJHz, CDCI):5 1 .41(s, 6H), 2.03(t, J =6.7Hz, 2H), 2.74(t, J 16 6.8H1z, 211), 3.73(s, 211), 7.24-7.32(m, 3M1, 7.42(dd, J 1.5, 7.9H1z, I H), 17 7.5 6 I 7.99(d, J 7.9Hz, 1IH), 9.40-10.00 (br s, 1 H).

18 r4-(5-cQyclopropyl-amnino-8.8-dinietyl- 5.678-tqpbyhdro-n4Vhthalene-2- 19 vl-ethyvnvl)-2-fluoro-phenvl1 acetic acid ethyl ester (Compound 16, General Formula 4) 21 Following general procedure G and using [2-fluoro-4-(8,8-dimethyl- 22 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl) phenyllacetic acid ethyl 23 ester (Compound 14, 0.258g, 0.68mmol), dichioromethane (4mL), 24 acetonitrile(2miL), cyclopropyl arnine(lmL, 14.45mmol), acetic acid (1lmL)and sodium cyanoborohydride (0.266g, 4.23mmol) followed by flash 26 column chromatography over silica gel (230-400 mesh) using 16-20-25% WO 02/18361 WO 0218361PCT/IJSOI/25443 100 1 ethyl acetate in hexane as the eluent, the title compound was obtained as a 2 pale yellow oil (0.2 1ig, 73%).

003 l'{-NMfi (3 00 MHz, CDCI 3 ):50.35-0.54 (in, 4M1, 1.25(t, J= 7.1Hz, 31-), 4 1.26(s, 311), 1.32(s, 3H4), 1.53-1.64(mn, 114), 1.82-2.05 (in, 314), 2.21-2.28(m, 114), 3.65(s, 2H), 3.78(t, J 5.0Hz, IH), 4.17(q, J= 7.1Hz, 2H1), 7.19-7.41 IND6 (mn, 5H), 7.47(d, J 1.MHz, 111).

7 [4-(5-(-Cvclopropyl-megthyl-amino)-8. 8-dime-tl-5,6.7.8-tetrahydro- 8 naphthalene-2-yl-etynyfl-2-fluoro-phenvll-acetic acid etl ester 9 (Compound 17, General Formula 8) Following general procedure H and using 11 8,8-diniethyl- 5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-2-fluoro- 12 phenyl]acetic acid ethyl ester (Compound 16, 0.21g, 0.Smmol), acetone 13 (5mL), potassium carbonate 13g, 8.l7mmol) and methyl iodide (0.SmL, 14 Smmol), the following work-up was used. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with 16 dichloromethane The combined organic extract was dried over 17 anhydrous sodium sulfate, filtered and evaporated in vacua to afford an oil.

18 Flash column chromatography over silica gel (230-400 mesh) using 8% ethyl 19 acetate in hexane as the eluent afforded the title compound (0.1 ISg, 69%).

'H-NMR (300 MHz, CDCI 3 8 0.39-0.53(m, 4H), 1.27(s, 311), 1.31 311), 21 1.66-1.81(m, 2H), 1.89-2.05(mn, 2H), 2.08-2.13 (mn, 1H1), 2.13 3H1), 3.62(s, 22 2H), 3.94 J= 8.0Hz, 1H), 4.16(q, J= 7.lHz, 2H), 7.20-7.29(m, 4H), 23 7.44(d, J= l.5Hz, I1H), 7.51 J= 8.2H4z, 1H).

24 [4-(5-(Cyclopropyl-methyl-amino)-8.8-dinaethl- 5 .6.7.8-tetrahydronaphthalene-2-vyl-ethynyl)-2-fluoro-phenyll-acetic acid (Compound 18, 26 General Formula 4) 27 Following general procedure J and using 28 axnino)-8,8-ditnethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-2-fluoro- WO 02/18361 WO 0218361PCT/US01/25443 101 I phenyl]-acetic acid ethyl ester (Compound 17, 0.025g, 0.OS9mmol), 2 methanol (1mb), tetrahydrofuran (1mb), water (0.5mb) and lithium 00 3 hydroxide monohydrate (0.060g, 1.43mmol), the title compound was 4 obtained as a white solid (0.023g, 'H-NMR (300 MHz, CDCI 3 0.52-0.54(m, 211), 0.68-0.70(m, 211), 1.27(s, 6 311), 1.29(s, 3H1), 1.63-1.80(m, 2H1), 1.95-2.17(m, 211), 2.19-2.24(m, 1H), 7 2.24(s, 311), 3.60(s, 2H1), 4.18(t, J =7.7Hz, 1H1), 7.19-7.28(m, 411), 7.45 J 8 5Hz, 11H), 7.49(d, J= 8.2Hz, 111), 8.80-9.20(br s, 111).

9 GENERAL PROCEDURE K: 8.8-Dimethyl-5 .6,7,8-tetrahydro-naphthalene- 1 -one-2-carboxylic acid-4-(tert-butoxycarbonylmethyl)phenyI este I1I Compound 19, General Formula 8) 12 A solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy- 1,2,3,4- 13 tetrahydronaphthalene- 1-one (Intermediate 11, 0. 14g, 0.434rnmol), t-butyl- 14 4-hydroxy-phenyl acetate (Reagent E, 0. 14g, 0.673mmo1), palladium acetate (0.054g, O.24mmol) and 1 ,3-bis(diphenylphosphino)propane (0.082g, 16 0.2mmol) in a mixture of dimethylsulfoxide (I mL), 1,2-dichioroethane 17 (1.5mL) and triethyl amine (1mb) was heated at 701C under an atmosphere 18 of carbon monoxide overnight. The volatiles were distilled of in vacuo and 19 the residue was diluted with water and extracted with diethyl. ether The combined organic extract was dried over anhydrous magnesium sulfate, 21 filtered and evaporated in vacuo to an oil which was subjected to flash 22 column chromatography over silica gel (230-400 mesh) using 15% ethyl 23 acetate in hexane as the eluent to afford the title compound 1 1g, 53%).

24 1 H-NMIR (300 MvHz, CDCl 3 6 1.44(s, 311), 1.44(s, 9H1), 1.46 3H), 2.07(t, J =6.9Hz, 21-1), 2.76(t, J =6.8Hz, 3 .55(s, 2H1), 7.17 J =8.5H4z, 2H-), 26 7.35(d, J= 8MHz, 2H1), 8.05-8.l3(mn, 211), 8.25 J= 1.5Hz, 1H).

WO 02/18361 WO 0218361PCTIUS01/25443 102 1 8.-iey--x-.,,-erhdonrhhln--ab~i acid-4- 2 (carboxymeth1)pheav1 este (Compound 20, General Formula 8) 003 A solution of 8,8-dimethyl-5-oxo-5 ,6,7,8-tetrahydro-naphthalene-2- 4 carboxylic acid 4-(tert-butoxycarbonylmethyl)phelyl ester (Compound 19, 0.11 ig, 0.229mmo1) in dichioromethane (2rnL) was treated with N 6 trifluoroacetic acid (0.85mL and stirred at ambient temperature for 7 The volatiles were distilled off in vacuc and the residue was dilutcd with 8 water and extracted with ethyl acetate The combined organic phase 9 was dried over anhydrous sodium sulfate, filtered and evaporated in vacua to afford a solid which was subjected to flash column chromatography over I11 silica gel (230-400 mesh) using ethyl acetate as the eluent to afford the title 12 compound (0.024g, 13 'H-NMR (300 Mffz, CDC1 3 8 1.46 611), 2.08(t, J 6.7H1z, 2H1), 2.80(t, J 14 6.7Hz, 2M1, 3.70(s, 2H1), 7.20(d, J =8.5Hz, 2H1), 7.3 7(d, J =8.5Hz, 2H), 8.08(dd, J= 1.4, 8.2Hz, 111), 8.14 J= 8.2Hz, 11H), 8.24 J= 1.2Hz, 16 1 5-Methoxy-3.3-dimthyl-indane (Intermediate 17 Following general procedure A and using titanium tetrachloride 18 (5.5mL,50mmoL), anhydrous dichiorornethane (8OrnL), 2M solution 19 dimethyl zinc (5OmL) in toluene and a solution of 6-methoxy-indane-lI-one (4.05g, 2Smmol) in dichioromethane (lOmL) the title compound was 21 obtained as an oil (3.13 g, 7 1 22 'H-NMR (300 M&z, CDC1 3 1.37 6H1), 2.04(t, J 7.2Hz, 2H), 2.94(t, J 23 7.2Hz, 2H1), 3.89(s, 311), 6.82(d, 2.1Hz, IM1, 7.28(dd, J 24 111), 7.35 J =7.0Hz, 111.

5-Methoxjy-3 .3 -dimethyl-indane- 1 -one. (Intermediate 16) 26 Following general procedure B and using 5-methoxy-3,3-dimnethyl 27 indane (Intermediate 15, 3.13g, 17.78nimol) in 2OmL of glacial acetic acid WO 02/18361 WO 0218361PCTIUS01/25443 103 I and a solution of chromium trioxide (3.91g, 39.lmmol) in 2OrmL of acetic 2 acid and 2OmL of water the title compound was obtained as a viscous yellow 00 3 oil (3.3g, 97%).

4 'H-NMR (300 Mhfz, CDCl 3 1.37 61-1), 2.54 2H1), 3.87(s, 311), 6.86- 6.87 (in, 2H1), 7.60 J =7.0Hz, I H).

6 6-Methoxy-4.-dimegthyl- 1.2.3 .4.-.gtthydro-isoquinoline- 1 -one 7 (Intermediate 17) 8 A solution of 5-methoxy-3 ,3-dimethyl-indane- 1 -one (Intermediate 9 16, 3 .3g, 1 7.4inmol) in benzene (5OmnL) was treated with concentrated sulfuric acid (IlOmL) and heated to 60'C. Sodium azide (1.95g, 3Ommol) I1I was added in small portions and after the addition was complete, the reaction 12 mixture was heated further for 4h. It was then cooled, diluted with water and 13 extracted with chloroform The combined organic phase was dried over 14 anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown solid (3.5g, quantitative by weight).

16 'H-NMR (300 M11z, CDCI 3 8 1.31 6H), 3.28 2H), 3.83(s, 3H1), 6.78 17 J 2.6Hz, I1H), 6.82(dd, J 2.6Hz, 8MHz, I 7.59 111), 8.02 J~ 18 8.211z, I H).

19 6-Methoxy-4.4-dimethyl-1I 2.3.4-tetrahydro-isocinoline (Intermediate 18) A solution of 6-methoxy-4,4-dimethiyl-1,2,3,4-tetrahydro- 21 isoquinoline-1-one (Intermediate 17, 3.5g, 17nimol) in lO0mL of 22 anhydrous tetrahydrofliran was treated with lithium aluminum hydride (1.3g, 23 34.2Smmol) in small portions and the resulting suspension was refluxed for 24 3 hours under argon. The reaction mixture was then cooled in an ice bath and cautiously quenched with saturated. aqueous sodium sulfate solution and 26 the resulting slurry was filtered and the filter-cake washed well with ethyl 27 acetate. The filtrate and washings were evaporated in vacuo to a brown oil WO 02/18361 WO 0218361PCTIUS01/25443 104 I which was dissolved in chloroform,4 the solution was dried over anhydrous 2 magnesium sulfate, filtered and evaporated in vacuo to afford the title 00 3 compound (3.2g, -1d00%).

4 'H-NMR (300 M ffz, CDCl 3 5 1.27 6M1, 2.22 1H), 2.84 2H1), 3.79 311), 3.95 2H), 6.68(dd, J 2.411z, 8.3Hz,1H), 6.86(d, J =2.4Hz, 1IM, 6 6.91 J =8.3H1z, 111).

76-Methoxy-4A4-dimethyl-1I.2.3.4-tetrahydr-isoguinoline-2-carbaldehvde 8 (Intermediate 19) 9 A solution of 6-methoxy-4,4-dixnethyl- 1 ,2,3,4-tetrahydro-isoquinoline (Intermediate 18, 3.

2 g, 16.7mmol) in anhydrous dichioromethane 11 was treated with formic acid (lmL, 26.Smmol) followed 1 12 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3 .9g, 20.34nunol) 13 and the resulting solution was stirred at ambient temperature overnight. It 14 was then diluted with chloroform and washed with water (xl) and brine (xl), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to 16 afford the title compound as pale brown viscous oil (3.26g, 17 'H-NM1R (300 MHz, CDCI 3 5 1.28 611, 3.32 0.711), 3.54 0.3H1), 18 3.79(s, 3M1, 4.54 0.31-1), 4.66(s, 0.7H), 6.7 1(dd, J =2.6H1z, 8.2Hz, I1H), 19 6.85-6.97(m, lH), 7.02-7.27(m, 1H1), 8.15(s, 0.7H1), 8.34(s, 0.3H1), 8.40-8.80 (br s, 1H).

21 6-Hydrox-4..4-dimnethyl- 1 .2.3.4-tetrahydro-isoguinoline-2-carbaldehyde 22 (Intermediate 20) A stirred, cooled (-78 0 C) solution of 6-methoxy-4,4- 23 dimethyl-l 2 ,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 19, 24 3.26g, 15mmol) in anhydrous dichioromethane (I1SmL) was treated with IM solution of boron tribromide in dichloromethane (5OmL) stirred at ambient 26 temperature for 3h. It was then cooled again to 78 0 C and quenched carefully 27 with saturated aqueous sodium carbonate solution, diluted with water and the 28 aqueous phase was extracted with ethyl acetate The combined organic WO 02/18361 WO 0218361PCT[US01/25443 105 i extract was dried over anhydrous sodium sulfate, filtered and evaporated in 2 vacua to afford the title compound as a solid foam (3g, 99%).

003 'H-NMIR (300 MHz, CDCl 3 8 1.23 6H1), 3.31 0.7H1), 3.54 0.31H), 4 4.51 0.311), 4.64 0.7H), 6.70-6.75(mn, 1H), 6.84-6.90(m, 7.50- 7.80(br s, 1H1), 8.12(s, 037H), 8.32(s, 0.311).

6 2-Cyloropy1-6-hydroxy-4,4-dime~t -1,2 3 4-tetrah dro-iso uinoline 7 (Intermediate 21) 8 A stirred, cooled (0 0 C)solution of 6-hydroxy-4,4-dimnethyl-l,2,3,4- 9 tetrahydro-isoquinoline-2-carbaldehyde (Intermiediate 20, 2.3 g, 11.21 mmol) in anhydrous tetrahydrofuran (40inL) under argon was treated with titanium I1I tetra-iso-propoxide (8.28mL, 28nunol) followed by 3M solution of ethyl 12 magnesium bromide in diethyl ether (I18.7mL) and the reaction mixture was 13 then heated at 55 0 C overnight. It was then cooled in an ice-bath, quenched 14 with saturated aqueous amnmonium chloride solution and extracted with diethyl ether The combined organic phase was dried over anhydrous 16 sodium sulfate, filtered and evaporated in vacuo to afford a yellow oily solid.

17 Flash column chromatography over silica gel (230-400 mesh) using 10-20% 18 ethyl acetate in hexane as the eluent afforded the title compound as a pale 19 yellow solid (1.55g, 63%).

'H-NMR (300 M~z, CD 3

COCD

3 8 0.016-0.16(m, 4H1), 0.847 611, 1.37 21 (in, IlH), 2.20(s, 211), 3.25 211), 6.22(dd, J 2.4, 8.2Hz, I1H), 6.4 1(d, J 22 2MHz, 1H), 6.47(d, J= 8.2Hz, Ili1), 7.62(s, 11H).

23 2 -Cyclopropyl-4.4-dimetl-6-trifluoromethylsulfonyiox 1,2,3,4- 24 tetrahydro-isoguinoline (Intermediate 22) Following general procedure C and using 2-cyclopropyl-6-hydroxy- 26 4,4-dimethyl- 1,2,3 ,4-tetrahydro-isoquinoline (Intermediate 21, 1 27 6.9mmol) in anhydrous dichioromethane (3OmL), triethyl amnine 28 1 0.39mmol) and WO 02/18361 WO 02/18361PCTIUSOI/25443 106 1 (2.75g, 7mmol) followed by flash column chromatography over silica gel 2 (230-400 mesh) using 8% ethyl acetate in hexane as the eluent the title 00 3 compound was obtained (2.23g, 92%) as oil. 1 H-NMR (300 Mflz, CDCl 3 3 4 0.42-0.54(m, 4H), 1 .25(s, 6H), 1 .76(m, 1H), 2.62(s, 211), 3.74(s, 2H), 6.98(dd, J 2.3, 8.4Hz, 111), 7.16(d, J 8.2Hz, 111), 7.14(d, J 2.311z, 6 1H).

7 Ethyl-2-cyclopropyl-4.4-dimethvl- 1 .2.3,4-tetrahydroisoquinoline-6- 8 carboxylate (Intermediate 23) 9 Following general procedure K and using 2-cyclopropyl-4,4dimetbyl-6-trifluoromethylsulfonyloxy- 1 ,2,3,4-tetrahydro-isoquinoline I11 (Intermediate 22, 1.6g, 4.6minol), palladium acetate 127g, 0.56mmol), 12 1 ,3-bis(diphenylphosphino)propane 160g, 0.39nimol), dimethylsulfoxide 13 (2mL), I ,2-dichloroethane (5mL), triethyl amine (2mL), ethanol (5mL) and 14 an atmosphere of carbon monoxide followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in 16 hexane as the eluent the title compound was obtained as an oil (1g, 79%).

17 'H-NMR (300 M1Hz, CDCI 3 0.44-0.54(m, 411), 1 .27(s, 6H), 1.38 J 18 7Hz, 3H1), 1.73(m, lH), 2.62(s, 211), 3.76(s, 211), 4.35 J= 7.1H1z, 211), 19 7.04(d,.J= 7.9Hz, 111, 7.74 (dd, J= 1.7, 7.9Hz, 111), 7.97(d, J= 1.8Hz, 1ff).

21 2-Cyclopropyl-6-hvdroxmethyl-4.4-dimethyl- 1.2.3 .4-tetrahydroisoguinoline 22 (Intermediate 24) 23 A stirred cooled (-78 0 C)solution of ethyl-2-cyclopropyl-4,4-dixnethyl- 24 1,2,3,4-tetrahydro, isoquinoline-6-carboxylate (Intermediate 23, 1 g, 3.66mmol) in anhydrous dichioromethane (20mL) under argon was treated 26 with a IM solution of di-iso-butyl aluminum hydride in dichioromethane 27 (lOML) and the reaction mixture was warmed to -20 0 C over 1lh. It was then 28 quenched with saturated aqueous amnmonium chloride solution and diluted WO 02/18361 WO 0218361PCT/US01/25443 107 I with dichloromethane and filtered over a bed of celite. The phases were 2 separated and the aqueous phase was extracted with dichioromethane (xl).

0C) 3 The combined organic extract was dried over anhydrous sodium sulfate, 4 filtered and evaporated in vacuo to afford the title compound as a viscous oil (0.74g, 87%).

6 'H-NM (300 M ffz, CDCI 3 8 0.45-0.53(m, 411), 1.25(s, 6H1), 1.72-1.82(m, 7 2H), 2.6 1 2H), 3.73(s, 2H), 4.61 J 5Hz, 2H), 6.9 8(d, J 7.9Hz, 111), 8 7.07 (dd, J 1.5, 7.6Hz, 1H1), 7.27(s, 111).

9 2-Cyclopropyl-4.4-dimethyl- 1.2.3.4-tetrahydroisoguinoline-6-carbaldehyde (intermediate 11 A solutiona of 2-cyclopropyl-6-hydroxymethyl-4,4-dimethyl-1,2,3,4- 12 tetrahydroisoquinoline (Intermediate 24, 0.74g, 3.2mmol) in 13 dichloromethane (1 OmL) and acetonitrile (2.5rnL) was treated sequentially 14 with 4AO molecular sieves powder (1 .06g), tetra-n-propyl ammonium perruthenate (0.050g, 0. 14mmol) and N-methyl morpholine N-oxide (1 g, 16 9.8mmol). After stirring at ambient temperature for 0.5h, it was diluted with 17 5rnL of hexane and subjected to flash column chromatography over silica gel 18 (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford 19 the title compound as an oil (0.27g, 37%).

'H-NMR (300 MHz, CDCI 3 0.44-0-56(m, 411), 1.30(s, 6H1), 1.79(m, 111), 21 2.66(s, 211), 3.82(s, 2H1), 7.17(d, J= 7.9Hz, 1H1), 7.60 (dd, J= 1.6,7.9Hz, 22 1 7.82(d, J 1.8Hz, 111), 9.95 I111).

23 6-(2.2-Dibromo-vinyl)-2-cyclopropvl-4,4-dimethyl- 1,2.3,4- 24 tetrahydroisoquinoline (Intermediate 26) A stirred, cooled (ice-bath) solution of triphenyl phosphine (0.53g, 26 2mmol) in anhydrous dichioromethane was treated with carbon tetrabrornide 27 (0.3 5g, lmm(?l) under argon. After 0.5h, a solution of 2-cyclopropyl-4,4- 28 dimethyl-1 ,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate WO 02/18361 WO 0218361PCTIUS01/25443 108 1 25, 0.13g, 0.57mmol) in dichioromethane (2mL) was cannulated into the 2 reaction mixture. After 1 .5h between 0 0 C and 10 0 C, the reaction mixture 00 3 was subjected to flash column chromatography over silica gel (230-400 4 mesh) using 3-5% ethyl acetate in hexane as the eluent to afford the title compound as a viscous, pale yellow oil 18g, 82%).

6 'H-NMR (300 MiHz, CDC1 3 0.49-0.57(m, 4H), 1.3 1 6H), 1.80(mn, IN), 7 2.67(s, 2H), 3.77(s, 211), 7.04(d, J =7.9H1z, 1H), 7.29 (dd, J 1.7, 7.911z, 8 1 7.49 I 7.50(d, J 1. 7Hz, I H).

9 2-Qyclopronvl-6-ethvnv 1 -4.4-dimetyl- I .2.3.4-tetrahydroisoguinoline (Intermediate 27) 11 A stirred, cooled (-78 0 CQ solution of 6-(2,2-dibromo-vinyl)-2- 12 cyclopropyl-4,4-dirnethyl- 1 ,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde 13 (Intermediate 26, 0.18g, 0.47mmol) in tetrahydrofuran (2mL) was treated 14 with 1 .6M solution of n-butyl lithium (0.6mL, 0.96mmol) under argon. The reaction mixture was allowed to warm to -20'C over 1.5h, quenched with 16 saturated aqueous ammonium chloride solution and extracted with diethyl 17 ether The combined organic phase was dried over anhydrous 18 magnesium sulfate, filtered and evaporated in vacuo to afford the title 19 compound as an oil 1g, 94%).

'H-NMR (300 MHz, CDCl 3 0.47-0.55(m, 4H), 1.28(s, 6H), 1.77(m, 1H), 21 2.63(s, 2H), 3.05(s, 1IM, 3.67(s, 2H), 6.98(d, J 7.6Hz, 1H), 7.26 (dd, J 22 1. 5, 7.9Hz, I 7.46(d J 1. 5Hz, 111).

23 [4-(2-Cycloprop2yl-4.4-dimethvl- 12.3 .4-tetrahvdro-isoquinolin-6-:yl-eth Iyl- 24 2-fluoro-phepyll-acetic acid ethyl ester (Compound 21, General Formula 3) 26 Following general procedure F and using 2-cyclopropyl-6-ethynyl- 27 4,4-dimethyl- 1,2,3 ,4-tetrahydro-isoquinoline(Intermediate 27, 0.13 g, WO 02/18361 WO 0218361PCT/US01/25443 0 109 1 0.57 immol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 2 0. 16g, 0.S52mmol), triethyl amnine 8mL), anhydrous tetrahycirofuran (2mL), 00 3 copper(I)iodide (0.05 ig, 0.27mamol) and 4 dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0. l4imol) followed by flash column chromatography over silica gel (230-400 mesh) using 6 ethyl acetate in hexane as the eluent, 0.l1g of the title compound was obtained 7 as an oil. It was further purified by preparative normal phase HPLC on a 8 partisil-lO silica column using 10% ethyl acetate in hexane as the mobile 9 phase (0.055Sg, 24%).

'H-NMR (300 M11z, CDCl 3 0.42-0.5 1(m, 1.26(t, J= 7.3Hz, 3H1), I1I 1-27(s, 611), 1.75(m, 1H1), 2.61(s, 2M1, 3.66(s, 211), 3.74(s, 211), 4.18 J= 12 7.3Hz, 2H1), 6.97 (di, J 7.9Hz, lH), 7.20-7.29(m, 411), 7.45(d, J 13 111).

14 [4-(2-!CYclopropyl-4,4-dimethl- 1,2.3 .4-tetrahydr-isoguinolin-6-vl-eh nvl'- 2-fluoro-phenyll-acetic acid (Compound 22, General Formula 3) 16 Following general procedure J and using [4-(2-cyclopropyl-4,4- 17 dimethyl- 1 ,2,3,4-tetrahydro-isoquinolin-6-ylethynyl)-2-fluoro-phenyl]-acetic 18 acid ethyl ester (Compound 21, 0.05 5g, 0. 13 5mmol), methanol (2mL), 19 tefrahydrofuran (4mL), water (lmL) and lithium hydroxide monohydrate 1 17g, 2.97mmol) the title compound was obtained as a pale yellow solid 21 foam (0,040g, 78%).

22 1 H..NMR (300 M~z, CDCl 3 8 0.52-0.65(m, 411), 1.27(s, 611), 1.84(m, 111), 23 2.71(s, 2H), 3.61l(s, 2H1), 3.85(s, 211), 6-98(d, J= 7.9Hz, 1H), 7.06 J= 24 7.6Hz, 111), 7.17-7.25(m, 3M1, 7.43(d, J 1.211z, 111), 8.60-9.00(br s, 1H1).

r44(2-Cyclopropyl-4.4-diniethyl- 1.2.3,4-tetrahvdro-isoguinolin-6-yl-ethy Lnyl)- 26 phenyll-acetic acid methyl ester (Compound 23, General Formula 3) WO 02/18361 WO 0218361PCT/U SO 1/25443 110 r-I Following general procedure F and using 2-cyclopropyl-4,4-dimcthyl- 02 6-ethynyl- 1,2,3,4-tetrahydro-isoquifloline(Iftermediate 27, 0.13 g, 00 3 0.57 immol), 4-iodo phenyl acetic acid methyl ester (Reagent B, 0. 16g, 4 0.58mmol), triethyl amine (0.5mL), anhydrous tctrahydrofuran (2mL), copper(I)iodide (0.04g, 0.2linmol) and 6 dichlorobis(triphenylphosphine)palladium(II) (0.12g, 0.1 7rmol) followed by 7 flash column chromatography over silica gel (230-400 mesh) using 8 ethyl acetate in hexane as the eluent, 0.05g of the title compound was 9 obtained as an oil. It was further purified by preparative normal phase HPLC on a partisil-l10 silica column using 10% ethyl acetate in hexane as the I1I mobile phase (0.01ig, 12 'H-NMR (3 00 MI-Lz, CDCI 3 8 0.42-0.5 8(m, 4H1), 1.29(m, 6H), 1.79(m, IT), 13 2.64(s, 2H1), 3.67(s, 3H1), 3.72(s, 211), 3.77(s, 211), 7.09 J 7.9H1z, 1M1, 14 7.28(dd, J1 1.5, 7.9Hz, 1H), 7.36 J =7.9Hz, 2H), 7.50 J =1.6Hz, 1 7.5 1(d, J 7.9Hz, 21-1).

16 [4-(2-Cyclopropyl-4.4-dimethvl- 1.2.3.4-tetrahydro-isoguinolin-6-yI-ethvnfl)- 17 phenyll-acetic -acid (Compound 24, General Formula 3) 18 Following general procedure J and using [4.(2-cyclopropyl-4,4- 19 dimethyl- 1 2 3 ,4-tetrahydro-isoquinolin-6ylethynyl)-phenyl] -acetic acid methyl ester (Compound 23, 0 .0 1ig, 0.027mmol), methanol (Imi), 21 tetmahydrofuran (lmL), water (0.5niL) and lithium hydroxide monohydrate 22 (0.042g, I mnol) the title compound was obtained as a pale yellow solid 23 foam (0.0065g, 68%).

24 'H-NMR (300 MHz, CDCl 3 6 0.35-0.52(m, 4H), 1.24(s, 1.74(m, 111), 2.59(s, 2H), 3.64(s, 2H), 3.71(s, 211), 7.03 J= 8.2Hz, 111), 7.22(dd, J 26 1.4, 7.9Hz, 111), 7.33 J= 8.2Hz, 2H1), 7.46 J= 8.2Hz, 2H1), 7 4 7 (s, 27 111).

WO 02/18361 WO 0218361PCT/USOI/25443 1 1 (s-rplmthlaio--righli gta-,-igt-.2.3.4- 2 tetrghydro-naphthalene (Intermediate 28) 003 Following general procedure G and using a solution of 4,4-dimnethyl- 4 6-trimethylsilanylethynyl- 1,2,3,4-tetrahydro-naphthalene 2-one (Intermediate 12, 0.2g, 0.78mmol), dichioromethane (4mL), acetonitrile 6 (2mL), acetic acid (ImL), isopropyl amine (1lmL, 11 .74mmol) and sodium 7 cyanoborohydride 19g, 3.O2nunol), after l5days of reaction time and work 8 up afforded an intermediate 14g, 60%, 0.47mmol) which was used 9 following general procedure H along with acetone (2mL), potassium carbonate (0.6g, 4.34mmol) and methyl iodide (0.5mL, 8mmol). The crude I1I product after work up was subjected to flash column chromatography over 12 silica gel (230-400 mesh) using 15% ethyl acetate in hexane as the eluent to 13 afford the title compound as a pale yellow oil 14g, 9 14 '11-NMvR (300 MHz, CDCI 3 8 0.00 1(s, 91f), 0.85 J= 6.4Hz, 6H), 0.98 3H), 1.03 311), 1.32-1.60 (in, 4H1), 1.81(s, 3H), 2.64(heptet, J= 6.4Hz, 16 1H1), 3.65 (dd, J 6.1, 9.414z, 6.97 (dd, J 1.7, 7.9Hz, 11H), 7.13 J 17 1.7Hz, 7.82 J= 7.914z, 11-1).

18 6-Ethynyl-l1-(iso-propyl-metl-amino)-4.4-dimetvl- 1.2.3 .4-tetrahyo 19 naphthalene (Intermediate 29) Following general procedure E and using I1-(inethyl-iso- 21 propylamino)-4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3 ,4-tetrahydro- 22 naphthalene (Intermediate 28, 0.14g, 0.4Smmol), methanol 23 potassium carbonate (0.61Ig, 4.41inuol) and ethyl acetate the title compound 24 (0.092g, 80%) was obtained as an oil.

'1I-N-MR (300 Mflz, CDC1 3 1.11 J= 6.4Hz, 6H1), 1.23(s, 3H), 1 .28(s, 26 311), 1.51-1.87 (in, 4M1, 2-09(s, 3H), 2.90 (heptet, J 6.4Hz, 1I1), 3.00(s, 27 1H), 3.91 (dd, J= 5.8, 10.0Hz, 1H), 7.25(dd, J= 1.7, 8.2H1z, 111), 7.41 J 28 1.7Hz, IH), 7.70(d, J 8.2Hz, 1H1).

WO 02/18361 WO 0218361PCT/IJS01/25443 112 1 44[5-Us-propyl-mthyl-amino)8.8-dimtl-S .6.7,8-tetrahydro- 2 naphthalene-2-yl-ehnyll-benzoic acid etl ester (Compound 00 3 General Formula 4) 4 Following general procedure F and 6-ethynyl-1I-(iso-propyl-methylamino)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-naphthalene (Intermediate 29, 6 0.092g, 0.36mmol), ethyl-4-iodo benzoate (Reagent A, 0.12g, 0.48mmrol), 7 triethyl amine (IniL), tetrahydrofuran (2mL), copper(I)iodide (0.028g, 8 0. l4mmol) and dichlorobis(triphenylphosphine)palladium(ll) (0.075g, 9 0. -I Immol) followed by flash column chromatography over silica gel (23 0- 400 mesh) using 10- 15% ethyl acetate in hexane as the eluent the title I1I compound was obtained (0.04g, 27%).

12 'H-NMR (300 M~fz, CDCl 3 8 1.12 J= 6.5Hz, 1.27 3H), 1.31 (s, 13 3H), 1.40 J 7.0Hz, 311), 1.62-1.89 (in, 4M1, 2.l1O(s, 3H1), 2.92 (heptet, J 14 6.4Hz, I 3.94(dd, J= 6.1, 9.7Hz, 1I1), 4.3 8(q, J= 7. 1Hz, 2M1, 7.3 1l(dd, J 8.2Hz, 1H), 7.46 (di, J 1.7Hz, 1H), 7.58 (di, J 8.2Hz, 2H1), 16 7.75(d, J= 8.2Hz, IH), 8.01(d, J 8.211z, 2H).

17 4-1 5-(so-propyl-mehyl-amino)-8,8-dimethyl-56,7.8-tetrahydro- 18 naphthalene-2-yl-ethynvl~l-benzoic acid (Compound 26, General Formula 19 4) Following general procedure I and using 21 amino)- 8 ,8-dinmethyl-5,6,7,8-tetrahydro-naphtIhaene2ylethynyl)}.benzoic 22 acid ethyl ester (Compound 25, 0.04g, 0.0 imnol), ethanol (2mL), 23 tetrahydrofuran (IniL) and IM aqueous sodium hydroxide solution (lmL) 24 followed by recrystallization from diethylether-hexane, the title compound was obtained as an off-white solid (0.0 1lOg, 27%).

26 'H-NMR (300 MlHz, CDCI 3 5 1 .30(d, J= 6.0Hz, 6H), 1.3 1 911), 1.67- 27 1.98(m, 4H), 2.3 5 311), 3.19 (heptet, J =6.4Hz, 4.36 J 7 .611z, WO 02/18361 WO 0218361PCT[US01/25443 113 I 1H), 7.28(dd, J 1.4, 8.2Hz, 11H), 7.48 J= 1.4Hz, 117, 7.55 (dJ 1= 2 8.2Hz, 211, 7.81 J 8.2Hz, IHM, 8.05 J =8.2Hz, 2H).

3 f4-(2,2,4,-Tetranetl-chroman-6-yl-th fl1) phenyl acetic acid nmetl 4 -ester (Compound 27, General Formula 8) Following general procedure F and using 6-ethynyl-2,2,4,4- 6 tetramethylchroman (synthesis described in U.S. Patent Nos. 5,045,5 51 and 7 5,616,597 incorporated herein by reference) (0.060g, 0.28mmoI), methyl-4- 8 iodo phenyl acetate (Reagent B, 0.078g, 0.28mmol), triethyl amnine (4miL), 9 tetrahydrofuran (4mL), copper(I)iodide (0.030Og, 0.1 6mmol) and dichlorobis(triphenylphosphine)paladiuxu(II) 11 g, 0.1 l6rmol) followed by I1I flash column chromatography over silica gel (230-400 mesh) using 5- 10 12 ethyl acetate in hexane as the eluent the title compound was obtained 13 (0.047g, 46%).

14 'H NMR (300 MHz, CDCl 3 8 7.48-7.45 (in, 3H), 7.25-7.23 (in, 311), 6.75 111, J= 8.2Hz), 3.70 311), 3.62 211), 1.84 211), 1.36 611), 1.35 16 (s,611).

17 GENERAL PROCEDURE L: r4-(2.2.4.4-Tetramethy-chroman-6-y1- 18 ethyayl) phen 1l1 acetic acid (Compound 28, General Formula 8) 19 A solution of [4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl] acetic acid methyl ester (Compound 27, 0.0 4 7g, 0.l13rnmol) in 5mL of 21 methanol was treated with 1M sodium hydroxide solution (2mL) and heated 22 at 5 5 0 C for 2h. The volatiles were distilled off in vacuo and the residue was 23 acidified with 10% hydrochloric acid and extracted with ethyl acetate (x2).

24 The combined organic phase was washed with brine (xlI), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue 26 which was purified by preparative reverse phase HPLC using 10% water in 27 acetonitrile as the mobile phase to afford the title compound (0.03 4 g, 82%).

WO 02/18361 WO 02/18361PCT/IUS0 1/25443 114 I 'H NMR (300 MII-Lz, CDCl 3 6 7.49-7.45 (mn, 311), 7.26-7.22 (in, 311), 6.75 2 IIH,J 8.2Hz), 3.65 2H), 1.84 214I), 1.36 611), 1.35 6H1).

00 3 2-loo4(.,.-ermfl-hoa--lgyy-ezi acid methyl 4 ese (Compound 29, General Formula 8) Following general procedure F and using 6-ethynyl-2,2,4,4- 6 tetramethylchroman 11 g, 0.5 Immol), methyl-2-fluoro-4-iodo-benzoate 7 (Reagent G, 0.14g, 0.5 imiol), triethyl amine (SrnL), 8 tetrahydrofiiran(lOmL), copper(§I)iodide(0.030g, 0.16rnmol) and 9 dichlorobis(triphenylphosphine)palladium(II) 11 Og, 0. 1 6mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10 11 ethyl acetate in hexane as the eluent, the title compound was obtained 12 (0.1l4g, 79%).

13 'H NMR (300 MHz, CDCI 3 5 7.82 111, J= 7.9Hz), 7.39 1H, J= 14 1.8Hz), 7.25-7.16 (in, 31M, 6.69 IH, J= M.Hz), 3.85 3H), 1.77 (s, 2H), 1.29 611, 1.28 6H).

16 2-Fluoro-4-(2.2A.,4-tetramethyl-chroman-6-vl-etnyD-benzoic acid 17 (Compound 30, General Formula 8) 18 Following general procedure L and using 2-fluoro-4-(2,2,4,4- 19 tetramnethyl-chroman-6-yl-ethynyl)-benzoic acid methyl ester (Compound 29, 0. 14g, 0.4mxnol), 5mL of methanol and IM sodium hydroxide solution 21 (2mL) followed by recrystallization from ethyl acetate, the title compound 22 was obtained (0.083g, 58%).

23 'H NMR (300 NMz, CD 3

COCD

3 8 8.00 111, J= 7.8Hz), 7.63 1H, J= 24 2.1Hz), 7.45 (dd, 1H, J= 1.5, 7.9Hz), 7.38 (dd, 1H1, 1.5, 11.4Hz), 7.32 (dd, IH,J= 2.1, 8.2Hz), 6.81 1H, J=8.511z), 1.92 2H), 1.41 6M1, 26 1. 3 8(s,6H).

WO 02/18361 WO 0218361PCTIUS01/25443 115 2 ethyl ester (Compound 31, General Formula 8) 0C) 3 Following general procedure F and using 6-ethynyl-2,2,4,4- 4 tetramethylchroman (0.204g, O.95mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.263g, 0.86mmol), triethyl amine, tctrahydrofuiran, 6 copper(I)iodide (0.025g, 0.l3mmol) and 7 dichlorobis(triphenylphosphine)palladium(H) (0.075g, 0. 1 Immol) followed N 8 by flash column chromatography over silica gel (230-400 mesh) using 5-10 9 ethyl acetate in hexane as the eluent the title compound was obtained (0.21g, 62%).

I1I 'H NMR (300 MHz, CDCI 3 6 7.46 111, J= 2.lHz), 7.25-7.2 1 (in, 4H), 12 6.69 lH, J= 8.5Hz), 4.16 2HK J= 7.1Hz), 3.65 2H), 1.82 2H), 13 1.35 611, 1.35 6H1), 1.24 3H, J= 7.2Hz).

14 r2-Fluoro-4-(2.2.4A4-teramety-chroman-6-vl-ethynvfl phenvll acetic acid (Compound 32, General Formula 8) 16 Following general procedure L and using [2-fluoro-4-(2,2,4,4- 17 tetramnethyl-chroman-6-ylethynyl) phenyll acetic acid ethyl ester 18 (Compound 31, 0.21g, 0.58mmol), 5mL of methanol and IM sodium 19 hydroxide solution (2mIL) followed by flash column chromatography over silica gel (230-400 mesh) using 50% ethyl acetate in hexane, the title 21 compound was obtained as a solid 1 84g, 93 22 'H NMR (300 MHz, CDC1 3 5ll.40 (br s, IHM, 7.48 KJ= 1.8Hz), 23 7.46-7.16 (in, 411), 6.76 1II, 8.2Hz), 3.69 2H), 1.82 2H1), 1.34 24 12H).

3-Metl-but-2-enoic acid 4-bromo-phenvi ester: 26 To a stirred, cooled (ice bath) suspension of sodium hydride (2.4g, 27 lO0mmol) in anhydrous teirahydrofliran (200mL), 4-bromo phenol (1 7 .3g, 28 l1 rninol) was added followed by 3,3,-dimethyl acryloyl chloride (I I. I4mL, WO 02/18361 PCT/US01/25443 d116 1 100mmol). After 4hours at ambient temperature, the reaction mixture was 2 poured into brine and extracted with diethyl ether The combined 0 3 organic phase was dried over anhydrous sodium sulfate, filtered and S4 evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in

C

6 hexane as the eluent to afford the title compound (15g, 59%).

7 'H-NMR (300 MHz, CDCl 3 2.00(s, 3H), 2.23(s, 3H), 5.89(s, 1H), 7.00(d, c' 8 J 8.8Hz, 2H), 7.49(d, J 8.8Hz, 2H).

9 6-Bromo-4.4-dimethyl-chroman-2-one: A solution of 3-methyl-but-2-enoic acid 4-bromo-phenyl ester (7g, 11 27.6mmol) in anhydrous dichloromethane (200mL) was cooled (ice bath) 12 and treated with aluminum chloride (6.6g, 49.6mmol) and the reaction 13 mixture was stirred overnight at ambient temperature. The reaction mixture 14 was quenched with saturated aqueous sodium bicarbonate solution and extracted with diethyl ether The combined organic extract was washed 16 woth brine dried over anhydrous sodium sulfate, filtered and 17 evaporated in vacuo to afford an oil which was purified by flash column 18 chromatography over silica gel (230-400 mesh) using 2.5% ethyl acetate in 19 hexane as the eluent to afford the title compound (4.2g, 57%).

'H-NMR (300 MHz, CDC1 3 1.36(s, 6H), 2.62(s, 2H), 6.95(d, J= 21 1H), 7.37(dd, J 2.4, 8.5Hz, 1H), 7.43(d, J 2.3Hz, 1H).

22 4-Bromo-2-(3-hvdroxv-1.1.3-trimethyl-butv)-phenol: 23 A solution of 6-bromo-4,4-dimethyl-chroman-2-one (1 g, 3.92mmol) 24 in anhydrous tetrahydrofuran (20mL) was treated with 3M solution of ethyl magnesium bromide (2.6mL) and stirred at ambient temperature for 2hours.

26 The reaction mixture was poured into cold dilute hydrochloric acid and 27 extracted with ethyl acetate The combined organic extract was dried WO 02/18361 WO 0218361PCT/US01/25443 117 1 over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a 2 residue which was subjected to flash column chromatography over silica gel 0C) 3 (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the 4 title compound as a pale yellow solid 1g, 100%).

'H-NMR (300 M&z, CDCI 3 1.14(s, 6H), 1.44(s, 6H), 2.20(s, 2H), 6.49(d, 6 J 8.4Hz,1H), 7.15(dd, J M.Hz, 1M, 7.37(d, J= 2.4H1z, 111).

7 6-Bromo-2.2.4.4-tetamethvl-chroman: 8 A solution of 4-bromo-2-(3-hydroxy- 1, 1,3-trirnethyl-butyl)-phenol 9 (1.1g, 3.92mmol) andp-toluene sulfonic acid (0.744g, 3.92mmol) in benzene (2OmL) was refluxed overnight. The reaction mixture cooled to ambient 11I temperature, filtered on silica gel and washed with 10% ethyl acetate in 12 hexane. The filtrate and washings were evaporated in vacuo to an oil which 13 was subjected to flash column chromatography over silica gel (23 0-400 14 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow oil (0.84g, 16 'H-NMR (300 M~z, CDCl 3 1.34(s, 6H), 1.35(s, 6M, 1.82(s, 2H1), 6.68(d, 17 J= 8.4Hz, 1H1), 7.16(dd, J 2.7, 8.7Hz, 1W), 7.37(d, J~ 2.6Hz, 1M'.

18 The synthesis of this compound, as described here, is in close analogy 19 to the synthesis of 6-bromo-2,2,4,4-tetramnethylthiochroman, as described in United States Patent No. 5,045,551 21 2,2.4.4-tetramethyl-6-(2-trime th Isilyflehyniyl chroman: 22 Following general procedure D and using 6-bromo-2,2,4,4- 23 tetramethyl chroman (0.5g, 1.87mrnol), triethyl amnine (5mL), anhydrous 24 tetrahydrofuran (1 5mL),copper(I)iodide 107g, 0. 1 6mmnol), trimethylsilyl acetylene (1.84g, 18.7mmol) and 26 diclaorobis(triphenylphosphine)palladiurn(II) (0.39g, 0.S6minol) the title 27 compound was obtained as a brown oil (0.61ig, 100%).

WO 02/18361 WO 0218361PCT/U SO1/25443 118 I 'H NMR (300 MII-z, CDCI 3 5 7.43 1H, J= 2.1lHz), 7.23 (dd, 1H, J= 2 7.9, 2. 1Hz), 6.73 1H, J= 8.2Hz), 1.83 2M), 1.36 12H), 0.28 9M).

00 3 6--Ethvnyl-2,2A44-tetramethyl chroman: 4 Following general procedure E and using 2,2,4,4-tetramethyl-6-(2trimethylsilyl)ethynyl chroman (0.61g, 1.87mmol), potassium carbonate INO6 (1.9g, 13.74mmol) and methanol the title compound was obtained (0.4g, 7 8 'H NMR (3 00 MHz, CDCI 3 8 7.47 (di, 1H, 2.1lHz), 7.24 (dcl, IH, J 9 7.9, 2.1Hz), 6.76 IH, J= 8.2Hz), 3.01 1H), 1.85 2H4), 1.37 6H4), 1.36 6H).

I11 An alternative synthesis for this compound is described in United 12 States Patent Nos. 5,045,5 51 and 5,616,597 13 GENERAL PROCEDURE M: 6-Bromo-2.2.4,4-tetramety-cbroman-8- 14 carbaldehyde (Intermediate A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl 16 chroman, (0.5g, 1 .865mmo1) in anhydrous dichioromethane (5mL) was 17 treated with a IM solution (1.86rnL, I .86mmol) of titanium tetrachloride in 18 dichioromethane followed by axcx-dichloro methyl ether (0-.214g, 19 1.865mmo1). The reaction mixture was allowed to warm to ambient temperature for 4h. The reaction midxture was diluted with diethyl ether, 21 washed with brine (xlI) and dried over anhydrous sodium sulfate, filtered and 22 evaporated in vacuo to a residue which was subjected to flash column 23 chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in 24 hexane to afford the title compound as a yellow solid (0.52g, 94%).

'H NMR (300 MHz, CDCI 3 5 10. 38 I 7.72 I1H, J 2.6Hz), 7.5 7 26 (di, l-I, J= 2.6Hz), 1.88 211), 1.41 6H), 1.36 6H).

WO 02/18361 WO 0218361PCT/US01/25443 119 I GENERAL PROCEDURE N: 6-Bromo-g-vinvl -2.2,4.-tetrametl- 2 chroman. (Intermediate 31) 003 A solution of methylidene triphenyl phosphorane [generated from 4 methyl triphenylphosphoniuxn bromide (7g, 2Ommol) and (I1.8mL, l9mmol) of a 1 .6M solution of n-butyl lithium in hexanes J was added 6-bromo- 6 2,2,4,4-tetramnethyl chroman-8-carbaldehyde (Intermediate 30, 0.52g, 7 1.75mmol). After 1h the reaction mixture was diluted with hexane, washed 8 with brine dried over anhydrous sodium sulfate, filtered and evaporated 9 in vacuo to a clear oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent I1I to afford the title compound as a clear oil (0.3 7g, 72%).

12 1 H NMIR (300 MHz, CDCl 3 6 7.46 1H, J= 2.5Hz), 7.33 1H, J= 13 2.5Hz), 7.03 (dd, 111,J= 11.3, 17.9H1z), 5.75 (dd, 111,J= 1.4, 17.9Hz), 5.30 14 (dd, 1H, J= 1.4, 11.3Hz), 1.85 2H), 1.39 6H), 1.37 6H).

GENERAL PROCEDURE 0: 6-Bromo-8-cyclopropyl-2.2.4.4-tetrarnethyI 16 chroman (Intermediate 32) 17 A stirred, cooled (-30 0 C) solution of 6-bromo-8-vinyl-2,2,4,4- 18 tetrametbyl chroman (Intermediate 31, 0.37g, 1 .26minol) in diethyl ether 19 was treated with a solution of diazomethane in diethyl ether and catalytic amount of palladium (II)acetate The reaction mixture was allowed 21 to warmn to ambient temperature and subjected to flash column 22 chromatography over silica gel (23 0-400 mesh) using 2% ethyl acetate in 23 hexane as the eluent to afford the title compound as a clear, pale yellow oil 24 (0.376g, 97%).

'H NMR (300 MHz, CDCl 3 567.17 11-, J= 2.3H1z), 6.73 111, J= 26 2MHz), 2.19-2.16 (in, IH), 1.83 2H), 1.37 6H), 1.33 6H), 0.94-0.88 27 (in, 2H1), 0.64-0.59 211).

WO 02/18361 WO 0218361PCTIUS01/25443 120 I8-Cycolopropyl-6-rmth-lsilfLV~th fYI22.terar1efil chromn 2 (Intermediate 33) 003 Following general procedure D and using 6-bromo-g-cyclopropyl- 4 2,2,4,4-tetrarnethyl chroman (Intermediate 32, 0.376g, I .22mmol), (trimethylsilyl)acetylene (4mL, 28mmol), triethyl amine (3mL), anhydrous 6 tetrahydrofuran (5mL), copper(I)iodide (0.025g, 0.13mmoI) and 7 dichlorobis(triphenylphosphine)palladium(II) (0.075g, 0.1 Immol), the title 8 compound was obtained as an oil 173 g, 43 9 'H NMR (300 M&z, CDC1 3 6 7.3 6 I1H, J 2.2Hz), 6.90 1 H, J 1.91Hz), 2.31-2.22 (in, 1H1), 1.96 211), 1.49 611), 1.46 6H), 1.05-0.88 11 (in, 2H), 0.78-0.72 (in, 211), 0.37 911).

12 8-Cy1clopropyl-6-ethynyl-2.2.4.4-tetramethyI chronian (Intermediate 34) 13 Following general procedure E and using 8-cyclopropyl-6- 14 trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman. (Intermediate 33, 0. 17g, 0.68mmol), methanol and potassium carbonate (0.2g, 1.47mmol) the 16 title compound was obtained as an oil (0.064g, 47%).

17 'H1 NMvR (300 MHz, CDC13): 6 7.38 1H, J= 1.9Hz), 6.92 1H-, J 18 1.911z), 3.08 1H1), 2.32-2.23 (mn, 1H1), 1.96 211), 1.50 611), 1.46 (s, 19 6H1), 1.05-0.99 (mn, 2H1), 0.77-0.72 (mn, 211'.

4 8 -!QCcOpropv-2.2.4.4-tetramethvl-chroman.6-yl.etynvn..benzoic acid 21 etl este (Compound 33, General Formula 8) 22 Following general procedure F and using 8-cyclopropyl-6-ethynyl- 23 2,2,4,4-tetramnethylchroman (Intermediate 34, 0. 1ig, 0. 3 Sinmol), ethyl-4- 24 iodo-benzoate (Reagent A, 0.1g, 0.34iniol), triethyl amine tetrahydrofuran(l OmL), copper(I)iodide(0.025g, 0. l3nimol) and 26 dichlorobis(triphenylphosphine)palladiumqlI) (0-075g, 0.1 iinol) followed 27 by flash column chromatography over silica gel (230-400 mesh) using 5-10 WO 02/18361 WO 0218361PCT[USOI/25443 121 I ethyl acetate in hexane as the eluent, the title compound was obtained 2 13 5g, 89%).

003 1H NMvR (300 MiL-l, CDC1 3 6 8.00 2H1, J 8.2Hz), 7.5 5 2H, J 4 8.2Hz), 7.30 111,J= 1.8H1z), 6.84 111, 2.014z), 4.38 2H, J 6.9Hz), 2.22-2.12 (in, 1H1), 1.85 211), 1.40 3H1, J= 6.9Hz), 1.38 611), 6 1.36 6H), 0.92-0.88 (in, 2H), 0.67-0.62 (in, 211).

7 4-(8-Cvclorov1-2.2.4.4-tetramethl-chroman-6-l-tglnl)-belzoic acid 8 (Compound 34, General Formula* 8) 9 Following general procedure L and using 4-(8-cyclopropyl-2,2,4,4tetramethyl-chroman-6-yl-ethynyl)-benzoic acid ethyl ester (Compound 33, 11 0.135g, 0.34mmol), 5inL of methanol and IM sodium hydroxide solution 12 (2inL) followed by preparative reverse phase HPLC us ing 10% water in 13 acetonitrile as the mobile phase, the title compound was obtained as a solid 14 (0.093g, 73%).

'H NMvR (300 MHz, CDCI 3 5 11.26 (br s, 1IM, 8.08 211 J= 8.2Hz), 16 7.5 9 2H1, J= 8.2Hz), 7.31 1H, J 8Hz), 6.8 5 11H, J 2. 1Hz), 17 2.22-2.13 (mn, 111), 1.85 2H), 1.38 611), 1.36 6H1), 0.95-0.87 (in, 18 211), 0.68-0.63 (in, 211).

19 4 8 -Cyclopropyl-2.2.4.4-tetramethyl-chroman-6v1-ethynyl) phepyll acetic acid mthyl ester (Compound 35, General Formula 8) 21 Following general procedure F and using 8-cyclopropyl-6-ethynyl- 22 2,2,4,4-tetrainethylchroman (Intermediate 34, 0.096g, 0.38mnmol), methyl- 23 4-iodo phenyl acetate (Reagent B, 0.094g, 0.34mmol), triethyl amine (3rnL), 24 tetrahydrofuran (3mL), copper(L)iodide (0.025g, 0.l3mmol) and dichlorobis(triphenylphosphine)palladium(nI) (0.075g, 0. 11 minol) the title 26 compound was obtained 137g, 1H NMR (300 MHz, CDCI 3 5 7.47 27 2H, J 7.9Hz), 7.29 111, J 1.811z), 7.24 211, J 7.9 Hz), 6.82 (d, WO 02/18361 WO 0218361PCTIUS01/25443 122 17- 1~ 1H, J=2.1Hz), 3.70 3ff,3.63 2.22-2.13(in, 1H), 1.85 2H), 2 1.38 6H), 1.36 6H), 0.94-0.86 (mn, 2H), 0.68-0.63 (mn, 2H).

003 [4-(8-Cyciopropv1-22.4.4tetramey-chromTal-6-V1-ethYflvl) phenyl acetic 4 acid (Compound 36, General Formula 8) Following general procedure L and using [4-(8-cyclopropyl-2, 2 4 ,4- 6 tetramnethyl-chroman-6-ylethynyl) phenyl] acetic acid methyl ester 7 (Compound 35, 0.137g, 0.30inmol), 5mL of methanol and IM sodium 8 hydroxide solution (2mL) followed by preparative reverse phase H.PLC 9 using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.11 ig, I1I 'H NMR (3 00 Mffz, CDCI 3 8 11.56 (br s, IH), 7.47 2H, J 8.9Hz), 12 7.28 1H, J= 1.911z), 7.23 2H, J= 8.514z), 6.82 1K, J= 1.911z), 13 3.62 211), 2.21-2.12 (in, 1H), 1.83 211), 1.36 6H), 1.34 6K), 0.93- 14 0.82 (in, 2H), 0.72-0.62 (in, 2H).

4 -(8-Cyclonropyl-2,2,4,4-tetramethyl-chroman-6-vl-ethynyl)-2- 16 fluorophenvl acetic acid ethyl ester (Compound 37, General Formula 8) 17 Following general procedure F and using 8-cyclopropyl-6-ethynyl- 18 2,2,4,4-tetramethylchroinan (Intermediate 34, 0.096g, 0.3 Smiol), ethyl-2- 19 fluoro-4-iodo phenyl acetate (Reagent C, 0. 1 04g, 0.34mmol), niethyl amine (3mL), tetrahydrofuran (3mL), copper(I)iodide (0.020g, 0.lmmnol) and 21 dichlorobis(triphenylphosphine)palladium(II) (0.060g, 0.08Sinunol) the title 22 compound was obtained 14g, 85 23 'H NUR(300 Mffz, CDCI 3 6 7.31 IK, J= 1.9Hz), 7.29-7.21 (in, 3H-), 24 6.85 1H, J= 1.9Hz), 4.20 2H, 7.1Hz), 3.68 2K1), 2.24-2.14 (mn, MH), 1.87 211), 1.40 611), 1.38 6H), 1.28 3H, J= 7.1Hz), 0.96- 26 0.85 (in, 2M), 0.70-0.64 2H).

WO 02/18361 WO 0218361PCT/US01/25443 123 1 [44(8-Cyclopropyl-2.2AA,-tetrameth1yIchromaf- 6 yL-f'Vn 1 2 fluoropheniyll acetic acid (Compound 38, General Formula 8) 003 Following general procedure L and using [4-(8-cyclopropyl- 2 2 4 4 4 tetramnethyl-chroman-6-yl-ethynyl)-2-fluorophel]l acetic acid ethyl ester (Compound 37, 0.14g, O.323mmo1), 5mL of methanol and IM sodium 6 hydroxide solution (2mL) followed by reverse phase HPLC using 10% water 7 in acetonitrile as the mobile phase, the title compound was obtained as a 8 solid (0.11Og, 9 'H NMR (300 MHz, CDC1 3 8 7.28 1H1, J= 2.1Hz), 7.27-7.17 (in, 3H), 6.82 1H, J= 1.811z), 3.70 2H), 2.21-2.11 (in, 111), 1.84 2H), 1.37 11 6H), 1.35 6H), 0.94-0.87 (in, 2H), 0.67-0.62 (mn, 2H).

12 GENERAL PROCEDURE P: 6-13romo-4,4-dimetyl-2-meth lene chroman 13 (Intermediate 14 A stirred, cooled (ice bath) solution of 6-bromo-4,4-dimethylchroman-2-one available in accordance with U.S. Patent No. 5,399,561 16 incorporated herein by reference (I g, 3 .92mmol) in 8mL, of anhydrous 17 tetrahydrofuran was treated with a 0.5 M solution of ji-chloro-ii-methylene- 18 [bis(cyclopentadienyl)itanium]dimethylaluminxm (Tebbe reagent) in 19 toluene (8.23rnL, 4 .l2rnmol). After 10 minutes, the reaction mixture was poured into ice-water mixture containing 5OmL, of 1M sodium hydroxide and 21 extracted with hexane. The hexane extract was washed with brine (xlI), 22 filtered over a bed of celite and evaporated in vacuw to an oil which was 23 subjected to flash column chromatography over silica gel (230-400 mesh) 24 using hexane as the eluent to afford the title compound (0.74g, 74%) as a clear oil.

WO 02/18361 WO 0218361PCTIUS01/25443 124 1 'H NMR (300 MHz, CDCI 3 57.34 1W, J=2.3Hz), 7.23 (ddl,11, J 2 2.3,8.5Hz), 6.77 11H, J= 8.0Hz), 4.61 1H, J= 0.73H1z), 4.17 1H, J 0C) 3 0.73Hz), 2.33 2H), 1.27 6H).

ci4 GENERAL PROCEDURE Q: 6-rm-,-iyr-.-ieIpr[H 1-benizopyran-2. 1'-cyclopropane] (Intermediate 36) NO6 A solution of diethyl zinc in hexane (IM, 7. 1mL) was treated with 7 diiodomethane (1 .89g, 7.lmmol). After 5 minutes, a solution of 6-bromoc-I8 4,4-dimnethyl-2-methylene chroman (Intermediate 35, 0.44g, 1 .77mmol) in 9 3mL of hexane was added and the solution was refluxed for lh. The reaction mixture was then cooled to ambient temperature, diluted with 1I Ibexane, washed with brine dried over anhydrous sodium sulfate, 12 filtered and evaporated in vacuo to a residue which was subjected to flash 13 column chromatography over silica gel (230-400 mesh) using hexane as the 14 eluent to obtain the title compound (0.44g, 93%).

'H NMv1R (300 M&z, CDCL 3 8 7.47 111, J= 2.3H1z), 7.23 (dd, 1H, J= 16 2.3,8.5Hz), 6.70 111,J= 8.011z), 1.96 2M, 1.47 6H1), 1.09-1.05 (in, 17 2H), 0.74-0.70 (mn, 211).

18 3 .4-Dihvdro-4,4-diinetl-6-(trixnetlsilgpyl)ethy nvilspjiro[2H- 1- 19 benzonvran-2. 1 '-cclopropanel (Intermediate 37) Following general procedure D and using 6-broino-3,4-dihydro-4,4- 21 dimnethylspiro[2H- 1-benzopyran-2, 1'-cyclopropane] (Intermediate 36, 22 0.44g, l.65mmoI), triethyl amine (4miL), anhydrous tetrahydrofuran 23 copper(I)iodide (0.95g, 0.Smmol), triinethylsilyl acetylene (1 .62g, 24 1 6.Smmol) and dichlorobis(triphenylphosphine)palladium(II) (0.4g,

.S

6 inmol), the title compound was obtained as a brown oil (0.4g, 86%).

WO 02/18361 WO 0218361PCTIUS01/25443 125 I 'H NMR (300 M~z, CDC1 3 37.44 H, J=2.1Hz), 7.18 (dd, 11, J 2 2.1,8.5Hz), 6.65 1HJ= M.Hz), 1.87 211), 1.37 6H1), 1.0 1-0.97 (in, 0C) 3 2H1), 0.65-0.61 (mn, 211), 0.26 9H).

4 6-Etyl-3.4-dihydro-4,-dinetlspiro[2H-1 -benzopvan-2. 1'cyclopropanel (Intermediate 38) 6 Following general procedure E and using 3,4-dihydro-4,4-dimnethyl- 7 6-(trimethylsilaniyl)ethynylspiro[2.H- 1-benzopyran-2, 1'-cyclopropane] 8 (Intermediate 37, 0.4g, 1 .42mmol), potassium carbonate (0.98g, 7.l1mmol) 9 and methanol, the title compound was obtained as a yellow oil (0.3 g, 100%).

1H NMR (300 M~z, CDCI 3 5 7.44 1H, J= 2. 1Hz), 7.18 (dd, 111, J= 11 2.1, 8.5Hz), 6.65 1H, J= M.Hz), 2.97 1H), 1.86 2H), 1.37 6M1, 12 1.00-0.95 (in, 211), 0.64-0.59 (in, 2H1).

13 Benzoic acid. 4-I (3.4-dihydro-4.4-dimethlpiro[2H- 1-benzopvyran-2. 1'- 14 cyclopropanel-6-yl)ethynyll-ethyI este (Compound 39, General Formula 1) 16 Following general procedure F and using 6-ethynyl-3,4-dihydro-4,4- 17 dimethylspiro[2H-1-benzopyran-2,1 '-cyclopropane] (Intermediate 38, 18 0.06g, 0.28mmol), ethyl-4-iodo-benzoate (Reagent A, 0.086g, 0.3 1Immol), 19 triethyl amine (4mL), tetrahydrofiiran(4mL), copper(I)iodide(0.032g, 0. l7rnmol) and dichlorobis(triphenylphosphine)palladium(II) 1 18g, 21 0. l7mxnol) followed by flash column chromatography over silica gel (23 0- 22 400 mesh) using 5-10 ethyl acetate in hexane as the eluent, the title 23 compound was obtained (0.07g, 24 1H NMR (300 MHz, CDCl 3 8 8.01 211, J= 8.2Hz), 7.56 2H1, J= 8.5Hz), 7.49 1U1 J= 2.1Hz), 7.24 (dd, lH, J= 2.1,8.5Hz), 6.70 1H, J 26 8.5Hz), 4.38 2H, J= 7.1Hz), 1.89 211), 1.40 6H), 1.40 3H-, J= 27 7.0Hz), 1.02-0.98 (in, 2H), 0.67-0.62 (in, 211).

WO 02/18361 WO 0218361PCTIUS01/25443 126 1 Benzoic acid. 4-r(3.4-dhvdro-4.4-dimthylspiror2H- 1-benzopyran-2. 1'- 2 cycloppaneI-6-yl)etnyIL- (Compound 40, General Formula 1) 00 3 Following general procedure L and using benzoic acid, 4-[(3,4-dihydro-4,4- 4 dimethylspiro[2H-1 -benzopyran-2, 1'-cyclopropanej-6-yl)ethynyl] -ethyl ester (Compound 39, 0.07g, O.l96rruol), 5mL of ethanol and I M sodium 6 hydroxide solution (2m.L) followed by preparative reverse phase HPLC 7 using 10% water in acetoriitrile as the mobile phase, the title compound was 8 obtained as a solid (0.034g, 52%).

9 1H NMvlR (300 Mliz, CD 3

COCD

3 8 8.05 2H, J =8.2Hz), 7.64 2H1, J~ 8.2Hz), 7.60 III, J=2.1lHz), 7.28 (dd, IH, J=2.1, M.Hz), 6.73 1H, J 11 1.95 2H), 1.43 611), 0.96-0.92 (in, 2H), 0.74-0.71 (mn, 2H).

12 Benzeneacetic acid. 4-[(3.4-dihydro-4,4-dinethvlspiro[2H- 1-benzopyran- 13 2.1 '-cclpropanel]-6-vyl)ethvnyl]-methyI este (Compound 41, General 14 Formula 1) Following general procedure F and using 6-ethynyl-3,4-dihydro-4,4- 16 dimethylspiro[2H- 1 -benzopyran-2, 1 -cyclopropane] (Intermediate 38, 17 0.060g, 0.28mmol), inethyl-4-iodo phenyl acetate (Reagent B, 0.078g, 18 0.28rnmol), triethyl amine (4mL), tetrahydrofuran (4mL), copper(I)iodide 19 (0.0 3 2g, 0. l7niiol) and dichlorobis(triphenylphosphine)palladium(ID) 11 8g, 0. 1 7mmol) followed by flash column chromatography over silica 21 gel (230-400 mesh) using 5 ethyl acetate in hexane as the eluent, the title 22 compound was obtained (0.084g, 84%).

23 'H NMR (300 MIHz, GDCI 3 5 7.48-7.45 (mn, 311), 7.26-7.20 (in, 3H1), 6.67 24 1H, J= 8.5Hz), 3.70 311, 3.63 211), 1.89 211), 1.40 3H), 1.40 3H1), 1.01-0.97 (in, 2H), 0.67-0.61 (in, 211).

26 Benzeneacetic acid. 4-r(3 .4-dihvdro-4.4-dimethylspiro[2H- 1-beuzopyran- 27 2.1 '-ccloproane]-6-yl)etnvl1- (Compound 42, Formula 1) WO 02/18361 WO 0218361PCTfUSOI/25443 127 I A solution of benzeneacetic acid, 4-[(3,4-dihydro-4,4- 2 dimethylspiroll2H- 1-benzopyran-2, 1 'cyclopropane]-6-y1)ethynyl]-methyl 00 3 ester (Compound 41, 0.084g, 0.24nmmol) in 5mL of methanol was treated 4 with IM sodium hydroxide solution (2mL) and heated at 551C for 2h. The volatiles were distilled off in vacuo and the residue was acidified with 6 hydrochloric acid and extracted with ethyl acetate The combined 7 organic phase was washed with brine dried over anhydrous sodium 8 sulfate, filtered and evaporated in vacuo to a residue which was purified by 9 preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title compound (0.080g, 100%).

I1 I H NMR (300 MHz, CD 3

COCD

3 8 7.49-7.46 (in, 3H), 7.25 2H, J= 12 8.2Hz), 7.22 (dci, 1H J= 2.1,8.5H1z), 6.68 1H, J= 8.5H4z), 3.66 2H), 13 1.88 2H), 1.44 6H), 1.01-0.97 (in, 2M, 0.67-0.61 (mn, 2H1).

14 2-Fluoro-benzoic acid. 4[(3 .4-diydro-4.4-dimethvlsniiro [21-1-1 -benzopv2ran- 2.1 '-cyclopropane-6-yl~ethynyllj-methyl ester (Compound 43, General 16 Formula 1) 17 Following general procedure F and 6-ethynyl-3,4-dihydro-4,4- 18 dimethylspiro[2H-1-benzopyran-2, 1'-cyclopropanel (Intermediate 38, 19 0.050g, 0.23mmol), methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.069g, 0.24mnrol), triethyl amine (5mL), 21 copper(I)iodide(0.013g, 0.07mniol) and 22 dichlorobis(triphenylphosphine)palladiuin(il) (0.049g, 0.O7mmol) followed 23 by flash column chromatography over silica gel (230-400 mesh) using 5-10 24 ethyl acetate in hexane as the eluent, the title compound was obtained (0.080g, 100%).

26 'H1 NMR (300 MHz, CDCl 3 5 7.90 1H, J= 7.9Hz), 7.63 (ci, 1H, J~= 27 1.-8H1z), 7.3 2 (dci, IKJ 1. 5, 8.2Hz), 7.26 (dci, I H, J= 1. 5,11.4Hz), 7.24 WO 02/18361 WO 0218361PCTUSO 1125443 128 I (dd, lHT, J= 2.1, M.Hz), 6.71 1H, J= 8MHz), 1.97 2H), 1.44 611), 2 0.98-0.94 (in, 2H), 0.76-0.71 (in, 2H).

003 2-Fluoro-benzoic acid, 4-1(3 .4-dihydro-4.4-dimetlspiro[2H-l1-benzopyran- 4 2.1 -cclgprppane1-6- yD~etyvl (Compound 44, General Formula 1) Following general procedure L and using 2-fluoro-benzoic acid, 4- 6 [(3,4-dihydro-4,4-dimethylspiro[2H- 1-benzopyran-2, 1,-cyclopropane]-6- 7 yl)ethynyl]-methyl ester (Compound 43, 0.08g, 0.23nimol), 5mL of C18 methanol and 2M sodium hydroxide solution (IlmL) followed by flash 9 column chromatography over silica gel (230-400 mesh) using ethyl acetate as the eluent, the title compound was obtained (0.020g, 11 'H NM (3 00 MHz, CD 3

COCD

3 5 7.99 I1H, J =7.9Hz), 7.63 I1H, J 12 2.1lHz), 7.44 (dd, 1H, J= 1.5, 7.9Hz), 7.37 (dd, 1H, J= 1.5, 11.4Hz), 7.31 13 (dd, lH, J1=2.1, 8MHz), 6.75 1H, J= 8.2Hz), 1.97 2H), 1.44 6H), 14 0.98-0.94 2H), 0.76-0.71 (in, 2H).

GENERAL PROCEDURE R: 2.2.4.4-Tetramethyl-chroman-6-carboxylic 16 acid (Intermediate 39) 17 A stirred, cooled (-78 0 C) solution of 6-bromo-2,2,4,4-tetrmnethyl 18 chroman (1 .2g, 4.47mmol) in 1 SmL of anhydrous tetrahydrofuran was 19 treated with a 13.M solution of tert-butyl lithium solution in pentane 5.27miL, 8.9mmol). After 10 minutes at -78'C, carbon dioxide (generated 21 from dry ice) was bubbled into the reaction mixture. The reaction mixture 22 was allowed to warm to ambient temperature. The reaction mixture was 23 diluted with ethyl acetate, washed with brine, dried over anhydrous sodiumn 24 sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using ethyl 26 acetate as the eluent to afford the title compound as a white solid I g, 27 92%).

WO 02/18361 WO 0218361PCTJUSO 1/25443 129 1 'HNMR(300MIiz, CDCl 3 ):8S12.17 (brs, IH), 8.09 (dIH,J''2.Hz), 2 7.85 (dci, 1H, J= 2.1, 8.5Hz), 6.83 (di, 1H, J= 8.2Hz), 1.87 2H1), 1.39 (s, 00 3 6H), 1.37 6H).

4 2.2.4.4Tetrametyl-chroman-6-carboXcylie acid 4(et butoxvycarbonylretl)phenyI ester (Compound 45, General Formula 8) 6 A solution of 2,2,4,4-tetramethyl cbroman-6-carboxylic acid 1ig, 7 0.43mrnol) in thionyl chloride (lOmL) was refluxed for 2h. The thionyl 8 chloride was evaporated under reduced pressure and the residue was 9 dissolved in 5mL of dichioromethane and treated with triethyl amine followed by tert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088g, I1I 0.427mrnol). After 0.5h, the reaction mixture was subjected to flash column 12 chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in 13 hexane as the eluent to afford the title compound 1g, 14 'H NMR (300 MiI-z, CDCI 3 8 8.15 (di, 1H-, 2.1lHz), 7.93 (dci, 111, J= 2.1, 8.5Hiz), 7.33 (ci, 2H, J =8.8Hz), 7.16 (di, 2H, J= 8.8Hz), 6.88 (di, III, J 16 8.5H1z), 3.54 211), 1.89 211), 1.45 9H), 1.41 611), 1.40 6H).

17 2.2.4.4-Tetrametl-chrornan-6-carboxvlic acid 4-(carboxymethvl)phenyl 18 ester (Compound 46, General Formula 8) 19 A solution of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4-(tertbutoxycarbonylmethyl)phenyl ester (Compound 45, 0. 1g, 0.23mmol) was 21 treated with 5mL of trifluoroacetic acid and stirred at ambient temperature 22 for lii. The trifluoroacetic acid was distilled off under reduced pressure and 23 the residue was subjected to preparative reverse phase HPLC using 24 water in acetonitrile as the mobile phase to afford the title compound as a white solid (0.045g, WO 02/18361 WO 0218361PCT/US01/25443

U

130 I 'H NMIR(300NMHz, CDC1 3 88.13 (ciH, J=2.1Hz), 7.92 (dci, 1I, 2 2.3, 8MHz), 7.35 2H1, J= 8.Hz), 7.17 2H1, J= 8.5H4z), 6.87 111, J= 00 3 8.Hz), 3.68 211), 1.89 2H1), 1.41 611), 1.39 6H).

4 6-Bromo-8-carbaldhyde34dihydro-44-diTg~etylstirof 2 H- 1-benzopyran- 21 I'-cycloropanel (Intermediate 6 Following general p rocedure M and using 6-bromo-3,4-dihydro-4,4- 7 dimethylspiro[2H- 1 -benzopyran-2, 1 '-cyclopropane](Intermediate 36, 2.3g, 8 8.6Smmol), anhydrous dichioromethane (25mL), I M solution (8.65mL, 9 8.6Smmol) of titanium tetrachloride in dichloromethane and a,ct-dichloro methyl. ether (1.09g, 9.52mmol) followed by flash column chromatography.

11 using 10% ethyl acetate in hexane as the eluent, the title compound was 12 obtained as a yellow solid (2.06g, 8 1 13 11HNMR (300 MHz, CDC 3 5 10.20 1i-i), 7.69 lH, J =2.611z), 7.58 14 1H, J= 2.6Hz), 1.92 211'), 1.40 6H1), 1.09-1.04 (in, 211), 0.73-0.69 (m,2H).

16 6-Bromo-3 .4-dihydo-4.4-dimetl-8-vinylspiro[2H- 1 -benzopyran-2. 1' 17 cyclopropanel (Intermediate 41) 18 Following general procedure N and using A solution of methylidene 19 triphenyl phosphorane [generated from methyl triphenylphosphoniurn bromide (7g, 2Ommol) and 1 .6M solution of n-butyl lithium in hexanes 21 (1 1.8mL, l9rnmol) 3, 6-bromo-8-carbonyl-3,4-dihydro-4,4- 22 dimnethylspiro[2H- 1-benzopyran-2, 1'-cyclopropane](Intermediate 23 2.06g, 7mmol) followed by flash columnn chromatography over silica gel 24 (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as a clear oil (1 .36g, 66%).

26 IH NWR (300 MH-k, CDCI 3 8 7.36 (di, 1H, 2.3Hz), 7.28 (di, 1H, J= 27 2.6Hz), 6.80 (dci, 1H, J= 11.1, 17.9Hz), 5.63 (dci, 1H,J= 1.2, l 7 .911z), 5.19 WO 02/18361 WO 0218361PCTIUS01/25443 131 17- 1~ (dd, 1H,J= 1.2, 11.1Hz), 1.84 211,1.35 61), 0.97 2H,J=6.3HZ), 2 0.62 111, J= 5.3H1z), 0.60 1H, J= 6.2Hz).

3 6-Bromo-8-cycloprol-3 A-dihydro-4.4-dimeth lti~2- 1 -benzopyran- 4 2.1 '-cycloropanel (Intermediate 42) Following general procedure 0 and using A 6-bromo-3,4-dihydro- 6 4,4-dimethyl-8-vinylspiro[2H- 1-benzopyran-2, 1' -cyclopropane] 7 (Intermediate 41, 1.36g, 4.6mmol), a solution of diazomethane in diethyl 8 ether and palladium (II)acetate (-30mg) followed by flash column 9 chromatography over silica gel (230-400 mesh) using hexan e as the eluent, the title compound was obtained as a clear oil (1.38g, 100%).

I1I 'H NMR (3 00 M&z, CDCl 3 8 7.19 I1H, J 2.2Hz), 6.71 11H, J 12 2.2Hz), 1.99-1.92 (in, 111), 1.87 211, 1.35 611), 1.00-0.95 (in, 2H), 13 0.90-0.82 (in, 211), 0.65-0.54 (mn, 4H{).

14 8-Cyclonronvl-3 .4-dihydro-4,4-dimethyl-6- (trimethylsilanyl)ethyvnvlspiro[2H- 1-benzopvyran-2. 1' -cyclonronaneI 16 (Intermediate 43) 17 Following general procedure D and 6-bromo-8-cyclopropyl-3,4- 18 dihydro-4,4-dimethylspiro[2H- 1-benzopyran-2, 1'-cyclopropane] 19 (Intermediate 42, 0.74g, 2.4nunol), (trimethylsilyl)acetylene (4mL, 28mmol), triethyl amine (8mL), anhydrous tetrahydrofuran, copper(I)iodide 21 (0.050g, 0.26inmol) and dichlorobis(triphenylphosphine)palladiuxn(ll) 22 1 5g, 0.22inmol), followed by flash column chromatography over silica gel 23 (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title 24 compound was obtained as an oil (0.62g, 'H NMR (300 Mvl-z, CDCl,): 8 7.28 III, J= 1.9Hz), 6.77 111, J= 26 1.9Hz), 2.03-1.94 (in, 111), 1.91 2H1), 1.40 611), 1.05-0.98 (mn, 2H1), 27 0.95-0.83 (in, 211), 0.69-0.59 (in, 411), 0.27 9H).

WO 02/18361 WO 0218361PCT/USOI/25443 132 1 8-Cyclopropyl-6-et~Ll-3 .4-dihydro-4.4-dimethylspirof2H- 1-benzovran- 2 2.1 -cclopropane] (Intermediate 44) 003 Following general procedure E, and 8-cyclopropyl-3,4-dihydlro-4, 4 4 dimethyl-6-(trimethylsilalyl)ethyfllspiro[2H- 1-benzopyran-2, 1'cyclopropane] (Intermediate 43, 0.62g, I .9mnrol), methanol and potassium 6 carbonate (0.5g, 3.6mmol) followed by flash column chromatography over 7 silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, 8 the title compound was obtained as an oil 5g, 100%).

9 'H NMR (300 M&z, CDCl 3 8 7.30 (di, 1H, J= 1.811z), 6.80 (di, 111, J= 2.0Hz), 2.97 IH), 2.04-1.95 (in, 1.91 211), 1.39 6H), 1.20-0.90 11 (in, 2H), 0.90-0.84 (in, 211), 0.75-0.58 (in, 411).

12 Benzeneacetic acid. 4-r(8-cyclopropyl-3 .4-diliydro-4..4-dimethylspiro[2H-1I- 13 benzopyran-2. 1'-cvclopropanel-6-yl)etynyll-methyIese (Compound 47, 14 General Formula 1) Following general procedure F and using 8-cyclopropyl-6-ethynyl- 16 3,4-dihydro-4,4-diinethylspiro[2H-1I-benzopyran-2, 1'-cyclopropane] 17 (intermediate 44, 0.11 g, 0.43minol), methyl-4-iodo phenyl acetate 18 (Reagent B, 0. 114g, 0.4l1mmol), triethyl amine (5mL), tetrahydrofuran 19 (3inL), copper(I)iodide (0.025g, 0.l3minol) and dichlorobis(triphenylphospltine)palladium(ll) (0.075g, 0.1 Inmmol), the title 21 compound was obtained as a clear oil (0.096g, 56%).

22 'H NMRl~ (300 MI-z, CDCI 3 8 7.46 (di, 2H1, J= 8.0Hz), 7.31 (di, 1H1, J= 23 1.9Hz), 7.24 2H, J= 8.211z), 6.81 (di, 1H, J= 1.9Hz), 3.69 311), 3.62 24 2M1, 2.04-1.95 (mn, 111), 1.90 211), 1.39 6H4), 1.03-0.99 (mn, 211), 0.90-0.83 (in, 211), 0.68-0.59 (mn, 4H1).

WO 02/18361 WO 0218361PCT/US01/25443 133 1 Benzeneacetic acid. 4-~-vll~ol34d Io44dml~ysio2- 2 benzopyran-2. V -pyclopropane1-6-yl~ethvnylj- (Compound 48, General 00 3 Formula 1) 4 Following general procedure L and using benzeneacetic acid, cyclopropyl-3 ,4-diliydro-4,4-dirmethylspiro[2H- 1 -benzopyran-2, 1'- 6 cyclopropane]-6-yl)ethynyl]-methyl ester (Compound 47, 0.96g, 0.24minol), 7 5mL of methanol and IM sodium hydroxide solution (2mL) followed by 8 flash column chromatography over silica gel (23 0-400 mesh) using 9 methanol in dichioromethane as the eluent, the title compound was obtained as a solid (0.084g, 91%).

11 'H NMR (3 00 M11-z, CDC1 3 8 10.27 (br s, I 7.46 (di, 2H, J =8.211z), 12 7.30 1H, J= 1.8Hz), 7.23 (di, 2H, J= 8.2Hz), 6.80 (di, IH, J= 13 3.63 214), 2.07-1.94 (in, 111), 1.89 214), 1.39 6H), 1.03-0.98 (in, 14 2H4), 0.89-0.82 (in, 214), 0.73-0.59 (in, 414).

4-[(8-Cyclopropl-3.4-ciihvciro-4,4-dimethvlspiror2H- 1-benzgoran-2. 1'- 16 cyc1opropane1-6ryl)thyn 1--fluoro-benzeneacetic acid methyl ester 17 (Compound 49, General Formula 1) 18 Following general procedure F and using 8-cyclopropyl-6-ethynyl- 19 3,4-dihydro-4,4-dimethylspiro[2H- 1-benzopyran-2, 1'-cyclopropane] (Intermediate 44, 0. 125g, 0.5mmol), methyl-2-fluoro-4-iodo phenyl acetate 21 (Reagent H, 0. 14g, 0.5mmol), triethyl. amine (3mL), tetrahydrofuran (3mL), 22 copper(I)iodide (0 .020g, 0. Iimol) and 23 dichlorobis(triphenylphosphine)pallaciiuin(n) (0.060g, 0.O8Sinmol) followed 24 by preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.096g, 46%).

26 'H NMR (300 Ml-lz, CDCl 3 8 7.30 (di, 111, J 2. 1Hz), 7.26-7.18 (in, 3H), 27 6.80 1H, J1= 1.8Hz), 3.71 311), 3.67 211), 2.04-1.94 (in, 1H), 1.90 WO 02/18361 WO 0218361PCTIUS01/25443 134 I 211), 1.40 6H1), 1.18-0.99 (in, 2H), 0.90-0.83 (in, 211I), 0.68-0.59 (mn, 2 4H1).

3 4-[(8-CQyclopropyl-3 .4-dihydro-4,4-dimethvlspiro[2H-1I-benzopyra-. 4 cloprooanel-6vP)ethyl-2-fluoro-belzefeacetic acid (Compound General Formula 1) 6 Following general procedure L and using 4-[(8-cyclopropyl-3,4- 7 dihydro-4,4-dimethylspiro[2H- 1-benzopyran-2, 1'-cyclopropane]-6- 8 yl)ethynyl]-2-fluoro-benzeneacetic acid methyl ester (Compound 49, 9 0.096g, 0.23mmol), 5mL of methanol and IM sodium hydroxide solution (2mL) followed by flash column chromatography over silica gel (230-400 11 mesh) using 15% methanol in dichioromethane as the eluent, the title 12 compound was obtained as a solid (0.093g, 100%).

13 'H1 NMvR (300 MI-Iz, CDCl 3 8 9.50 (br s, 111), 7.27 1H, J= 2.1lHz), 7.24- 14 7.15 (in, 311, 6.77 IH, J= 1.5Hz), 3.67 2H), 2.01-1.91 (in, 1H1), 1.87 2H), 1.36 611), 1.01-0.96 (in, 211), 0.87-0.80 (mn, 2H1), 0.65-0.56 (in, 16 4M1.

17 Benzoic acid. 4-f(8-cycloproLpyl-3.4-dihydro-4.4-diinethylspiror2H- 1- 18 benzopyran-2. I'-cyclopropanel-6-yl)ethynvl-ehyl ester (Compound 51, 19 General Formula 1) Following general procedure F and using 8-cyclopropyl-6-ethynyl- 21 3 ,4-dihydro-4,4-dimethylspiro[2H- 1-benzopyran-2, 1'-cyclopropaneI 22 (Intermediate 44, 0.05g, 0.2mmol), ethyl-4-iodo-benzoate (Reagent A, 23 0.055g, 0.2inmol), triethyl amine (3niL), tetrahydrofuran(3rnL), 24 copper(I)iodide(0.020g, 0. linmol) and dichlorobis(triphenylphosphine)palladium(III) (0.060g, 0.O85minol), the title 26 compound was obtained (0.06g, WO 02/18361 WO 0218361PCTIUS01/25443

U

135 1 ljHjNMR (300 MHz, CDC1 3 8 8.00 2H, J= 8.2Hz), 7.55 2H, J= 2 8.2Hz), 7.33 1W, J= 1.8H4z), 6.83 1H, J= 2.1Hz), 4.38 2H, J= 0C) 3 7.11Hz), 2.04-1.95 (in, 1H), 1.91 211), 1.40 6M1, 1.40 3H, J 4 1.05-0.95 (ni, 2H), 0.91-0.84 (in, 2F), 0.69-0.61 (in, 4M).

Benzoic acid. 4-r(8-cvclgpropyl-3 .4-dihvdro-4 4dimethvylspirnr2H- 6 benzopyran-2.1 '-cvclopropane]-6-yl)etyyl]- (Compound 52, General 7 Formula 1) 8 Following general procedure L and using benzoic acid, 9 cyclopropyl-3 ,4-dihydro-4,4-dimethylspiro[2H- I -benzopyran-2, 1'cyclopropane] -6-yl)ethynyl] -ethyl ester (Compound 51, 0.06g, 0.l1 mmol), 11 5mL of methanol and I M sodium hydroxide solution (2mL) followed by 12 preparative reverse phase HPLC using 10% water in acetonitrile as the 13 mobile phase, the title compound was obtained as a solid (0.040g, 72%).

14 'H NNIR (300 MHz, CDCI 3 8 8.08 2H, J= 8.8Hz), 7.60 2H, J 8.8Hz), 7.34 1H, J= 1.9H4z), 6.84 1H1,J= 1.9Hz), 2.05-1.96 (mn, 1A), 16 1.92 2H), 1.41 611), 1.05-0.95 (in, 2H), 0.92-0.83 (mn, 2H), 0.75-0.60 17 (m,4M).

18 4-r(8-Cyclopropvl-3,4-dihvdro-4,4-dinethylspiro[2H-1-.benzopvran-2. 1'- 19 clcopropane1-6-yl)ethyvnvJ-2-fluoro-benzoic acid metyl ester (Compound 53, General Formula 1) 21 Following general procedure F and using 8-cyclopropyl-6-ethynyl- 22 3,4-dihydro-4,4-diniethylspiro[2H- 1 -benzopyran-2, 1 '-cyclopropane] 23 (Intermediate 44, 0.03g, 0. 11 mmol), methyl-2-fluoro-4-iodo-benzoate 24 (Reagent G, 0.025g, 0.0ODl, triethyl amnine (3mL), tetrahyclrofuran(3m.L), copper(I)iodide(0.020g, 0.1 nmol) and 26 dichlorobis(triphenylphosphine)palladiuin(n) (0.06g, 0.O8Sim~ol) followed 27 by preparative normal phase HPLC using 10% ethylI acetate in hexane as the WO 02/18361 WO 0218361PCTIUSOI/25443 136 I mobile phase, the title compound was obtained as a white solid (0.0 19g, 2 003 1 H NMR (300M&z, CDCI 3 57.97 11, J=7.8H7z),7.34 (d,l11,J= 4 1.9Hz), 7.32-7.25 (in, 2H), 6.83 1H, J= 1.911z), 3.95 311), 2.06-1.96 (in, IH), 1.93 211), 1.42 6H), 1.06-1.02 (in, 2H1), 0.91-0.86 (mn, 2H), 6 0.71-0.61 (in, 4H).

7 4-[(8-Cvclopropyl-3.4-dihydro-4,4-dimethvlsiro2f1-l1-benzopyran-2. 1'- 8 cyclopropane]-6-vl)et-hvnyll-2-fluoro-benzoic acid (Compound 54, 9 General Formula 1) Following general procedure L and using 4-[(8-cyclopropyl-3,4- 11 dibydro-4,4-dimethylspiro[2H- 1-benzopyran-2, 1 '-cyclopropane]-6- 12 yl)ethynyl]-2-fluoro-benzoic acid methyl ester (Compound 53, 0.0 19g, 13 0.O47mmol), SrnL of methanol and IM sodium hydroxide solution (2mL) 14 followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.0O1g, 16 56%).

17 'H NUR (300 MI-z, CDCI 3 8 7.99 11H, J= 8.0Hz), 7.36 -7.28 (in, 3H-), 18 6.83 111, J= 1.9H4z), 2.18-1.95 (in, 111), 1.92 211), 1.41 611), 1.06- 19 1.01 (mn, 2H), 0.96-0.83 (in, 211), 0.76-0.60 (mn, 4H).

8-Acetyl-6-bromo-2.2.4.4-tetramethyI chroman (Intermediate 21 A stirred, cooled (ice bath) suspension of aluminum chloride (0.99g, 22 7.46mmol) in anhydrous dichioromethane (20 mL) was treated with acetyl 23 chloride (0.58g, 7.46rniol). After 5 minutes, a solution of 6-bromo-2,2,4,4- 24 tetrainethyl chroman (Ig, 3.73mmol)in dichioromethane was added. Thie reaction was allowed to warm to ambient temperature and stirred for 2h.

26 The reaction mixture was then poured into ice containing 10% hydrochloric 27 acid and extracted with diethyl ether The combined organic phase was 28 washed with saturated aqucous sodium bicarbonate solution, dried over WO 02/18361 WO 0218361PCT/USOI/25443 137 1 anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue 2 which was subjected to flash column chromatography over silica gel (230- 00 3 400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title 4 compound as a pale yellow oil (0.95g, It was used as such for the next step without any characterization.

6 6-Bromo-8-ethyl-2.2,4,-tetramethyl chroman (Intermediate 46) 7 A stirred, cooled (ice bath) solution of 8-acetyl-6-bromo-2,2,4,4- 8 tetramethyl chroman (Intermediate 45, 0.95g, 3.lmmol) in trifluoroacetic 9 acid (1 OmL was treated with triethylsilane (l0mL) and the resulting reaction mixture was allowed to warm to ambient temperature and stirred overnight.

I1I The volatiles were distilled off in vacuo and the residue was diluted with 12 water and extracted with hexane The combined organic phase was 13 dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an 14 oil which was subjected to flash column chromatography over silica gel (23 0-400 mesh) using hexane as the eluent to afford the title compound as a 16 clear oil, contaminated with a small amount to triethylsilane (0.5 Ig, 56%).

17 1 H NMR (300 M~fz, CDCI 3 5 7.23 1H, 2.3Hz), 7.08 1H, J= 18 2.3Hz), 2.58 2H, J= 7.6Hz), 1.81 1.34 6H), 1.33 6H), 1.17 19 3H,J =7.61z).

8 -Etyl-6-trimethylsilanvlethvnyl-22,4.4-tetramnethyI chroman 21 (Intermediate 47) 22 Following general procedure D and using 6-bromo-8-ethyl-2,2,4,4- 23 tetramethyl chroman (Intermediate 46, 0. 5g, 1.6 immol), 24 (Wrmethylsilyl)acetylene (1.57g, 16. Immol), triethyl amnine (8mL), anhydrous tetrahydrofuran (l0rmL), copper(I)iodide (0.025g, .l3mmol) and 26 dichlorobis(triphenylphosphine)palladium(ll) (0.075g, 0. 11 mmol), followed 27 by flash column chromatography over silica gel (230-400 mesh) using WO 02/18361 WO 0218361PCTfUS01/25443 138 1 ethyl acetate in hexane as the eluent, the title compound was obtained as an 2 oil 137g, 27%).

003 'H NMVR (300 N'flz, CDC1 3 857.27 III, J= 2. 1Hz), 7. 10 111, J= 4 2. 1Hz), 2.55 211, J= 7.6Hz), 1.81 2H1), 1.33 6H1), 1.32 1.15 3H, J= 7.6Hz), 0.24 9H).

6 8-Etl-6-ethynyl-2.2.4.4-tetrametyl chromn (Intermediate 48) 7 Following general procedure E and using 8-ethyl-6- 8 trimethylsilanylethynyl-2,2,4,4-tetraxnethyl chroman (Intermediate 47, 9 0. 13 7g, 0.44mmol), methanol and potassium carbonate (0.l1g, 0.72mmol) followed by flash column, chromatography over silica gel (23 0-400 mesh) 11I using 5% ethyl acctate in hexane as the eluent, the title compound was 12 obtained as an oil (0.066g, 62%).

13 'H NMIR (300 MlHz, CDCI 3 8 7.33 111, J= 2.2Hz), 7.15 1H, J= 14 1.611z), 2.99 1H1), 2.59 211, J= 7.6Hz), 1.84 2H), 1.37 1.35 6H), 1. 19 3H,J =7.6Hz).

16 [4-(8-Ethyl-2,2,4.4-tetramethyl-chroman-6.yl-ethvl Ihnl actic aci 17 metlyl es (Compound 55, General Formula 8) 18 Following general procedure F and using 8-ethyl-6-ethynyl-2,2,4,4- 19 tetrarnethylchroman (Intermediate 48, 0.033g, 0. 136mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.034g, 0.l12mmol), triethyl amine (2mL), 21 tetrahydrofliran (2mL), copper(I)iodide (0.025g, 0.l3mmoI) and 22 dichlorobis(triphenylphosphine)palladium(fl) (0.075g, 0.1 Immol) the title 23 compound was obtained (0.035g, 73%).

24 'H NMR (3 00 M*1z, CDCl 3 5 7.49 2H-, J 7.9Hz), 7.3 5 1 H, J= 1.8Hz), 7.26 2H-, J= 7.911z), 7.18 lH, J= 1.9Hz), 3.72 3H1), 3.65 26 2H1), 2.61 2H, 7.5Hz), 1.85 211), 1.38 1211), 1.21 3H, J= 27 WO 02/18361 WO 0218361PCT[US01/25443

U

139 1 [4-(8-Etl.2,2.44tetramtyl-cbroman- 6 :yI ethfyoU phnYll aceticai 2 (Compound 56, General Formula 8) 003 Following general procedure L and using [4-(8-ethyl-2,2,4, 4 4 tetrametbyl-chroman-6-ylethynyl) phenyl] acetic acid methyl ester (Compound 55, 0.035g, 0.lxnmol), 5mL of methanol and IM sodium 6 hydroxide solution (lmL) followed by preparative reverse phase 1HPLC 7 using 10% water in acetonitrile as the mobile phase, the title compound was 8 obtained as a solid (0.l1lg, 9 'H NMIR (300 MHz, CDCI 3 5 7.48 2H, J= 8.0Hz), 7.33 1H, J= 1.9Hz), 7.25 2H, J= 8.0Hz), 7.15 1H, J= 1.9H1z), 3.65 2H), 2.59 11 2H, J= 7.5Hz), 1.83 2M, 1.35 12H), 1.18 3H, J= 7.4Hz).

12 Sp~ixof2.-1-benzonvran-2. 1'-cyclopropanel-6-carboxylic acid. 8- 13 cyclopropvl-3.4-dihydro-4,4-dimethyl- (Intermediate 49) 14 Following general procedure R and using 6-bromo-8-cyclopropyl-3,4dihydro-4,4-dimethylspiro[2H- I -benzopyran-2, 1 '.cyelopropane] 16 (Intermediate 42, 0.

4 5g, 1.48mmol), anhydrous tetrahydrofuran 17 137M solution of tert-butyl lithium solution in pentane 1.74mL, 2.96mmol) 18 and carbon dioxide generated from dry ice, followed by flash column 19 chromatography over silica gel (230-400 mesh) using 50% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid 21 (0.34g, 22 'H NMR (300 MHz, CDC1 3 5 12.43 (br s, l1i), 7.94 1H, J= 2.1Hz), 23 7.42 1H, J= 1.8Hz), 2.06-1.96 (in, 1ff), 1.92 2H), 1.42 6H), 1.12- 24 0.97 (in, 2H), 0.95-0.8 1 (in, 2H), 0.77-0.60 (in, 4H).

Spirof2l{- -benzopvran-2.1 '-cycloprop~ane]-6-carboxylic acid. 8- 26 cyclopropyl-3.4-dihydr-4.4-dimethyl-, 4-(terz'-butoxycarbonvl-methv')hev 27 ester (Compound 57, General Formula 1) WO 02118361 WO 0218361PCTIUSOI/25443 0 140 1 A solution of spiro[2H- 1-benzopyrafl-2,l I -cyclopropane]-6- 2 carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, 00 3 0.06g, 0.22mmol) in anhydrous dichioromethane (5m.L) was treated with 4 lert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.05g, 0.22mxnol) followed by 1-(3-dimethylaminopropyl)-3-thyearbodiimlide hydrochloride 1 1g, 6 0.22mxnol) and 4-dimethylaininopyridine (0.028g, 0.22mmol). The resulting 7 solution was stirred at ambient temperature overnight. The reaction mixture ri8 was subjected to flash column chromatography over silica gel (230-400 9 mesh) using 7% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil that solidified on standing (0.048g, 48%).

11 'H NMvR(3 00MHz, CDCl 3 5 7.91 I H, J Hz), 7.41 I1H, J 12 1.8H1z), 7.24 2H1, J= 8.8Hz), 7.05 2H,J= 8.5H-z), 3.46 2H), 1.97- 13 1.90 (in, 1Hi), 1.87 211), 1.37 9H1), 1.36 6Hf), 1.04-0.90 (mn, 2H), 14 0.87-0.75 (in, 211), 0.65-0.56 (mn, 411).

Spiro[2H- 1-benzopvran-2. 1'-cvclonropanel-6-carboxvlic acid. 8- 16 cvclopropyl-3.4-dihdro-4,4-dimetvl-. 4-(carboxviethvlDnhenyl este 17 (Compound 58, General Formula 1) 18 A solution of spiro[2H-1-benzopyran-2,1 '-cyclopropane]-6- 19 carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 4-(tertbutoxycarbonylinethyl)phenyl ester (Compound 57, 0.048g, 0. 21 was treated with 2mL of trifluoroacetic acid and stirred at ambient 22 temperature for 2h. The trifluoroacetic acid was distilled off under reduced 23 pressure and the residue was subjected to preparative reverse phase HPLC 24 using 10% water in acetonitrile as the mobile phase to afford the title compound as a white solid (0.029g, 26 'H NMR (300 MHz, CDCl 3 867.99 111, J= 2.2Hz), 7.48 1H, J= 27 1.9Hz), 7.34 2H1, J= 8.Hz), 7.16 2H,J= 8.5Hz), 3.67 211), 2.07- WO 02/18361 WO 0218361PCTIUSOI/25443 141 1 1.97 (in, 1.95 211), 1.44 6H), 1.09-1.04 (mn, 211), 0.93-0.85 (mn, 2 211), 0.79-0.64 (mn, 4M).

3 Spiro[2H- 1-benzopyran-2. 1' ccopropanel-6-carboaylic acid, 8- 4 yclopropyl-3.4-dilbydro-4.4-diet-hyl-. 34(tert-btoxvaroUlmetY1 Ief~ ester (Compound 59, General Formula 1) 6 A solution of spiroll2H--1-benzopyran-2,1 '-cyclopropane)-6- 7 carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, 8 0.05g, 0. 1 8nunol) in anhydrous dichioromethane (5mL) was treated with 9 tert-butyl-3-hydroxy phenyl acetate (Reagent F, 0.04g, 0.1 8mmol) followed by 1-(3-dimethylasminopropyl)-3-ethylcarbodiimide hydrochloride (0.029g, I1I 0. immol) and 4-dimethylarninopyridine (0.022g, 0.1 8mmol). The resulting 12 solution was stirred at ambient temperature overnight. The reaction mixture 13 was subjected to flash column chromatography over silica gel (230-400 14 mesh) using 7% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil that solidified on standing (0.020g, 23%).

16 'H NMR (300 MHz, CDCI 3 8 7.98 111, J= 1.9Hz), 7.48 1H,J= 17 2.2Hz), 7.38 11,J= 7.7Hz), 7.19-7.11 (in, 3H), 3.68 2H), 2.05-1.94 18 (in, 111, 1.95 2H), 1.44 15H), 1.09-1.04 (mn, 2H), 0.96-0.82 (mn, 2H), 19 0.73-0.64 (in, 411).

Spiro[2H- 1-benzopvran-2. 1'-cyclopropanel-6-carboXylic acid, 8- 21 cyclopropvl-3,4-dihydro-4,4-dimethyl-. 3-(carboxymgthyl),phenyl ester 22 (Compound 60, General Formula 1) 23 A solution of spiro[2H-1-benzopyran-2, I'-cyclopropane] -6- 24 carboxylic acid, 8-cyclopropyl-3 ,4-dihydro-4,4-dimethyl-, 3-(tertbutoxycarbonylmethyl)phenyl ester (Compound 59, 0.020g, 0.O4mmol) was 26 treated with 2inL of trifluoroacetic acid and stirred at ambient temperature 27 for 2h. The trifluoroacetic acid was distilled off under reduced pressure and 28 the residue was subjected to preparative reverse phase LIPLC using WO 02/18361 WO 0218361PCT[US01/25443 142 I water in acetonitrile as the mobile phase to afford the title compound as a 2 white solid (0.0125g, 62%).

00 3 1H NMR (300 Mfz, CDC1 3 857.99 1H, J= 2.1Hz), 7.49 1H1, J= 4 2.1Hz), 7.36 1H, J= 7.8Hz), 7.18-7.08 (in, 3H), 3.56 2H), 2.06-1.95 (in, 111), 1.95 211), 1.45 61H), 1.09-1.05 (in, 2H), 0.96-0.84 (in, 2H), 6 0.74-0.65 (in, 4H).

7 6-Bromo-4.4-dim ethyl-i ,2.3,4-tetrahydro-ciuinoline- I -carbaldehyde 8 (Intermediate 9 A solution of 6-bromo-4,4-dimethyl- 1,2,3 ,4-tetrahydroquinoline, available in accordance with United States Patent No. 5,089,509, the I1I specification of which is incorporated herein by reference (1.8g, 7.5mmol) in 12 l0mL of formic acid was refluxed for 3h. The reaction mixture was then 13 cooled to ambient temperature and poured into ice-cold saturated aqueous 14 sodium bicarbonate solution and extracted with diethyl ether The combined organic phase was dried over anhydrous sodium sulfate, filtered 16 and evaporated in vacuo to a residue which was subjected to flash column 17 chromatography over silica gel (230-400 mesh) using 15-25% ethyl acetate 18 in hexane as the eluent to afford the title compound as a pale yellow solid 19 (1.8g, )H NMR (300 MHz, CDCI 3 5 8.71 IH), 7.45 1H, J= 2.2Hz), 7.28 21 (dd, 1H, J= 2.2, 8MHz), 6.98 1H, Jr= 8.Hz), 3.78 2H1, 6.3H~z), 22 1.74 2H, J 6.3Hz), 1.28 6H).

23 6-Broino- I -cvclopropyl-4.4-dimetl-1 .2.3 .4-tetrahydroguinoline 24 (Intermediate 51) A stirred, cooled solution of 6-broino-4,4-dimethyl-1,2,3,4- 26 teftrahydro-quinoline-l-carbaldehyde (Intermediate so, 21.8, 6.7mmol) in 27 anhydrous tetrahycirofuran (2OmL) under argon was treated with titanium 28 tetra-iso-propoxide (2.l5mL, 7.39imol) followed by 3M solution of ethyl WO 02/18361 WO 0218361PCT/USOI/25443 143 1 magnesium bromide in diethyl ether (5.6mL, 16.8inmol) and the reaction 2 mixture was then heated at 50 0 C overnight. It was then cooled in an ice- 00 3 bath, quenched with saturated aqueous ammonium chloride solution and 4 extracted with diethyl ether The combined organic phase was dried over anhydrous sodium sulfate, filtcred over celite and evaporated in vacuo 6 to residue which was subjected to flash column chromatography over silica 7 gel (23 0-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford 8 the title compound as an oil (1 .2g, 64%).

9 'H NMR (300 MfHz, CDCl 3 8 7.24 I H, J 2.5Hz), 7.12 (dd, IlH, J 2.2, 8.8Hz), 7.01 1H, J= M.Hz), 3.20 211, J= 6.0Hz), 2.27-2.20 (mn, I1I 1H1), 1.68 2H, J= 5.9Hz), 1.24 311), 1.23 3H), 0.83-0.77 (in, 21-), 12 0.60-0.5 5 (in, 211).

13 1 -Cyclpropyl-6-trirneth liavehynyl-4.4-dimethyl-1 .2.3 4-tetrah dro- 14 ciuinoline (Intermediate 52) Following general procedure D and using 6-bromo- 1 -cyclopropyl-4,4- 16 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 51, 0.8g, 2.86mmol), 17 (trimethylsilyl)acetylene (SniL, 3 5nuol), triethyl amine (IOrn-L), anhydrous 18 tetrahydrofliran, copper(I)iodide (0.080g, 0.42mmol) and 19 dichlorobis(triphenylphosphine)palladium(II) (0.

2 40g, 0.34inuol), the title compound was obtained as an oil (0.67g, 79%).

21 'H NMR (300 MHz, CDC1 3 8 7.33 1H, J 1. 8Hz), 7.22 (dd, 111, J= 22 2.1, 8.5Hz), 7.06 1H, J= 8.5Hz), 3.27 2H, J1=5.9Hz), 2.37-2.3 1 (in, 23 1H), 1.70 2H, 6.0Hz), 1.28 6H), 0.89-0.82 (in, 2H), 0.66-0.60 (in, 24 2H), 0.28 9M1.

1 -Cvclopropvyl-6-ethynyl-4,4-diniethyl-1I 2,3,4-tetrahydroquinoline: 26 (Intermediate 53) 27 Following general procedure E and using 1-cyclopropyl-6- 28 trirnethylsilanylethynyl4,4-diinethyl-1I,2,3,4-tetrahydroquinoline WO 02/18361 WO 0218361PCT/US01/25443 144 1 (Intermediate 52, 0,40g, 1.34mmol), methanol and potassium carbonate 2 (0.2g, 1.47mmol) followed by flash column chromatography over silica gel 00 3 (230-400 mesh) using 2% ethyl acetate in hexane as the eluent, the title 4 compound was obtained as an oil 17g, 56%).

'I14 NMvR (300 MiHz, CDCI 3 5 7.38 114, J= 2.1lHz), 7.27 (dd, 1H, J= 6 2.1, 8.Hz), 7.11 (di, 1K, J= 8.5Hz), 3.30 2H1, J= 6.0Hz), 3.02 111), 7 2.40-2.34 (mn, 1H), 1.74 2H1, J= 6.0Hz), 1.30 6H), 0.93-0.85 (in, 2H), 8 0.70-0.63 (mn, 2H1).

94-( I-Cyclopropyl-4A4-dimethyl- 1.2,3 .4-tetrahydro-guinolin-6-vl-eth ayl) benzoic acid ethyl ester (Compound 61, General Formula 7) 11 Following general procedure F and using I1-cyclopropyl-6-ethynyl- 12 4,4-dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, 0.1 1g, 13 0.43mmol), ethyl-4-iodo-benzoate (Reagent A, 0.11 ig, 0.9minol), triethyl 14 amine (3inL), tetrahydrofuran(3mL), copper(I)iodide(O.02g, 0.l1mmol) and dichlorobis(triphenylphosphine)palladium(ll) (0.060g, 0.O85mmol) followed 16 by flash column chromatography over silica gel (23 0-400 mesh) using 17 10% ethyl acetate in hexane as the eluent, the title compound was obtained 18 (0.05g, 3 19 'K NMR (300 MHz, CDCl 3 8 7.99 211, J =8.2Hz), 7.54 2H, J 8.2Hz), 7.3 7 (di, IK J 2. 1Hz), 7.26 (cid, I H, J 2.1, 8.5SHz), 7. 10 I H, J 21 =8.811z), 4.3 7 2K J 7. 1Hz), 3.28 2H, J 6.0OHz), 2.40-2.3 3 (mn, 22 1K), 1.71 211, J= M.Hz), 1.40 3H, J= 7.0Hz), 1.27 6H), 0.94-0.82 23 (in, 211, 0.65-0.60 (in, 2H), 24 1-Cyclopropyl-4.4-dimethyl- 1.2.3 .4-tetrahydroguinolin-6-yl-ethynyl)Y benzoic acid (Compound 62, General Formula 7) 26 Following general procedure L and using 4-(I-cyclopropyl-4,4- 27 dimethyl- 1,2,3 ,4-tetrahydro-quinolin-6-ylethynyl)-benzoic acid ethyl ester WO 02/18361 WO 0218361PCT/USOI/25443 145 I (Compound 61, 0.05g, 0.l3mmol), 5mL of ethanol and 5M sodium 2 hydroxide solution (2mL) followed by recrystallization from hot ethyl 00 3 acetate, the title compound was obtained as a solid (0.030g, 64%).

4 'H1 NMR (300 MEz, DMSO-d 6 8 7.92 2H, J= 8.2Hz), 7.57 2H, J= 8.2Hz), 7.33 1H,J= 1.9Hz), 7.23 (dd, 1H, J 1.9, M.Hz), 7.06 1H, J 6 =8.8H4z), 3.25 2H1, J= 5.8Hz), 2.41-2.34 (in, 1H1), 1.64 2H, J= 5.6Hz), 7 1.21 6H1), 0.87-0.81 (in, 211), 0.59-0.54 (in, 211).

8 [44(1 -Cyclopropyl-4,4-dinetl- 1,2.3 4-tetahdro-guinolin-6-vl- 9 etvnyl~phenyll acetic acid methyl ester (Compound 63, General Formula 7) 11 Following general procedure F and using 1-cyclopropyl-6-ethynyl- 12 4,4-dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, 0.05g, 13 0.22mmol), methyl-4-iodo-phenyl acetate (Reagent B, 0.055g, O.2mmol), 14 triethyl amine (5mL), tetrahydrofuran, copper(1)iodide(0 .025 g, 0. l3iniol) and dichlorobis(triphenylphosphine)palladiuin(ll) (0.75g, 0. 1 Iminol) 16 followed preparative normal phase 1{PLC using 10 ethyl acetate in hexane 17 as the mobile phase, the title compound was obtained 089g, 100%).

18 'H1 NN'R (300 MFz, CDCJ 3 5 7.47 211, J= 8.8Hz), 7.45 IlH, J= 19 1.8Hz), 7.35-7.22 (mn, 2H), 7.10 2H1, J= 8.8Hz), 3.70 3H), 3.63 (s, 211), 3.27 (t 211, J= 6.011z), 2.37-2.31 (mn, 1H1), 1.71 (t 211, J= 6.0Hz), 1.27 21 611, 0.89-0.8 1 (in, 211), 0.65-0.60 (mn, 211).

22 14-C 1-Cyclopropyl-4..4-dimethyl- 1 .23.4-tetrah dro-guinolin-6-yl-ehynyl).2- 23 fluoro-pheniyl] acetic acid. ethyl ester (Compound 64, General Formula 7) 24 Following general procedure F and using 1-cyclopropyl-6-ethynyl- 4,4-dimethyl- 1 ,2,3,4-tetrahydro quinoline (Intermediate 53, 0.11 g, 26 0.49mmol), ethyl-2-fluoro-4-iodo.phenyl acetate (Reagent C, 0. 11 g, 27 0.9mmol), triethyl amine (3mL), tctrahydrofuran(3mL), WO 02/18361 WO 0218361PCTIUS01/25443 146 1 copper(I)iodide(0.06g, 0.32mmol) and 2 dichlorobis(triphelylphosphfle)palladiufl(II) (0.25g, 0.36mmol) followed by 00 3 flash column chromatography over silica gel (23 0-400 mesh) using 10 4 ethyl acetate in hexane as the eluent, the title compound was obtained 1ig, 5 'H NMR (300 MHz, CDC1 3 8 7.34 1H, J=2.1Hz), 7.25-7.17 (in, 6 311), 7.09 211, J =8.8H1z), 4.17 2H, J 7. 1H-z), 3.6 5 2H), 3.27 (t, 7 2H1, J= 6.0H1z), 2.3 8-2.31 (in, 111), 1.69 2H, J= 6.0Hz), 1.27 61-1), 1.25 8 3H, J= 7.1]Hz), 0.88-0.81 (mn, 211), 0.65-0.59 (mn, 2H).

9 N-(4-Bromophenyl)-N-metvl-3-metvl-2-butenamide (Intermediate 54) 3,3-Dimethylacryloyl chloride (3mL, 27nunol) was added to a I I solution of 4-bromo-N-methyl-aniline (4.55g, 25mmol) in l5OmL of 12 dichioromethane followed after 5 minutes by triethyl amine (5mL, 3 3mxnol).

13 After 2.5h at ambient temperature, the reaction mixture was washed with 14 water and the organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title product as a brown oil in quantitative 16 yield.

17 'H-NM (300 MIz, CDCI 3 d 1.71 31-1), 2.1 1(s, 3H), 3.28(s, 311), 5.47(s, 18 1 7.05 J =8.511z, 211), 7.50(d, J 8.2Hz, 211.

19 6-Bromo- 1 .4.4-trimgthyl-2-oxo- 1.2.3 .4-tektravdoUinoline (Intermediate 21 N-( 4 -bromoPhenyl)-N-methyl-3-methyl.2..butenamide 22 (Intermediate 54, 6.42g, 24mmol) was heated to 130'C and aluminum 23 chloride (5g, 37.4minol) was added in portions over 0.5h. The reaction 24 mixture was stirred for 1 hour at the same temperature and then cooled to 2S room temperature. Ice was added cautiously to the solid, followed by 26 -200mL of iced water. The reaction mixture was then extracted with ether 27 and dichioromethane (xlI) and the combined organic phase was dried 28 over anhydrous magnesium sulfate and evaporated in vacuc to yield a brown WO 02/18361 WO 0218361PCTIUSOI/25443 147 1 solid. The solid was treated with hexane-dichioromethafle and filtered to 2 afford 1.7g of product. The mother liquor was evaporated and purified by 00 3 flash column chromatography on silica gel (230-400 mesh) to afford 2.9g of 4 the title compound as a solid (total 72%).

'H-NM (300 MHz, CDCI 3 61.29(s, 6H), 2.49(s, 2H), 3.36(s, 3H1), 6.87(d, ri6 J 8.2Hz, 1HM, 7.36(dd, J 2.0, 8.5Hz, 1H1), 7.39(d, J =2.0Hz, 1H).

7 6-Bromo- 1.4-trimpthylspiro[2H- 1- 1.2.3 .4-tetrahydroquinoline-2. V (718 cycloropanel (Intermediate 56) 9 A stirred, cooled (-78 0 C) 3M solution of ethyl magnesium bromidde in ether (8.lmL, 24.25mmol) under argon was treated with anhydrous I1I tetrahydrofuran (2OmL) followed by a solution of titanium tetra-iso- 12 propoxide (3.l5mL, 10.2mmol) in tetrahydrofuran (lOmL). A solution of 6- 13 bromo-1I,4,4-trimethyl-2-oxo- 1,2,3 ,4-tetrahydroquinoline (Intermediate 14 2.6g, 9.7mmol) was cannulated into the reaction mixture and the solution was allowed to warm to room temperature overnight. It was then cooled in 16 an ice-bath, quenched with saturated aqueous amimonium chloride solution, 17 filtered over celite and the aqueous phase was extracted with diethyl ether 18 Wx). The combined organic phase was dried over anhydrous magnesium 19 sulfate, filtered and evaporated in vacuo to afford an orange oil. Flash column chromatography over silica gel (230-400 mesh) using 2-4% ethyl 21 acetate in hexane as the eluent afforded the title compound as an oil which 22 was -70% pure (1.7g, 63%) and 0.5g of recovered starting material.

23 'H-NVMR (300 MlHz, CDCl 3 8 0.58(t, J= 6.0Hz, 2H), 0-91(t, J= 24 2H), 1.35 6H), 1.70(s, 2H), 2.68 3H), 6.59 8.8Hz, 111), 7.16(dd, J= 2.3, 8.8Hz, Ili), 7.33(d, J= 2.3Hz, 111).

26 1 .4.4-Trimethyl-6-(trim-tylsilanyl)ethvnylspirorH- 1-1.2.3.4- 27 tetrahydroguinoline-2. 1 -cycloprop~aneI (Intermediate 57) WO 02/18361 WO 0218361PCT/US01/25443 148 1 Following general procedure D and using 6-bromo-1,4,4- 2 triniethylspiro[2H- 1 -1,2,3 ,4-tetrahydroquinoline- 2 1'-cyclopropane] 00 3 (Intermediate 56, 0.56g, 2mmol), (trimethylsilyl)acetylene l3rL, 4 8mmol), triethyl amine (4mL), anhydrous tetrahydrofuran copper(I)iodide (0.08g, .4mniol) and 6 dichlorobis(triphenylphosphine)palladium(ll) (0.28g, 0.4mmol), followed by 7 flash column chromatography over silica gel (230-400 mesh) using hexane- 8 2% ethyl acetate in hexane as the eluent, the title compound was obtained as 9 an oil (0.42g, 'H NMIR (300 MfHz, CDCl 3 8 0.023(s, 9H), 0.3 3(t, J= 6.IHz-, 2H), 0.7 1 J I1I 6. 1Hz, 2H), 1. 1 6H), 1.45(s, 2H), 2.41 3H), 6.31 J I1H), 12 6.96 (dd, J 8.5Hz, INH), 7. 10(d, J 2. 1Hz, 1H1).

13 Benzoic acid. 4-r(i .4.4-trimetylspiro[2H- 1-1.2.3 .4-tetrahydroguinoline- 14 2.1' -cclopropanel-6-yflee-tnyll-etI esteL (Compound 65, General Formnulal1) 16 Following general procedure E and using a solution of 1,4,4- 17 trimethyl-6-(trimethylsilanyl)ethynylspiro[2H- 1- 1,2,3 ,4-tetrahydroquinoline- 18 2,1'-cyclopropane] (Intermediate 57, 0.416g, 1.4mmol), methanol (lrniL), 19 ethyl acetate (2mL) and potassium carbonate (1.08g, mmol) a silyl deprotected acetylenic intermediate was obtained which was used directly 21 for the next step (0.25g, Following general procedure F and using part 22 of the acetylenic intermediate obtained as above (0.11 ig, 0. rnmol), ethyl-4- 23 iodo benzoate (Reagent A, 0.ll 2 g, 0.4mmol), triethyl amnine (lmL), 24 tetrahydrofuiran (2.5mL), copper(1)iodide (0-050g, O.26mrnol) and tetrakis(triphenylphosphine)palladium(o)(0.096g, 0. 1 7xnmol) followed by 26 flash column chromatography over silica gel (230-400 mesh) using 8% ethyl 27 acetate in hexane as the eluent and preparative HPLC on Partisil 10 silica WO 02/18361 WO 0218361PCT/IJS01/25443 149 1 column using 10% ethyl acetate in hexane as the mobile phase, the title 2 compound was obtained as a yellow oil (0.048g, 26%).

00 3 'H-NMR (300 MHz, CDCl 3 8 0.60 J= 6.1Hz, 2H), 0.99(t, J= 6.1Hz, 4 211), 1.37(s, 6H), 1.42(t, J= 7MHz, 3H), 1.73(s, 2H), 2.68(s, 3H), 4.40 J =7.0Hz, 2H), 6.61 J 8.8H1z, 111), 7.28 (dd, J 2.1, 8.511z, 1H), 7.42 (d, 6 J 2.1Hz, 111), 7.57(d, J 8.2Hz, 2H), 8.01l(d, J 8.2Hz, 2H).

7 Benzoic acid, 1.4.4-timetylspiro[2H- 1-1.2,3 .4-tetrahydrociuinoline-- 8 2.1 -cyclopropaneI-6-yl)ethyllI- (Compound 66, General Formula 1) 9 Following general procedure I and using benzoic acid, trimethylspiro[2H- 1- 1,2,3 ,4-tetrahydroqunoline-2, 1 '-cyclopropane] -6- 11 yl)ethynyl]-ethyl ester (Compound 65, 0.03g, 0.O8mmol), ethanol (2mL), 12 tetrahydrofluran (2mL) and 1M aqueous sodium hydroxide solution (lmL), 13 the title compound was obtained as a yellow solid (0.020Og, 67%).

14 1 H-NMIR (300 IvIHz, CD 3

COCD

3 8 0.60 J= M.Hz, 2H), 1.03(t, J 5.8Hz, 2H), 1.34(s, 6H), 1.74(s, 2H), 2.69(s, 3H), 6.60(d, J 8.5Hz, 1M1, 16 7.23 (dd, J 2.0, 8.4Hz, 1H), 7.39 J 2.0Hz, 1H), 7.5 8(d, J 8.2Hz, 17 2H1), 8.0l1(d, J= 8.211z, 2H).

18 Esterilication Metbods: 19 Method A: The carboxylic acid was combined with a solution of the desired 21 alcohol and concentrated suli~c acid (20 to I v/v) and the resulting 22 mixture or solution (0.75 to 1.0 M) heated to rcflux overnight. Thc solution 23 was cooled to room temperature, diluted with Et 2 O, and washed with 1120, 24 saturated aqueous NaHCO 3 and saturated aqueous NaCi before being dried 2S over MgSO 4 Concentration of the dry solution under reduced pressure 26 afforded the desired carboxylic, ester of sufficient purity to be used directly 27 in the next reaction.

28 WO 02/18361 PCT/US01/25443 S150 SMethod B: O 2 To a solution (0.67 to 1.OM) of the carboxylic acid in acetone was 3 added 1.1equivalents of the desired alkyl halide and 1.0 equivalents of solid 00 4 potassium carbonate. The resulting mixture was heated to reflux for 2h and then allowed to stir at room temperature overnight. The mixture was filtered C 6 and the filtrate concentrated under reduced pressure. The product was 7 isolated from the residue by column chromatography using silica gel as the C 8 solid phase.

9 Method C: A solution (lM) of the carboxylic acid in thionyl chloride was heated 11 at reflux until analysis of a reaction aliquot by IR spectroscopy showed the 12 absence of the aryl carboxylic acid carbonyl band 1705 1680 The 13 solution was cooled to room temperature and concentrated under reduced 14 pressure to give the crude acyl chloride.

The acyl chloride was dissolved in CH 2 C1 2 and the resulting solution 16 (0.5 to 0.75M) treated with 1.1 equivalents the desired alcohol and 17 equivalents ofpyridinc. After stirring overnight at room temperature the 18 solution was diluted with Et 2 O and washed with H 2 0, 10% aqueous HCI, 19 saturated aqueous NaHCO 3 and saturated aqueous NaCI before being dried over Na 2

SO

4 Concentration of the dry solution under reduced pressure 21 followed by column chromatography afforded the desired ester.

22 GENERAL PROCEDURE 1 (preparation of Enol ethers): 23 A solution (0.35 M) of the aryl ester in anhydrous THF was cooled to 24 0 OC and treated with 1.0 equivalents of Tebbe's Reagent ([4-chloro-.Lmethylene[bis(cyclopentadienyl)titanium]-dimethylaluminum] 0.5 M in 26 toluene). After 30 minutes the solution was warmed to room temperature 27 and stirred for 30 minutes before being carefully added to a 0.1 N NaOH 28 solution at 0 OC. This mixture was treated with hexanes and the solids WO 02/18361 PCT/US01/25443 0 151 1 removed by filtration through a pad of Celite. The solids were washed with O 2 hexanes and the filtrate passed through a second pad of Celite to remove any 3 newly formed solids. The organic layer was dried (Na2SO 4 and 00 4 concentrated under reduced pressure. The desired enol ether was isolated from the residue by column chromatography using 1-2% of Et 3 N added to C 6 the eluant. (note: prolonged exposure of the product to the column can 7 result in hydrolysis and formation of the corresponding methyl ketone.) C1 8 GENERAL PROCEDURE 2 (cvclopropanation of the enol ethers): 9 To a solution (0.3 M) of the enol ether in anhydrous Et 2 O was added 2.0 equivalent of Et 2 Zn (as a solution in hexanes) and 2.0 equivalents of 11 CH 2 1 2 The resulting solution was heated to reflux until analysis of a 12 reaction aliquot (by TLC or 'H NMR) indicated that all of the starting enol 13 ether had been consumed. (note: Additional equal amounts of Et 2 Zn and 14 CH 2 I, can be added to drive the reaction to completion.) Upon cooling to room temperature the reaction was carefully quenched by the addition of 16 saturated aqueous NH 4 C1. The resulting mixture is extracted with Et 2 O and 17 the combined organic layers washed with H20 and saturated aqueous NaCI 18 before being dried over Na 2

SO

4 and concentrated under reduced pressure.

19 The product is isolated from the residue by column chromatography.

1-Bromo-4-(1 -methoxyvinyl)-benzene: (Intermediate 58) 21 Using General Procedure 1; methyl 4-bromo-benzoate (600.0 mg, 22 2.78 mmols), and 5.6 mL of Tebbe's Reagent (794.0 mg, 2.78 mmols) 23 afforded 420.0 mg of the title compound as a colorless oil after 24 column chromatography (100% hexanes).

'H NMR (CDCl 3 5: 7.48 7.45 (4H, 4.64 (1H, d, J 2.9 Hz), 4.23 (1H, 26 d, J 2.9 Hz), 3.73 (3H, s).

27 1-Bromo-4-(1-methoxycyclopropvl)-benzene (Intermediate 59) 28 Using General Procedure 2; 1-bromo-4-(1-methoxyvinyl)-benzene WO 02/18361 WO 0218361PCTIUS01/25443 152 I (Intermediate 58,410.0Omg, 1.92 mmols), Et 2 Zn (711.3 mg, 5.76 mmols), 2 and CH 2 1 2 (1.54 g, 5.76 mmols) in 4.0 mL Et2O afforded 300.0 mg of 00 3 the titic compound as a colorless oil after chromatography EtOAc 4 hexanes).

'H NMR (CDC1 3 7.46 (2H, d, I 8.5 Hz), 7.18 (2H, d, J =8.5 3.21 6 (3H1, 1. 19 (2H, in), 0.94 (2H, in).

7 r4-(I' MethoxvcvcloprOpv1-phenygethynyll-trimnehylsilafle (Intermediate 8 9 Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)benzene (Intermediate 59, 300.0 mg, 1.32 inmol) in triethylamine (4 mL) 11 and anhydrous tetrahydrofuran (4 mL) was treated with copper(I)iodide 12 (93.0 mng, 0. 13 mmol) and then sparged with argon for 5 minutes.

13 Trirnethylsilyl acetylene (1.39 g, 14.2 mmols) was then added followed by 14 dichlorobis(triphenylphosphiine)palladium(1I) (93.0 ing, 0. 13 mmol). The resulting reaction mixture was heated to 70 'C for 60h. The title compound 16 (286.0 mg, 90%) was isolated by chromatography (0 3% EtOAc 17 hiexanes).

18 'H NM(CDC 3 7.3 5 (2H, d, J =7.2 Hz), 7.14 (2H, d, J 7.2 Hz), 3.14 19 (31H, 1.14 (2H, mn), 0.88 (2H, mn), 0.17 (9H, s).

1 -Ethynyl-4-( 1-methoxycclopropyI)-benzene (Intermediate 61) 21 Using General Procedure E; 1-methoxycyclopropyl)- 22 phenylethynyl]-trimnethylsilane (Intermediate 60, 285.0 mg, 1. 18 inmols) in 23 methanol (l0mL) was treated with potassium carbonate (100.0 mng, 0.72 24 mmol) and stirred overnight at ambient temperature. The crude alkyne (220 mng, 100%) was used directly in the next reaction.

26 1H NNM (CDCI 3 8: 7.46 (2H, d, J =8.2 Hz), 7.24 (2H1, d, J =89.2 Hz), 3.23 27 (3H, 3.06 (1H, 1.22 (2H, mn), 0.98 (2H, mn).

WO 02/18361 WO 0218361PCTIUS01/25443 153 I Ethyl 4-r4-( 1 methocopropy)-pheylethYllbfnz-at-e(Cmod 2 67, General Formula 2) 003 Using General Procedure F; 1-ethynyl-4.(1-methoxycycl0pr0pyl)- 4 benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 inmol) in triethyl amine (6 mL) was 6 treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged 'with argon 7 for 5 minutes. Dichlorobis(triphenylphosphine)palladium(ll) (109 mg, 0. 16 8 mrnol) was added and the reaction mixture was stirred overnight at room 9 temperature. Column chromatography EtOAc hexanes) afforded 135.0 mg of the title compound as an orange solid.

11 'H NMR (CDCI 3 8: 8.02 (211, d, J 8.2 Hz), 7.58 (2H, d, J 8.8 Hz), 7.52 12 (2H4, d, J =8.2 Hz), 7.28 (211, d, J' 8.8 Hz), 4.39 (2H1, q, J3= 7.1 3.25 13 (311, 1.40 (3H, t, J =7.1 Hz), 1.23 (2H, in), 1.00 (2H, in).

14 Methyl 1-methoxiycyclopropyl)-phenylethnyl]-phenyl -acetate (Compound 68, General Formula 2) 16 Using General Procedure F; l-ethynyl-4-(1-methoxycyclopropyl)- 17 benzene (Intermediate 61, 120.0 mg, 0. 56 mmol) and methyl-(4- 18 iodophenyl)-acetate (Reagent B, 154.0 mg, 0.56 inmol) in triethyl amine (6 19 mL) was treated with copper(I)iodide (3 5.0 mg, 0. 19 minol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) 21 (130 mg, 0.19 minol) was added and the reaction mixture was stirred 22 overnight at room temperature. Column chromatography EtOAc 23 hexanes) afforded 140.0 Mg of the title compound as an orange solid.

24 'H NMR (CDC1 3 5: 7.50 (4H1, d, J 8.1 Hz), 7.28 (4H1, d, J 8.1 Hz), 3.76 (3H, 3.64 (2H1, 3.25 (3H1, 1.22 (2H, in), 0.99 (211, in).

26 1-Methoxvcyclopropyl)-phenylgtvnvll-benzoic acid (Compound 69, 27 General Formula 2) WO 02/18361 WO 0218361PCTIUS01/25443 154 I Using General Procedure 1; a solution of ethyl14-[4-( 1- 2 methoxycycopropyl)pheyletnyfl]Vbelzoate (Compound 67, 110.0 mng, 00 3 0.34 inmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with 4 NaOH (160.0 mg, 4.0 namols, 2.0 mL. of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 85.0 mg of the 6 title compound as an orange solid.

7 'H NMR (CDCI 3 5: 8.05 7.66 7.56 (2H, d, J3 8.5 Hz), 7.35 8 (2H, d, J1 8.6 Hz), 3.22 (3H, 1.21 (2H, mn), 1.01 (211, in).

9 1 -Methoxvcycloprovl)-n2henvlethvpn-phevl} -acetic acid (Compound 70, General Formula 2) 11 Using General Procedure I; a solution of methyl 12 methoxycyclopropyl)-phenylethynyl]-phenyl) -acetate (Compound 68, 13 100.0 mag, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 14 treated with NaOH (160.0 mg, 4.0 nimols, 2.0 nL. of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 80.0 mg 16 of the title compound as an orange solid.

17 1H NMR (CDC1 3 8: 7.49 7.27 (4Hf), 3.66 (2H, 3.25 (3K1 1.22 18 (2H, in), 0.99 (211, in).

19 Isopropyl 4-bromobenzoate (Intermediate 62) Using General Esterification Procedure A; 4-bromobenzoic acid 21 (1.50 g, 7.46 n~ols) was combined with isopropyl alcohol to give 1.76 g 22 of the title compound as a colorless oil.

23 1H NMR (CDC1 3 8: 7.90 (211, d, J 8.5 Hz), 7.57 (2H, d, J 24 Hz), 5.24 (111, septet, J 6.2 Hz), 1.37 (6H, d, J 6.2 Hz).

1 -Bromo-4-( 1-isoprovoxvviny-benzene (Intermediate 63) 26 Using General Procedure 1; isopropyl 4-broxnobenzoate 27 (Intermediate 62, 780.0 nag, 3.20 inmols) and 6.4 mL. of Tebbe's Reagent WO 02/18361 WO 0218361PCT/US01/25443 155 1 (910.7 mg, 3.20 mmols) afforded 328.0 mg of the title compound as a 2 colorless oil after column chromatography (100% hexanes).

00 3 'H NMIR (CDCI 3 8: 7.46 (4H, 4.66 (1H, d, J 2.6 Hz), 4.40 (1H, septet, 4 J =6.2 Hz), 4.21 (lH, d, J =2.6 Hz), 1.34 (6H, d, J =6.2 Hz).

1-Bromo-4-( 1-isopropoxyccopoY-1-benzenle (Intermediate 64) 6 Using General Procedure 2; 1-bromo-4-(1-isopropoxWvinyl)-belzefe 7 (Intermediate 63, 328. 0 mg, 1.3 6 mnmols), Et.

2 Zn (33 5.9 mg, 2.72 mmols), 8 and C11 2 1 2 (728.0 mg, 2.72 mxnols) in 4.0 mL Et 2 O afforded 240.0 mg 9 of the title compound as a colorless oil after chromatography EtOAc hexanes).

II 'H NN'IR (CDCl 3 5: 7.43 (2H, d, J3 8.5 Hz), 7.27 (2H, d, J =8.5 Hz), 3.70 12 septet, J 6.2 Hz), 1. 18 (2H, in), 1.06 (6H, d, J 6.2 Hz), 0.91 (2H-, 13 mn).

14 r4-( 1-Isopropoxvcclopropy1)-Rhnylehyn1-trimethylsilane (Intermediate 16 Using General Procedure D; I -bromo-4-( 1-isopropoxycyclopropyl)- 17 benzene (Intermediate 64, 240.0 mg, 0.94 mmol) in triethylamine (8 mL) 18 was treated with copper(l)iodide (18.0 mg, 0.094 inmol) and then sparged 19 with argon for 5 minutes. Triinethylsilyl acetylene (0.70 g, 7.1 inmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (66.0 21 ing, 0.094 inmol). The resulting reaction mixture was heated to 70 TC for 22 days. The title compound (250.0 mng, 98%) was isolated by chromatography 23 (0 3% EtOAc hexanes) as an orange oil.

24 'H NMR (CDCI 3 6: 7.41 (2H, d, J3 7.9 Hz), 7.31 (2H, d, J3 7.9 Hz), 3.70 (1l-H, septet, J =6.2 Hz), 1. 18 (2H, in), 1.05 (61H, d, J 6.2 Hz), 0.93 (2H, 26 in), 0.94 (9H, s).

27 1 -Ethynvl-4-( I-isopropoxycvcloprov1-benzene (Intermediate 66) WO 02/18361 WO 02/831i1PCT/U SO1/25443 156 1 Using General Procedure E; [4-(1-isopropoxycyclopropyl)- 2 phenylethynyl]-tiflethylsilafle (intermediate 65, 260.0 mg, 0.96 Mmnol) in 00 3 methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 4 mmol) and stirred overnight at ambient temperature. -The crude alkyne (220 mg, 100%) was used directly in the next reaction.

6 'H NMR (CDCl 3 8: 7.45 (21H, d, J 8.8 Hz), 7.3 5 d, J3 8.8 Hz), 3.72 7 (1H, septet, J 6.2 Hz), 3.06 (111, 1.20 (211, in), 1.07 (6H, d, J 6.2 H~z), 8 0.95 (2H, in).

9 Ethyl 1 isopropcloropyl)-phenvletvyl]-benzoate (Compound 71, General Formula 2) 11 Using General Procedure F; 1-ethynyl-4-( 1-isopropoxycyclopropyl)- 12 benzene (Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo 13 benzoate (Reagent A, 73 1.0 mg, 0.63 inmol) in triethylamnine (8 mL) was 14 treated with copper(I)iodide (36.0 mg, 0. 19 minol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(1I) (133 mg, 0. 19 16 mmol) was added and the reaction mixture was stirred overnight at room 17 temperature. Column chromatography EtOAc hexanes) afforded 18 15 1.0 mg of the title compound as an orange solid.

19 'H NMR (GDCL 3 8: 8.02 (2H, d, 3 7.6 Hz), 7.58 (2H, d, J =7.6 Hz), 7.50 (2H1, d, J =7.8 Hz), 7.39 (2H, d, J =7.8 Hz), 4.39 (2H4, q, J 7.1 Hz), 3.74 21 (11H, septet, J1 6.2 Hz), 1.40 (3H, t, J 7.1 Hz), 1.22 (2H, in), 1.08 (611, d, 22 J3 6.2 Hz), 0.97 (211, in).

23 Metl (4-r4-'1 -isopropoxyclopropyl)-phenylethynvl-phenvl}-acetate 24 (Compound 72, General Formula 2) Using General Procedure F; I1-ethynyl-4-(l -isopropoxycyclopropyl)- 26 benzene (Intermediate 66, 95 .0 mng, 0.45 inmol) and methyl-(4- 27 iodophenyl)-acetate (Reagent B, 13 1.0 mg, 0.45 minol) in triethylamine (6 WO 02/18361 WO 0218361PCT/US01/25443 157 1 mL) was treated with copper(I)iodide (30.0 mg, 0.16mo) dspge 2 with argon for 5 minutes. Dichlorobis(triphefllphosphe)palldium(ll) 00 3 (111 mg, 0. 16 mmol) was added and the reaction mixture was stirred 4 overnight at room temperature. Column chromatography EtOAc hexanes) afforded 1 10.0 mg of the title compound as an orange oil.

6 'H NNMR (CDCI 3 8: 7.20 (411), 7.08 (2H1, d, J 7.0 Hz), 6.97 (211, d, J 7.9 7 Hz), 3.45 (1H, septet, J 6.2 Hz), 3.41 (311, 3.35 (2H, 0.91 (214, m), 8 0.79 (6H, d, J =6.2 Hz), 0.68 (2K1 in).

9 44r4-(lI -Isopropoxvcclopropvl)-phenvlethyMl-benzoic acid (Compound 73, General Formula 2) I I Using General Procedure 1; a solution of ethyl 12 isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound 71, 110.0 13 mng, 0.32 mnmol) in ethanol (3 mnL) and tetrahydrofuran (3 mL) was treated 14 with NaOH (120.0 mg, 3.0 rmols, 3.0 rnL of a IN aqueous solution) and stirred overnight at room temperature. Work-up afforded 89.0 mg of 16 the title compound as a yellow solid.

17 'H NMR (CDCI 3 5: 8.06 (211, d, J =8.2 Hz), 7.66 (211, d, J =8.2 Hz), 7.55 18 (2H1, d, J =8.2 Hz), 7.46 (2H1, d, J 8.2 Hz), 3.73 (IH, septet, J =6.2 Hz), 19 1. 18 (2H, in), 1.04 (611, d, J3 6.2 H1z), 0.99 (2H4, in).

(4-r44(1 -Isopropoycclopropyl)-,phenvlethynvll-,phenyI I -acetic acid 21 (Compound 74, General Formula 2) 22 Using General Procedure 1; a solution of methyl 23 isopropoxycyclopropyl)-PhenYlethynyl)-phenyl}I-acetate (Compound 72, 24 80.0 mng, 0.23 mmol) in ethanol (3 mL) and tetrahydrofiran (3 mL) was treated with NaOH (80.0 mng, 2.0 inmols, 2.0 mL of a 1N aqueous solution) 26 and stirred overnight at room temperature. Work-up afforded 48.0 mg 27 of the title compound as a solid.

WO 02/18361 WO 0218361PCT/US01/25443 158 1 'H-INMR (CDCl 3 )5 67.20 (2H, d, J =8.2 Hz), 7.19 (2H, d, J 8. 8 Hz), 7.09 2 (2H1, d, J 8.8 Hz), 6.98 (2HK d, J 8.2 Hz), 3.46 (1H, septet, J 6.2 Hz), 00 3 3.37 (2H, 0.92 (2H, in), 0.79 (6H, d, J 6.2 Hz), 0.67 (2H, mn).

4 Benzyl 4-bromobenzoale (Intermediate 67) Using General Esterification Method B; 4-bromobenzoic acid (2.01 6 g, 10.0 mmols), benzyl bromide (1.89 g, 11.1 inmols), and K 2 C0 3 (1.40 g, 7 10.0 minols) afforded 2.33 g of the title compound as a colorless 8 solid after column chromatography (3-10% EtOAc hexanes).

9 'H NMR (CDCI 3 6: 7.89 (2H, d, J 8.5 Hz), 7.52 (2H, d, J 8.5 Hz), 7.43 7.31 5.33 (2H, s).

I1 I -Bromo-4-(1-benzyloxiyvinl)-benzene (Intermediate 68) 12 Using General Procedure 1; benzyl 4-bromobenzoate (Intermediate 13 67, 920.0 mg, 3.16 minols) and 6.3 mL of Tebbe's Reagent (897.0 mng, 3.16 14 inmols) afforded 640.0 mg of the title compound after column chromatography (100% hexanes).

16 'H NMR (CDCI,) 6: 7.55 7.35 4.95 (2H, 4.73 (IH, d, J 2.9 Hz), 17 4.3 4(1 H,d, J =2.9Hz).

18 I-romo-4-Ll-be locclgp-pyl-belzene (Intermediate 69) 19 Using General Procedure 2; 1 -bromo-4-(1 -benzyloxyvinyl)-benzene (Intermediate 68, 280. 0 mg, 0 .97 mnmol), Et 2 Zn (247.0 mg, 2.0 mmnols), 21 and CH 2 I. (536.0 mg, 2.0 mnmols) in 2.0 ML Et 2 O afforded 159.0 mg (53%) 22 of the title compound as a colorless solid after chromatography 23 EtOAc hexanes).

24 'H NMIR (CDCI 3 8: 7.49 7.24 4.41 (2H, 1.29 (2H, in), 1.00 (2H, mn).

26 I-Benzloxc-YcloprOpyl)-phenlethvnyll-trimethyisilane (Intermediate 27 WO 02/18361 WO 0218361PCT/IUS01/25443 159 1 Using General Procedure D; 1-bromo-4-(-benzy1oxycyc1opropyl)- 2 benzene (Intermediate 69, 160.0 mg, 0.53 mmol) in triethylamnife (5 mL) 00 3 was treated with copper(I)iodide (10.0 mg, 0.05 rnnol) and then sparged 4 with argon for 5 minutes. Triniethylsilylacetylefle (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenyphosphine)paladiumT(II) (37.0 6 mrg, 0.05 mmol). The resulting reaction mixture was heated to 70T 0 for 7 The title compound (150.0 mng, 83%) was isolated by chromatography (0 8 3% EtOAc hexanes) as a pale-yellow oil.

9 'H NMR (CDCI 3 8: 7.21 (3H1, in), 7.09 7.01 (6H1, in), 4.18 (2H, 1.07 (21H, mn), 0.79 (2H, in), 0.02 (9H1, s).

111-Eth nyl-4-(l-benzloxcycvclonropyl)-benzele (Intermediate 71) 12 Using General Procedure E; [4-(l1-benzyloxycyclopropyl)- 13 phenylethynyl)-timethylsilane (Intermediate 70, 150.0 mg, 0.47 mmols) in 14 methanol (6 inL) was treated with potassium carbonate (100.0 mg, 0.72 inmol) and stirred overnight at ambient temperature. The crude alkyne (115 16 mg, 100%) was used directly in the next reaction.

17 'H NIMR (CDC1 3 8: 7.67 7.50 (211, d, J 8.2 Hz), 7.34 7.26 (711, in), 18 4.43 (211, 3.07 (111, 1.32 (2H1, mn), 1.04 (2H, in).

19 Ethyl 4-14-( 1-benzloxycyclopropyl)-phevlethynyll-benzoate (Compound 75, General Formula 2) 21 Using General Procedure F; 1 -ethynyl-4-( 1-benzyloxycyclopropyl)- 22 benzene (Intermediate 71, 60.0 mg, 0.24 inmol) and ethyl-4-iodo benzoate 23 (Reagent A, 72.0 mg, 0.26 rnmol) in triethylamine (4 mL) was treated with 24 copper(I)iodide (17.0 ing, 0.09 mmol) and sparged, with argon for 5 minutes.

Dichlorobis(triphenylphosphine)palladiuin(I) (61 mng, 0.09 rmol) was 26 added and the reaction mixture was stirred overnight at room temperature.

27 Column chromatography EtOAc hexanes) afforded 85 .0 mng (9 1 WO 02/18361 WO 0218361PCTIUS01/25443 160 1 of the title compound as an orange oil.

2 1H NMv~R (CDCI 3 6: 8.03 (2H, d, J3 8.2 Hz), 7.62-7.54 (4H, mn), 7.39-7.26 00 3 (7H, in), 4.47 (2H, 4.40 (2HK q, J 7.1 Hz), 1.42 (3H, t, J 7.1 Hz), 1.36 4 in), 1.07 (2H, in).

Metl f4f-1bM c~pov) t vih -acetate 6 (Compound 76, General Formula 2) 7 Using General Procedure F; 1 -ethynyl-4-(1 -benzyloxycyclopropyl)- 8 benzene (Intermediate 71, 60.0 mg, 0.20 mmiol) and methyl-(4- 9 iodophenyl)-acetate (Reagent B, 66.0 mng, 0.24 mmnol) in triethylamine mQ. was treated with copper(I)iodide (15.0 mg, 0.08 minol) and sparged 11 with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 12 mg, 0.08 nimol) was added and the reaction mixture was stirred overnight at 13 room temperature. Column chromatography EtOAc hexanes) 14 afforded 64.0 mig (8 of the title compound as a yellow oil.

'H NMR (CDCI 3 8: 7.52-7.47 (4H, mn), 7.37-7.25 (9H, in), 4.44 (2H, s), 16 3.70 (3H, 3.64 (2H, 1.32 (2H, mn), 1.06 (2H, mn).

17 4-F4-( 1-Benzyloxyclopropyv:h-pnletnyll-ben-zoi-c acid (Compound 18 77, General Formula 2) 19 Using General Procedure 1; a solution of ethyl benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound 75, 789.0 mg, 21 0.20 inmol) in ethanol (3 mL.) and tetrahydrofuiran (3 mL) was treated with 22 NaOH (80.0 mg, 2.0 inmols, 2.0 mL. of a IN aqueous solution) and stirred 23 overnight at room temperature. Work-up afforded 65.0 mig of the 24 title compound as a solid.

'H NMR (CDCI 3 8: 7.97 (2H, d, J 8.5 Hz), 7.67 (2H, d, J 8.7 Hz), 7.58 26 (2H1, d, J 8.5 Hz), 7.41-7.28 (7K1 mn), 4.44 (2H, 1.33 (2H1, mn), 1.12 (2H, 27 mn).

WO 02118361 WO 0218361PCT/US01/25443 161 1 1 -Benzylouyclprp1phfVehflle~Y}-ctcai 2 (Compound 78, General formula 2) 00 3 Using General Procedure 1; a solution of methyl 1- 4 benzyloxycyclopropyl)Phelylethyll.phel) -acetate (Compound 76, 45.0 mg, 0. 11 mrnol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 6 treated with NaQH (80.0 mg, 2.0 inmols, 2.0 mL of a IN aqueous solution) 7 and stirred overnight at room temperature. Work-up afforded 3 5. 0mg 8 (8 of the title compound as a pale-yellow solid.

9 1 H NMR (CDC1 3 8: 7.49 (4H1, in), 7.37-7.25 (9H, in), 4.44 (2H1, 3.66 (2H1, 1.32 (2H, in), 1.05 (211, in).

I1I Benzyl 4-bromo-2-netlbenzoate (Intermediate 72) 12 Using General Esterification Method C; 2-methyl-4-broino-benzoic 13 acid (2.15 g, 10.0 inmols) was refluxed for 3h with 10 ml SOC1 2 The 14 resulting solution concentrated under reduced pressure and the crude acyl chloride was combined with benzyl alcohol (1.08 g, l0.Ommols) and 16 pyridine (1.6 m.L, 20.0 rnmols) to give the title compound (2.4 g, 80%) after 17 work-up and column chromatography EtOAc hexanes) as a 18 colorless oil.

19 'H NMIR (CDCL 3 5: 7.81 (11H, d, J =8.5 Hz), 7.41-7.33 (7H, mn), 5.32 (211, 2.57 (3H, s).

21 4-Broino- -benzvloxvvinyl)-2-methylbenzene (Intermediate 73) 22 Using General Procedure 1; benzyl 4-bromo-2-methylbenzoate 23 (Intermediate 72, 840.0 mg, 2.77 mmols) and 5.4 mL of Tebbe's Reagent 24 (788.0 mng, 2.77 mmols) afforded 640.0 mg of the title compound after column chromatography (100% hexanes).

26 'H1 NMIR (CDCl 3 5: 7.38-7.19 (8H, in), 4.88 (2H1, 4.45 (11H, d, J 2.6 27 Hz), 4.25 (211, d, 3 2.6 Hz), 2.35 (3H1, s).

WO 02/18361 WO 0218361PCT/IJS01/25443 162 I 4-Bromo- 11 benzvox-CYccopropyl)-2-Ifethlbenzene (Intermediate 74) 2 Using General Procedure 2; 4-rm-1- bnylxvnl--ehl 00 3 benzene (Intermediate 73,400. 0 mng, 1.32 mmols), Et 2 Zn (325.0 mg, 2.63 4 mmols), and 011212 (704.0 mg, 2.63 minds) in 4 mL Et 2 O afforded 380.0 mg of the title compound as a colorless oil after chromatography 6 EtOAc hexanes).

7 'H NMR (CDCd 3 8: 7.42-7.20 (8H, mn), 4.31 2.5 8 (3H, 1.25 (2H, 8 mn), 0.94 (2H1, m).

9 4-(I-e~oWco2oy)3mty-hyeyl-rmt 1l (Intermediate 11 Using General Procedure D; 4-broino- 1 -benzyloxycyclopropyl)- 2 12 methyl-benzene (Intermediate 74, 320.0 mg, 1.00 inmol) in triethylamine 13 (8 mL) was treated with copper(I)iodide (19.0 mg, 0. 1 mmol) and then 14 sparged with argon for 5 minutes. Trimethylsilylacetylene: (0.70 g, 7.1 mmols) was then added followed by dichlorobis- 16 (triphenylphosphine)palladium(fl) (70.0 mng, 0.05 nimol). The resulting 17 reaction mixture was heated to 7000C for 5d. The title compound (300.0 mg, 18 89%) was isolated by chromatography (0 2% EtOAc hexanes).

19 'H NMvR (CDC1 3 8: 7.34-7.13 (8H, in), 4.24 (211, 2.52 (311, 1.20 (211, mn), 0.88 (2H1, in), 0.25 (9H, s).

21 4-Etyni- 1-(1 -benzvoxycclonropyl)-2-methyl-benzene (Intermediate 22 76) 23 Using General Procedure E; 1-benzyloxycyclopropyl)-3-methyl- 24 phenylethYnyll-trimethylsilane (Intermediate 75, 300.0 mng, 0.95 inmols) in methanol (6 niL) was treated with potassium carbonate (120.0 mg, 0.87 26 nimol) and stirred overnight at ambient temperature. The crude alkyne (185 27 mng, 79%) was used directly in the next reaction.

WO 02/18361 WO 0218361PCTIUS01/25443 163 1 11H NMR (CDCl 3 8: 7.37-7.16 (8H, in), 4.27 (211, 3.07 (1H1, 2.55 2 (3H, 1.21 (211, in), 0.92 (211, in).

3 tyl4414-(1b .benzloxvcoprgopl)3mnethV1Phenylethynyll:benz-Oate 4 (Compound 79, General Formula 2) Using General Procedure F; I1-ethynyl-4-(1 -benzyl0xycycl0propyl)- 3 6 methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and ethyl-4-iodo 7 benzoate (Reagent A, 95.0 mg, 0.34 mmnol) in triethylamine (6 mL) was 8 treated with copper(I)iodide (23.0 mng, 0.12 mmol) and sparged with argon 9 for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0. 11 rnrol) was added and the reaction mixture was stirred overnight at room I1I temperature. Column chromatography EtOAc hexanes) afforded 12 68.0 mng of the title compound.

13 'H NMR (CDCI 3 5: 8.03 (211, d, J =8.2 Hz), 7.5 8 (2H, d, J 8.2 Hz), 14 7.33-7.16 (8H, mn), 4.39 (2H1, q, J 7.1 Hz), 4.29 (2H1, 2.57 (3H, 1.40 (3H, t, J 7.1 Hz), 1.22 (2H1, in), 0.93 (2H, in).

16 Me-tyl 1-[4-(l1 benzvoxvccoropvl3-methyl-phenaylthyl1phfLnyl)- 17 acetate (Compound 80, General Formula 2) 18 Using General Procedure F; I -ethynyl-4-( 1-benzyloxycyclopropyl)-3- 19 methyl-benzene (Intermediate 76, 90.0 mg, 0.34 nmol) and methyl-(4iodophenyl)-acetate (Reagent B, 95.0 mng, 0.34 mmol) in triethylamine 21 mL) was treated with copperQI)iodide (22.0 mg, 0. 11 mmol) and sparged 22 with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(1I) 23 mng, 0. 11 inmol) was added and the reaction mixture was stirred overnight at 24 room temperature. Column chromatography EtOAc hexanes) afforded 90.0 mng (7 of the title compound as a pale-yellow oil.

26 'H1 NMR (CDC1 3 8: 7.49 (2H, d, J 8.2 Hz), 7.32-7.16 (1011, mn), 4.28 27 (2K1 3.70 3.64 (211, 2.56 (3K1 1.22 (2H1, in), 0.92 (2H, in).

WO 02/18361 WO 0218361PCT/US01/25443 164 1 l-BenzIoxcyclopropyl)-3-mthylpheflyI tLnly'benzoic acid 2 (Compound 81, General Formula 2) 003 Using General Procedure 1; a solution of ethyl 4-[4-(l1- 4 benzyloxycyclopropy)3-mthyl-phenlethyfl1Ibenzoate (Compound 79, 68.0 mg, 0. 17 nimol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 6 treated with NaOH (360.0 mg, 9.0 nimols, 3.0 mL of a 3N aqueous solution) 7 and stirred overnight at room temperature. Work-up afforded 48.0 mg 8 of the title compound as a solid.

9 'H NMR (CDCI 3 8.10 (2H, d, J S.1I Hz), 7.63 (2H, d, J =8.1 Hz), 7.44- 7.16 (8H, in), 4.29 (2H, in), 2.58 (3H1, 1.24 (2H, in), 0.94 (2H, m).

11I 14-r4-( 1-Benzyloxycyclopropy)3-mthyllphnylethYflI-phenyl-aceC 12 acid (Compound 82, General Formula 2) 13 Using General Procedure I; a solution of methyl 14 benzyloxycyclopropyl)-3-mcthyl-phenylethyny]-pheny} -acetate (Compound 80, 75.0 mg, 0.18 inmol) in ethanol (3 mL) and 16 tetrahydrofuran (3 mL) was treated with NaOlH (120.0 ing, 3.0 minols, 17 ML of a IN aqueous solution) and stirred overnight at room temperature.

18 Work-up afforded 30.0 mng of thle title compound.

19 'H NMvR(CDCl 3 8: 7.51 (2H, d, J 8.2 Hz), 7.42 (1H1, 7.33-7.17 (9H, in), 4.36 (2H, 3.67 (2H, 2.57 (3H1, 1.23 (2H, in), 0.94 (2H, in).

21 Isgoropy 3 -inthyl-4-bromobenzoate (Intermediate 77) 22 Using General Esterification Procedure A; 4-bromo-2-incthylbenzoic 23 acid (1.6 g, 7.4 iniols) was combined with isopropyl alcohol to give 1.5 g 24 of the title compound as a colorless oil.

'H NMR (CDCI 3 8: 7.76 (1H, d, J =8.2 Hz), 7.40 (111, d, J =7.4 Hz), 7.37 26 (1H, dd, J1 1.4, 8.2 Hz), 5.23 (1H, septet, J 6.2 Hz), 2.57 (3H, 1.37 27 (6H, d, J=6.2 Hz).

WO 02/18361 WO 0218361PCTIUS01/25443 0 165 1 4-Bromo- 14(1isopropoxyvinyl-2-meth]-benlzene (Intermediate 78) 2 Using General Procedure 1; isopropyl 2-methyl-4-bromobelzoate 00 3 (Intermediate 77, 800.0 mg, 3.11 rmmols) and 6.2 mL of Tebbe's Reagent 4 (885.2 mg, 3.11 mmols) afforded 595.0 mg of the title compound as a colorless oil after column chromatography (100% hexanes).

6 1H1 NNM (CDCl 3 8: 7.3 1-7.25 (2H, in), 7.16 (11H, d, J 8.2*Hz), 4.34 (IH, 7 septet, J3 6.0 Hz), 4.31 (11-1, d, J3= 2.1 Hz), 4.18 (1H1, d, J 2.1 Hz), 2.33 8 (3H, 1.31 (6H, d,J 94-Bromo- 1-isoproNyxvcclorol)-2-methyl-belzef (temediate 79) 11 Using General Procedure 2; 4-bromo-1-(1-isopropoxyvinyl)- 2 12 methyl-benzene (Intermediate 78, 389. 0 mg, 1.53 ummols), Et 2 Zn (376.6 13 mg, 3.05 inmols), and C11 2 1 2 (817.0 mg, 3.05 minols) in 3.0 mL Et 2

O

14 afforded 340.0 mg of the title compound as a colorless oil after chromatography EtOAc hexanes).

16 'H1 NMIR (CDC1 3 8: 7.33 (114, d, J 2.3 Hz), 7.24 (1I-H, dd, J3 2.3, 8.2 Hz), 17 7.13 (IH1, d, J3 8.2 Hz), 3.57 (1H1, septet, J 6.1 Hz), 2.49 (3H1, 1.00 18 (2H, in), 0.97 (6H, d, J 6.1 Hz), 0.82 (2H, in).

19 F4-( 1-Isopropoxycvclopropvl)3-methyl-phenvl ty v "trIetvsilane (Intermediate 21 Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)- 22 2-metbyl-benzene (Intermediate 79, 250.0 mng, 0.95 inmol) in triethylamine 23 (8 mL) was treated with copper(I)iodide (19.0 mg, 0.10 inmol) and then 24 sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 inmols) was then added followed by dichiorobis- 26 (triphenylphosphine)palladium(1I) (70.0 mng, 0. 1 romol). The resulting 27 reaction mixture was heated to 70 OG for 5d. The title compound (250.0 ing, WO 02/18361 WO 0218361PCTIUSOI/25443 0 166 1 91%) was isolated by chromatography (0 3% EtOAc hexanes).

2 1 11 MR (CDCl 3 8: 7.32-7.17 (311 in), 3.56 (111I, septet, J 6.2 Hz), 2.48 00 3 (3H, 1.00 (211, mn), 0.95 (6H, d, J =6.2 Hz), 0.83 (2H1, in), 0.24 (911, s).

4- 4-Ehyl- 1 isopropoLxycclopro~yfl--m2intyl ~I e (Intermediate 81) ID6 Using General Procedure E; [4-(1-isopropoxycyc1opropyl)-3-methyl- 7 phenylethynyl]-trinethylsilafle (Intermediate 80, 250.0 ing, 0.87 minol) in 8 methanol (10 ruL) was treated with potassium carbonate (100.0 mg, 0.72 9 minol) and stirred overnight at ambient temperature. The crude alkyne (180 mg, 98%) was used directly in the next reaction.

II '1H NMR (CDCI 3 8: 7.32 (1H, 7.23 (2H, mn), 3.57 (1lH, septet, J =6.2 12 Hz), 3.05 (1H1, 2.50 (311, 1. 11 (2K1 in), 0.96 (6H, d, J =6.2 Hz), 0.83 13 (2H, in).

14 Ethyl 4-f I isoropgoxcpropfl)3-meh1heYlglynlYWbgrtzoate (Compound 83, General Formula 2) 16 Using General Procedure F; 4-ethynyl- 1 -isopropoxycyclopropyl)- 17 3-methyl-benzene (Intermediate 81, 80.0 mg, 0. 13 minol) and ethyl-4-iodo 18 benzoate (Reagent A, 100.0 mng, 0.36 mmol) in triethylainine (5 mL) was 19 treated with copper(I)iodide (25.0 mng, 0. 13 inmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (91 ing, 0. 13 21 minol) was added and the reaction mixture was stirred overnight at room 22 temperature. Column chromatography EtOAc hexanes) afforded 23 75.0 mg of the title compound as an orange solid.

24 'H NMR (CDC1 3 8: 8.02 (2H1, d, J =8.2 Hz), 7.57 (211, d, J 8.2 Hz), 7.39 (111, 7.29-7.20 (2H, mn), 4.39 (2H1, q, J =7.1 Hz), 3.60 (111, septet, J 6.2 26 Hz), 1.40 (3H1, t, J 7.1 Hz), 1.13 (211, mn), 0.97 (611, d, J1 6.2 Hz), 0.87 27 (2H1, in).

WO 02/18361 WO 0218361PCT/US01/25443 0 167 I Methyl ([441 -isopropoxycyclopro lY-3-mcthy1-pheiylttyn]-phe-nvYI 2 acetate (Compound 84, General Formula 2) 00 3 Using General Procedure F; Il-ethyny1-4( isopropoxycyc1OProPYl)- 4 3-methyl-benzene (Intermediate 81, 100.0 mg, 0.47 mmol) and methyl-(4iodophenyl)-acetate (Reagent B, 129.0 mg, 0.45 nimol) in triethylamine (6 6 rnL was treated with copper(I)iodide (3 0.0 mg, 0. 16 nunol) and sparged 7 with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladillm(fl) N 8 (110 mg, 0. 16 mol) was added and the reaction mixture was stirred 9 overnight at room temperature. Column chromatography EtOAc hexanes) afforded 120.0 mg (7 of the title compound.

I I 'H NMR (CDCI 3 5: 7.48 (2H, d, J =8.5 Hz), 7.36 7.29-7.22 (4H1, 12 in), 3.70 (3H, 3.63 (2H, 3.60 (1H1, septet, J 6.2 Hz), 2.52 (311I, s), 13 1.09 (2L in), 0.97 (611, d, J3 6.2 Hz), 0.86 (2H, mn).

14 4-r4-( 1 Isopropoxycycloropy)-3-netIpenylthM1-belzoic acid (Compound 85, General Formula 2) 16 Using General Procedure 1; a solution of ethyl 17 isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 83, 18 60.0 mg, 0. 17 mmol) in ethanol (2 niL) and tetrahydrofuran (2 mL) was 19 treated with NaOH (80.0 mig, 2.0 inmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 38.0 mg 21 of the title compound as a colorless solid.

22 '11 NMR (d 6 -acetone) 8: 8.06 (2H1, d, J =8.5 Hz), 7.66 (211, d, J =8.5 Hz), 23 7.42 (1H, 7.35 (211, in), 3.59 (111, septet J =6.2 Hz), 2.52 (3H1, 1.07 24 (211, in), 0.93 (611, d, J =6.2 Hz), 0.88 (211, in).

B-be I-4( -acetic 26 acid (Compound 86, General Formula 2) 27 Using General Procedure I; a solution of methyl WO 02/18361 WO 0218361PCT/US01/25443 0 168 1 isopropoxycyclopropyl)-3-methY[-PhenYlethynyl1IphenyI I acetate 2 (Compound 84, 100.0 mg, 0.28 minol) in ethanol (3 niL) and 00 3 tetrahydrofuraii (3 mL) was treated with NaOH (120.0 mg, 3.0 minols, 3 .0 4 niL of a IN aqueous solution) and stirred overnight at room temperature.

Work-up afforded 60.0 mg of the title compound as a colorless solid.

6 'H NMvfl (CDCI 3 5: 7.48 (211, d, J 7.6 Hz), 7.36 (1H, 7.25 (4H, in), 7 3.65 (2H, 3.60 (LH, septet, J =6.2 Hz), 2.51 (3H, 1. 12 (2H1, 0.97 8 (6H1, d, J 6.2 Hz), 0.86 (2H, mn).

9 2.2-Dimnetylprpyl 2:Methyl-4-bromobenzoate (Intermediate 82) Using General Esterification Method C; 2-inethyI-4-brono-benzoic I1I acid (1.82 g, 8.47 minols) was refluxed for 3h with 10 iL SOCl 2 The 12 resulting solution was concentrated under reduced pressure and the crude 13 acyl chloride combined with 2,2-dimethylpropanol (0.75 g, 8.47 iniols) and 14 pyridine (1.4 mL, 16.9 inmols) to give the title compound (1.64 g, 68%) after work-up and column chromatography EtOAc hexanes) as a 16 colorless oil.

17 'H NMR (CDC1 3 5: 7.81 (11H, d, J =8.2 Hz), 7.42 (1IH, J 2. 0 Hz), 7.3 9 18 (1H, cid, J 8.2 Hz), 3.99 (2H, 2.60 (3H1, 1.03 (9H1, s).

19 4-Bromo- I-ri -(2.2-dime~tvipropyloxyvinvll-2-ineth'yl-benzene (Intermediate 83) 21 Using General Procedure 1; 2,2-dimethylpropyl 2-methyl-4- 22 broinobenzoate (Intermediate 82, 820.0 mg, 2.87 inmols) and 5.8 mL of 23 Tebbe's Reagent (817.0 mg, 2.87 nimols) afforded 800.0 mg of the 24 title compound as a colorless oil after column chromatography (100% hexanes). 'H NMR (CDC1 3 8: 7.32 (IH, d, J =2.0 Hz), 7.28 (11-1, cid, J 26 2.0, 8.2 Hz), 7.18 (11H, d, J =8.2 Hz), 4.27 (11H, d, J =2.1 Hz), 4. 10 (11H, d, 27 J 2.1 Hz), 3.43 (211, 2.33 (3H, 0.98 (9H, s).

WO 02/18361 WO 0218361PCTIUS01/25443 169 1 4-Bromo-11- (2,2-direthylpryly)yCprP12ehbnze 2 (Intermediate 84) 00 3 Using General Procedure 2; 4-bromo- 1-Li (2,2-dimethylpropyloxy)- 4 cyclopropyl-2-methyl-belzefe (Intermediate 83, 400. 0 mg, 1.43 mmols), Et 2 Zn (353.2 mg, 2.86 minols), and CH 2 1 2 (760.0 mg, 2.86 mmols) in 6 mL. Et 2 O afforded 370.0 mg of the title compound as a colorless oil 7 after chromatography EtOAc hexanes).

8 'H1 NMR (CDCI 3 8: 7.36 (1H, s),7.27 (1H, di, J 8.5 Hz), 7.09 (11H, d, J 9 7.9 Hz), 2.86 (2H, 2.52 (3H, 1.08 (2H, in), 0.83 (2H, in), 0.80 s).

R-f 14 1-(2,2-Dimethylpropyioxy'-gyclopropyl-3-mth1helthylll.

I I trimethylsilane (Intermediate 84a) 12 -Using General Procedure D; 4-bromo-1.{1-(2,2-dirnethylpropyloxy)- 13 cyclopropyl]-2-methyl-benzene (Intermediate 84, 255.0 mng, 0.86 inmol) in 14 triethylamine (8 mL.) was treated with copper(I)iodide (17.0 mng, 0.09 nimol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 16 7.1 mmnols) was then added followed by dichlorobis- 17 (triphenylphosphine)palladium(ll) (63.0 mg, 0.09 nimol). The resulting 18 reaction mixture was heated to 70 -C for 5d. The title compound (220.0 mng, 19 81 was isolated by chromatography (1 EtOAc hexanes).

'H NN4R (CDCI 3 5: 7.30 (IH, 7.21 (1H1, d, J3 7.6 Hz), 7.12 (lH, d, J 21 8.6 Hz), 2.80 (2H, 2.47 (3K, 1.05 (2H, mn), 0.82 in), 0.75 (9H,s) 22 0.24 (911, s).

23 4-Ethyyl- 1-[14-2,2-dimettylpronvlxv-qclopropyll-2-methyl-benzene 24 (Intermediate Using General Procedure E; I-(2,2-dm ethyipropyloxy)- 26 cyclopropyl]]-3-methyl-phenylethynyl)-timethylsilane (Intermediate 84a, 27 220 .0 mng, 0.83 minol) in methanol (10 mL) was treated with potassium WO 02/18361 WO 0218361PCTIUS01/25443 170 1 carbonate (80.0 mg, 0.58 mmol) and stirred overnight at ambient 2 temperature, The crude alkyne (15 5 mg, 7 was used directly in the next 00 3 reaction.

4 'H NMR (CDC1 3 5: 7.32 (IH, 7.24 (1HK d, J =7.1 Hz), 7.15 (11-1, d, J 7.1 Hz), 3.04 (1H, 2.83 2.49 (3H1, 1.06 (2H1, in), 0.83 (2H, in), 6 0.76 (911, s).

7Ehyl 4444 (2..2-djmethylprop Ixy-cyclopropyll- 3 -met- 8 phe gylthnyll-benzoate (Compound 87, General Formula 2) 9 Using General Procedure F; 4-ethynyl-1-[l-(2,2-dimethylpropyloxy)cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and 11 ethyl-4-iodo benzoate (Reagent A, 86.0 mg, 0.31 rmnol) in triethylamnine 12 niL) was treated with copper(I)iodide (2 1.0 mg, 0. 11 mrnol) and sparged 13 with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladiunl(II) 14 (78 mng, 0. 11 mniol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography EtOAc 16 hexanes) afforded 60.0 mg of the title compound as an orange solid.

17 'H NMR (CDCI 3 8: 8.02 (2H, d, J =8.4 Hz), 7.56 (2H, d, J 8.4 Hz), 7.38 18 (1H, 7.30 (1H, dd, J3 1. 1, 8.0 Hz), 7.20 (1H, d, J =8.0 Hz), 4.3 8 (2H, q, 19 J =7.1 Hz), 2.84 (21H, 2.52 (3H, 1.40 (3H, t, J 7.1 Hz), 1.07 (2H, in), 0.84 (2H, in), 0.77 (9H1, s).

21 Methyl {4-[4-[l142.2-dimetlpropyloxy)-cyclopronyll-3-rneth J- 22 phenvlethynvl-phenyl} -acetate (Compound 88, General Formula 2) 23 Using General Procedure F; 4-ethynyl- I -[1-(2,2-dimethylpropyloxy)- 24 cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mng, 0.31 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 86.0 mng, 0.31 minol) in 26 triethylamine (6 mL) was treated with copper(I)iodide (2 1.0 mg, 0. 11 inrol) 27 and sparged with argon for 5 minutes.

WO 02/18361 PCTIUS01/25443 171 I1 Dichlorobis(triphenylphosphine)palladium(W) (78 mg, 0.11 mmol) was 2 added and the reaction mixture was stirred overnight at room temperature.

3 Column chromatography EtOAc hexanes) afforded 100.0 mg (83%) 00 4 of the title compound.

'H NMR (CDCl 3 8: 7.48 (2H, d, J 7.9 Hz), 7.36-7.24 (4H, 7.18 (1H, 6 d, J 7.9 Hz), 3.70 (3H, 3.63 (2H, 2.84 (2H11, 2.51 (3H, 1.07 7 (2H, 0.83 (2H, 0.77 (9H, s).

N 8 4-4- 1-(2.2-Dimethylprovpyoxy)-cycloprovll-3-methyl-henvlethvnvll- 9 benzoic acid (Compound 89, General Formula 2) Using General Procedure I; a solution of ethyl 11 dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate 12 (Compound 87, 60.0 mg, 0.15 mmol) in ethanol (3 mL) and 13 tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 14 mnL of a IN aqueous solution) and stirred overnight at room temperature.

Work-up afforded 24.0 mg of the title compound as a colorless solid.

16 'H NMR (CDCl 3 6: 8.06 (2H, d, J= 7.9 Hz), 7.65 (21H1, d, J= 7.9 Hz), 7.42 17 (1H, 7.33 (2H, 2.89 (2H, 2.53 (3H, 1.07 (2H, mn), 0.90 (2H, m), 18 0.77 (9H, s).

19 {4-[4-[1-(2,2-Dimtylprol )-ycpropll-3-metyl-ph ithyllphenvl}-acetic acid (Compound 90, General Formula 2) 21 Using General Procedure I; a solution of methyl 22 dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl -acetate 23 (Compound 88, 95.0 mg, 0.24 mmol) in ethanol (3 mL) and 24 tetrahydrofuran (3 mnL) was treated with NaOH (120.0 mg, 3.0 mmols, mL of a IN aqueous solution) and stirred overnight at room temperature.

26 Work-up afforded 49.0 mg of the title compound as a colorless solid.

27 'H NMR (CDC1 3 6: 7.49 (2H, d, J 8.2 Hz), 7.36 (1H, 7.27 (3H, m), WO 02/18361 WO 0218361PCT/US0l/25443 172 1 7.18 (114, d, J =7.9 Hz), 3.66 (2H, 2.84 (2H, 2.51 (3H, 1.07 (21H, 2 mn), 0.83 (2H1, in), 0.77 (9H1, s).

00 3 BenzV1 4-bromo-2-ethyl-beflzoate (Intermediate 86) 4 Using General Esterification Method B; 4-bromo-2-ethyl-belzoic acid (0.98 g, 4.25 ninols), benzyl bromide (0.80 g, 4.68 minols), and KC0 3 6 (0.64 g, 4.68 mnaols) afforded 1.0 g of the title compound after 7 column chromatography EtOAc hexanes).

8 'H1 NMvR (CDCI 3 8: 7.76 (111, d, J =8.5 Hz), 7.41-7.33 (711, in), 5.32 (211, 9 2.95 (211, q, J 7.6 Hz), 1.20 (3H1, t, J =7.6 Hz).

4-Bromo-1 -benzloxyviny)-2eth1-belzefe (Intermediate 87) 11 Using General Procedure 1; beazyl 4-bromo-2-ethylbenzoate 12 (Intermediate 86, 1.20 g, 3.78 nimols) and 7.6 mL of Tebbe's Reagent 13 (1.08 g, 3.78 minols) afforded 800.0 mg of the title compound after 14 column chromatography (100% hexanes).

'H1 NMR (CDCl 3 )S :7.37-7.17 (811, 4.88 (211, 4.43 (1H, d, S3=2.1 16 Hz), 4.25 (11H, d, J 2.1 Hz), 2.71 (2H, q, J 7.6 Hz), 1. 18 (311, t, J 7.6 17 Hz).

18 4-Bromo-l1-(1 -ben yclprpvL'M)-2-ethyl-benzene (Intermediate 88) 19 Using General Procedure 2; 4-bromo- 1 -benzyloxyvinyl)-2-ethylbenzene (Intermediate 87, 330. 0 ing, 1.04 nixols), Et 2 Zn (257.0 mg, 2.08 21 inmols), and CH 2 1 2 (557.0 mg, 2.08 minols) in 4 mL Et 2 O afforded 241.0 mg 22 of the title compound as a colorless oil after chromatography 23 EtOAc hexanes).

24 'H1 NMR (CDC 3 8: 7.43-7.15 (8H1, mn), 4.27 (211, 3.00 (2fl, q, J3 7.6 Hz), 1.29-1.21 (5H1, in), 0.90 (2H, mn).

26 f4-(l1 Benzvoxycclopropvfl3-e-tylphenvletyll-triMthylsilanl 27 (Intermediate 89) WO 02/18361 WO 0218361PCTIUS01/25443 0 173 IUsing General Procedure D; 4-bromo-1 -benzyloxycycopropyl)- 2 2 ethyl-benzene (Intermediate 88, 220.0 mg, 0.66 mmol) in triethylamidne (8 00 3 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and then 4 sparged with argon for 5 minutes. TrimethylsilylaCetylefle (0.70 g, 7.1 mmols) was then added followed by dichiorobis- 6 (triphenylphosphifle)palladiurn(I) (50.0 mg, 0.07 nimol). The resulting 7 reaction mixture was heated to 70 'C for 5d. The title compound was 8 isolated by chromatography (0 EtOAc hexanes).

9 'H NNM (CDCl 3 8: 7.41-7.13 (8H1, in), 4.24 (2H1, 2.98 q, J =7.6 Hz), 1.25 t, J =7.6 Hz), 1.20 (2H1, in), 0.90 (2H, in), 0.26 (9H, s).

I1I 4-Ethynyl- 141 -benzyloxycyclopopy)-2ethYl-beflzene (Intermediate 12 Using General Procedure E; 14-(l1-benzyloxycyclopropyl)-3 -ethyl- 13 phenylethynyl]-trimethylsilane (intermediate 89, 240 mg, 0.69 nimol) in 14 methanol (6 rnL) wats treated with potassium carbonatc: (10.0 mg, 0.72 mxnol) and stirred overnight at ambient temperature. The crude alkcyne (190 16 mng, 99%) was used directly in the next reaction. 'H1 NUVR (CDC1 3 8: 7.43- 17 7.15 (8H1, mn), 4.27 (2H4, 3.08 (1H1, 3.01 (2H, q, J =7.6 Hz), 1.26 (3H1, 18 t, J 7.6 Hz), 1.22 (2H, in), 0.92 (2H, in).

19 Etyl -benzyloxyycloprolh3-etl-phevylethynvl-benzoate (Compound 91, General Formula 2) 21 Using General Procedure F; I -ethynyl-4-( I-benzyloxycyclopropyl) -3- 22 ethyl-benzene (Intermediate 90, 90.0 mng, 0.33 nimol) and ethyl-4-iodo 23 benzoate (Reagent A, 100.0 mg, 0.36 minol) in triethylarnine (5 ML) was 24 treated with copper(I)iodide (2 1.0 mng, 0. 11 inmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladiurn(II) (77 mg, 0. 11 26 mi-nol) was added and the reaction mixture was stirred overnight at room 27 temperature. Column chromatography EtOAc hexanes) afforded WO 02/18361 WO 0218361PCT/USOI/25443 174 1 100.0 mg of the title compound.

2 'H1 NMR (CDCI 3 8: 8.03 (211, d, J =7.9 Hz), 7.59 (2H1, d, J =7.9 Hz), 7.49 00 3 (1H, 7.36-7.16 (7H, in), 4.38 (2H1, q, J 7.1 Hz), 4.28 (2H1, 3.04 (211, 4 q, J 7.6 Hz), 1.40 (3H1, t, J =7.1 Hz), 1.29 (3K1 t, J =7.6 Hz), 1.23 (2H1, in), 0.94 (2H, in).

6 Mty I benzloxyycoropy'~~t~~ellt~~Fh l

-L

7 acetate (Compound 92, General Formula 2) 8 Using General Procedure F; I -ethynyl-4-(1 -benzyloxycyclopropyl)- 3 9 ethyl-benzene (Intermediate 90, 107.0 mg, 0.39 inmol) and methyl-(4iodophenyl)-acetate (Reagent B, 110.0 mg, 0.39 ramol) in triethylamine 11I mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmnol) and sparged 12 with argon for 5 minutes. Dichlorobis(triphenylphosphifle)palladium(fl) (91 13 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at 14 *room temperature. Column chromatography EtOAc hexanes) afforded 130.0 mg of the title compound as a pale-yellow oil.

16 'H NMR (CDCI 3 8: 7.49 (311, in), 7.32-7.16 (9H, in), 4.28 (2H1, 3.71 17 (3H1, 3.64 (2H, 3.03 (2K1 q, J =7.6 Hz), 1.32-1.23 in), 0.94 (211, 18 in).

19 -Benzylox;ycyclopropy1)-3-etl-phenylethvnll-benzoic acid (Compound 93, General Formula 2) 21 Using General Procedure 1; a solution of ethyl 4-[4-(l1- 22 benzyloxycyclopropyl)-3-ethyl-phenylethyflyl)-benzoate (Compound 91, 23 100.0 mg, 0.24 mmhol) in ethanol (3 mL) and tetmahydrofuran (3 mL) was 24 treated with NaO11 (120.0 mg, 3.0 inmols, 3.0 mL of a IN aqueous solution) and stirred overnight at room temperature. Work-up and purification by 26 HIPLC (Partisil 10-pac, 10% 11 2 0/CH 3 CN) afforded the title compound as a 27 colorless solid.

WO 02/18361 WO 0218361PCT/IJS01/25443 0 175 I 1 NM (CC1 3 6:.1(2H1, d, J =8.5 Hz), 7.64 (211, d, J =8.5 Hqz), 7.50 2 (1H, 7.35-7.16 (711, in), 4.29 (211, 3.04 (2H, q, J 7.6 Hz), 1.30 (3H, 0C) 3 t, J =7.6 Hz), 1.25 (211, in), 0.95 (2H, mn).

4lp I§ff }ylph -ac etic acid (Compound 94, General Formula 2) 6 Using General Procedure 1; a solution of methyl 7 benzyloxycyclopropy)3-ethyI-phelylethyfl]liphenyl} -acetate (Compound 8 92, 130.0 mg, 0.31 minol) in ethanol (3 mL) and tetrahydrofuran (3 maL) was 9 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a IN aqueous solution) and stirred overnight at room temperature. Work-up and purification by Ii IPLC (Partisil I10-pac, 10% 11 2 0/CH 3 CN) afforded the title compound.

12 411 NM~R (CDCI 3 6: 7.49 (3H, mn), 7.3 1-7.16 (911, mn), 4.28 (2H1, 3.66 13 (211, 3.02 (211, q, J 7.6 Hz), 1.29 (3H1, t, J 7.6 Hz), 1.23 (2H, mn), 0.94 14 (2H, in).

Isopropyl 2-gthvl-4-bromobenzoate (Intermediate 91) 16 Using General Esterification Procedure A; 4-broino-2-ethyl-benzoic 17 acid (2.25 g, 9.9 mnmols) was combined with isopropyl alcohol to give the 18 title compound as a colorless oil after column chromatography EtOAc- 19 hexanes).

'H NMR (CDCI 3 6: 7.69 (1IH, di, J 8.5 Hz), 7.41 (11H, 7.3 6 (1 H, d, J= 21 8.5 Hz), 5.23 (1H, septet, J =6.2 Hz), 2.95 (2H, q, J 7.6 Hz), 1.37 (6H, d, 22 J =6.2 Hz), 1.23 (311, t, J =7.6 Hz).

23 4-Bromo- 141 -isopropoxyinvl)-2-ethyl-benzene (Intermediate 92) 24 Using General Procedure 1; isopropyl 2-ethyl-4-bromobenzoate (Intermediate 91, 1.21 g, 4.46 inmols) and 8.9 mL of Tebbe's Reagent 26 (1.27 g, 4.46 mmols) afforded 570.0 mng of the title compound after 27 column chromatography (100% hexanes).

WO 02/18361 WO 0218361PCT[US01/25443 0 176 11 IHI NM (CDCI 3 6: 7.36 (11L, d, J 2.0 Hz), 7.28 (1H1, Ad J 2.0, 8.0 Hz), 2 7.17 (111, d, J1 8.0 Hz), 4.39 (1H1, septet, J 6.2 Hz), 4.31 (114, d, J 2.1 003 Hz), 4.26 (111, d, J1 2.1 Hz), 2.73 (2H, q, J 7.6 Hz), 1.35 (6H1, d, J=6.2 4 Hz), 1.24 (3H, t, J=7.6 Hz).

4-Bromno-:14(1 isopropoxvcylopr IY1-2-ethbenlzefe (Intermediate 93) 6 Using General Procedure 2; 4-bromo-l-(1-isopopXYviflyl)- 2 -ethyl- 7 benzene (Intermediate 92, 570. 0 mg, 2.11 minols), Et 2 Zn (521.0 mg, 4.22 8 mmols), and CH 2 1 2 (1.13 g, 4.22 mmols) in 7.0 ML Et 2 O afforded 500.0 mg 9 of the title compound as a colorless oil after chromatography (3% EtOAc hexanes).

I1I 'H NMR (CDC1 3 6: 7.3 9 (11H, d, J 2.1 liz), 7.2 5 (1 H, dd, J 1, 8.1 Hz), 12 7.15 (IH d, J =8.1 Hz), 3.59 (1H, septet,J =6.2 Hz), 2.97 (2H, q, J=7.6 13 Hz), 1.27 (3H, t, J 7.6 Hz), 1.11 (2H1, in), 0.97 (6H, d, J =6.2 Hz), 0.83 14 (2H, mn).

1 Isoprgpoxycclpropy)-3-ethyl-phn~thl1.-trimetb~silanl 16 (Intermediate 94) 17 Using General Procedure D; 4-bromo-1 -isopropoxycyclopropyl)- 18 2-ethyl-benzene (Intermediate 93, 300.0 ing, 1.07 mmol) in triethylamine 19 (8 mnL) was treated with copper(I)iodide (20. 0 mg, 0. 11 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 21 mniols) was then added followed by dichiorobis- 22 (triphenylphosphine)palladium(II) (75.0 mg, 0.11 mmol). The resulting 23 reaction mixture was heated to 70T 0 for 5d. The title compound (320.0 mg, 24 99%) was isolated by chromatography (0 EtOAc hexanes) as an orange oil.

26 1H NMR (CDC1 3 6: 7.37-7.21 in), 3.56 (1H, septet, J =6.2 Hz), 2.96 27 (2H1, q, J 7.6 Hz), 1.27 (3H, t, J =7.6 Hz), 1.10 (2H, mn), 0.94 (6H, d, J WO 02118361 WO 0218361PCTIUJS01/25443 0 177 1 6.2 Hz), 0.84 (211, in), 0.25 (9H, s).

2 4-Ethynl- 1 -(1isogropoxc clo rop1l-2 ethyl-beflzee (Intermediate 003 Using General Procedure E; 1 -isopropoxycycopropyl)- 3 -ethyl- 4 phenylethynyII-trimfethylsllalC (Intermediate 94, 330.0 mg, 1. 10 mmols) in methanol (10 rnL) was treated with potassium carbonate (150.0 mg, 1. 6 mnxol) and stirred overnight at ambient temperature. The crude alkyne (238 7 mg, 95%) was used directly in the next reaction.

8 'H NMIR (CDCI 3 8: 7.40-7.22 (311, in), 3.59 (11H, septet, J 6.2 Hz), 3.07 9 (IH, 2.97 (211, q, J 7.6 Hz), 1.28 (311, t, J 7.6 Hz), 1.12 (211, mn), 0.96 (6H1, d, J 6.2 Hz), 0.85 (2H, in).

I1I Etl 4-f4-( 1-isopropoxycvcloprol)-3 -ethyl-phenylethvnyll-belzoate 12 (Compound 95, General Formula 2) 13 Using General Procedure F; 4-ethynyl-l1-(1 -isopropoxycyclopropyl)- 14 3-ethyl-benzene (Intermediate 95, 108.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 130.0 mg, 047 inmol) in triethylamine (5 ml) was 16 treated with copper(I)iodide (30.0 mg, 0. 16 minol) and sparged with argon 17 for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (1 10 mng, 0. 16 18 mmol) was added and the reaction mixture was stirred overnight at room 19 temperature. Column chromatography EtOAc hexanes) afforded 125.0 mg of the title compound as an oil.

21 'H NMR (CDCl 3 8: 8.02 (211, d, J 8.2 Hz), 7.59 (211, d, J 8.2 Hz), 7.46 22 (1H1, 7.33-7.26 (21H, mn), 4.39 (211, q, J 7.1 Hz), 3.62 (111, septet, J 6.2 23 Hz), 3.01 (211, q, J 7.6 Hz), 1.41 (311, t, J 7.1 Hz), 1.31 (3H1, t, J 7.1 24 Hz), 1. 14 (2H1, mn), 0. 97 (611, d, J =6.2 Hz), 0. 88 (2H, in).

Metyl 4-r4-(1 -isoprooxvgycloprovl)-3-etyl-phegvlethvnyl-hell- 26 acetate (Compound 96, General Formula 2) 27 Using General Procedure F; 1 -ethynyl-4-( 1 -isopropoxycyclopropyl)- WO 02/18361 WO 0218361PCTIUS01/25443 178 1 3-ethyl-benzefle (Intermediate 95, 130.0 mg, 0.57 mniol) and methyl-(4- 2 iodophenyl)-acetate (Reagent B, 157.0 mg, 0.57 mmxol) in triethylamine 00 3 rnL) was treated with copper(I)iodide (36.0 mg, 0.19 nunol) and Sparged 4 with argon for 5 minutes. Dichlorobis(triphelphosphine)palladium(LI) (133 mg, 0. 19 mmol) was added and the reaction mixture was stirred 6 overnight at room temperature. Column chromatography EtOAc 7 hexanes) afforded 150.0 mg of the title compound as an orange oil.

8 'H NMvR (CDCl 3 5: 7.50-7.44 (311, in), 7.27 (4H1, in), 3.70 (3H, 3.64 9 (21L 3.62 (111, septet, J =6.2 Hz), 3.00 (2H1, q, J 7.6 Hz), 1.30 (3H1, t, J 7.6 Hz), 1. 13 (2H1, mn), 0.97 (6H, d, J =6.2 Hz), 0. 87 mn).

I1I 1 Isopropvoxvcvcloproyl)-3-ethyl-PhenVlethyflYI-benzoic acid 12 (Compound 97, General Formula 2) 13 Using General Procedure I; a solution of ethyl 1- 14 isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-belzoate (Compound 110.0 mg, 0.29 inmol) in ethanol (3 rnL) and tetrahydrofuran (3 mL) was 16 treated with NaOH (120.0 mg, 3.0 minols, 3.0 mL of a IN aqueous solution) 17 and stirred overnight at room temperature. Work-up and isolation by HPLC 18 (partisil I10-pac, 10% H 2 0/CH 3 CN) afforded the title compound as a 19 colorless solid.

'H1 NMR (d 6 -acetone) 8: 8.06 (2H1, d, J 8.2 Hz), 7.67 (211, d, J 8.2 Hz), 21 7.49 7.40-7.34 (21H, in), 3.61 (IH, septet, J3 6.2 Hz), 3.01 q, J 22 7.6 Hz), 1.29 (314, t, J 7.6 Hz), 1.08 (211, in), 0.93 (611, d, J =6.2 Hz), 23 0.88 (211, in).

24 f{4-rf44(1 -Isopropoxycyclppropvl)-3-ethvl-ph Iy let yll-phenyl} -acetic acid (Compound 98, General Formula 2) 26 Using General Procedure 1; a solution of methyl 27 isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl) -acetate WO 02/18361 WO 0218361PCT/US01/25443 179 I (Compound 96, 156.0 mg, 0.41 mmol) in ethanol (3 and 2 tetrahydrofuran (3 mL.) was treated with NaOH (120.0 mg, 3.0 minols, 00 3 mL. of a IN aqueous solution) and stirred overnight at room temperature.

4 Work-up and isolation by HIPLC (partisil I10-pac, 10% H 2 0/CH 3

CN)

afforded 85.0 mg of the title compound.

6 NNM (CDCI 3 8: 7.54-7.48 (3H, in), 7.34-7.27 (4H1, mn), 3.68 (2H1, s), 7 3.66 (1 H, septet, J =6.2 Hz), 3.03 (2H, q, J =7.6 Hz), 1.3 3 (2H1, t' J 7.6 8 Hz), 1. 17 (2H, mn), 1.0 1 (6H, d, J =6.2 Hz), 0.90 (2H, in).

9 4Bon--sp~:peo dioE Isln (Intermediate 96) To a solution of 4-bromo-3-isopropylphenol (880.0 mng, 4.09 minols) I1I and imidazole (417.0 mg, 6.13 minols) in 10 mL DMF was added chioro- 12 trilsopropylsilane (946.0 mng, 4.90 inmols). After stirring overnight at room 13 temperature the solution was diluted with H 2 0 and extracted with EtOAc.

14 The combined organic layers were washed with H 2 0 and saturated aqueous NaCI before being dried NOW 04 and concentrated under reduced pressure.

16 The title compound, 1.30 g was isolated by column cbromatography 17 EtOAc-hexanes) as a colorless oil.

18 'H NUR (CDC1 3 8: 7.34 (1H, d, J =8.5 Hz), 6.81 (1H, d, J 2.9 Hz), 6.59 19 (1H, dd, J3 2.9, 8.5 Hz), 3.31 (IH, septet J 7.0 Hz), 1.33-1.21 (3H1, in), 1.24 (6K1 d, J =7.0 Hz), 1. 13 (18H, d, J =7.0 Hz).

21 Ethyl 2-isop1royl-4-triisopropylsilgnyloxv-benzoate (Intermediate 97) 22 To a solution of (4-bromo-3-isopropyl-phenoxy)-triisopropyl-silane 23 (Intermediate 96, 1.3 g, 3.8 mumols) in 15 mL Et 2 O cooled to -78 0 C was 24 added 4.9 mL of tert-butyllithium in pentane (532.0 mg, 8.3 mmols; 1.7 M).

After stirring for 30 minutes ethyl chloroformate (832.0 mng, 7.8 minols) was 26 added. The resulting solution was warmed to room temperature and 27 quenched by the addition of saturated aqueous NII 4 C. The mixture was WO 02/18361 WO 0218361PCT[US01/25443 0 180 I extracted with EtOAc and the combined organic layers dried (MgSO 4 2 concentrated under reduced pressure and the residue chromatographed (4% 00 3 EtOAc-hexanes) to give 1.09 g of the title compound as a colorless 4 oil.

'H NMiR (CDC1 3 5: 7.72 (1H, d, J =8.5 Hz), 6.87 (1H, d, J 2.3 Hz), 6.69 6 (1H4, dd, J 8.5 Hz), 3.88 (11-H, septet; J =7.1 Hz), 4.30 (2W, q, J =7.1 7 Hz), 1.36 (3H, t, J 7.1 Hz), 1.31-1.17 (9H, 1.09 (18W).

8 L4(-to iy)3io~oy-peoy-rio~oplsln (Intermediate 9 98) Using General Procedure 1; ethyl 2-isopropyl-4- .11 triisopropylsilanyloxy-benzoate (Intermediate 97, 450.0 mg, 1.34 xnmols) 12 and 2.0 mL of Tebbe's Reagent (398.0 mg, 1.40 mmols) afforded the title 13 compound after column chromatography (100% hexanes).

14 'H NMR (CDCI 3 7.11 (1lH, d, J 8.2 Hz), 6.78 (1H4, d, J =2.3 Hz), 6.63 (11H, dd, J 8.2 Hz), 4.23 (1IH, d, J 1.7 Hz), 4. 10 (1W4, d, J 1.7 Hz), 16 3.86 (2H, q, J 7.0 Hz), 3.16 (1H, septet, J3 7.0 Hz), 1.35 (314, t, J 7.1 17 Hz), 1.28-1.19 (3H, 1. 19(6K d, J =7.0OHz), 1. 11 (1 8H).

18 I -Ethoxycclopropyl)-3 -isoproyl-phenoxv]-triisopropvl-si lane 19 (Intermediate 99) Using General Procedure 2; [4-(1-ethoxyvinyl)-3-isopropyl- 21 phenoxy]-triisopropyl-silane (Intermediate 98, 300. 0 mg, 0. 83 mmnols), 22 Bt 2 Zn (325.0 mng, 2.63 mmols), and CH 2 1 2 (704.0 mg, 2.63 minols) in 23 mL Et 2 O afforded 270.0 mg of the title compound as a colorless oil 24 alter chromatography EtOAc hexanes).

'H NMR (CDCI 3 8: 7.06 (1IH, d, J =8.2 Hz), 6. 81 1H, d, J =2.6 Hz), 6.5 9 26 (1H, dd, J 2.6, 8.2 Hz), 3.76 (111, septet J 7.0 Hz), 3.25 q, J 27 Hz), 1.30-1.20 (3W, mn), 1. 19 (6W, d, J 7.0 Hz), 1. 15 (2H, in), 1. 10 (18W), WO 02/18361 WO 0218361PCTIIJS01/25443 181 1 1.02 (2H1, t, J 7.0 Hz), 0.82 (2H, in).

2 1 EthoxcycloproyI-3iso roPnvvl-Pt)h l (Intermediate 100) 003 To a solution of [4-(1-ethoxycyclopropyI)-3isopropyl-phenoxcyF 4 triisopropyl-silane (Intermediate 99, 360.0 mng, 0.96mmol) in 3 mL TH9 at 0 IC was added tetrabutylammoniuni fluoride (625.0 mg, 2.39 mniols, 2.4 6 mL of a 1 M solution in 'UHF). The solution was stirred at 0 'C for 7 minutes and then quenched by the addition of H 2 0. The mixture was 8 extracted with EtOAc and the combined organic layers were washed with 9 H.0 and saturated aqueous NaCi before being dried (MgSO 4 and concentrated under reduced pressure. The title compound (180 mig, 86%) 11 was, isolated from the residue by column chromatography (4-10% EtOAc- 12 hexanes) as a colorless solid.

13 'H NMR (CDCl 3 8: 7.13 (IH, d, J 8.2 Hz), 6.79 (1H, d, J 2.6 6.57 14 dd, J 8.2 Hz), 5.48 (LH, 3.79 (1H, septet, J1 7.0 Hz), 3.32 (214,q, J=7.0OHz), 1.21 (611,d,J =7.0Hz), 1.12 (2H, in), 1.05 (311,t, J 16 7.0 Hz), 0.84 (2H-Lm).

17 4-(1 -Ethoxcvclopropy1)-3-iso~rpvl-phenyI 1.1.1 -trifluoromethansulfonate 18 (Intermediate 101) 19 A solution of 4-(l1-ethoxycyclopropyl)-3-isopropyl-phenol (Intermediate 100, 172.0 mg, 0.78 mmnol) in 5 mL of CH 2

CI

2 j was cooled to 21 0 "C and to it was added 22 chloropyridine (32 1.0 mng, 0. 82 mmol) and triethylamnine (240.0 mg, 2.4 23 mmols). The resulting solution was warmed to room temperature and stirred 24 overnight. The reaction was quenched by the addition of H 2 0 and the mixture extracted with EtOAc and the combined organic layers were washed 26 with 10% aqueous HCl, saturated aqueous NaHCO 3 1HA0 and saturated 27 aqueous NaCI. The solution was dried (MgSO 4 and concentrated under WO 02/18361 WO 0218361PCT/US01/25443 182 1 reduced pressure. The title compound was isolated by column 2 chromatography EtOAc-hexanes) as a colorless oil, 240.0 mg, 87%.

00 3 'H NMR (GDC1 3 8: 7.31 (11L, d, J -8.6 Hz), 7.18 (111, d, J =2.6 Hz), 7.00 4 (111, dd, J3 2.6, 8.6 Hz), 3.87 (1W, septet, J 7.0 Hz), 2.38 (2H, q, 3 Hz), 1.24 (611, d, J 7.0 Hz), 1.15 (21L 1.04 (3H1, t,JI=7.0 Hz), 0.86 6 (2H, in).

7 1 EthoxvcvcloprgpyU.3-isgprop lPefYetMl1kM§MMlil 8 (Intermediate 102) 9 Using General Procedure D; 4-(1 -ethoxycyclopropy)-3-isopropylphenyl 1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 11 mmol) in triethylamine (2 mL) and DMIF (6 xnL) was sparged with argon for 12 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added 13 followed by dichlorobis-(triphenylphosphine)pa1adiumI(II) (38.0 mg, 0.05 14 mmol). The resulting reaction mixture was heated to 95 'C for 5d. The title compound, 200.0 mng was isolated by chromatography (0 -2% 16 EtOAc hexanes) as an orange oil.

17 'H NR (CDC1 3 8: 7.43 (111, d, J 1.7 Hz), 7.25 (1 H, dd, I 1.7, 7.9 Hz), 18 7.16 (1W, d, J =7.9 Hz), 3.80 (IH, septet, J3 6.8 Hz), 3.26 (2H, q, J3 19 Hz), 1.24 (611, d, J =6.8 Hz), 1.24-1.10 (2H, in), 1.03 (311, t, J3 7.0 Hz), 0.87 (2H, 0.26 (911, s).

21 1 -Ethoxcyclopropfl)-4-ethyny-2-isopropylbenzene (Intermediate 103) 22 Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-isopropyl- 23 phenylethynyl]-trimethylsilane (Intermediate 102, 210.0 mg, 0.70 mmol) in 24 methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mniol) and stirred overnight at ambient temperature. The crude alkyne was 26 used directly in the next reaction.

27 'Hl NMR (CDCI 3 8: 7.47 (1IH, d, J3 1.7 Hz), 7.23 (111, dd, J3 1.7, 7.6 Hz), WO 02/18361 PCTIUS1/25443 0 183 1 7.19 (1H, d, J 7.6 Hz), 3.80 (1H, septet, J 7.0 Hz), 3.27 (11H, q, J 2 Hz), 3.07 (1H, 1.23 (6H, d, J 7.0 Hz), 1.13 (2H, 1.03 (3H, t, J 0 3 Hz), 0.85 (2H, m).

4 Ethyl 4 4 (l-ethoxvycoIropy-3-isoropldphenYiethvn l-benzoate (Compound 99, General Formula 2) S6 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2- 7 isopropylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo S8 benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was 9 treated with copper()iodide (14.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(I) (51 mg, 0.07 11 mmol) was added and the reaction mixture was stirred overnight at room 12 temperature. Column chromatography EtOAc hexanes) afforded 13 28.0 mg of the title compound.

14 'H NMR (CDCI 3 8: 8.01 (2H, d, J= 8.2 Hz), 7.59 (2H11, d, J 8.2 Hz), 7.51 (1H, d 3 1.7 Hz), 7.28 (1H1, dd, J 1.7, 7.9 Hz), 7.21 (1H, d, J 7.9 Hz), 16 4.38 (2H, q, J= 7.1 Hz), 3.83 (1H, septet, J 6.7 Hz), 3.29 (2H, q, J= 17 Hz), 1.40 (3H, t, J= 7.1 1Iz), 1.26 (6H, d, J= 6.7 Hz), 1.14 (2H, 1.04 18 (3H, t, J 7.0 Hz), 0.87 (2H, m).

19 Methyl l-ethoxycyclopropyvl)-3-isopropyl-phevyethvnvl-phenyllacetate (Compound 100, General Formula 2) 21 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2- 22 isopropylbenzene (Intermediate 103, 120.0 mg, 0.52 mmol) and methyl-(4- 23 iodophenyl)-acetate (Reagent B, 150.0 mg, 0.52 mmol) in triethylamine (8 24 mL) was treated with copper(I)iodide (32.0 mg, 0.17 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(I) 26 (121 mg, 0.17 mmol) was added and the reaction mixture was stirred 27 overnight at room temperature. Column chromatography EtOAc 28 hexanes) afforded 140.0 mg of the title compound as a pale-yellow WO 02/18361 WO 0218361PCTIUSOI/25443 184 I oil.

2 'H NMR (CDCl 3 6: 7.53 (3H, in), 7.31-7.23 (4H, rn), 3.86 (111, septet, J 00 3 6.7 Hz), 3.73 (3H, 3.67 (2H, 3.33 (2H1, q, J 7.0 Hz), 1.30 (6H1, d, J 4 6.7 Hz), 1. 15 (2H,mr), 1.0 8(31,t, J =7.0 Hz), 0.90 (2H, m).

I-Ethoxygycloprop I 3 -isoproyl-phenylethyfl-belzoiCai 6 (Compound 101, General Formula 2) 7 Using General Procedure 1; A solution of ethyl 8 ethoxycyclopropy)-3-isopropy-phenylethyfl)l-beflzoate (Compound 99, 9 28.0 mng, 0.07 mmol) in ethanol (2 mQL and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 inmols, 2.0 mL of a IN aqueous solution) I1I and stirred overnight at room temperature. Work-up afforded 24 mg (92%) 12 the title compound as a pale-yellow solid.

13 'H NMR (d 6 -acetone) 5: 8.06 (211, di, J 8.2 Hz), 7.66 (2H, d, J3 8.2 Hz), 14 7.58 (1H, 7.33 (214I, mn), 3.87 (111, mn), 2.27 (2H, q, J 7.0 Hz), 1.26 (6H1, di, J 6.7 Hz), 1.09 (2H, in), 0.99 (3H, t, J 7.0 Hz), 0.88 (2H1, m).

16 1 444-( 1 -Ethoxyclopropyl)-3-isopropvl-pheniylethvnvl]-phenyl} -acetic 17 acid (Compound 102, General Formula 2) 18 Using General Procedure 1; a solution of methyl 19 ethoxycyclopropyl)-3-isopropyl-phenylethynyl)-phenyl) -acetate (Compound 100, 130.0 mag, 0.35 inmol) in ethanol (5 mL) and 21 tetrahydrofiuan (5 mL) was treated with NaOH (120.0 mg, 3.0 inmols, 22 rnL of a IN aqueous solution) and stirred at 50 *C for 4h. Work-up and 23 isolation by HAPLC (Partisil 10-pac, 10% H 2 0/CH 3 CN) afforded 88.0 mng 24 of the title compound.

1H NMR (CDCI 3 8: 7.50 (3H1, 7.28-7.19 (4H, in), 3.82 (1LH, in), 3.65 26 (2H1, 3.29 (2H, q, J =7.0 Hz), 1.25 (6H1, di, J =6.7 Hz), 1. 14 (211, in), 27 1.04 (3K1 t, J 7.0 Hz), 0.86 (2H1, mn).

WO 02/18361 WO 0218361PCTIUS01/25443 185 I 4-Bromo-3-tert-b typhenol (Intermediate 104) 2 To a mixture of 3-tert-butyl-methoxy benzene (1.00 g, 6.09 inmols) 00 3 in CCI 1 (20 mL), molecular sieves, and silica get was added N- 4 bromosuccininlide (1.19 g, 6.70 mmols). This mixture was stirred at 5 5 'C for 48h. The resulting mixture was cooled to room temperature, filtered to 6 remove the solids, and the filtrate diluted with EtOAc. This solution was 7 washed with H20, 10% aqueous UCi, H 2 01 saturated aqueous Na1C 0 3 and 8 saturated aqueous NaCI before being dried (MgSO 4 and concentrated under 9 reduced pressure. Column chromatography EtOAc-hexanes) afforded 1. 15 g of a 3 to I mixture of 1 -bromo-2-tert-butyl methoxy 11I benzene and l-bromo-2-methoxy-4-tert-butyl benzene as a colorless oil.

12 A solution of the isomeric methoxy compounds in 10 mL of C1-{C1 2 13 was cooled to 0 *C and treated with a solution (18.5 niL) of BBr 3 in CI- 2 C1 2 14 (4.63 g, 18.5 mmols). After 10 minutes the solution was warmed to room temperature, stirred for lh, and then quenched with 1120. The mixture was 16 extracted with EtOAc and the combined organic layers washed with 17 saturated aqueous NaCl, dried (MgSO 4 and concentrated under reduced 18 pressure. The title compound was isolated, 1. 17 g by column 19 chromatography EtOAc-hexanes).

'H NMR (CDCI 3 8: 7.39 (1H1, d, J =8.5 Hz), 6.96 (1H, d, J =2.9 Hz), 6.54 21 (11H, dd, J 2.9, 8.5 Hz), 1.46 (9H1, s).

22 (4-Bromo-3-tert-butyl-phenoxv)-triisopropvl-silane (Intermediate 105) 23 To a solution of 4-bromo-3-tert-butylphenol (Intermediate 104, 1.17 24 g, 5. 10 nimols) and imidazole (520.0 mg, 7.65 mnmols) in 10 mnL DMF was added chloro-triisopropylsilane (1.18 g, 6.10 mnnols). After stirring 26 overnight at room temperature the solution was diluted wirth 1120 and 27 extracted with EtOAc. The combined organic layers were washed with H 2 0 WO 02/18361 WO 0218361PCTIUS01/25443 186 1 and saturated aqueous NaCI before being dried (gSO 4 and concentrated 2 under reduced pressure. The title compound, 1.80 g was isolated by 00 3 column chromatography EtOAc-hexafleS) as a colorless oil.

4 '1 H NMR (CDCl 3 8: 7.3 8 (1 H, d, J 8 .0 Hz), 6.97 (11-H, d, J 2.9 Hz), 6.5 6 5 (1H, dd, J 8.5 1iz), 1.47 (9H, 1.29-1.24 in), 1.09 (1 8H-, di, J= 6 6.7 Hz).

7 Etl 2-tert-bpUtyl4-triisop~ylsil~yloXybeflzoate (Intermediate 106) 8 To a solution of (4boo3tr-uy-hnoy-riorplsln 9 (Intermediate 105, 1.00 g, 2.60 mnmols) in 15 mL Et 2 O cooled to -78 'C was added 3.6 mL of tert-butyllitbium, 1.7 M in pentane (395.0 mng, 6.2 11 inmols). After stirring for 30 minutes ethyl chloroformnate (607.6 mig, 5.6 12 minols) was added. The resulting solution was warmed to room temperature 13 and quenched by the addition of saturated aqueous NII 4 CI. The mixture was 14 extracted with EtOAc and the combined organic layers dried (MgSO 4 concentrated under reduced pressure The residue was chromatographed (2- 16 5% EtOAc-hexanes) to give 1.23 g (8 of the title compound as a 17 colorless oil.

18 'H NM (CDCI 3 8: 7.24 (1H, d, J 8.2 Hz), 6.97 (1H, d, J =2.6 Hz), 6.69 19 (11-H, dd, J 2.6, 8.2 Hz), 4.33 (2H, q, J =7.1 Hz), 1.39 (9H1, 1.37 (31H, t, J 7.1 Hz), 1.29-1.21 (3H, in), 1.10 (18H, d, J 6.7 Hz).

21 I-Ethoxyvinyl)-3-tert-buty1-phenoMI-triisopropy-silane (Intermediate 22 107) 23 Using General Procedure 1; ethyl 2-tert-butyl-4- 24 triisopropylsilanyloxy-benzoate (Intermediate 106, 1.30 g, 3.44 nimols) and 7.2 ml of Tebbe's Reagent (1.03 g, 3.61 inmols) were reacted. The 26 reaction required 7 days at room temperature to go to completion. The 27 standard work-up afforded 1.29 g of the title compound after column WO 02/18361 WO 02/18361PCT/US01/25443 0 187 I chromatography EtOAc-hexanes).

2 '1H NMR (CDC1 3 5: 7.05 (1H1, d, J =8.2 Hz), 6.94 (1H1, d, I1 2.6 Hz), 6.63 00 3 (1H, dd, J3 2.6, 8.2 Hz), 4.20 (1H1, d, J 1.7 Hz), 4.08 (1H, d, IJ 1.7 Hz), 4 3.83 (2H, q,J =7.1 Hz), 1.37 1.36 (3H, t,J =7.1 Hz), 1.27-1.20 (3H1, in), 1. 10 (1 8H, d, J 6.7 Hz).

6 14-( -tyI roy)3tr-uvphnxltislo 7 (Intermediate 108) 8 Using General Procedure 2; [4-(1-ethoxyviny1)-3-tert-butyl- 9 phenoxy]-triisopropyl-silafle (Intermediate 107, 320. 0 mg, 0.85 inmols), Et 2 Zn (325.0 mg, 2.63 mmols), and CH 2 1 2 (704.0 mg, 2.63 mmols) in 11 niL Et 2 O afforded 257.0 mg of the title compound as a colorless oil 12 after chromatography EtOAc hexanes).

13 'H NMR (CDCI 3 8: 7.24 (1H1, d, J 8.5 Hz), 7.06 (114, d, J =2.6 Hz), 6.60 14 (IIH, dd, J 2.6, 8.5 Hz), 3.24 (2H, q, J 7.1 Hz), 1.50 (9HK 1.29-1.21 O3R 1. 11(1 8H, d, J= 6.7 Hz), 1.04 (311, t,J =7.1 Hz).

16 4-(1 -Ethoxvclcoprovl-3-tert-butyl-phenoI (Intermediate 109) 17 To a solution of I-ethoxycyciopropyl)-3-tert-butyl-phenoxy]- 18 triisopropyl-silane (Intermediate 108, 600.0 mg, 1.54 mxnol) in 3 rnL THF 19 at 0 0 C was added tetrabutylamnmonium fluoride (802.8.0 mg, 3.07 mmols; 3.1 mL of a 1 M solution in THF). The solution was stirred at 0 0 C for 21 minutes and then quenched by the addition of 1120. The mixture was 22 extracted with EtOAc and the combined organic layers were washed with 23 1120 and saturated aqueous NaCL before being dried (MgSO 4 and 24 concentrated under reduced pressure. The title compound (400 mig, 88%) was isolated from the residue by column chromatography 10% EtOAc- 26 hexanes) as a colorless solid.

27 'H NMR (CDC1 3 5: 7.29 (1H, d, J 1 8.2 Hz), 7.01 (1H1, d, J 2.6 Hz), 6.57 WO 02/18361 PCT/US01/25443 188 1 (LH, dd, J 2.6, 8.2 Hz), 3.29 (2H, q, J 7.1 Hz), 1.59 (9H, 1.08-1.04 2 (7H, m).

3 4-(1-Ethoxvcvcloproyl-3-tert-butvl-ph 1.1.1-trifluoromethlfoate 4 (Intermediate 110) A solution of 4-(1 -ethoxycyclopropyl)-3-tert-butyl-phenol 6 (Intermediate 109, 400.0 mg, 1.71 mmol) in 10 mL of CH 2 Cl 2 was cooled

\O

7 to 0 OC and to it was added 8 chloropyridine (705.0 mg, 1.79 mmol) and triethylamine (522.0 mg, 5.1 9 mmols). The resulting solution was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of H20 and the 11 mixture extracted with EtOAc and the combined organic layers were washed 12 with 10% aqueous HCI, saturated aqueous NaHCO 3 HO20, and saturated 13 aqueous NaC1. The solution was dried (MgSO 4 and concentrated under 14 reduced pressure. The title compound was isolated by column chromatography EtOAc-hexanes) as a colorless oil, 542.0 mg 16 'II NMR (CDC 3 8: 7.48 (IH, d, J= 8.5 Hz), 7.39 (1H, d, J= 2.6 Hz), 7.01 17 (1H, dd, J 2.6, 8.5 Hz), 3.26 (2H, q, J= 7.1 hz), 1.52 (9H, 1.12 (2H, 18 bs), 1.08-1.04 (5H, m).

19 -Ethoxcyclopropyl)-3-tert-butyl-phenylethynyl-trimethylsilane (Intermediate 111) 21 Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-tert-butyl- 22 phenyl 1,1,1-trifluoromethansulfonate (Intermediate 110, 260.0 mg, 0.71 23 mmol) in triethylamine (4 mL) and DMF (6 mL) was sparged with argon for 24 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06 26 mmol). The resulting reaction mixture was heated to 95 OC for 18 hours.

27 The title compound, 215.0 mg was isolated by chromatography (0 WO 02/18361 WO 0218361PCT/US01/25443 0 189 1 2% EtOAc hexanes) as an orange oil.

2 'H NMR (CDCI 3 8: 7.63 (111, d, J1 1.7 Hz), 7.32 (111, di, J 7.9 Hz), 7.19 00 3 (IH, dci, J3 1.7, 7.9 Hz), 3.24 (2H1, q, J =7.1 H4z), 1. 51 (9H, 1. 10 (2H1, 4 bs), 1.06-1.01 in), 0.25 (9H, s).

1 -(1-Ehxcco~ -eh (nemdiate 112) 6 Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-tert-butyl- 7 phenylethynyl]-timethylsilane (Intermediate 111, 215.0 mng, 0.69 inmol) in 8 methanol (10 mL) was treated with potassium carbonate (80.0 mg, 0. 58 9 mmol) and stirred overnight at ambient temperature. The crude alkyne, 169 mg, was used directly in the next reaction.

I1I 'H NMR (CDCl 3 5: 7.68 (111, d, J =1.8 Hz), 7.36 (111, d, J =7.9 Hz), 7.23 12 (114, dd, J 1.8, 7.9 Hz), 3.26 (2H, q, J =7.1 Hz), 3.06 (1H1, 1.51 (9H1, s), 13 1. 11 (2H1,bs), 1.07-1.02 (511,m).

14 Etyl 4-44-( 1-ethoxycclopropyfl-3-tert-butl-phevctyl-belzoate (Compound 103, General Formula 2) 16 Using General Procedure F; 1 -ethoxycyclopropyl)-4-ethynyl-2- 17 tert-butylbenzene (Intermediate 112, 70.0 mng, 0.30 nunol) and ethyl-4-iodo 18 benzoate (Reagent A, 85.0 mg, 0.30 mrnol) in triethylamine (5 xnL) was 19 treated with copper(I)iodide (19.0 mg, 0.0 1 mrnol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladiuna(II) (70 mg, 0.01 21 mmol) was added and the reaction mixture was stirred overnight at room 22 temperature. Columnn chromatography (1 EtOAc hexanes) afforded 23 70.0 mg of the title compound.

24 'H NM (CDCL 3 8: 8.02 (2H1, d, J 8.8 Hz), 7.72 (1 H, d, J =1.7 H4z), 7.59 (2H1, d, J 8 Hz), 7.40 (lH, d, J 7.9 Hz), 7.28 (1 H, dci, J 1.7, 7.9 Hz), 26 4.3 9 211, q, J 7.1 Hz), 3.28 (211, q, J3 7.1 Hz), 1.5 5 1.40 (3HJ, t' 27 J 7.1 Hz), 1.12 (214, bs), 1.08-1.04 (5H4, in).

WO 02/18361 WO 0218361PCT/LJS01/25443 190 1 Methl 1444-0 1ethon cclop-ropyl)-3-tertb~lphenylethvnyl)PDheny-ll- 2 acetate (Comnpound 104, General Formula 2) 00 3 Using General Procedure F; 1 -(1-ehoxycyclopropyl)-4-ethrynl- 2 4 tert-butylbenzene (Intermediate 112, 95.0 mg, 0.39 mmol) and methyl-(4iodophenyl)-acetate (Reagent B, 108.0 mg, 0.39 mmol) in triethylanine, (8 6 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged 7 with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(ll) (91 8 mg, 0. 13 mmol) was added and the reaction mixture was stirred overnight at 9 room temperature. Column chromatography EtOAc hexanes) afforded 100.0 mg of the title compound.

11I 'H NMR (CDC 3 8: 7.70 (11H, d, J =1.5 Hz), 7.50 (214I, d, J =7.9 Hz), 7.3 8 12 (1H, d, J =7.9 Hz), 7.27 (3H, in), 3.70 (3H, 3.64 (2H, 3.28 (2H, q, J 13 7.1 Hz), 1.54 (9H, 1.12 (2H, bs), 1.08-1.03 (5H, in).

14 4-r4-:(l -Ethoxycyclopropyl)-3-ter-buv1-h1thl~yll-benzoic acid (Compound 105, General Formula 2) 16 Using General Procedure 1; a solution of ethyl 17 ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate (Compound 103, 18 70.0 mg, 0. 18 mmol) in ethanol (3 miL) and tetrahydrofuran (3 mL) was 19 treated with NaOH (240.0 mg, 6.0 inmols, 3.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40 mg (62%) 21 the title compound as a pale-yellow solid.

22 'H-INMvR (d.-acctonc) 8: 8.06 (21H, d, J 8.7 Hz), 7.76 (1H, d, J =1.8 Hz), 23 7.67 (2K~ d, J 8.7 Hz), 7.5 0 (11H, d, J 7.9 Hz), 7.3 3 (1IH, dd, J 1. 8, 7.9 24 Hz), 3.28 (2H, q, J3 7.3 Hz), 1.54 (9H1, 1. 13 (2H, bs), 1. 10 (2H, in), 1.02 (3H, t, J 7.3 Hz).

26 (4-14-(l -Ethoxvcclopropyl-3 -tert-butl-nhenylthyyll-'heyl-acetic 27 acid (Compound 106, General Formula 2) WO 02/18361 WO 0218361PCTIUS01/25443 191 I Using General Procedure 1; a solution of methyl 2 ethoxycyclopropyl)-3-tertbutyl-phenyethynY1H-phenylI aett 00 3 (Compound 104, 100.0 mg, 0.26 mmol) in ethanol (4 mL) and 4 tetrahydrofuran (4 iii) was treated with NaOH (240.0 mg, 6.0 mmols, mL of a 2N aqueous solution) and stirred at 50 'C for 4h. Work-up and 6 isolation by I-PLC (Partisil 1 0-pac, 10% H 2 0/CH 3 CN) afforded 70.0 mg 7 of the title compound.

8 'H1 NMR (CDCl 3 8: 7.73 (1IH, d, J =1.3 Hz), 7.53 (2H1, d, J =7.9 Hz), 7.41 9 (1H, d, J 7.9 7.28 (3H, in), 3.69 (2H, 3.31 (211, q, J =7.1 Hz), 1.56 (9H1, 1.15 (2H1, bs), 1.11-1.05 (514, in).

11 1 -(4-Bromophenyfl)-yclopropanecarboflitrile (Intermediate 113) 12 To a 50% aqueous NaOH solution (40.0 g, wtlwt) was added benzyl 13 trieihylaznmonium chloride (1.0 g, 4.4 mmols), 4-bromobenzonitrile (19.6 g, 14 0.10 mol), and 1,2-dibromoethane (56.4 g, 0.30 mol). The mixture was stirred overnight at room temperature and then diluted with 100 mL of H 2 0.

16 This mixture was extracted with EtOAc and the combined extracts were 17 washed with saturated aqueous NaHS 2

O

3 1120, and saturated aqueous NaCi 18 before being dried (MgSO 4 and concentrated under reduced pressure.

19 Bulb-to-bulb distillation afforded 18.8 g (8 of the title compound as a colorless solid.

21 'H1 NMvR (CDC1 3 5: 7.48 (2H, d, J =8.6 Hz), 7.17 (2H, d, J 8.6 Hz), 1.75 22 (2H, dd, J 5.2, 7.6 Hz), 1.39 (211, dd, J 5.2, 7.6 Hz).

23 1 -(4-Bromophenyl)-cyclopropanecarboxylic acid (Intermediate 114) 24 To a solution of KOH (6.06 g, 0. 11 mol) in 10 mL of H120 was added 40 ML of ethylene glycol and I -(4-bromopheny1)-cyclopropanecarboflitrile 26 (Intermediate 113, 10.0 g, 0.45 mol). Thbis solution was heated to 135-140 27 'C for 4h, cooled to room temperature, and then poured into a mixture of WO 02/18361 WO 02/18361PCTIUS01/25443 192 I 100 mL ice and 10% aqueous HCI. The resulting mixture was allowed to 2 stand overnight at 5 0 C, the solid was collected by filtration and washed 0C) 3 with H20. The colorless solid was dried under reduced pressure to give 4 10.6 g of the title compound.

1 H NMR (CDCI 3 5: 7.43 (2H, d, J =8.5 Hz), 7.21 d, J =8.5 Hz), 1.68 6 (211, dd, J 7.1 Hz), 1.24 (2H, dd, J 4.0, 7.1 Hz).

7 Tert-bulyl [l-(4-bromgphen~l)-pclg~pro yl]-cabamlate (Intermediate 115) 8 A solution of 1-(4-bromophenyl)-cycopropaflecarboxylic acid 9 (Intermediate 114,2.32 g, 9.62 mmols), diphenyiphosphoryl azide (2.65 g, 9.62 rnmols), triethylamine (973.0 mg, 9.62 mmols) in 40 mL tert-BuQH 11I (distilled from Na 0 was heated to reflux for 1 7h. The solution was 12 concentrated under reduced pressure and the residue dissolved in EtOAc 13 and washed with 5% aqueous HCl, H 2 0, saturated aqueous NaH{C0 3 and 14 saturated aqueous NaCI before being dried over MgSO 4 Concentration of the dry solution under reduced pressure and column chromatography 16 10% EtOAc hexanes) afforded 2.01 g of the title compound as a 17 colorless solid.

18 'H NMR (CDCl 3 8: 7.3 9 (211, d, J =8.3 Hz), 7.08 (2H1, d, J =8.3 Hz), 5.3 19 01H, bs), 1.43 (911, 1.26 (211, in), 1. 17 (211, in).

1.(4-BromoPhenyl)-cycloprovlainine (Intermediate 116) 21 To a solution of tert-butyl [l1-(4-bromophenyl)-cyclopropyl]r 22 carbamate (Intermediate 115, 1.08 g, 3.40 inmols) in 20 niL MeOH and 23 mL TI{F was added 20 niL of 3M aqueous HCl. The solution was warmed 24 to 35 'C for 3 hours and then stirred for 17h at 25 0 C. The reaction was quenched by adjusting the p1-1 of the solution to 12 with 3M aqueous NaOH-.

26 The mixture was extracted with. Et 2 O and the combined organic layers were 27 washed with H 2 0 and saturated aqueous NaCi before being dried (MgSO 4 WO 02/18361 PCT/US01/25443 0 193 1 and concentrated under reduced pressure. The title compound 613 rag O 2 was used without further purification.

3 1 HNMR (CDCl 3 8: 7.43 (2H, d, J 8.3 Hz), 7.17 (2H, d, J 8.3 Hz), 1.89 00 4 (2H, bs), 1.07 (2H, 0.95 (2H, m).

N-[1-(4-bromophenvl)-cyclopropvll-propionamide (Intermediate 117) N 6 To a solution of l-(4-bromophenyl)-cyclopropylamine (Intermediate 07 116, 84 mg, 0.4 mmol) in 4 mL CH 2

C,

2 at room temperature was added 8 propionyl chloride (43.0 mg, 0.47 mmol) and pyridine (56.0 mg, 0.71 9 mmol). After stirring 17 hours at room temperature the reaction was quenched by the addition of H20 and extracted with EtOAc. The combined 11 extracts were washed with 10% aqueous HC1, saturated aqueous NaHCO 3 12 and saturated aqueous NaCI before being dried (MgSO4) and concentrated 13 under reduced pressure. The title compound 85.0 mg was isolated 14 by column chromatography (20-50% EtOAc-hexanes) as a colorless solid.

'H NMR (CDCI 3 6: 7.48 (2H, d, J 8.5 Hz), 7.09 (2H, d, J 8.5 Hz), 6.40 16 (1H, 2.19 (2H, q, J 7.2 Hz), 1.18-1.24 (4H, 1.12 (3H, t, J 7.2 Hz).

17 1 -(4-Bromophenyl)-cyclopropyl]-propylamine (Intermediate 118) 18 To a solution of N-[1-(4-bromophenyl)-cyclopropyl]-propionamide 19 (Intermediate 117, 85.0 mg, 0.32 mmol) in THF (5 mL) at 0 OC was added

BH

3 -Me 2 S (48.0 mg, 0.63 mmol; 0.31 mL of a 2M solution in THF). The 21 solution was heated to 55 °C for 17 hours, cooled to room temperature, 22 saturated aqueous NaHCO 3 was added and the resulting mixture was stirred 23 for 2 hours. This mixture was extracted with EtOAc and the combined 24 organic layers were washed with H20 and saturated aqueous NaCl before being dried (MgSO 4 and concentrated under reduced pressure. The title 26 compound was isolated by column chromatography (10-30% EtOAc- 27 hexanes).

WO 02118361 WO 0218361PCTIUS01/25443 0 194 I 'HL NMIR (CDCI 3 8: 7.42 (211, d, J =8.5 Hz), 7.19 (2H1, d, J =8.5 Hz), 2.46 2 (2H1, t, J 7.3 Hz), 1.40 (2H, in), 0.98 (2H1, in), 0.86 (5H, in).

003 Propvl-f 1-(-imfii~gyIpey)a )%ol-m 4 (Intermediate 119) Using General Procedure D; [I -(4-bromopheny1)-CYClopropyl]- 6 propylamine (Intermediate 118, 100.0 ing, 0.39 nunol) in triethylamine (8 7 mL) was treated with copper(I)iodide (13.0 mg, 0.06 innol) and then 8 sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 9 minols) was then added followed by dichlorobis(triphenylphosphine)palladiUIQ (48.0 ing, 0.06 mmol). The I1I resulting reaction mixture was heated to 70 'C for 5days. The title 12 compound (80.0 mig, was isolated by chromatography (0 10% EtOAc 13 hexanes) as an orange oil.

14 'H NMvR (CDCI 3 8: 7.41 (2H, d, J =8.5 Hz), 7.21 (2H4, d, J =8.5 Hz), 2.45 (2H, t, J 7.3 Hz), 1.39 (2K1 in), 0.98 mn), 0.87 (211, in), 0.84 (311, t, J 16 7.3 Hz), 0.24 (911, s).

17 [1-(4-Ethvnvlphenyfl)-cclopropyll-propylamfifle (Intermediate 120) 18 Using General Procedure E; propy1-[I1-(4-triinethyIsilaflylethynyl- 19 phenyl)-cyclopropyl)-axnine (Intermediate 119, 80.0 mg, 0.30 minols) in methanol (8 inL) was treated with potassium carbonate (80.0 mg, 0.59 21 minol) and stirred overnight at ambient temperature. The crude alkyne (58 22 mg, 100%) was used directly in the next reaction.

23 'H NMR (CDC 3 )8 :7.44 (211, d, J =8.5 Hz), 7.24 (2H1, d, J 8.5 Hz), 3.05 24 (1H, 2.46 (214, t, J 7.3 Hz), 1.41 (2H, mn), 1.00 (21-1, mn), 0.90 (2H, in), 0.86 t, J 7.3 Hz).

26 Etyl I prgolamino-cvclopropvfl-phenyletn-belzoate 27 (Compound 107, General Formula 2) WO 02/18361 WO 0218361PCT[USOI/25443 195 r-I Using General Procedure F; [1 -(4-ethynylphenYl)-CYC0POPYl1 0 2 propylamine (intermediate 120, 3 8.0 mg, 0. 19 mmol) and ethyl1-4-iodo 00 3 benzoate (Reagent A, 58.0 mng, 0.21 mmol) in triethyl. amine (6 mL) was 4 treated with copper(I)iodide (8.0 mg, 0.04 mniol) and sparged with argon for 5 minutes. Dichlorobis(tripheflphosphine)palladium(U') (27 mg, 0.04 6 mmol) was added and the reaction mixture was stirred overnight at room 7 temperature. Column chromatography (5-15% EtOAc hexanes) afforded 8 40.0 mg of the title compound as an orange oil.

9 1H NMR (CDCl 3 8.'01 (2H, d, J 8.5 Hz), 7.57 (2H, d, J 8.5 Hz), 7.49 (2H, d, 3 9 .5 Hz), 7.28 (2H4, d, J 8.5 Hz), 4.39 (2H, q, J 7.1 Hz), 2.49 11 (24,tJ17.3 Hz), 1.46 (2H, 1.41 (3H,t, J =7.1 Hz), 1.01 (211,m), 0.89 12 (2H4, in), 0.87 (31, t, J 7.3 Hz).

13 44[4-(1 FPropylamino-eycpropyl1)-pheniyletygyll-benzoic acid 14 (Compound 108, General Formula 2) Using General Procedure 1; a solution of ethyl 4-[4-(1-propylamino- 16 cyclopropyl)-phenylethynyl]-benzoate (Compound 107, 40.0 mg, 0. 12 17 mmol) in ethanol (3 niL) and tetrahydrofuran (3 nL) was treated with 18 NaOH (160.0 mig, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred 19 overnight at room temperature. Work-up afforded 25.0 mng of the title compound as a solid.

21 'H1 NNvMi (d 6 -DMSO) 8: 7.97 (2H, d, J 8.5 Hz), 7.65 (2H, di, J 8.5 Hz), 22 7.5 0 (2H1, di, J 8. 5 Hz), 7.3 6 (2H, d, J 8.5 Hz), 2.3 9 (2H1, t, J3 7.3 Hz), 23 1.37 (2H, in), 1.00 (211, in), 0.93 (2H1, mn), 0.84 (3H1, t, J1 7.3 Hz).

24 r 1-(4-Bromophenvl)-CYclopropvl]-diprop~ylaniine (Intermediate 121) To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 26 116) in CH- 3 CN HOAc (5 mL, 9: 1, v/v) and THF 3 mL at 0 'C was added 27 propionaldehyde (277.0 mng, 4.95 inmols) and NaCNBN 3 (153.0 mg, 2.47 WO 02/18361 WO 0218361PCTIU S01/25443 196 1 mmols). The reaction was warmed to room temperature and after 2 quenched with 1120. The pH of the solution was adjusted to 8-9 using 00 3 aqueous NaOH and extracted with EtOAc. The combined extracts were 4 washed with 1120 and saturated aqueous NaCi, dried (MgSO 4 and concentrated under reduced pressure. The title compound, 190.0 mg 6 was isolated by coluim chromatography EtOAc-hexanes).

7 'H1 NMR (CDCI 3 8: 7.42 (21H, d, J =8.3 Hz), 7.18 (2H, d, J 8.3 H4z), 2.39 8 (4H, t, J =7.3 Hz), 1.62-1.40 (4H, in), 0.96 (211, in), 0.86 (6H, t, J 7.3 9 Hz), 0.80 (2H, m).

Dipropyl-f 1-(4-triMethylsila fnvlyn1pheyycoPropyl-arflfl I1I (Intermediate 122) 12 Using General Procedure D; [1-(4-broinophenyl)-cyclopropyll- 13 dipropylainine (Intermediate 121, 150.0 mg, 0.50 inmol) in triethylamine 14 (5 mL) was treated with copper(1)iodidc (10.0 mg, 0.05 inmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 16 minols) was then added followed by 17 dichlorobis(triphenylphosphine)palladium(I1) (35.0 mng, 0.05 inmol). The 18 resulting reaction mixture was heated to 70 0 C for 5d. The title compound 19 was isolated by chromatography (0 3% EtOAc hexanes).

'H NMIR (CDCI 3 5: 7.3 5 (211, d, J 8.3 Hz), 7.24 (2H1, d, J =8.3 Hz), 2.3 9 21 (4H, t, J =7.3 Hz), 1.55-1.42 (4H, in), 0.96 (2H, in), 0.88-0.79 (81-1, in), 0.25 22 (9H, s).

23 f 1 -(4-Ethynylnhenv1-cvclopropvll-dipropvlamine (Intermediate 123) 24 Using General Procedure E; dipropyl-[1I (4ftrimethylsilanylethynylphenyl)-cyclopropyl]-amine (Intermediate 122, 45.0 mig, 0. 14 nimols) in 26 methanol (5 niL) was treated with potassium carbonate (50.0 mg, 0.37 27 inmol) and stirred overnight at ambient temperature. The crude atkyne (34 WO 02/18361 PCTIUS01/25443 197 1 mg, was used directly in the next reaction.

2 'H4 NMR (CDCI 3 6: 7.42 (2H1, d, J 8.3 Hz), 7.28 (2H, d, J 8.3 Hz), 3 2.40(4H1, t, J 7.3 Hz), 1.53-1.40 (4HL in), 0.96 (2H1, in), 0.90-0.79 mn).

00 4 Ethl 4[4 diproylaxnino-cyclopropV1)-phefVehnlbzoe (Compound 109, General Formula 2) 6 Using General Procedure F; [1-(4-ethynylphenyl)-cycIopropyl]- 7 dipropylamine (Intermediate 123, 34.0 mg, 0. 16 inmol) and ethyl-4-iodo 8 benzoate (Reagent A, 59.0 mng, 0.21 mmol) in triethyl amine (6 mnL was 9 treated with copperq)iodide (13.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(fl) (49 mg, 0.07 11 inmol) was added and the reaction mixture was stirred overnight at room 12 temperature. Column chromatography EtOAc hexanes) afforded 13 the title compound as a yellow oil.

14 'H NMR (CDCI 3 8: 8.03 (211, d, J 8.2 Hz), 7.58 (2H, d, J =8.2 Hz), 7.49 (2H1, d, J 8.2 Hz), 7.30 (2H, d, J 8.2 Hz), 4.39 (2H, J 7.1 Hz), 2.43 16 (4H, t, J =7.3 Hz), 1.52-1.42 (4H, in), 1.41 (311, t, J =7.1 Hz), 0.99 (2H1, 17 in), 0.88-0.83 (8H, in).

18 4-r4-(l1-Dipropylamino-cyclojpropyl)-phenlelthynyl]-benzoic acid 19 (Compound 110, General Formula 2) Using General Procedure I; a solution of ethyl 21 dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 109, 22 5 1.0 mng, 0. 13 imol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 23 treated with NaOH (80.0 mg, 2.0 iniols, 2.0 mL of a IN aqueous solution) 24 and stirred overnight at room temperature. Work-up afforded 32.0 mg of the title compound as a colorless solid.

26 'H NMR (d 6 -DMSO) 8: 7.98 (211 d, J 8.3 Hz), 7.67 (6H, in), 3.05-2.89 27 (411, in), 1.98 (2H1, in), 1.72 (4H, in), 1.23 (2K1 mn), 0.88 (611, t, J 7.3 Hz).

WO 02/18361 PCT/US01/25443 198 1 Benzvl- 1-(4-bromophel)-cyclopro ll-amine (Intermediate 124) and 2 Dibenzyl-1 -(4-bromophenvl-cvyclopropyl-aine (Intermediate 125) 3 A solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 00 4 116, 244.0 mg, 1.15 mmols) and benzyl bromide (255.0 mg, 1.50 mmols) in 4 mL DMF was stirred at 85 'C for 6 hours, cooled to room temperature and 6 stirred overnight. The solution was diluted with H0O and the pH adjusted to 7 8-9 with aqueous NaOH. The solution was extracted with EtOAc and the 8 combined organic layers were washed with HO20 and saturated aqueous 9 NaC1, dried (MgSO 4 and concentrated under reduced pressure. Column chromatography (5-10% EtOAc-Hexanes) afforded 110 mg of the N- 11 benzyl amine.

12 'H NMR (CDCl 3 8: 7.48 (2H, d, J 8.4 Hz), 7.30-7.23 (7H, 3.68 (2H, 13 1.07 (2H, mn), 0.93 (2H, and 100 mg of the NN-dibenzyl 14 amine, 'H NMR (CDCI 3 8: 7.55 (2H, d, J 8.3 Hz), 7.40-7.19 (12H, m), 3.61 (4H1, 0.87 (2H11, 0.71 (2H, m).

16 Benzvl-f 1-(4-trimethylsilanvlethynl-phenyl-cyclopropyll-anine 17 (Intermediate 126) 18 Using General Procedure D; benzyl-[1-(4-bromophenyl)- 19 cyclopropyl]-amine (Intermediate 124, 110.0 mg, 0.36 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) 21 and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 22 7.1 mmols) was then added followed by 23 dichlorobis(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol). The 24 resulting reaction mixture was heated to 70 OC for 5d. The title compound 85 mg was isolated by chromatography (1 10% EtOAc hexanes).

26 'H NMR (CDCl 3 8: 7.46 (2H, d, J= 8.3 Hz), 7.31-7.22 (71H1, 3.67 (2H, 27 1.06 (2H, 0.94 (211, 0.26 (91H1, s).

WO 02/18361 WO 0218361PCT/US01/25443 0 199 1 Benzyl-fl (4-ethvnvlphny):ctoprOPallamile (Intermediate 127) 2 Using General Pocedure E; benzyl-[ I (4-trimethy1silanylethylylI- 0C) 3 phenyl)-cyclopropyl)-arnife (Intermediate 126, 85.0 mg, 0.27 ninol) in 4 methanol (5 inL) was treated with potassium carbonate (50.0 mg, 0.37 mmnol) and stirred overnight at ambient temperature. The crude alkyne 6 mg, 100%) was used directly in the next reaction.

7 'H NMR (CDC1 3 8: 7.49 (211, d, J =7.9 Hz), 7.32 (2H1, d, J =7.9 Hz), 7.23 8 (5H1, mn), 3.68 (2K1 3.08 (111, 1.07 (2H, in), 0.95 (2H, mi).

9 Etyl 1-benzvamino-gcc~oropyl)-pheVethvyfll-beflZate (Compound 111, General Formula 2) I1I Using General Procedure F; benzyl-[l-(4-ethynylphenyl)- 12 cyclopropyl]-amiue (Intermediate 127, 65.0 mg, 0.27 minol) and ethyl-4- 13 iodo, benzoate (Reagent A, 68.0 mng, 0.27 inmol) in triethyl amine (8 mL) 14 was treated with copper(1)iodide (16.0 mg, 0.08 minol) and sparged with argon for 5 minutes. Dichiorobis (triphenylphosphine)palladiun(II) (58 mg, 16 0.08 minol) was added and the reaction mixture was stirred overnight at 17 room temperature. Column chromatography EtOAc hexanes) 18 afforded 90 mg of the title compound as an orange solid.

19 'H NMR (CDCI 3 5: 8.05 (2H, d, J 8.3 Hz), 7.61 (211, d, J 8.3 Hz), 7.55 (211, d, J 8.1 Hz), 7.43 (2H1, d, J 8.1 Hz), 7.32-7.22 (511, mn), 4.40 (2H, q, 21 J 7.1 3.72 (2H1, 1.42 (211, t, J =7.1 Hz), 1.01 (2H, in), 0.99 (2H4, 22 in).

23 4-(4-(1-Benzlaxnino-eyclopropyflphenyle~tynl]-benzoic acid 24 (Compound 112, General Formula 2) Using General Procedure I; a solution of ethyl 4-[4-(1-benzylarnino- 26 cyclopropyl)-phenylethynyl]-benzoate (Compound 111, 75.0 ing, 0.19 27 nnmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) was treated with WO 02/18361 WO 0218361PCT/US01/25443 200 I NaOH (80.0 mng, 2.0 mmols, 2.0 ml of a IN aqueous solution) and stirred 2 overnight at room temperature. Work-up afforded 35.0 mg of the 00 3 title compound as a colorless solid.

4 'H NM(CD 3 OD) 8: 7.93 (2H, d, J =8.3 Hz), 7.61-7.5 1 (614, in), 7.32-7.23 (5H, in), 3.98 (2H4, 1.33(211, in), 1.19 (2H4, in).

6 Dibenzyl- 1 (-rmtysl~tnlphnl-corpl-mn 7 (Intermediate 128) 8 Using General Procedure D; dibenzyJ-jjl -(4-bromophenl- 9 cyclopropyl] -amine (Intermediate 125, 45.0 mg, 0. 11 inmol) in triethylainine (8 inL) was treated with copper(1)iodide (10.0 mg, 0.05 inmol) 11 and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.35 g, 12 3.6 inmols) was then addcd followed by 13 dichlorobis(triphenylphosphine)palladium(ll) (35.0 mg, 0.05 nimol). The 14 resulting reaction mixture was heated to 70T 0 for 5d. The title compound 40 mg was isolated by chromatography (hexanes).

16 'H NMR (CDCl 3 8: 7.52 (2H1, d, .1 8.3 Hz), 7.36-7.24 (12H, mn), 3.60 (4H1, 17 0.87 (2H4, mn), 0.67 (2H, rn), 0.29 s).

18 Dibenzyl-r 1-(4-ethy lpeyl)-cclopropyll-amine (Intermediate 129) 19 Using General Procedure E; dibenzyl-[ 1-(4-trimethylsilanylethynylphenyl)-cyclopropyll-amine (Intermediate 128, 100.0 ing, 0.26 inmol) in 21 methanol (5 mL) was treated with potassium carbonate (60.0 mng, 0.44 22 rnmol) and stirred overnight at ambient temperature. The crude alkyne 23 mg, 99%) was used directly in the next reaction.

24 'H1 NMR (CDCI 3 7.53 (21-1, d, J =7.9 Hz), 7.36 (2141, d, J =7.9 Hz), 7.28- 7.2 5 (10OH, in), 3.62 (4H4, 3. 11 (11H, 0. 88 (211, mn), 0. 68 (2H, mn).

26 Etl 4-f 1-dibenzvlainino-cyclopropyl)-phenvlethvnvyll-benzoate 27 (Compound 113, General Formula 2) WO 02/18361 WO 0218361PCT/US01/25443 0 201 1Using G eneral Procedure F; dibenzy1-[ I-(4-ethyflPheflYl) 2 cyclopropyl]-amifle (intermediate 129, 40 .0 mg, 0. 12 mrnol) and ethyl-4- 00 3 iodo benzoate (Reagent A, 60.0 mg, 0.22 mrnol) in triethylamine (5 mL) 4 was treated with copper(I)iodide (8.0 mg, 0.04 inmol) and sparged with argon for 5 minutes. Dichiorobis (triphenylphosphifle)palladium(ll) (27 mg, 6 0.04 mmol) was added and the reaction mixture was stirred overnight at 7 room temperature. Column chromatography EtOAc hexanes) 8 afforded the title compound as an oil.

9 'H NMiR (CDCl 3 5: 8.04 (2H1, d, J =8.5 Hz), 7.79 (411, in), 7.42 (211, d, J 7.9 Hz), 7.29-7.17 (1011, in), 4.40 (2H1, q, J 7.1 Hz), 3.63 (4H, 1.42 11 (311, t, J 7.1 Hz), 0.88 (211, in), 0.73 (2H, mn).

12 4-r4-( 1 DibenzyIamino-cvclonronv1)-phenvyetvnvll-benzoic acid 13 (Compound 114, Formula 2) 14 Using General Procedure I; a solution of ethyl dibenzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 113, 16 4 8.0 ing, 0.-10 mxnol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was 17 treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a IN aqueous solution) 18 and stirred overnight at room temperature. Work-up afforded 42.0 mg 19 of the title compound as a colorless solid.

'H NMR (d 6 -DMSO0) 6: 7.98 (2H, d, J 8.2 Hz), 7.67 (211, d, J =8.2 Hz), 21 7.64 (2H, d, J 7.9 Hz), 7.47 (2K1 d, J =7.9 Hz), 7.28-7.20 (1IOH, in), 3.57 22 (41, 0.84 (211, in), 0.69 (211, in).

23 Benzvl4 1 -(4-bromonhenvU)-cvclopropyl]-methylainine (Intermediate 130) 24 To a solution of benzyl-I(4-bromopheny1)-cyclopropy1-arniine (Intermediate 124, 100.0 mng, 0.33 mmol) in 5 mL of acetone was added 26 K 2 C0 3 (91 ing, 0.66 inmol) and iodomethane (2.28 g, 16.1 mmols). The 27 resulting mixture was stirred at 25 0 C for 20 hours, diluted with Et 2 O, and WO 02/18361 PCTUSOI/25443 202 1 washed with HO 2 0 and saturated aqueous NaCI. The solution was dried 2 (MgSO 4 and concentrated under reduced pressure to give 90 mg of oO 3 the title compound.

ri 4 'H NMR (CDCl 3 8: 7.47 (2H, d, J 8.5 Hz), 7.29-7.18 (7H, 3.53 (2H, 2.07 (3H, 1.07 (2H, 0.86 (2H, m).

IO 6 Benzyl-1-(4-trimethylsilanylethynyl-phenyl)-cyclopropvyll-methYlamin 7 (Intermediate 131) 8 Using General Procedure D; benzyl-[l-(4-bromophenyl)- 9 cyclopropyl]-methylamine (Intermediate 130, 90.0 mg, 0.28 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (6.0 mg, 0.03 mmol) 11 and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 12 7.1 mmols) was then added followed by 13 dichlorobis(triphenylphosphine)palladium(II) (20.0 mg, 0.03 mmol). The 14 resulting reaction mixture was heated to 70 C for 5 days. The title compound 80 mg was isolated by chromatography EtOAc- 16 hexanes).

17 'H NMR (CDC 3 8: 7.46 (2H, d, J 8.2 Hz), 7.32-7.18 (7H, 3.52 (2H, 18 2.06 (3H, 1.06 (2H, 0.87(2H, 0.26 (9H, s).

19 Benzvl-r1 -(4-ethynvlphenyl)-cvclopropyll-methvlamine (Intermediate 132) 21 Using General Procedure E; benzyl-[1-(4-trimethylsilanylethynyl- 22 phenyl)-cyclopropyl]-methylamine (Intermediate 131, 80.0 mg, 0.24 mmol) 23 in methanol (5 mL) was treated with potassium carbonate (80.0 mg, 0.59 24 mmol) and stirred overnight at ambient temperature. The crude alkyne mg, 99%) was used directly in the next reaction.

26 'H NMR (CDC1 3 8: 7.49 (21H1, d, J= 8.2 Hz), 7.33-7.21 (7H, 3.55 (2H, 27 3.08 (1H, 2.08 (3H11, 1.07 (2H, 0.89 (2H, m).

WO 02/18361 WO 0218361PCTfUSOI/25443 203 1Ethy I (benZyl-mtylaniino)-cyclopropvU-pheflyletynyl -benzoate 2 (Compound 115, General Formula 2) 00 3 Using General Procedure F; benzy1-[j1-(4-ethynylphenyl)- 4 cyclopropyll-methylamine (Intermediate 132, 70.0 mg, 0.28 mmol) and ethyl-4-iodo benzoate (Reagent A, 77.0 mg, 0.28 mmol) in triethylamine IND 6 mnL) was treated with copper(I)iodide (18.0 mg, 0. 10 mmol) and sparged 7 with argon for 5 minutes. Diehiorobis (triphenylphosphine)palladium(fl) 8 (65 mg, 0. 10 nunol) was added and the reaction mixture was stirred 9 overnight at room temperature. Column chromatography EtOAc hexanes) afforded 86 mg of the title compound as an oil.

11 'H NUR (CDCI 3 8: 8.03 (2H, di, J 8.5 Hz), 7.59 (2H, d, J 8.5 Hz), 7.53 12 (211, di, J 8.2 Hz), 7.36 (2H1, d, J 8.2 Hz), 7.25 (5H, in), 4.39 (2H, q, J= 13 7.1 Hz), 3.57 (2H, 2.10 (3H, 1.41 (3H, t, J 7.1 Hz), 1. 10 (2H, in), 14 0.92 (2H1,m).

4-r4-(1 -Bcnzlmethylarnino-cvclopropvl)-p2henylthynyll-benzoic acid 16 (Compound 116, General Formula 2) 17 Using General Procedure I; a solution of ethyl 4-{4-[1-(benzyl- 18 methylamnino)-cyclopropyl]-phenylethynyl}-benzoate (Compound 115, 65.0 19 mg, 0. 16 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a IN aqueous solution) and 21 stirred overnight at room temperature. Work-up afforded 45.0 mg of 22 the title compound as a solid.

23 'H1 NMR (d 6 -DMSO) 5: 7.96 (2H, di, J =8.3 Hz), 7.66 (2H, di, J 8.3 Hz), 24 7.58 (211, d, J 8.2 Hz), 7.42 (2H1, dI, J =8.2 Hz), 7.29-7.18 in), 3.52 (2K-I 2.00 (311, s),1.02 (21H, in), 0.87 (211, in).

26 (4-Bromo-2-methyl-vhenyl-methanol (Intermediate 133) 27 A solution of methyl 4-bromo-2-methyl-benzoate (1.05 g, 4.58 WO 02/18361 PCTUS01/25443 204 1 mmols) in 10 mL of Et 2 O was cooled to 0 C and treated with LiAIH 4 2 (177.0 mg, 4.58 mmols), stirred for 3 hours, and then carefully quenched 00 3 with H20. The mixture was extracted with Et 2 O and the combined organic C' 4 layers were washed with H20 and saturated aqueous NaC1, dried (MgSO 4 and concentrated under reduced pressure. The title compound, 830.0 mg 6 was isolated by column chromatography (10-30% EtOAc-hexanes) 7 as a colorless oil.

8

L

H NMR (CDCI 3 8: 7.30 (2H, 7.18 (1H, d, J 8.8 Hz), 4.57 (2H, d, J 9 5.5 Hz), 2.27 (3H, 2.13 (1H, t, J 5.5 Hz).

(4-Bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134) 11 To a solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 12 133, 500.0 mg, 2.48 mmols), in 10 mL THF was added triethylamine (374.0 13 mg, 3.70 mmols) and chlorotrimethylsilane (297.0 mg, 2.70 mmols). The 14 resulting solution was stirred for 17 hours at 25 °C and then treated with HO and extracted with Et 2 O. The combined organic layers were washed 16 with H 2 0, 10% aqueous HC1, saturated NaHCO 3 and saturated NaCI before 17 being dried (MgSO 4 and concentrated under reduced pressure. The title 18 compound, 550.0 mg was isolated by column chromatography 19 EtOAc-hexanes) as a colorless oil.

'H NMR (CDCl 3 8: 7.35-7.28 (3H, 4.64 (2H, 2.29 (3H, 0.20 (9H, 21 s).

22 2-Methyl-4-trimethylsilanylethynyl-1-trimethylsilanyloxymethyl-benzene 23 (Intermediate 135) 24 Using General Procedure D; (4-bromo-2-methyl-benzyloxy)trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine 26 (8 mL) was treated with copper(I)iodide (38.0 mg, 0.20 mmol) and then 27 sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.05 g, 10.6 WO 02/18361 WO 0218361PCT/USOI/25443 205 1 mmols) was then added followed by 2 dichlorobis(triphenylphosphine)palladium(ll) (142.0 mg, 0.20 mrnol). The 00 3 resulting reaction mixture was heated to 70 TC for 5 days. The title 4 compound (380.0 mg, 65%) was isolated by chromatography (0 2% EtOAc hexanes) as an orange oil.

IND 6 'H NMR (CDCl 3 8: 7.31 in), 4.64 2.24 (3 H, 0.24 (9H, s), 7 0. 15(911,s).

8(4-Eth yvl-2-methyl-phenyfl-methanol (Intermediate 136) 9 Using General Procedure E; 2-methyl-4-trimethylsilanylethynyl-1Itrimethylsilananyloxyinethyl-benzene (Intermediate 135, 380.0 mg, 1.30 11 inmols) in methanol (10 mL) was treated with potassium carbonate (180.0 12 mg, 1.3 mmol) and stirred overnight at ambient temperature. The crude 13 ailcyne was purified by column chromatography (5-20% EtOAc-hexanes) to 14 give 100.0 mg of the title compound.

'H NMR (CDCI 3 8: 7.06 (3H, in), 4.42 (2H, d, J 5.2 Hz), 2.81 (1H4, s), 16 2.05 1.59 (1H, t, J =5.2 Hz).

17 Ethyl 4-(4-hydroxymthy-3-metl-phenyletgynl)-benzoate (Compound 18 117, General Formula 6) 19 Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanoI (Intermediate 136, 100.0 mg, 0.44 inmol) and ethyl-4-iodo, benzoate 21 (Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treated 22 with copper(1)iodide (29 mg, 0. 15 mm 01) and sparged with argon for 23 minutes. Dichlorobis(riphenylphosphine)palladium(II) (102mig, 0.15 24 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (20-40% EtOAc hexanes) afforded 26 130.0 mng of the title compound as an orange solid.

27 'H NMVR (CDCI 3 8: 7.98 (2H, d, J 8.2 Hz), 7.56 (2H1, d, J =8.2 Hz), 7.3 6 WO 02/18361 WO 0218361PCT[US01/25443 206 1 (3H, in), 4.65 (2H, 4.36 (2H, q, J 7.1 Hz), 2.40 (1H1, 2.30 (3H1, s), 2 1.39 (3H, t,J =7.1Hz).

00 3 Etl 4-(4-bromomethyl-3-mgetl-phenylethnyl)-benzoate (Intermediate 4 137) A solution of ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)- IND 6 benzoate (Compound 117, 130.0 mg, 0.44 mmol) and triphenyiphosphine 7 (150.0 mg, 0.57 mmol) in 5 mL CH 2

I

2 was cooled to 0 'C and N- 8 bromosuccemimide (10 1.0 mg, 0.57 mmol) was added in 5 portions over 9 minutes. The solution was warmed to 25 *C and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO 3 The 11 resulting mixture was extracted with Et 2 O and the combined organic layers 12 were washed with H 2 0 and saturated aqueous NaCi before being dried 13 (Na2SO 4 and concentrated under reduced pressure. The title compound, 14 120.0 mg was isolated by column chromatography EtOAchexanes) as a colorless solid.

16 'H1NMIR (CDCI 3 8.01 (2H, d, J 8.1 Hz), 7.56 (2H, d, J 8.1 Hz), 7.32 17 (3H4, mn), 4.48 (2H4, 4.38 (2H4, q, J 7.1 Hz), 2.40 (3H4, 1.39 (3H, t, J= 18 7.1 Hz).

19 Etyl 4-(4-imidazol-l1 yl-methyl-3-mgthvl-p~henylthynyfl-benzoate (Compound 118, General Formula 6) 21 A solution of imidazole (30.0 mg, 0.44 mmol) in 2 mL DIff was 22 treated with NaHl (11. 0 mg, 0.44 iniol) and heated to 90 0 C. After Ilh a 23 solution of ethyl 4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate 24 (Intermediate 137, 120.0 mng, 0.34 minol) in 2 mL DMF was added and stirring at 90 'C continued for 1 hour. The solution was cooled to room 26 temperature and concentrated under reduced pressure. The title compound, 27 90.0 mng (7 1 was isolated by column chromatography (20-100% EtOAc- WO 02/18361 WO 02/836 1PCT[USOI/25443 207 I hexanes) as a colorless solid.

2 ]H NMR (CDC1 3 8: 8.02 (2H, d, J 8.5 Hz), 7.57 (2K1 d, J 8.5 Hz), 7.51 00 3 (1H, 7.40 (111, 7.36 (11-L dd, J 1.2, 7.9 Hz), 7. 10 (1H, 6.93 (1H, 4 d, J =7.9 Hz), 6.88 (1H, t, J =1.7 Hz), 5.12 (2H1, 4.38 (21-1, q, J 7.1 Hz), 2.27 (3H1, 1.40 (3H, t, J 7.1 Hz).

IND 6 4-(4-Imidazol- 1 -vl-methyl-3-methyl-phenvlethynyl)-benzoic acid 7 (Compound 119, General Formula 6) 8 Using General Procedure 1; a solution of ethyl 4-(4-imidazol- 1 9 ylmnethyl-3-methyl-phenylethynyl)-benzoate (Compound 118, 82.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with I11 NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a IN aqueous solution) and stirred 12 overnight at room temperature. Work-up afforded 5 1.0 mg of the 13 title compound as a solid.

14 'H NMvR (d 6 -DMSO) 8: 9.20 (111, 7.97 (211, d, J =8.2 Hz), 7.73 (21-1, in), 7.65 (2H4, d, J 8.2 Hz), 7.52 (111, 7.46 (111, d, J =7.9 Hz), 7.13 (1lH, d, 16 J =7.9 Hz), 5.50 (2H, 2.32 (311, s).

17 4-Bromo-l1-bromomethyl-2-methyl-benzene (Intermediate 138) 18 A solution of (4-bromo-2-methyl-pheny 1)-methanol (Intermediate 19 133, 319.0 mg, 1.58 mnol) and triphenyiphosphine (466.0 mg, 1.74 mmol) in 5 mL. CH 2 C1 2 was cooled to 0 TC and N-bromosuccininide (309.0 mg, 21 1.74 minol) was added in 5 portions over 20 minutes. The solution was 22 warned to 25 OC and stirred for 17 hiours. The reaction was quenched by 23 the addition of dilute aqueous NaHCO 3 The resulting mixture was 24 extracted with Et 2 Q and the combined organic layers were wa.&hd with H 2 0 and saturated aqueous NaCI before being dried (N% 2

SO

4 and concentrated 26 under reduced pressure. The title compound, 350.0 mg; was isolated 27 by column chromatography EtOAc-hexanes) as a colorless oil.

WO 02/18361 WO O21~361PCTIUSOI/25443 208 1 'H NMR (CDCl 3 8: 7.32 d, J =2.0 Hz), 7.29 (11, dd, J 7.9 Hz), 2 7.15 (1H, d, J 7.9 Hz), 4.43 (2H, 2.37 (3H, s).

00 3 1 .44-Bromo-2-methyl-benzvl)- 1H-imidazole (Intermediate 139) 4 A solution of imidazole (58.0 mg, 0.86 mmnol) in 3 mL DM1? was treated with NaHl (20.0 mg, 0.86 inmol) and heated to 90 After lh a IND6 solution of 4-bromo-l1-bromomethyl-2-methyl-benzene (Intermediate 138, 7 190.0 mg, 0.72 mmol) in 3 miL DMF was added and stirring at 90 TC 8 continued for ihour. The solution was cooled to room temperature and 9 concentrated under reduced pressure. The title compound, 160.0 mg (88%) was isolated by column chromatography MeOH-EtOAc) as a colorless 11 solid.

12 'H NMR (CDCl 3 5: 7.46 (111, 7.34 (1H1, dcl, J =1.8 Hz), 7.30 (lH, dd, J 13 1.8, 8.2 Hz), 7.08 (IH, t, J 1.2 Hz), 6.83 (1IH, t, J =1.2 Hz), 6.80 (1H, d, 14 J =8.2 Hz), 5.03 (211, 2.23 (31H, s).

1 -(2-Methyl-4-trimethylsilanylthynvl-benZyl)-lIH-imidazole (Intermediate 16 140) 17 Using General Procedure D; 1-(4-bromo-2-methyl-benzyl)-IH- 18 imidazole (Intermediate 139, 160.0 mg, 0.64 mmol) in triethylamine (8 19 mnL) was treated with copper(I)iodide (12.0 mg, 0.07 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 0.71 21 mmols) was then added followed by 22 dichlorobis(triphenylphosphine)palladium(II) (45.0 mg, 0.07 mnmol). The 23 resulting reaction mixture was heated to 70' 0 C for 5 days. The title 24 compound (140.0 mg, 82%) was isolated by chromatography MeOH- EtOAc as an orange oil.

26 1H NMR (CDCI 3 8: 7.53 (111, 7.38 (111, 7.34 (11-1, d, J =8.0 Hz), 27 7.15 (1H1, 6.94 (111, 6.91 (111, d, J 8.0 Hz), 5.14 (2H, 2.29 (311, WO 02/18361 WO 0218361PCTfUS01/25443 209 1 0.31 (9H, s).

2 1 -(4-Ethvnyl-2-methyl-benzyl)- lH-imidazole (Intermediate 141) 0C) 3 Using General Procedure E; l-(2-methyl-4-trimethylsilanylethynyl- 4 benzyl)-LIH-imidazole (Intermediate 140, 140.0 mg, 0.53 mmols) in methanol (5 mL) was treated with potassium carbonate (100. 0 mg, 0.72 6 mmol) and stirred overnight at ambient temperature. The crude alkyne (105 7 mg, 100%) was used directly in the next reaction.

8 'H NMIR (CDCl 3 8: 7.49 (I14, 7.35 (1H, 7.31 (1H, dd, J 1.7, 7.9 9 Hz), 7. 10 (1H, 6.69 (111, d, J =7.9 Hz), 6.85 (1H, t, J 1.2 Hz), 5.14 (2H, 3.08 (IH, 2.26 (3H, s).

11 Methyl [4-(4-imidazol- 1 -yl-methyl-3-metyl-phenylethypyl)-phenyll-acetate 12 (Compound 120, General Formula 6) 13 Using General Procedure F; l-(4-ethynyl-2-methyl-benzyl)-1H- 14 imidazole (Intermediate 141, 101.0 mg, 0.53 mmol) and methyl-(4iodophcnyl)-acetate (Reagent B, 145.0 nmg, 0.53 mmol) in triethylamine 16 mL) was treated with copper(I)iodide (34.0 mg, 0. 18 mmol) and sparged 17 with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) 18 (124 mg, 0. 18 mmol) was added and thc reaction mixture was stirred 19 overnight at room temperature. Column chromatography MeGH- EtOAc) afforded 45.0 mg of the title compound as an orange o .il.

21 'H NMvR (CDCl 3 8: 7.47 (311, in), 7.35 (3H, in), 7.27 (3H, mn), 6.91 (LH, d, 22 J 7.3 Hz), 5.11 (211, 3.70 (311, 3.64 (2H, 2.26 (3H, s).

23 r4-(4-Imidazol- 1 -yl-metl-3 -methvl-phenvlethyUYl):phenv Fl -acetic acid 24 (Compound 121, General Formula 6) Using General Procedure I; a solution of methyl [4-(4-imidazol-1I- 26 ylmethyl-3 -methyl-phenylethynyl)-phenyl] -acetate (Compound 120, 45.0 27 mng, 0. 13 nnol) in ethanol (2 mL) and tetrahydrofliran (2 mL) was treated WO 02/18361 PCT/US01/25443 210 1 with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a IN aqueous solution) and 2 stirred overnight at room temperature. Work-up afforded 30.0 mg of 00 3 the title compound as a pale-orange solid.

4 'H NMR (d 4 -MeOH) 8: 8.97 (1H, 7.60 (2H, d J 8.8 Hz), 7.47 (3H, m), 7.41 (1H, d, J 7.9 Hz), 7.30 (2H, d, J 7.9 Hz), 7.23 (1H, d, J 7.9 Hz), S6 5.51 (2H, 3.64 (2H, 2.33 (3H, s).

7 1-Isopropyl-3-methoxy-benzene (Intermediate 142) 8 To a solution of 3-isopropyl-phenol (5.00 g, 36.2 mmols) in 50 mL of 9 acetone was added K 2

CO

3 (7.50 g, 54.3 mmols) and iodomethane (10.3 g, 72.5 mmols). The resulting solution was heated to 50 °C and stirred for 18 11 hours, cooled to room temperature, and concentrated under reduced 12 pressure. The residual oil was dissolved in Et 2 O and washed with 13 saturated aqueous NaHCO 3 and saturated aqueous NaCl before being dried 14 (MgSO 4 and concentrated under reduced pressure. The crude methyl ether was used without further purification.

16 'H NMR (CDCl 3 5: 7.22 (1H, t, J 8.1 Hz), 6.84-6.72 (3H, 3.81 (3H, 17 2.88 (1H, septet, J 7.0 Hz), 1.25 (6H, d, J 7.0 Hz).

18 1-Bromo-2-isopropyl-4-methoxy-benzene (Intermediate 143) 19 A mixture of 1-isopropyl-3-methoxy-benzene (Intermediate 142, 3.50 g, 23.3 mmols), molecular sieves, and silica gel in 150 mL CC1 4 was 21 treated with N-bromosuccinimide (4.98 g, 28.0 mmols) at 35 °C for 18 22 hours. An additional portion of N-bromosuccinimide (830.0 mg, 4.46 23 mmols) was added and stirring continued for 6 hours. The mixture was 24 cooled to room temperature, H20 was added, and the mixture was filtered to remove the solids. The mixture was extracted with EO 2 and the combined 26 organic layers were washed with 10% aqueous HC1, H 2 0, saturated aqueous 27 NaHCO 3 and saturated NaCI before being dried (MgSO 4 and concentrated WO 02/18361 PCT/US01/25443 S211 1 under reduced pressure. Column chromatography EtOAc-hexanes) 2 afforded 4.34 g of the title compound as a pale-yellow oil.

00 3 'H NMR (CDCI 3 8: 7.41 (IH, d, J= 8.8 Hz), 6.82 (1H, d, J 2.6 Hz), 6.61 4 (IH, dd, J 2.6, 8.8 Hz), 3.79 (3H, 3.31 (1H, septet, J 6.7 Hz), 1.23 (6H, d, J 6.7 Hz).

IND 6 4-Bromo-3-isopropyl-phenol (Intermediate 144) 7 To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene 8 (Intermediate 143, 2.20 g, 9.60 mmols) in 50 mL CH 2 Clz at -78 °C was 9 added BBr 3 (4.81 g, 19.2 mmols; 19.2 mL of a 1M solution in CH 2 C1l).

After stirring for 3 hours at -78 °C the solution was warmed to 0 OC for 3 11 hours and then at 25 OC for 1 hour before being quenched with H20. The 12 mixture was diluted with Et 2 O and washed with HzO and saturated aqueous 13 NaCI, dried (Na 2

SO

4 and concentrated under reduced pressure. Column 14 chromatography (2.5-10% EtOAc-hexanes) afforded the title compound as a colorless oil.

16 'H NMR (CDC 3 8: 7.38 (1H, d, J 8.5 Hz), 6.79 (1H, d, J 2.9 Hz), 6.57 17 (1H, dd, J 2.9, 8.5 Hz), 3.31 (1H, septet, J 7.0 Hz), 1.22 (6H, d, J 18 Hz).

19 (4-Bromo-3-isopropyl-phenoxy-tert-butyl-dimethyl-silane (Intermediate 145) 21 A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13 22 g, 5.25 mmols), chloro-tert-butyl-dimethylsilane (0.95 g, 6.30 mmols), and 23 imidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25 °C for 3 24 hours. The solution was diluted with H0O and extracted with Et 2 O and the combined organic layers were washed with H20, saturated aqueous NaC1, 26 and dried (MgSO 4 before being concentrated under reduced pressure.

27 Column chromatography EtOAc-hexanes) afforded 1.50 g of WO 02/18361 PCTIUSO1/25443 Q212 1 the title compound as a colorless oil.

2 'HNMR (CDC 3 8: 7.32 (1H, d, J 8.8 Hz), 6.73 (1H, d, J 3.0 Hz), 6.52 00 3 (1H, dd, J 3.0, 8.8 Hz), 3.26 (1H, septet, J 6.7 Hz), 1.19 (6H, d, J 6.7 4 Hz), 0.96 (9H, 0.17 (6H, s).

4 5 4-(Tert-butyl-dimethyl-silanyloxy)-2-isopropyl-benzaldehyde 6 (Intermediate 146) 7 A solution of (4-bromo-3-isopropyl-phenoxy)-tert-butyl-dimethyl- 8 silane (Intermediate 145, 1.03 g, 3.13 mmols) in 25 mL EzO was cooled to 9 -78 °C and treated with tert-butyllithium (401.0 mg, 6.26 mmols; 3.7 mL of a 1.7M solution in pentane). After 30 minutes the reaction was quenched 11 with DMF (913.0 mg, 12.5 mmols) and warmed to room temperature. The 12 solution was diluted with H20, extracted with Et 2 O and the combined 13 organic layers washed with H 2 0 and saturated aqueous NaCl before being 14 dried (MgSO 4 and concentrated under reduced pressure. Column chromatography EtOAc-hexanes) afforded 480.0 mg of the title 16 compound as a colorless oil.

17 'H NMR (CDC3) 8: 10.19(1H, 7.72 (1H, d, J= 8.5 Hz), 6.85 (1H, d, J= 18 2.3 Hz), 6.77 (1H, dd, J 2.3, 8.5 Hz), 3.97 (1H, septet, J 6.7 Hz), 1.27 19 (6H, d, J 6.7 Hz), 1.00 (9H, 0.25 (6H, s).

4-Hydroxy-2-isopropyl-benzaldehvde (Intermediate 147) 21 To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl- 22 benzaldehyde (Intermediate 146, 880.0 mg, 3.17 mmols) in 6 mL THF at 0 23 OC was added tetrabutylammonium fluoride (1.66 g, 6.33 mmols; 6.3 mL of 24 a 1M solution in THF). The pale-yellow solution was stirred for 30 minutes and quenched by the addition of ice cold HO0. The mixture was extracted 26 with EtO2 and the combined organic layers were washed with H20 and 27 saturated aqueous NaCl before being dried (Na 2

SO

4 and concentrated under WO 02/18361 WO 0218361PCT[USOI/25443 213 1 reduced pressure. Column chromatography (20% EtOAc-hexanes) afforded 2 500.0 mg of the title compound as a colorless solid.

00 3 'H NMR (CDCl 3 8: 10.15 (1 H, 7.79 (11H, d, J =8.5 Hz), 6.95 (1 H, d, J 4 2.3 Hz), 6.86 (1IH, dd, J 2.3, 8.5 Hz), 3.96 (111, septet, J 6.7 Hz), 1.29 (6H, d, J =6.7Hz).

ID6 4-Formyl-3 -isopropyl-phenyl 1..1-trifluoro-methansulfonate.

7 (Intermediate 148) 8 A solution of 4-hydroxy-2-isopropyl-benzaldehyde (intermediate 9 147, 300.0 mg, 1.83 mnaol) in 10 mL of CH 2

CI

2 Was cooled to 0 'C and to it was added 11 (754.0 mg, 1.92 mxnol) and triethylamine (592.0 mg, 5.85 mmols). The 12 resulting solution was warmed to room temperature and stirred for 13 hours. The reaction was quenched by the addition of H120 and the mixture 14 extracted with EtOAc and the combined organic layers were washed with 10% aqueous HCl, saturated aqueous NaHCO 3 H120, and saturated aqueous 16 NaCl. The solution was dried (MgSO 4 and concentrated under reduced 17 pressure. The title compound was isolated by column chromatography 18 10% EtOAc-hexanes) as a colorless oil, 470.0 mg; 19 'H NMR (CDC1 3 8: 10.37 7.94 (1H, d, J =8.5 Hz), 7.33 (IH, d, J 2.3 H1z), 7.26 (1 H, dd, J 2.3, 8.5 Hz), 4.00 (1 H, septet, J3=6.7 Hz), 1.3 3 21 (6H, d,J =6.7Hz), 22 4-Llydrox;ymetyl-3-isopropy-phenyl 1,1,1 -trifluoro-methansulfonate 23 (Intermediate 149) 24 To a solution of 4-formyl-3-isopropyl-phenyl 1, 1, 1 -trifluoromethansulfonate (Intermediate 148, 540.0 mg, 1.82 mmols) in 7 mL 26 MeOH at 0 'C was added NaBH 4 (72.0 mg, 1.91 mmols). After stirring 2 27 hours at 0 'C the reaction was carefully quenched with H120 and extracted WO 02/18361 WO 0218361PCTIUSOI/25443 214 1 with Et 2 O. The combined organic layers were washed with H 2 0 and 2 saturated aqueous NaCI, dried (MgSO 4 and concetrated under reduced 00 3 pressure. The title compound was isolated by column chromatography 4 10% EtOAc-hexanes) as a colorless oil, 355.0 mg 'H NM (CDCI 3 8: 7.45 (111, d, J 8.5 Hz), 7.17 (1lH, d, J =2.7 Hz), 7.08 6 (1H, dd, J 2.7, 8.5 Hz), 4.74 (2H, d, J =5.3 Hz), 3.21 (1lH, septet J 7 Hz), 2.12 (IH, t, J 5.3 Hz), 1.24 (611, d, J =7.0 Hz).

8 4-(Tert-butyl-dimetl-silanylox ymetyl)-3-isoproyl-phenyI 1,1,1- 9 trifluoro-methansulfonate (Intermediate 150) A solution of 4-hydroxymethyl-3-isopropyl-phenyl 1,1, 1-trifluoro- 11 methansulfonate (Intermediate 149, 760.0 mg, 2.55 mniols), chloro-tert- 12 butyl-dimethylsilane (470.0 mg, 3.18 mmols), and imidazole (225.0 mg, 13 3.25 mmols) in 6 mL DMFf was stirred at 25 'C for 17 hours. The solution 14 was diluted with H 2 0 and extracted with Et 2 O and the combined organic layers were washed with 10% aqueous HCI, saturated aqueous NaHCO 3 16 1120, and saturated aqueous NaCI, and dried (MgS 04) before being 17 concentrated under reduced pressure. Column chromatography 18 EtOAc-hexanes) afforded 970.0 mg of the title compound as a 19 colorless oil.

'H NMR (CDCI 3 6:7.49 (1H1, d, J 8.5 Hz), 7.10 (111, d, J =2.3 Hz), 7.06 21 (1H, dd, J 2.3, 8.5 Hz), 4.75 (21H, 3. 10 (1 H, septet, J3 6.7 Hz), 1.21 22 (6H, d, J 6.7 Hz), 0.93 (9H1, 0. 10 (6H, s).

23 1 -(Tert-bgUtl-dimetl-silanyjpxymthyl)-2-isoprop 1-4- 24 trimetylsilanyldtynl-benzene (Intermediate 151) To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-3- 26 isopropyl-phenyl 1, 1, 1 -trifluoro-methansulfonate (Intermediate 150, 970.0 27 mg, 2.35 nimols) in triethylamine (2 mL) and 6 mL DMF was sparged with WO 02/18361 WO 0218361PCTfUSOI/25443 215 I argon for 15 minutes. Trimethylsilyl acetylene (1.00 g, 10.6 mniols) was 2 then added followed by dichlorobis(triphenylphosphine)palladium(II) (66.0 0C) 3 mg, 0.09 minol). The resulting reaction mixture was heated to 95 TC for 4 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound (200.0 mg, 78%) was isolated by 6 chromatography (0-25% EtOAc-hexanes) as an orange oil.

7 1 fH NMR (CDC1 3 8: 7.37-7.25 (3H, in), 4.75 (211 3.08 (111, septet, J 8 7.0 Hz), 1.21 (611, d, J 7.0 Hz), 0.92 (9H, 0.25 (914, 0.09 (6H, s).

9 Tert-butvl-(4-etnyl-2-isopropyl-benzyoxy)-dimetvl-silane (Intermediate 152) 11 Using General Procedure E; 1 -(tert-butyl-dimethyl- 12 silanyloxymethyl)-2-isopropyl-4-triinethylsilanylethynyl-benzene 13 (Intermediate 151, 850.0 mng, 2.36 mmols) in methanol (25 mL) was 14 treated with potassium carbonate (250.0 mng, 1.81 inmols) and stirred overnight at ambient temperature. The crude alkyne (650 mg, 95%) was 16 used directly in the next reaction.

17 1H NMR (CDC 3 8: 7.41-7.25 (3H, mn), 4.77 (2H1, 3.07 (lH, septet, J= 18 7 .0 Hz), 3.05 (1 H, 1.22 (611, d, J 7.0 0. 94 (9H, 0. 11 (6H, s).

19 Ety 4-F4-(tert-butl-dimeth2yl-silanyloxyinethyl-3-isopropyI phenyle~thynyll-benzoate (Intermediate 153) 21 Using General procedure F; tert-butyl-(4-ethynyl-2-isopropyl- 22 benzyloxy)-dimethyl-silane (Intermediate 152, 300.0 mg, 1.04 mmols) and 23 ethyl-4-iodo benzoate (Reagent A, 287.0 mg, 1.04 mmols) in triethylamine 24 (8mL) was treated with copper(I)iodide (50.0 mg, 0.26 minol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(JI) 26 (182 mg, 0.26 inmol) was added and the reaction mixture was stirred 27 overnight at room temperature. Column chromatography EtOAc WO 02/18361 WO 0218361PCTfUSOI/25443 216 I hexanes) afforded 310.0 mg of the title compound as an orange solid.

2.

00 3 'H NMR (CDCl 3 8: 8.03 (2H, d, J3 8.5 Hz), 7.60 (2H4, d, J =8.5 Hz), 7.48- 4 7.37 (311, mn), 4.80 (211 4.39 (2H1, q, J 7.1 Hz), 3.14 (1H1, septet, J 6.8 Hz), 1.40 (3 H, t, J 7.1 Hz), 1.27 (6H, d, J 6.8 Hz), 0.96 (9H1, 0. 12 6 (6H, s).

7 Methyl (4-r4-(tert-butyl-dimnetl-silanloxMethyl)-3 -isopropyl- 8 pheniylethvnyl1-phenvyll-acetate (Intermediate 154) 9 Using General Procedure F; tert-butyl-(4-ethynyl-2-isopropylbenzyloxy)-dimethyl-silane (Intermediate 152, 355.0 mng, 1.26 inmols) and 11 methyl-(4-iodophenyl)-acetate (Reagent B, 349.0 mg, 1.26 mrnols) in 12 triethylamine (8 mL) was treated with copper(I)iodide (60.0 mg, 0.32 inmol) 13 and sparged with argon for 5 minutes.

14 Dichlorobis(triphenylphosphine)palladium(ll) (222 mg, 0.32 inmol) was added and the reaction mixture was stirred overnight at room temperature.

16 Column chromatography EtOAc-hexanes) afforded 288.0 nag (66%) 17 of the title compound as an orange oil.

18 'H NMvR (CDCI 3 8: 7.49 (2H1, d, J 8.5 Hz), 7.43-7.3 5 (3H, in), 7.25 (2H, 19 d, J 8.5 4.77 (21L, 3.69 (311, 3.63 (2H, 3.11 (11H, septet, J 6.7 Hz), 1.25 (6H, d, J 6.7 Hz), 0.94 (9H, 0. 10 s).

21 Ethyl r4-(4-hydroxcymethyl-3-isoropyl-pheniylethyniyl)-benzoate 22 (Compound 122, General Formula 6) 23 To a solution of ethyl 4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3- 24 isopropyl-phenylethynyl]-benzoate (Intermediate 153, 3 10.0 mg, 0.71 mmol) in 4 mL THF at 0 'C was added tetrabutylainmonium fluoride (371.0 26 mng, 1.42 nimols; 1.4 niL of a IM solution in THlE). The pale-yellow 27 solution was stirred for 10 minutes and quenched by the addition of ice cold WO 02/18361 WO 0218361PCT1USOI/25443 217 1 H 2 0, The mixture was extracted with Et2O and the combined organic layers 2 were washed with 1120 and saturated aqueous NaCI before being dried 0C) 3 (Na 2

SO

4 and concentrated under reduced pressure. Column 4 chromatography (20-30% EtOAc-hexanes) afforded 200.0 mg of the title compound as a colorless solid.

6 'H NMR (CDCl 3 8: 7.98 (2H1, d, J 8.5 Hz), 7.58 (2H, d, J 8.5 Hz), 7.48 7 (1 H, 7.3 5 (2H, in), 4.71 (2H, 4.3 5 (2H, q, J =7.1 Hz), 3.19 (1 H, 8 septet, J =7.0 Hz), 2.51 (111 1.39 (3H, t, I 7.1 Hz), 1.25 (6H, d, J 9 Hz).

Megthyl 4-hydro~metyl-3-isopropl-phenyehyy)-phnv1-actt I1I (Compound 123, General Formula 6) 12 To a solution of methyl f{4-[4-(tert-butyl-dimnethyl-silanyloxymethyl)- 13 3 -isopropyl-phenylethynyl]-phenyl}I-acetate (Intermediate 154, 288.0 mg, 14 0.66 mmol) in 5 inL THE at 0 *C was added tetrabutylamrnoniurn fluoride (471.0 mg, 1.80 rnrols; 1.8 mL of a IM solution in THE). The pale-yellow 16 solution was stirred for 15 minutes and quenched by the addition of ice cold 17 H 2 0. The mixture was extracted with Et.O and the combined organic layers 18 were washed with H120 and saturated aqueous NaCI before being dried 19 (Na 2

SO

4 and concentrated under reduced pressure. Column chromatography (5-10% EtOAc-hexanes) afforded 180.0 mg of the 21 title compound as a colorless solid.

22 'H NMR (CDCI 3 8: 7.48 (3H, in), 7.32 (2H, in), 7.24 (2H, d, J 8.5 Hz), 23 4.69 (2H, 3.68 (3H, 3.62 (2H, 3.18 (111, septet, J 7.0 Hz), 2.21 24 (111, 1.25 (61-I, d, J =7.0 Hz).

Ethyl [4-(4-bromomethyl-3-.isopropyl-p2heylethnyfl-benzoate 26 (Intermediate 155) 27 A solution of ethyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)- WO 02/18361 PCT/US01/25443 218 1 benzoate (Compound 122, 200.0 mg, 0.62 mmol) and triphenylphosphine 2 (211.0 mg, 0.81 mmol) in 5 mL CHICl 2 was cooled to 0 °C and N- 00 3 bromosuccinimide (144.0 mg, 0.81 mmol) was added in 5 portions over 4 minutes. The solution was warmed to 25 OC and stirred for 17 hours. The 5 reaction was quenched by the addition of dilute aqueous NaHCO 3 The I\ 6 resulting mixture was extracted with Et 2 O and the combined organic layers S7 were washed with H20 and saturated aqueous NaC1 before being dried 8 (Na 2

SO

4 and concentrated under reduced pressure. The title compound, 9 220.0 mg was isolated by column chromatography EtOAchexanes) as a pale-yellow solid.

11 'H NMR (CDC1 3 6: 8.03 (2H, d, J 8.2 Hz), 7.59 (2H, d, J 8.2 Hz), 7.48 12 (1H, 7.31 (2H, m) 4.55 (2H, 4.39 (2H, q, J 7.1 Hz), 3.29 (1H, septet, 13 J= 7.0 Hz), 1.40 (3H, t, J 7.1 Hz), 1.30 (6H, d, J= 7.0 Hz).

14 Methyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Intermediate 156) 16 A solution of methyl [4-(4-hydroxymethyl-3-isopropyl- 17 phenylethynyl)-phenyl]-acetate (Compound 123, 180.0 mg, 0.56 mmol) and 18 triphenylphosphine (190.0 mg, 0.73 mmol) in 5 mL CH 2 C1 2 was cooled to 0 19 °C and N-bromosuccinimide (130.0 mg, 0.73 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25 °C and stirred for 17 21 hours. The reaction was quenched by the addition of dilute aqueous 22 NaHCO 3 The resulting mixture was extracted with Et 2 O and the combined 23 organic layers were washed with H20 and saturated aqueous NaCI before 24 being dried (Na 2

SO

4 and concentrated under reduced pressure. The title compound, 212.0 mg was isolated by column chromatography 26 10% EtOAc-hexanes) as a pale-yellow oil.

27 'H NMR (CDC1,) 8: 7.48 (3H, 7.28 (4H, 4.55 (2H, 3.69 (3H, s), WO 02/18361 WO 0218361PCTfUS01125443 219 1 3.63 (2H, 3.28 (11H, septet, J 7.0 Hz), 1.30 (6H, d, J 7.0 Hz).

2 Etl [4-(4-imidazol- 1 -y-methyl-3-isopropyl-phenyletyl)-vDhenvll- 00 3 benzoate (Compound 124, General Formula 6) 4 A solution of ethyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)bcnzoatc (Intermediate 155, 120.0 mg, 0.31 mimol) and 1-acetylimidazole 6 (36.0 mg, 0.33 mrnol) in 5 mL CH 3 CN was heated at 65 'C for 4 hours and 7 then at 55 'C for 16 hours. The solution was cooled to room temperature, 8 diluted with 1120 and made basic by addition of Na 2 C0 3 and extracted with 9 EtOAc. The combined organic layers were washed with H.0 and saturated aqueous NaCl, dried (MgSO 4 and concentrated under reduced pressure.

11 Column chromatography Et 3 N in 5% MeOH-EtOAc) afforded 75.0 mg 12 of the title compound as a colorless solid.

13 'H NMR (CDCl 3 8: 8.03 (2H1, d, J =8.5 Hz), 7.60 (2H, d, J 8.5 Hz), 7.53 14 (1H1, d, J 1.5 Hz), 7.49 (lH, 7.35 (1H, dd, J 1.5, 7.9 Hz), 7.09 (1H, bs), 6.98 (1H, d, J 7.9 Hz), 6.85 (1UL bs), 5.19 (2H, 4.39 (2H, q, J 7.1 16 Hz), 3.08 (1H, septet, J 6.8 Hz), 1.40 (3141, t, J 7.1 1.20 (6H1, d, J= 17 6.8 Hz).

18 Metl [4-(4-imidazol- 1-yl-mety-3-ispropvyl-phenylethynvh-phenyll- 19 acetate (Compound 125, General Formula 6) A solution of methyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)- 21 phenyll -acetate (Intermediate 156, 72. 0 mg, 0. 19 mrnol) and 1 22 acetylimidazole (22.0 mg, 0.20 mmol) in 5 mL CH 3 CN was heated at 65 0

C

23 for 8h and then at 55 TC for 16 hours. The solution was cooled to room 24 temperature, diluted with H 2 0 and made basic by addition of Na 2

CO

3 and extracted with EtOAc. The combined organic layers were washed with H 2 0 26 and saturated aqueous NaCl, dried (MgSO 4 and concentrated under 27 reduced pressure. Column chromatography Et 3 N in 5% MeO11- WO 02/18361 WO 0218361PCTfUSOI/25443 220 1 EtOAc) afforded 40.0 mg of the title compound as a colorless solid.

2 'H NM (CDCI 3 8: 7.49 (4H, in), 7.33 (1H, dcl, J 1.5, 7.9 Hz), 7.28 (2H, 00 3 d, J 8.5 Hz), 7.08 (1H, t, J 1.2 Hz), 6.95 (1W, d, J 7.9 Hz), 6.84 (LW, t, 4 J 1.2 Hz), 5.17 (2H, 3.70 (3H1, 3.64 (2H, 3.06 (1H, septet, J 6.8 1.20 (6H,d, J =6.8 Hz).

6 4-(4-Imidazol- 1-yl-methyl-3-isopropy-phenyletyff l-phenyl-benzoic 7 acid (Compound 126, General Formula 6) 8 Using General Procedure 1; a solution of ethyl [4-(4-imidazol-1I- 9 ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-benzoate (Compound 124, 75.0 mg, 0.20 mmol) in ethanol (4 mL) and tetrahydrofliran (1 miL) was 11 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 niL of a IN aqueous solution) 12 and stirred overnight at room temperature. Work-up afforded 68.0 mg 13 (8 of the title compound as a colorless solid.

14 'H NMR (d 4 -MeOH) 8: 9.01 (LH, 8.01 (2H, d, J 8.2 Hz), 7.63-7.57 (5H, in), 7.44 (1W, d, J 7.9 Hz), 7.29 (1H, d, J 7.9 Hz), 5.59 (2H, s), 16 3.17 (1H, septet, J 6.8 Hz), 1.20 (6H, d, J 6.8 Hz).

17 f 4-(4-Imidazol- I -yl-mcitl-3-ispropyl-phenylethvnyL-phenvlI-acetic acid 18 (Compound 127, General Formula 6) 19 Using General Procedure I; a solution of methyl [4-(4-imidazol-1ylxnethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 125, 40.0 21 mg, 0. 11 mmol) in ethanol (4 niL) and tetrahydrofuran (1 niL was treated 22 with NaCH (120.0 mg, 3.0 mmols, 3.0 niL of a iN aqueous solution) and 23 stirred overnight at room temperature. Work-up afforded 22.0 mg of 24 the title compound as a colorless solid.

'H NMR (d 4 -MeOH) 8: 9.02 (1H, bs), 7.62 (1H, t, J 1.4 Hz), 7.58 (211, in), 26 7.49 (2H, d, J =8.2 Hz), 7.43 (1H, dd, J 7.9 Hz), 7.31 (3H, mn), 5.58 27 (2H1, 3.68 (2H, 3.16 (1IIK septet, J =6.7 Hz), 1. 18 (6H, d, J 6.7 Hz).

WO 02/18361 PCTUS01/25443 S221 1 4-Bromo-N-cyclopropyl-2-methyl-benzamide (Intermediate 157)

O

2 A solution of4-bromo-2-methylbenzoic acid and SOC1 2 was refluxed 00 3 for 3 hours, cooled to room temperature and concentrated under reduced 4 pressure. The residue was dissolved in 30 mL CH 2 Cl1 and combined with cyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine (2.05 g, 26.0 6 mmols). The solution was stirred for 18 hours and then diluted with EtOAc 7 before being washed with 5% aqueous HCI, saturated NaHCO 3 and 8 saturated aqueous NaCI. The solution was dried (MgSO 4 and concentrated 9 under reduced pressure leaving the title compound as a colorless solid.

tH NMR (CDCI 3 8: 7.34 (1H, d, J 2.3 Hz), 7.28 (1H, dd, J 2.3, 8.2 Hz), 11 7.13 (1H, d, J= 8.2 Hz), 6.10 (1H, bs), 2.85 (1H, 2.37 (3H, 0.85 (2H, 12 0.59 (2H, m).

13 (4-Bromo-2-methyl-benzyl)-cyclopropyl-amine (Intermediate 158) 14 To a solution of 4-bromo-N-cyclopropyl-2-methyl-benzamide (Intermediate 157, 1.81 g, 7.12 mmols) in THF (12 mL) was added 16 BH 3 .SMe 2 (1.08 g, 14.24 mmols). The solution was heated to 60 OC for 6 17 hours, cooled to room temperature and carefully treated with saturated 18 aqueous Na 2

CO

3 (30 mL) and stirred for 17 hours. This mixture was 19 extracted with EtOAc and the combined organic layers were washed with

H

2 O, saturated aqueous NaCI before being dried (MgSO 4 and concentrated 21 under reduced pressure. The title compound was isolated by column 22 chromatography (10-15% EtOAc-hexanes).

23 'H NMR (CDC 3 8: 7.26 (2H, 7.12 (1H, d, J 7.9 Hz), 3.76 (2H, s), 24 2.31 (3H, 2.14 (1H, 0.44 (2H, 0.36 (2H, m).

(4-Bromo-2-methyl-benzvl)-cyclopropvl-ethyl-amine (Intermediate 159) 26 A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine 27 (Intermediate 158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0 WO 02/18361 WO 0218361PCTIUSOI/25443 222 1 mmols), and K 2 C0 3 (690.0 mg, 5.00 mmols) in 10 mL acetone was heated at 2 60 0 C for 18 hours. The mixture was cooled to room temperature, diluted 00 3 with H 2 0, and extracted with EtOAc. The combined organic layers were 4 washed with H120 and saturated aqueous NaC] before being dried (MgSO 4 and concentrated under reduced pressure. The title compound was isolated IND 6 by column chromatography EtOAc-hexanes).

7 'H NMR (CDCl 3 5: 7.23 (211, in), 7.12 (1 H, d, J =7.6 Hz), 3.62 (2H, s), 8 2.56 (2H1, q, J 7.3 Hz), 2.29 (3H, 1.75 (1H1, rn), 1.04 (3H4, t' J 7.3 Hz), 9 0.39 (2H, mn), 0.30 (2K1 in).

Cyclopropyl-etl4(2-methyl-4-timethylsilanlethynyl-benzfl)-amine 11 (Intermediate 160) 12 Using General Procedure D; (4-bromo-2-methyl-benzyl)- 13 cyclopropyl-ethyl-ainine (Intermediate 159, 620.0 mg, 2.31 inmols) in 14 triethylamine (8 mL) was treated with copper()iodide (44.0 mg, 0.23 mmol) and then sparged with argon for 15 minutes. Trimethylsilylacetylene (1.04 16 g, 10.6 mmols) was then added followed by dichlorobis- 17 (triphenylphosphine)palladium(fl) (162.0 mg, 0.23 nunol). The resulting 18 reaction mixture was heated to 70 T for 5 days. The title compound (650.0 19 mg, 98%) was isolated by chromatography EtOAc hexanes).

'H NMvR(CDC 3 8: 7.32 (1H, 7.20 (214, in), 3.65 (2H1, 2.55 (2H, q, I 21 =7.3 Hz), 2.28 (3H, 1.74 (1H1, in), 1.03 (3H1, t, J 7.3 Hz), 0.36 (2H1, m), 22 0.27 (211, in), 0.24 (911, s).

23 Cvclopropl-etl44-ethynyl-2-methyl-benzyfl-amine (Intermediate 161) 24 Using General Procedure E; cyclopropyl-ethyl-(2-inethyl-4triiethylsilanylethynyl-benzyl)-amine (Intermediate 160, 650.0 mg, 2.30 26 nimols) in methanol (1lOmL) was treated with potassium carbonate (100. 0 27 mng, 0.72 minol) and stirred overnight at ambient temperature. The crude WO 02/18361 WO 0218361PCT[USOI/25443 223 1 alkyne (495 mg, 99%) was used directly in the next reaction.

2 'H NMIR (CDCI 3 6: 7.32 (1K, 7.21 (211 in), 3.66 (211, 3.01 (111 s), 00 3 2.56 (2H, q, J 7.3 Hz), 2.29 (31L 1.76 (11, mn), 1.04 (311, t, J 7.3 Hz), 4 0.40 (2H, in), 0.29 (211, m).

Ethyl 4-i4-(ccoproy-ethw1-anino)-nethyll-3-methyl-phnlethynyll~- 6 benzoate (Compound 128, General Formula 6) 7 Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl- 8 benzyl)-amine (Intermediate 161, 190.0 mg, 0.89 mmol) and ethyl-4-iodo 9 benzoate (Reagent A, 245.0 mg, 0.89 mmol) in triethylamine (5 mL) was treated with copper(1)iodide (56.0 ing, 0.30 inmol) and sparged with argon I1I for 15 minutes. Dicblorobis(triphenylphosphine)-palladium(fl) (208 mg, 12 0.30 mmol) was added and the reaction mixture was stirred overnight at 13 room temperature. Column chromatography EtOAc hexanes) 14 afforded the title compound.

'H NMR (CDCl 3 5: 8.01 (211, d, 3 8.2 Hz), 7.56 (2H, d, J =8.2 Hz), 7.3 1- 16 7.24 (3H1, in), 4.38 (2H, q, J 7.1 Hz), 3.68 (211, 2.58 (2H1, q, J 7.3 17 Hz), 2.32 (3H1, 1.77 (LH, mn), 1.39 (3H1, t, J =7.1 Hz), 1.05 (3H1, t, J 7.3 18 Hz), 0.39 (2H1, in), 0.31 (2H, mn).

19 Methyl f4-(cclopropyl-ethyl-amino)-methyll-3-methvl-phenylethynylI phenyl)-acctate) (Compound 129, General Formula 6) 21 Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl- 22 benzyl)-amine (Intermediate 161, 300.0 mg, 1.41 inmols) and methyl-(4- 23 iodophenyl)-acetate (Reagent B, 388.0 mg, 1.41 inmols) in triethylamine (8 24 mL) was treated with copper(I)iodide (67.0 ing, 0.35 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) 26 (246 mg, 0.35 inmol) was added and the reaction mixture was stirred 27 overnight at room temperature. Column chromatography EtOAc WO 02/18361 WO 02Th361PCTrUSOI/25443 224 1 hexanes) afforded 270.0 mg of the title compound as a pale-yellow 2 oil.

003 'H NMvR (CDCI 3 5: 7.47 (211, d, J =7.9 Hz), 7.30-7.22 in), 3.70 (3H, 4 3.68 (2H, 3.63 (21L, 2.58 (2H, q, J 7.3 Hz), 2.32 (3H1, 1.77 (111, in), 1.05 (3K-I t, J 7.3 Hz), 0.39 (211, in), 0.30 (2H, mn).

6 4-{4-[(Cyclopropyl-etyl-amnino)-meth l-3-netl-phenvlethynyl 1-benzoic 7 acid: (Compound 130, General Formula 6) 8 Using General Procedure 1; a solution of ethyl 4- {4-[(cyclopropyl- 9 ethyl-axnino)-methyl]-3-methyl-phenylethynyl}-benzoate (Compound 128, 130.0 mg, 0.36 inmol) in ethanol (5 mL) and tetrahydrofuran (5 inL) was 11I treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) 12 and stiffed overnight at room temperature. Work-up afforded 115.0 mg 13 of the title compound as a colorless solid.

14 'H NMiR (d 6 -acetone) 8: 8.05 (2H, d, J 8.2 Hz), 7.64 (2H4, d, J 8.2 Hz), 7.32 (311, mn), 3.73 (211, 2.59 (2H, q, J 7.3 Hz), 2.35 (3H, 1.83 (111 16 in), 1.05 (3H, t, J 7.3 Hz), 0.38 (2H, mn), 0.27 (2H, in).

17 {4-I(Cyclopropyl-etlwl-axnino)-methyll-3-methyl-phenylethvnvl 18 phenfl-acetic acid (Compound 131, General Formula 6) 19 Using General Procedure I; a solution of methyl (4-{4-[cyclopropylethyl-aniino)-methyl]-3-inethyl-phenylethynyl}.phenyl)-acetate (Compound 21 129, 140.0 ing, 0.3 9 inmol) in ethanol (5 mL) and tetrahydrofuiran (5 inL) 22 was treated with NaOH (360.0 mg, 9.0 nmmols, 3.0 mL of a 3N aqueous 23 solution) and stirred overnight at room temperature. Work-up followed by 24 HPLC (Partisil- 10 pac 10% H 2 0-CH 3 CN) afforded the title compound.

'IH NMR (CDCI 3 8: 7.45 (2H, d, J3 8.2 Hz), 7.25 (5H, in), 4.16 (2H1, m), 26 3.82 3.56 (2K1 2.75 (2H, q, J 7.3 Hz), 2.30 (3H1, 1.86 (111, 27 in), 1. 14 (311, t, J 7.3 0. 54 (211, mn), 0.46 (211, mn).

WO 02/18361 PCT/US01/25443 S225 1 Ethyl {4-(4-cyclopropylaminomethyl-3-isopropyl-phenylethynyl -benzoate

O

2 (Compound 132, General Formula 6) 00 3 A solution of ethyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)- S4 benzoate (Intermediate 155, 110.0 mg, 0.29 mmol) and cyclopropylamine (420.0 mg, 7.4 mmols) in EtOH (5 mL) was stirred at 25 °C for 6 hours and 6 then concentrated under reduced pressure. The residue was dissolved in 7 EtOAc and washed with saturated aqueous NaHCO 3 H20 and saturated 8 aqueous NaCI. The solution was dried (MgSO 4 and concentrated under 9 reduced pressure to give 103 mg of the title compound as an orange oil.

11 1H NMR (CDC13) 8: 8.01 (2H, d, J 8.5 Hz), 7.59 (2H, d, J 8.5 Hz), 7.47 12 (1H, 7.30 (2H, 4.38 (2H, q, J 7.1 Hz), 3.89 (2H, 3.26 (lH, 13 septet, J= 7.0 Hz), 2.17 (1H, 1.40 (3H, t, J 7.1 Hz), 1.26 (6H, d, J 14 7.0 Hz), 0.45 (2H, 0.39 (2H, m).

Ethyl 4-{4-[(cyclopropyl-ethyl-amino)-methyl-3-isopropyl-phenylethynl}- 16 benzoate (Compound 133, General Formula 6) 17 To a solution of ethyl {4-(4-cyclopropylaminomethyl-3-isopropyl- 18 phenylethynyl}-benzoate (Compound 132, 103.0 mg, 0.29 mmol) in 6 mL 19 of acetone was added ethyl iodide (67.0 mg, 0.43 mmol) and K 2

CO

3 (79.0 mg, 0.57 mmol). The mixture was stirred at 60 °C for 6 hours, cooled to 21 room temperature and quenched by the addition of H20. The mixture was 22 extracted with EtOAc and the combined organic layers were washed with 23 HzO and saturated aqueous NaCl before being dried (MgSO 4 and 24 concentrated under reduced pressure. Column chromatography EtOAc hexanes) afforded 68.0 mg of the title compound.

26 'H NMR (CDCl 3 8: 8.01 (2H, d, J 8.6 Hz), 7.58 (2H, d, J 8.6 Hz), 7.44 27 (1H, 7.28 (2H, 4.39 (2H, q, J 7.1 Hz), 3.73 (2H, 3.55 (1H, WO 02/1836t WO 0218361PCTfUSOI/25443 226 I septet, J3 6.6 Hz), 2.57 (211, q, J 7.3 Hz), 1.75 (1H1, in), 1.40 (3H, t, J 2 7.1 hz), 1.22 (611, d, J =6.6 Hz), 1.05 (311, t, J 7.3 Hz), 0.37 (2H, mn), 0.28 00 3 (2H1, in).

4 4- {4-r(Cyclopropyl-ethyl-amino)-metyll-3-isopropyl-Rhenylethvnvl benzoic acid (Compound 134, General Formula 6) 6 Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropyl- 7 ethyl-amino)-methyl]-3-isopropyl-phenylethynyl)-benzoate (Compound 8 133, 6 8.0 mg, 0. 17 minol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 9 treated with NaOH (600.0 mg, 15.0 inmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55 *C for 9 11 hours. Work-up followed by crystallization of the solid residue from hot 12 CH 3 CN afforded 45.0 mg of the title compound as a pale-yellow 13 solid.

14 'H NN4R (d -acetone) 5: 8.05 (2H, d, J 8.1 Hz), 7.66 (2H, d, J3 8.1 Hz), 7.49 (1H1, 7.32 (2H1, in), 3.78 (214, 3.44 (1H1, septet J 6.7 Hz), 2.59 16 (211, q, J =7.3 Hz), 1.80(111, in), 1.21 (6H1, d, J3 6.7 Hz), 1.05 (3H4, t, J 17 7.3 Hz), 0.40 (2H, mn), 0.26 (2K1 in).

18 Methyl [4-(8.8-dithyl-5-oxo-5.6.7.8-lttrhydro-naphthalen-2-vl-ethynyl)- 19 phenyll-acetate (Compound 4, General Formula 8) Using General Procedure F; 6-ethynyl-4,4-dmethyl-3,4-dihydro-2H- 21 naphthalen-lI-one (Intermediate 13, 190.0 mg, 0.96 mmol) and methyl-(4- 22 iodophenyl)-acetate (Reagent B, 245.0 mng, 0.96 imnol) in triethyl amnine (8 23 niL) was treated with copper(1)iodide (46 mg, 0.24 nimol) and sparged with 24 argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(ll) (168 mg, 0.24 minol) was added and the reaction mixture was stirred overnight at 26 room temperature. Column chromatography (10-20% EtOAc hexanes) 27 afforded 250.0 mng of the title compound as a pale-yellow solid.

WO 02/18361 WO 0218361PCTfUS01/25443 227 I 'H NMvR(CDC1 3 7.99(1H,d, J=7.9 Hz),7.57(1H,d, J =1.5 Hz), 7.51 2 (2H, d, J 8.5 Hz), 7.43 (114, dd, J 1.5, 7.9 Hz), 7.29 (2H, d, J 8.5 Hz), 00 3 3.70 (3H, 3.65 (211, 2.73 (214, t, J 7.0 Hz), 2.04 (2H, t, J =7.0 Hz), 4 1.41 (6H, s).

Metl [4-(5-hydroxvy-88-dimnetl-5,6.7.8-tetrahvdro-naphthalen-2-vl- IND6 ethynyl)-phenyll-acetate (Compound 135, General Formula 4) 7 To a solution of methyl [4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro- 8 naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 4) in 5 mL MeOH at 9 0 *C was added NaBH 4 (18.0 mg, 0.48 mmol). The reaction was stirred at 0 "C for 2 hours and then quenched by the addition of H 2 0, The solution was 11I diluted with Et 2 O and washed with H 2 0 and saturated aqueous NaCI before 12 being dried (MgSO 4 and the solvents were removed under reduced pressure.

13 Column chromatography (20-40% EtOAc-hexanes) afforded 140.0 mg 14 of the title compound as a colorless oil.

'H NMR (CDCl 3 8: 7.49 (3H, in), 7.39 (1IH, d, J3 7.9 Hz), 7.31 (1LH, dcl, J 16 1.5, 7.9 Hz), 7.25 (211I, d, J 8.2 Hz), 4.58 (1H, bs), 3.68 (311, 3.62 (2H1, 17 2.05 (111, in), 1.79 (2H, mn), 1.60 (111, in), 1.33 (3H, 1.26 (3H,s).

18 Methyl r4-(5-imidazol-lI yl-8.8-dirnetl-5.6.7.8-tetrahydro-naht-halen-2- 19 ylethvnvl)-phe~nyl1-acetate (Compound 136, General Formula 4) A solution of methyl [4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro- 21 naphthalen-2-ylethynyl)-phenyl]-acetate (Compound 135, 140.0 mg, 0.40 22 mmol) and carbonyldiin-idazole (136.0 mg, 0.84 minol) in 5 m.L THY was 23 heated to 65 'C for 48 hours. The solution was cooled to room temperature 24 and concentrated under reduced pressure. The residue was dissolved in Et 2

O

and washed with 5% aqueous NaOH, H120, and saturated aqueous NaCl 26 before being dried (Na 2

SO

4 and concentrated under reduced pressure.

27 Column chromatography MeOH-CH 2 Cl 2 afforded 50.0 mg (3 of WO 02/18361 WO 0218361PCT[US01/25443 228 1 the title compound as a colorless solid.

2 'H NMR (CDCl3) 8: 7.57 (114, d, J 1.5 Hz), 7.52-7.45 (314, in), 7.27 (311, 00 3 in), 7.08 (111, 6.81 (2H, in), 5.30 (1H, t, J 5.8 Hz), 3.71 (3H4, 3.65 4 (2H, 2.20 (211, in), 1.75 (2H4, in), 1.40 (311, 1.36 (3H, s).

r4-'5-Imidzl-l1-vl-8,8-dimethyl-5.6.7.8-tetrahvdro-naphthalen-2-vl- 6ethyny-phenyll-acetic acid (Compound 137, General Formula 4) 7 Using General Procedure 1; a solution of methyl [4-(5-imidazol-1-yl- 8 8,8-dimnethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate 9 (Compound 136, 50.0 mg, 0. 13 minol) in ethanol (4 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 niL of a IN aqueous solution) and stirred I I overnight at room temperature. Work-up afforded 40.0 mg of the title 12 compound as a pale-orange solid.

13 1H NMR (d 4 -MeOH) 8: 8.93 (111, 7.68 (1H1, 7.61 (114, 7.54 (114I, s), 14 '7.47 (2K1 d, J 8.2 Hz), 7.31 (3H, in), 6.95 (111, d, J3 8.2 Hz), 5.83 (111, t, J 5.8 Hz), 3.68 (111, 3.63 (IH4, 2.38 (IH, mn), 2.26 (11, in), 1.76 (211, 16 in), 1.45 (3H, 1.36 (311, s).

17 Etl [4-(5-imidazol- 1-yl-8,8-dimethyl-5.6.7,8-tetrahydro-naphthalen-2-yl- 18 etyl)-benzoat (Compound 138, General Formula 4) 19 A solution of ethyl [4-(5-hydroxy-8,8-dimethyl-5 ,6,7,8-tetrahydronaphthalen-2-yl-cthynyl)-benzoate (180.0 mng, 0.52 minol) and 21 carbonyldlimidazole (176.0 mg, 1.08 minol) in 5 mL THF was heated to 22 TC for 21 hours. The solution was cooled to room temperature and 23 concentrated under reduced pressure. The residue was dissolved in Et 2 O and 24 washed with 55 aqueous NaOH, H120, and saturated aqueous NaCI before being dried (Na 2

SO

4 and concentrated under reuced pressure. Column 26 chromatography MeOH-C- 2 C1 2 afforded 50.0 mng of the title 27 compound as a colorless solid.

WO 02/18361 WO 0218361PCT[USOI/25443 229 1 'H NMR (CDG1 3 5: 8.03 (2H, d, J =7.9 Hz), 7.59 (3H,mi), 7.46 (11, s), 2 7.29 (1H1, dd, J 1.5, 8.3 Hz), 7.09 (1H, 6.82 (1H, d, J 8.2 Hz), 6.81 0C) 3 (111, 5.31 (11-1, t, J 5.8 Hz), 4.39 (2H, q, J 7.1 Hz), 2.20 (2H, in), 1.75 4 (2K1 mn), 1.40 (911, in).

r4-(5-Imidazol- 1 -v-8.8-dirnethyl-5,6.7.8-tetrahydro-naphthaen-2-vl- 6 ethynyl)-benzoic acid (Compound 139, General Formula 4) 7 Using General Procedure I; a solution of ethyl [4-(5-imidazol-1-yl- 8 .8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate 9 (Compound 138, 5 0.0 mg, 0. 13 minol) in ethanol (3 niL and tetrahydrofuran (1 inL was treated with NaGH (120.0 mg, 3.0 nimols, 11 mL of a iN aqueous solution) and stirred overnight at room temperature.

12 Work-up afforded 40.0 mng of the title compound as a colorless solid.

13 'H NMvR (d 4 -MeOH) 8: 8.92 (1H, 8.04 (211, d, J 8.2 Hz), 7.74 (11H, d, J 14 1.5 Hz), 7.62 (3H1, mn), 7.57 (1li, t, SJ 1.5 Hz), 7.38 (111, dd, J 7.9 Hz), 6.97 (11H, d, J 7.9 Hz), 5.83 (IH, t, J =5.8 Hz), 2.33 (2H, in), 1.78 16 (2H, in), 1.47 (311, 1.39 (3H, s).

17 2-Isopropy-4-trifluorometharnesulfonlx-bny actt0Itreit 18 162) 19 To a solution of 4-hydroxymethyl-3-isopropylphenyl 1,1,1trifluoromethanesulfonate (Intermediate 149, 190.0 mg, 0.64 mmol) in 21 mL CH 2 Cl 2 was added acetyl chloride (75.0 mg, 0.96 inmol) and 22 pyridine( 0 1.0 mng, 1. 38 iniols). After stirring for 3 hours at 25 'C the 23 reaction was quenched by the addition of 1120 and the resulting mixture 24 extracted with EtOAc. The combined organic layers were washed with H 2 0 and saturated aqueous NaCi, dried (MgSO 4 and concentrated under reduced 26 pressure. The title compound, 182 mig was isolated from the residual 27 oil by column chromatography (5 10% EtOAc-hexanes) as a colorless oil.

WO 02118361 WO 0218361PCTIUSOI/25443 230 I 'H NMR (CDC1 3 8: 7.43 (1H, d, J 8.7 Hz), 7.19 (1H1, d, I1 2.7 Hz), 7.09 2 (11H, dd, J 2.7, 8.5 Hz), 5.17 (2H, 3.18 (1H1, septet, J 6.7 Hz), 2. 00 3 (311, 1.26 (6H, d, J 6.7 Hz).

4 4-Isopropenloxymethyl-3-isopropyl-phenyI 1.1.1trifluoromethanesulfonate (Intermediate 163) ID6 Using General Procedure 1; 2-isopropyl-4- 7 trifluoromethanesulfonyloxy-benzyl acetate (Intermediate 162, 182.0 mg, 8 0.54 mmols), and 1. 1 niL of Tebbe's Reagent (159.0 mg, 0.56 mniols) 9 afforded 130.0 mg of the title compound as a colorless oil after column chromatography EtOAc-hexanes).

11 'H NMR (CDCl 3 5: 7.43 (1H d, J =8.5 Hz), 7.18 (111, d, J 2.6 Hz), 7.09 12 (11H, dd, J 2.6, 8.5 Hz), 4.75 (2H, 3.98 (211, 3.12(111, septet, J 6.7 13 Hz), 1.88 (3H1, 1.25 (6H1, d, J Hz).

14 3-Isopronvl-4-( 1-methy1-cyclorooxmgetl)-v~henly 1.1.1trifluoromethanesulfonate (Intermediate 164) 16 Using General Procedure 2; 4-isopropenyioxymethyl-3 17 isopropylphenyl 1,1,1-trifluoromethanesulfonate (Intermediate 163, 130. 0 18 mg, 0.39 mmol), Et Zn (272.0 mg, 2.2 mmols), and CH 2 1 2 (702.0 mg, 2.6 19 nimols) in 3.0 niL Et 2 O afforded 120.0 mg of the title compound as a colorless oil after column chromatography EtOAc hexanes).

21 'H NMR (CDCl 3 8: 7.39 (1H, d, J 8.5 Hz), 7.13 (1H1, d, J 2.7 Hz), 7.05 22 (1IH, dd, J1 2.7, 8.5 Hz), 4.54 (2H, 3.16 (11H, septet, J 6.7 Hz), 1.47 23 (311, 1.24 (611, d, J 6.7 Hz), 0.86 (2HL in), 0.48 (211, in).

24 r3 -Isoprolpyl4-( I-metyl-cycloprooymetyl)-phenyleyv1 trimthylsilane (Intermediate 165) 26 Using General Procedure D; 3-isopropyl-4-(1-methyl- 27 cyciopropoxymethyl)-phenyl 1,1,1 -trifluoromethanesulfonate (Intermediate WO 02/18361 WO 0218361PCT/USOI/25443 231 1 164, 120.0 mg, 0.34mmol) in triethylamine (2 mL) and anhydrous DMF 2 mL) was sparged with argon for 5 minutes. Trimethylsilyl acetylene (700.0 00 3 mg, 0.71 mmol) was then added followed by 4 dichlorobis(triphenylphosphine)palladium(II) (24.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 95 IC for 60 hours. The title 6 compound 110.0 mg, was isolated by chromatography EtOAc 7 -hexanes).

8 'H NMR (CDCl 3 8: 7.36 (1H, 7.24 (2H, bs), 4.53 (2H, 3.11 (lH1, 9 septet, J 6.7 Hz), 1.45 (3H, 1.22 (6H, d, J 6.7 Hz), 0.85 (211, in), 0.44 (2H, in), 0.25 (9H1, s).

I1I 4-Ethynayl-2-isopropyl- 1 -methyl-cvclopropoxvmetyh-benzene 12 (Intermediate 166) 13 Using General Procedure E; [3-isopropyl-4-(l -methyl- 14 cyrlopropoxymethyl)-phenylethynyl]-trimethylsilane (Intermediate 165, 110.0 mg, 0. 37 mmol) in methanol (6 mL) was treated with potassium 16 carbonate (80.0 mng, 0.58 mmol) and stirred overnight at ambient 17 temperature. The crude alkyne (84 mg, 100%) was used directly in the next 18 reaction.

19 'H NM'R (CDCl 3 5: 7.55 (1H, 7.41 (2H, mn), 4.68 (2H, 3.26 (1H1, septet, J 6.8 Hz), 3.18 (111, 1.60 (3H, 1.37 (6H, d, J 6.8 Hz), 0.99 21 (2H, in), 0.59 (2H, m).

22 Methyl f4-r3 -isop~ropyl-4-( 1-inetlt-cyclopropogxvmethyl)-phenlethynyl- *23 phenvfll-acetate (Compound 140, General Formula 6) 24 Using General Procedure F; 4-ethynyl-2-isopropyl- 1 -methylcyclopropoxymethyl)-benzene (Intermediate 166, 78.0 ing, 0.34 minol) and 26 inethyl-(4-iodophenyl)-acetate (Reagent B, 94.0 mng, 0.34 iniol) in 27 triethylainine (8 inL) was treated with copper(I)iodide (22.0 mng, 0.11 imol) WO 02/18361 WO 0218361PCT[US01/25443 232 I and sparged with argon for 5 minutes.

2 Dichlorobis(triphenylphosphine)palladium(II) (79 mg, 0. 11 minol) was 00 3 added and the reaction mixture was stirred at room temperature for 4 hours. Column chromatography EtOAc hexanes) afforded 77.0 mg of the title compound as a yellow oil.

6 1H NMR (CDCI 3 5: 7.49 d, J 8.2 Hz), 7.43 (lH, d, J3 1.5 Hz), 7.33- 7 7.24 (4H, in), 4.55 (211 3.70 (3H, 3.63 (211, 3.14 (1H, septet, J= 8 6.8 Hz), 1.47 (311, 1.25 (6H, d, J 6.8 Hz), 0.86 (2H, mn), 0.46 (2H, mn).

9 [3-lsopropyl-4-( 1-methyl-cyclopropoxymethyl)-phenletyll-p2heyll acetic acid (Compound 141, Formula 6) 11 Using General Procedure I; a solution methyl {4-[3-isopropyl-4-( 1- 12 methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl }-acetate (Compound 13 140, 70.0 mg, 0. 19 rinol) in ethanol (3 niL) and tetrahydrofuran (3 niL was 14 treated with NaOH (240.0 mg, 6.0 inmols, 2.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up and purification by 16 HPLC (Partisil lO-pac, 10% 11 2 0/CH 3 CN) afforded of the title compound as 17 a colorless solid.

18 'H NMR (CDCI 3 8: 7.50 (2H, d, J =8.2 Hz), 7.43 (1H, 7.33-7.24 (411, 19 mn), 4.55 (2H, 3.65 (2H1, 3.14 (111, septet, J 6.7 Hz), 1.47 (311, s), 1.25 (6H1, d, J =6.7 Hz), 0.87 (211, in), 0.46 (2H, in).

21 2.6-Di-tert-butyLI-4-trimethylsilanylethynyl-phenol: (Intermediate 167) 22 Following General Procedure D and using 4-bromo-2,6-di-r-butyl- 23 phenol (1.43g, 5nunol), triethyl amine (l5mL), anhydrous tetrahycirofuran 24 (1 5inL), copper(I)iodide (0.06g, 0.3 Immnol), trimethylsilyl acetylene (4.9g, 50mniol) and dichlorobis(triphenylphosphine)palladium(II) 1 8g, 26 0.26nimol) followed by flash column chromatography over silica gel (230- 27 400 mesh) using hexane as eluent, the title compound was obtained (1.35g, WO 02/18361 WO 0218361PCT[USOI/25443 233 1 2 'H NMR (300 MHz, CDC1 3 8 7.29 2H1), 5.35 1H1), 1.42 18H), 0.24 00 3 9H).

4 (3,5-Di-tert-butyl-4-methox-phenylethynyl)-trimeh Yl-silan: (Intermediate 168) 6 A solution 2,6-di-tert-butyl-4-trimethylsilanylethynyl-phenol 7 (Intermediate 167, 0.3 02g, 1immol) in acetone (SniL) was treated with 8 potassium carbonate (0.138g, immol) and methyl iodide 142g, Iminol) 9 and stirred overnight at room temperature. The volatiles were distilled off in vacuo and the residue was purified by flash column chromatography on I11 silica gel (230-400 mesh) using ethyl acetate as the eluent to afford the title 12 compound as a white solid (0.28g, 13 'H NMR (3 00 MHz, CDCI 3 8 7.41 211), 3.70 3H), 1.49 18H), 0.3 0 14 9H).

1 .3-Di-tert-butyl-5-ethvnyl-2-methoxy-benzene: (Intermediate 169) 16 Following General Procedure E and (3,5-di-tert-butyl-4-methoxy- 17 phenylethynyl)-trimethyl-silane (Intermediate 168, 0.28g, 0.9mniol), 18 potassium carbonate (0.98g, 7.lImmol) and methanol (iliuL) followed by 19 flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound was obtained (0.23g, 100%).

21 1'H NMR (300 MHz, CDC1 3 8 7.46 211), 3.75 311), 3.05 1H), 1.49 22 1811).

23 .5-Di-tert-butv-4-methoxy-phenylethynvl)-phenyll-acetic acid methyl 24 eser (Compound 142, General Formula Following General Procedure F and using 26 2-methoxy-benzene (Intermediate 169, 0.094g, 0.3 6mmol), methyl-4-iodo 27 phenyl acetate (Reagent B, 0.09g, O.32mmol), triethyl amine WO 02/18361 WO 02/836 1PCTfUSOI/25443 234 I anhydrous tetrahydrofuran (5mL), copper(I)iodide (0.02g, 0. Immol) and 2 dichlorobis(triphenylphosphine)palladium(II) (0.06g, 0.OS5mmol) followed 00 3 by flash column chromatography over silica gel (230-400 mesh) using 10 4 ethyl acetate in hexane as the eluent, the title compound 1 14g, 81 was obtained as an oil.

6 'H NIVR (300 MEz, CDCl 3 8 7.52 2H, J= 8.0Hz), 7.46 2H), 7.28 (d, 7 21-1, J 8.2Hz), 3.72 3H), 3.7 1(s, 311), 3.66 2H), 1.47 I SH).

8 r4-(3.5-Di-tert-buMy-4-methon-n2henvlthvnvl)-phenvl1-acetic acid: 9 (Compound 143, General Formula Following General Procedure I and using [4-(3,5-di-tert-butyl-4- I I methoxy-phenylethynyl)-phenyl]-acetic acid methyl ester (Compound 142, 12 0. 1 14g, 0.29mmol), 5M aqueous sodium hydroxide solution (2mL) and 13 ethanol (4mL), followed by preparative reverse phase 1{PLC using 14 water in acetonitrile as the mobile phase, the title compound was obtained as a white solid (0.097g, 88%).

16 'H NMR (300 Mffz, CDCI 3 8 7.55(d, 2H, J= 8.0Hz), 7.48 2H1), 7.30 (d, 17 211, J =8.2Hz), 3.74 3H), 3.69 211), 1.49 18H).

18 f4-(3.5-Di-tert-buty-4-methoxy-phenylethynyl)-2-fluoro--phenyll-acetic acid 19 methyl ester: (Compound 144, General Formula Following General Procedure F and using 1,3-di-tert-butyl-5-ethynyl- 21 2-methoxy-benzene (Intermediate 169, 0.087g, 0.33mmol), methyl-2- 22 fluoro-4-iodo phenyl acetate (Reagent H, 0.088g, 0.3Ommol), triethyl amine 23 (5mL), anhydrous tetrahydrofuran (I OnL), copper(I)iodide (0.02g, 0.lImmol) 24 and dichlorobis(triphenylphosphine)palladium(Il) (0.06g, 0.O85mmol) followed by flash column chromatography over silica gel (230-400 mesh) 26 using 10 ethyl acetate in hexane as the eluent, the title compound (0.l122g, 27 89%) was obtained.

O

S235 'H NMR (300 MHz, CDCI 3 6 7.46 2H), 7.33-7.24 3H), 3.75 3H), 3.73(s, 3H), 3.72 2H), 1.48 18H).

00 [4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid: (Compound 145, General Formula C' 5 Following General Procedure I and using [4-(3,5-di-tert-butyl-4- O methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid methyl ester C' (Compound 144, 0.122g, 0.29runol), 5M aqueous sodium hydroxide solution (lmL) and ethanol (4mL), followed preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a white solid (0.077g, 'H NMR (300 MHz, CDCl3): 6 7.42 2H), 7.29-7.19 3H), 3.71 2H), 3.69 3H). 1.43 18H).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (128)

1. A pharmnaceutical composition comprising a compound of the 00 formnula -LV AZ-A(R 2 -(CH 2 )-COONe (RII wherein A is a phenyl or naphthyl group, or. heteroaryl selected from a group consisting of pyridyl, thienyl, finyl, pynidazinyl, pyrirnildinyl, pyrazinyl, thiazolyl, oxazoly], imidazolyl 'and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R, groups; X is 0, S or NR where R is H, alkyl of I to 6 carbons or benzvl;. Y is H, alkyl of I to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of I to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I.; Zis -(CRI=CR)n, where n'is an integer having the value I -CO-NR I- NR 1 -CO-; -Co-o-, _0-Go_, -CS-NRm-, NR 1 -CS-, -Co-s-, 237 -S-CO-, R 1 is independently H or alkyl of 1 to 6 carbons; p is an integer having the values of 0 to 4; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF,, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R 3 is independently alkyl of I to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values 0 to 2; R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen; o is an integer having the values of 0 to 2; n is an integer having the values of 0 to 4, and Rg is H, alkyl of 1 to 6 carbons, -CH20(C 1 .6-alkyl), or a cation of a pharmaceutically acceptable base.

2. A composition in accordance with Claim 1 where A is phenyl, naphthyl, pyridyl, thienyl or furyl.

3. A composition in accordance with Claim 1 where n is 0, 1 or 2.

4. A composition in accordance with Claim 1 where Z is -CO- NRI-, or -(CRi=CRI)n, where n' is 1. A composition in accordance with Claim I where the Z group is attached to the 6-position of the bicyclic moiety.

6. A composition in accordance with Claim 1 where X is O.

7. A composition in accordance with Claim I where Y is H, lower O 238 alkyl of 1 to 3 carbons or cyclopropyl.

8. A composition in accordance with Claim 1 where A is phenyl.

9. A composition in accordance with Claim 8 where Z is or r0 CO-O-.

10. A composition in accordance with Claim 9 where Y is H or Scyclopropyl.

11. A pharmaceutical composition comprising a compound of the formula Z 1S Y(CH 2 )n-COOR 8 R2 Y where X is O or CH 3 N; Y is H or cyclopropyl; Z is or -CO-O-; R2 is H or F; n is 0 or 1, and Rg is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.

12. A composition in accordance with Claim 11 where X is O.

13. A composition in accordance with Claim 12 where Y is H and Z is -CEC-.

14. A composition in accordance with Claim 13 where the (CH 2 )nCOORg group is in the 4 position of the phenyl ring. A composition in accordance with Claim 14, which is selected from the group consisting of: 239 benzoic acid, ,4-dihydro-4,4-dimethylspiro[2H- 1 -beazopyran- 2,1' -cyclopropane]-6-y)ethynyl]-, benzeneacetic acid, 4-[(3,4-dihydro-4,4- 00 dimethylspiro[2H- I-benzopyran-2,1' -cyclopropane]-6-yl)ethynyl]- and 2- fluoro-benzoic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H- 1-benzopyran- 2,1 '-cyclopropane]-6-yl)ethynyll- or a salt with a pharmaceutically acceptable base or a C 16 alkyl ester of said compound.

16. A composition in accordance with Claim 12 where Y is cyclopropyl and Z is

17. A composition in accordance with Claim 16 where the (CH 2 )COORg group is in the 4 position of the phenyl ring.

18. A composition in accordance with Claim 17, which is selected from the group consisting of: benzeneacetic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4- direthylspiro[2H- 1-benzopyran-2,1' -cyclopropane]-6-yl)ethynyl]-, cyclopropyl-3 ,4-dihydro-4,4-dimethylspiro[2H- 1 -benzopyran-2, 1'- cyclopropane]-6-y])ethynyl]-2-fluoro-benzeneacetic acid, benzoic acid, 4- [(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2- I -benzopyran-2, 1'- cyclopropane]-6-yl)ethynyl]- and 4-[(8-cyclopropyl-3,4-dihydro-4,4- dimethylspiro[2H- I -benzopyran-2,1' -cyclopropane]-6-yl)ethynyl]-2-fluoro- benzoic acid or a salt with a pharmaceutically acceptable base or a C 6 alkyl ester of said compound.

19. A composition in accordance with Claim 12 where Y is cyclopropyl and Z is -CO-O-. A composition in accordance with Claim 19 where the (CH 2 )nCOORS group is in the 4 position of the phenyl ring.

21. A composition in accordance with Claim 20 which is spiro[2H-1- benzopyran-2,1 '-cyclopropane]-6-carboxylic acid, 8-cyclopropyl-3,4- dihydro-4,4-dimethyl-, 4-(carboxymethyl)phenyl ester or a salt with a cIN 240 pharmaceutically acceptable base or a C 1 -6 alkyl ester of said compound.

22. A composition in accordance with Claim 19 where the 00 (CH 2 ),COOR 8 group is in the 3 position of the phenyl ring. c-i23. A composition in accordance with Claim 22 which is spiro[2H- 1 benzopyran-2,l '-cyclopropane]-6-carboxylic acid, 8-cyclopropyl-3,4- dihydro-4,4-dimethyl-, 3-(carboxymethyl)phenyl ester or a salt with a pharmaceutically acceptable base or a C 1 alkyl ester of said compound. ci24. A composition in accordance with Claim 11I where X is CH3N, Y is Hand Zis A composition in accordance with Claim 22 which is benzoic acid, 1,4,4-trimethylspiro[2H- 1-1,2,3 ,4-tetrahydroquinoline-2, 1'- cyclopropane]-6-yl)ethynyl]- or a salt with a pharmaceutically acceptable base or a C,- 6 alkyl ester of said compound.

26. A pharmaceutical composition comprising a compound of the formula (R 3 4 Z-A(R 2 )-(GH 2 )-COOR 8 R 5 X wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; O 241 X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl; Z is 00 -(CRI=CRi)n where n' is an integer having the value 1 -CO-NRI-, NR 1 -CO-, cI -CO-O-, -O-CO-, c( -CS-NR 1 NRi-CS-, -CO-S-, -S-CO-, R 1 is independently H or alkyl of 1 to 6 carbons; p is an integer having the values of 0 to 4; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values 0 to 4; R s is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 carbons, benzyl, or lower alkyl or halogen substituted benzyl; n is an integer having the values of 0 to 4, and Rg is H, alkyl of I to 6 carbons, -CH20(C-.6-alkyl), or a cation of a pharmaceutically acceptable base.

27. A composition in accordance with Claim 26 where A is phenyl, naphthyl, pyridyl, thienyl or furyl. O 242

28. A composition in accordance with Claim 26 where n is 0, 1 or 2.

29. A composition in accordance with Claim 26 where Z is 00 CO-NRI-, or -(CRI=CRI) n where n' is 1. A composition in accordance with Claim 26 where the Z group is attached to the 4-position of the phenyl moiety. I\ 31. A composition in accordance with Claim 26 where X is O.

32. A composition in accordance with Claim 26 where X is NR.

33. A pharmaceutical composition comprising a compound of the formula R3- (CH2)n-COORe Rs x where X is O, NR where R is H, n-propyl or benzyl; R 3 is H or lower alkyl of 1 to 6 carbons; R 5 is benzyl or lower alkyl of 1 to 6 carbons; n is 0 or 1, and Rg is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.

34. A composition in accordance with Claim 33 where X is NR. A composition in accordance with Claim 34 where R is n-propyl and R s is n-propyl.

36. A composition in accordance with Claim 35 which is dipropylamino-cyclopropyl)-phenylethynyl]-benzoic acid or a salt with a pharmaceutically acceptable base or a alkyl ester of said compound.

37. A composition in accordance with Claim 34 where R is H and R, INO 243 is n-propyl or benzyl.

38. A composition in accordance with Claim 37 which is selected from 00 the group consisting of -propylamino-cyclopropyl)-phenylethynyl]- benzoic acid and 1-benzylamino-cyclopropyl)-phenylethynyl]-benzoic acid or a salt with a pharmaceutically acceptable base or a C 1 -6 alkyl ester of said compound.

39. A composition in accordance with Claim 34 where R is benzyl or methyl and R is benzyl. A composition in accordance with Claim 39 which is selected from the group consisting of 4-[4-(l-dibenzylamino-cyclopropyl)- phenylethynyl]-benzoic acid and 4-[4-(1-benzylmethylamino-cyclopropyl)- phenylethynyl]-benzoic acid or a salt with a pharmaceutically acceptable base or a C 1 -6 alkyl ester of said compound.

41. A composition in accordance with Claim 33 where X is O.

42. A composition in accordance with Claim 41 where R is benzyl and n is 0.

43. A composition in accordance with Claim 42 which is selected from the group consisting of 4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]- benzoic acid, -benzyloxycyclopropyl)-3-methyl-phenylethynyl]- benzoic acid and 4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]- benzoic acid or a salt with a pharmaceutically acceptable base or a C 1 6 alkyl ester of said compound.

44. A composition in accordance with Claim 41 where Rs is benzyl and n is 1. A composition in accordance with Claim 44 which is selected from the group consisting of -benzyloxycyclopropyl)-phenylethynyl]- phenyl}-acetic acid, {4-[4-(1-benzyloxycyclopropyl)-3-methyl- phenylethynyll-phenyl) -acetic acid and {4-[4-(1-benzyloxycyclopropyl)-3- IN 244 ethyl-phenylethynyl]-phenyl} -acetic acid or a salt with a pharmaceutically acceptable base or a C 1 6 alkyl ester of said compound. 00 46. A composition in accordance with Claim 41 where R. 5 is methyl, ethyl, iso-propyL, or (CH )-CH 2 and n is 0.

47. A composition in accordance with Claim 46 which is selected from the group consisting of 4-[4-(l1 -methoxycyclopropyl)-phenylethynyl]- beazoic acid, 1-isopropoxycyclopropyl)-phenylethynyl]-benzoic acid, 4- 1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoic acid, 4- -(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]- benzoic acid and 4- 1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]- beuzoic acid or a salt with a pharmaceutically acceptable base or a C 1 6 alkyl ester of said compound.

48. A composition in accordance with Claim 41 where JR 5 is methyl, ethyl, fso-propyl, or (CH 3 3 -CH 2 and in is 1.

49. A composition in. accordance with Claim 48 which is selected from the group consisting of 4-[4-(l1-methoxycyclopropyl)-phenylethynyl]- phenyll}-acetic acid, 1-isopropoxycyclopropyl)-phenylethynyl]- phenyl }-acetic acid, -isopropoxycyclopropyl)-3 -methyl- phenylethynyl]-phenyl) -acetic acid, 1-(2,2-dimethylpropyloxy)- cyclopropyl]-3 -methyl-phenylethynyl]-phenyl} -acetic acid, 1- benzyloxycyclopropyl)-3-ethyl-phenylethynyl] -phenyll -acetic acid, (1 -isopropoxycyclopropyl)-3 -ethyl-phenylethynyl]-phenyl -acetic acid and -ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl} -acetic acid or a salt with a pharmaccutically acceptable base or a C 1 6 alkyl ester of said compound. IN 245 A pharmaceutical composition comprising a compound of the formnula 00 R, R, (R 3 (R4)o 5 6 Z-A(R 2 )-(CH 2 )r-COOR 8 N7 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, fuiryl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, iniidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons', cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 1 to 6 carbons, CI, Br, or I; Z is -CE-C-, -(CR 1 where n' is an integer having the value I -CO-NR 1 NRI-CO-, -Co-a-, -0-Ca-, -CS-NR 1 NR 1 -CS-, -C0-s-, -s-Go-, \O 246 R is independently H or alkyl of 1 to 6 carbons; p is an integer having the values of 0 to 0 R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values 0 to 2; R 4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen; o is an integer having the values of 0 to 4; n is an integer having the values of 0 to 4, and Rg is H, alkyl of 1 to 6 carbons, -CH 2 0(Cl.6-alkyl), or a cation of a pharmaceutically acceptable base.

51. A composition in accordance with Claim 50 where A is phenyl, naphthyl, pyridyl, thienyl or furyl.

52. A composition in accordance with Claim 50 where n is 0, 1 or 2.

53. A composition in accordance with Claim 50 where Z is -CeC-, CO-NR-, or -(CRI=CR)n. where n' is 1.

54. A composition in accordance with Claim 50 where the Z group is attached to the 6-position of the bicyclic moiety. A composition in accordance with Claim 50 where Y is H, lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen.

56. A composition in accordance with Claim 50 where A is phenyl. O O U 247

57. A pharmaceutical composition comprising a compound of the formula 00 C H 2 )n- C OOR 8 Swhere R z is H or halogen; Sn is 0 or 1 and Rg is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.

58. A composition in accordance with Claim 57 where n is 1 and R 2 is F.

59. A composition in accordance with Claim 58 which is cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-2- fluoro-phenyl]-acetic acid or a salt with a pharmaceutically acceptable base. A composition in accordance with Claim 57 where n is 1 and R 2 is H.

61. A composition in accordance with Claim 60 which is cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)- phenyl]-acetic acid or a salt with a pharmaceutically acceptable base.

62. A pharmaceutical composition comprising a compound of the formula O U 248 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting ofpyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, 00 pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and Sheteroaryl groups being optionally substituted with one or two R 2 groups; X 1 is 1-imidazolyl, or lower alkyl or halogen substituted 1- Simidazolyl, OR, SR, NRR 6 where R is H, alkyl of 1 to 6 carbons or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I; Z is -(CRI=CRi)n, where n' is an integer having the value 1 -CO-NRI-, NRI-CO-, -CO-O-, -O-CO-, -CS-NR-, NRI-CS-, -CO-S-, -S-CO-, RI is independently H or alkyl of 1 to 6 carbons; R, is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R 3 is independently alkyl of I to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, 249 alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values 0 to 2; R 4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen; o is an integer having the values of 0 to 4; R 6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons; n is an integer having the values of 0 to 4, and R 8 is H, alkyl of 1 to 6 carbons, -CH20(C 1 -6-alkyl), or a cation of a pharmaceutically acceptable base, with the proviso that when Y is H, A is phenyl and X 1 is OH then n is 1 to 4.

63. A composition in accordance with Claim 62 where A is phenyl, naphthyl, pyridyl, thienyl or furyl.

64. A composition in accordance with Claim 62 where n is 0, 1 or 2. A composition in accordance with Claim 62 where Z is CO-NRI- or -(CRI=CRI)n, where n' is 1.

66. A composition in accordance with Claim 62 where the Z group is attached to the 6-position of the bicyclic moiety.

67. A composition in accordance with Claim 62 where X 1 is 1- imidazolyl, halogen or C 1 -6 substituted l-imidazolyl, or NRR6, where R 6 is preferably cyclopropyl or branched-chain alkyl of I to 6 carbons.

68. A composition in accordance with Claim 62 where Y is H, lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen. IN 250

69. A pharmaceutical composition comprising a compound of the formula 00 CH 2 )=-COOR 8 wherein X 1 is 1-imidazolyl, or dialkyl-N or alkyl,cyclopropyl-N where the alkyl group has 1 to 6 carbons; R2~ is H or halogen; n is 0 or 1, and is H, akIy of I to 6 carbons, or a cation of a pharmaceutically acceptable base. A composition in accordance with Claim 69 where X, is methyl,cyclopropyl-N and n is 0.

71. A composition in accordance with Claim 70 which is selected from the group consisting of 4-[(5-cyclopropyl-methyl-amino)-8,8-dimethyl- 6 7 8 -tetrahydro-naphthalene-2yI-ethynyl]-benzoic acid and 4- (cyclopropyl-methyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-napbthalene- 2-yI-ethynyl]-2-fluoro benzoic acid or a salt with a pharmaceutically acceptable base or a C 6 alkyl ester of said compound.

72. A composition in accordance with Claim 69 where X, is methyl,cyclopropyl-N and n is 1.

73. A composition in accordance with Claim 72 which is selected from the group consisting of 4-[(5-(cyclopropyl-methyl-amino)-8,8-dimethyl- 6 7 ,8-terahydro-naphthalene-2-y-ethynylyphenyl] acetic acid and O 251 (cyclopropyl-methyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2- yl-ethynyl)-2-fluoro-phenyl]-acetic acid or a salt with a pharmaceutically acceptable base or a C 1 6 alkyl ester of said compound. 00

74. A composition in accordance with Claim 69 where X, is 1 methyl,iso-propyl-N. N 75. A composition in accordance with Claim 74 which is propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl- N ethynyl)]-benzoic acid or a salt with a pharmaceutically acceptable base or a C 1 -6 alyl ester of said compound.

76. A composition in accordance with Claim 69 where X 1 is 1- imidazolyl and n is.0.

77. A composition in accordance with Claim 76 which is imidazol- 1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)- benzoic acid or a salt with a pharmaceutically acceptable base or a C 1 6 alkyl ester of said compound.

78. A composition in accordance with Claim 69 where X, is 1- imidazolyl and n is 1.

79. A composition in accordance with Claim 78 which is imidazol- 1 -yl- 8 ,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)- phenyl]-acetic acid or a salt with a pharmaceutically acceptable base or a C, 6 alkyl ester of said compound. A pharmaceutical composition comprising a compound of the formula (R 3 )m Z- A(R2)-(CH 2)7 COOR 8 IN 252 wherein A is a phenyl or iiaphthiyl group, or heteroaryl selected from a group consisting of pyridyl, tienyl, furyl, pyridazinyl, pyrimidinyl, 00 pyrazinyl, thiiazoly], oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R, groups; X is 0, S or NR where R is H. alkcyl of I to 6 carbons, C 1 6 trialkylsilyl or benzyl; Y is alkyl of I to 10 carbons, benzyl, lower alkyl or halogen substituted beazyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lowver alkyl substituted cycloalkyl of 3 to 6 carbons, Cl1, Br, or]1; Z is -(CR 1 where n' is an integer having the value I -CO-NR 1 NRI-CO-, -Co-0-, -0-GO-, -CS-NR F' NR 1 -CS-, -CO-S-, -S-GO., RI is independently H or alkcyl of 1 to 6 carbons; R, is independently H, alkcyl of I to 6 carbons, F, Cl, Br, 1, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of I to 6 carbons;, R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, 1, fluoro substituted alkyl of I to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;, 253 m is an integer having the values 0 to 3; R 7 is H, alkyl ofl to 6 carbons, cycloalkyl of 3 to 6 carbons or lower alkyl substituted cycloalkyl of 1 to 6 carbons; n is an integer having the values of 1 to 4, and Rg is H, alkyl of 1 to 6 carbons, -CH20(C,. 6 -alkyl), or a cation of a pharmaceutically acceptable base.

81. A composition in accordance with Claim 80 where A is phenyl, naphthyI, pyridyl, thienyl or furyl.

82. A composition in accordance with Claim 80 where n is 1 or 2.

83. A composition in accordance with Claim 80 where Z is -C CO-NRI-, or -(CR,=CRI)n, where n' is 1.

84. A composition in accordance with Claim 80 where the Z group is attached to the 4-position of the phenyl moiety. A composition in accordance with Claim 80 where X is O.

86. A composition in accordance with Claim 80 where Y is lower alkyl of I to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen.

87. A composition in accordance with Claim 80 where A is phenyl.

88. A composition in accordance with Claim 80 where n is 1.

89. A pharmaceutical composition comprising a compound of the formula O S254 wherein Y is branched-chain alkyl of 3 to 6 carbons; R z is H or F; 00 R 3 is branched-chain alkyl of 3 to 6 carbons; R 7 is lower alkyl of 1 to 6 carbons, and R 8 is H, alkyl of 1 to 6 carbons, -CH20(Ci_ 6 -alkyl), or a cation of a Spharmaceutically acceptable base. A composition in accordance with Claim 89 where Y is t-butyl. S91. A composition in accordance with Claim 90 where R3 is t-butyl.

92. A composition in accordance with Claim 91 where R 7 is methyl.

93. A composition in accordance with Claim 92 which is selected from the group consisting of [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)- phenyl]-acetic acid and [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2- fluoro-phenyl]-acetic acid or a salt of said compound with a pharmaceutically acceptable base.

94. A pharmaceutical composition comprising a compound of the formula (R 3 )m v\4 XZ- A(R)-(CIJ) COORI Y wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R, groups; X 2 is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl, IN 255 OR 7 SR 7 or NRR, 7 where R is H, alk of I to 6 carbons or benzyl; Y is H, alkyl of I to 10 carbons, benzyl, lower alkyl or halogen 00 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, CZ Zis -CE-C-, -(CR 1 =CR)n, where n' is an integer having the value 1 C-I -CO-NR 1 NRI-CO-, -CO-O-, -CS-NR 1 NR 1 -CS-, -C0-S-, -s-GO-, R, is independently H or alkyl of I to 6 carbons; R 2 is independently H, akl of 1 to 6 carbons, F, Cl, Br, 1, fluoro substituted ailcyl of 1 to 6 carbons, alkoxy of I to 6 carbons, or alkytthio of I to 6 carbons; R 3 is alkyl of 1 to 6 carbons, F, CI, Br, 1, fluoro substituted alkyl of I to 6 carbons, OH, SH, alkoxy of I to 6 carbons, alkylthio of I to 6 carbons or benzyl; m is an integer having the values 0 to 3; R 7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons or C I 6 -trialkylsilyl. n is an integer having the values of 0 to 4, and R 8 is H, aflcl of I to 6 carbons, -CH 2 0(Cl. 6 -alkyl), or a cation of a O 256 pharmaceutically acceptable base. A composition in accordance with Claim 94 where A is phenyl, o0 naphthyl, pyridyl, thienyl or furyl.

96. A composition in accordance with Claim 94 where n is 0, 1 or 2.

97. A composition in accordance with Claim 94 where Z is -C g CO-NR 1 S-CO-O-, or -(CRI=CRi)n, where n' is 1.

98. A composition in accordance with Claim 94 where the Z group is attached to the 4-position of the phenyl moiety.

99. A composition in accordance with Claim 94 where X 2 is 1- imidazolyl, lower alkyl or halogen substituted 1-imidazolyl.

100. A composition in accordance with Claim 94 where Y is H, lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen.

101. A composition in accordance with Claim 94 where A is phenyl.

102. A composition in accordance with Claim 94 where n is 1.

103. A pharmaceutical composition comprising a compound of the formula wherein R 3 is alkyl of I to 6 carbons; X. is 1-imidazolyl, OR 7 or NRR 7 where R is alkyl of 1 to 6 carbons or cyclopropyl, and R 7 is alkyl of 1 to 6 carbons, cyclopropyl or lower alkyl substituted cyclopropyl; n is 0 or 1, and O U 257 R is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.

104. A composition in accordance with Claim 103 wherein X 2 is 1- 00 Simidazolyl.

105. A composition in accordance with Claim 104 wherein n is 07 106. A composition in accordance with Claim 105 which is selected Sfrom the group consisting of 4-(4-imidazol-1-yl-methyl-3-methyl- C phenylethynyl)-benzoic acid and [4-(4-imidazol-1-yl-methyl-3-isopropyl- phenylethynyl)-phenyl]-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C-. 6 alkyl ester of said compound.

107. A composition in accordance with Claim 104 wherein n is 1.

108. A composition in accordance with Claim 107 which is selected from the group consisting of [4-(4-imidazol-l-yl-methyl-3-methyl- phenylethynyl)-phenyl]-acetic acid and [4-(4-imidazol-1-yl-methyl-3- isopropyl-phenylethynyl)-phenyl]-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C.-6 alkyl ester of said compound.

109. A composition in accordance with Claim 103 where X 2 is ethyl,cyclopropyl-N-.

110. A composition in accordance with Claim 109 wherein n is 0.

111. A composition in accordance with Claim 110 which is selected from the group consisting of 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3- methyl-phenylethynyl}-benzoic and 4-{4-[(cyclopropyl-ethyl-amino)- methyl]-3-isopropyl-phenylethynyl}-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1 -6 alkyl ester of said compound.

112. A composition in accordance with Claim 109 wherein n is 1.

113. A composition in accordance with Claim 112 which is IN 258 [(cyclopropyl-ethyl-amino)-methyl]-3 -methyl-phenylethynyl}-phenyl)-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a 00 C 1 6 alkcyl ester of said compound. 1 14. A composition in accordance with Claim 103 where X7, is (1- methyl)cyclopropyl-oxy. (71115. A composition in accordance with Claim 114 wherein n is 1.

116. A composition in accordance with Claim 115 which is (71 isopropyl-4-( 1 -methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl} -acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1 6 alkyl ester of said compound.

117. A pharmaceutical composition comprising a compound of the formula Z-A(R 2 )-(CH 2 )Y--COOR 8 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; Y is H, ailkyl of 1 to 10 carbons, benzyl, lower ailkyl or halogen substituted benzyl, fluoro-substituted alkyl of I to 10 carbons, cycloalkyl of O ID S259 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, CI, Br, or I; Z is 00 -(CRI=CRI)n, where n' is an integer having the value 1 OC -CO-NRi-, NRI-CO-, 0 -CO-O-, CN -O-CO-, -CS-NR 1 NRi-CS-, -CO-S-, -S-CO-, RI is independently H or alkyl of 1 to 6 carbons; p is an integer having the values of 0 to R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values 0 to 2; R 4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen; o is an integer having the values of 0 to 4; n is an integer having the values of 0 to 4, and Rg is H, alkyl of 1 to 6 carbons, -CH20(C 1 6 -alkyl), or a cation of a pharmaceutically acceptable base. 260

118. A composition in accordance with Claim 117 where A is phenyl, naphthyl, pyridyl, thienyl or furyl.

119. A composition in accordance with Claim 117 where n is 0, 1 or 2.

120. A composition in accordance with Claim 117 where Z is CO-NR 1 or -(CRI=CRI)n where n' is 1.

121. A composition in accordance with Claim 117 where the Z group is attached to the 6-position of the bicyclic moiety.

122. A composition in accordance with Claim 117 where Y is H, lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen.

123. A composition in accordance with Claim 117 where A is phenyl.

124. A composition in accordance with Claim 117 where n is 1.

125. A pharmaceutical composition comprising a compound of the formula (CH 2 )n-COON wherein R z is hydrogen, alkyl of 1 to 6 carbons, or halogen n is 0 or 1, and R s is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.

126. A composition in accordance with Claim 125 wherein n is 0.

127. A composition in accordance with Clalin 126 which is 4-(1 00 cyrlopropyl-4,4-ditnethyl- I ,2,3,4-tetrahydroquinolin-6-y l-ethiynyl)-benzoic cid r sl of said cmoud with apharmaceutically acceptable base o c-iC,- 6 alkcyl ester of said compound.

128. A composition in accordance with Claim 125 wherein n is 1. N 129. A composition in accordance with Claim 128 which is cyclopropyl-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinolin-6-yl-ethynyl)phenyl] acetic acid methyl ester.

130. A pharmaceutical composition comprising a compound of the formula Z-A(R 2 )-(CH 2 )-COOR 8 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridy), thienyl, fliryl, pyndazinyl, pyrimidinyl,* pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R, groups; X 3 is S, or 0, C(R 1 2 or CO; Y 1 is lower alkyl of I to 3 carbons, cycloalkyl of 3 to 6 carbons, benzy], lower alkyl substituted cycloalkyl of.3 to 6 carbons; Z is -Cs-C-, where n'is an integer having the value I -CO-NR I-, O 262 NRI-CO-, -CO-O-, 0 -O-CO-, -CS-NR I NRi-CS-, c'I -CO-S-, S-S-CO-, R, is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, 1, CF 3 fluoro substituted alkyl of 1 to 6 carbons, alkoxy of I to 6 carbons, or alkylthio of 1 to 6 carbons; R, is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF,, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values 0 to 2; R, is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen; o is an integer having the values of 0 to 4; n is an integer having the values of 0 to 4, and Rg is H, alkyl of 1 to 6 carbons, -CH20(C-. 6 -alkyl), or a cation of a pharmaceutically acceptable base, the compound meeting at least one of the provisos selected from the group consisting of: Y 1 is cycloalkyl, when Y 1 is not cycloalkyl then X 3 is O or S and n is 1, when Y 1 is not cycloalkyl then X 3 is CO, and n is 1, when Y 1 is not cycloalkyl then X 3 is CO and the moiety A is substituted with at least one F group. O 263 S131. A composition in accordance with Claim 130 where A is phenyl, naphthyl, pyridyl, thienyl or furyl. 00 132. A composition in accordance with Claim 130 where n is 0, 1 or C 2.

133. A composition in accordance with Claim 130 where Z is IN CO-NR 1 0-CO-O-, or -(CRI=CRI)n, where n' is 1.

134. A composition in accordance with Claim 130 where the Z group is attached to the 6-position of the bicyclic moiety.

135. A composition in accordance with Claim 130 where Y 1 is H, lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl.

136. A composition in accordance with Claim 130 where A is phenyl.

137. A composition in accordance with Claim 130 where n is 1.

138. A composition in accordance with Claim 130 where X 3 is O or CO.

139. A pharmaceutical composition comprising a compound of the formula 3 Z(CH 2 )n-COOR 8 R3 X3 R2 YI wherein R 2 is H or F; R 3 is H or lower alkyl of 1 to 6 carbons; X 3 is O or CO; YI is H, alkyl of 1 to 6 carbons, or cyclopropyl; O IND 264 Z is or -CO-O-; n is 0 or 1, and 00 R 8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically C acceptable base, the compound meeting at least one of the provisos selected Sffrom the group consisting of: YI is cyclopropyl, Swhen Yj is not cyclopropyl then X 3 is O and n is 1, when Y 1 is not cyclopropyl then X 3 is CO, and n is 1, when Y 1 is not cyclopropyl then X 3 is CO and the moiety A is substituted with at least one F group.

140. A composition in accordance with Claim 139 wherein Z is -C=C-

141. A composition in accordance with Claim 140 wherein X 3 is CO, Y1 is H and n is 0.

142. A composition in accordance with Claim 141 which is 2-fluoro- 4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl-ethynyl)-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1 6 alkyl ester of said compound.

143. A composition in accordance with Claim 140 wherein X 3 is CO, Y1 is H and n is 1.

144. A composition in accordance with Claim 143 which is selected from the group consisting of 4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro- naphthalene-2-yl-ethynyl)-phenyl]-acetic acid and [2-fluoro-4-(8,8- dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthaene-2-yl-ethynyl)phenyl] -acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C.-6 alkyl ester of said compound.

145. A composition in accordance with Claim 140 wherein X 3 is O, O IND 265 Y, is H and n is 0.

146. A composition in accordance with Claim 145 which is 2-fluoro- 00 4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1 -6 alkyl ester of said compound. 0 147. A composition in accordance with Claim 140 wherein X 3 is O, Y, is H or ethyl and n is 1.

148. A composition in accordance with Claim 147 which is selected from the group consisting of [4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl] acetic acid, [2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl] acetic acid and [4-(8-ethyl-2,2,4,4-tetramethyl-chroman-6-yl- ethynyl) phenyl] acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C,. 6 alkyl ester of said compound.

149. A composition in accordance with Claim 140 wherein X 3 is O, Y 1 is cyclopropyl and n is 0.

150. A composition in accordance with Claim 149 which is 4-(8- cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1 -6 alkyl ester of said compound.

151. A composition in accordance with Claim 140 wherein X 3 is O, Y1 is cyclopropyl and n is 1.

152. A composition in accordance with Claim 151 which is selected from the group consisting of [4-(8-cyclopropyl-2,2,4,4-tetramethyl- chroman-6-yl-ethynyl) phenyl] acetic acid and [4-(8-cyclopropyl-2,2,4,4- tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl] acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C 1 -6 alkyl ester of said compound.

153. A composition in accordance with Claim 139 where Z is -CO-O-, O ID S266 SX3 is CO and n is 1.

154. A composition in accordance with Claim 153 which is 8,8- 00 dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid-4- C (carboxymethyl)phenyl ester or a salt of said compound with a pharmaceutically acceptable base or a C -6 alkyl ester of said compound. N0 155. A composition in accordance with Claim 139 where Z is -CO-O-, O X 3 is O and n is 1.

156. A composition in accordance with Claim 155 which is 2,2,4,4- tetramethyl-chroman-6-carboxylic acid 4-(carboxymethyl)phenyl ester or a salt of said compound with a pharmaceutically acceptable base or a C 1 -6 alkyl ester of said compound.

157. A pharmaceutical composition according to any one of claims 1 to 156 which further includes retinoic acid or other retinoids.

158. A method for the manufacture of a pharmaceutical composition including the step of bringing one or more compounds as defined in any one of claims 1 to 156 into association with a pharmaceutically acceptable excipient.

159. Use of a pharmaceutical composition according to any one of claims 1 to 157 as a retinoid in therapy.