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AU2708700A - Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents - Google Patents

Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents Download PDF

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Publication number
AU2708700A
AU2708700A AU27087/00A AU2708700A AU2708700A AU 2708700 A AU2708700 A AU 2708700A AU 27087/00 A AU27087/00 A AU 27087/00A AU 2708700 A AU2708700 A AU 2708700A AU 2708700 A AU2708700 A AU 2708700A
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Prior art keywords
carbons
methyl
alkyl
nitrophenylimino
thiazolidine
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AU27087/00A
Inventor
Cedo M. Bagi
Catherine R. Brennan
David R. Brittelli
William H. Bullock
Jinshan Chen
William L. Collibee
Robert Dally
Brian R. Dixon
Jeffrey S. Johnson
Harold C.E. Kluender
William F. Lathrop
Peiying Liu
Carol Ann Mase
Aniko M. Redman
William J. Scott
Klaus Urbahns
Donald J. Wolanin
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Bayer Corp
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Bayer Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Steroid Compounds (AREA)

Description

WO 00/42031 PCT/US99/29601 Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents FIELD: 5 This invention relates to heterocyclic pharmaceuticals, and more particularly, to 2-arylimino heterocycles, pharmaceutical compositions containing them, and their use in modulating progesterone receptor mediated processes. BACKGROUND: 10 An agent which binds to the progesterone receptor may be employed for a wide variety of indications, including those shown in the lettered paragraphs below: Al) to enhance bone formation in bone weakening diseases, for the prevention of and/or treatment of osteopenia or osteoporosis (Manzi, et al., J. Soc. Gynecol. Invest., 1, 302 (1994); Scheven, et al., Biochem. Biophys. Res. Commun., 15 186, 54 (1992); Verhaar, et al., Bone, 15, 307 (1994); Ontjes, In "Calcium and Phosphorus in Health Diseases", Anderson and Garner (Eds.), CRC Press, 207 (1996); Scheven et al., Biochem. Biophys. Res. Commun., 186, 54 (1992)) including corticosteroid-induced osteoporosis (Picardo, et al., Drug Safety 15, 347 (1996)), postmenopausal osteoporosis, or Paget's disease; 20 A2) as an agent to enhance fracture healing; B1) as a female contragestive agent, (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Heikinheimo Clin. Pharmacokinet., 33, 7 (1997); Li et al., Adv. Contracept., 11, 285 (1995); Spitz et al., Adv. Contracept. 8, 1 (1992); Spitz et al., Annu. Rev. Pharmacol. Toxicol., 36, 47 (1996)); 25 B2) for prevention of endometrial implantation (Cadepond et al., Annu. Rev. Med., 48, 129 (1997)); B3) for the induction of labor (Heikinheimo Clin. Pharmacokinet., 33, 7 (1997); Karalis et al., Ann. N. Y. Acad. Sci., 771, 551 (1995)), including the case of foetus mortus (Heikinheimo, Clin. Pharmacokinet., 33, 7 (1997); Cadepond et 30 al., Annu. Rev. Med., 48, 129 (1997)); B4) for treatment of luteal deficiency (Pretzsh et al., Zentralbl. Gynaekol., 119 (Suppl. 2), 25 (1997); Bezer et al., In "Molecular and Cellular Aspects of Periimplantation Processes", Dey (Ed.), Springer-Verlag, p. 27 (1995)); B5) to enhance recognition and maintanence of pregnancy (Bezer et al., In 35 "Molecular and Cellular Aspects of Periimplantation Processes", Dey (Ed.), Springer-Verlag, p. 27 (1995)); 1 WO 00/42031 PCT/US99/29601 B6) for counteracting preeclampsia, eclampsia of pregnancy and preterm labor (Yallampalli et al., WO 97/34,922); B7) for the treatment of infertility, including promotion of spermatogenesis, the induction of the acrosome reaction, oocyte maturation, and in vitro 5 fertilization of oocytes (Baldi et al., J. Steroid Biochem. Mol. Biol., 53, 199 (1995); Baldi et al., Trends Endocrinol. Metab., 6, 198 (1995); Blackwell et al., Colloq. INSERM, 236, 165 (1995); Blackmore et al., Cell. Signalling, 5, 531 (1993); Cork et al., Zygote, 2, 289 (1994); Meizel, Biol. Reprod., 56, 569 (1997)); 10 Cl) for treatment of dysmenorrhea (Coll Capdevila et al., Eur. J. Contracept. Reprod. Health Care, 2, 229 (1997); Adashi et al., Keio J. Med., 44, 124 (1995)); C2) for treatment of dysfunctional uterine bleeding (Coll Capdevila et al., Eur. J. Contracept. Reprod. Health Care, 2, 229 (1997); Adashi et al., Keio J. Med., 15 44, 124 (1995)); C3) for treatment of ovarian hyperandrogynism (Schaison et al., Androg. Excess Disord. Women, 715 (1997)); C4) for treatment of ovarian hyperaldosteronism (Adashi et al., Keio J. Med., 44, 124 (1995)); 20 C5) for treatment of premenstral syndrome and/or premenstral tension (Mortola, Curr. Opin. Endocrinol. Diabetes, 2, 483 (1995)); Adashi et al., Keio J. Med., 44, 124 (1995)); C6) for treatment of perimenstrual behavior disorders (Constant et al., Hormone Res., 40, 141 (1993)); 25 C7) for treatment of climeracteric disturbance, i.e. menopause transition (Adashi et al., Keio J. Med., 44, 124 (1995)) including hot flushes (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997); Backstr6m et al., Ciba Found. Symp., 121, 171 (1995)), mood changes (Backstrtim et al., Ciba Found. Symp., 121, 171 (1995)), sleep disturbance (Sarrel, Int. J. Fertil. Women's Med., 42, 78 30 (1997)) and vaginal dryness (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997)); C8) for enhancement of female sexual receptivity (Dei et al., Eur. J. Contracept. Reprod. Health Care, 2(4), 253 (1997); McCarthy et al., Trends Endocrinol. Metab., 7, 327-333 (1996); Mani et al., Horm. Behav., 31, 244 (1997)) and 35 male sexual receptivity (Johnson et al., In "Essential Reproduction, 2 "d ed., Blackwell Scientific Pub., London p 17 7 (1984)); C9) for treatment of post menopausal urinary incontinence (Makinen et al., Maturitas, 22, 233 (1995); Batra et al., J. Urology, 138, 1301 (1987)); 2 WO 00/42031 PCT/US99/29601 C1O) to improve sensory and motor functions (Backstr6m et al., Ciba Found. Symp., 121, 171 (1995)); CI1) to improve short term memory (Backstrbm et al., Ciba Found. Symp., 121, 171 (1995)); 5 C 12) for treatment of postpartum depression (Dalton, Practitioner, 229, 507 (1985)); C13) for treatment of genital atrophy (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997)); C14) for prevention of postsurgical adhesion formation (Ustun, Gynecol. Obstet. 10 Invest., 46, 202 (1998)); C15) for regulation of uterine immune function (Hansen et al., J. Reprod. Fertil., 49(Suppl.), 69 (1995)); C16) for prevention of myocardial infarction (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997)); 15 D1) for hormone replacement therapy (Casper et al., J. Soc. Gynecol. Invest., 3, 225 (1996)); El) for treatment of cancers, including breast cancer (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997)), uterine cancer (Heikinheimo Clin. Pharmacokinet., 33, 7 (1997)), ovarian 20 cancer (Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997); Hughes, WO 98/10,771), and endometrial cancer (Satyaswaroop, Contrib. Oncol., 50, 258 (1995); Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997)); E2) for treatment of endometriosis (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Heikinheimo, Clin. Pharmacokinet., 33, 7 (1997); Edmonds, Br. J. 25 Obstet. Gynaecol., 103 (Suppl. 14), 10 (1996); Adashi et al., Keio J. Med., 44, 124 (1995)); E3) for treatment of uterine fibroids (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Adashi et al., Keio J. Med., 44, 124 (1995)); Fl) for treatment of hirsutism (Orentreich et al., US 4684635; Azziz et al., J. Clin. 30 Endocrinol. Metab., 80, 3406 (1995)); F2) for inhibition of hair growth (Houssay et al., Acta Physiol. Latinoam., 28, 11 (1978)); G1) as a male contraceptive (Hargreave et al., Int. Congr., Symp. Semin. Ser., 12, 99 (1997); Meriggiola et al., J. Androl., 18, 240 (1997)); 35 G2) as an abortifacient (Michna et al., Pharm. Ztg., 141, 11 (1996)); and Hi) for the promotion of mylin repair (Baulieu et al., Cell. Mol. Neurobiol., 16, 143 (1996); Baulieu et al., Mult. Scler., 3, 105 (1997); Schumaker et al., Dev. Neurosci., 18, 6 (1996); Koenig et al., Science, 26, 1500 (1995)). 3 WO 00/42031 PCT/US99/29601 Currently, progesterone or progestins alone or in combination with estrogens are clinically indicated: for contraception (Merck Manual; Merck & Co. (1992)); for treatment of gastrointestional bleeding due to arteriovenous malformations (Merck 5 Manual; Merck & Co. (1992)); for treatment of recurrent metatarsal stress fractures complicated by oligiomenorrhea or amenorrhea (Merck Manual; Merck & Co. (1992)); for treatment of premenstral syndrome (PMS, premenstral tension; Merck Manual; Merck & Co. (1992)); for postmenopausal hormone replacement therapy (Merck Manual; Merck & Co. (1992)); for treatment of hot flashes and subsequent 10 insomnia and fatigue during menopause (Merck Manual; Merck & Co. (1992)); for treatment of dysfunctional uterine bleeding when pregnancy is not desired (Merck Manual; Merck & Co. (1992)); and for suppression of endometriosis (Merck Manual; Merck & Co. (1992)), breast cancer (Merck Manual; Merck & Co. (1992)), endometrial cancer (Merck Manual; Merck & Co. (1992)), or luteal insufficiency 15 (Merck Manual; Merck & Co. (1992)). For example, medroxyprogesterone, a progestin, alone or in combination with estrogens is indicated for prevention of osteoporosis, treatment of vulvar and/or vaginal atrophy, treatment of moderate to severe vasomotor symptoms associated with menopause, treatment of secondary amenorrehea, treatment of abnormal uterine bleeding due to hormonal imbalance in 20 the absence of organic pathology, prevention of pregnancy, or as adjunctive therapy and palliative treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma (Merck Manual; Merck & Co. (1998)). SUMMARY: 25 This invention provides nonsteroidal 2-arylimino- and 2-heteroarylimino heterocyclic compounds which have affinity for the progesterone receptor, and therefore can act as progestins and/or antiprogestins thus modulating progesterone receptor mediated processes. 30 This invention relates to compounds having the formula (I) (T)tR\ N ,R(G)g X N (Q)R2 (QgR3 (CH2nsp (Q)qR 4 wherein Ris 4 WO 00/42031 PCT/US99/29601 aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S, with the proviso that R is other than benzofuran or benzothiophene; 5 R' is alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings; heterocycloalkyl of 4 - 7 carbons and containing 1 - 3 rings and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; 10 alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons;
R
2 , R 3 , and R 4 are independently selected from the group consisting of H; 15 alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons; aryl of 6 - 13 carbons; 20 heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; C0 2
R
5 ; wherein R' is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 25 carbons; halogen; and =0 , representing two of the groups R 2 , R 3 , and R; X is 0 or S(O), ; wherein y is 0, 1, or 2; 30 nis2,3,4,or5; p is the sum of non-H substituents R2, R3, and R 4 ; T is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; 35 aryl of 6 - 10 carbons; CO 2 H; C0 2 R; alkenyl of 2 - 4 carbons; 5 WO 00/42031 PCT/US99/29601 alkynyl of 2 - 4 carbons; C(O)C 6
H
5 ;
C(O)N(R
6
)(R
7 ) ;wherein R is H or alkyl of 1 - 5 carbons; and 5 R'is H or alkyl of 1 - 5 carbons; S(O),,RB; wherein y' is 1 or 2; and R' is alkyl of 1 - 5 carbons; SO 2 F; 10 CHO; OH;
NO
2 ; CN; halogen; 15
OCF
3 ; N-oxide;
O-C(R
9
)
2 -0 , the oxygens being connected to adjacent positions on R; and wherein
R
9 is H, halogen, or alkyl of 1 - 4 carbons; 20 C(O)NHC(O) , the carbons being connected to adjacent positions on R; and
C(O)C
6
H
4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; t is 1 - 5; 25 provided that when substituent moiety T is alkyl of 1 - 4 carbons, alkoxy of 1 - 4 carbons, aryl of 6 - 10 carbons, C0 2 R', alkenyl of 2 - 4 carbons, alkynyl of 2 - 4 carbons, C(O)C 6
H
5 , C(O)N(R 6
)(R
7 ), S(O),,R,
O-C(R
9
)
2 -O , or C(O)C 6
H
4 , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 30 carbons; alkoxy of 1 - 4 carbons; C0 2 R'; CO 2 H; C(O)N(R)(R 7 ); CHO; OH; NO 2 ; CN; halogen; S(O)yR; or =0, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level; G is a substituent selected from the group consisting of 35 halogen; OH; OR'; =0 , representing two substituents G; 6 WO 00/42031 PCTIUS99/29601 alkyl of 1 - 4 carbons; alkenyl of 1 - 4 carbons; cycloalkyl of 3 - 7 carbons; heterocycloalkyl of 3 - 5 carbons and 1 - 3 heteroatoms selected from 5 the group consisting of N, 0, and S; cycloalkenyl of 5 - 7 carbons; heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S;
CO
2 R; 10 C(0)N(R)(R7); aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S;
NO
2 ; 15 CN; S(O),R; S0 3 R; and
SO
2
N(R
6 )(R'); g is 0 - 4, with the exception of halogen, which may be employed up to the 20 perhalo level; provided that when substituent G is alkyl of 1 - 4 carbons, alkenyl of 1 - 4 carbons, cycloalkyl of 3 - 7 carbons, heterocycloalkyl of 3 - 5 carbons, cycloalkenyl of 5 - 7 carbons, or heterocycloalkenyl of 4 - 6 carbons, then G optionally may bear secondary substituents of 25 halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen; 30 Q is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; haloalkyl of 1 - 4 carbons; cycloalkyl of 3 - 8 carbons; alkoxy of 1 - 8 carbons; 35 alkenyl of 2 - 5 carbons; cycloalkenyl of 5 - 8 carbons; aryl of 6 - 10 carbons; 7 WO 00/42031 PCT/US99/29601 heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; C0 2
R
5 ; =0 , representing two substituents Q; 5 OH; halogen; N(R6)(R7); S(O),R; S0 3 R; and 10 SO 2
N(R)(R
7 ); q is0 -4 provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the 15 number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and with the further provisos that: a) two of (Q)qR', (Q)qR 2 , (Q)qR 3 , and (Q)qR 4 may be joined, and taken together with the atom(s) to which they are attached, form a spiro or 20 nonspiro nonaromatic ring of 3 - 8 members containing 0 - 2 heteroatoms selected from the group consisting of N, 0, and S; b) when n = 2 or 3, at least one of R 2 , R 3 , and R 4 is other than H; c) when n = 2, and X = 0, if t = 1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3 25 oxazolidine ring must bear a substituent; d) when n = 3 and X = 0, if t is equal to or greater than 1, then at least one T is selected from the list of substituents T above, excepting alkyl and alkoxy; e) when n = 2 or 3 and X = 0 or S, then the sum of non-hydrogen atoms 30 in R', R2, R 3 , and RW is at least 5; f) when n = 2, X = 0, the 4-position of the 1,3-oxazolidine ring bears a carbonyl group, and R bears halogen at its 2- and 4- positions, then the 5-position of R bears H; g) when n = 2 and X = 0, the 4-position of thel,3-oxazolidine ring may 35 bear a carbonyl only if the 5-position of said ring bears at least one non-H substituent; 8 WO 00/42031 PCT/US99/29601 h) when n = 2, X = S(O), , the 4-position of the 1,3-thiazolidine ring bears a carbonyl group, R' is a substituted methyl group, and G is a phenyl group, then said phenyl group bears a secondary substituent; i) when n = 4, X = S, and G is C0 2 R' , then R' contains at least two 5 carbons; and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions which include a 10 compound of formula (I) as disclosed above, plus a pharmaceutically acceptable carter. As a result of their affinity for the progesterone receptor and their resultant ability to act as progestins and/or antiprogestins, and thus modulate progesterone 15 receptor mediated processes, the compounds of this invention, as well as certain related compounds of the prior art, are believed to be useful for the purposes listed in the background section. It is to be noted that the definition of the set of compounds for use in the claimed method of treatment (formula II) is broader than the set of compounds defined by 20 formula I, because the treatment method may employ certain compounds of the prior art which have not been recognized previously as being useful for this purpose. Accordingly, the invention relates further to a method of treating a mammal to achieve an effect, wherein the effect is: Al) enhancement of bone formation in bone weakening diseases for the treatment 25 or prevention of osteopenia or osteoporosis; A2) enhancement of fracture healing; B1) activity as a female contragestive agent; B2) prevention of endometrial implantation; B3) induction of labor; 30 B4) treatment of luteal deficiency; B5) enhanced recognition and maintanence of pregnancy; B6) counteracting of preeclampsia, eclampsia of pregnancy, and preterm labor; B7) treatment of infertility, including promotion of spermatogenesis, induction of the acrosome reaction, maturation of oocytes, or in vitro fertilization of 35 oocytes; Cl) treatment of dysmenorrhea; C2) treatment of dysfunctional uterine bleeding; C3) treatment of ovarian hyperandrogynism; 9 WO 00/42031 PCT/US99129601 C4) treatment of ovarian hyperaldosteronism; C5) alleviation of premenstral syndrome and of premenstral tension; C6) alleviation of perimenstrual behavior disorders; C7) treatment of climeracteric disturbance, including. menopause transition, mood 5 changes, sleep disturbance, and vaginal dryness; C8) enhancement of female sexual receptivity and male sexual receptivity; C9) treatment of post menopausal urinary incontinence; C10) improvement of sensory and motor functions; C1 1) improvement of short term memory; 10 C12) alleviation of postpartum depression; Cl3) treatment of genital atrophy; C14) prevention of postsurgical adhesion formation; C15) regulation of uterine immune function; C16) prevention of myocardial infarction; 15 Dl) therapy for hormone replacement; El) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer, and endometrial cancer; E2) treatment of endometriosis; E3) treatment of uterine fibroids; 20 Fl) treatment of hirsutism; F2) inhibition of hair growth; GI) activity as a male contraceptive; G2) activity as an abortifacient; and HI) promotion of mylin repair; 25 which comprises administering to said mammal an effective amount of a compound of the formula (II) (T)t R K ,R (G)g X N (Q)qR 2 (Q)q R3 CnH2n-p-2s)' (Q)qR4 30 wherein Ris aryl of 6 - 14 carbons; or 10 WO 00/42031 PCT/US99/29601 heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S, with the proviso that R is other than benzofuran or benzothiophene; R' is 5 alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings; heterocycloalkyl of 4 - 7 carbons and containing 1 - 3 rings and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; aryl of 6 - 10 carbons; 10 heteroaryl of 3 - 9 carbons and containing 1 - 3 rings and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons; 15 R2, R, and R 4 are independently selected from the group consisting of H; alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; alkenyl of 2 - 10 carbons; 20 cycloalkenyl of 5 - 12 carbons; aryl of 6 - 13 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; C0 2 R ; wherein 25 R' is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; halogen; and =0 , representing two of the groups R2, R 3 , and RW; 30 X is 0 or S(O), ; wherein y is 0, 1, or 2; n is 2, 3, 4, or 5; p is the sum of non-H substituents R2, R 3 , and R4; s represents the number of double bonds in the ring, and is 0, 1, or 2; 35 T is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; 11 WO 00/42031 PCT/US99/29601
CO
2 H; C0 2 R; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; 5 C(O)C 6
H
5 ;
C(O)N(R
6
)(R
7 ) ;wherein
R
6 is H or alkyl of 1 - 5 carbons; and R' is H or alkyl of 1 - 5 carbons; S(O),,R ; wherein 10 y' is I or 2; and R' is alkyl of 1 - 5 carbons; SO2 F; CHO; OH; 15
NO
2 ; CN; halogen;
OCF
3 ; N-oxide; 20 O-C(R 9
)
2 -0 , the oxygens being connected to adjacent positions on R; and wherein
R
9 is H, halogen, or alkyl of 1 - 4 carbons; C(O)NHC(O) , the carbons being connected to adjacent positions on R; and 25 C(O)C 6
H
4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; tis 1 - 5; provided that when substituent moiety T is alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; C0 2 R; alkenyl of 2 - 4 30 carbons; alkynyl of 2 - 4 carbons; C(O)C 6
H
5 ; C(O)N(R 6
)(R
7 ); S(O),.R' ; O-C(R 9
)
2 -O , or C(O)C 6
H
4 , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; C0 2 R'; CO 2 H; C(O)N(R 6 )(R7); CHO; OH; NO 2 ; CN; halogen; S(O)yR; or =0, the number of said 35 secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level; G is a substituent selected from the group consisting of halogen; 12 WO 00/42031 PCT/US99/29601 OH; OR'; =0 , representing two substituents G; alkyl of 1 - 4 carbons; 5 alkenyl of 1 - 4 carbons; cycloalkyl of 3 - 7 carbons; heterocycloalkyl of 3 - 5 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; cycloalkenyl of 5 - 7 carbons; 10 heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; CO 2 R'; C(O)N(R')(R7); aryl of 6 - 10 carbons; 15 heteroaryl of 3 - 9 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S;
NO
2 ; CN; S(O),R'; 20 S0 3 R; and
SO
2
N(R
6
)(R
7 ); g is 0 - 4, with the exception of halogen, which may be employed up to the perhalo level; provided that when substituent G is alkyl of 1 - 4 carbons, alkenyl of 1 25 - 4 carbons, cycloalkyl of 3 - 7 carbons, heterocycloalkyl of 3 - 5 carbons, cycloalkenyl of 5 - 7 carbons, or heterocycloalkenyl of 4 - 6 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents 30 independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; 35 haloalkyl of 1 - 4 carbons; cycloalkyl of 3 - 8 carbons; alkoxy of 1 - 8 carbons; alkenyl of 2 - 5 carbons; 13 WO 00/42031 PCT/US99/29601 cycloalkenyl of 5 - 8 carbons; aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; 5 C0 2
R
5 ; =0 , representing two substituents Q; OH; halogen; N(R6)(R7); 10 S(O),R'; S0 3
R
8 ; and
SO
2
N(R
6
)(R
7 ); q is 0 - 4 provided that when substituent Q is aryl or heteroaryl, then Q 15 optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and with the further proviso that two of (Q)qR', (Q)qR 2 , (Q)qR 3 , and (Q)qR 4 may be 20 joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3 - 8 members containing 0 - 2 heteroatoms selected from the group consisting of N, 0, and S; and pharmaceutically acceptable salts thereof. 25 DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The compounds of formula (I) have been defined broadly in the summary above. In the compounds of formula (I), the following group preferences apply: R is preferably phenyl or pyridyl. 30 R' is preferably alkyl of 1 - 10 carbons, cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings, alkenyl of 2 - 10 carbons, cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings, or alkynyl of 3 - 10 carbons. R' is more preferably alkyl of 1 10 carbons, cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings, alkenyl of 2 - 10 carbons, or cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings. 35 R 2 , R 3 , and R 4 are preferably H, alkyl of 1 - 10 carbons, cycloalkyl of 3 - 12 carbons, alkenyl of 2 - 10 carbons, cycloalkenyl of 5 - 12 carbons, or =0 , in which the carbonyl represents two of the groups R 2 , R 3 , and R 4 . R 2 , RW, and R4 are more 14 WO 00/42031 PCT/US99/29601 preferably H, alkyl of 1 - 10 carbons, cycloalkyl of 3 - 12 carbons, alkenyl of 2 - 10 carbons, or cycloalkenyl of 5 - 12 carbons. X is preferably 0 or S(O), , wherein y is 0, 1, or 2. The subscript n, representing the number of carbons in the ring, is preferably 5 2 or 3. The subscript p, representing the sum of non-H substituents R 2 , R 3 , and R, is preferably 1 or 2. T is a substituent preferably selected from the group consisting of alkyl of 1- 4 carbons, alkoxy of 1 - 4 carbons, alkenyl of 2 - 4 carbons, alkynyl of 2 - 4 carbons, 10 NO 2 , CN, and halogen. T is more preferably alkyl of 1 - 4 carbons, alkenyl of 2 - 4 carbons, NO 2 , CN, or halogen. The subscript t, representing the number of substituents T, is 1 - 5, more preferably 1 - 3. When substituent moiety T is alkyl of 1 - 4 carbons, alkoxy of 1 - 4 carbons, 15 alkenyl of 2 - 4 carbons, or alkynyl of 2 - 4 carbons, then T optionally may bear secondary substituents preferably selected from the group consisting of alkyl of 1 - 4 carbons, alkoxy of 1 - 4 carbons, C0 2 R, CO 2 H, C(O)N(R)(R 7 ), CHO, OH, NO 2 , CN, halogen, S(O)yR, and =0, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level. 20 As employed in this application, the term "secondary substituent" means a substituent on a substituent, not "secondary" as used in defining the degree of substitution at a carbon. As employed in this application, the terms "haloalkyl" and "halocycloalkyl" are employed to refer to groups which may contain halogen atoms in any number up 25 to the per-halo level. G is preferably selected from the group consisting of halogen, OR', alkyl of 1 - 4 carbons, alkenyl of 1 - 4 carbons, cycloalkyl of 3 - 7 carbons, cycloalkenyl of 5 7 carbons, aryl of 6 - 10 carbons, and CN. G is more preferably halogen, alkyl of 1 4 carbons, alkenyl of 1 - 4 carbons, cycloalkyl of 3 - 7 carbons, cycloalkenyl of 5 - 7 30 carbons, or aryl of 6 - 10 carbons. The subscript g, representing the number of substituents G, is 0 - 4, more preferably 0 - 2, with the exception of halogen, which may be employed up to the perhalo level. Q is preferably selected from the group consisting of alkyl of 1 - 4 carbons, 35 haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 8 carbons, alkoxy of 1 - 8 carbons, alkenyl of 2 - 5 carbons, cycloalkenyl of 5 - 8 carbons, C0 2 R' , =0 , OH, halogen,
N(R
6
)(R
7 ), and S(O),R. Q is more preferably alkyl of 1 - 4 carbons, haloalkyl of 1 15 WO 00/42031 PCT/US99/29601 4 carbons, cycloalkyl of 3 - 8 carbons, alkoxy of 1 - 8 carbons, alkenyl of 2 - 5 carbons, cycloalkenyl of 5 - 8 carbons, or halogen. The present invention also includes pharmaceutically acceptable salts of the compounds of Formula I. Suitable pharmaceutically acceptable salts are well known 5 to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic 10 acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li' Na* or K), alkaline earth cations (e.g., Mg+ 2 , Ca+ 2 or Ba+ 2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or 15 peralkylation of triethylamine, NN-diethylamine, NN-dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5 diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of 20 enantiomeric and diastereomeric mixtures are well known to the skilled in the art. The present invention encompasses any racemic or optically active forms of compounds described in Formula I which possess progesterone receptor binding activity. The most preferred 2-imino-1,3-thiazolidines and ring expanded homologues 25 of 2-imino-1,3-thiazolidines of the invention are the following:
(
4
S)-
2
-(
2 -methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thiazolidine; (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine;
(
4
S)-
2
-(
2 -methyl-4-nitrophenylimino)-3-isobutyl-4-(trifluoromethyl)-1,3 thiazolidine; 30 (4S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isobutyl-1,3-thiazolidine; (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thiazolidine;
(
4
S)-
2
-(
2 -methyl- 4 -nitrophenylimino)-3-cyclopentyl-4-isopropyl-1,3-thiazolidine; (4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyltetrahydro-2H-1,3 thiazine; 35 (4S)-2-(4-nitro-1-naphthylimino)-3-cyclopentyl-4-((1R)-1-hydroxyethyl)-1,3 thiazolidine; 2 -(4-cyano-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane; 2 -(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane; 16 WO 00/42031 PCT/US99/29601 2-(4-cyanophenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro [4.4]nonane; 2-(4-cyano-2-methylphenylimino)- 1 -isobutyl-3 -thia- 1 -azaspiro [4.4]nonane; 2-(4-cyano-2,3 -dimethylphenylimino)- 1 -isobutyl-3-thia- 1 -azaspiro[4.4]nonane; 2-(4-cyano-2-methylphenylimino)- 1 -(1-ethyl-i -propyl)-3 -thia- 1 5 azaspiro[4.4]nonane; 2-(4-cyano- 1 -naphthylimino)- 1 -isobutyl-3-thia- 1 -azaspiro[4.4]nonane; 2-(2-methyl-4-nitrophenylimino)- 1 -(prop-2-en- 1-yl)-3 -thia- 1 -azaspiro [4.4]nonane; 2-(2-methyl-4-nitrophenylimino)- 1 -isopropyl-3 -thia- 1 -azaspiro [4.4]nonane; 2-(2-methyl-4-nitrophenylimino)- 1 -isobutyl-3-thia- 1 -azaspiro [4.4]nonane; 10 2-(2-methyl-4-nitrophenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro[4.4]nonane; 2-(3 -methyl-4-nitrophenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro[4.4]nonane; 2-(2-methyl-4-nitrophenylimino)- 1 -cyclohexyl-3 -thia- 1 -azaspiro[4.4]nonane; 2-(2,3 -dimethyl-4-nitrophenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro[4.4]nonane; and 15 2-(4-cyano-2,3-dimethylphenylimino)- 1 -cyclopentyl-3-thia- 1 -azaspiro [4.4]nonane. The most preferred thiazolidin-4-ones of the invention are the following: 2-(2-methyl-4-nitrophenylimino)-3-isobutyl- 1,3 -thiazolidin-4-one; 2-(3-methyl-4-nitrophenylimino)-3-isobutyl- 1,3-thiazolidin-4-one; 20 2-(2-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one; 2-(3-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-i -butyl)- 1,3-thiazolidin-4-one; 2-(3-methyl-4-nitrophenylimino)-3-(2-methyl- 1 -butyl)- 1,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-(1 -cyclohexyl- -ethyl)- 1,3-thiazolidin-4-one; 25 2-(3-methyl-4-nitrophenylimino)-3-(1 -cyclohexyl- 1-ethyl)- 1,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl- 1 -butyl)- 1,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methylene-1,3-thiazolidin-4-one; and 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methyl-1,3-thiazolidin-4-one. 30 The most preferred oxazolidines of the invention are the following: 2
-(
2 -methyl-4-nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-oxazolidine; 1-cyclopentyl-2-(4-cyano-2-ethylphenylimino)-3-oxa-1-azaspiro[4.4]nonane; 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane; and 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane. 35 The therapeutic agents of the invention may be employed alone or concurrently with other therapies. For example, when employed as in Al or A2, the agent may be used in combination with a calcium source, vitamin D or analogues of 17 WO 00/42031 PCT/US99/29601 vitamin D, and/or antiresorptive therapies such as estrogen replacement therapy, treatment with a fluoride source, treatment with calcitonin or a calcitonin analogue, or treatment with a bisphosphonate such as alendronate. When employed as in Bl through B7, the agent may be used with therapies such as estrogen replacement 5 therapy. When employed as in Cl through C16, El through E3, or Fl or F2, the agent may be used concurrently with therapies such as estrogen replacement therapy and/or a gonadotropin-releasing hormone agonist. When employed as in GI or G2, the agent may be used concurrently with therapies such as an androgen. The method of the invention is intended to be employed for treatment of 10 progesterone receptor mediated conditions in both humans and other mammals. The compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations. The term 'administered by injection' includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of 15 infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired, other active ingredients. Compositions intended for oral use may be prepared according to any suitable 20 method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic 25 pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may 30 be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form. 35 Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein 18 WO 00/42031 PCT/US99/29601 the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. 5 Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, 10 or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan 15 monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Dispersible powders and granules suitable for preparation of an aqueous 20 suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present. 25 The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such 30 as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti oxidant such as ascorbic acid. Pharmaceutical compositions of the invention may also be in the form of oil in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or 35 arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, 19 WO 00/42031 PCT/US99/29601 for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example 5 glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary 10 temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols. Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien; "Transdermal 15 Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 3Mar94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be 20 formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve. Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl 25 alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower 30 ketones , lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons. Suitable penetration enhancing materials for transdermal delivery systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated 35 or unsaturated C 8
-C,
8 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C 8
-C
8 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric 20 WO 00/42031 PCT/US99/29601 acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl 5 derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8
-C
18 fatty alcohols, saturated or unsaturated C 8
-C
8 fatty acids, 10 saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, aides, ketones, ureas and their derivatives, and ethers. Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block 15 polymers, styrene-butadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix. For all regimens of use disclosed herein for compounds of Formula I, the 20 daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. 25 The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of 30 total body weight. It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, 35 including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition 21 WO 00/42031 PCT/US99/29601 undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using 5 conventional treatment tests. The entire disclosures of all applications, patents and publications cited above and below are hereby incorporated by reference. 10 The compounds of Formula I may be prepared by use of known chemical reactions and procedures, from known compounds (or from starting materials which, in turn, are producible from known compounds) through the preparative methods shown below as well as by other reactions and procedures known to the skilled in the art. Nevertheless, the following general preparative methods are presented to aid 15 practitioners in synthesizing the compounds of the invention, with more detailed particular examples being presented in the experimental section. The examples are for illustrative purposes only and are not intended, nor should they be construed, to limit the invention in any way. 20 LIST OF ABBREVIATIONS AND ACRYONYMS As employed herein, the following terms have the indicated meanings. AcOH acetic acid anh anhydrous BOC tert-butoxycarbonyl 25 conc concentrated dec decomposition DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DME 1,2-dimethoxyethane 30 DMF NN-dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EtOH ethanol (100%) Et 2 O diethyl ether 35 Et 3 N triethylamine KMnO 4 potassium permanganate Magnosil* MgSiO 3 -xH 2 0 m-CPBA 3-chloroperoxybenzoic acid 22 WO 00/42031 PCT/US99/29601 MeOH methanol pet. ether petroleum ether (boiling range 30-60 *C) THF tetrahydrofuran TFA trifluoroacetic acid 5 GENERAL PREPARATIVE METHODS Aryl amines, aryl isocyanates, aryl isothiocyanates, unsymmetrical aryl thioureas, aryl isocyanate dichlorides and 2-arylimino- 1,3 -heterocycles may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive 10 Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984). March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985)). For example, aryl isocyanates (2) are available from the reaction of phosgene, or a phosgene equivalent, such as carbonyl diimidazole, diphosgene or triphosgene, and aryl isothiocyanates (3) are available from reaction of an aryl amine with thiophosgene or 15 a thiophosgene equivalent, such as thiocarbonyl diimidazole (Scheme I). Also, many aryl isocyanates and aryl isothiocyanates are commercially available. Reaction of an aryl isothiocyanate with a primary amine then affords thiourea 4 (Hahn et al. Han'guk Nonghwa Hakhoechi 1997,40, 139; Dfirr US Patent 4,079,144; Enders US Patent 4,148,799). 20 Scheme I 0 CI .lCl -W. AC 'ArNCO ArNH 2 S 2 1 CI CI R'NH 2 Ar-s Nk ,R - ArNCS - . N N H H 3 4 As shown in Scheme II, thioureas react with ax-haloketones, e.g. a bromoketone 5, to afford, after dehydration, the thiazoline (6) (Hahn et al. Han'guk 25 Nonghwa Hakhoechi 1997,40, 139; Dirr US Patent 4,079,144; Enders US Patent 4,148,799). Scheme II 23 WO 00/42031 PCT/US99/29601 0 S Br,,.
R
2 ArN Ars. N A N, R 1 5 S N.-R1 H 4H =R2 6 Similarly, thioureas react with c-haloacid halides (Giri et al. Asian J. Chem. 1992, 4, 785; Lakhan et al. Agric. Biol. Chem. 1982,46, 557), c-haloacids (Dogan et al. Spectrosc. Lett. 1983, 16, 499; Seada et al. Indian J. HeterocycL. Chem. 1993, 3, 5 81), and c-haloesters (Seada et al. Indian J. HeterocycL. Chem. 1993, 3, 81) to afford 4-thiazolidinones (10). Scheme III 0 Br C1 R 2 7 0 Br OH Ars N ArN N N' 8 ASN-R H H OR O 4 0 R 10 O0 Br OR R2 9 10 Aryl isothiocyanates (3) also react with allylamines (Tsoi et al. Zh. Org. Khim. 1983, 19, 2605) and propargylamines (Azerbaev et al. Khim. Geterotsikl. Soedin. 1972, 471) to form the corresponding thioureas, which on acid treatment afford the 5-substituted thiazolidines (Scheme IV). 15 Scheme IV 24 WO 00/42031 PCT/US99/29601 ArSCN ' NHR3 HC"C NHR' 11 12 S S ArsN N'R1 ArsN N'R H H) 13 HCC) 14 Ar..N ArsN S AN'R SK N'R Me H 2 C 15 16 Aryl isothiocyanates may also be reacted with hydroxylamines (17) to form N-hydroxyalkylthiourea 18 (Scheme V). Treatment of the thiourea with acid then leads to 2-imino-1,3-heterocycle 19 (Jen et al. J.Med Chem. 1975, 18, 90; 5 Tyukhteneva et al. Khim. Geterotsikl. Soedin. 1985, 12, 1629; Olszenko-Piontkowa et al. Org. Prep. Proced Int. 11971, 3, 27). Reaction of hydroxyalkylthiourea 18 with SOCl 2 affords cloroalkyl analogue 20, which on treatment with base will cyclize to afford heterocycle 19 (Cherbuliez et al. Helv. Chim. Acta 1967, 50, 331; Felix et al. US Patent 4,806,653). 10 Scheme V 25 WO 00/42031 PCT/US99/29601
R'NH(CH
2 )nOH S Ar. N 17 Ar, N JL N'R HA 1 ArSCN ' H I S N'R 3 HO-(CH2)n CH2)n 18 19 O1 2 S base ArsN N'R1 H
CI'(CH
2 )n 20
R'NH(CH
2 )nCI S Ar.N 21 ArN N'R N ArSCN H 'I S7KN'R 3 cI'(CH2)n j'CH 2 )n 1 20 19 Alternatively, as shown in Scheme VI, treatment of N-hydroxyalkylthiourea 18 with either HgO or an alkylating agent, such as methyl iodide followed by base 5 affords the corresponding oxygen-containing heterocycle (Jen et al. J.Med Chem. 1975, 18, 90; Ignatova et al. Khim. Geterotsikl. Soedin. 1974, 354). Scheme VI R'NH(CH2)nOH S Ar..N 1 7 Ar. N kN' R HgO 1 ArSCN H I - OANN'R 3 HO-(CH2)n or L('H2)1 18 1) Mel 22 2) OH~ 10 Chloroalkyl isothiocyanates have been reported to react with arylamines to afford the corresponding sulfur 2-phenylimino-1,3-heterocycle (Sagner et al. US Patent 3,651,053; Ibid US Patent 3,737,536). 15 Scheme VII Ar-. N ArN H 2 U
CI-(CH
2 )nNCS A S NH 23 (CH2)n-1 24 Aryl amines react with a formylating source, such as formic acetic anhydride, to form formanilide 25, which may then be oxidatively converted to the aryl 26 WO 00/42031 PCT/US99/29601 isocyanide dichloride (Ferchland et al. DE 3,134,134; for a review, see: Kuehle et al. Angew. Chem. 1967, 79, 663). Aryl isocyanide dichlorides (26) react with hydroxylamines (27) to give oxygen-containing 2-phenylimino-1,3-heterocycle 30 (Wollweber US Patent 3,787,575; Ibid US Patent 3,686,199) and with 5 hydroxylamide 28 to give thiazolidinone 31. In addition, aryl isoyanide dichlorides have been shown to react with aminomercaptans (29) to give the sulfur-containing 2 phenylimino-1,3-heterocycle 32 (Thibault French Patent 1,510,015). Scheme VIII 0 0 H 0 CH3 ArsNH S0 2
C
2 ArsN ArNH 2 - O O l I C 10-l H SOC 2 c1 Ac1 25 26
HO-(CH
2 )nNHR HO HN'R HS-(CH 2 )nNHR 27 29 28 O Ar...N ArNN ArsN OK N'R O N'R S ANR (--CH2)n1 O- (-CH2)n-1 10 30 31 32 Treatment of hydroxylamines with CS 2 in the presence of base will generate the 1,3-thiaza-2-thione (Scheme IX). It has been reported that thione 34 reacts with SOC1 2 to give hydroscopically labile imidate 35, which on treatment with an aryl 15 amine affords the sulfur-containing 2-imino-1,3-heterocycle (Hanefeld et al. Arch. Pharm. 1985, 318, 60; Ibid 1988, 321, 199). Scheme IX S CI ArsN H R 1
CS
2 A ' R 1 SOC1 2 N. ArNH 2 N 'R 1 HO HN' S N' S N-R1 S N base K> K> K 20 33 34 35 36 Both oxygen-containing and sulfur-containing 2-imino- 1,3 -heterocycles may be further elaborated. Thus, for example, as shown in Scheme X, treatment of N3 unsubstituted 2-phenylimino- 1,3-heterocycles with electrophiles, typically in the 27 WO 00/42031 PCT/US99/29601 precense of base, affords the N3-substituted product (Ambartsumova et al. Chem. Heterocycl. Compd. 1997, 33, 475; Mizrakh et al. Khim. Geterotsikl. Soedin. 1990, 563; Olszenko-Piontkowa et al. Org. Prep. Proced. Int. 11971, 3, 27). 5 Scheme X Ri-Y Ar, N 38 R S X N Y = halogen I'CH2)n 42
CO
2 Me Ars, N ArsN X 'N N\.CO 2 Me k- (CH 2 )n X NH O 43 (--CH2)n RAC Ars, R CIN 37 4k 0 X=OorS 40X N'R (--CH2)n 0 44 Br... . Ars N 0 R 41 R OJ 'X N . ('CH2)n 45 In addition, as shown in Scheme XI, sulfur-containing 2-imino-1,3 heterocycles may be oxidized to the sulfoxide or sulfone (Chizhevskayaet al. Khim. Geterotsikl. Soedin. 1971, 96; Pandey et al. J. Indian Chem. Soc. 1972, 49, 171). 10 Scheme XI Ar. N ArsN Ars N S A NH KMn0 4 0:ZS N H S NH + S NH
W(CH
2 )n or
-('CH
2 )n 04 \_('CH2 46 mCPBA 47 48 DETAILED EXPERIMENTAL PROCEDURES 15 Detailed examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In the tables of compounds to follow, the synthesis of each compound is referenced back to these exemplary preparative steps. 28 WO 00/42031 PCT/US99/29601 EXAMPLES All reactions were carried out in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or 5 cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg. Bulb-to-bulb concentrations were conducted using an Aldrich Kugelrohr apparatus, and in these 10 cases temperatures refer to oven temperatures. All temperatures are reported uncorrected in degrees Celcius (*C). . Unless otherwise indicated, all parts and percentages are by volume. Thin-layer chromatography (TLC) was performed on Whatman* pre-coated glass backed silica gel 60A F-254 250 ptm plates. Visualization of plates was effected by 15 one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column 20 chromatography (flash chromatography) was performed using 230-400 mesh EM Science* silica gel. Rotary chromatography was performed using pre-cast SiO 2 plates (Alltech*) from Harrison Research Chromatotron. Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. 25 Fourier transform infrared sprectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton ( 1 H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (6 0.00) or residual protonated solvent (CHC1 3 8 7.26; MeOH 6 3.30; DMSO 6 2.49) as 30 standard. Carbon ("C) NMR spectra were measured with a General Electric GN Omega 300 (75 MHz) spectrometer with solvent (CDCl 3 6 77.0; MeOD-d 3 ; 8 49.0; DMSO-d 6 6 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were obtained as electron impact (EI), chemical ionization (CI), or as fast atom 35 bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 'C. Electron impact ionization was performed with 29 WO 00/42031 PCT/US99/29601 electron energy of 70 eV and a trap current of 300 pA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment, were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with 5 methane or ammonia as the reagent gas (1x1O 4 torr to 2.5xl04 torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( ~1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett 10 Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source. Gas chromatography - ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas 15 chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ. NMR spectra, LRMS, elemental analyses, and HRMS of the compounds were 20 consistant with the assigned structures. Examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In the tables of compounds to follow, the synthesis of each compound is referenced back to these exemplary preparative steps. 25 A. Synthesis of Imine Precursors Ala. General method of synthesis of anilines from nitrobenzenes. Synthesis of 4-cyano-2-methylaniline. NC 30 NH 2 4-Cyano-2-methylaniline was synthesized as previously described (J. Med. Chem. (1991), 34, 3295): To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.34 mmol) in acetic acid (20 L) was added dropwise a solution of SnCl 2 (9.6 g, 49.38 mmol) in conc. HCl (20 mL). After stirring for 3 h, the mixture was added carefully 35 to a saturated NH 4 0H solution (120 mL) at 0 'C. The resulting mixture was extracted with EtOAc (4x30 mL). The combined organic layers were sequentially washed with 30 WO 00/42031 PCT/US99/29601
H
2 0 (30 mL) and a saturated NaCl solution (30 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc/hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92%): TLC (30% EtOAc in hexane) Rf 0.23. This material was used without 5 further purification. A2a. General method for the synthesis of isothiocyanates. Synthesis of 4 nitro-2-n-propyl isothiocyanate. aN H 10 Step 1 To a solution of 2-n-propylaniline (8.91 g, 66 mmol) and Et 3 N (14 mL, 106 mmol) in CH 2 Cl 2 (60 mL) was added acetic anhydride (10.9 mL, 99 mmol) dropwise. The resulting mixture was allowed to stir at room temp. overnight, then was treated with a iN HCl solution (40 mL). The acidic mixture was extracted with CH 2 C1 2 15 (2x30 mL). The combined organic layers were sequentially washed with H 2 0 (40 mL), a 1N NaOH solution (40 mL), H 2 0 (40 mL) and a saturated NaCl solution (40 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The resulting powder was purified by crystalization ( EtOAc) to give 2-n-propylacetanilide as white needles (7.85 g, 67%). TLC (30% EtOAc/hex) Rf0.37. 0 2 N 20 N H 2 Step 2 To a solution of 2-n-propylacetanilide (1.15 g, 6.50 mmol) in TFA (20 mL) at -5 *C was added NaNO 2 (0.55 g, 6.50 mmol). The mixture was allowed to stir at -5 *C for 3 h, then was treated with H 2 0 (30 mL). The resulting aqueous solution was 25 extracted with EtOAc (3x20 mL). The combined organic layers were washed with a iN NaOH solution (30 mL), H 2 0 (30 mL) and a saturated NaCl solution (40 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The residue was dissolved in a conc. HCl solution (30 mL) and heated at 100 *C overnight. The resulting mixture was cooled to 0 *C with an ice bath, then was carefully adjusted to pH 10 30 with a 50% NaOH solution. The basic mixture was extracted with EtOAc (4x30 mL). The combined organic layers were sequentially washed with H20 (30 mL) and a saturated NaCl solution (40 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc/hex) to give 31 WO 00/42031 PCTIUS99/29601 2-n-propyl-4-nitroacetanilide as a yellow solid (0.56 g, 48%): TLC (20% EtOAc/hex) Rf 0.47. 0 2 N Step 3 5 To a solution of 2-propyl-4-nitroacetanilide (0.56 g, 0.31 mmol) in toluene (30 mL) was added thiophosgene (0.24 mL, 0.31 mmol) dropwise. The mixture was heated at the reflux temp. overnight, then cooled to room temp. and concentrated under reduced pressure. The residue was purified by flash chromatography (1% EtOAc/hex) to give 2-propyl-4-nitrophenyl isothiocyanate as a yellow oil (0.65 g, 10 95%): TLC (20% EtOAc/hex) RfO.82. A2b. General method for the synthesis of isothiocyanates. Synthesis of 4-cyano 2-ethylphenyl isothiocyanate. CN Et N ,C, ,S 15 To a solution of 4-amino-3-ethylbenzonitrile, (75 g, 0.51 mol) in toluene (1 L) was added thiophosgene, (43 mL, 0.56 mol, 1.1 equiv.) slowly via syringe. Within 5 min. a viscous slurry formed. The reaction mixture was heated to the reflux temp. and the viscosity diminished. The reaction mixture was heated at the reflux temp. for 5 h then allowed to cool to room temp. The resulting mixture was 20 concentrated under reduced pressure and the residue was treated with CH 2 Cl 2 (600 mL) and concentrated under reduced pressure to give 4-cyano-2-ethylphenyl isothiocyanate as a light tan crystalline solid (98 g, 100%): 'H NMR (DMSO-d 6 ) 6 1.18 (t, J=7.4 Hz, 3H), 2.69 (q, J=7.4 Hz, 2H), 7.55 (d, J=7.0 Hz, IH), 7.75 (d, J=7.0 Hz, 2H), 7.84 (s, 1H); MS (CI-MS) m/z 189 ((M+H)*). 25 A2c. General method for the synthesis of isothiocyanates. Synthesis of 2,4 dimethyl-3-cyano-5-pyridyl isothiocyanate. Me N C : _
-
N N , MeN A suspension of 6 -amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0.68 mmol) in 30 CH 2 Cl 2 (1 mL) was added to a vigorously stirred mixture of CaCO 3 (0.41 g, 4.11 32 WO 00/42031 PCT/US99/29601 mmol) in a 1:2 water:CH 2 Cl 2 mixture (9 mL total) at room temp. The reaction mixture was cooled to 0 *C and thiophosgene (0.09 g, 0.78 mmol) was added dropwise. The resulting mixture was allowed to warm to room temp and was stirred overnight. The resulting aqueous layer was back-extracted with CH 2 Cl 2 (3 x 10 mL). 5 The combined organic layers were washed with water (10 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , 10% EtOAc/hex) to give 2,4-dimethyl-3-cyano-6-pyridyl isothiocyanate (0.12 g, 91%): CI-MS m/z 190 ((M+H)+). 10 A2d. General method for the synthesis of isothiocyanates. Synthesis of 2,3 dimethyl-4-nitrophenyl isothiocyanate. Me 0 2 N Me To a solution of 2,3-dimethyl-4-nitroaniline (0.5 g, 1.0 equiv.) in toluene (50 mL) was added thiophosgene (0.3 mL, 1.3 equiv.) and the reaction mixture was 15 heated at the reflux temp. overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (25% CH2Cl2/hex) to afford 2,3-dimethyl-4-nitrophenyl isothiocyanate as a light yellow solid (0.30 g, 48%): 'H NMR (CDCl 3 ) 8 2.39 (s, 3H), 2.41 (s, 3H), 7.20 (d, J=8.4 Hz, 1H); CI-MS m/z 200 ((M+H)*). 20 A2e. General method for the synthesis of isothiocyanates. Synthesis of 2,3 dimethyl-6-nitrophenyl isothiocyanate. Me Me N
NO
2 To a solution of 2,3-dimethyl-6-nitroaniline (3.0 g, 1.0 equiv.) in toluene (150 25 mL) was added thiophosgene (2.5 mL, 1.8 equiv.) and the reaction mixture was heated at the reflux temp. overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (10%
CH
2 Cl 2 /hex) to afford 2,3-dimethyl-6-nitrophenyl isothiocyanate as a light yellow solid (3.63 g, 95%): 'H NMR (CDCl 3 ) 8 2.39 (s, 3H), 2.40 (s, 3H), 7.17 (d, J=8.4 30 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H). 33 WO 00/42031 PCTIUS99/29601 A3a. General method of synthesis of aryl isonitrile dichlorides. Synthesis of 4-cyano-2-ethylphenyl isocyanide dichloride. NC Et o NH Step 1 5 Acetic anhydride (235 mL, 2.5 mol, 2.6 equiv.) was added to formic acid (118 mL 3.1 mol, 3.2 equiv.) and the resulting solution was heated at 60 *C for 2 h. After the reaction had cooled to room temp., a solution of 4-amino-3 ethylbenzonitrile (140 g, 0.96 mol) in anh. THF (700 mL) was added at such a rate that the reaction temp. did not exceed 45 *C (approximately 20 min.). When the 10 resulting solution had cooled to room temp. it was concentrated under reduced pressure, treated with EtOH (600 mL), and concentrated again under reduced pressure to afford 4-cyano-2-ethylformanilide as a light tan solid (167 g, 100%): 'H NMR (CDCl 3 ) 6 1.13 (t, J=7.3 Hz, 3H), 2.48 (q, J=7.3 Hz, 2H), 7.65 (d, J=8.5 Hz, 1H), 8 35 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 9.89 (br s, 1H). 15 NC Et Cl C Step 2 To a solution of 4-cyano-2-ethylformanilide (167 g, 0.96 mol, 1.0 equiv.) in SOCl 2 (525 mL, 6.05 mol, 6.3 equiv.) which had been cooled to 0 *C with an ice bath 20 was added sulfuryl chloride, (112 mL, 1.4 mol, 1.4 equiv.) via syringe. The cooling bath was then removed and the reaction was heated at 50 *C overnight. The resulting mixture was concentrated under reduced pressure, treated with CH 2 C1 2 (600 mL), and concentrated again under reduced pressure. The residue was dissolved in Et 2 O (800 mL) and filtered through a pad of Magnosil* to give 4-cyano-2-ethylphenyl 25 isocyanide dichloride as an oil (210 g, 96%): 'H NMR (CDCl 3 ) 6 1.13 (t, J=7.3 Hz, 3H), 2.49 (q, 2H, J = 7.3 Hz), 7.15 (d, J=8.2 Hz, 1H), 8.35-8.40 (in, 2H). A3b. General method of synthesis of aryl isonitrile dichlorides. Synthesis of 2-methyl-4-nitrophenyl isocyanide dichloride. 34 WO 00/42031 PCT/US99/29601 0 2 N Me NH O H Step 1 Acetic anhydride (400 mL, 4.26 mol, 2.6 equiv.) was added to formic acid (200 mL, 5.25 mol, 3.2 equiv.) and the resulting solution was heated at 60 *C for 5 2.25 h. After cooling to room temp., a solution of 2-methyl-4-nitroaniline (152 g, 1.64 mol, 1.0 equiv.) in anh. THF (1.2 L) was added at such a rate that the reaction temp. did not exceed 45 *C (approximately 30 min.). When the resulting solution had cooled to room temp. it was concentrated to half the volume under reduced pressure and the reaction product was removed by filtration yielding 2-methyl-4 10 nitroformanilide as a light tan solid (295g, 100%): 'H NMR (CDCl 3 ) 6 2.31 (s, 3H) 8.03 (m, 2H), 8.24 (d, J=8.8 Hz, 1H), 8.39 (br s, 1H), 9.94 (br s, 1H). 0 2 N Me N CI CI Step 2 SOCl 2 (525 mL, 6.05 mol, 6.3 equiv.) was added to 2-methyl-4 15 nitroformanilide (167 g, 0.96 mol) and the resulting solution was cooled to 0 *C. Sulfuryl chloride, (112 mL, 1.4 mol, 1.4 equiv.) was added via syringe, the cooling bath was removed and the reaction was heated at 60 *C for 4 h, then allowed cool to room temp. overnight. The reaction mixture was concentrated to half the volume under reduced pressure and the resulting slurry was filtered. The solids were washed 20 with a 50% Et 2 O/hex solution to yield 2-methyl-4-nitrophenyl isocyanide dichloride as a yellow solid (323 g, 85%): 'H NMR (CDCl 3 ) 6 2.19 (s, 3H), 7.20 (d, J=8.5Hz, 1H), 8.15 (d, J=8.5Hz, 1H), 8.2 (s, 1H). A4a. General method for the synthesis of nitroanilines from anilines. 25 Synthesis of 2,3-dimethyl-6-nitroaniline and 2,3-dimethyl-4-nitroaniline. Me Meo N Me H Step 1 To a solution of 2,3-dimethylaniline (1.1 mL, 1.00 equiv.) and Et 3 N (1.5 mL, 1.30 equiv.) in CH 2 C1 2 (15 mL) at 0 *C was added acetyl chloride (0.73 mL, 1.25 35 WO 00/42031 PCT/US99/29601 equiv.) over 30 min.. The reaction mixture was allowed to stir overnight at room temp., then was treated with a 2N HCl solution (10 mL) and CH 2 C1 2 (25 mL). The resulting mixture was extracted with EtOAc (3x25 mL). The combined organics were washed with a 2N HCl solution (2x25 mL), water (2x25 mL), a saturated 5 NaHCO 3 solution (2x25 mL) and a saturated NaCl solution (2x25 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure to give 2,3-dimethylacetanilide as a white solid (1.25 g, 93%): 'H NMR (CDCl 3 ) 6 2.05 (s, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 6.95 (d, J=7.5 Hz, 1H) 7.02 (app t, J=7.5 Hz, 1H), 7.35 (d, J=6.9 Hz, 1H). Me Me MeO 0 2 N Meo N Me N Me
NO
2 H H 10 Step 2 To a solution of 2,3-dimethylacetanilide (14.0 g, 1.0 equiv.) in conc. H 2 SO4 (35 mL) at 0 *C was added HNO 3 (5.1 mL, 1.25 equiv) over 30 min. The resulting mixture was allowed to stir at room temp. for 15 min., then was treated with ice water (500 mL) to form a yellow precipitate. The solids were removed and washed 15 with water to afford a 1:1 mixture of 2,3-dimethyl-6-nitroacetanilide and 2,3 dimethyl-4-nitroacetanilide (16.0 g, 90%): 'H NMR (CDCl 3 ) 6 2.15 (s, 1.5H), 2.22 (s, 1.5H), 2.37 (s, 1.5H), 2.38 (s, 1.5H), 2.41 (s, 1.5H), 5.93 (br s, 1H), 7.15 (d, J=8.7 Hz, 0.5H), 7.63 (d, J=8,7 Hz, 0.5H), 7.76 (d, J=8.1 Hz, 1H). This mixture was used in the next step without further purification. Me Me Me 0 2 N Me
NH
2 NH 2 20 NO 2 Step 3 To a solution of the mixture of nitroacetanilides (16.0 g, 1.0 equiv.) was added a 60% H 2
SO
4 solution (150 mL). The solution was heated at the reflux temp. for 1 h, then cooled to room temp. and treated with a 2N NaOH solution in ice water 25 (100 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with a saturated NaHCO 3 solution (2x50 mL) and a saturated NaCl solution (2x50 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The residue was purified by column chromatography (10%
CH
2 Cl 2 /hex) to afford 2,3-dimethyl-6-nitroaniline (5.5 g, 43%), followed by 2,3 30 dimethyl-4-nitroaniline (1.5 g, 12%). 2,3-Dimethyl-6-nitroaniline (5.5 g, 43%): 'H NMR (CDCl 3 ) 6 2.05 (s, 3H), 2.20 (s, 3H), 6.15 (br s, 2H), 6.45 (d, J=8.7 Hz, 1H), 36 WO 00/42031 PCT/US99/29601 7.63 (d, J=9.0 Hz, 1H); 'H NMR (DMSO-d 6 ) 8 2.10 (s, 3H), 2.30 (s, 3H), 6.50 (d, J=8.7 Hz, 111), 7.15 (br s, 2H), 7.75 (d, J=9.0 Hz, 1H). 2,3-Dimethyl-4-nitroaniline: 'H NMR (CDC1 3 ) 8 2.10 (s, 3H), 2.45 (s, 3H), 4.05 (br s, 2H), 6.45 (d, J=9.0 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H); 'H NMR (DMSO-d 6 ) 5 2.00 (s, 3H), 2.35 (s, 3H), 6.12 5 (br s, 2H), 6.53 (d, J=9.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H). A5a. General method for the synthesis of iodoanilines. Synthesis of 4-iodo-2-n propylaniline. 'lNH 2 10 To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHCO 3 (5.0 g, 59.5 mmol) in H20 (25 mL). Iodine (8.4 g, 33.3 mmol) was added portionwise over 70 min. while maintaining the temp. at 10 *C, then the mixture was allowed to stir at 10 *C for 30 min. The resulting mixture was diluted with H20 (30 mL) and extracted with EtOAc (4x40 mL). The combined organic layers were 15 sequentially washed with a 5% Na 2
S
2 0 3 solution (30 mL) and a saturated NaHCO 3 solution (30 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure to give 4 iodo-2-n-propylaniline (9.4 g, 98%): TLC (20% EtOAc/hex) Rf 0.43. This material was used in the next step without further purification. 20 B. Methods for Forming Precursors to 2-Iminoheterocycles Bla. General method for the synthesis of ethanolamines via reduction of amino acid derivatives. Synthesis of 1-amino-1 (hydroxymethyl)cyclohexane. 0 HO HN 0 25 Step 1 To a solution of 1-aminocyclohexane-1-carboxylic acid (10.0 g, 70.0 mmol) in a IM NaOH solution (100 mL) was added benzyl chloroformate (12.0 ml, 84.0 mmol). The reaction mixture was stirred for 2 h while maintaining pH 9 by addition 30 of a 1M NaOH solution as necessary. The resulting solution was washed with Et 2 0 (2x100 mL), then the aqueous layer was adjusted to pH 0 with a conc. HCl solution and the solution was extracted with EtOAc (3x150 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield 1 37 WO 00/42031 PCT/US99/29601 (benzyloxycarbonylamino)cyclohexane-1-carboxylic acid (17.3 g, 89%): TLC (25% EtOAc/hex) Rf 0.07. 0 HO HN 0 Step 2 5 To a solution of 1-(benzyloxycarbonylamino)cyclohexane-1-carboxylic acid (4.16 g, 15.0 mmol) and N-methylmorpholine (1.81 mL, 16.5 mmol) in DME (15 mL) at 4 *C was slowly added isobutyl chloroformate (2.14 mL, 16.5 mmol) and the reaction mixture was stirred for 5 min, then filtered into a pre-cooled (4 *C) flask. Sodium borohydride (0.85 g, 22.5 mmol) in water (7 mL) was added followed 10 immediately by water (500 mL). The reaction was then warmed to 20 'C and stirred for 30 min. The reaction mixture was extracted with CH 2 Cl 2 and concentrated under reduced pressure to yield 1 -(benzyloxycarbonylamino)- 1 (hydroxymethyl)cyclohexane (4.0 g, 100%): TLC (25% EtOAc/hex) Rf 0.11. HO
NH
2 15 Step 3 A slurry of 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane (4.0 g, 15 mmol) and 10% Pd/C (0.40 g) in MeOH (75 ml) was stirred under H2 (1 atm.) for 1 h, then treated with Celite*. The resulting mixture was filtered and concentrated under reduced pressure to give 1-amino-I 20 (hydroxymethyl)cyclohexane. Bib. General method for the synthesis of ethanolamines via reduction of amino acid derivatives. Synthesis of (1S)-1-(hydroxymethyl)-3 methylbutylamine. MeO NH 2 HCI 0 25 Step 1 To a suspension of (L)-leucine, (315 g, 2.4 mol) in MeOH (3.2 L) at -15 'C was added SOCl 2 (315 mL, 4.32 mol, 1.8 equiv.) dropwise at such a rate that the temp. of the reaction did not exceed 5 'C. After the addition was complete, the 30 reaction mixture was allowed to warm to room temp. and was stirred overnight. The 38 WO 00/42031 PCTIUS99/29601 resulting mixture was concentrated under reduced pressure and Et 2 O (3 L) was slowly added to the residue to produce a precipitate. The mixture was cooled with an ice bath, then treated with additional MeOH (3 L) relatively rapidly. After 1 h at 0 'C, the crystals were collected and dried to give (L)-leucine methyl ester HCl salt as 5 a white crystalline solid (394 g, 86%): mp 147-149 *C; 'H-NMR (CD 3 OD) 5 0.78 0.98 (in, 6h), 1.58-1.72 (in, 3H), 3.76 (s, 3H), 3.92 (t, J=7.3 Hz, 1H). HO
NH
2 Step 2 To a mixture of (L)-leucine methyl ester HCl salt (254 g, 1.4 mol), NaHCO 3 , 10 (118 g, 1.4 mol, 1.0 equiv.) and water (1.8 L) in EtOH (1.8 L) at 5"C was added NaBH 4 , (159 g, 4.2 mol, 3.0 equiv.) in portions at such a rate that the reaction temp. did not exceed 15"C (approximately 70 min). After the addition of NaBH 4 was complete, the ice bath was removed and the reaction was heated to the reflux temp. overnight. The resulting mixture was cooled to room temp. with the aid of an ice 15 bath. The resulting slurry was filtered and the solids were washed with EtOH (750 mL). The combined filtrates were concentrated to approximately 950 mL under reduced pressure. The residue was diluted with EtOAc (2.5 L) and extracted with a 1N NaOH solution (2x1 L). The aqueous layer was back-extracted with EtOAc (2x750 mL). The combined organics were dried (MgSO 4 ) and concentrated under 20 reduced pressure to yield (1S)-1-(hydroxymethyl)-3-methylbutylamine as a pale yellow oil (112 g, 65%): 'H NMR (CDCl 3 ) 6 0.88-0.93 (in, 6H), 1.17 (t, J=7.7 Hz, 2H), 1.68-1.80 (in, 211), 1.82 (br s, 2H), 2.86-2.91 (in, 1H), 3.22 (dd, J=10.7, 8.1 Hz, 1H), 3.56, (dd, J=10.3, 3.6 Hz, 1H). 25 B1c. General method for the synthesis of ethanolamines via reduction of amino acid derivatives. Synthesis of 1-hydroxymethylcyclopentanamine MeO NH 2 HCI O Step 1 To a suspension of 1-aminocyclopentanecarboxylic acid, (675 g, 5.23 mol, 30 1.0 equiv.) in MeOH (6.5 L) held at -15 *C with an ice/MeOH bath was added SOCl 2 (687 mL, 9.4 mol, 1.8 equiv.), dropwise at such a rate that the reaction temp. did not exceed 7 'C. After the addition was complete, cooling was removed, the reaction was allowed to stir at room temp. overnight, then was concentrated under reduced 39 WO 00/42031 PCT/US99/29601 pressure. The residue was treated with CH 2 C1 2 (1 L) and concentrated under reduced pressure to afford methyl 1-aminocyclopentanecarboxylate HCl salt as a white solid (938 g, 100%): 'H NMR (CD 3 0D) d 1.87-1.94 (m, 8H), 3.83 (s, 311); NMR (DMSO d 6 ) 6 1.67-1.71 (m, 2H), 1.83-1.98 (m, 4H), 2.06-2.14 (m, 2H), 3.73 (s, 3H), 8.81 (br 5 s 3H). This material was used in the next step without further purification. HO
NH
2 Step 2 A solution of methyl 1 -aminocyclopentanecarboxylate HCl salt (310 g, 1.73 mol) in a solution of EtOH (12.5 L) and water (2.5 L) was treated with NaHCO 3 10 (145 g, 1.73 mol, 1.0 equiv.). The resulting mixture was then cooled to 5 *C with an ice bath and NaBH 4 (196 g, 5.2 mol, 3.0 equiv.) was added in portions at such a rate that the reaction temp. did not exceed 15 'C (approximately 75 min.). After the addition of NaBH 4 was complete, the ice bath was removed and the reaction was heated at the reflux temp. overnight, cooled to room temp. with the aid of an ice bath, 15 and filtered. The resulting solids were washed with EtOH (750 mL) and the combined filtrates were concentrated under reduced pressure. The resulting slurry was then treated with EtOAc (2.5 L). The organic layer was washed with a IN NaOH solution (2x750 mL) and the aqueous layer was back-extracted with EtOAc (2x500 mL). The combined organic layers were dried (MgSO 4 ) and concentrated 20 under reduced pressure to afford 1-hydroxymethylcyclopentanamine as a low melting wax (169 g, 85%): 'H NMR (CDCl 3 ) 6 1.38-1.44 (m, 211), 1.58-1.69 (m, 411), 1.70-1.84 (m, 2H), 2.11 (br s, 311), 3.36 (s, 211). CI-MS m/z 116 ((M+H)*). B2a. General method for the N-alkylation of ethanolamines via substitution 25 reactions. Synthesis of 2-(isobutylamino)-2-(hydroxymethyl)norbornane. HO HN 2-Aminonorbornane-2-carboxylic acid was converted into 2-amino-2 (hydroxymethyl)norbornane as a diastereomeric mixture in a manner analogous to Method Bla. A solution of the amino alcohol (0.31 g, 2.16 mmol) and isobutyl 30 bromide (0.23 ml, 2.16 ml) in DMF (3 mL) was heated at 90 'C for 92 h, then cooled to room temp. and partitioned between EtOAc (100 mL) and a saturated NaHCO 3 solution (100 mL). The organic layer was washed with a saturated NaCl solution (50 mL), dried (MgSO 4 ), and concentrated under reduced pressure to yield 2 40 WO 00/42031 PCT/US99/29601 (isobutylamino)-2-(hydroxymethyl)norbomane as a diastereomeric mixture (0.24 g, 55%): GC-MS m/z 197 (M*). B2b. General method for the N-alkylation of ethanolamines via substitution 5 reactions. Synthesis of N-hydroxyethyl-N-cyclohex-1-enylmethylamine. OH Step 1 To a stirred solution of methyl cyclohex-1-enecarboxylate (4.56 g, 32 mmol) in THF (100 mL) at -78 *C was added DIBAL (1 M in THF, 130 mmol, 130 mL) 10 dropwise. The mixture was allowed to stir at -78 *C for 4 h then treated with a saturated NaHCO 3 solution (40 mL). The aqueous layer was extracted with EtOAc (4x20 mL) and the combined organic layers were washed with H 2 0 (40 mL) and a saturated NaCl solution (40 mL), dried (Na 2
SO
4 ),and concentrated under reduced pressure. The residual cyclohex-1-enylmethanol was used directly for the next step 15 without purification: TLC (30% EtOAc/hex) Rf0.44. Br Step 2 To a solution of cyclohex-1-enylmethanol (3.58 g, 32 mmol) in CH 2 Cl 2 (40 mL) at 0 *C was added PPh 3 (36 mmol, 9.39 g) and CBr 4 (39 mmol, 12.96 g). The 20 mixture was allowed to stir at room temp. overnight then concentrated under reduced pressure. The residue was diluted with pentane (60 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (5% EtOAc/hex) to give 1-bromomethyl-1-cyclohexene as an oil (3.25 g, 57% over two steps): TLC (30% EtOAc/hex) Rf 0.91. N MOH I H 25 Step 3 A solution of 1-bromomethyl-1-cyclohexene (3.25 g) and 2-aminoethanol (6 mL) in trichloroethylene (40 mL) was heated at the reflux temp. for 3 d, cooled to room temp., and diluted with a IN NaOH solution (30 mL). The aqueous layer was 30 extracted with CH 2 C1 2 (4x20 mL) and the combined organic layers were washed with
H
2 0 (30 mL) and a saturated NaCl solution (30 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue was purified by vacuum distillation to give N-hydroxyethyl-N-cyclohex-1-enylmethylamine as a colorless oil (1.78 g, 62%): bp 92-94 'C (6 mmHg). 41 WO 00/42031 PCT/US99/29601 B3a. General method for the N-alkylation of ethanolamines via reductive alkylation. Synthesis of (R)-N-isobutylserine methyl ester HCl salt. HO HN HCI
CO
2 Me 5 To a suspension of (D)-serine methyl ester HCl salt (2.13 g, 13.7 mmol) in 1,2-dichloroethane was added isobutyraldehyde (1.5 mL, 16.4 mmol) and sodium triacetoxyborohydride (4.3 g, 20.5 mmol). The reaction mixture was stirred at room temp. for 24 h, then partitioned between Et 2 O (100 mL) and a saturated NaHCO 3 solution (100 mL). The organic layer was washed with a saturated NaHCO 3 solution 10 (3x100 mL), dried (MgSO 4 ), and treated with a IM HCI solution in ether (25 mL). The resulting mixture was concentrated under reduced pressure to yield (R)-N isobutylserine methyl ester HCl salt (2.27 g, 79%): NMR (DMSO-d 6 ) 8 0.94 (dd, J=6.7, 3.0 Hz, 6H); 1.97-2.11 (m, 1H); 2.76-2.91(m, 1H); 3.76 (s, 3H); 3.86 (dd, J=12.1, 4.1 Hz, 1H), 3.99 (dd, J=12.4, 3.2 Hz, 1H), 4.13-4.21 (m, 1H). 15 B4a. General method for the N-alkylation of ethanolamines via 2-alkyl-1,3 oxazolidine formation followed by reduction. Synthesis of 1 (cyclohexylamino)-1-(hydroxymethyl)cyclopentane. O NH 20 Step 1 To a solution of 1-amino-1-(hydroxymethyl)cyclopentane (Method Bc; 1.44 g, 12.54 mmol) in CH 2 C1 2 (10 mL) at 4 *C was added TFA (0.097 mL, 1.25 mmol), cyclohexanone (1.30 mL, 12.54 mmol) and sodium sulfate (2 g) and the reaction was warmed to 20 *C. The reaction was stirred for 72 h and was sequentially washed 25 with water (10 mL) and a saturated NaHCO 3 solution (20 mL), dried (MgSO 4 ), and concentrated under reduced pressure to give 14-aza-7-oxadispiro[4.2.5.1]tetradecane (2.38 g, 97%): GC-MS m/z 195 (M*). HO HN-Q Step 2 42 WO 00/42031 PCT/US99/29601 To a solution of LiAlH 4 (0.93 g, 24.4 mmol) and AICl 3 (3.24 g, 24.4 mmol) in THF at 4 *C was added dropwise a solution of 14-aza-7 oxadispiro[4.2.5.1]tetradecane (2.38 g, 12,2 mmol) in THF (15 mL). The resulting mixture was warmed to 20 *C and stirred for 45 min., then cooled to 4 *C. Water (5 5 mL) was slowly added to quench the reaction and a IN NaOH solution (85 mL) was added to dissolve the resulting solids. The resulting solution was extracted with Et 2 O (200 mL). The organic layer was dried (Na2SO 4 ) and concentrated under reduced pressure to yield 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane 1.89 g (79%): GC-MS m/z 197 (M*). 10 B4b. General method for the N-alkylation of ethanolamines via 2-alkyl,3 oxazolidine formation followed by reduction. Synthesis of N-cyclopentyl (1,1-dimethyl-2-hydroxyethyl)amine. 15 Step 1 A mixture of 2-amino-2-methyl-1-propanol (15.0 g, 0.168 mol), cyclopentanone (14.9 mL, 0.168 mol, 1.0 equiv.) and p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol, 0.05 equiv.) in toluene (300 mL) was stirred at the reflux temp. overnight. The reaction mixture was then cooled to room temp., diluted 20 with EtOAc (500 mL), then washed with a saturated NaHCO 3 (250 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure to yield 4-aza-3,3-dimethyl-l oxaspiro[4.4]nonane as a pale yellow oil (15.5 g, 60%): 'H NMR (CDCl 3 ) 6 1.12 (s, 6H), 1.65 (m, 5H), 1.80 (m, 2H), 1.97 (m, 2H), 3.45 (s, 2H). HO HN-K2 25 Step 2 To a solution of 4 -aza-3,3-dimethyl-1-oxaspiro[4.4]nonane (15.5 g, 0.10 mol) in EtOH (85 mL) at 0 *C was then added NaBH 4 (5.47 g, 0.145 mol, 1.45 equiv.) at a rate that the reaction temp. did not exceed 10 *C (approximately 1 h). The reaction mixture was then allowed to warm to room temp. and stirred for 18 h. The resulting 30 mixture was treated with water (100 mL) and concentrated to a paste under reduced pressure. MeOH (100 mL) was added and the mixture was reconcentrated under reduced pressure. The residue was treated with EtOAc (300 mL) and water (150 mL). The organic layer was dried (Na 2
SO
4 ) and concentrated under reduced pressure 43 WO 00/42031 PCT/US99/29601 to yield N-cyclopentyl-(1,1-dimethyl-2-hydroxyethyl)amine as a pale yellow oil (13.0 g, 83%): 'H NMR (CDCl 3 ) S 1.07 (s, 6H), 1.24 (in, 3H), 1.50 (m, 2H), 1.65 (m, 2H), 1.87 (in, 2H), 3.0 (m, 1H), 3.22 (s, 2H); CI-MS m/z 158 ((M+H)*). 5 B4c. General method for the N-alkylation of ethanolamines via 2-alkyl,3 oxazolidine formation followed by reduction. Synthesis of (2S)-4-methyl 2-(isobutylamino)pentan-1-ol. OXNH Step 1 10 A solution of (1 S)- 1 -(hydroxymethyl)-3 -methylbutylamine (Method BIb; 152 g, 1.3 mol) and isobutyraldehyde (118 mL, 1.3 mol, 1.0 equiv.) in toluene (1.5 L) was heated at the reflux temp. until the theoretical amount of water had been collected in a Dean-Stark trap (23.4 mL). The reaction mixture was concentrated by distillation to approximately 700 mL. The resulting mixture was cooled to room 15 temp. and was concentrated under reduced pressure to a constant weight to give (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine as a pale yellow oil (223 g, 100%): 'H NMR (CDC1 3 ) 8 0.88-0.99 (in, 12H), 1.18-1.35 (in, 1H), 1.42-1.56 (m, 1H), 1.61 1.79 (m, 4H), 3.08 (t, J=7.4 Hz 1H), 3.20-3.34 (m, 1H), 3.85 (t, J=7.4 Hz, 1H), 4.18 (dd, J = 7.3, 3.4 Hz, 1H). HO HN 20 Step 2 To a solution of ( 4
S)-
2 -isopropyl-4-isobutyl-1,3-oxazolidine (223g, 1.3 mol) in EtOH (1.1 L) cooled to -13 *C with an ice/MeOH bath was added NaBH 4 (70.3 g, 1.82 mol) in portions at such a rate that the reaction temp. did not exceed 10 *C 25 (approximately 2 h). The reaction mixture was allowed to warm to room temp., stirred overnight, then filtered through a coarse sintered glass funnel. The resulting solids were washed with EtOH. The combined filtrate was concentrated under reduced pressure and the residue was treated with EtOAc (2 L) and water (1 L). The organic layer was dried (Na 2
SO
4 ) and concentrated under reduced pressure to yield 30 (2S)-4-methyl-2-(isobutylamino)pentan-1-ol as a viscous pale yellow oil (192 g, 85%): 'H NMR (CDCl 3 ) 6 0.90-0.96 (in, 12H), 1.18-1.24 (m, 1H), 1.32-1.39 (in, 1H), 44 WO 00/42031 PCT/US99/29601 1.58-1.72 (m, 21), 2.33 (dd, J=11.1, 7.0 Hz, 1H), 2.49 (dd, J=11.1, 7.0 Hz, 1H), 2.63-2.67 (m, 1H), 3.19 (dd, J=10.3, 6.2 Hz, 1H), 3.60 (dd, J=10.3, 6.2 Hz, 1H). B4d. General method for the N-alkylation of ethanolamines via 2-alkyl,3 5 oxazolidine formation followed by reduction. Synthesis of 1 (cyclopentylamino)-1-(hydroxymethyl)cyclopentane. ON H Step 1. A solution of 1-hydroxymethylcyclopentanamine (Method Blc; 263 g, 2.3 10 mol) and cyclopentanone (220 mL, 1.3 mol, 1.1 equiv.) in toluene (2.7 L) was heated at the reflux temp. with azeotropic removal of water until the theoretical amount of water had been collected (41.4 mL). The reaction mixture was concentrated to 700 mL by simple distillation, then cooled to room temp. and concentrated to constant weight under reduced pressure to give 6-aza-12-oxadispiro[4.1.4.2]tridecane (414 g, 15 100%) as a pale yellow oil: 1 H NMR (CDC 3 ) 61.55-1.89 (m, 17H), 3.60 (s, 214). HO HN Step 2 To a solution of 6-aza-12-oxadispiro[4.1.4.2]tridecane (124 g, 0.69 mol) 20 dissolved in EtOH (600 mL) held at -13 *C with an ice/MeOH bath was added NaBH 4 (38 g, 1.0 mol, 1.45 equiv.) in portions at a rate that the temp. did not exceed 10 'C (approximately 30 min.). The reaction mixture was allowed to warm to room temp. and stirred overnight. The reaction mixture was diluted with water (500 mL) and concentrated under reduced pressure. The residual paste was separated between 25 EtOAc (1 L) and water (600 mL). The organic layer was dried (Na 2
SO
4 ) and concentrated under reduced pressure to yield 1 -(cyclopentylamino)- 1 (hydroxymethyl)cyclopentane as a white powder (107 g, 85%): 'H NMR (CDCl 3 ) 6 1.23-1.28 (m, 2H), 1.46-1.57 (m, 81), 1.58-1.69 (m, 4H), 1.82-1.86 (m, 2H), 2.94 3.06 (m, 1H,), 3.30 (s, 211). 30 B5a. General method for the synthesis of ethanolamines via reaction of amines with epoxides. Synthesis of N-(hydroxyethyl)-N-(2-butyl)amine. 45 WO 00/42031 PCT/US99/29601 N ,- OH H To a solution of sec-butylamine (60 mL, 0.60 mmol) in MeOH (40 mL) at room temp. was added ethylene oxide (10 mL, 0.20 mmol) dropwise via cannula. The mixture was stirred for 4 h at room temp., then concentrated under reduced 5 pressure. The residue was purified by vacuum distillation to give N-(hydroxyethyl) N-(2-butyl)amine as a colorless oil (16.4 g, 70%): bp 109-112 *C (6 mmHg). B5b. General method for the synthesis of ethanolamines via reaction of amines with epoxides. Synthesis of N-(3-phenyl-2-hydroxypropyl)-N-isobutylamine N OH H 10 2,3-Epoxypropyl benzene (10 g, 74.5 mmol) and isobutylamine (5.4 g, 74.5 mmol) were mixed then treated with water (2 mL). The mixture was stirred overnight at 110 'C, then distilled to yield N-(3-phenyl-2-hydroxypropyl)-N-isobutylamine (6.5 g): bp 115-117 'C (1 mmHg). 15 B6a. General method for the synthesis of propanolamines via Arndt Eisert homologation of amino acids followed by reduction. Synthesis of (R)-3 (tert-butylamino)-4-methylpentanol. HN Ok
N
2 0 20 Step 1 To a solution of N-(tert-butoxycarbonyl)-(L)-valine (4.32 g, 19.9 mmol) and N-methylmorpholine (2.3 mL, 20.9 mmol) in DME (30 mL) at -10 *C was added isobutyl chloroformate (2.27 mL, 21.0 mmol). The resulting mixture was stirred at room temp. for 15 min, then filtered, and the solids were washed with cold DME. 25 The filtrate was cooled to -10 *C, then treated with a solution of CH 2
N
2 in Et 2 O until a yellow color persisted, the resulting mixture was warmed to 20 *C and stirred at that temp. for 45 min., then the mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , gradient from hexane to 30 % EtOAc/hex) to yield (S)-3-(tert-butoxycarbonylamino)-1-diazo-4-methylpentan-2 30 one (1.82 g, 38%): TLC (10% EtOAc/hex) RfO.11. 46 WO 00/42031 PCT/US99/29601 0 O HN 0 MeO Step 2 A solution of (S)-3-(tert-butoxycarbonylamino)-1-diazo-4-methylpentan-2 one (1.83 g, 7.6 mmol) in MeOH (100 mL) was heated at the reflux temp. and a 5 filtered solution of silver benzoate in Et 3 N (0.50 g silver benzoate in 5 mL Et 3 N, 0.5 mL) was added. After the initial gas evolution stopped (ca. 0.5 minute) additional silver solution (0.5 mL) was added. This process was repeated until the addition of silver salt caused no more gas to be evolved. The resulting mixture was cooled to 20 *C, treated with Celite* and filtered. The filtrate was concentrated under reduced 10 pressure. The residue was dissolved in Et 2 O (100 mL) and was sequentially washed with a IN HCl solution (100 mL), a saturated NaHCO 3 solution (100 mL), and a saturated NaCl solution (50 mL), dried (MgSO 4 ), and concentrated under reduced pressure to give methyl (R)-3-(tert- butoxycarbonylamino)-4-methylpentanoate (1.63 g, 87%): TLC (10% EtOAc/hex) Rf0.29. 0 HN 'k0 HHNO 15 HO Step 3 Methyl (R)-3-(tert-butoxycarbonylamino)-4-methylpentanoate (1.62 g, 6.6 mmol) was treated with lithium borohydride in a manner analogous to Method B8a, Step 2 to afford (R)-3-(tert- butoxycarbonylamino)-4-methylpentanol (93%). 20 B7a. General method for the synthesis of chloroethylamines. Synthesis of (lS)-1-(chloromethyl)-3-methylbutanammonium chloride. C1 NH 2 HCI A solution of (lS)-1-(hydroxymethyl)-3-methylbutylamine (Method Blb; 25 5.40g, 46.1 mmol) in CH 2 Cl 2 (200 mL) was cooled over an ice bath and saturated with HCl gas. SOCl 2 (4.0 mL, 55.3 mmol) was added, the reaction was heated at the reflux temp. for 2.5 h, then cooled to room temp. and concentrated under reduced pressure. The residue was triturated with Et 2 O to yield (lS)-1-(chloromethyl)-3 methylbutanammonium chloride (5.67 g, 71%): EI-MS m/z 136 ((M+H)*). 47 WO 00/42031 PCT/US99/29601 B7b. General method for the synthesis of chloroethylamines. Synthesis of 1 (chloromethyl)-1-(cyclohexylamino)cyclopentane HCI salt. CI HN HCI 5 A 4M HCI solution (p-dioxane, 40 mL) containing 1-(cyclohexylamino)-1 (hydroxymethyl)cyclopentane (Method B4a; 1.9 g, 9.6 mmol) and SOCl 2 (0.84 mL, 11.5 mmol) was heated to 70 *C for 18 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure to yield crude 1-(chloromethyl)-1 (cyclohexylamino)cyclopentane HC salt (2.84 g), which was used in the next step 10 without further purification. B7c. General method for the synthesis of chloroethylamines. Synthesis of N-(1 S)-(1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)amine HCl salt. CI HN HCI 15 To a solution of (2S)-4-methyl-2-(isobutylamino)pentan-1-ol (Method B4c; 256 g, 1.5 mol) and toluene (2.5 L) was added SOCl 2 (167 mL) over 15 min. After the addition of SOC 2 was complete the reaction was heated at 90 *C overnight. The reaction solution was then cooled to room temp. and concentrated under reduced pressure. The dark oily residue was dissolved in CH 2 Cl 2 (2 L) and concentrated 20 under reduced pressure. The red-brown residue was dissolved in Et 2 O (1 L), and hexane (750 mL) was added dropwise over a period of 8 h. The resulting slurry was stirred overnight, filtered, and washed with a 40% EtOAc/hex solution to give N-(1 S)-(1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)amine HCl salt as a dark brown solid (276 g): 1H NMR (CDCl 3 ) 6 0.93-1.00 (m, 6H), 1.10-1.12 (m, 6H), 1.85 (m, 25 4H), 2.24-2.34 (m, 2H), 2.80-2.88 (m, 1H), 2.90-3.02 (m, 1H), 3.50-3.57 (m, 1H), 3.96 (dd, J=12.9, 5.6 Hz, 1H), 4.10 (dd, J=13.2, 3.6 Hz, 1H). B7d. General method for the synthesis of chloroethylamines. Synthesis of 1 (chloromethyl)-1-(cyclopentylamino)cyclopentane HCI salt. CI HN-KQ HCI 30 48 WO 00/42031 PCT/US99/29601 To a solution of 1-(cyclopentylamino)-1-(hydroxymethyl)cyclopentane (Method BIc; 140 g, 0.76 mol, 1.0 equiv.) in toluene (1.4 L). was added SOCl 2 (84 mL) over a period of 15 min. After the addition of SOCl 2 was complete the reaction mixture, which had already warmed to 40 'C, was heated at 60 *C overnight. The 5 resulting solution was cooled to room temp. and treated with HCl (4N in p-dioxane, 100 mL), and the reaction was heated to 60 *C for 3 h then stirred at room temp. overnight. The resulting mixture was concentrated to half of the original volume under reduced pressure, at which time a precipitate began to form. The resulting slurry was diluted with Et 2 0 and allowed stir for 4 h. The resulting precipitate was 10 filtered and washed with Et 2 O (2x50 mL) to yield 1-(chloromethyl)-l (cyclopentylamino)cyclopentane HCl salt as an off-white powder (125 g, 70%): 'H NMR (CDCl 3 ) 6 1.53-1.66 (m, 4H), 1.76-1.94 (m, 2H) 1.95-2.22 (m, 10H), 2.28-2.34 (m, 211), 3.40 (s, 211), 3.63-3.73 (m, 1H). 15 B7e. General method for the synthesis of chloroethylamines. Synthesis of 1 chloromethylcyclopentanamine HCI salt CI NH 2 HCI To a solution of 1-hydroxymethylcyclopentanamine HCl salt (Method Blc; 20 g, 0.17 mol) in anh. p-dioxane (65 mL) was added HCl (4M in p-dioxane; 65 mL, 20 0.26 mol). The resulting solution was stirred for 20 min. at room temp., then SOCl 2 (22.7 g, 0.19 mol) was added dropwise. The reaction mixture was heated at 80 *C for 2 d, cooled to room temp., and concentrated under reduced pressure to give 1 chloromethylcyclopentanamine HCl salt (29g, 100%): CI-MS m/z 171 ((M+H)+). 25 B8a. General method for the synthesis of 2-aminoethylsulfonate esters. Synthesis of (lR,2R)-1-(methanesulfonyloxymethyl)-2-(tert butoxy)propaneammonium chloride. MeO HN 00 0 Step 1 30 A solution of (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt (2.15 g, 4.4 mmol) in CH 2 Cl 2 (50 mL) was treated with a solution of CH 2
N
2 in Et 2 O until a yellow color persisted. The resulting solution was 49 WO 00/42031 PCT/US99/29601 concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed sequentially with a IN HCL solution (2x100 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4 ), and concentrated under reduced pressure to yield (lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine methyl ester (1.44 g, 100%): 5 TLC (25% EtOAc/hex) RfO.54. 0 0 Step 2 To a solution of (1 S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine methyl ester (1.4 g, 4.4 mmol) in Et 2 O (20 mL) was added a saturated solution of LiBH 4 in 10 Et 2 O (9 mL) and the reaction mixture was heated at the reflux temp. for 2 h., then cooled to 20 *C. Water (5 mL) was added to the resulting mixture, then a iN HCl solution was added until no more gas evolved. The ether layer was washed with a saturated NaCl solution (50 mL), dried (MgSO 4 ), and concentrated under reduced pressure to yield (1 R,2R)-N-(benzyloxycarbonyl)- 1 -(hydroxymethyl)-2-(tert 15 butoxy)propanamine (1.69 g, 99%): TLC (25% EtOAc/hex) Rf0.20. 0 MsO ON~ 0 Step 3 To a solution of (1R,2R)-N-(benzyloxycarbonyl)-1-(hydroxymethyl)-2-(tert butoxy)propanamine (1.6 g, 5.4 mmol) in anh. pyridine (30 mL) at 4 *C was added 20 methanesulfonyl chloride (0.75 mL, 9.7 mmol) dropwise. The reaction was stirred for 5.5 h, then was diluted with EtOAc (200 mL) and washed with a iN HCl solution (4x200 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to yield (1R,2R)-N-(benzyloxycarbonyl)-1 (methanesulfonyloxymethyl)-2-(tert-butoxy)propanamine as an oil (2.03 g, 100%): 25 TLC (25% EtOAc/hex) RfO.3 1. MsO
NH
3 + CI 0 50 WO 00/42031 PCT/US99/29601 Step 4 To a solution of (1 R,2R)-N-(benzyloxycarbonyl)- 1 (methanesulfonyloxymethyl)-2-(tert-butoxy)propanamine (2.03 g, 5.5 mmol) in MeOH (50 mL) was added a 4M HCl solution (dioxane; 1.5 mL, 6.0 mmol) and 10% 5 Pd/C (0.20 g). The resulting slurry was stirred under H 2 (1 atm.) for 2 h, then treated with Celite*, filtered and concentrated under reduced pressure to yield (1R,2R)-1 (methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride (1.6 g, 100%). 10 B8b. General method for the synthesis of 2-aminoethylsulfonate esters. Synthesis of N-(2-tosyloxyethyl)- 2-methylprop-2-en-1-ammonium trifluoroacetate. 0 O=( o N 0 Step 1 15 To a solution of N-(tert-butoxycarbonyl)glycine tert-butyl ester (3.97 g, 17.2 mmol) in DMF (70 mL) at 0 'C was added sodium hexamethyldisilazide (3.78 g, 20.6 mmol) and the resulting mixture was stirred for 25 min., then allowed to warm to room temp. The resulting solution was treated with 3-bromo-2-methylpropene (2.60 mL, 25.7 mmol), stirred at room temp. for 10 min., and diluted with EtOAc 20 (300 mL). The EtOAc solution was sequentially washed with water (4x500 mL) and a saturated NaCl solution (4x500 mL), dried (MgSO 4 ), and concentrated under reduced pressure to afford N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester (4.03 g, 82%): TLC (10% EtOAc/hex) Rf0.5 1. 0 O=( HO N 25 Step 2 A solution of N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert butyl ester (0.26 g, 0.93 mmol) in Et 2 O (3 mL) was treated with lithium borohydride (0.011 g), then stirred at room temp. overnight. To the resulting mixture was added water (2 mL), then a 1N HCl was added dropwise until gas evolution stopped. The 30 organic phase was washed with a saturated NaHCO 3 solution (20 mL), dried (MgSO 4 ), and concentrated under reduced pressure. The residue was purified by 51 WO 00/42031 PCT/US99/29601 chromatography (SiO 2 , gradient from 10% EtOAc/hex to 50% EtOAc/hex) to give N (tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methylprop-2-ene (0.113 g, 57%): TLC (10% EtOAc/hex) Rf 0.66.
O
0 O=< TsO N 5 Step 3 To a solution of N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2 methylprop-2-ene (21.1 g, 98 mmol) in Et 2 O (800 mL) at -78 *C was slowly added potassium tert-butoxide (1M in tert-butanol, 103 mL, 103 mmol). The reaction mixture was allowed to warm briefly to -45 *C, then was cooled to -78 'C, and 10 treated with a solution of p-toluenesulfonyl chloride (18.7 g, 98.0 mmol) in Et 2 0 (100 mL). The resulting mixture was then warmed to -45 'C and treated with water (500 mL). The organic phase was washed with a saturated NaCl solution (800 mL), dried (MgSO 4 ), and concentrated under reduced pressure to give N-(tert butoxycarbonyl)-N-(2-tosyloxyethyl)-1-amino-2-methylprop-2-ene ( 36.4 g, 101%): 15 TLC (25% EtOAc/hex) Rf0.56. TsO HN \--./
CF
3
CO
2 H Step 4 Solid N-(tert-butoxycarbonyl)-N-(2-tosyloxyethyl)-1-amino-2-methylprop-2 ene (15 g, 55.7 mmol) was cooled to 0 *C and dissolved in TFA (200 mL). The 20 reaction mixture was allowed to warm to room temp., then was concentrated under reduced pressure. The residual oil was crystallized using Et 2 O (500 mL) to afford N (2-tosyloxyethyl)-2-methylprop-2-en- 1 -ammonium trifluoroacetate (16.7 g, 78%). B9a. General method for the synthesis of 3-chloropropyl- and 4 25 chlorobutylamines. Synthesis of N-isobutyl-3-chloropropylamine HCI salt. HN O Step 1 To a solution of 3-aminopropanol (91 g, 65.4 mmol) in toluene (100 mL) was 30 added isobutraldehyde (9.0 mL, 99.1 mmol, 1.5 equiv.) and MgSO 4 (7.5 g) to generate an exotherm. The slurry was stirred for 30 min. and an additional portion of 52 WO 00/42031 PCT/US99/29601 MgSO 4 was added (7.5 g), and the slurry was stirred overnight. The resulting mixture was filtered and concentrated under reduced pressure. The condensate was again concentrated under reduced pressure and the two residues were combined to afford 2-isopropyltetrahydro-1,3-oxazine as a colorless oil (5.18 g, 61%): 'H NMR 5 (CDCl 3 ) 8 0.84-0.88 (m, 6H), 1.24-1.29 (m, 1H), 1.51-1.66 (in, 3H), 2.77-2.87 (m, 1H), 3.07-3.13 (in, 1H), 3.60-3.76 (m, 2H), 4.00-4.05 (m, 1H). HO HN Step 2 To a solution of 2-isopropyltetrahydro-1,3-oxazole (4.94 g, 38.2 mmol) in 10 abs. EtOH (100 mL) at 0 *C was added NaBH 4 (2.17 g (57.4 mmol, 1.5 equiv.) in small portions over 15 min. and the resulting mixture was stirred at room temp.overnight. The resulting mixture was concentrated under reduced pressure, then treated with EtOAc (150 mL) and water (100 mL) (CAUTION: gas evolution), and stirred at room temp for 30 min. The resulting organic layer was washed with a 15 saturated NaCl solution. The combined aqueous layers were back-extracted with EtOAc (150 mL). The combined organic layers were dried (Na 2
SO
4 ) and concentrated under reduced pressure to afford N-isobutyl-3-hydroxypropylamine as a colorless oil (5.04 g, 100%): 'H NMR (CDCl 3 ) 6 0.84 (d, J=6.6 Hz, 6H), 1.60-1.71 (m, 3H), 2.36 (d, J=6.6 Hz, 2H), 2.80 (dd, J=5.9, 5.9 Hz, 2H), 3.10-3.30 (br s, 2H), 20 3.74 (dd, , J=5.5, 5.5 Hz, 2H); "C NMR (CDCl 3 ) 6 20.5, 28.1, 30.6, 50.0, 57.8, 64.1. HCI Step 3 To a solution of N-isobutyl-3-hydroxypropylamine (1.01 g, 7.70 mmol) in toluene (100 mL) was added SOCl 2 (1.37 g, 11.6 mmol, 1.5 equiv.) and the resulting 25 mixture was stirred at room temp. for 4 h. The resulting slurry was concentrated under reduced pressure to afford N-isobutyl-3-chloropropylamine HCl salt: 'H NMR
(CDC
3 ) 6 1.12 (s, 9H), 1.28 (t, J=7.0 Hz, 3H), 4.24 (q, J=7.0 Hz, 2H), 4.55 (s, 1H), 5.00 (s, 2H); 13 C NMR (CDCl 3 ) 6 13.9, 27.8, 38.2, 61.5, 67.1, 67.3, 117.0, 167.1, 180.7; CI-LRMS m/z (rel abundance) 150 ((M+H)*, 100%). 30 B10a. General method for the synthesis of 2-chlorothiazolidinium salts. Synthesis of (4S)-2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride. 53 WO 00/42031 PCT/US99/29601 S S N Step 1 To a mixture of ( 2 S)-4-methyl-2-(isobutylamino)pentan-1-ol HCI salt (Method B4c; 0.21 g, 1.0 mmol) and CS 2 (0.30 mL, 5.0 mmol, 5.0 equiv.) in 2 5 butanone (20 mL) was added Cs 2
CO
3 (0.72 g, 2.20 mmol, 2.2 equiv.) and the resulting mixture was heated at the reflux temp. overnight. The resulting orange solution was concentrated under reduced pressure and the residue was triturated with EtOAc (25 mL). The remaining solids were washed with EtOAc (25 mL), and the combined EtOAc phases were concentrated under reduced pressure. The residue was 10 absorbed onto SiO 2 and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc/hex) to give (4S)-3,4-diisobutyl-1,3-thiazolidin-2-thione as a yellow oil (0.11 g, 52%). CI Cr S) N Step 2 15 A solution of (4S)-3,4-diisobutyl-1,3-thiazolidin-2-thione (5.0 g, 21.6 mmol) in SOC 2 (31 mL, 0.43 mol) and was heated at 70 *C for 2.5 h, then was cooled to room temp. and concentrated under reduced pressure to afford (4S)-2-chloro-3,4 diisobutyl-4,5-dihydro-1,3-thiazolinium chloride as a semisolid: 'H NMR 6 0.99 1.10 (m, 12H), 1.59-1.67 (m, 1H1), 1.72-1.84 (m, 1H), 2.00-2.10 (m, 1H), 2.17-2.29 20 (br m, 1H), 3.61-3.68 (m, 1H), 3.86-3.95 (br m, 2H), 4.50-4.57 (m, 1H1), 4.97-5.06 (br m, 1H). This material was dissolved in dichloroethane (180 mL) to make a 0.12 M stock solution (assuming quantitative conversion to the thiazolidinium chloride). C. Methods for the Synthesis of Imino Heterocycles 25 Cla. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) 2
-(
2 -methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. 54 WO 00/42031 PCT/US99/29601 0 2 N Me N S NH To a mixture of (1S)-1-(chloromethyl)-3-methylbutanammonium chloride (Method B7a; 1.14 g, 3.71 mmol) and 2-methyl-4-nitrophenyl isothiocyanate (0.72 g, 3.71 mmol) suspended in CH 2 Cl 2 (15 mL) was added Et 3 N (1.08 mL, 7.78 mmol) via 5 syringe. The resulting solution was stirred for 18 h at room temp. The reaction mixture was washed with a saturated NaHCO 3 solution and concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , gradient from 10% EtOAc/hex to 30% EtOAc/hex) to afford (4S)-2-(2-methyl-4 nitrophenylimino)-4-isobutyl-1,3-thiazolidine (0.91 g, 47%): TLC (25% EtOAc/hex) 10 Rf 0.46. Cib. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) 2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-thiazolidine HCI salt. NC Et I HCI S N 15 To a solution of N-(1-S)-(1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)amine HC salt (Method B7c; 95 g, 0.41 mol, 1.08 equiv.) in CH 2 C1 2 (1.1 L) at 15 'C was added 4-cyano-2-ethylphenyl isothiocyanate (Method A2b; 72 g, 0.38 mol) followed by diisopropylethylamine, (200 mL, 1.15 mol, 3.0 equiv.) generating a slight 20 exotherm. When the reaction had cooled back to room temp., the ice bath was removed and the reaction was stirred at room temp. for 4 h. The reaction was then diluted with CH 2 Cl 2 (500 mL), washed with a 1N NaOH solution (3x500 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residual dark oil (132 g) was dissolved in CH 2 C1 2 (50 mL) and filtered through a plug of silica gel (5 g SiO 2 /g 25 crude product) with the aid of a 5% EtOAc/hexane solution to give an oil (120 g), which was dissolved in EtOAc (400 mL) and slowly treated with an HCI solution (1M in Et 2 0, 500 mL) to give ( 4 S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl 55 WO 00/42031 PCT/US99/29601 1,3-thiazolidine HCI salt as a white solid (95 g, 66%): 'H NMR (CDC1 3 ) 8 0.96 (d, J=5.9 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H), 1.12 (m, 6H), 1.23 (t, J=7.7 Hz, 3H), 1.46 1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J=7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J=11.4, 7.7 Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J=14.3, 8.1 Hz, 1H), 7.32 (d, 5 J=8.1 Hz 1H), 7.51 (dd, 1H, J=8.1, 1.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H). C1c. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) 2
-(
2 -chloro-4-cyano-6-methylphenylimino)-4-isobutyl-1,3-thiazolidine. NC Me N CIS NH 10 To a slurry of 2-chloro-4-cyano-6-methylphenyl isothiocyanate (0.10 g, 0.50 mmol) and poly(4-vinylpyridine) (0.030 g) in CH 2 Cl 2 was added a solution of (1S)-1 (chloromethyl)-3-methylbutanammonium chloride (Method B7a; 0.086 g, 0.50 mol, 1.0 equiv) in DMF (2 mL) and the resulting mixture was stirred at 55 *C for 16 h, 15 then concentrated under reduced pressure. The residue was purified by column chromatography (30 g, gradient from 10% EtOAc/hex to 20% EtOAc/hex) to give (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl-1,3-thiazolidine (0.052 g, 34%). 20 Cld. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) 2
-(
4 -chloro-2-(trifluoromethyl)phenylimino)-3-isobutyl-1,3-thiazolidine. CI jaCF 3 S N N-(Hydroxyethyl)-N-isobutylamine was converted into N-(chloroethyl)-N 25 isobutylammonium chloride in a manner analogous to Method B7c. To a slurry of N-(chloroethyl)-N-isobutylammonium chloride (0.10 mmol, 0.10 M) and poly(4 vinylpyridine) (0.030 g) in DMF (1.0 mL) was added a 4-chloro-2 (trifluoromethyl)phenyl isothiocyanate solution (0.25 M in THF, 0.40 mL, 0.10 56 WO 00/42031 PCT/US99/29601 mmol) and the resulting mixture was heated at 55 *C for 16 h in a sand bath. The resulting slurry was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C- 18 column, gradient from 0.1% TFA/20% CH 3 CN/79.9% water to 0.1% TFA/99.9% CH 3 CN) to furnish 5 (4S)-2-(4-chloro-2-(trifluoromethyl)phenylimino)-3-isobutyl-1,3-thiazolidine (0.020 g, 59%). Cle. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2-(2,4-dimethyl 10 3-cyano-6-pyridylimino)-3-thia-1-azaspiro[4.4]nonane. Me NC / N Me N S NH To a solution of 1-chloromethylcyclopentanamine HCl salt (Method B7e; 0.25 g, 1.32 mmol) and 2,4-dimethyl-3-cyano-5-pyridyl isothiocyanate (Method A2c; 0.23 g, 1.32 mmol) in anh. 1,2-dichloroethane (10 mL) was added Et 3 N (1 mL) 15 dropwise via syringe. The resulting mixture was heated at 50 *C overnight, then cooled to room temp., and treated with a saturated NaHCO 3 solution. The resulting mixture was extracted with CH 2 C1 2 (3x25 mL). The combined organic layers were dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , 40% EtOAc/hex) to give 2-(2,4-dimethyl-3-cyano-6 20 pyridylimino)-3-thia-l-azaspiro[4.4]nonane (0.192 g, 51%): Cl-MS m/z 287 ((M+H)+). CIf. General method for the synthesis of 2-imino-1,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2-(3 25 quinolylimino)-3,5-diisobutyl-1,3-thiazolidine. N N 57 WO 00/42031 PCTIUS99/29601 3-Quinoline isothiocyanate was prepared in a manner analogous to Method A2c. To a solution of 3-quinoline isothiocyanate (0.1 g, 0.54 mmol) and N-(1-S)-(1 (chloromethyl)-3-methylbutyl)-N-(isobutyl)amine HCl salt (Method B7c; 0.113g, 0.54 mmol) in anh. CH 2 C1 2 (2 mL) was added diisopropylethylamine (0.208 g, 1.61 5 mmol) dropwise. The resulting mixture was allowed to stir at room temp. overnight, then was concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , 30% EtOAc/hex) to give 2-(3-quinolylimino)-3,5-diisobutyl 1,3-thiazolidine (0.02 g, 0.9%): ES-MS m/z 342 ((M+H)+). 10 C2a. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2-(2-methyl-4 nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. 0 2 N Me N S NH 15 To a solution of 1-amino-1 -(hydroxymethyl)cyclopentane (Method B 1 c; 20.7 g, 180 mmol) and HCI (4M in p-dioxane, 400 mL) was added SOCl 2 (15.7 mL, 216 mmol) and the resulting solution was heated at 100 *C for 18 h. The reaction mixture was concentrated under reduced pressure, then treated with 2-methyl-4 20 nitrophenyl isothiocyanate (31.4 g, 162 mmol) and 1,2-dichloroethane (400 ml), followed by N-methylmorpholine (49 mL, 449 mmol). The resulting mixture was heated at 70 *C for 18 h, cooled to room temp. and concentrated under reduced pressure. The residue was treated with hot EtOAc, filtered and concentrated under reduced pressure. The residue was recrystallized (MeOH) to yield 2-(2-methyl-4 25 nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (38.3 g, 81%): TLC (25% EtOAc/hex) Rf 0.27. C2b. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by 30 reaction with isothiocyanates. Synthesis of 1-isobutyl-2-(2-methyl-4 nitrophenylimino)-3-thia-1-azaspiro[4.5]decane. 58 WO 00/42031 PCT/US99/29601 0 2 N Me S N 1-Amino-i -(hydroxymethyl)cyclohexane (Method B 1 a) was dissolved in p dioxane (80 mL) then treated with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2-(2-methyl-4 5 nitrophenylimino)-3-thia-l-azaspiro[4.5]decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield 1-isobutyl-2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (0.026 g, 2%): TLC (20% EtOAc/hex) Rf 0.69. 10 C2c. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2-(2-methyl-4 nitrophenylimino)-3-isobutylspiro[1,3-thiazolidine-4,2' bicyclo [2.2.1]heptane]. 02N Me S N 15 2-(Isobutylamino)-2-(hydroxymethyl)norbomane (Method B2a; 0.24 g, 1.2 mmol) was treated with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to yield 2-(2-methyl-4-nitrophenylimino)-3-(2 isobutylspiro[1,3-thiazolidine-4,2'-bicyclo[2.2.1]heptane] as an oil (0.022 g, 5%): 20 TLC (25% EtOAc/hex) Rf 0.72. C2d. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 3-isobutyl-4-methylene-2-(2 25 methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one and (4S)-3-isobutyl-4 carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt. 59 WO 00/42031 PCT/US99/29601 0 2 N Me 2 N Me N SN 0OCH 2
CO
2 Me (R)-N-Isobutylserine methyl ester HCl salt (Method B3a; 2.28 g, 10.8 mmol) was treated with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a. The resulting material was purified by column 5 chromatography (SiO 2 , gradient from hexane to 10% EtOAc/hex) to give 3-isobutyl 4-methylene-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one (0.028 g, 10%) followed by (S)-3-isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3 thiazolidine HCl salt (0.192 g, 56%). 3-Isobutyl-4-methylene-2-(2-methyl-4 nitrophenylimino)-1,3-thiazolidin-5-one: TLC (25% EtOAc/hex) Rf 0.40. (S)-3 10 isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt: TLC (free base, 25% EtOAc/hex) Rf0.50. C2e. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by 15 reaction with isothiocyanates. Synthesis of 1-cyclohexyl-2-(2-methyl-4 nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. 0 2 N Me N S N 1-(Cyclohexylamino)-1-(hydroxymethyl)cyclopentane (Method B4a; 1.89 g, 9.59 mmol) was reacted with SOCl 2 followed by 2-methyl-4-nitrophenyl 20 isothiocyanate in a manner analogous to Method C2a to yield 1-cyclohexyl-2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (0.44 g, 17%): CI-MS m/z 374 ((M+H)*). C2f. General method for the synthesis of 2-imino-1,3-thiazolidines via 25 conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2-(2-methyl-4 nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-thiazolidine. 60 WO 00/42031 PCTIUS99/29601 0 2 N Me N S N-Isobutyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a. HCl was bubbled into a solution of N-isobutyl-1,1 dimethyl-2-hydroxyethanamine (1.45 g, 10 mmol) in toluene (20 mL) until 5 saturation. SOCl 2 (10 mmol) was added to the solution dropwise at room temp., stirred at room temp. for 1 h and at 50 *C, for 1 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in CHCl 3 (20 mL). To the resulting solution was added 2-methyl-4-nitro-phenyl isothiocyanate (1.94 g, 10 mmol), then a solution of Et 3 N (10 mmol) in CHCl 3 (10 mL) was added 10 dropwise at room temp. The resulting mixture was heated at the reflux temp. for 3 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), and the resulting solution was sequentially washed with a 10% aq. NaOH solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by chromatography 15 (9% EtOAc/pet. ether) and the resulting solids were recrystallized (pet. ether) to give 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-thiazolidine (0.6 g, 63%): mp 97 *C. When appropriate, the product was converted into the HCl salt by dissolving the free base (5 mmol) in Et 2 O (50 mL) and treating this solution with a 2N ethereal HCl solution until no more solid precipitated. The resulting slurry was 20 filtered and the resulting solids were washed with Et 2 O (25 mL) followed by EtOAc (25 mL). C3a. General method for the synthesis of 2-imino-1,3-thiazolidine homologues via conversion of hydroxyalkylamines into chloroalkylamines followed 25 by reaction with isothiocyanates. Synthesis of (R)-4-isopropyl-2-(2 methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-1,3-thiazine. 0 2 N Me N S NH (R)-3-(tert- Butoxycarbonylamino)-4-methylpentanol (Method B6a) was reacted with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner 61 WO 00/42031 PCT/US99129601 analogous to Method C2a to afford (R)-4-isopropyl-2-(2-methyl-4 nitrophenylimino)-2,3,4,5-tetrahydro-1,3-thiazine (100%). C4a. General method for the synthesis of 2-imino-1,3-oxazolidines via reaction 5 of 2-chloroethylamines with isocyanates. Synthesis of 1-cyclohexyl-2-(2 methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane. 0 2 N Me N 0 N To a solution of 1-(chloromethyl)-1-(cyclohexylamino)cyclopentane HCl salt (Method B7b; 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenyl isocyanate (0.75 g, 4.2 10 mmol) in 1,2-dichloroethane (10 mL) was added N-methylmorpholine (0.92 mL, 8.4 mmol). The resulting mixture was heated to 50 *C for 18 h, then cooled to 20 *C and concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , gradient from hexane to 10% EtOAc/hex) to yield 1-cyclohexyl-2-(2-methyl 4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane (0.021 g, 1.4%): CI-MS m/z 358 15 ((M+H)*). C5a. General method for the synthesis of 2-iminoheterocycles via reaction of aminoethylsulfonate esters with isocyanates or isothiocyanates. Synthesis of 2-(2-methyl-4-nitrophenylimino)-3-(2-methylprop-2-enyl) 20 1,3-oxazolidine. 02N Me N o N To a solution of N-( 2 -tosyloxyethyl)-2-methylprop-2-en-1-ammonium trifluoroacetate (Method B8b, Step 4; 0.21 g, 0.548 mmol) inp-dioxane (5 mL) was added 2-methyl-4-nitrophenyl isocyanate (0.0955 g, 0.536 mmol), followed by Et 3 N 25 (0.080 mL, 1.15 mmol). The resulting mixture was stirred at 37 'C overnight, cooled to room temp., and concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 (50 mL) and washed with water (50 mL). The organic layer was extracted with a 2N HCl solution. The aqueous layer was made basic with a IN NaOH solution, and was extracted with CH 2
C
2 (50 mL). The organic phase was dried 62 WO 00/42031 PCT/US99/29601 (Na 2
SO
4 ) and concentrated under reduced pressure to give 2-(2-methyl-4 nitrophenylimino)-3-(2-methylprop-2-enyl)-1,3-oxazolidine as a yellow oil (0.020 g, 14%) Cl-MS m/z 276 ((M+H)*). 5 C5b. General method for the synthesis of 2-iminoheterocycles via reaction of aminoethylsulfonate esters with isocyanates or isothiocyanates. Synthesis of (4S)-4-(1(R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4 nitrophenylimino)-1,3-thiazolidine. 0 2 N Me N S N +0 10 (1R,2R)-1-(Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride (Method B8a; 1.5 g, 5.5 mmol) was reacted with 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to that described in Method Cl a to afford 4(S) (1 (R)-tert-butoxyethyl)-2-(2-methyl-4-nitrophenylimino)- 1,3-thiazolidine (1.2 g, 67%). The (4S)-2-(2-methyl-4-nitrophenylimino)-4-(1(R)-tert-butoxyethyl)-1,3 15 thiazolidine was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4S)-4-(1(R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4 nitrophenylimino)-1,3-thiazolidine (0.26 g, 56%): TLC (25% EtOAc/hex) Rf0.67. C6a. General method for the synthesis of 2-imino-1,3-thiazolidines via 20 conversion of chloroethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of (4S)-2-(4-cyano-2 ethylphenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt. NC Et I HCI S N To a solution of sodium hydrogen sulfide (69 g, 1.2 mol, 2.2 equiv.) in water 25 (500 mL) was added N-(1-S)-(1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)amine HCl salt (Method B7c; 126 g, 0.55 mol, 1.0 equiv.). The resulting mixture was stirred at room temp. for 8 h, then 4 -cyano-2-ethylphenyl isocyanide dichloride 63 WO 00/42031 PCT/US99/29601 (Method A3a; 125 g, 0.5 mol, 1.0 equiv.) was added followed by isopropyl alcohol (500 mL). The resulting mixture was stirred at room temp. for 1 h, then a 3.6M
K
2 C0 3 solution (305 mL, 2.0 equiv., 1.1 mol) was added and the mixture was stirred at room temp. overnight. The resulting organic layer was concentrated under reduced 5 pressure and the residue treated with EtOAc (2 L). The organic layer was washed with water (2x500 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give a dark oil (160 g). The oil was dissolved in CH 2 Cl 2 (150 mL) and passed through a silica gel plug (3 g SiO 2 /1 g crude product) with the aid of a 5% EtOAc/hex solution to afford an oil containing the desired product and some residual 10 isocyanide dichloride (134 g). The oil was dissolved in EtOAc (500 mL) and treated with HCl (IN in Et 2 O, 500 mL). The resulting (4S)-2-(4-cyano-2-ethylphenylimino) 3,4-diisobutyl-1,3-thiazolidine HCl salt was removed by filtration (147 g, 70%): 'H NMR (CDCl 3 ) 6 0.96 (d, J=5.9 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H), 1.12 (m, 6H), 1.23 (t, J=7.7 Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J=7.7 Hz, 2H), 15 3.06-3.14 (m, 2H), 3.55 (dd, J=11.4 , 7.7 Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J=14.3, 8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.1, 1.8 Hz, 1H), 7.58 ( d, J=1.8 Hz, 1H). C6b. General method for the synthesis of 2-imino-1,3-thiazolidines via 20 conversion of chloroethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of 1-cyclopentyl-2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane HCl salt. 0 2 N Me HCI SN 25 To a solution of sodium hydrogen sulfide (31 g, 0.55 mol, 2.2 equiv.) in water (250 mL) was added 1-(chloromethyl)-1-(cyclopentylamino)cyclopentane HCl salt. (Method B7d; 60 g, 0.25 mol, 1.0 equiv.) The reaction mixture was stirred at room temp. for 8 h then 2-methyl-4-nitrophenyl isocyanide dichloride (Method A3b; 125 g, 0.25 mol, 1.0 equiv.) was added followed by isopropyl alcohol (300 mL). The 30 reaction mixture was stirred at room temp. for 1 h, then a 3.6M K 2 C0 3 solution (305 mL, 2.0 equiv., 0.5 mol) was added. The reaction was stirred at room temp. overnight. The resulting upper aqueous organic layer was separated and concentrated under reduced pressure and the residue was treated with EtOAc (1 L). The resulting 64 WO 00/42031 PCTIUS99/29601 organic layer was washed with water (2x200mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residual oil (86 g) was dissolved in CH 2 Cl 2 (50 mL) and filtered through a plug of silica gel (3 g SiO 2 /1 g crude product) with the aid of a 5% EtOAc/hex solution to afford an oil (34 g) containing the desired product and some 5 residual isocyanide dichloride. This oil was dissolved in EtOAc (300 mL) and with HCl (IN in Et 2 O, 1.5 L). The resulting solids were removed by filtration to give 1 cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane HCl salt as a white powder (36.8 g): 'H NMR (CD 3 0D) 8 1.40-1.55 (m, 2H), 1.55-1.68 (m, 2H) 1.68-1.80 (m, 8H), 1.80-2.00 (m, 4H), 2.16 (s, 3H), 3.16 (s, 2H), 3.60-3.70 (m, 10 1H) 6.70 (br s, 1H), 6.93 (d, J=8.4 Hz, 1H), 7.96-8.04 (m, 1H), 8.03 (d, J=3 Hz, 1H). C6c. General method for the synthesis of 2-imino-1,3-thiazolidines via conversion of hydroxyethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of 1-cyclopentyl-2-(2 15 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. 0 AS HN'Q Step 1 To a 0 *C solution of Ph 3 P (27.9 g, 0.107 mol, 1.3 equiv.) in anh. THF (400 mL) were successively added diisopropyl azodicarboxylate (21.5 g, 0.107 mol, 1.3 20 equiv.) and 1-cyclopentylamino-1-(hydroxymethyl)cyclopentane (Method B4d; 15.0 g, 0.082 mol). The resulting slurry was stirred for 30 min., then was treated with thiolacetic acid (7.6 mL, 0.107 mol, 1.3 equiv.). The resulting yellow solution was stirred for 15 min. and concentrated under reduced pressure to about 100 mL. The residue was dissolved in EtOAc (200 mL) and the resulting solution was extracted 25 with a IN HCl solution (5x125 mL). The combined aqueous layers were washed with EtOAc (2x200 mL), neutralized with K 2
CO
3 to pH 7.0-7.5, then extracted with EtOAc (5x200 mL). The organic layers were combined, dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue was dried in vacuo to afford 1 cyclopentylamino-1-(thioacetylmethyl)cyclopentane as a yellow oil (19.1 g): TLC 30 (10% EtOAc/hexanes) Rf 0.16; 'H NMR (CDCl 3 ) 8 1.20-1.87 (m, 16H), 2.34 (s, 3H), 2.92-3.02 (m, 1H), 3.15 (s, 2H); 13 C NMR (CDCl 3 ) 8 23.9, 25.2, 29.3, 36.4, 40.1, 55.8, 73.0, 169.8; CI-LRMS m/z (rel abundance) 242 ((M+H)*, 100%). 65 WO 00/42031 PCT/US99/29601 HS HN Step 2 A solution of 1-cyclopentylamino-1-(thioacetylmethyl)cyclopentane (19.1 g) in a 0.33 M KOH solution in 9:1 MeOH:H 2 0 (273 mL, 0.090 mol, 1.1 equiv.) was 5 stirred for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dried in vacuo for to afford crude 1-cyclopentylamino-1 (thiomethyl)cyclopentane as a yellow oil: TLC (10% EtOAc/hexanes) Rf 0.18 (streak); 'H NMR (CD 3 0D) 8 1.32-1.71 (m, 14H), 1.87-1.94 (m, 2H), 2.67 (s, 2H), 3.07-3.14 (m, 1H); FAB-LRMS m/z (rel abundance) 200 ((M+H)*, 19%). This 10 material was used immediately in the next step without further purification
O
2 N Me SN N Step 3 A solution of crude 1-cyclopentylamino-1-(thiomethyl)cyclopentane anh.
CH
2 C1 2 (100 mL) at 0 *C was treated with a slurry of crude 2-methyl-4-nitrophenyl 15 isocyanide dichloride (Method A3b; 19.1 g, 0.082 mol, 1.0 equiv. based on 1 cyclopentylamino-1-(thioacetylmethyl)cyclopentane) in CH 2 Cl 2 (200 mL) followed by Et 3 N (30 mL, 0.215 mol, 2.6 equiv.), and the reaction mixture was allowed to warm to room temp. and stirred for 2 d. NN-Dimethylethylenediamine (92 g, 0.023 mol, 0.3 equiv.) was added and the reaction mixture was stirred for 1 h. Silica gel 20 (50 g) was added and the resulting mixture was concentrated under reduced pressure. The residue was dried in vacuo overnight and purified by flash chromatography (11x10 cm Si0 2 , 5% EtOAc/hex) to afford 1-cyclopentyl-2-(2-methyl-4 nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane as a yellow granular solid (17.8 g, 60% overall): mp 120-121 *C; TLC (10% EtOAc/hexanes) Rf 0.45; 'H NMR 25 (CDCl 3 ) 6 1.47-1.91 (m, 14H), 2.22 (s, 3H), 2.46-2.55 (m, 2H), 3.03 (s, 2H), 3.66 (pent, J=8.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 7.95-8.03 (m, 2H); 3 C NMR (CDCl 3 ) 6 18.3, 24.3, 25.6, 28.5, 36.0, 40.6, 56.7, 75.3, 120.6, 122.3, 125.3, 132.0, 142.3, 155.1, 157.4; LC-LRMS m/z (rel abundance) 360 ((M+H)*, 100%). Anal. Calcd. For CjH 25
N
3 0 2 S: C, 63.48; H, 7.01; N, 11.69. Found: C, 63.48; H, 6.89; N, 11.76. 30 66 WO 00/42031 PCT/US99/29601 C7a. General method for the synthesis of 2-imino-1,3-oxazolidines via reaction of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of 2 (4-cyano-2-ethylphenylimino)-3-cyclopentyl-4,4-dimethyl-1,3 oxazolidine. NC Et N
ON
5 \7 A solution of N-cyclopentyl-(1,1-dimethyl-2-hydroxyethyl)amine (Method B4b; 0.12 g, 0.69 mmol) in THF (2.5 mL) was added dropwise via syringe to a slurry of NaH (95%, 0.05 g, 1.2 mmol) in THF (5 mL) room temp. The reaction mixture was stirred 15 min, then a solution of 4-cyano-2-ethylphenyl isocyanate dichloride 10 (Method A3a; 0.15 g, 0.63 mmol) in THF (2.5 mL) was added dropwise via syringe. The resulting mixture was stirred overnight, then treated with a 5% citric acid solution (10 mL), followed by EtOAc (25 mL). The organic phase was sequentially washed with 5% citric acid solution (20 mL), H 2 0 (20 mL) and a saturated NaCl solution (20 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The 15 residue was purified by chromatography (SiO 2 , 5% EtOAc/hex) to give 2-(4-cyano 2-ethylphenylimino)-3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine as a yellow solid (0.09 g, 43%): mp 112-114 *C; TLC (15% EtOAc/hex) Rf 0.60; 'H NMR (CDCl 3 ) 8 1.16 (t, J=7.5 Hz, 3H), 1.32 (s, 6H), 1.49-1.61 (m, 2H), 1.71-1.81 (m, 2H), 1.82-1.92 (m, 2H), 2.38-2.50 (m, 2H), 2.61 (q, J=7.6 Hz, 2H), 3.52-3.58 (m, 1H), 3.97 (s, 2H), 20 7.04 (d, J=8.3 Hz, 1H), 7.35 (dd, J=8.1, 1.8 Hz, 1H), 7.40 (d, J=1.8 Hz, 1H); CI-MS m/z (rel abundance) 312 ((M+H)*, 100%). HRMS Cacld for C 7
H
2 3
N
3 0 3 : 311.1998. Found: 311.1991. C7b. General method for the synthesis of 2-imino-1,3-oxazolidines via reaction 25 of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of
(
4
S)-
2 -(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-oxazolidine. NC c Et N ON 67 WO 00/42031 PCT/US99/29601 A solution of 4-cyano-2-ethylphenyl isocyanide dichloride (Method A3a; 0.42 g, 1.83 mmol, 1.2 equiv.) and (2S)-4-methyl-2-(isobutylamino)pentan-1-ol (Method B4c; 0.26 g, 1.52 mmol) in THF (5 mL) was added Et 3 N (0.5 mL). The resulting mixture was stirred at room temp. for 1 h, then was treated with 2 5 (dimethylamino)ethylamine (0.5 mL). This mixture was stirred at room temp. for 1 h, then concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 5% EtOAc/hex to 10% EtOAc/hex) to give (4S)-2 (4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-oxazolidine as a yellow oil (0.15 g): TLC (10% EtOAc/hex) Rf0.35; 1 H NMR (CDCl 3 ) 8 0.81-1.00 (m, 12H), 1.14 (t, 10 J=4.8Hz, 3H), 1.25-1.43 (m, 2H), 1.53-1.70 (m, 2H), 2.57 (sept, J=7.5 Hz, 111), 2.58 (q, J=7.5 Hz, 2H), 3.01 (dd, J=14.0, 6.3.Hz, 1H), 3.33 (dd, J=13.6, 8.8 Hz, 1H), 3.73 3.83 (m, 1H), 3.94 (app t, J=7.5 Hz, 1H), 4.37 (app t, J=7.9 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 7.33 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H); 13C NMR (CDCl 3 ) S 13.8, 19.9, 20.3, 21.8, 23.6, 24.7, 24.9, 26.7, 40.6, 50.1, 55.3, 70.1, 104.1, 120.2, 15 123.4, 129.9, 131.8, 138.4, 151.4, 152.9; HPLC ES-MS m/z 328 ((M+H)*, 100%). C8a. General method for the synthesis of 2-inimo-4-oxoheterocycle synthesis via reaction of an isothiocyanate with an amine, followed by reaction with a haloacid halide. Synthesis of 2-(2-methyl-4-nitrophenylimino)-3 20 isobutyl-1,3-thiazolidin-4-one. 0 2 N Me N S To a solution of 2-methyl-4-nitrophenyl isothiocyanate (0.190 g, 1.0 mmol) in DMF (5.3 mL) was added isobutylamine (0.4 M solution in DMF, 5.3 mL) and the reaction mixture was allowed to stir for 4 h at which time TLC analysis 25 (hexane:EtOAc 3:1) indicated consumption of the isothiocyanate. To the resulting mixture was added chloroacetic acid (0.8 M solution in DMF, 4.0 mL) followed by N-methylmorpholine (0.7 mL, 6.4 mmol). The reaction mixture was stirred at 80 *C for 18 h, then was partitioned between water (10 mL) and EtOAc (25 mL). The aqueous phase was back-extracted with EtOAc (2x10 mL). The combined organic 30 layers were washed with a saturated NaCI solution (25 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The resulting residue was purified by MPLC (Biotage 40 S silica gel column, gradient from 5% EtOAc/hex to 33% EtOAc/hex) to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one as a pale yellow oil (0.52 g, 85%). 68 WO 00/42031 PCT/US99/29601 C9a. General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of hydroxyethylamines with isothiocyanates followed by acid catalyzed ring closure. Synthesis of 2-(2,6-dichlorophenylimino)-3 5 cyclohexyl-4,4-dimethyl-1,3-thiazolidine. CI "N CIS N N-Cyclohexyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a. A solution of 2,6-dichlorophenyl isothiocyanate (1.2 g, 6.0 mmol) and N-cyclohexyl-1,1-dimethyl-2-hydroxyethanamine (1.0g, 6.0 mmol) in 10 CH 2 Cl 2 (10 mL) was stirred for 20 h at room temp. The resulting mixture was concentrated under reduced pressure, then treated with a 33% HCl solution (15 mL). The resulting mixture was heated at the reflux temp. for 1 h, cooled to room temp. and neutralized with a 45% NaOH solution. The resulting slurry was filtered, and the resulting solids were washed with water (20 mL), then recrystallized (EtOH) to yield 15 2-(2,6-dichlorophenylimino)-3-cyclohexyl-4,4-dimethyl-1,3-thiazolidine (0.70 g, 33%): mp 134 *C. When appropriate, the product was converted into the HCl salt by dissolving the free base (5 mmol) in Et 2 O (50 mL) and treating this solution with a 2N ethereal HCl solution until no more solid precipitated. The resulting slurry was filtered and the resulting solids were washed with Et 2 O (25 mL) followed by EtOAc 20 (25 mL). C10a. General method for the reaction of 2-chlorothiazolinium salts with anilines. Synthesis of 2-(2-(N-phenylcarbamoyl)phenylimino)-3,4 diisobutyl-1,3-thiazolidine. 0N-O I H SA N 25 A solution of 2-(N-phenylcarbamoyl)aniline (0.097 g, 0.36 mmol, 1.0 equiv.) and Et 3 N (0.5 mL, 3.6 mmol, 10 equiv.) in p-dioxane (5 mL) was added to a solution 69 WO 00/42031 PCT/US99/29601 of (4S)-2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride in dichloroethane (Method Bl0a; 0.12 M, 0.5 mL, 0.36 mmol). The resulting mixture was heated at 70 *C overnight, then was cooled to room temp., and diluted with EtOAc (25 mL). the EtOAc mixture was sequentially washed with water (2x25 mL) 5 and a saturated NaCl solution (25 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The residue was absorbed onto SiO 2 , and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc/hex) to give 2-(2-(N phenylcarbamoyl)phenylimino)-3,4-diisobutyl-1,3-thiazolidine (0.090 g, 61%). 10 C11a. General method for synthesis of 2-imino-1,3-thiazolidin-5-ones via reaction of amino acid esters with isothiocyanates. Synthesis of 2-(2 methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-5-one. 02N N S N A solution of N-isobutylglycine ethyl ester (0.41 g, 2.57 mmol) in water (5 15 mL) was treated with Et 3 N (0.71 mL, 5.15 mmol), followed by a solution of 2 methyl-4-nitrophenyl isothiocyanate (0.50 g, 2.57 mmol) in acetone (5 mL). The resulting mixture waxs heated at 40 *C for 2 h, then cooled to room temperature and concentrated under reduced pressure. The residue was separated between water (25 mL) and ethyl acetate (25 mL). The organic phase was dried (MgSO 4 ) and 20 concentrated under reduced pressure to afford 2-(2-methyl-4-nitrophenylimino)-3 isobutyl-1,3-thiazolidin-5-one (0.16 g, 88%): mp 152 *C. D. General Methods for the Interconversion of Iminoheterocycles 25 Dia. General method for the neutralization of iminoheterocycle salts. Synthesis of ( 4 S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3 thiazolidine. NC Et N SN 70 WO 00/42031 PCT/US99/29601 To a mixture of (4S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3 thiazolidine HCl salt (Method C6a; 304 g, 0.8 mol), water (1 L) and EtOAc (1.4 L) was added NaHCO 3 (150 g, 1.78 mol, 2.2 equiv.). The resulting mixture was stirred 5 for 1 h. The organic layer was dried (MgSO 4 ) and concentrated under reduced pressure. The resulting viscous oil was treated with EtOH and concentrated under reduced pressure twice to afford (4S)-2-(4-cyano-2-ethylphenylimino)-3,4 diisobutyl-1,3-thiazolidine as a low melting solid (264 g, 96%): mp 50 *C; [a]D = +2.4, (c 1.0, CH 3 0H); 'H NMR (CDCl 3 ) 6 0.92-0.99 (m, 12H), 1.13 (t, J=7.4 Hz, 10 3H), 1.47-1.52 (m, 1H), 1.58-1.67 (m, 2H), 2.07-2.11 (m, 1H), 2.54 (q, J=7.4 Hz, 2H), 2.84-2.90 (m, 2H), 3.28 (dd, J=10.6, 6.6 Hz, 1H), 3.68 (dd, J=13.6, 8.1, Hz, 1H), 3.81-3.87 (m, 1H), 6.85 (d, J=7.9 Hz, 1H), 7.36-7.42 (m, 2H); CI-MS m/z 344 ((M+H)*). 15 D1b. General method for the neutralization of iminoheterocycle salts. Synthesis of 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1 azaspiro[4.4]nonane. 0 2 N Me N To 1 -cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3 -thia- 1 20 azaspiro[4.4]nonane HCl salt (Method C6b; 52.4 g, 0.132 mol) dissolved in a mixture of water (300 mL) and EtOAc (500 mL) was added NaHCO 3 (15 g, 0.178 mol, 1.3 equiv.). The mixture was stirred for 1 h and the resulting organic layer was dried (MgSO 4 ) concentrated under reduced pressure. The resulting light yellow solid was treated with EtOH (100mL), and concentrated under reduced pressure twice to 25 give 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (46 g, 97%): mp 111-112 *C; 1 H NMR (CDCl 3 ) 6 1.49-1.53 (m, 2H), 1.63-1.80 (m, 8H), 1.81-1.91 (m, 4H), 2.21 (s, 3H), 3.02 (s, 2H), 3.60-3.70 (m, 1H), 6.87 (d, J=8.5 Hz, 1H), 8.02 (m, 2H); CI-MS m/z 360 ((M+H)*). 30 D2a. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3 thiazolidine HCI salt. 71 WO 00/42031 PCT/US99/29601 0 2 N Me N HCI S N A slurry of ( 4 S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine (Method Cla; 0.10 g, 0.34 mmol), isobutyl bromide (0.11 mL, 1.03 mmol) and Cs 2
CO
3 (0.12 g, 0.38 mmol) in DMF (2 mL) was heated at 90 *C for 18 h, then 5 cooled to 20 *C, diluted with EtOAc (50 mL) and washed with water (2x200 mL). The organic phase was dried (MgSO 4 ), concentrated under reduced pressure, and the residue was purified by chromatography (SiO 2 , gradient from 100% hex to 10% EtOAc/hex). The resulting material was dissolved in CH 2 Cl 2 (10 mL), treated with an HCl solution (IM in Et 2 O, 2 mL), then concentrated under reduced pressure to 10 afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt (0.088 g, 68%): TLC (free base, 20% EtOAc/hex) Rf 0.74. D2b. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1 15 azaspiro[4.4]nonane. 0 2 N Me N Sk N- A solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (Method C2a; 33.2 g, 114 mmol) in DMF (1 L) was treated with NaOH (690 g, 17.3 mol) and cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was 20 stirred at 20-40 *C for 18 h, then cooled to 4 'C, and treated with water (1.5 L). A conc. HCl solution was added to adjust the pH to 0, and the mixture was extracted with EtOAc (80 mL). The organic phase was washed with a IN HCI solution (1 L), dried (MgS04) and concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 (500 mL) and filtered through a pad of silica gel (9x4 cm). Hexane was 25 added to the resulting solution and volatiles were slowly removed by partial vacuum until crystals formed. The solids were collected to yield 1-cyclopentyl-2-(2-methyl 4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane as yellow crystals (10.9 g, 26%): mp 118-9 'C; TLC (5% EtOAc/hex) RfO.34. 72 WO 00/42031 PCT/US99/29601 D2c. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of (4R)-3-isobutyl-4-isopropyl-2-(2-methyl-4 nitrophenylimino)tetrahydro-2H-1,3-thiazine. 02N Me N S N 5 (R)-4-Isopropyl-2-(2-methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-1,3 thiazine Method C3a) was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4R)-3-isobutyl-4-isopropyl-2-(2-methyl-4 nitrophenylimino)tetrahydro-2H-1,3-thiazine (0.081 g, 32%). TLC (33% 10 EtOAc/hex) Rf 0.76. D2d. General method for the ring-nitrogen alkylation of 2-imino heterocycles. 2-(2-Methyl-4-nitrophenylimino)-3-propanoyl-1,3-thiazolidine. 0 2 N Me IN 0 S N 15 To a solution of 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (prepared in a manner analogous to that described in Method Cla; 0.084 g, 0.35 mmol) in
CH
2 Cl 2 (5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and Et 3 N (0.049 mL, 0.35 mmol). The mixture was allowed to stir at room temp for 1 h, then was diluted with CH 2 C1 2 (40 mL). The resulting solution was sequentially washed with 20 H 2 0 (10 mL) and a saturated NaCl solution (10 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc/hex) to give 2
-(
2 -methyl-4-nitrophenylimino)-3-propanoyl-1,3 thiazolidine (0.036 g, 35%): FAB-MS m/z 294 ((M+H)*). 25 D2e. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of 1-(cyclohexylmethyl)-2-(2-methyl-4-nitrophenylimino)-3 thia-1-azaspiro[4.4]nonane. 73 WO 00/42031 PCT/US99/29601 02N Me N To a solution of 2-(2-methyl-4-nitrophenylimino)-3 -thia- 1 azaspiro[4.4]nonane (Method C2a; 0.1 Og, 0.3432 mmol) and bromomethylcyclohexane (1.00 mL) in DMF (1.00 mL) was added NaOH (approx. 5 0.13 g). The resulting mixture was stirred at 45 *C for 2 d during which it turned from deep red to bright orange. The reaction mixture was then cooled to room temp., filtered and concentrated under reduced pressure. The residual oil was purified by chromatography (SiO 2 ; 5% EtOAc/hex) to afford 1-(cyclohexylmethyl)-2-(2-methyl 4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (0.042 g, 32%) mp 85-7 *C. 10 D2f. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-3,4 diisobutyl-1,3-thiazolidine trifluoroacetate salt. NC Me 0 HO
CF
3 N S N 15 To a solution of (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl 1,3-thiazolidine (Method Cic; 0.050 g, 0.16 mmol) in DMF (1.0 mL) was added NaH (0.0045 g, 1.1 equiv.), and the resulting mixture was stirred at room temp. for 5 min. Isobutyl bromide (0.053 mL, 3 equiv.) was then added and the resulting mixture was stirred at 98 *C for 4 h. The reaction mixture was filtered, then 20 concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C-18 column, gradient from 0.1% TFA/20% CH 3 CN/79.9% water to 0.1% TFA/99.9% CH 3 CN) to furnish (4S)-2-(2-chloro-4-cyano-6 methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt (0.030 g, 52% yield). 25 D2g. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of 2
-(
2 -methyl-4-nitrophenylimino)-3-(2-methyl-prop-2-enyl) 74 WO 00/42031 PCT/US99/29601 4,4-dimethyl-1,3-thiazolidine HBr salt. 02N Me N HBr S N 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-1,3-thiazolidine was prepared in a manner analogous to that described in Method Cla. To a suspension of 2-(2 5 methyl-4-nitrophenylimino)-4,4-dimethyl-1,3-thiazolidine (1.5 mmol) in toluene (10 mL) was added 2-methylprop-2-en-1-yl bromide (4.5 mmol) and the reaction mixture was heated at the reflux temp. for 3 h at which time the reaction was judged complete by TLC. The resulting precipitate was filtered at 50 *C. The collected solids were washed with toluene (20 mL) and CH 2 Cl 2 (20 mL) to yield 2-(2-methyl-4 10 nitrophenylimino)-3-(2-methyl-prop-2-enyl)-4,4-dimethyl-1,3-thiazolidine HBr salt (1.14 g, 77%): mp 229 *C. D2h. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of 2-(2,4-dimethyl-3-cyano-6-pyridylimino)-1-isobutyl-3-thia-1 15 azaspiro[4.4]nonane. Me NC N Me N S To a solution of 2-(2,4-dimethyl-3-cyano-6-pyridylimino)-3-thia-1 azaspiro[4.4]nonane (Method Cle; 0.192 g, 0.669 mmol) and isobutyl bromide (0.5 mL) in anh. DMF (0.5 mL) was added NaH (95%; 0.62 g, 6.69 mmol) portionwise. 20 The resulting mixture was heated at 50 *C for 3 h, then treated with MeOH (approximately 0.5 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , gradient from 20% EtOAc/hex to 100% CH 2 Cl 2 ) to give 2
-(
2
,
4 -dimethyl-3-cyano-6-pyridylimino)-1-isobutyl-3-thia-1 azaspiro[4.4]nonane (0.04 g, 17%): CI-MS m/z 343 ((M+H)+). 25 D3a. General method for the deprotection of tert-butoxycarbamoyl-protected alcohols. Synthesis of (4S)-4-(1(R)-hydroxyethyl)-3-isobutyl-2-(2-methyl 4 -nitrophenylimino)-1,3-thiazolidine. 75 WO 00/42031 PCT/US99/29601 02N Me N S HO A solution of TFA (8 mL) was cooled to 4 'C and added to solid (4S)-4 (1(R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (Method C5b; 0.16 g, 0.42 mmol) via cannula. The resulting solution was warmed to 5 20 'C and stirred at that temp. for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between Et 2 O (100 mL) and a saturated NaHCO 3 solution (100 mL). The ether layer was dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 ; gradient from hexane to 10% EtOAc/hex) to yield (4S)-4-(1 (R)-hydroxyethyl) 10 3-isobutyl-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (0.13 g, 90%): TLC (25% EtOAc/hex) Rf0.13. D4a. General method for the synthesis of 2-imino-1,3-thiazolidine 3-oxides and 2-imino-1,3-thiazolidine 3,3-dioxides via oxidation of 2-imino-1,3 15 thiazolidines. Synthesis of 1-cyclopentyl-2-(2-methyl-4 nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane 3-oxide and 1 cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1 azaspiro[4.4]nonane 3,3-dioxide. 0 2 N Me O2N Me N N O SA NKII RIS N 20 A solution of 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1 azaspiro[4.4]nonane (Method D2b; 0.041 g, 0.11 mmol) and m-chloroperbenzoic acid (approximately 80%, 0.040 g, 0.19 mmol) in CH 2 C1 2 (5 mL) was stirred for 30 min., then washed with a saturated NaHCO 3 , dried (MgSO 4 ), and concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , gradient from 25 hexane to 30% EtOAc/hex) to yield 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino) 3-thia-1-azaspiro[4.4]nonane 3,3-dioxide (0.030 g, 67%) followed by 1-cyclopentyl 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane 3-oxide (0.011 g, 26%). 1-Cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane 76 WO 00/42031 PCT/US99/29601 3,3-dioxide: TLC (25% EtOAc/hex) Rf 0.27. 1 -Cyclopentyl-2-(2-methyl-4 nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane 3-oxide: TLC (25% EtOAc/hex) Rf 0.10. 5 D5a. General method for the reduction of heterocycles containing ketones or aldehydes. Synthesis of 2-(2-methyl-4-nitrophenylimino)-3-(3,3 dimethyl-2-hydroxybutyl)-1,3-thiazolidine. 02N Me N S N HO 2-(2-Methyl-4-nitrophenylimino)-1,3-thiazolidine was prepared in a manner 10 analogous to that described in method C2a and was alkylated with 1-bromo-3,3 dimethyl-2-butanone in a manner analogous to that described in Method D2a to give 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2-oxobutyl)-1,3-thiazolidine. To a solution of 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2-oxobutyl)-1,3 thiazolidine (0.022 g, 0.065 mmol) in MeOH (2 mL) was added NaBH 4 (0.0096 g, 15 0.26 mmol) in portions. The resulting mixture was stirred at room temp for 4 h, then was separated between EtOAc (10 mL) and H 2 0 (5 mL) and the aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were sequentially washed with H 2 0 (15 mL), a saturated NaCl solution (15 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The residue was purified by preparative TLC 20 (20% EtOAc/hexane) to yield 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2 hydroxybutyl)-1,3-thiazolidine (0.024 g, 92%): FAB-MS m/z 338 ((M+H)*). D6a. General method for the interconversion of carboxylic acid derivatives. Synthesis of (4S)-2-(4-carbamoyl-2-methylphenylimino)-3,4-diisobutyl 25 1,3-thiazolidine. 0 HO ,- Me N SK N Step 1 77 WO 00/42031 PCT/US99/29601 To a solution of (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-3,4 diisobutyl-1,3-thiazolidine (prepared in a manner analogous to that described in Method D2a; 0.035 g, 0.097 mmol) in a mixture of MeOH (1.5 mL) and H 2 0 (1.5 mL) was added LiOH (0.016 g, 0.39 mmol). The resulting mixture was stirred for 2 d 5 at room temp., then was concentrated under reduced pressure. The residue was adjusted to pH 1 with a 1% HCl solution, then extracted with EtOAc (4x10 mL). The combined organic layers were sequentially washed with H 2 0 (15 mL), a saturated NaCl solution (15 mL), and dried (Na 2
SO
4 ). Concentration under reduced pressure gave (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine (0.034 10 g, 100%): TLC (40% EtOAc/hex) Rf 0.08. This material was used in the next step without further purification. 0
H
2 N Me S N Step 2 To a solution of (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3 15 thiazolidine (0.035 g, 0.10 mmol) in CH 2 C1 2 (5 mL) was added carbonyl diimidazole (0.047 g, 0.29 mmol). The mixture was allowed to stir at room temp. for 2 h, then anh NH 3 (approximately 30 drops) was condensed into the solution at -78 *C. The resulting mixture was warmed to room temp. overnight, then treated with H 2 0 (20 mL). The aqueous layer was extracted with CH 2 Cl 2 (3x20 mL), sequentially washed 20 with H 2 0 (20 mL) and a saturated NaCl solution (20 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc/hexane) to give (4S)-2-(4-carbamoyl-2 methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine as a white solid (0.027 g, 73%): mp 130-131 *C. 25 D6b. General method for the interconversion of carboxylic acid derivatives. Synthesis of 2
-(
2 -ethyl-4-(N-methylcarbamoyl)phenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 78 WO 00/42031 PCTIUS99/29601 0 MeHN SN To a solution of 2-(4-carboxy-2-ethylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane (Method D9a; 0.58 g, 0.167 mmol) in CHCl 3 (5 mL) was added SOCl 2 (0.06 mL, 0.83 mmol). The reaction mixture was heated at the reflux temp. for 5 3 h, then concentrated under reduced pressure. The residue was dissolved in CH 2 C1 2 (3 mL) and treated with methylamine (2.OM in THF, 4 mL). The reaction mixture was stirred at room temp. for 2 h, then treated with a IN NaOH solution (10 mL). The resulting mixture was extracted with CH 2 Cl 2 (3x20 mL), and the combined organic layers were washed with a saturated NaCl solution (20 mL), dried (Na 2
SO
4 ) 10 and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc/hexane) to give 2-(2-ethyl-4-(N-methylcarbamoyl)phenylimino) 1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (36 g, 56%): TLC (30% EtOAc/hex) Rf 0.44. 15 D7a. General method for the synthesis of cyanoarylimines from iodoarylimines. Synthesis of 2-(4-cyano-2-propylphenylimino)-3-thia-1 azaspiro[4.4]nonane. NC S NH 4-Iodo-2-n-propylaniline was converted into 4-iodo-2-n-propylphenyl 20 isothiocyanate in a manner analogous to Method A2b. Concurrently, 1-amino-i (hydroxymethyl)cyclopentane was converted to the chloromethyl analogue, then reacted with the isothiocyanate in a manner analogous to Method C2a to give 2-(4 iodo-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane. A slurry of 2-(4-iodo-2 propylphenylimino)-3-thia-1-azaspiro[4.4]nonane (0.54 g, 1.35 mmol) and CuCN 25 (0.24 g, 2.70 mmol) in DMF (4 mL) was heated at 140 *C overnight. The resulting mixture was cooled to room temp, concentrated under reduced pressure and purified by flash chromatography (10% EtOAc/hex) to give 2-(4-cyano-2 79 WO 00/42031 PCT/US99129601 propylphenylimino)-3-thia-l-azaspiro[4.4]nonane as a white solid (0.26 g, 65%): TLC (30% EtOAc/hex) Rf0.37. D8a. General method for the synthesis of phenylacetylenes. Synthesis of 2 5 (2,3-dimethyl-4-ethynylphenylimino)-1-isobutyl-3-thia-1 azaspiro[4.4]nonane. Me 3 Si Me Me N S N Step 1 4-Iodo-2,3-dimethylaniline was converted into 4-iodo-2,3-dimethylphenyl 10 isothiocyanate in a manner analogous to Method A2b. 2-(2,3-Dimethyl-4 iodophenylimino)-3-thia-l-azaspiro[4.4]nonane was prepared in a manner analogous to that described in Method C2a, then was alkylated with isobutyl bromide in a manner analogous to that described in Method D2a. A mixture of the iodophenyl compound (0.009 g, 0.021 mmol), (trimethylsilyl)acetylene (30 mL, 0.21 mmol), 15 Pd(PPh 3
)
2 Cl 2 (0.005 g) and Cul (0.012 g, 0.063 mmol) in Et 3 N (2 mL) was stirred at room temp. for 18 h. The resulting slurry was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (2% EtOAc/hex) to give 2-(2,3-dimethyl-4-(2-trimethylsilyl- 1 -ethynyl)phenylimino) 1-isobutyl-3-thia-1-azaspiro[4.4]nonane (0.005 g, 59%). H Me Me N 20 D Step 2 A mixture of 2-(2,3-dimethyl-4-(2-trimethylsilyl-1-ethynyl)phenylimino)-1 isobutyl-3-thia-1-azaspiro[4.4]nonane (0.005 g, 0.0125 mmol) and NaOH (0.006 g, 0.15 mmol) in MeOH (2 mL) was stirred overnight at room temp. The reaction 25 mixture was diluted with CH 2 C1 2 (20 mL), filtered, and the filtrate was concentrated under reduced pressure. Thre residue was purified by preparative TLC (2% 80 WO 00/42031 PCT/US99/29601 EtOAc/hex) to give 2-(2,3-dimethyl-4-ethynylphenylimino)-1-isobutyl-3-thia-1 azaspiro[4.4]nonane (0.003.2 g, 78%): TLC (20% EtOAc/hex) Rf0.70. D9a. General method for the synthesis of benzoic acids via hydrolysis of 5 benzonitriles. Synthesis of 2-(4-carboxy-2-ethylphenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 0 H O -N S N 2-(4-Cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane was prepared in a manner analogous to Method C2a and the thiazolidine was alkylated in a manner 10 analogous to Method D2b to give 2
-(
4 -cyano-2-ethylphenylimino)-1-cyclopentyl-3 thia- 1 -azaspiro[4.4]nonane. A solution of 2-(4-cyano-2-ethylphenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane (0.32 g, 9.42 mmol) in conc. HCl (15 mL) was heated at 100 *C overnight, then was cooled to room temp. to give a white precipitate. The resulting mixture was adjusted to pH 6.5 with a IN NaOH solution,, 15 then extracted with CH 2 Cl 2 (4x40 mL). The combined organic layers were sequentially washed with water (30 mL) and a saturated NaCl solution (30 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. to give 2-(4-carboxy-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a white solid (0.34 g, 100%): mp 208-209 *C. 20 D10a. General method for the conversion of carboxylic acids into ketones. Synthesis of 2
-(
4 -acetyl- 2 -ethylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane. 0 Me S N 25 To a solution of the 2-(4-carboxy-2-ethylphenylimino)-1-cyclopentyl-3-thia 1-azaspiro[4.4]nonane (Method D9a; 0.046 g, 0.128 mmol) in THF (10 mL) at -78 *C was added methyllithium (1.4 M in Et 2 O, 0.91 mL, 1.28 mmol). The reaction 81 WO 00/42031 PCT/US99/29601 mixture was while allowed to gradually warm to room temp., then was stirred overnight. Trimethylsilyl chloride (0.5 mL) was added and the mixture was stirred at room temp. for 2 h, then a IN HCl solution (2 mL) was added. The mixture was stirred for 0.5 h, then was treated with a saturated NaHCO 3 solution (10 mL). The 5 resulting mixture was extracted with EtOAc (4x20 mL), and the combined organic layers were washed with a saturated NaCl solution (30 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue was purified by preparative TLC (10% EtOAc/hex) to give 2-(4-acetyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane as a white solid (0.032 g, 73%): mp 114 -115 *C. 10 D11a. General method for the conversion of nitriles into aldehydes. Synthesis of 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane. OHCj N S 'kN 15 2-(4-Cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane was prepared in a manner analogous to Method C2a and the thiazolidine was alkylated in a manner analogous to Method D2b to give 2 -(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3 thia-1-azaspiro[4.4]nonane. To a solution of 2-(4-cyano-2-ethylphenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane (0.21 g, 0.60 mmol) in anh. toluene (20 20 mL) at -78C was added DIBAL (1.OM in toluene, 1.20 mL, 1.20 mmol). The reaction mixture was stirred at -78 *C for 3 h, then EtOAc (3 mL) was added at -78 *C, stirring was continued for 0.5 h, and wet silica gel (5% water, 2 g) was added. The reaction mixture was warmed to room temp., stirred for 3 h, then filtered through a pad of through Celite*. The filtrate was concentrated under reduced pressure, and the 25 residue was purified by preparative TLC (30% EtOAc/hex) to give 2-(2-ethyl-4 formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a white solid (0.16 g, 75%): mp 104 - 105*C. D12a. General methods for the chain homologation of aldehydes or ketones. 30 Synthesis of 2
-(
2 -ethyl-4-((1E)-2-ethoxycarbonylvinyl)phenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 82 WO 00/42031 PCTIUS99/29601 0 EtO N To a solution of 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane (Method Dlla; 0.053 g, 0.149 mmol) in CH 3 CN was added LiC1 (0.0076 g, 0.182 mmol) followed by DBU (0.025 g, 0.167 mmol) and triethyl 5 phosphonoacetate (0.041 g, 0.182 mmol). The reaction mixture was stirred at room temp. for 18 h, then concentrated under reduced pressure. The residue was purified by flash chromatography (3% EtOAc/hex) to give 2-(2-ethyl-4-((1E)-2 ethoxycarbonylvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a colorless oil (0.029 g, 48%): TLC (30% EtOAc/hex) Rf0.68. 10 D12b. General methods for the chain homologation of aldehydes or ketones. Synthesis of 2
-(
2 -ethyl-4-((1E)-2-nitrovinyl)phenylimino)-1-cyclopentyl 3-thia-1-azaspiro[4.4]nonane. 0 2 N N "-Of 15 To a solution of 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane (Method D 11a; 0.041 g, 0.115 mmol) in CH 2 Cl 2 (10 mL) was added MeNO 2 (2 drops) and piperidine (4 drops). The reaction mixture was heated at the reflux temp. overnight, them cooled to room temp. and concentration under reduced pressure. The residue was purified by flash chromatography (3% 20 EtOAc/hex) to give 2-(2-ethyl-4-((1E)-2-nitrovinyl)phenylimino)-1-cyclopentyl-3 thia-l-azaspiro[4.4]nonane as a red solid (0.022 g, 48%): mp 141-142 *C. D12c. General methods for the chain homologation of aldehydes or ketones. Synthesis of 2
-(
2 -ethyl- 4 -(2,2-dicyanovinyl)phenylimino)-1-cyclopentyl-3 25 thia-1-azaspiro[4.4]nonane. 83 WO 00/42031 PCT/US99/29601 NC CNS N CN ' N To a solution of 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane (Method Dlla; 0.037 g, 0.104 mmol) in EtOH (10 mL) was added malononitrile (0.007 g, 0.104 mmol) and piperidine (4 drops). The reaction 5 mixture was stirred at room temp. for 2 h, then concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/hex) to give 2-(2-ethyl-4 (2,2-dicyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a yellow solid (0.012 g, 28%): mp 135-136 *C. 10 D12d. General methods for the chain homologation of aldehydes or ketones. Synthesis of 2
-(
2 -ethyl- 4
-(
2 -cyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane. NC N To a solution of KOH (0.024 g, 0.36 mmol) in CH 3 CN (20 ml) at the reflux 15 temp. was added 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane (Method D 11a; 0.127 g, 0.36 mmol). The reaction mixture was heated at the reflux temp. for 4 h, cooled to room temp., and concentrated under reduced pressure The residue was diluted with water (15 mL) and extracted with
CH
2 C1 2 (3x15 mL). The combined organic layers were washed with a saturated NaCl 20 solution and dried (Na 2
SO
4 ). The resulting material was purified by preparative TLC (30% EtOAc/hex) to give 2
-(
2 -ethyl-4-(2-cyanovinyl)phenylimino)-1-cyclopentyl-3 thia-1-azaspiro[4.4]nonane as 1:3 cis/trans mixture of isomers (0.050 g): TLC (30% EtOAc/hex) Rf0.56. 25 D13a. General method for the alkylation of chloromethyl side chains. Synthesis of 2
-(
2 -methyl- 4 -nitrophenylimino)-4-(N-methylaminomethyl)-1,3 thiazolidine. 84 WO 00/42031 PCT/US99/29601 0 2 N Me S NH MeHN To a solution of methylamine in methanol (2.OM, 5 mL) was added 2-(2 methyl-4-nitrophenylimino)-4-(chloromethyl)-1,3-thiazolidine (prepared in a manner analogous to that described in Method C2a; 0.040 g, 0.140 mmol) and the 5 resulting mixture was stirred at room temp for 72 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (5% MeOH/CH 2
C
2 ) to give 2-(2-methyl-4-nitrophenylimino)-4-(N methylaminomethyl)-1,3-thiazolidine as a solid (0.014 g, 35%). 10 D14a. Acid-catalyzed rearrangement of carbon-carbon double bonds. Synthesis of 2 -(4-nitrophenylimino)-3-(2-methylprop-1-en-1-yl)-1,3 thiazolidine. N NO 2 2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl 15 isothiocyanate according to Method Cla to give 2-(4-nitrophenyl)-1,3-thiazolidine. The thiazolidine was reacted with 1 -bromo-2-methyl-2-propene according to Method D2a to give 2
-(
4 -nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine. A mixture of 2 -(4-nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine (0.20 g) in poly(phosphoric acid) (0.4 mL) was heated at 80 *C for 5 h. The reaction 20 mixture was then dissolved in 0 *C water (20 mL) with the aid of sonication. The aqueous mixture was adjusted to pH 12 with a IN NaOH solution, then extracted with EtOAc (3 x 25 mL). The combined organic phases were dried (K 2 C0 3 ) and concentrated under reduced pressure. The residue (0.21 g) was purified by preparative HPLC to afford 2-(4-nitrophenylimino)-3-(2-methylprop-1-en-1-yl)-1,3 25 thiazolidine. SPECIFIC COMPOUND PREPARATIONS Descriptions of the detailed preparative steps used to prepare the specific 30 compounds listed in Tables 1-4 are provided below. Many of the compounds listed 85 WO 00/42031 PCTIUS99/29601 in the Tables can be synthesized following a variety of methods. The specific examples below are therefore provided by way of illustration only and should not be construed to limit the scope of the invention in any way. 5 Entry 1 N NO 2 H Me 2-Chloroethylamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method CIa to give 2-(2-methyl-4-nitrophenylimino)- 1,3 -thiazolidine. 10 Entry 2 N NO 2 i-Bu 2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give 2-(4-nitrophenylimino)-1,3 thiazolidine, which was reacted with isobutyl bromide according to Method D2a to 15 give 2-(4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine. Entry 3 N NO 2 i-Bu Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 20 isothiocyanate, which was reacted with isobutyl bromide according to Method D2a to give 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine. Entry 4 N i-Bu CI CI 25 2-Chloroethylammonium chloride (Entry 1) was reacted with 2,3-dichlorophenyl isothiocyanate according to Method Cla to give 2-(2,3-dichlorophenylimino)-1,3 thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2-(2,3-dichlorophenylimino)-3-isobutyl-1,3-thiazolidine. 30 Entry 5 86 WO 00/42031 PCT/US99/29601 C >=N Q NO 2 i-Bu MeO N-Chloroethyl-N'-isobutylammonuim chloride (prepared as described in Method B7c) was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to method 5 Cld to give 2-(2-methoxy-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine. Entry 6 C N CN i-Bu N-Chloroethyl-N'-isobutylammonuimchloride (prepared as described in Method 10 B7c) was reacted with 4-cyanophenyl isothiocyanate according to method Cld to give 2-(4-cyanophenylimino)-3-isobutyl-1,3-thiazolidine. Entry 7 HCI
NO
2 N __ i-Bu Me 15 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-5-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2-(2-methyl-5 nitrophenylimino)-3-isobutyl-1,3-thiazolidine HCl salt. 20 Entry 8 LI>=N \ CN 1-Bu Etp N-Chloroethyl-N'-isobutylammonuimchloride (prepared as described in Method B7c) was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to method Cld to give 2
-(
4 -cyano-2-ethylphenylimino)-3-isobutyl-1,3-thiazolidine. 25 Entry 9 C N ,, CI i-Bu F 3 C 87 WO 00/42031 PCT/US99/29601 N-Chloroethyl-N'-isobutylammonium chloride (prepared as described in Method B7c) was reacted with 4-chloro-2-(trifluoromethyl)phenyl isothiocyanate according to method Cld to give 2-(4-chloro-2-(trifluoromethyl)phenylimino)-3-isobutyl-1,3 thiazolidine. 5 Entry 10 C>N NO 2 2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted 10 with 1-bromo-2-methyl-2-propene according to Method D2a to give 2-(4 nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine. The 3-allyl-1,3 thiazolidine was rearranged according to Method D14a to give 2-(4 nitrophenylimino)-3-(2-methylprop-1-en-1-yl)-1,3-thiazolidine. 15 Entry 11 NN P NO 2 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted 20 with 1-bromo-2-methyl-2-propene according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(2-methylprop-2-en- 1-yl)-1,3 -thiazolidine. Entry 12 C>N NO 2 25 2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2-(4 nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine. 30 Entry 13 88 WO 00/42031 PCT/US99/29601 IC S > NQ CI N C C1 2-Chloroethylammonium chloride (Entry 1) was reacted with 3,4-dichlorophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2-(3,4 5 dichlorophenylimino)-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine. Entry 14 =C >N
NO
2 Me N-(2-Hydroxyethyl)-N-(2-methylbutyl)amine was reacted with SOCl 2 according to 10 Method B7a to give N-(2-chloroethyl)-N-(2-methylbutyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give to give 2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-1 butyl)-1,3-thiazolidine. 15 Entry 15 IC ==N - NO 2 N Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 4-bromobut-l-ene according to Method D2a to give 2-(2-methyl-4 20 nitrophenylimino)-3-(but- 1 -en-4-yl)- 1,3-thiazolidine. Entry 16 C N>N mp NO 2 ---- Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 25 isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromobut-2-yne according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(but-2-yn-1-yl)-1,3-thiazolidine. Entry 17 89 WO 00/42031 PCT/US99/29601 N NO 2 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 2-ethylbutyl bromide according to Method D2a to give 2-(2-methyl-4 5 nitrophenylimino)-3-(2-ethyl-1-butyl)-1,3-thiazolidine. Entry 18 C >N -
NO
2 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 10 isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 2-methylbutyl bromide according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidine. Entry 19 N
NO
2 15 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-nonyl bromide according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(1-nonyl)-1,3-thiazolidine. 20 Entry 20 C>N
NO
2 N Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted 25 with 2,2-dimethylpropyl bromide according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(2,2-dimethylpropyl)-1,3-thiazolidine. 90 WO 00/42031 PCT/US99/29601 Entry 21 C >==N - NO 2 Me 2-Butylamine was converted to N-(2-hydroxyethyl)-N-(2-butyl)amine according to Method B5a. The amine was reacted with SOCl 2 according to Method B7a to give 5 N-(2-chloroethyl)-N-(2-butyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method CIa to give to give 2-(2-methyl-4-nitrophenylimino)-3-(2-butyl)-1,3-thiazolidine. Entry 22 IC >=N \,P NO 2 10 Me 3-Pentylamine was converted to N-(2-hydroxyethyl)-N-(3-pentyl)amine according to Method B5a. The amine was reacted with SOC 2 according to Method B7a to give N-(2-chloroethyl)-N-(3-pentyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method CIa to give 15 to give 2
-(
2 -methyl-4-nitrophenylimino)-3-(3-pentyl)-1,3-thiazolidine. Entry 23 N NO 2 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 20 isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-heptyl bromide according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(1-heptyl)-1,3-thiazolidine. Entry 24 IC>=N NO 2 25 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 8-bromo-1-octene according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(oct-1-en-8-yl)-1,3-thiazolidine. 91 WO 00/42031 PCT/US99/29601 Entry 25 N NO 2 2-Propyl-1-hydroxypentane was converted to 1-bromo-2-propylpentane according to 5 Method B2b, Step 2. 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-bromo-2-propylpentane according to Method D2a to give 2-(2-methyl-4-nitrophenylimino)-3-(2-propyl-1-pentyl)-1,3-thiazolidine. 10 Entry 26 S >_N>
NO
2 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1,1 -dicyclopropylbut- 1 -en-4-yl bromide according to Method D2a to give 2-(2 15 methyl-4-nitrophenylimino)-3-(1,1 -dicyclopropylbut- 1 -en-4-yl)- 1,3-thiazolidine. Entry 27 CI O N
NO
2 C1 2,6-Dichloro-4-nitrophenyl isothiocyanate was reacted with 2-butylamine followed 20 by chloroacetic acid according to Method C8a to afford 2-(2,6-dichloro-4 nitrophenylimino)-3-(2-butyl)-1,3-thiazolidin-4-one. Entry 28 Br C>N mp NO2 K)Me 25 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with (E/Z)-1,3-dibromopropene according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(bromoprop-1-en-3-yl)-1,3-thiazolidine as an E-/Z-mixture. 92 WO 00/42031 PCT/US99/29601 The mixture was separated using preparative TLC to afford 2-(2-methyl-4 nitrophenylimino)-3-((Z)-bromoprop-1-en-3-yl)-1,3-thiazolidine. Entry 29 N NO 2 5 CI Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method CIa to give the thiazolidine, which was reacted with (E)-1,3-dichloropropene according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-((E)-chloroprop-1-en-3-yl)-1,3-thiazolidine. 10 Entry 30 N NO 2 --- Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 15 isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 3-chloro-1-propyne according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3 -(prop-i -yn-3-yl)- 1,3-thiazolidine. Entry 31 N
NO
2 Me 20 Br 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with (E/Z)-1,3-dibromopropene according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(bromoprop-1-en-3-yl)-1,3-thiazolidine as an E-/Z-mixture. 25 The mixture was separated using preparative TLC to afford 2-(2-methyl-4 nitrophenylimino)-3-((E)-bromoprop-1-en-3-yl)-1,3-thiazolidine. Entry 32 N ,, NO 2 EtO Me O OEt 93 WO 00/42031 PCT/US99/29601 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with ethyl (Z)-4-chloro-3-ethoxybut-2-enoate according to Method D2a to give 2-(2 methyl-4-nitrophenylimino)-3-(1-ethoxycarbonyl-2-ethoxyprop-1 -en-3-yl)-1,3 5 thiazolidine. Entry 33 0 C =N- NO 2 MeO Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 10 isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with methyl 4-bromobutanoate according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(1-methoxycarbonyl-3-propyl)-1,3-thiazolidine. Entry 34 CeS >N P NO 2 MeO N 15 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with methyl chloroacetate according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(1-methoxycarbonylmethyl)-1,3-thiazolidine. 20 Entry 35 Ph N NO 2 >-j Me HO 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted 25 with a-chloroacetophenone according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(1-oxo-1-phenyl-2-ethyl)-1,3-thiazolidine. The ketone was reduced according to Method D5a to give 2-(2-methyl-4-nitrophenylimino)-3-(1 hydroxy- 1 -phenyl-2-ethyl)- 1,3-thiazolidine. 30 Entry 36 94 WO 00/42031 PCT/US99/29601 0ICN = NO 2 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to give 2-(2 5 methyl-4-nitrophenylimino)-3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazolidine. Method 37 0 N NO 2 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 10 isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-chloro-2-butanone according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(2-oxo-1-butyl)-1,3-thiazolidine. Method 38 HO N N NO 2 15 -Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-chloro-2-butanone according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(2-oxo-1-butyl)-1,3-thiazolidine. The ketone was reducded 20 according to Method D5a to give 2
-(
2 -methyl-4-nitrophenylimino)-3-(2-hydroxy-1 butyl)-1,3-thiazolidine. Method 39 HO NNO Me 25 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to give 2-(2 95 WO 00/42031 PCT/US99/29601 methyl-4-nitrophenylimino)-3-(2-oxo-3,3-dimethyl- 1 -butyl)- 1,3-thiazolidine. The ketone was reduced according to Method D5a to give 2-(2-methyl-4 nitrophenylimino)-3-(2-hydroxy-3,3-dimethyl-1-butyl)-1,3-thiazolidine. 5 Entry 40 O NM NO 2 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted 10 with 5-bromo-2-pentanone according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-(2-oxo-5-pentanyl)-1,3-thiazolidine. 15 Entry 41 C1 N NO 2 ,KJMe CI 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted 20 with 1,1,3-trichloro-1-propene according to Method D2a to give 2-(2-methyl-4 nitrophenylimino)-3-( 1,1 -dichloroprop-1-en-3-yl)-1,3-thiazolidine. Entry 42 C >N - NO 2 O Me 25 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with propionyl chloride according to Method D2d to give 2-(2-methyl-4 nitrophenylimino)-3-(1-oxo-1-propyl)-1,3-thiazolidine. 30 Entry 43 96 WO 00/42031 PCT/US99/29601 C >==N NO 2 Me OMe 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with (E)-l-chloro-5-methoxy-2-pentene according to Method D2a to give 2-(2 5 methyl-4-nitrophenylimino)-3-((E)-5-methoxypent-2-en-1-yl)-1,3-thiazolidine. Entry 44 N NO 2 8Me 2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, 10 Step 1 to afford 4-aza-1-oxaspiro[4.4]nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N-cyclopentyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to afford N cyclopentyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methyl-4 nitrophenyl isothiocyanate according to Method Cld to afford 2-(2-methyl-4 15 nitrophenylimino)-3-(cyclopentyl)-1,3-thiazolidine. Entry 45 N NO 2 6 MeO 2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, 20 Step 1 to afford 4 -aza-1-oxaspiro[4.4]nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N-cyclopentyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to afford N cyclopentyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4 nitrophenyl isothiocyanate according to Method Cld to afford 2-(2-methoxy-4 25 nitrophenylimino)-3-(cyclopentyl)-1,3-thiazolidine. 97 WO 00/42031 PCT/US99/29601 Entry 46 N C1 C1 2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-1-oxaspiro[4.4]nonane. The oxazolidine was reduced 5 according to method B4b, Step 2 to afford N-cyclopentyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOC 2 according to Method B7c to afford N cyclopentyl-N-(2-chloroethyl)amine. The amine was reacted with 2,3 dichlorophenyl isothiocyanate according to Method Cld to afford 2-(2,3 dichlorophenylimino)-3-cyclopentyl-1,3-thiazolidine. 10 Entry 47 C =N- NO2 Me Cyclohex-2-en-1-one was reduced according to Method B2b, Step 1 to afford cyclohex-2-en-1-ol. The alcohol was converted to the 3-bromo-1-cyclohexene 15 according to Method B2b, Step 2. The halide was converted to N-(cyclohex-2-en-1 yl)-N-(2-hydroxyethyl)amine according to Method B2b, Step 3. The alcohol was reacted with SOCl 2 according to Method B7a to afford N-(cyclohex-2-en-1-yl)-N-(2 chloroethyl)ammmonium chloride. The chloroethylamine was reacted with 2 methyl-4-nitrophenyl isothiocyanate according to method Cla to afford 2-(2-methyl 20 4-nitrophenylimino)-3-(cyclohex-2-en-1-yl)-1,3-thiazolidine. Entry 48 C>N NO 2 Me 2-Hydroxyethylamine and cyclohexanone were reacted according to Method B4a, 25 Step 1 to afford 4-aza-1-oxaspiro[4.5]decane. The oxazolidine was reduced according to method B4a, Step 2 to afford N-cyclohexyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to afford N cyclohexyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4 98 WO 00/42031 PCT/US99/29601 nitrophenyl isothiocyanate according to Method Cld to afford 2-(2-methyl-4 nitrophenylimino)-3-cyclohexyl-1,3-thiazolidine. Entry 49 N NO 2 N M e 5 M N-(2-Hydroxyethyl)aniline was reacted with SOC1 2 according to Method B7a to give N-2-chloroethyl)anilinium chloride. The chloroethylamine was reacted with 2 methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl 4-nitrophenylimino)-3-phenyl-1,3-thiazolidine. 10 Entry 50 N NO 2 Me 2-Hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to give N-cycloheptyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with 15 SOCl 2 according to Method B7c to give N-cycloheptyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2 -(2-methyl-4-nitrophenylimino)-3-cycloheptyl-1,3 thiazolidine. 20 Entry 51 C >=N NO 2 Me 2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOC1 2 25 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2
-(
2 -methyl-4-nitrophenylimino)-3-cyclooctyl-1,3 thiazolidine. 99 WO 00/42031 PCT/US99/29601 Entry 52 N >=N -P/ NO 2 MeO 2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a 5 to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2
-(
2 -methoxy-4-nitrophenylimino)-3-cyclooctyl-1,3 thiazolidine. 10 Entry 53 CI CI 2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOC1 2 15 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3 -dichlorophenylimino)-3 -cyclooctyl- 1,3 -thiazolidine. 20 Entry 54 N C1 C 2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to 25 Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOC 2 according to Method B7c to give N-cyclopropylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3 100 WO 00/42031 PCT/US99/29601 dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3 (cyclopropylmethyl)- 1,3-thiazolidine. Entry 55 N NO 2 5 Me 2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclopropylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl 10 4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3 (cyclopropylmethyl)- 1,3-thiazolidine. Entry 56 N CI C1 15 2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclopropylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4 dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3 20 (cyclopropylmethyl)-1,3-thiazolidine. 25 Entry 57 C N CI CI 2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclopropylmethyl-N-(2 101 WO 00/42031 PCT/US99/29601 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4 dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3 (cyclopropylmethyl)-1,3-thiazolidine. 5 Entry 58 [N>NRI CI CI 2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclobutylmethyl-N-(2 10 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,2 dichlorophenyl isothiocyanate to give 2-(2,2-dichlorophenylimino)-3 (cyclobutylmethyl)-1,3-thiazolidine. Entry 59 C N>N : CI CI 15 2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclobutylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4 20 dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3 (cyclobutylmethyl)-1,3-thiazolidine. Entry 60 [C >N CI C 25 2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclobutylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4 102 WO 00/42031 PCT/US99/29601 dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3 (cyclobutylmethyl)- 1,3-thiazolidine. Entry 61 N 5Me Me 5E 2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclobutylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3 10 dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3 (cyclobutylmethyl)-1,3-thiazolidine. Entry 62 N Me CI 15 2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclobutylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro 2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3 20 (cyclobutylmethyl)-1,3-thiazolidine. Entry 63 N CI CI 2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to 25 Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOC 2 according to Method B7c to give N-cyclopentylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3 dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3 (cyclopentylmethyl)- 1,3-thiazolidine. 103 WO 00/42031 PCT/US99/29601 Entry 64 N CI C1 2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to 5 Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclopentylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4 dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3 (cyclopentylmethyl)- 1,3 -thiazolidine. 10 Entry 65 C =N
NO
2 Me 2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol 15 was reacted with SOC 2 according to Method B7c to give N-cyclopentylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl 4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3 (cyclopentylmethyl)- 1,3 -thiazolidine. 20 Entry 66 N CI CI 2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOC 2 according to Method B7c to give N-cyclopentylmethyl-N-(2 25 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4 dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3 (cyclopentylmethyl)- 1,3 -thiazolidine. 104 WO 00/42031 PCT/US99/29601 Entry 67 Me Me 2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol 5 was reacted with SOCl 2 according to Method B7c to give N-cyclopentylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3 dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3 (cyclopentylmethyl)-1,3-thiazolidine. 10 Entry 68 Me CI 2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cyclopentylmethyl-N-(2 15 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro 2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3 (cyclopentylmethyl)-1,3-thiazolidine. Entry 69 N CI CI 20 2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOC 2 according to Method B7c to give N-cyclohexylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3 25 dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3 (cyclohexylmethyl)- 1,3-thiazolidine. 105 WO 00/42031 PCT/US99/29601 Entry 70 N NO 2 Me 2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to 5 Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOC1 2 according to Method B7c to give N-cyclohexylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl 4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3 (cyclohexylmethyl)-1,3-thiazolidine. 10 Entry 71 C >N
NO
2 MeO 2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol 15 was reacted with SOCl 2 according to Method B7c to give N-cyclohexylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2 methoxy-4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3 (cyclohexylmethyl)- 1,3 -thiazolidine. 20 Entry 72 N >=N mp NO 2 Me 1 -Cyclohexyl- 1 -ethylamine was converted to N-(2-hydroxyethyl)-N-(1 -cyclohexyl- 1 ethyl)amine according to Method B5a. The alcohol was reacted with SOCl 2 according to Method B7a to give N-(2-chloroethyl)-N-(1-cyclohexyl-1 25 ethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4 nitrophenyl isothiocyanate according to Method Cla to give 2-(2-methyl-4 nitrophenylimino)-3-(1 -cyclohexyl- 1-ethyl)- 1,3-thiazolidine. 106 WO 00/42031 PCT/US99/29601 Entry 73 C II>==N N Bn Me CI 5 2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3-benzyl-1,3-thiazolidine. 10 Entry 74 N- CI Bn CI 2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 15 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2 (3,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine. Entry 75 NCI 20 Bn CI 2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2 25 (2,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine. Entry 76 C >N NO 2 Bn Me 2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to 30 give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. 107 WO 00/42031 PCT/US99/29601 The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidine. Entry 77 N 5 Bn CI CI 2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2 10 (2,3-dichlorophenylimino)-3-benzyl-1,3-thiazolidine. Entry 78 CI>=N CN Et CI 2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method 15 B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 4-cyano-2 ethylphenyl isothiocyanate to give 2-(4-cyano-2-ethylphenylimino)-3-(4 chlorobenzyl)-1,3-thiazolidine. 20 Entry 79 NCN CI CI 2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted 25 with SOCl 2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro 4-cyanophenyl isothiocyanate to give 2 -(2-chloro-4-cyanophenylimino)-3-(4 chlorobenzyl)- 1,3-thiazolidine. 108 WO 00/42031 PCT/US99/29601 Entry 80 C=N NO 2 Me 2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol 5 was reacted with SOC1 2 according to Method B7c to give N-cycloheptylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl 4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3 (cycloheptylmethyl)-1,3-thiazolidine. 10 Entry 81 C =N NO 2 MeO 2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cycloheptylmethyl-N-(2 15 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2 methoxy-4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3 (cycloheptylmethyl)-1,3-thiazolidine. Entry 82 N CI CI 20d 2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cycloheptylmethyl-N-(2 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3 25 dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3 (cycloheptylmethyl)-1,3-thiazolidine. Entry 83 109 WO 00/42031 PCT/US99/29601 N CN 2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl 2 according to Method B7c to give N-cycloheptylmethyl-N-(2 5 chloroethyl)ammonium chloride. The chloroethylamine was reacted with 4 cyanophenyl isothiocyanate to give 2 -(4-cyanophenylimino)-3-(cycloheptylmethyl) 1,3-thiazolidine. Entry 84 C>N NO2 10 N Me Methyl cyclododecanecarboxylate was reduced according to Method B2b, Step 1 to give cyclododecylmethanol. The alcohol was converted to cyclododecylmethylbromide according to Method B2b, Step 2. The halide was reacted with 2-hydroxyethylamine according to Method B2b, Step 3 to give N-(2 15 hydroxyethyl)-N-(cyclododecylmethyl)amine. The alcohol was reacted with SOC1 2 according to Method B7a to give N-(2-chloroethyl)-N (cyclododecylmethyl)ammonium chloride. The chloroethylamine was reacted with 2 methyl-4-nitrophenyl isothiocyanate according to Method CIa to give 2-(2-methyl-4 nitrophenylimino)-3-(cyclododecylmethyl)-1,3-thiazolidine. 20 Entry 85 11 N u,,NO 2 Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2-methyl-4-nitrophenylimino) 25 1,3-thiazolidine, which was reacted with 3-(chloromethyl)-6,6 dimethylbicyclo[3.1.1]hept-2-ene according to Method D2a to give 2-(4 nitrophenylimino)-3-((6,6-dimethylbicyclo[3.1. 1 ]hept-2-en-3-yl)methyl)- 1,3 thiazolidine. 110 WO 00/42031 PCT/US99/29601 Entry 86 C >=N - NO 2 NJr Me 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 5 isothiocyanate according to Method Cla to give 2-(2-methyl-4-nitrophenylimino) 1,3-thiazolidine, which was reacted with 5-(bromomethyl)bicyclo[2.2.1]hept-2-ene according to Method D2a to give 2-(4-nitrophenylimino)-3-((bicyclo[2.2.1]hept-2 en-5-yl)methyl)-1,3-thiazolidine. 10 Entry 87 N i-Bu 3-Aminoquinoline was converted to 3-quinoline isothiocyanate according to Method A2c. (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted 15 to (2S)-4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(iS)-1-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride as described in Method B7c. 3-Quinoline isothiocyanate was reacted with N-(1S)-1-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride according to Method Clf to give 2-(3-quinolylimino) 20 3,5-diisobutyl-1,3-thiazolidine. Entry 88 N NO 2 N i-Bu (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 25 ester as described in Method BIb. The 2-hydroxyethylamine was converted to (2S) 4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(1S)-i -(chloromethyl)-3 -methylbutyl)-N (isobutyl)ammonium chloride as described in Method B7c. 4-Nitrophenyl isothiocyanate was reacted with N-(1S)-1-(chloromethyl)-3-methylbutyl)-N 111 WO 00/42031 PCT/US99/29601 (isobutyl)ammonium chloride according to Method Clf to give 2-(4 nitrophenylimino)-3,5-diisobutyl-1,3-thiazolidine. Entry 89
S
N CN 5 i-Bu (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method BIb. The 2-hydroxyethylamine was converted to (2S) 4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(1S)-1-(chloromethyl)-3-methylbutyl)-N 10 (isobutyl)ammonium chloride as described in Method B7c. 4-Cyanophenyl isothiocyanate was reacted with N-(1S)-1-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride according to Method Clf to give 2-(4 cyanophenylimino)-3,5-diisobutyl-1,3-thiazolidine. 15 Entry 90 N /NO 2 i-Bu Me HCI (1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1S)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-3 20 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4 nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt. 25 Entry 91 S C N / NO 2 i-Bu Me HCI (lS)-1 -(Hydroxymethyl)-3-methylbutylamine was converted to (1R)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3 30 methylbutanammonium chloride according to Method Cla to give (4R)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 112 WO 00/42031 PCT/US99/29601 isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl-4 nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCI salt. Entry 92
NO
2 N 5 i-Bu Me HCI (1 S)- 1 -(Hydroxymethyl)-3-methylbutylamine was converted to (1R)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-5-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method Cla to give (4R)-2-(2-methyl 10 5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl-5 nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCL salt. Entry 93
NO
2
S
N 15 i-Bu Me HCI (1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (iS)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-5-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 20 5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-5 nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt. 25 Entry 94 N \/ NO 2 MMe e HCI (1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1R)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3 30 methylbutanammonium chloride according to Method CIa to give (4R)-2-(2-methyl 113 WO 00/42031 PCT/US99/29601 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4R)-2-(2-methyl-4 nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCl salt. 5 Entry 95 S =-P 0 N NO 2 N Me Me HCI (1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1S)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-3 10 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4S)-2-(2-methyl-4 nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCL salt. 15 Entry 96
NO
2
S
N Me Me HCI (1S)-i-(Hydroxymethyl)-3-methylbutylamine was converted to (1R)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-5-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3 20 methylbutanammonium chloride according to Method CIa to give (4R)-2-(2-methyl 5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4R)-2-(2-methyl-5 nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCl salt. 25 Entry 97 Me S > N -N0 N NO 2 ), N HCI (1S)-i-(Hydroxymethyl)-3-methylbutylamine was converted to (1S)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-3 30 methylbutanammonium chloride according to Method Cia to give (4S)-2-(2-methyl 114 WO 00/42031 PCT/US99/29601 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-bromo-2-ethylbutane according to Method D2a to afford (4S)-2-(2-methyl-4 nitrophenylimino)-4-isobutyl-3-(2-ethyl-1-butyl)-1,3-thiazolidine HCl salt. 5 Entry 98 Me >N NO2 N 0 (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (IS) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 10 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to afford (4S)-2-(2 methyl-4-nitrophenylimino)-4-isobutyl-3-(2-oxo-3,3-dimethyl-1-butyl)-1,3 15 thiazolidine. Entry 99 N CN i-Bu Et (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 20 ester as described in Method BIb. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Ethyl-4-cyanophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 25 isobutyl bromide according to Method D2f to afford (4S)-2-(2-ethyl-4 cyanophenylimino)-4-isobutyl-3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazolidine. Entry 100 115 WO 00/42031 PCT/US99/29601 S=N - N0 N NO 2 N Me (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 5 Methyl-4-nitrophenyl isothiocyanate was reacted with (IS)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method Cla to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4 nitrophenylimino)-4-isobutyl-3-(cyclopropylmethyl)-1,3-thiazolidine. 10 Entry 101 S =N - N0 >N NO 2 Me (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S) 15 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclobutylmethyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4 20 nitrophenylimino)-4-isobutyl-3-(cyclobutylmethyl)- 1,3-thiazolidine. Entry 102
S
N
NO
2 Me OH (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 25 ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 116 WO 00/42031 PCT/US99/29601 2-chloro-3,3-dimethyl-2-butanone according to Method D2a to give (4S)-2-(2 methyl-4-nitrophenylimino)-4-isobutyl-3-(2-oxo-3,3-dimethyl-1-butyl)-1,3 thiazolidine. The ketone was reduced according to Method D5a to afford (4S)-2-(2 methyl-4-nitrophenylimino)-4-isobutyl-3-(3,3-dimethyl-2-hydroxy-1-butyl)-1,3 5 thiazolidine. Entry 103 Me >S N - N0 >N /NO 2 N i-Bu Me HCI (1S)- 1 -(Hydroxymethyl)-3 -methylbutylamine was converted to (1S)-i 10 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2,6 Dimethyl-4-nitroaniline was converted into 2,6-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. 2,6-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method Cla to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3 15 thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(2,6-dimethyl-4-nitrophenylimino)-3,4-diisobutyl-1,3 thiazolidine HCl salt. 20 Entry 104 CI CI S >N N (IS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 25 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2,3-Dichlorophenyl isothiocyanate was reacted with (lS)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to give (4S)-2-(2,3-dichlorophenylimino) 30 4-isobutyl-3-(3-pentyl)-1,3-thiazolidine. Entry 105 117 WO 00/42031 PCT/US99/29601 Me
S
N /NO 2 (1S)-i-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 5 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give (4S)-2-(2-methyl-4 nitrophenylimino)-4-isobutyl-3-(5-heptyl)-1,3-thiazolidine. 10 Entry 106 Cl CI S >N N i-Bu (IS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 15 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2,3-Dichlorophenyl isothiocyanate was reacted with (iS)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(2,3 20 dichlorophenylimino)-3,4-diisobutyl- 1,3-thiazolidine. Entry 107 N NO 2 H F 3 C CF 3
CO
2 H (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 25 ester as described in Method Bib. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 (Trifluoromethyl)-4-nitrophenyl isothiocyanate was reacted with (1S)-i (chloromethyl)-3-methylbutanammonium chloride according to Method Clc to give
(
4
S)-
2 -(2-(trifluoromethyl)-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine 30 trifluoroacetate salt. 118 WO 00/42031 PCT/US99/29601 Entry 108 N /NO 2 i-Bu FsC
CF
3
CO
2 H (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 5 ester as described in Method BIb. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 (Trifluoromethyl)-4-nitrophenyl isothiocyanate was reacted with (1S)-1 (chloromethyl)-3-methylbutanammonium chloride according to Method Clc to give (4S)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The 10 thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt. 15 Entry 109 N CN i-Bu
F
3 C
CF
3
CO
2 H (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 20 ester as described in Method Bib. The 2-hydroxyethylamine was converted to (IS) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4 Cyano-2-(trifluoromethyl)phenyl isothiocyanate was reacted with (1S)-1 (chloromethyl)-3-methylbutanammonium chloride according to Method Clc to give (4S)-2-(4-cyano-2-(trifluoromethyl)phenylimino)-4-isobutyl-1,3-thiazolidine. The 25 thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(4-cyano-2-(trifluoromethyl)phenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt. Entry 110 Ci N /CN N-B M 30 i-Bu me CF 3
CO
2 H 119 WO 00/42031 PCT/US99/29601 (IS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method BIb. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Chloro-4-cyano-6-methylphenyl isothiocyanate was reacted with (lS)-i 5 (chloromethyl)-3-methylbutanammonium chloride according to Method Clc to give (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt. 10 Entry 111 N OMe i-Bu Me (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (IS) 15 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4 (Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (lS)-1 (chloromethyl)-3-methylbutanammonium chloride according to Method Cla to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 20 (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. Entry 112 Me
S
N NO 2 i-Bu Me (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 25 ester as described in Method Blb. The 2-hydroxyethylamine was converted to (IS) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 3,5-Dimethyl-4-nitroaniline was converted to 3,5-Dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 3,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-3-methylbutanammonium 30 chloride according to Method CIa to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino) 4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-3,4 diisobutyl- 1,3-thiazolidine. 120 WO 00/42031 PCT/US99/29601 Entry 113 S - 0 N
NH
2 i-Bu Me (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 5 ester as described in Method Bib. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4 (Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (lS)-1 (chloromethyl)-3-methylbutanammonium chloride according to Method Cla to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. 10 The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. The thiazolidine was saponified according to Method D6a, Step 1 to give (4S)-2-(4 carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. The acid was coupled with ammonia as described in Method D6a, Step 2 to afford (4S)-2-(4 15 carbamoyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. Entry 114 S >=-P N i-Bu Me (1S)-i-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 20 ester as described in Method BIb. The 2-hydroxyethylamine was converted to (IS) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4 Fluoro-2-methylphenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(4-fluoro 2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted 25 with isobutyl bromide according to Method D2a to give (4S)-2-(4-fluoro-2 methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. Entry 115 N CI i-Bu Me 30 (1S)-i-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method BIb. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4 121 WO 00/42031 PCT/US99/29601 Chloro-2-methylphenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-3 methylbutanammonium chloride according to Method Cia to give (4S)-2-(4-Chloro 2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-chloro-2 5 methylphenylimino)-3,4-diisobutyl- 1,3-thiazolidine. Entry 116
S
N- Br i-Bu Me (1S)-i-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 10 ester as described in Method BIb. The 2-hydroxyethylamine was converted to (lS) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4 Bromo-2-methylphenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-3 methylbutanammonium chloride according to Method Cla to give (4S)-2-(4-bromo 2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted 15 with isobutyl bromide according to Method D2a to give (4S)-2-(4-bromo-2 methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. Entry 117
S
N CN i-Bu Et 20 (IS)-i-(Hydroxymethyl)-3-methylbutylamine was reacted with SOCl 2 followed by 4 cyano-2-ethylphenyl isothiocyanate according to Method C2a to give (4S)-2-(4 cyano-2-ethylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2 ethylphenylimino)-3,4-diisobutyl- 1,3-thiazolidine. 25 Entry 118 N NO 2 i-Bu Me (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (2S) 30 4-methyl-2-(isobutylamino)pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(1S)-i-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride according to Method B7c. 2-Methyl-4-nitrophenyl 122 WO 00/42031 PCT/US99/29601 isothiocyanate was reacted with N-(lS)-i-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride to Method Clb to afford (4S)-2-(2-methyl-4 nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine. 5 Entry 119 N'N i-Bu Me (lS)-i-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method BIb. The 2-hydroxyethylamine was converted to (2S) 4-methyl-2-(isobutylamino)pentan-1-o1 as described in Method B4c. The resulting 10 2-hydroxyethylamine was converted to N-(lS)-i-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride according to Method B7c. 4-Amino-3-methylpyridine was converted to 3-methyl-4-pyridylisocyanate according to Method A2b. 3-Methyl 4-pyridyl isothiocyanate was reacted with N-(lS)-i-(chloromethyl)-3-methylbutyl) N-(isobutyl)ammonium chloride to Method Clb to afford (4S)-2-(2-methyl-4 15 nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine. Entry 120 S N~ /NO 2 i-Bu (IS)-i-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 20 ester as described in Method B1b. 4-Nitro-1-naphthylamine was converted to 4-nitro I-naphthyl isothiocyanate according to Method A2b. 4-Nitro-I-naphthyl isothiocyanate was reacted with (IS)-1-(hydroxymethyl)-3-methylbutylamine to Method C2a to give (4S)-2-(4-nitro-1-naphthylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 25 (4S)-2-(4-nitro-1 -naphthylimino)-3,4-diisobutyl-1,3-thiazolidine. Entry 121
S
N >N /
NO
2 i-Bu (lS)-i-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 30 ester as described in Method Bib. The 2-hydroxyethylamine was converted to (2S) 4-methyl-2-(isobutylamino)pentan-1-ol as described in Method B4c. The resulting 123 WO 00/42031 PCT/US99/29601 2-hydroxyethylamine was converted to N-(iS)-1-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride according to Method B7c. 4-Nitrophenyl isothiocyanate was reacted with N-(1S)-i-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride to Method CIf to afford (4S)-2-(4-nitrophenylimino) 5 3,4-diisobutyl-1,3-thiazolidine. Entry 122
S
N CN i-Bu (1S)-i-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl 10 ester as described in Method B1b. The 2-hydroxyethylamine was converted to (2S) 4-methyl-2-(isobutylamino)pentan-1-o as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(1S)-i-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride according to Method B7c. 4-Cyanophenyl isothiocyanate was reacted with N-(1S)-i-(chloromethyl)-3-methylbutyl)-N 15 (isobutyl)ammonium chloride to Method Clf to afford (4S)-2-(4-cyanophenylimino) 3,4-diisobutyl-1,3-thiazolidine. Entry 123 0 >N \ N i-Bu Me 20 (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (2S) 4-methyl-2-(isobutylamino)pentan-1-o1 as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(1S)-i-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride according to Method B7c. 4-Amino-3-methylpyridine 25 was converted to 3-methyl-4-pyridylisocyanate according to Method A2b. 3-Methyl 4-pyridyl isothiocyanate was reacted with N-(iS)-1-(chloromethyl)-3-methylbutyl) N-(isobutyl)ammonium chloride to Method Clb to afford (4S)-2-(2-methyl-4 nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine. The thiazolidine was oxidized according to Method D4a to afford ( 4 S)-2-(2-methyl-4-nitrophenylimino)-3,4 30 diisobutyl-1,3-thiazolidine 1-oxide. Entry 124 124 WO 00/42031 PCT/US99/29601 =N
NO
2 i-Bu Me HCI (1S,2S)-1-(Hydroxymethyl)-2-methylbutylamine was converted to (1S,2S)-1 (chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S,2S)-1-(chloromethyl)-2 5 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-((2S)-2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4 nitrophenylimino)- 4-((2S)-2-butyl)-3-isobutyl-1,3-thiazolidine HC salt. 10 Entry 125 N
NO
2 i-Bu Me HCI N-(tert-Butoxycarbamoyl)-(l S,2R)- 1 -(hydroxymethyl)-2-methylbutylamine was prepared from N-(tert-butoxycarbamoyl)-(L)-allo-isoleucine as described in Method Bla, Step 2. The carbamate was converted to (1S,2R)-1-(chloromethyl)-2 15 methylbutanammonium chloride as described in Method B7b. 2-Methyl-4 nitrophenyl isothiocyanate was reacted with (IS,2R)-1-(chloromethyl)-2 methylbutanammonium chloride to Method Cle to give (4S)-2-(2-methyl-4 nitrophenylimino)-4-((2R)-2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4 20 nitrophenylimino)-4-((2R)-2-butyl)-3-isobutyl-1,3-thiazolidine HCI salt. Entry 126 S> = - N0 N /NO 2 N i-Bu Me HCI N-(tert-Butoxycarbamoyl)-(1S)- 1 -cyclohexyl-2-hydroxyethylbutylamine was 25 prepared from N-(tert-Butoxycarbamoyl)-(L)- -cyclohexylglycine according to Method Bla, Step 2. The carbamate was reacted with SOC1 2 according to Method Bib, and the resulting material was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give (4S)-2-(2-methyl-4 nitrophenylimino)-4-cyclohexyl-1,3-thiazolidine. The thiazolidine was reacted with 30 isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4 nitrophenylimino)-4-cyclohexyl-3-isobutyl-1,3-thiazolidine HCl salt. 125 WO 00/42031 PCT/US99/29601 Entry 127 S- 0 )z=N / N OMe i-Bu Me HCI 5 (1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4 Methoxycarbonyl-2-methylphenyl isothiocyanate was reacted with (1S)-i (chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (4S)-2-(4 10 methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-3-isobutyl-1,3 thiazolidine. 15 Entry 128
S
=N
NO
2 N i-Bu Me (1 S)- 1 -Isopropyl-2-hydroxyethylamine was converted to (lS)-2-chloro-1 isopropylethylammonium chloride according to Method B7a. 2-Methyl-4 nitrophenyl isothiocyanate was reacted with (lS)-2-chloro-1 20 isopropylethylammonium chloride according to Method Cla to give (4S)-2-(2 methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl 4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine HCl salt. 25 Entry 129 S > N- a N 4i-Bu (1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (IS) 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 5 30 Aminoindan-1-one was converted to 1-oxo-5-indanyl isothiocyanate according to Method A2a. The isothiocyanate was reacted with (1S)-i-(chloromethyl)-2 126 WO 00/42031 PCT/US99/29601 methylbutanammonium chloride to Method Cla to give (4S)-2-(1-oxo-5 indanylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(1-oxo-5-indanylimino) 4-(2-butyl)-3-isobutyl-1,3-thiazolidine. 5 Entry 130 >=N CI N q i-Bu CF 3 (1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 10 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4 Chloro-3-(trifluoromethyl)aniline was converted to 4-chloro-3 (trifluoromethyl)phenyl isothiocyanate according to Method A2a, Step 3 4-Chloro-3 (trifluoromethyl)phenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-2 methylbutanammonium chloride according to Method Cia to give (4S)-2-(4-chloro 15 3-(trifluoromethyl)phenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-chloro-3 (trifluoromethyl)phenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine. Entry 131
S
>=N CN N 20 i-Bu CF 3 (1S)-i-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4 Cyano-3-(trifluoromethyl)aniline was converted to 4-cyano-3 25 (trifluoromethyl)phenyl isothiocyanate according to A2a, Step 3. The isothiocyanate was reacted with (lS)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method CIa to give (4S)-2-(4-cyano-3 -(trifluoromethyl)phenylimino)-4-(2-butyl) 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-cyano-3-(trifluoromethyl)phenylimino)-4-(2-butyl) 30 3-isobutyl-1,3-thiazolidine. Entry 132 127 WO 00/42031 PCT/US99/29601 S = N NO 2 N i-Bu (1S)-i-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (IS) 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4 5 Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. 4-Nitro-i-naphthyl isothiocyanate was reacted with (lS)-1 (chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (4S)-2-(4 nitro- 1 -naphthylimino)-4-(2-butyl)- 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-nitro-1 10 naphthylimino)-4-butyl-3-isobutyl-1,3-thiazolidine. Entry 133
S
>=N - /CN N i-Bu Et (1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl 15 ester as described in Method Bib. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4 Cyano-2-ethylphenyl isothiocyanate was reacted with (1S)-i-(chloromethyl)-2 methylbutanammonium chloride to Method Cla to give (4S)-2-(4-cyano-2 ethylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with 20 isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2 ethylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine. Entry 134
S
>=N CN N i-Bu Me 25 (lS)-i-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4 Cyano-2-methylaniline was synthesized as described in Method Ala. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate as described in Method 30 A2a, Step 3. 4-Cyano-2-methylphenyl isothiocyanate was reacted with (1S)-i (chloromethyl)-2-methylbutanammonium chloride to Method CIa to give (4S)-2-(4 128 WO 00/42031 PCT/US99/29601 cyano-2-methylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2 methylphenylimino)-4-butyl-3-isobutyl- 1,3-thiazolidine. 5 Entry 135 Me N CN i-Bu Me (1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 10 2,5-Dimethyl-4-nitrobenzonitrile was converted to 4-cyano-2,5-methylaniline according to Method Ala. The aniline was converted to 4-cyano-2,5-dimethylphenyl isothiocyanate as described in Method A2a, Step 3. 4-Cyano-2,5-dimethylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (4S)-2-(4-cyano-2,5-dimethylphenylimino)-4-(2 15 butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2,5-dimethylphenylimino)-4 butyl-3-isobutyl-1,3-thiazolidine. Entry 136 Me
S
N NO 2 20 i-Bu Me (1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method BIb. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2,5-methylaniline was converted to 2,5-dimethyl-4-nitrophenyl isothiocyanate 25 according to Method A2a. 2,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (1S)-l-(chloromethyl)-2-methylbutanammonium chloride to Method Cla to give ( 4
S)-
2
-(
2 ,5-dimethyl-4-nitrophenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give
(
4
S)-
2 -(2,5-dimethyl-4-nitrophenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine. 30 Entry 137 129 WO 00/42031 PCT/US99/29601 ==N
NO
2 i-Bu Me (1R)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl 2 followed by 2 Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2 methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was 5 reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl 4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine. Entry 138
S
N /NO 2 8N Me 10 (1S)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl 2 followed by 2 methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2 methyl-4-nitrophenylimino)-4-isopropyl- 1,3-thiazolidine. The thiazolidine was reacted with cyclopentyl bromide according to Method D2a to afford (4S)-2-(2 methyl-4-nitrophenylimino)-4-isopropyl-3-cyclopentyl-1,3-thiazolidine. 15 Entry 139
S
>N / NO 2 N i-Bu Me HCI (IS)- 1 -Benzyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1 benzylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl 20 isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride according to Method Cla to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-benzyl 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-benzyl-3-isobutyl 1,3-thiazolidine HCl salt. 25 Entry 140 130 WO 00/42031 PCTIUS99/29601 S =N - N0 N NO 2 i-Bu Me HCI (1S)- 1 -Phenyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1 phenylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride 5 according to Method Cla to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-3-isobutyl 1,3-thiazolidine HCl salt. 10 Entry 141
S
N
NO
2 N= Me 2-Piperidenemethanol was made from methyl pipecolinate as described in Method Blb. The 2-hydroxyethylamine was converted to 2-chloromethylpiperidinium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was 15 reacted with 2-chloromethylpiperidinium chloride according according to Method CIa to give 9-(2-methyl-4-nitrophenylimino)- 1 -aza-8-thiabicyclo [4.3.0]nonane. Entry 142
S
N /NO 2 Me 20 2-Pyrrolidinemethanol was made from proline methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to 2-chloromethylpyrrolidinium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloromethylpyrrolidinium chloride according according to Method Cla to give 3-(2-methyl-4-nitrophenylimino)-2,5,6,7,7a-pentahydro-2 25 thiapyrrolizine. Entry 143 131 WO 00/42031 PCTIUS99/29601
S
>=N - /CN N i-Bu Et HCI OH (1S)-1-(4-Hydroxyphenylmethyl)-2-hydroxyethylamine was made from (L)-tyrosine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4--(4-hydroxyphenylmethyl)-1,3-oxazolidine according to 5 Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1-(4 hydroxyphenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl 2 according to Method B7c to give N-((lS)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with 10 N-((1S)- 1 -(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method Clb to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(4 hydroxyphenylmethyl)-3-isobutyl-1,3-thiazolidine HCl salt. Entry 144
S
=N /CN N i-Bu Et HCI 15 CI (1S)-1-(4-Chlorophenylmethyl)-2-hydroxyethylamine was made from (L)-4 chlorophenylalanine methyl ester as described in Method Bib. The 2 hydroxyethylamine was converted to (4S)-2-isopropyl-4--(4-chlorophenylmethyl) 1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to 20 N-((1S)-i-( 4 -chlorophenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl 2 according to Method B7c to give N-((IS)-1-(4-chlorophenylmethyl)-2-chloroethyl) N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-i -( 4 -chlorophenylmethyl)-2-chloroethyl)-N-isobutylammonium 25 chloride according to Method Cib to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4 (4-chlorophenylmethyl)-3-isobutyl-1,3-thiazolidine HCI salt. Entry 145 132 WO 00/42031 PCT/US99/29601
S
N CN N i-Bu Et HCI (1S)- 1 -(Benzylthiomethyl)-2-hydroxyethylamine was made from (L)-S benzylcysteine methyl ester as described in Method BIb. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4--(benzylthiomethyl)-1,3-oxazolidine according 5 to Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1 (benzylthiomethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl 2 according to Method B7c to give N-((1S)-i-(benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-1 10 (benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method Clb to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(benzylthiomethyl)-3 isobutyl-1,3-thiazolidine HCl salt. Entry 146 ,fC>=M- NO 2 MeO N 15 O i-Bu Me HCI (R)-N-isobutylserine methyl ester HCl salt was made from (D)-serine methyl ester as described in Method B3a. The ester was reacted with SOCl 2 , followed by 2-methyl 4-nitrophenyl isothiocyanate according to Method C2a to afford (4S)-2-(2-methyl-4 nitrophenylimino)-4-(methoxycarbonyl)-3-isobutyl-1,3-thiazolidine HCl salt. 20 Entry 147
S
MeO -LINN N
NO
2 25 O i-Bu Me HCI (S)-N-isobutylserine methyl ester HCl salt was made from (L)-serine methyl ester as described in Method B3a. The ester was reacted with SOCl 2 , followed by 2-methyl 133 WO 00/42031 PCTIUS99/29601 4-nitrophenyl isothiocyanate according to Method C2a to afford (4R)-2-(2-methyl-4 nitrophenylimino)-4-(methoxycarbonyl)-3-isobutyl-1,3-thiazolidine HCl salt. Entry 148 Me N
NO
2 - i-Bu Me 5 (1R,2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,2R)-1 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted 10 with 2-methyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((1R)-1-tert butoxyethyl)-3-isobutyl-1,3-thiazolidine. Entry 149 Me 'IIN N
NO
2 15Me (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,2R)-1 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted 20 with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((1R)-1 tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. Entry 150 S =N - N0 Me N NO 2 25 >Me (1 R,2S)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,2S)-l 134 WO 00/42031 PCT/US99/29601 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((1S)-1 tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. 5 Entry 151 Me N i-Bu Me (1 R,2S)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(IS,2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine 10 dicyclohexylamine salt as described in Method B8a. (1R,2S)-1 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((1S)-1-tert butoxyethyl)-3-isobutyl-1,3-thiazolidine. 15 Entry 152
S
Me N MP/CN >rO Me (1R,2S)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S, 2 S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine 20 dicyclohexylamine salt as described in Method B8a. (1R,2S)-1 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-cyano-2-methylphenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-cyano-2-methylphenylimino)-4-((1S) 1-tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. 25 Entry 153
S
Me N O i-Bu 135 WO 00/42031 PCTIUS99/29601 (lR,2S)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(lS, 2 S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Nitro-l-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (1R,2S)-1 5 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((IS)-1-tert-butoxyethyl) 3-isobutyl-1,3-thiazolidine. 10 Entry 154 S Me N N NO 2 (1 R,2S)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S, 2 S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Nitro-1-naphthylamine was 15 converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (1R,2S)-1 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((1S)-1-tert-butoxyethyl) 3-cyclopentyl-1,3-thiazolidine. 20 Entry 155 Me N NO 2 25 (1R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propananmonium chloride was made from (L)-(1S, 2 R)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-Amino-5,6,7,8 tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (lR,2R)-1-Methanesulfonyloxymethyl)-2 30 (tert-butoxy)propanammonium chloride was reacted with 4-nitro-5,6,7,8 tetrahydronaphth-1-yl isothiocyanate followed by cyclopentyl bromide according to 136 WO 00/42031 PCT/US99/29601 Method C5b to afford (4R)-2-(4-nitro-5,6,7,8-tetrahydronaphth- 1 -ylimino)-4-((1 R)- 1 tert-butoxyethyl)-3-cyclopentyl- 1,3-thiazolidine. Entry 156 Me N /N
NO
2 5 i-Bu 5 (1R,2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-Amino-5,6,7,8 tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl 10 isothiocyanate according to Method A2a. (1R,2R)-1-Methanesulfonyloxymethyl)-2 (tert-butoxy)propanammonium chloride was reacted with 4-nitro-5,6,7,8 tetrahydronaphth-1-yl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(4-nitro-5,6,7,8-tetrahydronaphth- 1 -ylimino)-4-((1 R)- 1 tert-butoxyethyl)-3 -isobutyl- 1,3 -thiazolidine. 15 Entry 157 Me I N
NO
2 - i-Bu i-Pr (1R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine 20 dicyclohexylamine salt as described in Method B8a. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a. (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2-isopropyl-4 25 nitrophenylimino)-4-((1 R)- 1 -tert-butoxyethyl)-3-isobutyl- 1,3 -thiazolidine. Entry 158
S
Me N
NO
2 A6 i-Pr 137 WO 00/42031 PCT/US99/29601 (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a. 5 (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-isopropyl-4 nitrophenylimino)-4-((1 R)- 1 -tert-butoxyethyl)-3 -cyclopentyl- 1,3-thiazolidine. 10 Entry 159
S
Me NNO ><8 Me Me (1 R,2R)- 1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline 15 was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (lR,2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2,3-dimethyl-4 nitrophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. 20 Entry 160 Me J1>=N \
NO
2 i-Bu Me Me (1R,2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine 25 dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1R,2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2,3-dimethyl-4 30 nitrophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine. 138 WO 00/42031 PCT/US99/29601 Entry 161
S
Me N / NO 2 6 OMe Me (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine 5 dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by 2 ethyl-l-butyl bromide according to Method C5b to afford (4R)-2-(2,3-dimethyl-4 10 nitrophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-(2-ethyl-1-butyl)-1,3-thiazolidine. 15 Entry 162 S Me N N CN (1R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-amino-4-cyano-5,6,7,8 20 tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (1R,2R)-1-Methanesulfonyloxymethyl)-2 (tert-butoxy)propanammonium chloride was reacted with 4-cyano-5,6,7,8 tetrahydronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((1R)-1 25 tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. Entry 163 139 WO 00/42031 PCT/US99/29601 Me N N CN i-Bu (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-amino-4-cyano-5,6,7,8 5 tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (1R,2R)-1-Methanesulfonyloxymethyl)-2 (tert-butoxy)propanammonium chloride was reacted with 4-cyano-5,6,7,8 tetrahydronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((1R)-1 10 tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine. Entry 164 Me N NO2 OH i-Bu Me (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride 15 was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,2R)-1 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-((1R)-1-tert-butoxy) 20 3-isobutyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((1R)-1 hydroxyethyl)-3-isobutyl-1,3-thiazolidine. Entry 165
S
Me N NNO 2 25 OH (1 R,2S)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S, 2 S)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (1R,2S)-1 140 WO 00/42031 PCT/US99/29601 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((1S)-1-tert-butoxyethyl) 3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to 5 Method D3a to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((1S)-1-hydroxyethyl)-3 cyclopentyl-1,3-thiazolidine. Entry 166
S
Me N > /PNO 2 OH i-Bu Me 10 (1R,2S)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2S)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,2S)-1 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide 15 according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((1S)-1 tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2-methyl-4 nitrophenylimino)-4-((1S)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine. 20 Entry 167 Me N NO 2 H Me (1R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,2R)-1 25 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((1R)-1 tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2-methyl-4 30 nitrophenylimino)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine. Entry 168 141 WO 00/42031 PCT/US99/29601
S
Me N >=N
NO
2 H Me (1 R,2S)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,2S)-1 5 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-methyl-4-nitrophenylimino)-4-((IS)-1 tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2-methyl-4 10 nitrophenylimino)-4-((1S)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine. Entry 169 S -== Me N / NO 2 H t-Bu (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride 15 was made from (L)-(IS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-tert-Butyl-4-cyanoaniline was converted to 2-tert-butyl-4-cyanophenyl isothiocyanate according to Method A2b. (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-tert-butyl-4-cyanophenyl isothiocyanate followed by cyclopentyl 20 bromide according to Method C5b to afford (4R)-2-(2-tert-butyl-4 cyanophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2-tert butyl-4-cyanophenylimino)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine. 25 Entry 170 Me N CN - I H i-Bu t-Bu (1R,2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-tert-Butyl-4-cyanoaniline was 142 WO 00/42031 PCT/US99/29601 converted to 2-tert-butyl-4-cyanophenyl isothiocyanate according to Method bA2a. (1R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-tert-butyl-4-cyanophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2-tert-butyl-4 5 cyanophenylimino)-4-((1R)-1-tert-butoxyethyl)-3- isobutyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2-tert butyl-4-cyanophenylimino)-4-((1R)-1-hydroxyethyl)-3- isobutyl-1,3-thiazolidine. Entry 171 S Me N N
NO
2 -I 10 OH \ (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Nitro-l-naphthylamine was converted to 4-nitro-l-naphthyl isothiocyanate according to Method A2b. (1R,2R)-1 15 Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((1R)-1-tert-butoxyethyl) 3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(4-nitro-1-naphthylimino)-4-((1R)-1-hydroxyethyl)-3 20 cyclopentyl-1,3-thiazolidine. Entry 172 S Me ,J00N N
NO
2 OH (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propananmionium chloride 25 was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-Amino-5,6,7,8 tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (1R,2R)-1-Methanesulfonyloxymethyl)-2 (tert-butoxy)propanammonium chloride was reacted with 4-nitro-5,6,7,8 30 tetrahydronaphth-1-yl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-nitro-5,6,7,8-tetrahydronaphth- 1 -ylimino)-4-((1 R)- 1 tert-butoxyethyl)-3 -cyclopentyl- 1,3 -thiazolidine. The tert-butyl ether was 143 WO 00/42031 PCT/US99/29601 deprotected according to Method D3a to afford (4R)-2-(4-nitro-5,6,7,8 tetrahydronaphth-1-ylimino)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine. Entry 173 S Me N > / NO 2 5 OH i-Bu (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-Amino-5,6,7,8 tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl 10 isothiocyanate according to Method A2a. (1R,2R)-1-Methanesulfonyloxymethyl)-2 (tert-butoxy)propanammonium chloride was reacted with 4-nitro-5,6,7,8 tetrahydronaphth-1-yl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(4-nitro-5,6,7,8-tetrahydronaphth- 1 -ylimino)-4-((1R)- 1 tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine. The tert-butyl ether was deprotected 15 according to Method D3a to afford (4R)-2-(4-nitro-5,6,7,8-tetrahydronaphth-1 ylimino)-4-((1R)-1-hydroxyethyl)-3-isobutyl-1,3-thiazolidine. Entry 174
S
Me N Pr /-NO 2 OH i-Bu i-Pr 20 (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S, 2 R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a. (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride 25 was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2-isopropyl-4 nitrophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine. The tert butyl ether was deprotected according to Method D3a to afford (4R)-2-(2-isopropyl 4-nitrophenylimino)-4-((1R)-1-hydroxyethyl)-3-isobutyl-1,3-thiazolidine. 30 Entry 175 144 WO 00/42031 PCT/US99/29601 Me N
NO
2 OH (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2-Isopropylaniline was 5 converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a. (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2-isopropyl-4 nitrophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The 10 tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2 isopropyl-4-nitrophenylimino)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3 thiazolidine. Entry 176
S
Me N NO2 OH Me Me 15 (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S, 2 R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method 20 A2b. (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by 2 ethyl-1-butyl bromide according to Method C5b to afford (4R)-2-(2,3-dimethyl-4 nitrophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-(2-ethyl-1-butyl)-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2,3 25 dimethyl-4-nitrophenylimino)-4-((1R)-1-hydroxyethyl)-3-(2-ethyl-1-butyl)-1,3 thiazolidine. Entry 177
S
Me N NO2 OH i-Bu Me Me 145 WO 00/42031 PCT/US99/29601 (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method 5 A2b. (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(2,3-dimethyl-4 nitrophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine. The tert butyl ether was deprotected according to Method D3a to afford (4R)-2-(2,3-dimethyl 10 4-nitrophenylimino)-4-((1R)-1-hydroxyethyl)-3-isobutyl-1,3-thiazolidine. 15 Entry 178
S
Me N >N / NO 2 OH § Me Me (1R,2R)-1-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 2,3-Dimethyl-4-nitroaniline 20 was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(2,3-dimethyl-4 nitrophenylimino)-4-((1R)-1-tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The 25 tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2,3 dimethyl-4-nitrophenylimino)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3 thiazolidine. Entry 179
S
Me 1N >N CN 30 (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S, 2 R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine 146 WO 00/42031 PCT/US99/29601 dicyclohexylamine salt as described in Method B8a. 1-amino-4-cyano-5,6,7,8 tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (1R,2R)-1-Methanesulfonyloxymethyl)-2 (tert-butoxy)propanammonium chloride was reacted with 4-cyano-5,6,7,8 5 tetrahydronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R)-2-(4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((1R)-1 tert-butoxyethyl)-3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(4-cyano-5,6,7,8 tetrahydronaphthylimino)-4-((1R)-1-hydroxyethyl)-3-cyclopentyl-1,3-thiazolidine. 10 Entry 180 S - Me N NCCN Me N OH i-Bu 15 (1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (L)-(1S,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 1-amino-4-cyano-5,6,7,8 tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (1R,2R)-1-Methanesulfonyloxymethyl)-2 20 (tert-butoxy)propanammonium chloride was reacted with 4-cyano-5,6,7,8 tetrahydronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R)-2-(4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((1R)-1 tert-butoxyethyl)-3-isobutyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(4-cyano-5,6,7,8 25 tetrahydronaphthylimino)-4-((1R)-1-hydroxyethyl)-3-isobutyl-1,3-thiazolidine. Entry 181 NNNO i-Bu Me 2-Amino-1,3-propanediol was reacted with excess SOC 2 followed by 2-methyl-4 30 nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4 nitrophenylimino)-4-(chloromethyl)-1,3-thiazolidine. The thiazolidine was reacted with N-methylamine according to Method D13a to give 2-(2-methyl-4 nitrophenylimino)-4-(N-methylaminomethyl)-1,3-thiazolidine, which was reacted 147 WO 00/42031 PCT/US99/29601 with isobutyl bromide according to Method D2a to afford 2-(2-methyl-4 nitrophenylimino)-3-isobutyl-4-(N-isobutyl-N-methylaminomethyl)-1,3-thiazolidine. Entry 182
S
N NO 2 5 i-Bu Me 2-Amino-1,3-propanediol was reacted with excess SOCl 2 followed by 2-methyl-4 nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4 nitrophenylimino)-4-(chloromethyl)-1,3-thiazolidine. The thiazolidine was reacted with dimethylamine according to Method D13a to give 2-(2-methyl-4 10 nitrophenylimino)-4-(N-isobutyl-N-methylaminomethyl)-1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to afford 2-(2-methyl-4 nitrophenylimino)-3-isobutyl-4-(N,N-dimethylaminomethyl)- 1,3-thiazolidine. Entry 183 N N N NO 2 N N 15 i-Bu Me (L)-Histidinol was reacted with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2-methyl-4 nitrophenylimino)-4-(1 -(isobutylimidazoly)methyl)- 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 20 (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(1-(isobutylimidazolyl)methyl) 1,3-thiazolidine. Entry 184 N N N-
NO
2 N N i-Bu Me 25 (L)-Histidinol was reacted with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2-methyl-4 nitrophenylimino)-4-(1 -(isobutylimidazoly)methyl)- 1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(3-(isobutylimidazolyl)methyl) 30 1,3-thiazolidine. 148 WO 00/42031 PCT/US99/29601 Entry 185 N / NO 2 Me HBr 2-Hydroxypropylamine was converted to 2-chloropropylammonium chloride 5 according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloropropylammonium chloride according to Method CIa to give 2-(2-methyl-4 nitrophenylimino)-5-methyl-1,3-thiazolidine. The thiazolidine was reacted with 2 methylprop-2-en-1-yl bromide according to Method D2g to afford 2-(2-methyl-4 nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-5-methyl-1,3-thiazolidine HBr salt. 10 Entry 186 S .sN \/
CF
3 N i-Bu CI HCI 2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine 15 was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2 hydroxyethylamine. The ethanolamine was reacted with SOCl 2 followed by 2 chloro-4-(trifluoromethyl)phenyl isothiocyanate according to Method C2f to afford 2-(2-chloro-4-(trifluoromethyl)phenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidine HCl salt. 20 Entry 187 N i-Bu CI CI 2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2 -isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine 25 was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2 hydroxyethylamine. The ethanolamine was reacted with SOC1 2 followed by 2,3 dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3 dichlorophenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidine. 149 WO 00/42031 PCT/US99/29601 Entry 188 S N N i-Bu C CI HCI 3-Phenyl-2-hydroxypropylamine was reacted with isobutyraldehyde according to 5 Method B4c, Step 1 to give 2 -isopropyl-5-benzyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-3-phenyl-2 hydroxypropylamine. The propanolamine was reacted with SOC1 2 followed by 2,3 dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3 dichlorophenylimino)-3-isobutyl-5-benzyl-1,3-thiazolidine HCl salt. 10 Entry 189 CI
S
N CI 2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. 15 The oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl 2-methyl-2-hydroxypropylamine. The propanolamine was reacted with SOCl 2 followed by 2,6-dichlorophenyl isothiocyanate according to Method C2f to afford 2 (2,6-dichlorophenylimino)-3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine. 20 Entry 190 S >N-p N ,"'Me C1 CI HCI (1R)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((lR)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2 hydroxyethyl)amine. N-((lR)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2 25 hydroxyethyl)amine was reacted with SOCl 2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3 ((lR)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt. 150 WO 00/42031 PCT/US99/29601 Entry 191 N CI Me HCI (1S)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2 hydroxyethyl)amine. N-((lS)-i-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2 hydroxyethyl)amine was reacted with SOCl 2 followed by 2,4-dichlorophenyl 10 isothiocyanate according to Method C2f to afford 2-(2,4-dichlorophenylimino)-3 ((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCI salt. Entry 192 S -=N R N CI CI Me HCI 15 (1S)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2 hydroxyethyl)amine. N-((1S)- 1 -Cyclohexyl- 1 -ethyl)-N-(2,2-dimethyl-2 hydroxyethyl)amine was reacted with SOCl 2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3 20 ((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt. Entry 193
S
N HO CI CI HCI 2-Methyl-2-hydroxypropylamine was reacted with SOCl 2 followed by 2,3 25 dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3 dichlorophenylimino)-5,5-dimethyl-1,3-thiazolidine. 2-(2,3-Dichlorophenylimino) 151 WO 00/42031 PCT/US99/29601 5,5-dimethyl-1,3-thiazolidine was reacted with ethylene oxide according to Method B5b to afford 2-(2,3-dichlorophenylimino)-5,5-dimethyl-1,3-thiazolidine HCl salt. Entry 194 - S>N - N0 N /NO 2 N 5 H Me 2-Methyl-2-hydroxypropylamine was reacted with SOCl 2 followed by 2-methyl-4 nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl-4 nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine. 10 Entry 195 N NO 2 Me HBr 2-Methyl-2-hydroxypropylamine was reacted with SOCl 2 followed by 2-methyl-4 nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl-4 nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with 15 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2-(2-methyl-4 nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-5,5-dimethyl-1,3-thiazolidine HBr salt. Entry 196
S
N / NO 2 20 i-Bu Me 2-Methyl-2-hydroxypropylamine was reacted with SOCl 2 followed by 2-methyl-4 nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl-4 nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2-(2-methyl-4 25 nitrophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine. Entry 197 152 WO 00/42031 PCT/US99/29601 S -=:R N i-Bu CI CI HCI 2-Methyl-2-hydroxypropylamine was reacted with SOCl 2 followed by 2,3 dichlorophenyl isothiocyanate according to Method Cla to afford 2-(2,3 dichlorophenylimino)-5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted 5 with isobutyl bromide according to Method D2g to afford 2-(2,3 dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine. Entry 198 = N
NO
2 Me 10 2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl 2-methyl-2-hydroxypropylamine. The propanolamine was reacted with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to 15 afford 2-(2-methyl-4-nitrophenylimino)-3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine. Entry 199
S
N CI CI 2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde 20 according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl 2-methyl-2-hydroxypropylamine. The propanolamine was reacted with SOCl 2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2 (2,3-dichlorophenylimino)-3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine. 25 Entry 200 153 WO 00/42031 PCT/US99/29601
S
N N NO 2 'Me MeH HCI (1R)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2 hydroxyethyl)amine. N-((1R)- 1 -Cyclohexyl- 1 -ethyl)-N-(2,2-dimethyl-2 5 hydroxyethyl)amine was reacted with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino) 3-((lR)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt. Entry 201
S
N / NO 2 Me 10 M HCI (1S)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((lS)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2 hydroxyethyl)amine. N-((1S)- 1 -Cyclohexyl- 1 -ethyl)-N-(2,2-dimethyl-2 hydroxyethyl)amine was reacted with SOCl 2 followed by 2-methyl-4-nitrophenyl 15 isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino) 3-((1S)-i-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt. Entry 202
S
N /PNO 2 i-Pr Me 20 Isopropylamine was reacted with 1, 2 -epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isopropyl-N (2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl 2 followed by 2-methyl 4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4 nitrophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidine. 25 Entry 203 154 WO 00/42031 PCT/US99/29601 S -=NR N i-Pr CI CI Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isopropyl-N (2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl 2 followed by 2,3 5 dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3 dichlorophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidine. Entry 204 N CI i-Bu CI HCI 10 Isobutylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isobutyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isobutyl-N-(2,2 dimethyl-2-hydroxyethyl)amine was reacted with SOCl 2 followed by 2,4 dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,4 dichlorophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine HCl salt. 15 Entry 205 N /NO 2 N Me HBr 1,1 -Dimethyl-2-hydroxyamine was converted to 1,1 -dimethyl-2 chloroethylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl 20 isothiocyanate was reacted with 1,1-dimethyl-2-chloroethylammonium chloride according to Method Cla to give 2
-(
2 -methyl-4-nitrophenylimino)-4,4-dimethyl-1,3 thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2
-(
2 -methyl-4-nitrophenylimino)-4,4-dimethyl-3 (2-methylprop-2-en-1-yl)-1,3-thiazolidine HBr salt. 25 Entry 206
S
N /NO 2 N i-Bu Me 155 WO 00/42031 PCT/US99/29601 Methyl aminoisobutyric acid was converted to methyl aminoisobutyrate HCl salt according to method Blc, Step 1. The ester was reduced to 3-hydroxy-2-methyl-2 propylamine according to Method Blc, Step 2. The 2-hydroxyethylamine was treated with SOCl 2 according to Method B7b, followed by 2-methyl-3-nitrophenyl 5 isothiocyanate according to Method Cla to give 2-(2-methyl-4-nitrophenylimino) 4,4-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-3 isobutyl-1,3-thiazolidine. 10 Entry 207
S
N / NO 2 Me 1-Amino-i -(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. 1-(Cyclohexylamino)-1-hydroxymethylcyclopentane was synthesized as 15 described in Method B4a. The 2-hydroxyethylamine was treated with SOCl 2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to afford 3-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-1-thia-3-azaspiro[4.4]nonane. Entry 208 C N
NO
2 6Et 20 2-Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl 25 isothiocyanate according to Method A2a, Step 3. 1-Amino-I (hydroxymethyl)cyclopentane was synthesized as described in Method BIc. The 2 hydroxyethylamine was reacted with with SOC 2 according to Method B7a to give 1 amino-i -(chloromethyl)cyclopentane HCI salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2 30 ethyl-4-nitrophenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was 156 WO 00/42031 PCT/US99/29601 reacted with cyclopentyl bromide according to Method D2b to afford 3-cyclopentyl 2-(2-ethyl-4-nitrophenylimino)-1-thia-3-azaspiro[4.4]nonane. Entry 209 S N =N CN n-Pr 5 2-n-Propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. The aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method BIc. The 2-hydroxyethylamine was reacted with 10 SOCl 2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-n-propylphenyl isothiocyanate according to Method Cla to give 2-(4-iodo-2-n-propylphenylimino) 1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-n 15 propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-n propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. 20 Entry 210 S -= N / CN 6 i-Pr 25 2-Isopropylaniline was converted to 4 -iodo-2-isopropylaniline according to Method A5a. The aniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B 1 c. The 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl 30 salt. The 2-chloroethylamine was reacted with 4-iodo-2-isopropylphenyl 157 WO 00/42031 PCT/US99/29601 isothiocyanate according to Method CIa to give 2-(4-iodo-2-isopropylphenylimino) 1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2 isopropylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted 5 with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2 isopropylphenylimino)-1-thia-3-azaspiro[4.4]nonane. Entry 211 = N CN ( t-Bu 10 2-tert-Butylaniline was converted to 4-iodo-2-tert-butylaniline according to Method A5a. The aniline was converted to 4-iodo-2-tert-butylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOC1 2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl 15 salt. The 2-chloroethylamine was reacted with 4-iodo-2-tert-butylphenyl isothiocyanate according to Method CIa to give 2-(4-iodo-2-tert-butylphenylimino) 1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-tert butylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted 20 with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-tert butylphenylimino)-1-thia-3-azaspiro[4.4]nonane. Entry 212 Yf N>N -NO 2 Me 25 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The amino alcohol was reacted with 2-methylcyclopentanone according to Method B4a, Step 1 to give 13-aza-1-methyl-6-oxodispiro[4.2.4.1]tridecane, which was reduced with NaBH 4 according to Method B4a, Step 2 to afford 1-(2 methylcyclopentyl)amino- 1 -(hydroxymethyl)cyclopentane. The 2 30 hydroxyethylamine was reacted with SOCl 2 followed by 2-methyl-4-nitrophenyl 158 WO 00/42031 PCT/US99/29601 isothiocyanate according to Method C2a to afford 3-(2-methylcyclopentyl)-2-(2 methyl-4-nitrophenylimino)-1-thia-3-azaspiro[4.4]nonane. Entry 213 S N / NO 2 CN 5 i-Bu Me 1-Amino-1 -(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOC1 2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCI salt. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 10 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. Entry 214 S N /NO 2 15 i-Bu Et 2-Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl 20 isothiocyanate according to Method A2a, Step 3. 1-Amino-1 (hydroxymethyl)cyclopentane was synthesized as described in Method B 1 c. The 2 hydroxyethylamine was reacted with SOCl 2 according to Method B7a to give 1 amino-i -(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2 25 ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2 ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. Entry 215 S N / NO 2 30 i-Bu n-Pr 2-n-Propylaniline was converted to 2-n-propylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2 -n-propyl-4-nitroacetanilide according to 159 WO 00/42031 PCT/US99/29601 Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-n-propyl-4-nitroaniline. The aniline was converted to 2-n-propyl-4 nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1 (hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2 5 hydroxyethylamine was reacted with SOCl 2 according to Method B7a to give 1 amino-1-(chloromethyl)cyclopentane HCI salt. The 2-chloroethylamine was reacted with 2-n-propyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2 n-propyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-n 10 propyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. Entry 216 S N /NO 2 C N i-Bu i-Pr 2-Isoropylaniline was converted to 2-isopropylacetanilide according to Method A2a, 15 Step 1. The acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-isopropyl-4-nitroaniline. The aniline was converted to 2-isopropyl 4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1 (hydroxymethyl)cyclopentane was synthesized as described in Method B 1 c. The 2 20 hydroxyethylamine was reacted with SOC 2 according to Method B7a to give 1 amino-1-(chloromethyl)cyclopentane HCI salt. The 2-chloroethylamine was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2 isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2 25 isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. Entry 217
S
N /NO 2 N i-Bu Me Me 2,3-Dimethyl-4-nitroaniline was synthesized as described in Method A4a. The 30 aniline was converted into 2,3-dimethyl-4-nitrophenyl isothiocyanate as described in method A2d. 1-Amino-1 -(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7e to give 1-amino-1-(chloromethyl)cyclopentane HCI salt. The 2 chloroethylamine was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate 160 WO 00/42031 PCT/US99/29601 according to Method Cle to give 2-(2,3-dimethyl-4-nitrophenylimino)-3-thia-1 azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-1 azaspiro[4.4]nonane. 5 Entry 218 -S >=N
NO
2 i-Bu Me 3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-i -(hydroxymethyl)cyclopentane was 10 synthesized as described in Method BIc. The 2-hydroxyethylamine was reacted with SOC1 2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(3-methyl-4-nitrophenylimino)-3 thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide 15 according to Method D2a to afford 1-isobutyl-2-(3-methyl-4-nitrophenylimino)-3 thia- 1 -azaspiro[4.4]nonane. Entry 219 S - N / NO 2 N i-Bu 20 1-Amino-5,6,7,8-tetrahydronaphthaline was converted to 1-acetamino-5,6,7,8 tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide was converted to 1-acetamino-4-nitro-5,6,7,8-tetrahydronaphthaline according according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline was 25 converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1 -(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOC1 2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCI salt. The 2-chloroethylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthyl 30 isothiocyanate according to Method Cla to give 2-(4-nitro-5,6,7,8-tetrahydro-l naphthylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-nitro-5,6,7,8 tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane. 161 WO 00/42031 PCT/US99/29601 Entry 220 = N CN N i-Bu 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method 5 B1c. The 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7e to give 1-amino-1-(chloromethyl)cyclopentane HCI salt. The 2-chloroethylamine was reacted with 4-cyanophenyl isothiocyanate according to Method Cla to give 2-(4 cyanophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4 10 cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane. 15 Entry 221
-S
N / CN N i-Bu Me 4-Cyano-2-methylaniline was synthesized as described in Method Ala. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-i -(hydroxymethyl)cyclopentane was synthesized as described in 20 Method Blc. The 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7a to give 1-amino-l-(chloromethyl)cyclopentane HCl salt. The 2 chloroethylamine was reacted with 4-cyano-2-methylphenyl isothiocyanate according to Method Cla to give 2-(4-cyano-2-methylphenylimino)-1-thia-3 azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according 25 to Method D2b to give 3-isobutyl-2-(4-iodo-2-methylphenylimino)-l-thia-3 azaspiro[4.4]nonane. Entry 222 S N /CN N i-Bu Et 30 1-Amino-i -(hydroxymethyl)cyclopentane was synthesized as described in Method BIc. The 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7a to give 1-amino-i -(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was 162 WO 00/42031 PCT/US99/29601 reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cla to give 2-(4-cyano-2-methylphenylimino)- 1 -thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4 cyano-2-methylphenylimino)-1-thia-3-azaspiro[4.4]nonane. 5 Entry 223 S >z=N CN i-Bu 1-Amino-i -(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7a to 10 give 1-amino-i -(chloromethyl)cyclopentane HCl salt. 1-Amino-4-cyanonaphthalene was converted into 4-cyano-1-naphthyl isothiocyanate according to Method A2a, Step 3. The 2-chloroethylamine was reacted with 4-cyano-1-naphthyl isothiocyanate to Method Cla to give 2-(4-cyano-1-naphthylimino)-1-thia-3 azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according 15 to Method D2b to give 3-isobutyl-2-(4-cyano-1-naphthylimino)-1-thia-3 azaspiro[4.4]nonane. Entry 224
-S
S>N -CN N i-Bu Me Me 20 2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-I (hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2 hydroxyethylamine was reacted with SOCl 2 according to Method B7e to give 1 25 amino-1 -(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method Cle to give 2 (2,3-dimethyl-4-iodophenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2-(4 iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was 30 reacted with CuCN according to Method D7a to afford 3-isobutyl-2-(2,3-dimethyl-4 cyanophenylimino)- 1 -thia-3 -azaspiro [4.4]nonane. Entry 225 163 WO 00/42031 PCT/US99/29601 N ~- H N i-Bu Me Me 2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-I 5 (hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2 hydroxyethylamine was reacted with SOC1 2 folloowed by 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method C2a to give 2-(2,3-dimethyl-4 iodophenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 3-isobutyl-2-(4-iodo-2-n 10 propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with trimethylsilylacetylene according to Method D8a, Step 1 to give 3-isobutyl-2 (2,3-dimethyl-4-(2-trimethylsilylethynyl)phenylimino)-1-thia-3-azaspiro[4.4]nonane. The silylacetylene was deprotected according to Method D8a, Step 2 to afford 3 isobutyl-2-(2,3-dimethyl-4-ethynylphenylimino)-1-thia-3-azaspiro[4.4]nonane. 15 Entry 226 S N i-Bu Me Me 2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl 20 isothiocyanate according to Method A2a, Step 3. 1-Amino-1 (hydroxymethyl)cyclopentane was synthesized as described in Method B 1 c. The 2 hydroxyethylamine was reacted with SOCl 2 according to Method B7e to give 1 amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method Cle to give 2 25 (2,3-dimethyl-4-iodophenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2-(4 iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. Entry 227 0 2 N
-S
N 30 i-Bu Me Me 164 WO 00/42031 PCT/US99/29601 2,3-Dimethylaniline was converted to 2,3-dimethyl-6-nitroaniline according to Method A4a. The aniline was converted to 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method A2d. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was converted to 1 5 chloromethylcyclopentanamine HCl salt according to Method B7e. 1 Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-6 nitrophenyl isothiocyanate according to Method Cle to give 2-(2,3-dimethyl-6 nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to afford 2-(2,3-dimethyl-6 10 nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane. Entry 228 S S CN N | 15 i-Bu 2-Cyano-5-nitrothiophene was reduced to 2-amino-5-cyanothiophene according to Method Ala. The aminothiophene was converted to 5-cyano-1-thiophene isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was converted to 1 20 chloromethylcyclopentanamine HCl salt according to Method B7e. 1 Chloromethylcyclopentanamine HCl salt was reacted with 5-cyano-l-thiophene isothiocyanate according to Method Cle to give 2-(5-cyanothienylimino)-3-thia-1 azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 2-(5-cyanothienylimino)-1-isobutyl-3-thia-1 25 azaspiro[4.4]nonane. Entry 229 Me S N >=N CN i-Bu Me 6-Amino-3-cyano-2,3-dimethylpyridine was converted to 3-cyano-2,3-dimethyl-6 30 pyridyl isothiocyanate according to Method A2c. 1 Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 165 WO 00/42031 PCT/US99/29601 with 3-cyano-2,3-dimethyl-6-pyridyl isothiocyanate according to Method Cle to give 2-(3-cyano-2,3-dimethyl-6-pyridylimino)-3-thia- 1 -azaspiro [4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2h to give 2 (5-bromothienylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane. 5 Entry 230
-S
N /PNO 2 Me HCI 1-(Hydroxymethyl)cyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was sequentially reacted with SOCl 2 and 2-methyl-4 10 nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4 nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 1-bromo-2-ethylbutane according to Method D2a to afford 2-(2-methyl-4 nitrophenylimino)-1-(2-ethyl-1-butyl)-3-thia-1-azaspiro[4.4]nonane. 15 Entry 231
-S
N CN N Et 1 -Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 20 with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 3-bromopentane according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-(3-pentyl)-3-thia-1-azaspiro[4.4]nonane. 25 Entry 232 = N
NO
2 Me 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCI salt was reacted 166 WO 00/42031 PCT/US99/29601 with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isopropyl bromide according to Method D2e to give 2-(2-methyl-4 nitrophenylimino)-1-(2-propyl)-3-thia-1-azaspiro[4.4]nonane. 5 Entry 233 NM
NO
2 N P 10 1 -Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HC1 salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was 15 reacted with 3-bromo-2-methylpropene according to Method D2e to give 2-(2 methyl-4-nitrophenylimino)-1-(2-methylprop-1-en-3-yl)-3-thia-1 azaspiro[4.4]nonane. Entry 234
-S
=N
NO
2 N 20 Me 1-Hydroxymethylcyclopentanamine was prepared according to Method BIc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCI salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 25 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with allyl bromide according to Method D2e to give 2-(2-methyl-4 nitrophenylimino)- 1 -(prop-1 -en-3-yl)-3-thia- 1 -azaspiro[4.4]nonane. Entry 235 167 WO 00/42031 PCT/US99/29601 S >=N
MPNO
2 Me 1-Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 5 with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2e to give 2-(2 methyl-4-nitrophenylimino)-1-(cyclopropylmethyl)-3-thia-1-azaspiro[4.4]nonane. 10 Entry 236 S N NO 2 Me 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 15 with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexylmethyl bromide according to Method D2e to give 2-(2 methyl-4-nitrophenylimino)-1 -(cyclohexylmethyl)-3-thia-1-azaspiro[4.4]nonane. 20 Entry 237 S N N NO 2 Me 00 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 25 with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 2-(bromomethyl)tetrahydro-2H-pyran according to Method D2e to give 168 WO 00/42031 PCT/US99/29601 2-(2-methyl-4-nitrophenylimino)- 1 -(tetrahydro-2H-pyran-2-ylmethyl)-3-thia- 1 azaspiro[4.4]nonane. 5 Entry 238 S >=C N
NO
2 Me 00 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 10 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCI salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 2-(2-bromoethyl)-1,3-dioxane according to Method D2e to give 2-(2 15 methyl-4-nitrophenylimino)-1-(2-(1,3-dioxan-2-yl)ethyl)-3-thia-1 azaspiro[4.4]nonane. Entry 239
S
>=N
NO
2 N N Me 20 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 methyl-4-nitrophenylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine 25 was reacted with cyclobutyl bromide according to Method D2e to give 2-(2-methyl 4-nitrophenylimino)-1-cyclobutyl-3-thia-1-azaspiro[4.4]nonane. Entry 240 169 WO 00/42031 PCT/US99/29601 NM NO 2 N P 6 M 1-(Hydroxymethyl)cyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was treated with SOC1 2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4 5 nitrophenylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2-methyl-4 nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 241 0 I/
-S
>=N
NO
2 8Me 10 1-Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was reacted with SOCl 2 followed by with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4 nitrophenylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted 15 with cyclopentyl bromide according to Method D2b to give 2-(2-methyl-4 nitrophenylimino)--l-2-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was oxidized with m-CPBA according to Method D4a to afford 2-(2-methyl-4 nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane 3-oxide. 20 Entry 242 0
-
N NO 2 6Me 1 -Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was reacted with SOC1 2 followed by with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4 25 nitrophenylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2-methyl-4 nitrophenylimino)- 1 -2-cyclopentyl-3-thia- 1 -azaspiro [4.4]nonane. The thiazolidine 170 WO 00/42031 PCT/US99/29601 was oxidized with m-CPBA according to Method D4a to afford 2-(2-methyl-4 nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane 3,3-dioxide. Entry 243 S N /NO 2 N Et 5 2-Ethylaniline was protected as 2-ethylacetanilide according to Method A2a, Step 1. The acetamide was converted to 2-ethyl-4-nitroaniline, then deprotected according to Method A2a, Step 2. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1 10 Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCI salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2 ethyl-4-nitrophenylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was 15 reacted with cyclopentyl bromide according to Method D2b to give 2-(2-ethyl-4 nitrophenylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 244 S =N
NO
2 N Q Me 20 3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was converted to 1 chloromethylcyclopentanamine HCl salt according to Method B7e. 1 Chloromethylcyclopentanamine HCl salt was reacted with 3-methyl-4-nitrophenyl 25 isothiocyanate according to Method Cle to give 2-(3-methyl-4-nitrophenylimino)-3 thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2 -(3-methyl-4-nitrophenylimino)-1-cyclopentyl-3 thia- 1 -azaspiro[4.4]nonane. 30 171 WO 00/42031 PCT/US99/29601 Entry 245
S
N NO 2 6N Me Me 2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, Step 1. The acetamide was converted to 2,3-dimethyl-4-nitroaniline, then 5 deprotected according to Method A2a, Step 2. The aniline was converted to 2, dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1 Hydroxymethylcyclopentanamine was prepared according to Method BIc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 10 with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2 (2,3-dimethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2,3 dimethyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 15 Entry 246 0 2 N -S N N Me Me 2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, step 1. The acetamide was converted to 2,3-dimethyl-6-nitroaniline, then deprotected according to Method A2a, step 2. The aniline was converted to 2, 20 dimethyl-6-nitrophenyl isothiocyanate according to Method A2a, step 3. 1 Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCI salt was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method Cle to give 2 25 (2,3-dimethyl-6-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2,3 dimethyl-6-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 247 172 WO 00/42031 PCT/US99/29601
S
N CN 6 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1 -chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 5 with 4-iodophenyl isothiocyanate according to Method Cle to give 2-(4 iodophenylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodophenylimino) 1-2-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D2h to afford 2 -(4-cyanophenylimino)-1-cyclopentyl-3 10 thia- 1 -azaspiro[4.4]nonane. Entry 248
S
=N CN N P 6Me 4-Cyano-2-methylaniline was prepared according to Method Ala. The aniline was 15 converted to 4-cyano-2-methylphenyl isothiocyanate according to Method A2b. 1 Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCI salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-methylphenyl isothiocyanate according to Method Cle to give 2-(4 20 cyanophenylphenylimino)-3-thia- 1 -azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 methylphenylimino)- 1 -cyclopentyl-3-thia- 1 -azaspiro[4.4]nonane. Entry 249
-S
N d CN N Et 25 5 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HC salt was reacted 173 WO 00/42031 PCT/US99/29601 with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 5 Entry 250
-S
N / CN 6n-Pr 4-Iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared 10 according to Method Blc. The 2-hydroxyethylamine was sequentially reacted with SOCl 2 and 4-iodo-2-n-propylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-n-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2 n-propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl 15 iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2-n propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 251 -S =N /CN N i-Pr 20 4-Iodo-2-isopropylaniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was sequentially reacted with SOCl 2 and 4-iodo-2-isopropylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-isopropylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine 25 was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2 isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2 isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 30 Entry 252 174 WO 00/42031 PCT/US99/29601
S
= N CN N 6N Me Me 4-Iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was sequentially 5 reacted with SOCl 2 and 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2,3-dimethylphenylimino)-3-thia-1 azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2,3-dimethylphenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with 10 CuCN according to Method D7a to afford 2-(4-cyano-2,3-dimethylphenylimino)-l cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 253 S - 0 Nt OH 15 1-Hydroxymethylcyclopentanamine was prepared according to Method BIc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was 20 reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was hydrolyzed according to Method D9a to afford 2-(4-carboxy-2-ethylphenylimino)- 1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 25 Entry 254 S > =N
-
- 0 N MOH 6Me 4-Cyano-2-methylaniline was prepared according to Method Ala. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to Method A2b. 1 175 WO 00/42031 PCT/US99/29601 Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCI salt according to Method B7e. 1-Chloromethylcyclopentanamine HCI salt was reacted with 4-cyano-2-methylphenyl isothiocyanate according to Method Cl e to give 2-(4 5 cyanophenylphenylimino)-3-thia- 1 -azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was hydrolyzed according to Method D9a to afford 2-(4-carboxy-2-methylphenylimino) 1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 10 Entry 255 N Me 6E 1-Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCI salt 15 according to Method B7e. 1-Chloromethylcyclopentanamine HC salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro [4.4]nonane. The nitrile was 20 hydrolyzed according to Method D9a to give 2-(4-carboxy-2-ethylphenylimino)-1-2 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The benzoic acid was converted to 2-(4 acetyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane according to Method D1Oa. 25 Entry 256 S
-
0 N OMe 6 M Methyl 4-amino-3-methylbenzoate was converted to 4-methoxycarbonyl-2 methylphenyl isothiocyanate according to Method A2b. 1 30 Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was sequentially reacted with SOCl 2 and 4-methoxycarbonyl-2 176 WO 00/42031 PCT/US99/29601 methylphenyl isothiocyanate according to Method C2a to give 2-(4 methoxycarbonyl-2-methylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2h to give 2-(4-methoxycarbonyl-2-methylphenylimino)- 1 -cyclopentyl-3 -thia- 1 5 azaspiro[4.4]nonane. Entry 257 S 0 >N CN P'NHMe 6 Et 1 -Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 10 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCI salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 15 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was hydrolyzed according to Method D9a to give 2-(4-carboxy-2-ethylphenylimino)- 1-2 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The benzoic acid was reacted with methylamine according to Method D6b to afford 2-(4-(N-methylcarbamoly)-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 20 Entry 258 S - 0 N / NMe 2 6Et 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt 25 according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was 30 hydrolyzed according to Method D9a to give 2-(4-carboxy-2-ethylphenylimino)-1-2 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The benzoic acid was reacted with 177 WO 00/42031 PCT/US99/29601 dimethylamine according to Method D6b to afford 2-(4-(NN-dimethylcarbamoly)-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 259 S N >N :R/ N C'NI 5 6CF 3
CO
2 H 2,3-Dichloroaniline was converted to the 2,3-dichloroformanilide according to Method A3a, Step 1. The formanilide was converted to 2,3-dichlorophenyl isocyanide dichloride according .to Method A3a, Step 2. 1 Hydroxymethylcyclopentanamine HC1 salt was synthesized according to Method 10 Blc. The 2-hydroxyethylamine was converted to 13-aza-6 oxadispiro[4.2.4. 1 ]tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1 -(cyclopentylamino)- 1 (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to 1-(cyclopentylamino)-1-(acetylthiomethyl)cyclopentane according to Method C6c, 15 Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 (cyclopentylamino)-1-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 2,3-dichlorophenyl isocyanide dichloride according to Method C6c to afford 2 (2,3-dichlorophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 20 Entry 260
-S
F
3 C 25 2-(Trifluoromethyl)aniline was converted to the 2-(trifluoromethyl)formanilide according to Method A3a, Step 1. The formanilide was converted to 2 (trifluoromethyl)phenyl isocyanide dichloride according to Method A3a, Step 2. 1 Hydroxymethylcyclopentanamine HC1 salt was synthesized according to Method 30 Blc. The 2-hydroxyethylamine was converted to 13-aza-6 oxadispiro[4.2.4. 1]tridecane according to Method B4d, Step 1. The oxazolidine was 178 WO 00/42031 PCT/US99/29601 reductively opened according to Method B4d, Step 2 to give 1 -(cyclopentylamino)- 1 (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to 1-(cyclopentylamino)-1-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 5 (cyclopentylamino)-1-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 2-(trifluoromethyl)phenyl isocyanide dichloride according to Method C6c to afford 2-(2-(trifluoromethyl)phenylimino)- 1 -cyclopentyl-3 -thia- 1 azaspiro[4.4]nonane. 10 Entry 261
S
N / CF 3 4-(Trifluoromethyl)aniline was converted to the 4-(trifluoromethyl)formanilide according to Method A3a, Step 1. The formanilide was converted to 4 (trifluoromethyl)phenyl isocyanide dichloride according to Method A3a, Step 2. 1 15 Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method Blc. The 2-hydroxyethylamine was converted to 13-aza-6 oxadispiro[4.2.4. 1]tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1 (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted 20 to 1-(cyclopentylamino)-1-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 (cyclopentylamino)-1-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 4-(trifluoromethyl)phenyl isocyanide dichloride according to Method C6c to afford 2-(4-(trifluoromethyl)phenylimino)-1-cyclopentyl-3-thia-1 25 azaspiro[4.4]nonane. Entry 262 -S N N 6 CI Me
CF
3
CO
2 H 2-Chloro-3-methylaniline was converted to the 2-chloro-3-methylformanilide 30 according to Method A3a, Step 1. The formanilide was converted to 2-chloro-3 methylphenyl isocyanide dichloride according to Method A3a, Step 2. 1 179 WO 00/42031 PCT/US99/29601 Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method Blc. The 2-hydroxyethylamine was converted to 13-aza-6 oxadispiro[4.2.4. I]tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1 -(cyclopentylamino)- 1 5 (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to 1-(cyclopentylamino)-1-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 (cyclopentylamino)-1-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 2-chloro-3-methylphenyl isocyanide dichloride according to Method C6c to 10 afford 2-(2-chloro-3-methylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane. Entry 263 N
CF
3 15 3-(Trifluoromethyl)aniline was converted to the 3-(trifluoromethyl)formanilide according to Method A3a, Step 1. The formanilide was converted to 3 (trifluoromethyl)phenyl isocyanide dichloride according to Method A3a, Step 2. 1 Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method Blc. The 2-hydroxyethylamine was converted to 13-aza-6 20 oxadispiro[4.2.4. 1]tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1 (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to 1-(cyclopentylamino)-1-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 25 (cyclopentylamino)-1-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 3-(trifluoromethyl)phenyl isocyanide dichloride according to Method C6c to afford 2
-(
3 -(trifluoromethyl)phenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane. 30 Entry 265 -S >N C1 CN 8 Me CI
CF
3
CO
2 H 180 WO 00/42031 PCT/US99/29601 3-Chloro-2-methylaniline was converted to the 3-chloro-2-methylformanilide according to Method A3a, Step 1. The formanilide was converted to 3-chloro-2 methylphenyl isocyanide dichloride according to Method A3a, Step 2. 1 Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method 5 Blc. The 2-hydroxyethylamine was converted to 13-aza-6 oxadispiro[4.2.4. 1 ]tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1 (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to 1-(cyclopentylamino)-1-(thioacetylmethyl)cyclopentane according to Method C6c, 10 Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 (cyclopentylamino)-1-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 3-chloro-2-methylphenyl isocyanide dichloride according to Method C6c to afford 2 -(3-chloro-2-methylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane. 15 Entry 265 -S N ' Me CI
CF
3
CO
2 H 2,3-Dichloro-4-methylaniline was converted to the 2,3-dichloro-4-methylformanilide according to Method A3a, Step 1. The formanilide was converted to 2,3-dichloro-4 20 methylphenyl isocyanide dichloride according to Method A3a, Step 2. 1 Hydroxymethylcyclopentanamine HCl salt was synthesized according to Method Blc. The 2-hydroxyethylamine was converted to 13-aza-6 oxadispiro[4.2.4.1]tridecane according to Method B4d, Step 1. The oxazolidine was reductively opened according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1 25 (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to 1 -(cyclopentylamino)- 1 -(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 (cyclopentylamino)-1-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 2,3-dichloro-4-methylphenyl isocyanide dichloride according to Method C6c to 30 afford 2 -(2,3-dichloro-4-methylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane. Entry 266 181 WO 00/42031 PCT/US99/29601 S N / Br N 6Me 1-Hydroxymethylcyclopentanamine was prepared according to Method BIc. The 2 hydroxyethylamine was sequentially reacted with SOCl 2 and 4-bromo-2 methylphenyl isothiocyanate according to Method C2a to give 2-(4-bromo-2 5 methylphenylimino)-3-thia- 1 -azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-bromo-2 methylphenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro [4.4]nonane. Entry 267 -S O a N H 10 1-Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was converted to 1 -chloromethylcyclopentanamine HCI salt according to Method B7e. 1-Chloromethylcyclopentanamine HCI salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 15 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dlla to give 2-(4-formyl-2-ethylphenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 20 Entry 268 N O 6 Et OEt 1-Hydroxymethylcyclopentanamine was prepared according to Method BIc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt 25 according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was 182 WO 00/42031 PCT/US99/29601 reduced according to Method Dlla to give 2-(4-formyl-2-ethylphenylimino)-l cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a according to afford 2-(2-ethyl-4-((1E) 2-ethoxycarbonylvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 5 Entry 269 tN N
NO
2 1-Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt 10 according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was 15 reduced according to Method Dlla to give 2-(4-formyl-2-ethylphenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with nitromethane according to Method D12b according to afford 2-(2-ethyl-4-((1E)-2 nitrovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 20 Entry 270 C S N Et OH 6E 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 25 with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dlla to give 2-(4-formyl-2-ethylphenylimino)-1 30 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a according to afford 2-(2-ethyl-4-((1E) 2-ethoxycarbonylvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. 183 WO 00/42031 PCT/US99/29601 The ester was saponified according to Method D6a to afford 2-(2-ethyl-4-((1E)-2 carboxyvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 271 N CN
-S
5Et NC 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 10 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1 -azaspiro[4.4]nonane. The nitrile was reduced according to Method Dlla to give 2-(4-formyl-2-ethylphenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with 15 malononitrile according to Method D12c according to afford 2-(2-ethyl-4-(2,2 dicyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 272 JNiFN Et Me 20 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCI salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was 25 reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dlla to give 2-(4-formyl-2-ethylphenylimino)-1 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with diethyl (2 oxopropyl)phosphonate according to Method D12a according to afford 2-(2-ethyl-4 30 ((1E)-2-acetylvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 273 184 WO 00/42031 PCT/US99/29601 S Etp Me 6E 1-Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted 5 with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cle to give 2-(4 cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2 ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dlla to give 2-(4-formyl-2-ethylphenylimino)-1 10 cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with acetonitrile according to Method D12d according to afford 2-(2-ethyl-4-((]E)-2 cyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. Entry 274
-S
N
NO
2 N Me 15 1-Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2 hydroxyethylamine was sequentially reacted with SOCl 2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3 thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexyl bromide 20 according to Method D2e to give 2 -(2-methyl-4-nitrophenylimino)-1-cyclohexyl-3 thia-1-azaspiro[4.4]nonane. Entry 275 -S N /NO 2 Me C6 25 1-Hydroxymethylcyclopentanamine was prepared according to Method B 1 c. The 2 hydroxyethylamine was sequentially reacted with SOC1 2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3 thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cycloheptyl bromide 185 WO 00/42031 PCT/US99/29601 according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-cycloheptyl-3 thia-1 -azaspiro[4.4]nonane. Entry 276 S >=N
/NO
2 5 i-Bu Me 1 -Aminocyclohexane- 1 -carboxylic acid was protected as the benzyloxycarbonylamine according to Method Bla, Step 1. 1 (Benzyloxycarbonylamino)cyclohexane-1-carboxylic acid was reduced to 1 (benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane according to Method 10 Bla, Step 2. The carbamate was deprotected according to Method Bla, Step 3 to give 1-amino-i -(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOC 2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1 azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide 15 according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3 thia-1-azaspiro[4.5]decane. Entry 277
-S
/N NO 2 N O i-Bu Me 20 2-Methyl-4-nitroaniline was converted to the 2-methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a, Step 2. 3-Aminotetrahydro-2H pyran-3-carboxylic acid was converted to the methyl ester according to Method BIb, Step 1. Methyl 3 -aminotetrahydro-2H-pyran-3-carboxylate was reduced to 3-amino 25 3-(hydroxymethyl)tetrahydro-2H-pyran according to Method Bib, Step 2. The 2 hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford 2 -isopropyl-1-aza-3,7-dioxaspiro[4.5]decane. The oxazolidine was reduced to 3-isobutylamino-3-(hydroxymethyl)tetrahydro-2H-pyran. The substituted 2-hydroxyethylamine was converted to 3-isobutylamino-3 30 (acetylthiomethyl)tetrahydro-2H-pyran according to Method C6c, Step 1. The thioacetate was saponified according to Method C6c, Step 2 to give 3-isobutylamino 3-(thiomethyl)tetrahydro-2H-pyran. The 2-thioethylamine was reacted with 2 186 WO 00/42031 PCT/US99/29601 methyl-4-nitrophenyl isocyanide dichloride to afford 2-(2-methyl-4 nitrophenylimino- 1 -isobutyl- 1 -aza-7-oxa-3-thiaspiro[4.5]decane. Entry 278 S N / NO 2 N 5 i-Bu Me 2-Methyl-4-nitroaniline was converted to the 2-methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a, Step 2. 4-Aminotetrahydro-2H pyran-4-carboxylic acid was converted to the methyl ester according to Method BIb, 10 Step 1. Methyl 4-aminotetrahydro-2H-pyran-4-carboxylate was reduced to 4-amino 4-(hydroxymethyl)tetrahydro-2H-pyran according to Method Blb, Step 2. The 2 hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford 2 -isopropyl-1-aza-3,8-dioxaspiro[4.5]decane. The oxazolidine was reduced to 4 -isobutylamino-4-(hydroxymethyl)tetrahydro-2H-pyran. The substituted 15 2-hydroxyethylamine was converted to 4-isobutylamino-4 (acetylthiomethyl)tetrahydro-2H-pyran according to Method C6c, Step 1. The thioacetate was saponified according to Method C6c, Step 2 to give 4-isobutylamino 4-(thiomethyl)tetrahydro-2H-pyran. The 2-thioethylamine was reacted with 2 methyl-4-nitrophenyl isocyanide dichloride to afford 2-(2-methyl-4 20 nitrophenylimino-1-isobutyl-1 -aza-8-oxa-3-thiaspiro[4.5]decane. Entry 279
S
=N
NO
2 -Bu Me 2-Amino-2-norbomane-1-carboxylic acid as a mixture of isomers was converted to 25 the N-benzyloxycarbonyl analogue according to Method Bla, Step 1. 1 (Benzyloxycarbonylamino)-2-norbomane-1-carboxylic acid was reduced to 1 (benzyloxycarbonylamino)-1-(hydroxymethyl)-2-norbornane according to Method Bla, Step 2. The carbamate was deprotected according to Method Bla, Step 3 to give 1-amino-i -(hydroxymethyl)-2-norbornane. The 2-hydroxyethylamine was 30 alkylated with isobutyl bromide according to Method B2a to give N-isobutyl-1 amino-1 -(hydroxymethyl)-2-norbornane. The alkylated 2-hydroxyethylamine was treated with SOCl 2 according to Method B7a to give N-isobutyl-2-chloroethylamine HCl salt. The chloroethylamine was treated with 2-methyl-4-nitrophenyl 187 WO 00/42031 PCT/US99/29601 isothyiocyanate according to Method CIa to afford 2-(2-methyl-4-nitrophenylimino) 3-isobutylspiro[1,3-thiazolidine-4,3'-bicyclo[3.2.1 ]octane]. Entry 280 N
NO
2 N i-Bu Me HCI 5 N-(tert-Butoxycarbonyl)-(L)-valine was converted to (S)-3-(tert butoxycarbonylamino)-1-diazo-4-methylpentan-2-one according to Method B6a, Step 1. The diazo compound was converted to methyl (R)-3-(tert butoxycarbonylamino)-4-methylpentanoate according to Method B6a, Step 2. The 10 ester was reduced according to Method B6a, Step 3 to give (R)-3-(tert butoxycarbonylamino)-4-methylpentan-1-ol. The carbamate was deprotected and converted to (R)-3-amino-l-chloro4-methylpentane according to Method B7e. The 3-chloropropylamine was treated with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give ( 4 R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl 15 1,3-thiazine. The thiazine was alkylated with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3 thiazine HCl salt. Entry 281 CS>N
NO
2 20 i-Bu Me 3-Aminopropanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydrol,3-oxazine. The oxazine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxypropylamine. The 3 hydroxypropylamine was reacted with SOC 2 according to Method B9a, Step 3 to 25 give N-isobutyl-3-chloropropylamine HCl salt. The 3-chloropropylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazine. Entry 282 SN NO 2 30 i-Bu Me 188 WO 00/42031 PCT/US99/29601 4-Aminobutanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydrol,3-oxazepine. The 1,3-oxazepine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxybutylamine. The 3 hydroxybutylamine was reacted with SOCl 2 according to Method B9a, Step 3 to give 5 N-isobutyl-3-chlorobutylamine HCI salt. The 3-chlorobutylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2-(2 methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazepine. 10 Entry 283 O N-
NO
2 a i-Bu Me 3-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by chloroacetic acid according to Method C8a to afford 2-(3-methyl-4 nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one. 15 Entry 284 j NNO 2 Me 3-Methyl-4-nitrophenyl isothiocyanate was reacted with benzylamine followed by chloroacetic acid according to Method C8a to afford 2-(3-methyl-4 20 nitrophenylimino)-3-(phenylmethyl)-1,3-thiazolidin-4-one. Entry 285 N >NQ NO 2 Me 3-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-1-butylamine 25 followed by chloroacetic acid according to Method C8a to afford 2-(3-methyl-4 nitrophenylimino)-3-(2-methylbutyl)-1,3-thiazolidin-4-one. Entry 286 189 WO 00/42031 PCT/US99/29601 O N
NO
2 Me 3-Methyl-4-nitrophenyl isothiocyanate was reacted with 1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2-(3-methyl-4 nitrophenylimino)-3-(1 -cyclohexylethyl)- 1,3-thiazolidin-4-one. 5 Entry 287 O N
NO
2 0 i-Bu Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4 10 nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one. Entry 288 O N NO 2 Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-1-butylamine 15 followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4 nitrophenylimino)-3-(2-methylbutyl)-1,3-thiazolidin-4-one. Entry 289 O N NO 2 Me 20 2-Methyl-4-nitrophenyl isothiocyanate was reacted with benzylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4 nitrophenylimino)-3-(phenylmethyl)-1,3-thiazolidin-4-one. Entry 290 190 WO 00/42031 PCT/US99/29601 N NO 2 i-Bu Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by a-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4 nitrophenylimino)-3-isobutyl-5-methyl-1,3-thiazolidin-4-one. 5 Entry 291 O N NO 2 Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4 10 nitrophenylimino)-3-(1 -cyclohexylethyl)- 1,3-thiazolidin-4-one. Entry 292 O N
NO
2 Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (IS)-1-amino-i 15 cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexylethyl)-1,3-thiazolidin-4-one. Entry 293 0j I N
NO
2 Me 20 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (JR)-1-amino-1 cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1R)-1-cyclohexylethyl)-1,3-thiazolidin-4-one. Entry 294 191 WO 00/42031 PCT/US99/29601 O = N
NO
2 i-Bu Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by a-chloro-a-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4 nitrophenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidin-4-one. 5 Entry 295 MeTS O : >N NO2 Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1R)-1-amino-I cyclohexylethane followed by a-chloropropionic acid according to Method C8a to 10 afford 2-(2-methyl-4-nitrophenylimino)-3-((1R)-1-cyclohexylethyl)-5-methyl-1,3 thiazolidin-4-one. Entry 296 O N.." M NO 2 15 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1R)-1-amino-1 cyclohexylethane followed by a-chloro-a-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1R)-1-cyclohexylethyl)-5-phenyl 1,3-thiazolidin-4-one. 20 Entry 297 Me Oew N NO 2 Me 192 WO 00/42031 PCT/US99/29601 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-amino-1 cyclohexylethane followed by a-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexylethyl)-5-methyl-1,3 thiazolidin-4-one. 5 Entry 298 O N N M
NO
2 Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-amino-1 10 cyclohexylethane followed by a-chloro-a-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexylethyl)-5-phenyl 1,3-thiazolidin-4-one. Entry 299 Me O N NO 2 Me 15 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by ax-chloropropionic acid according to Method C8a to afford 2-(2-methyl 4-nitrophenylimino)-3-(2-ethyl-1-butyl)-5-methyl-1,3-thiazolidin-4-one. 20 Entry 300 N /NO 2 i-Bu Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to afford 2-(2-methyl-4 nitrophenylimino)-3-isobutyl-5-isobutyl-1,3-thiazolidin-4-one. 25 Entry 301 193 WO 00/42031 PCT/US99/29601 N
NO
2 i-Bu Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to afford 2 (2-methyl-4-nitrophenylimino)-3-isobutyl-5-(2-ethyl-1-butyl)-1,3-thiazolidin-4-one. 5 Entry 302
S
N
/NO
2 0 N Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methylbutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to afford 2 10 (2-methyl-4-nitrophenylimino)-3-(2-butyl)-5-isobutyl-1,3-thiazolidin-4-one. Entry 303
S
= N
NO
2 0 N Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methylbutylamine 15 followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2-(2 methyl-4-nitrophenylimino)-3-(2-butyl)-5-isopropyl-1,3-thiazolidin-4-one. Entry 304
S
N / NO 2 i-Bu Me 20 2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2-(2-methyl-4 nitrophenylimino)-3-isobutyl-5-isopropyl-1,3-thiazolidin-4-one. Entry 305 194 WO 00/42031 PCT/US99/29601 O&N N NO2 Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (2S)-2-methyl- 1 -butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4 nitrophenylimino)-3-((2S)-2-methyl-1-butyl)- 1,3-thiazolidin-4-one. 5 Entry 306
S
N / NO 2 Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2-(2 10 methyl-4-nitrophenylimino)-3-(2-ethyl-1-butyl)-5-isopropyl-1,3-thiazolidin-4-one. Entry 307 H
NNO
2
H
2 C N i-Bu Me (R)-N-isobutylserine methyl ester HCl salt was prepared from (D)-serine methyl ester 15 as described in Method B3a. The alcohol was reacted with SOC 2 according to Method B7b, followed reaction with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4 methylene-1,3-thiazolidin-5-one. 20 Entry 308 C1 O N CI C1 2,4,6-Trichlorophenyl isothiocyanate was reacted with 2-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2,4,6-trichlorophenylimino) 3-(2-butyl)-1,3-thiazolidin-4-one. 195 WO 00/42031 PCT/US99/29601 Entry 309 0 N CIQ C1 5 3,4-Dichlorophenyl isothiocyanate was reacted with 2-methylbutylamine followed by chloroacetic acid according to Method C8a to afford 2-(3,4-dichlorophenylimino)-3 (2-butyl)- 1,3-thiazolidin-4-one. Entry 310 O =N
NO
2 10 i-Bu Me N-Isobutylglycine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1 la to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3 thiazolidin-5-one. 15 Entry 311 0 -N
NO
2 0 Me 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4 nitrophenylimino)-3-(2-ethyl-1-butyl)-1,3-thiazolidin-4-one. 20 Entry 312 0 s = N
NO
2 N i-Bu Me N-Isobutylleucine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cl1a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4 25 diisobutyl-1,3-thiazolidin-5-one. Entry 313 196 WO 00/42031 PCTIUS99/29601 N NO2 Me N-Isobutylproline ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Clla to afford 4-(2-methyl-4-nitrophenylimino)-1 oxoperhydro-2-thiapyrrolizine. 5 Entry 314 N NO 2 Me N-(tert-Butoxycarbonyl)glycine tert-butyl ester was reacted with 3-bromo-2 methylpropene according to Method B8b, Step 1 to give N-(tert-butoxycarbonyl)-N 10 (2-methylprop-2-enyl)glycine tert-butyl ester. The ester was reduced according to Method B8b, Step 2 to give N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2 methylprop-2-ene. The alcohol was treated with p-toluenesulfonyl chloride according to Method B8b, Step 3 to give N-(tert-butoxycarbonyl)-N-(2 tosyloxyethyl)- 1 -amino-2-methylprop-2-ene. The carbamate was deprotected 15 according to Method B8b, Step 4 to give N-(2-tosyloxyethyl)-2-methylprop-2-en-1 ammonium trifluoroacetate. The tosylate was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C5a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2 methylprop-2-enyl)-1,3-oxazolidine. 20 Entry 315 0 N N / NO 2 i-Bu Me (L)-Valine methyl ester was reduced to (1S)-1I-(hydroxymethyl)-2 methylpropylamine according to Method Bib, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2,4 25 diisopropyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (lS)-1-(hydroxymethyl)-N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7b to give (1 S)- 1 -(chloromethyl)-N-isobutyl-2-methylpropylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to 197 WO 00/42031 PCT/US99/29601 Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl 1,3-oxazolidine. Entry 316 N M - NO 2 5 i-Bu Me (L)-Leucine methyl ester was reduced to (1S)-i-(hydroxymethyl)-3 methylbutylamine according to Method Bib, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2 isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to 10 Method B4c, Step 2 to give (1S)-i-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-3-methylbutylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3 15 oxazolidine. Entry 317 N CN i-Bu Et (L)-Leucine methyl ester was reduced to (1S)-1-(hydroxymethyl)-3 20 methylbutylamine according to Method Bib, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2 isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-i-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according 25 to Method A3a, Step 1. The formanilide was reacted with SOC 2 and S0 2 Cl2 according to Method A3a, Step 2 to give 4-cyano-2-ethylphenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 4-cyano-2 ethylphenyl isocyanide dichloride according to Method C7b to afford (4S)-2-(4 cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-oxazolidine. 30 Entry 318 198 WO 00/42031 PCT/US99/29601 N /PNO 2 6Me 2-Amino-2-methyl-1-propanol was reacted with cyclopentanone according to Method B4b, Step 1 to afford 4-aza-3,3-dimethyl-1-oxaspiro[4.4]nonane. The oxazolidine was reduced according to Method B4b, Step 2 to give N-cyclopentyl 5 (1,1-dimethyl-2-hydroxyethyl)amine. 2-Methyl-4-nitroaniline was converted to 2 methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was reacted with SOC1 2 and S0 2 Cl 2 according to Method A3a, Step 2 to give 2-methyl-4 nitrophenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride according to Method C7a to 10 afford 2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine. Entry 319 >N CN N 6Et 2-Amino-2-methyl-1-propanol was reacted with cyclopentanone according to 15 Method B4b, Step 1 to afford 4-aza-3,3-dimethyl-1-oxaspiro[4.4]nonane. The oxazolidine was reduced according to Method B4b, Step 2 to give N-cyclopentyl (1,1-dimethyl-2-hydroxyethyl)amine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOC1 2 and S0 2 Cl 2 according to Method A3a, Step 2 to give 4-cyano-2 20 ethylphenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 4-cyano-2-ethylphenyl isocyanide dichloride according to Method C7a to afford 2-(4-cyano-2-ethylphenylimino)-3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine. 25 Entry 320 199 WO 00/42031 PCTIUS99/29601 cc0 >=- N0 N NO 2 bMe 1 -Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B 1 c, Step 1. The ester reduced to 1 -hydroxymethylcyclopentanamine according to Method B 1 c, Step 2. The hydroxyethylamine was reacted with 5 cyclopentanone according to Method B4d, Step 1 to give 6-aza-12 oxadispiro[4.1.4.2]tridecane. The oxazolidine was reduced according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl 2 according to Method B7b to 1-(cyclopentylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine 10 was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane. Entry 321 0 =N
NO
2 N ~$Me 15 1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method Blc, Step 2. The 2-hydroxyethylamine was reacted with cyclobutanone according to Method B4a, Step 1 to give 5-aza-12 oxadispiro[3.1.4.2]dodecane. The oxazolidine was reduced according to Method 20 B4a, Step 2 to give 1-(cyclobutylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOC 2 according to Method B7b to 1-(cyclobutylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1 cyclobutyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane. 25 Entry 322 200 WO 00/42031 PCT/US99/29601 N NO 2 Me 1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method Blc, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method Blc, Step 2. The hydroxyethylamine was reacted with 5 cyclohexanone according to Method B4a, Step 1 to give 6-aza-13 oxadispiro[4.1.5.2]tetradecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOC 2 according to Method B7b to 1-(cyclohexylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was 10 reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1 cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane. Entry 323 cc0 >N- C N /CN N6 Et 15 1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method Blc, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method Blc, Step 2. The hydroxyethylamine was reacted with cyclopentanone according to Method B4d, Step 1 to give 6-aza-12 oxadispiro[4.1.4.2]tridecane. The oxazolidine was reduced according to Method 20 B4d, Step 2 to give 1-(cyclopentylamino)-1-(hydroxymethyl)cyclopentane. 4 Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOCl 2 and S0 2 Cl 2 according to Method A3a, Step 2 to give 4-cyano-2-ethylphenyl isocyanide dichloride. The substituted 2-hydroxyethylamine was reacted with 2-methyl-4-nitrophenyl 25 isocyanide dichloride according to Method C7a to afford 1-cyclopentyl-2-(2-methyl 4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane. Entry 324 201 WO 00/42031 PCT/US99/29601 S /NO 2 N i-Bu (lS)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method BIb. The 2-hydroxyethylamine was converted to (2S) 4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The 5 alcohol was converted to N-(iS)-1-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride as described in Method B7c. 4-Nitrophenyl isothiocyanate was reacted with N-(lS)-1-(chloromethyl)-3-methylbutyl)-N (isobutyl)ammonium chloride according to Method Clf to give 2-(4 nitrophenylthio)- 1,5-diisobutylimidazoline. 10 Entry 325 Me
S
N /NO 2 N (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (lS) 15 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method CIa to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give (4S)-2-(N-(4-heptyl)-N-(2-methyl-5 20 nitrophenyl)amino)-4-isobutyl-1,3-thiazoline. Entry 326 N NO 2 HCI Me (1R)-1-(Hydroxymethyl)-3-methylbutylamine was made from (D)-leucine methyl 25 ester according to Blb. The 2-hydroxyethylamine was converted to (lR)-1 (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-5-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method Cla to give (4R)-2-(2-methyl 5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 202 WO 00/42031 PCTIUS99/29601 isobutyl bromide according to Method D2a to afford (4R)-2-(N-isobutyl-N-(2 methyl-5-nitrophenyl)amino)-4-isobutyl-1,3-thiazoline HCl salt. Entry 327
S
5>-N
NO
2 ) , N Me 5 (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2 Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 10 methylbutanammonium chloride according to Method Cla to give (4S)-2-(2-methyl 4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with neopentyl bromide according to Method D2a to afford (4S)-2-(N-(2,2 dimethylpropyl)-2-methyl-4-nitrophenylamino)-4-isobutyl-1,3-thiazoline. 15 Entry 328 CI CI S N (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method Blb. The 2-hydroxyethylamine was converted to (1S) 1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 20 2,3-Dichlorophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3 methylbutanammonium chloride according to Method Cla to give (4S)-2-(2,3 dichlorophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to afford (4S)-2-(N-(3-pentyl)-2-methyl-4 nitrophenylamino)-4-isobutyl-1,3-thiazoline. 25 203 WO 00/42031 PCT/US99/29601 TABLES The compounds listed in Tables 1-4 below were synthesized according to the methods described above. 5 Table 1.2-Imino-1,3-thiazolidines and Ring Expanded Homologues TLC Mass Spec. mp HPLC TLC Solvent [Source] Synth. Entry Compound (*C) (min.) Rf System Method SS>=N - N2 90- 0.36 30% 238 Cla N 92 EtOAc/ (M+H)+ H Me hex [FAB] 2 S>N - N2 0.49 20% 280 Cla, N EtOAc/ (M+H)+ D2a i-Bu pentane [CI] 3 C N N02 0.52 20% 294 Cla, N EtOAc/ (M+H)+ D2a i-Bu Me pentane [CI] 4 S N 0.78 20% 303 Cla, N EtOAc/ (M+H)+ D2a i-Bu CI CI pentane [CI] 5 S N NO 11.9 310 Cld N (h) (M+H)+ i-Bu MeO [HPLC ES-MS] 6 N CN 9.9 260 Cld N (h) (M+H)+ i-Bu [HPLC ES-MS] 7 HCI NO 2 0.50 20% Cla, S N EtOAc/ D2a N hex i-Bu Me 8 S>N CN 25.0 288 Cld N (h) (M+H)+ i-Bu Et [HPLC ES-MS] 204 WO 00/42031 PCT/US99/29601 9 r N C1 32.0 337 Cld N (h) (M+H)+ i-Bu F 3 C [HPLC ES-MS] 10 S>N - N2 0.23 20% 278 Cla, N EtOAc/ (M+H)+ D2a, pentane [CI] D14a 11 S N NO2 0.49 20% 292 Cla, N EtOAc/ (M+H)+ D2a Me pentane [CI] 12 CSN - N2 0.33 20% 278 Cla, N EtOAc/ (M+H)+ D2a pentane [CI] 13 CS-N C 0.43 11% 301 Cla, N EtOAc/ (M+H)+ D2a >1 c1 pentane [CI] 14 C S N NO2 0.77 30% 308 B2b N EtOAc/ (M+H)+ steps Me hex [FAB] 1-3, B7a, Cla 15 S >N NO2 69- 0.78 30% 292 Cla, N M 70 EtOAc/ (M+H)+ D2a Me hex [FAB] 16 C N NO 2 108- 0.78 30% 290 Cla, N 109 EtOAc/ (M+H)+ D2a Me hex [FAB] 17 S >N NO2 0.77 30% 322 Cla, N EtOAc/ (M+H)+ D2a Me hex [FAB] 18 C N - N2 0.77 30% 308 Cla, N EtOAc/ (M+H)+ D2a Me hex [FAB] 205 WO 00/42031 PCT/US99/29601 19 0.72 40% 364 Cla, S N NO 2 EtOAc/ (M+H)+ D2a N hex [FAB] 20 N NO2 0.67 30% 308 Cla, N EtOAc/ (M+H)+ D2a Me hex [FAB] 21 S N NO 2 0.71 40% 294 B5a, N MEtOAc/ (M+H)+ B7a, Me hex [FAB] Cla 22 S >N NO2 0.71 40% 308 B5a, N EtOAc/ (M+H)+ B7a, Me hex [FAB] Cla 23 S N 0.72 40% 336 Cla, IIIN EtOAc/ (M+H)+ D2a Me hex [FAB] 24 0.71 40% 348 Cla, S NNO 2 EtOAc/ (M+H)+ D2a N Me hex [FAB] 25 >=N NO2 0.71 40% 350 B2b, N NO 2 EtOAc/ (M+H)+ step 2, Me hex [FAB] Cla, D2a 26 r> N NO 2 0.68 30% 372 Cla, N EtOAc/ (M+H)+ D2a Me hex [FAB] 28 r>=N NO2 0.74 40% 356 Cla, Br N "" EtOAc/ (M+H)+ D2a ,) Me hex [FAB] 29 c N NO2 0.74 40% 312 Cla, N p EtOAc/ (M+H)+ D2a Me hex [FAB] 30 r N - N2 129- 276 Cla, M 131 (M+H)+ D2a e [FAB] 206 WO 00/42031 PCT/US99/29601 31 S\N NO2 112- 356 Cla, N 113 (M+H)+ D2a Br Me [FAB] 32 cS >N 7 NO2 394 Cla, N (M+H)+ D2a EtO Me [FAB] ____ O OEt 33 0 C 7N NO 2 0.40 40% 238 Cla, O N EtOAc/ (M+H)+ D2a MeO Me hex [FAB] 34 N NO2 0.63 40% 309 (M+) Cla, MeO N EtOAc/ [EI] D2a J Me hex 35 C _S>=N- NO2 358 Cla, Ph N "' (M+H)+ D2a, [FAB] D5a HO 36 rs>=N -N2 0.65 40% 336 Cla, o N M EtOAc/ (M+H)+ D2a Me hex [FAB] 37 S)=N NO2 0.63 40% 308 Cla, oKN M EtOAc/ (M+H)+ D2a Me hex [FAB] 38 s)>=N N 2 310 Cla, HO N (M+H)+ D2a, Me [FAB] D5a 39 Cs)==N NO 2 338 Cla, HO N (M+H)+ D2a, Me [FAB] D5a 40 Cs)=N NO2 0.65 40% 321 Cla, N Me 2 EtOAc/ (M+H)+ D2a 0 Mep hex [FAB] 207 WO 00/42031 PCT/US99/29601 41 S N NO2 0.74 40% 346 Cla, c1 N EtOAc/ (M+H)+ D2a CI Me hex [FAB] 42 S N NO2 0.63 40% 394 Cla, N M EtOAc/ (M+H)+ D2d 4 Me hex [FAB] 43 r N NO2 0.40 40% 335 Cla, N EtOAc/ (M+H)+ D2a Me hex [FAB] _ OMe 44 S>N NO2 14.9 306 B4b, N (f) (M+H)+ B7c, [HPLC Cld ES-MS] 45 c N NO2 14.4 322 B4b, N (h) (M+H)+ B7c, MeO [HPLC Cld ES-MS] 46 c N 15.6 315 B4b, N (f) (M+H)+ B7c, CI CI [HPLC Cld ES-MS] 47 c N NO 2 0.77 30% 318 B2b N EtOAc/ (M+H)+ steps Me hex [FAB] 1-3, B7a, Cla 48 c N NO 2 320 B4a, N (M+H)+ B7c, Me [HPLC Cld ES-MS] 49 c N NO2 119- 0.37 20% 314 B7a, N 121 EtOAc/ (M+H)+ Cla Me hex [HPLC ES-MS] 208 WO 00/42031 PCT/US99/29601 50 r sv>N NO2 15.4 334 B2a, N (h) (M+H)+ B7c, Me [HPLC Cld ES-MS] 51 s>N NO2 19.1 348 B2a, N (h) (M+H)+ B7c, Me [HPLC Cld ES-MS] 52 KS >=N NO2 16.9 364 B2a, KN (h) (M+H)+ B7c, MeO [HPLC Cld ES-MS] 53 sN 22.1 357 B2a, KN (h) (M+H)+ B7c, CI CI[HPLC Cid ES-MS] 54 C N 2.63 301 B2a, N (i) (M+H)+ B7c, CI CI [HPLC Cld ES-MS] 55 =N NO 2 2.31 292 B2a, N(i) (M+H)+ B7c, Me [HPLC Cld ES-MS] 56 SN CI 2.78 301 B2a, N (i) (M+H)+ B7c, C1 [HPLC Cld ES-MS] 57 r=N C 2.95 301 B2a, N (i) (M+H)+ B7c, CI [HPLC Cld ES-MS] 209 WO 00/42031 PCT/US99/29601 58 SK N 3.18 315 B2a, N (i) (M+H)+ B7c, CE C1 [HPLC Cld ES-MS] 59 c N C1 3.29 315 B2a, N (i) (M+H)+ B7c, CE [HPLC Cld ES-MS] 60 KS ==N CI 3.48 315 B2a, N (i) (M+H)+ B7c, CI [HPLC Cld ES-MS] 61 S >N 3.18 275 B2a, N (i) (M+H)+ B7c, Me Me [HPLC Cld ES-MS] 62 C >N 3.23 295 B2a, N ? (i) (M+H)+ B7c, Me Cl [HPLC Cld ES-MS] 63 C K 5 N 3.99 329 B2a, N (i) (M+H)+ B7c, CI CI [HPLC Cld ES-MS] 64 s>N CI 4.13 329 B2a, N (i) (M+H)+ B7c, CI [HPLC Cld &_ ES-MS] 65 C >N N 2 3.60 320 B2a, N (i) (M+H)+ B7c, Me [HPLC Cld ES-MS] 66 C >N C 4.08 329 B2a, N (i) (M+H)+ B7c, CI [HPLC Cld ES-MS] 210 WO 00/42031 PCT/US99/29601 67 sN 3.99 289 B2a, N (i) (M+H)+ B7c, Me Me [HPLC Cld ES-MS] 68 C s\N 4.05 309 B2a, N (i) (M+H)+ B7c, Me C1 [HPLC Cld &_ ES-MS] 69 C - 17.0 343 B2a, N / (f) (M+H)+ B7c, Ci Cl [HPLC Cld ES-MS] 70 C N NO2 16.7 334 B2a, N (f) (M+H)+ B7c, Me [HPLC Cld ES-MS] 71 C >N NO2 16.3 350 B2a, N (f) (M+H)+ B7c, MeO [HPLC Cld ES-MS] 72 N- NO2 125- 0.77 30% 348 B5a, N 126 EtOAc/ (M+H)+ B7a, Me hex [FAB] Cla 73 C N 3.40 317 B2a, N(i) (M+H)+ B7c, Bn Me CI [HPLC Cld ES-MS] 74 s)=N CI 3.63 337 B2a, N (i) (M+H)+ B7c, Bn Cl [HPLC Cld ES-MS] 75 s =N Cl 3.68 337 B2a, N (i) (M+H)+ B7c, Bn CI [HPLC Cld ES-MS] 211 WO 00/42031 PCT/US99/29601 76 r >N NO 2 3.45 328 B2a, N (i) (M+H)+ B7c, Bn Me [HPLC Cld ES-MS] 77 S N 3.66 337 B2a, N (i) (M+H)+ B7c, Bn CI Cl [HPLC Cld ES-MS] 78 S N CN 13.9 356 B2a, N (g) (M+H)+ B7c, Et [HPLC Cld 7' ES-MS] CI 79 C N CN 15.3 362 B2a, N (g) (M+H)+ B7c, C1 [HPLC Cld ES-MS] CI 80 c 5 N NO2 19.6 348 B2a, N (h) (M+H)+ B7c, Me [HPLC Cld ES-MS] 81 S>N NO2 18.1 364 B2a, N (h) (M+H)+ B7c, MeO [HPLC Cld ES-MS] 82 C >N 18.7 357 B2a, N (h) (M+H)+ B7c, CI C1 [HPLC Cld ES-MS] 83 N - CN 15.4 314 B2a, N (f) (M+H)+ B7c, [HPLC Cld ES-MS] 212 WO 00/42031 PCT/US99/29601 84 S >N NO 2 0.68 30% 404 B2b N Me EtOAc/ (M+H)+ steps hex [FAB] 1-3, B7a, Cla 85 K SN NO2 0.68 30% 372 Cla, N EtOAc/ (M+H)+ D2a hex [FAB] 86 CS=N NO2 0.71 40% 344 Cla, N EtOAc/ (M+H)+ D2a Me hex [FAB] 87 S - N 0.38 30% 342 A2c, N EtOAc/ (M+H)+ Blb, i-Bu hex [HPLC B4c, ES-MS] B7c, Cif 88 S==N- NO2 0.78 30% 336 Blb, N EtOAc/ (M+H)+ B4c, i-Bu hex [HPLC B7c, ES-MS] Clf 89 S - 0.79 30% 316 Blb, N ==N CN EtOAc/ (M+H)+ B4c, i-Bu hex [HPLC B7c, ES-MS] Cif 90 )=N NO 2 0.74 20% B7a, N EtOAc/ Cla, i-Bu Me HCI hex D2a 91 S>=N - N2 7.85 0.74 20% 350 B7a, e N (b) EtOAc/ (M+H)+ Cla, i-Bu Me HCI hex [FAB] D2a 92
NO
2 0.77 20% B7a, N =N EtOAc/ Cla, i-Bu Me HCI hex D2a 213 WO 00/42031 PCTIUS99/29601 93
NO
2 0.76 20% B7a, EtOAc/ Cla, i-Bu Me HCI hex D2a 94 S N NO2 0.50 20% B7a, N EtOAc/ Cla, Me Me HCI hex D2a 95 N NO2 0.50 20% B7a, N EtOAc/ Cla, Me Me HCI hex D2a 96 NO 2 0.52 20% B7a, N / EtOAc/ Cla, __oN hex D2a Me Me HCI hexDa 97 Me 0.79 20% B7a, N /NO 2 EtOAc/ Cla, HCI hex D2a 98 Me 0.70 30% 391 Blb, N / NO 2 EtOAc/ (M+) B7a, Nhex [E ] C a, D2a 99 N /CN 46- 0.65 10% 344 Blb, N 49 EtOAc/ (M+H)+ B7a, i-Bu Et hex [HPLC Cla, ES-MS] D2f 100 N2 347 Blb, N>N (M+) B7a, Me [EI] Cla, D2a 101 sNN NO 2 0.63 30% 361 Blb, N EtOAc/ (M+) B7a, Me hex [FAB} Cla, D2a 214 WO 00/42031 PCT/US99/29601 102 s=N- N2 0.63 30% 394 Blb, N EtOAc/ (M+H)+ B7a, M hex [FAB] Cla, OH D2a, D5a 103 Me 7.67 363 A2b, N
INO
2 (b) (M+) B7a, N -0 -[El] Cia, i-Bu Me HCI D2a 104 C C1 0.74 30% 387 Blb, >-N EtOAc/ (M+H)+ B7a, hex [FAB] Cla, D2a 105 Me 0.81 30% 392 Blb, N /NO 2 EtOAc/ (M+H)+ B7a, hex [FAB] Cla, I D2a 106 C1 CI 53- 360 Blb, ==N 55 (M+H)+ B7a, i-Nu [FAB] Cla, D2a 107 )N17.5 348 Blb, N (d) (M+H)+ B7a, H F 3 C CF 3
CO
2 H [HPLC Clc ES-MS] 108 N NO2 28.9 404 Blb, - F (d) (M+H)+ B7a, i-Bu
F
3 C
CF
3
CO
2 H [HPLC Clc, ES-MS] D2f 109 N CN 23.7 383 Blb, N (e) (M+H)+ B7a, i-Bu
F
3 C
CF
3
CO
2 H [HPLC Clc, ES-MS] D2f 110 C 23.8 364 Blb, )N /CN (d) (M+H)+ B7a, i-Bu Me CF3CO2H [HPLC Clc, IFICI I ES-MS] D2f 215 WO 00/42031 PCT/US99/29601 S - 0 0.36 30% 363 Bib, N OMe EtOAc/ (M+H)+ B7a, i-Bu M hex [FAB] Cla, D2a 112 Me 0.79 30% 364 A2a, = N NO 2 EtOAc/ (M+H)+ step 3, i-Bu Me hex [CI] Bib, B7a, Cla, D2a 113 N 130- 348 Bib, N
NH
2 131 (M+H)+ B7a, i-Bu Me [CI] Cla, D2a, D6a 114 N 0.74 30% 323 Bib, ">=N j;/ F N EtOAc/ (M+H)+ B7a, i-Bu Me hex [FAB] Cla, D2a 115 S==N CI 0.74 30% 338 Bib, N EtOAc/ (M+) B7a, i-Bu Me hex [EI] Cla, D2a 116 / =N Br 0.74 30% 383 Bib, N EtOAc/ (M+H)+ B7a, i-Bu Me hex [FAB] Cla, D2a 117 / =N CN 0.54 50% C2a, N EtOAc/ D2a i-Bu Et hex 118 =NO2 0.44 5% 350 Bib, N M EtOAc/ (M+H)+ B4c, i-Bu Me hex [CI] B7c, Clb 119 S =N N 0.50 80% 306 A2b, N EtOAc/ (M+H)+ Bb, i-Bu Me hex [CI] B4c, 216 WO 00/42031 PCTIUS99/29601 B7c, Clb 120 _N2 124- 0.43 10% A2b, N 126 EtOAc/ Bib, i-Bu hex C2a, D2a 121 N NO2 0.80 30% 336 Bib, N EtOAc/ (M+H)+ B4c, i-Bu hex [HPLC B7c, ES-MS] Clf 122 -SN-CN 0.85 30% 316 Bib, N EtOAc/ (M+H)+ B4c, i-Bu hex [HPLC B7c, ES-MS] Clf 123 0.26 100% 322 A2b, ) N EtOAc (M+H)+ Blb, N [HPLC B4c, i-Bu Me ES-MS] B7c, Clb, D4a 124 - N NO2 0.51 10% B7a, N EtOAc/ Cla, i-Bu Me HCI hex D2a 125 -)~~N NO2 8.83 350 Bla N (b) (M+H)+ step 2, i-Bu Me HCI [CI] B7b, Cle, D2a 126 S )=N NO2 0.50 10% Bla N EtOAc/ step 2, i-Bu Me HCI hex Bib, Cla, D2a 127 -=0.36 30% 362 Bib, S / N OMe EtOAc/ (M+H)+ B7a, i-Bu Me HCI hex [EI] Cla, D2a 217 WO 00/42031 PCT/US99/29601 128 S N NO2 0.80 25% B7a, N EtOAc/ Cla, i-Bu Me hex D2a 129 N O 62- 345 A2a, N -Q f 64 (M+H)+ B7a, 6u [FAB] Cla, D2a 130 S#N \ /C 0.91 30% 393 A2a, N EtOAc/ (M+H)+ step 3, i-Bu
CF
3 hex [FAB] Bib, B7a, Cla, D2a 131 S-N CN 0.70 30% 384 A2a N EtOAc/ (M+H)+ step 3, i-Bu
CF
3 hex [FAB] Bib, B7a, Cla, D2a 132 S N NO2 386 A2b, N i- u 2 (M+H)+ Bib, [FAB] B7a, Cla, D2a 133 N CN 0.72 20% 343 Bib, N EtOAc/ (M+) B7a, i-Bu Et hex [EI] Cla, I _D2a 134 S>N - /CN 0.70 30% 330 Ala, N EtOAc/ (M+H)+ A2a i-Bu Me hex [FAB] step 3, Bla, B7a, D2a 135 Me 0.70 30% 344 Ala, N /CN EtOAc/ (M+H)+ A2a N u hex [FAB] step 3, i-2u Me 218 WO 00/42031 PCTIUS99/29601 Bla, B7a, D2a 136 Me 0.74 30% 364 A2a, N /NO 2 EtOAc/ (M+H)+ Blb, N u hex [FAB] B7a, i-Bu Me Cla, D2a 137 S N NO2 8.18 336 C2a, N (b) (M+H)+ D2a i-Bu Me [FAB] 138 N NO2 7.91 0.73 25% C2a, N / (b) EtOAc/ D2a 6Me hex 139 N NO2 0.82 33% B7b, N EtOAc/ Cla, i-Bu Me hex D2a I HCI 140 S-N NO2 0.80 33% B7b, N EtOAc/ Cla, i-Bu Me HCI hex D2a 141 he-~ 141 N NO 2 0.59 50% 292 Bib, N EtOAc/ (M+H)+ B7a, Me hex [CI] Cla 142 S NO 2 0.49 50% 278 Bib, N EtOAc/ (M+H)+ B7a, Me hex [FAB] Cla 143 N CN 0.24 20% 394 Blb, N EtOAc/ (M+H)+ B4c, i-Bu Et hex [HPLC B7c, I HCI ES-MS] Cib OH 219 WO 00/42031 PCT/US99/29601 144 s NCN 0.43 10% 412 Blb, N EtOAc/ (M+H)+ B4c, i-Bu Et hex [HPLC B7c, HCI ES-MS] Clb C1 145 s N CN 88- 0.20 10% 424 Blb, N 90 EtOAc/ (M+H)+ B4c, s i-Bu Et hex [HPLC B7c, HCI ES-MS] Clb 146 SN \ /p NO 2 0.40 25% B3a, MeO N EtOAc/ C2a Oi-Bu Me HChe o HCIhex 147 SN /P NO 2 0.40 25% B3a, MeOy N M EtOAc/ C2a O i-Bu Me HCI hex 148Me N
NO
2 8.79 B8a, - i-Bu Me 149 S>=N \/P NO 2 9.11 406 B8a, Me N (b) (M+H)+ C5b Me [CI] 150 s N- N2 8.84 406 B8a, Me N M (b) (M+H)+ C5b O Me >ro 6[CI] 151 S-N NO2 8.63 394 B8a, Me N (b) (M+H)+ C5b 0 i-Bu Me [CI] 152 S N CN 4.05 385 B8a, Me YN p (a) (M+H)+ C5b 6 Me [HPLC ES-MS] 220 WO 00/42031 PCT/US99/29601 153 N NO2 5.26 430 A2b, Me N (a) (M+H)+ B8a, \ /u[HPLC C5b ES-MS] 154 s N NO2 5.44 442 A2b, Me N (a) (M+H)+ B8a, >O [HPLC C5b ES-MS] 155 S=N NO2 4.19 446 A2a, Me..IN N O(a) (M+H)+ B8a, [HPLC C5b ES-MS] 156 s N NO2 4.80 434 A2a, Me N (a) (M+H)+ B8a, 6 (-Bu [HPLC C5b ES-MS] 157 rS)N NO2 3.98 422 A2a, Me N (a) (M+H)+ B8a, 6 i-Bu i-Pr [HPLC C5b ES-MS] 158 S N - / NO 2 6.12 434 A2a, Me N (a) (M+H)+ B8a, Si-Pr [HPLC C5b ES-MS] 159 S-N - /NO 2 5.74 420 A2b, Me N (a) (M+H)+ B8a, 0Me Me [HPLC C5b Me _ Me ES-M S] 160 S N NO 2 5.40 408 A2b, Me N (a) (M+H)+ B8a, 6 i-Bu Me Me [HPLC C5b ES-MS] 161 N /: NO 2 3.65 436 A2b, Me N (a) (M+H)+ B8a, Me Me [HPLC C5b ES-MS] 221 WO 00/42031 PCT/US99/29601 162 s N CN 5.07 426 A2b, Me N (a) (M+H)+ B8a, [HPLC C5b _ _ ES-MS] 163 -N CN 5.00 414 A2b, Me N (a) (M+H)+ B8a, 0 i-Bu [HPLC C5b ES-MS] 164 s N- N2 0.13 25% B8a, Me N EtOAc/ C5b, OH i-Bu Me hex D3a 165 S N NO2 4.75 386 A2b, Me N (a) (M+H)+ B8a, 6H [HPLC C5b, ES-MS] D3a 166 N NO2 7.29 338 B8a, Me N (b) (M+H)+ C5b, OH i-Bu Me [CI] D3a 167 S >=N NO 2 0.16 25% B8a, Me N EtOAc/ C5b, OH Me hex D3a 168 s N NO2 7.18 350 B8a, Me N (b) (M+H)+ C5b, OH Me [CI] D3a 169 S N NO2 5.07 372 A2b, Me N (a) (M+H)+ B8a, H t-Bu [HPLC C5b, ES-MS] D3b 170 S N CN 4.75 360 A2b, Me N (a) (M+H)+ B8a, 6H i-Bu t-Bu [HPLC C5b, ES-MS] D3b 171 S N NO2 4.68 374 A2b, Me _ N (a) (M+H)+ B8a, OH iBu [HPLC C5b, ES-MS] D3b 222 WO 00/42031 PCT/US99/29601 172 C N NO2 5.02 390 A2a, Me .' N (a) (M+H)+ B8a, OH [HPLC C5b, ES-MS] D3b 173 >-N NO2 4.55 378 A2a, Me N (a) (M+H)+ B8a, OH i-Bu [HPLC C5b, ES-MS] D3b 174 s N NO2 5.86 366 A2a, Me N (a) (M+H)+ B8a, 5H i-Bu i-Pr [HPLC C5b, ES-MS] D3b 175 S N NO2 6.00 378 A2a, Me N (a) (M+H)+ B8a, H i-Pr [HPLC C5b, ES-MS] D3b 176 N NO2 0.89 380 A2b, Me N (a) (M+H)+ B8a, OH Me Me [HPLC C5b, ES-MS] D3b 177 KS\ N NO 2 5.42 352 A2b, Me N (a) (M+H)+ B8a, OH i-Bu Me Me [HPLC C5b, ES-MS] D3b 178 s N >/NO 2 5.64 364 A2b, Me - N (a) (M+H)+ B8a, H Me Me [HPLC C5b, ES-MS] D3b 179 N CN 4.26 370 A2b, Me N (a) (M+H)+ B8a, H8 [HPLC C5b, ES-MS] D3b 180 s N CN 3.94 358 A2b, Me N (a) (M+H)+ B8a, OH i-Bu [HPLC C5b, ES-MS] D3b 223 WO 00/42031 PCT/US99/29601 181 8.46 C2a, N>N
NO
2 (b) D13a, i-Bu Me 182 s NO 2 0.82 5% C2a, N N MeOHI/ D13a, i-Bu Me CH2Cl2 D2a 183 0.15 25% C2a, s EtOAc/ D2a >=N
NO
2 CH2C12 i-Bu Me 184 N O 2 0.04 25% C2a, N N- EtOAc/ D2a i-Bu Mep CH2CI2 185 S N NO2 211 0.78 10% B7a, N MeOH/ Cla, MeHBr 90% D2g CH2C12 186 159 0.28 10% B4c, S - EtOAc/ C2f N
CF
3 90% pet. i-Bu CI HCI ether 187 0.26 10% B4c, s EtOAc/ C2f N 90% pet. i-Bu CI CI ether 188 S N -- 177 0.24 10% B4c, N EtOAc/ C2f i-Bu C1 Cl 90% pet. HCI ether 189 Cl 134 C2f N -0 N CI 224 WO 00/42031 PCT/US99/29601 190 s _ 209 B5b, N N \ / C2f "'M e i c Me CHCI 191 s 162 B5b, N / CI C2f Me 0 -11 HCI 192 s 209 B5b, N N C2f MCI CI Me HCI 193 s 164 C2f, N N B5b HO Cl CI HCI 194 s 178 0.80 10% C2f NN /NO 2 MeOH/ N H Me 90% CH2Cl2 195 s - 181 Cla, N
NO
2 D2g Me Me) HBr 196 s N 97 Cla, N NO 2 D2g i-Bu Me 197 s 154 Cla, N D2g i-Bu Cl Ci HCI 198 s - 156 B4c, N
NO
2 C2f Me 225 WO 00/42031 PCTIUS99/29601 199 s 154 B4c, N N C2f CI CI 200 s N 196 B5b, N N \/NO 2 C2f N C 'Me Me HCI 201 s 188 0.28 10% B5b, N N
NO
2
-
EtOAc/ C2f Me 190 90% pet. HCI ether 202 s - 108 0.16 10% B5b, N NO 2 EtOAc/ C2f i-Pr Me 90% pet. ether 203 s 63 0.26 10% B5b, N EtOAc/ C2f i-Pr CI CI 90% pet. ether 204 s N 95- 0.34 10% B5b, N C1 97 EtOAc/ C2f i-Bu CI 90% pet. HCI I ether 205 N NO2 229 B7a, N# P / O Ca, Me HBr D2g 206 N NO2 7.83 321 Blc, N (b) (M+H)+ B7b, i-Bu Me [EI] Cla, D2a 226 WO 00/42031 PCT/US99/29601 207 8.59 374 Blc, N NO 2 (b) (M+H)+ B4a N Me[CI] C2a 208 0.64 30% 374 A2a, N /D NO 2 EtOAc/ (M+H)+ Blc, N t hex [CI] B7a, Cla, 6 _D2b 209 S 0.74 20% 368 A5a, N CN EtOAc/ (M+H)+ A2b, N N n-Pr hex [CI] Blc, B7a, Cla, D2b, D7a 210 S 0.74 20% 368 A5a, N CN EtOAc/ (M+H)+ A2b, 6 i-Pr hex [CI] Blc, B7a, Cla, D2b, D7a 211 ( 200 0.74 20% 382 A5a, N / CN - EtOAc/ (M+H)+ A2b, N t-Bu 201 hex [CI] Blc, B7a, Cla, D2b, D7a 212 8.65 374 Blc, S N NO 2 (b) (M+H)+ B4a, N e [CI] C2a 227 WO 00/42031 PCT/US99/29601 213 dNNO2 0.82 25% Blc, N EtOAc/ B7a, i-Bu Me hex Cle, D2a 214 6NNO2 0.86 30% 362 A2a, N EtOAc/ (M+H)+ Blc, i-Bu Et hex [FAB] B7a, Cla, D2a 215 - NNO2 0.80 30% 376 A2a, N EtOAc/ (M+H)+ Blc, i-Bu n-Pr hex [FAB] B7a, Cla, D2a 216 6 N NO2 0.86 30% 376 A2a, N EtOAc/ (M+H)+ Blc, i-Bu i-Pr hex [FAB] B7a, Cla, D2a 217 N NO2 0.83 30% 362 A4a, N EtOAc/ (M+H)+ A2d, i-Bu Me Me hex [CI] Blc, B7e, C1c, D2a 218 6N NO2 68- 348 A2a N 70 (M+H)+ Blc, i-Bu Me [CI] B7a, Cla, D2a 219 6 N NO 2 0.64 30% 383 (M+) A2a, N EtOAc/ [EI] Blc, i-Bu hex B7a, Cla, D2a 228 WO 00/42031 PCT/US99/29601 220 N CN 71- Blc, N 72 B7e, i-Bu Cla, D2a 221 S N CN 98- 327 (M+) Ala, N 100 [El] A2a, i-Bu Me step 3, Blc, B7a, Cla, D2b 222 N CN 26.5 342 Blc, N (j) (M+H)+ B7a, i-Bu Et [HPLC Cla, ES-MS] D2b 223 -S N CN 0.73 20% 364 A2a N EtOAc/ (M+H)+ step 3, i-Bu hex [FAB] Blc, B7a, Cla, D2b 224 /SONCN 0.16 50% 342 A5a, N CH2Cl2/ (M+H)+ A2a i-Bu Me Me hex [CI] step 3, Blc, B7e, Cle, D2h, D7a 225 S>=N \ - H 0.70 20% A5a, N EtOAc/ A2a i-Bu Me Me hex step 3, Blc, C2a, D2a, D8a 229 WO 00/42031 PCT/US99/29601 226 6 S N I 0.39 50% 443 A5a, N CH2Cl2/ (M+H)+ A2a i-Bu Me Me hex [CI] step 3, Blc, B7e, Cle, D2h 227 0 2 N 362 A4a, S N (M+H)+ A2d, N -0 [CI] Blc, i-Bu Me Me B7e, Cle, D2b 228 S CN 58- 320 Ala, N 60 (M+H)+ A2b, i-Bu [CI] Blc, B7e, Cle, D2a 229 Me 140 0.68 30% 343 A2c, 6 N CN - EtOAc/ (M+H)+ Blc, -u Me 143 hex [CI-MS] B7e, Cle, D2h 230 N NO2 0.83 25% Blc, N EtOAc/ C2a, e HCI hex D2a 231 S N CN 86- 0.74 20% 356 Blc, N 88 EtOAc/ (M+H)+ B7e, Et hex [CI] Cle, D2b 232 N NO2 135 Blc, N P -- B7e, Me 137 Cle, D2e 230 WO 00/42031 PCT/US99/29601 233 N N2 95 N 97 B7e, Cle, D2e 234 N NO2 0.28 40% BIc, N EtOAc/ B7e, Me hex Cle, D2h 235 N N2 100 B1c, NN - O B7e, Me 102 Cle, D2e 236 __ = - - N2 85- BI1c, 236 N NO 2 N 87 B7e, Me Cle, D2e 237 N- 96- BC, N>= O 98 B7e, Me Cle, 0O D2e 238 N NO2 4.81 406 BIc, N (a) (M+H)+ B7e, Me [HPLC Cle, O ES-MS] D2e 239 S N NO2 5.29 346 BIc, N (a) (M+H)+ B7e, [HPLC- Cle, ES-MS] D2e 240 s N NO 2 120 0.45 10% BIc, N - EtOAc/ C2a, 121 hex D2b 231 WO 00/42031 PCT/US99/29601 241 0 126- 0.10 25% Blc,
S
>=N NO 2 128 EtOAc/ C2a, N P -hex D2b, 6Me D4a 242 O 181 0.27 25% Blc, S NNO 2 DEC EtOAc/ C2a, N hex D2b, 6 _D4a 243 s N- N2 0.86 30% 374 A2a, N NO 2 EtOAc/ (M+H)+ Blc, Et hex [CI] B7e, Cle, D2b 244 S-N NO2 136- 360 A2a N 137 (M+H)+ step 3, Me [FAB] Blc, B7e, Cle, D2b 245 S NO2 83- 374 A2a, N 84 (M+H)+ Blc, M Me [CI] B7e, Cle, D2b 246 0 2 N 374 A2a, S N (M+H)+ Blc, Me Me [CI] B7e, Cle, D2b 247 NCN 158- B1c, c - /NC 159 B7e, Cle, D2b D2h 232 WO 00/42031 PCT/US99/29601 248 N CN 106- 0.73 30% 340 Ala, N 107 EtOAc/ (M+H)+ A2b, Me hex [CI] Blc, B7e, Cle, D2b 249 s=N- CN 18.1 0.66 20% 354 Ala, N (j) EtOAc/ (M+H)+ A2b, Et hex [HPLC B7a, ___1 ES-MS] D2f 250 -sNC 0.74 20% 368 Blc, N nEtOAc/ (M+H)+ B7e, hex [CI] Cle, D2b 251 -s 0.74 20% 368 A2b, N EtOAc/ (M+H)+ Blc, hex [CI] C2a, D2b, D7a 252 sj>=N CN 0.18 50% 354 A2b, N CH2C12/ (M+H)+ Blc, Me Me hex [CI] C2a, D2b, D7a 253 S=N - 208- Blc, N OH 209 B7e, Et C2e, D2b, D9a 254 S>N- 228- Al a, 2 N OH 229 A2b, Me Blc, BMe, Cle, D2b, D9a 233 WO 00/42031 PCTIUS99/29601 255 S N Me 114- Blc, N>= F 4W 115B7e, Et C2e, D2b, D9a D10a 256 N 0.63 30% A2b, N OMe EtOAc/ Bic, Me hex C2a, I I ID2h 257 s N 0 0.44 30% Blc, N / NHMe EtOAc/ B7e, Et hex Cle, D2b, D9a, D6b 258 -_ 0 0.44 30% Blc, N NMe 2 EtOAc/ B7e, Et hex Cle, D2b, D9a, D6b 259 - N 0.71 10% 369 A3a, N EtOAc/ (M+H)+ Blc, CI CI hex [CI] B4d,
CF
3
CO
2 H C6c 260 S N 0.62 10% 369 A3a, N EtOAc/ (M+H)+ Blc, C: F 3 C hex [CI] B4d, C6c 261 s N CF 3 0.78 10% 369 A3a, N EtOAc/ (M+H)+ Blc, hex [CI] B4d, C6c 234 WO 00/42031 PCT/US99/29601 262 S ~~ 0.84 10% 349 A3a, N EtOAc/ (M+H)+ BIc, Cl Me hex [CI] B4d,
CF
3
CO
2 H I C6c 263 S N ~ 0.80 10% 369 A3a, N EtOAc/ (M+H)+ Blc,
CF
3 hex [CI] B4d, 6C6c 264 / =N Cl 0.44 2% 383 A3a, N EtOAc/ (M+H)+ Blc, C hex [CI] B4d,
CF
3
CO
2 H C6c 265 s)==N 0.65 2% 349 A3a, N EtOAc/ (M+H)+ Blc, 6 Me CI hex [CI] B4d,
CF
3
CO
2 H I C6c 266 ') N Br 0.71 20% C2a, N EtOAc/ D2a 6Me hex 267 0 == 104- 0.16 10% Blc, N H 105 EtOAc/ B7e, Et hex Cle, D2b, Dlla 268 >=N / 0.68 30% Blc, N EtOAc/ B7e, Etp QEt 6 hex Cle, D2b, Dlla D12a 269 S N 141- 0.61 20% Blc, N
NO
2 142 EtOAc/ B7e §Et hex Cle D2b, Dlla D12b 235 WO 00/42031 PCT/US99/29601 270 N 182- Bc, NN \/ "" H 183 B7e, Et OH Cl e, D2b, Dlla D12a D6a 271 S N 135- 0.52 20% BIC, N -P / \CN 136 EtOAc/ B7e, Et NC hex Cle, D2b, Dl~a D 12c 272 >N o 0.68 30% BIc, N EtOAc/ B7e, hex Cle, D2b, D11a D12a 273 N 0.56 30% BIc, N CN EtOAc/ B7e, 5 Et hex Cle, D2b, DIla D12d 274 N- 155- B1c, Me D2e 275 N NO 2 157 C, Me D2e 276 (NM NO2 0.69 20% Bla, N EtOAc/ C2a, i-Bu Me hex D2b 236 WO 00/42031 PCT/US99/29601 277 - N NO2 101- 0.15 10% 364 A3a, N 104 EtOAc/ (M+H)+ Bib, 0 i-Bu Me hex [HPLC B4c, ES-MS] C6c 278 -S - NO2 102- 0.29 10% 364 A3a, N 105 EtOAc/ (M+H)+ Bib, i-Bu Me hex [HPLC B4c, ES-MS] C6c 279 S>N NO2 0.72 25% Bla, N EtOAc/ B2a, i- Me hex B7a, Cla 280 S N NO2 0.76 33% B6a, N EtOAc/ B7e, i-Bu Me HCI hex C2a, D2a 281 CS N NO2 0.53 20% 308 B9a, N EtOAc/ (M+H)+ Cla i-Bu Me hex [HPLC ES-MS] 282 S N NO2 0.51 20% 322 B9a, N EtOAc/ (M+H)+ Cla i-Bu Me hex [HPLC I ES-MS] (a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2x300 mm Phenomenex 3 uM C-18 column; flow rate 1.0 mL/min.; Buffer A: 0.02% TFA/2% CH 3 CN/water, Buffer B: 5 0.018% TFA/98% CH 3 CN/water; hold at 100% Buffer A for 1 min., gradient from 100% Buffer A to 100% Buffer B over 3 min., hold at 100% Buffer B 1 min., gradient from 100% Buffer B to 100% Buffer A over 0.5 min., hold at 100% Buffer A 1.5 min. 10 (b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4x100 mm Dynamax 3 uM C-18 column; flow rate 1.5 mL/min.; Buffer A: 0.5% TFA/water, Buffer B: 237 WO 00/42031 PCT/US99/29601 0.5% TFA/CH 3 CN; gradient from 100% Buffer A to 100% Buffer B over 10 min, hold at 100% Buffer B 5 min. (c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) 5 and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H 3
PO
4 /water, Buffer B: 0.01 mol%
H
3
PO
4 / CH 3 CN; 10% Buffer B for 1 min., gradient from 10 Buffer B to 90% Buffer B over 8 min., gradient from 90% Buffer B to 10% Buffer B over 4 min. 10 (d) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 30% Buffer B to 15 100% Buffer B over 25 min., hold at 100% Buffer B 30 min. (e) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, 20 Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 50% Buffer B to 60% Buffer B over 25 min., gradient from 60% to 100% over 32 min. (f) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 25 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 30 min. (g) Ranin Dynamax HPLC equipped with UV-DII dual wavelength 30 detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 50% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 7 min. 35 (h) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, 238 WO 00/42031 PCT/US99/29601 Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 10% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. (i) Ranin Dynamax HPLC equipped with UV-DII dual wavelength 5 detector (254 and 220 nm) and a 4.6x100 mm Microsorb 5 uM C-8 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min. 10 (j) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. 15 Table 2.2-Imino-1,3-thiazolidin-4-ones and 2-Imino-1,3-thiazolidin-5-ones TLC Mass Spec. mp HPL TLC Solvent [Source] Synth. Entry Compound ('C) (min.) Rf System Method 283 >=N NO2 8.03 0.44 100% 307 (M+) C8a O N / 2(c) CH2Cl2 [EI] i-Bu Me 284 S >N NO2 7.98 0.20 100% 341 (M+) C8a O N (c) CH2Cl2 [El] Me 285 r >=N NO2 8.46 0.26 100% 321 (M+) C8a O N N (c) CH2Cl2 [El] Me 286 rS N NO2 9.46 0.30 100% 361 (M+) C8a O N (c) CH2Cl2 [El] Me 239 WO 00/42031 PCT/US99/29601 287 s >=N NO2 8.03 0.58 100% 307 (M+) C8a O, N (c) CH2Cl2 [EI] i-Bu Me 288 s N 8.45 0.62 100% 321 (M+) C8a O N N 2 (c) CH2Cl2 [EI] Me 289 j >N NO2 8.02 0.61 100% 341 (M+) C8a N NO (c) CH2Cl2 [EI] Me 290 S> N NO2 8.53 0.67 100% 321 (M+) C8a o N (c) CH2Cl2 [EI] i-Bu Me 291 s>N NO2 9.37 0.62 100% 361 (M+) C8a (c) CH2Cl2 [EI] Me 292 S >N NO2 9.35 0.76 100% 361 (M+) C8a O N (c) CH2Cl2 [EI] Me 293 CS >N NO2 98 9.36 0.76 100% 361 (M+) C8a O N N 2 (c) CH2Cl2 [EI] ,Me 294 9.01 0.78 100% 383 (M+) C8a S> S - (c) CH2Cl2 [EI] N /NO 2 i-Bu Me 295 Me s=N NO2 63- 9.78 0.73 100% 375 (M+) C8a N NO 67 (c) CH2CI2 [EI] 0Me 240 WO 00/42031 PCTfUS99/29601 296 62- 10.1 0.86 100% 437 (M+) C8a s N N- 2 63 1 (c) CH2Cl2 [EI] Me 297 Me s=N N2 68- 9.77 0.74 100% 375 (M+) C8a 0AN 71 (c) CH2Cl2 [EI] Me 298 1 69- 10.0 0.91 100% 437 (M+) C8a s -- 71 0 (c) CH2Cl2 [EI] N)=N
NO
2 Me 299 Me )t=N NO2 9.23 0.70 100% 349 (M+) C8a 0):N (c) CH2Cl2 [EI] Me 300 S N 9.47 0.79 100% 363 (M+) C8a O' N NO 2 (c) CH2Cl2 [EI] i-Bu Me 301 S N 10.2 0.86 100% 391 (M+) C8a o NO0 (c) CH2Cl2 [EI] i-Bu Me 302 S) 9.83 0.82 100% 377(M+) C8a N (c) CH2Cl2 [EI] Me 303 9.61 0.34 50% 363 (M+) C8a S N NO 2 (c) CH2C12/ [EI] N Me' cyclohex 304 9.23 0.32 50% 349 (M+) C8a =N NO 2 (c) CH2CI2/ [EI] N cyclohex i-Bu -Me 241 WO 00/42031 PCT/US99/29601 305 s N NO2 8.37 0.55 100% 321 (M+) C8a 0 NN (c) CH2Cl2 [EI] Me 306 9.90 0.78 100% 377 (M+) C8a O =N5N
NO
2 (c) CH2Cl2 [EI] Me 307 O - 0.50 25% B3a, N NNO 2 EtOAc/ B7b,
H
2 C : i-Bu Me hex C2a 27 C1 8.97 0.40 30% 362 C8a N / NO 2 (c) EtOAc/ (M+H)+ CN hex [FAB] 308 C1 7.95 0.35 10% 365 C8a SS>N CI (c) EtOAc/ (M+H)+ N C hex [FAB] 309 s NC 7.95 0.35 10% 635 C8a O C N (c) EtOAc/ (M+H)+ C1 hex [FAB] 310 S >N N2 152 7.28 307(M+) C1la N (c) [EI] i-Bu Me_ 311 s N NO2 8.79 0.66 100% 335 (M+) C8a O N (c) CH2Cl2 [EI] Me 312 S N NO2 8.66 0.17 100% 363 (M+) ClIa /NN (c) CH2Cl2 [EI] i-Bu Me_ 242 WO 00/42031 PCT/US99/29601 313 0 -- 138 5.88 0.57 2% 291 (M+) Cla N)M=N / NO 2 (c) MeOH/ [EI] Me- CH2Cl2 (a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2x300 mm Phenomenex 3 uM C-18 column; flow rate 1.0 mL/min.; Buffer A: 0.02% TFA/2% CH 3 CN/water, Buffer B: 5 0.018% TFA/98% CH 3 CN/water; hold at 100% Buffer A for 1 min., gradient from 100% Buffer A to 100% Buffer B over 3 min., hold at 100% Buffer B 1 min., gradient from 100% Buffer B to 100% Buffer A over 0.5 min., hold at 100% Buffer A 1.5 min. 10 (b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4x100 mm Dynamax 3 uM C-18 column; flow rate 1.5 mL/min.; Buffer A: 0.5% TFA/water, Buffer B: 0.5% TFA/CH 3 CN; gradient from 100% Buffer A to 100% Buffer B over 10 min, hold at 100% Buffer B 5 min. 15 (c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H 3
PO
4 /water, Buffer B: 0.01 mol%
H
3
PO
4 / CH 3 CN; 10% Buffer B for 1 min., gradient from 10 Buffer B 20 to 90% Buffer B over 8 min., gradient from 90% Buffer B to 10% Buffer B over 4 min. (d) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 25 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% Buffer B 30 min. (e) Ranin Dynamax HPLC equipped with UV-DII dual wavelength 30 detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 50% Buffer B to 60% Buffer B over 25 min., gradient from 60% to 100% over 32 min. 243 WO 00/42031 PCT/US99/29601 (f) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 30% Buffer B to 5 100% Buffer B over 25 min., hold at 100% B 100% for 30 min. (g) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, 10 Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 50% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 7 min. (h) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 15 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 10% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. (i) Ranin Dynamax HPLC equipped with UV-DII dual wavelength 20 detector (254 and 220 nm) and a 4.6x100 mm Microsorb 5 uM C-8 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min. 25 (j) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. 30 244 WO 00/42031 PCT/US99/29601 Table 3.2-Imino-1,3-oxazolidines TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry Compound ('C) (min.) Rf System [Source] ethod 314 0 N - N2 0.30 30% 276 B8a N EtOAc/ (M+H)+ C5a Me hex [CI] 315 >=N M NO 2 6.77 0.30 20% 319 Blb N (c) EtOAc/ (M+) B4c i-Bu Me hex [EI] B7b C4a 316 N NO2 7.42 0.25 30% 334 BTUb N (c) EtOAc/ (M+H)+ B4c i-Bu Me hex [CI] B7b C4a 317 N 0.35 10% 328 A3a N EtOAc/ (M+H)+ i-Bu Et hex [HPLC B4c ES-MS] C7b 318 O N NO2 134- 0.55 15% 318 A3a N 136 EtOAc/ (M+H)+ B4c M hex [CI] C7a 319 0 >N - CN 112- 0.60 15% 312 A3a, N 114 EtOAc/ (M+H)+ B4c, E hex [CI] C7a 320 N NO2 8.25 344 BIc, CN NO (b) (M+H)+ B4d, Me [CI] B7b, _ _C4a 321 0 =N N 2 7.83 BIc, N NO 2 (b) B4a, B7b, C4a 245 WO 00/42031 PCT/US99/29601 322 0)==N NO2 8.30 358 Blc, N (b) (M+H)+ B4a, Me [CI] B7b, C4a 323 O->=N CN 0.38 10% 338 A3a, N EtOAc/ (M+H)+ Blc, hex [FAB] B4d, I_ C7a (a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2x300 mm Phenomenex 3 uM C-18 column; flow rate 1.0 mL/min.; Buffer A: 0.02% TFA/2% CH 3 CN/water, Buffer B: 5 0.018% TFA/98% CH 3 CN/water; hold at 100% Buffer A for 1 min., gradient from 100% Buffer A to 100% Buffer B over 3 min., hold at 100% Buffer B 1 min., gradient from 100% Buffer B to 100% Buffer A over 0.5 min., hold at 100% Buffer A 1.5 min. 10 (b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4x100 mm Dynamax 3 uM C-18 column; flow rate 1.5 mL/min.; Buffer A: 0.5% TFA/water, Buffer B: 0.5% TFA/CH 3 CN; gradient from 100% Buffer A to 100% Buffer B over 10 min, hold at 100% Buffer B 5 min. 15 (c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H 3
PO
4 /water, Buffer B: 0.01 mol%
H
3
PO
4 / CH 3 CN; 10% Buffer B for 1 min., gradient from 10 Buffer B 20 to 90% Buffer B over 8 min., gradient from 90% Buffer B to 10% Buffer B over 4 min. (d) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 25 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% Buffer B 30 min. 246 WO 00/42031 PCT/US99/29601 (e) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 50% Buffer B to 5 60% Buffer B over 25 min., gradient from 60% to 100% over 32 min. (f) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, 10 Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 30 min. (g) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 15 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 50% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 7 min. (h) Ranin Dynamax HPLC equipped with UV-DII dual wavelength 20 detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 10% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. 25 (i) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4.6x100 mm Microsorb 5 uM C-8 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min. 30 (j) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 20% Buffer B to 35 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. 247 WO 00/42031 PCT/US99/29601 Table 4. Additional Examples TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry Compound ('C) (min.) Rf System [Source] Meth. 324 S NO 2 0.67 30% 336 Blb, N EtOAc/ (M+H)+ B4c, i-Bu hex [HPLC B7c, ES-MS] Clf 325 Me 0.81 30% 392 B7a, N /NNO 2 EtOAc/ (M+H)+ Cla, N hex [FAB] D2a 326 S NO7.99 0.59 20% 350 Bib )/-NON (b) EtOAc/ (M+H)+ B7a, HCI Me hex [FAB] Cla, D2a 327 - 0.81 30% 364 B7a, N L Ne EtOAc/ (M+H)+ Cla, Me hex [FAB] D2a 328 CI C1 .74 30% 387 B7a, N0 EtOAc/ (M+H)+ Cla, N hex [FAB] D2a (a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS 5 detector and a 2x300 mm Phenomenex 3 uM C-18 column; flow rate 1.0 mL/min.; Buffer A: 0.02% TFA/2% CH 3 CN/water, Buffer B: 0.018% TFA/98% CH 3 CN/water; hold at 100% Buffer A for 1 min., gradient from 100% Buffer A to 100% Buffer B over 3 min., hold at 100% Buffer B 1 min., gradient from 100% Buffer B to 100% Buffer 10 A over 0.5 min., hold at 100% Buffer A 1.5 min. (b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 4x100 mm Dynamax 3 uM C-18 column; flow rate 1.5 mL/min.; Buffer A: 0.5% TFA/water, Buffer B: 248 WO 00/42031 PCT/US99/29601 0.5% TFA/CH 3 CN; gradient from 100% Buffer A to 100% Buffer B over 10 min, hold at 100% Buffer B 5 min. (c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) 5 and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H 3
PO
4 /water, Buffer B: 0.01 mol%
H
3
PO
4 / CH 3 CN; 10% Buffer B for 1 min., gradient from 10 Buffer B to 90% Buffer B over 8 min., gradient from 90% Buffer B to 10% Buffer B over 4 min. 10 (d) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 30% Buffer B to 15 100% Buffer B over 25 min., hold at 100% Buffer B 30 min. (e) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 uM C-18 column; flow rate 18 mL/min.; Buffer A: 0.1% TFA/99.9% water, 20 Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 50% Buffer B to 60% Buffer B over 25 min., gradient from 60% to 100% over 32 min. (f) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 25 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 30% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 30 min. (g) Ranin Dynamax HPLC equipped with UV-DII dual wavelength 30 detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 50% Buffer B to 100% Buffer B over 25 min., hold at 100% B 100% for 7 min. 35 (h) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a 21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, 249 WO 00/42031 PCT/US99/29601 Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 10% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. (i) Ranin Dynamax HPLC equipped with UV-DII dual wavelength 5 detector (254 and 220 nm) and a 4.6x100 mm Microsorb 5 uM C-8 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min. 10 (j) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and a.21x2500 mm Microsorb 5 uM C-18 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH 3 CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. 15 Biological Protocol The activity of a given compound to bind to the progesterone receptor can be assayed routinely according to procedure disclosed below. This procedure was used 20 to determine the progesterone binding activities of the compounds of the invention. Progesterone Receptor Binding Assay To siliconized glass test tubes cooled over an ice water bath was added binding buffer (100 mL; 50 mM Tris, pH 7.4, 10 mM molybdic acid, 2 mM EDTA, 25 150 mM NaCl, 5% Glycerol, 1% DMSO) containing various concentrations of a compound to be assayed, T47D cell cytosol (100 pL of a solution which will give at least 4000 cpm of binding) and 3 H-progesterone (50 pL, 10 nM, NET-381). The mixture was incubated for 16 h at 4 *C, and treated with charcoal (250 pL of a 0.5% mixture of 0.05% dextran-coated charcoal which had been washed twice with 30 binding buffer). The resulting mixture was incubated for 10 min. at 4 *C. The tubes were centrifuged (20 min at 2800 x g) at 4 'C. The supernatant was transferred into scintillation vials containing scintillation fluid (4 mL). Remaining 3 H-progesterone was determined with a Packard 1900TR beta counter. Each assay included the following control groups: 1) total binding group (without compound), 2) non-specific 35 binding group (with 400 nM progesterone), and 3) positive control group (with 2 nM progesterone or a known inhibitor). The compounds of the present invention were found to cause greater than or equal to 30% inhibition of binding of 3 H-progesterone to the progesterone receptor at 250 WO 00/42031 PCT/US99/29601 a compound concentration of 200 nM. Activity ranges of the compounds of the present invention in the Progesterone Receptor Binding Assay at a compound concentration of 200 nM are listed in Table 5. 5 Table 5. Inhibitory Activity of Exemplified Compounds Compounds Which Cause 30- Compounds Which Cause 60- Compounds Which Cause 59% Inhibition at 200 nM 79% Inhibition at 200 nM (Entry 80-100% Inhibition at (Entry Number) Number) 200 nM (Entry Number) 1 2 3 5 4 8 6 9 11 7 15 14 10 16 17 12 19 18 13 26 20 27 29 21 34 30 22 43 31 23 45 32 24 48 35 25 49 36 28 56 37 33 57 38 40 59 39 41 61 42 44 64 46 47 66 54 50 67 60 51 74 63 52 75 71 53 79 73 55 83 77 58 84 78 62 87 81 65 89 82 68 92 86 69 251 WO 00/42031 PCT/US99/29601 94 88 70 96 95 72 108 103 76 113 106 80 120 110 85 123 112 90 129 114 91 130 119 93 131 134 97 135 144 99 136 149 102 141 150 104 143 153 105 146 154 107 147 155 109 148 160 111 151 162 115 152 164 116 156 166 117 157 170 118 158 174 121 159 180 122 161 188 125 163 193 126 169 198 127 175 200 128 181 201 132 182 210 133 183 211 137 184 212 138 185 225 139 186 236 140 187 241 145 189 242 165 190 246 167 191 258 168 252 WO 00/42031 PCT/US99/29601 192 260 171 194 261 172 195 269 173 199 277 176 202 279 177 203 290 178 204 294 179 205 296 196 207 297 197 226 300 206 227 301 208 228 317 209 229 213 238 215 254 218 257 219 262 220 263 221 264 223 265 224 266 230 270 231 272 232 273 233 308 234 309 235 310 237 312 240 313 243 314 244 321 245 324 247 326 248 327 249 328 250 251 253 WO 00/4203 1 PCTIUS99/29601I ____ ____ ___ ____ ___252 ____ ___ ___ ___ ____ _ _ ___ ___ ____ ___ ___ ___253 255 ____ ___ ____ ___ ____ ___ ____ ___ ____ ___ ___256 259 267 268 ____ ____ ____ ____ ___271 274 ____ ____ ____ ____ ___275 276 278 280 281 282 ____ ___ ___ ___ ____ _ _ ___ ___ ____ ___ ___ ___283 284 285 286 ____ ___ ____ ___ ___ ___ ___ ___ ____ ___ ___287 288 ____ ____ ___ ____ ___289 ____ ____ ___ ____ ___291 292 ____ ____ ____ ____ ___293 295 ____ ____ ___ ____ ___298 299 302 303 304 305 306 307 ____ ___ ___ ____ ___ ___311 ____ ___ ____ ___ ___ ___ ___ ___ ____ ___ ___315 254 WO 00/42031 PCT/US99/29601 316 318 319 320 322 323 325 The preceeding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceeding examples. 5 Other embodiments of the invention will be apparent to the skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following 10 claims. 255

Claims (7)

1. A compound having the formula (T)t R\ N ,R(G)g X N (Q)qR 2 (Q)qR 3 CnH 2 n-p (Q)qR 4 5 wherein Ris aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S, with the proviso that 10 R is other than benzofuran or benzothiophene; R 1 is alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings; heterocycloalkyl of 4 - 7 carbons and containing 1 - 3 rings and 1 - 3 15 heteroatoms selected from the group consisting of N, 0, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons; R 2 , R(, and R 4 are independently selected from the group consisting of 20 H; alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons; 25 aryl of 6 - 13 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; C0 2 R ; wherein R' is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, 30 cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; halogen; and =0 , representing two of the groups R 2 , R 3 , and R 4 ; 256 WO 00/42031 PCT/US99/29601 X is 0 or S(O), ; wherein y is 0, 1, or 2; n is 2, 3, 4, or 5; p is the sum of non-H substituents R2, R', and R 4 ; 5 T is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; CO 2 H; 10 C0 2 R'; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C 6 H 5 ; C(O)N(R 6 )(R 7 ) ;wherein 15 R 6 is H or alkyl of 1 - 5 carbons; and R 7 is H or alkyl of 1 - 5 carbons; S(0),,R' ; wherein y' is 1 or 2; and R' is alkyl of 1 - 5 carbons; 20 SO 2 F; CHO; OH; NO 2 ; CN; 25 halogen; OCF 3 ; N-oxide; O-C(R 9 ) 2 -0 , the oxygens being connected to adjacent positions on R; and wherein 30 R' is H, halogen, or alkyl of 1 - 4 carbons; C(O)NHC(O) , the carbons being connected to adjacent positions on R; and C(O)C 6 H 4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; 35 t is 1 - 5; provided that when substituent moiety T is alkyl of 1 - 4 carbons, alkoxy of 1 - 4 carbons, aryl of 6 - 10 carbons, C0 2 R', alkenyl of 2 - 4 carbons, alkynyl of 2 - 4 carbons, C(O)C 6 H 5 , C(O)N(R 6 )(R 7 ), S(O),R, 257 WO 00/42031 PCT/US99/29601 O-C(R') 2 -0 , or C(O)C 6 H 4 , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; C0 2 R'; CO 2 H; C(O)N(R 6 )(R 7 ); CHO; OH; NO 2 ; CN; halogen; S(O)yR'; or =0, the number of said 5 secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level; G is a substituent selected from the group consisting of halogen; OH; 10 OR'; =0 , representing two substituents G; alkyl of 1 - 4 carbons; alkenyl of 1 - 4 carbons; cycloalkyl of 3 - 7 carbons; 15 heterocycloalkyl of 3 - 5 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; cycloalkenyl of 5 - 7 carbons; heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; 20 C0 2 R; C(O)N(RW)(R7); aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; 25 NO 2 ; CN; S(O),R'; S0 3 R'; and SO 2 N(R 6 )(R 7 ); 30 g is 0 - 4, with the exception of halogen, which may be employed up to the perhalo level; provided that when substituent G is alkyl of 1 - 4 carbons, alkenyl of 1 - 4 carbons, cycloalkyl of 3 - 7 carbons, heterocycloalkyl of 3 - 5 carbons, cycloalkenyl of 5 - 7 carbons, or heterocycloalkenyl of 4 - 6 35 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and 258 WO 00/42031 PCT/US99/29601 halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; 5 haloalkyl of 1 - 4 carbons; cycloalkyl of 3 - 8 carbons; alkoxy of 1 - 8 carbons; alkenyl of 2 - 5 carbons; cycloalkenyl of 5 - 8 carbons; 10 aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; CO 2 R'; =0 , representing two substituents Q; 15 OH; halogen; N(R6)(R7); S(O),R8; S0 3 R; and 20 SO 2 N(R 6 )(R 7 ); q is 0 - 4 provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the 25 number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and with the further provisos that: a) two of (Q)qR', (Q)qR 2 , (Q)qR 3 , and (Q)qR 4 may be joined, and taken together with the atom(s) to which they are attached, form a spiro or 30 nonspiro nonaromatic ring of 3 - 8 members containing 0 - 2 heteroatoms selected from the group consisting of N, 0, and S; b) when n =2 or 3, at least one of R 2 , R 3 , and R 4 is other than H; c) when n = 2, and X = 0, if t = 1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3 35 oxazolidine ring must bear a substituent; d) when n = 3 and X = 0, if t is equal to or greater than 1, then at least one T is selected from the list of substituents T above, excepting alkyl and alkoxy; 259 WO 00/42031 PCT/US99/29601 e) when n = 2 or 3 and X = 0 or S, then the sum of non-hydrogen atoms in R', R 2 , R 3 , and R 4 is at least 5; f) when n = 2, X = 0, the 4-position of the 1,3-oxazolidine ring bears a carbonyl group, and R bears halogen at its 2- and 4- positions, then the 5 5-position of R bears H; g) when n = 2 and X = 0, the 4-position of thel,3-oxazolidine ring may bear a carbonyl only if the 5-position of said ring bears at least one non-H substituent; h) when n = 2, X = S(O), , the 4-position of the 1,3-thiazolidine ring 10 bears a carbonyl group, R' is a substituted methyl group, and G is a phenyl group, then said phenyl group bears a secondary substituent; i) when n = 4, X = S, and G is C0 2 R' , then R 5 contains at least two carbons; 15 and pharmaceutically acceptable salts thereof.
2. A compound having the formula (T)t R N Ak ,R'(G)g X N ( Q ) g R 2 (Q)q R3 4 CnH2n-p (Q)qR 4 wherein 20 Ris phenyl; or pyridyl; R 1 is alkyl of 1 - 10 carbons; 25 cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons; R 2 , Ri, and R 4 are independently selected from the group consisting of 30 H; alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; alkenyl of 2 - 10 carbons; 260 WO 00/42031 PCT/US99/29601 cycloalkenyl of 5 - 12 carbons; and =0 , representing two of the groups R 2 , R 3 , and R 4 ; X is 0 or S(O), ; wherein y is 0, 1, or 2; 5 n is 2 or 3; p is the sum of non-H substituents R 2 , R 3 , and R 4 ; T is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; 10 alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; NO 2 ; CN; and halogen; 15 t is 1 - 5; provided that when substituent moiety T is alkyl of 1 - 4 carbons, alkoxy of 1 - 4 carbons, alkenyl of 2 - 4 carbons, or alkynyl of 2 - 4 carbons, then T optionally may bear secondary substituents selected from the group consisting of 20 alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; C0 2 R; wherein R' is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 25 3 - 6 carbons; CO 2 H; C(O)N(R)(R'); wherein R is H or alkyl of 1 - 5 carbons; and R 7 is H or alkyl of 1 - 5 carbons; 30 CHO; OH; NO 2 ; CN; halogen; 35 S(O)yR; wherein R' is alkyl of 1 - 5 carbons; and =0, representing two secondary substituents; 261 WO 00/42031 PCT/US99/29601 the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level; G is a substituent selected from the group consisting of halogen; 5 OR'; alkyl of 1 - 4 carbons; alkenyl of 1 - 4 carbons; cycloalkyl of 3 - 7 carbons; cycloalkenyl of 5 - 7 carbons; 10 aryl of 6 - 10 carbons; and CN; g is 0 - 4, with the exception of halogen, which may be employed up to the perhalo level; provided that when substituent G is alkyl of 1 - 4 carbons, alkenyl of 1 15 - 4 carbons, cycloalkyl of 3 - 7 carbons, or cycloalkenyl of 5 - 7 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the 20 number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; haloalkyl of 1 - 4 carbons; 25 cycloalkyl of 3 - 8 carbons; alkoxy of 1 - 8 carbons; alkenyl of 2 - 5 carbons; cycloalkenyl of 5 - 8 carbons; C0 2 R 5 ; 30 =0 , representing two substituents Q; OH; halogen; N(R 6 )(R7); and S(O),RW; 35 q is 0 - 4; and with the further provisos that: 262 WO 00/42031 PCT/US99/29601 a) two of (Q)qR', (Q)qR 2 , (Q)qR 3 , and (Q)qR 4 may be joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3 - 8 members containing 0 - 2 heteroatoms selected from the group consisting of N, 0, and S; 5 b) when n = 2 or 3, at least one of R 2 , R 3 , and R 4 is other than H; c) when n = 2, and X = 0, if t = 1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3 oxazolidine ring must bear a substituent; d) when n = 3 and X = 0, if t is equal to or greater than 1, then at least 10 one T is selected from the list of substituents T above, excepting alkyl and alkoxy; e) when n = 2 or 3 and X = 0 or S, then the sum of non-hydrogen atoms in R', R 2 , R 3 , and R 4 is at least 5; f) when n = 2, X = 0, the 4-position of the 1,3-oxazolidine ring bears a 15 carbonyl group, and R bears halogen at its 2- and 4- positions, then the
5-position of R bears H; g) when n = 2 and X = 0, the 4-position of thel,3-oxazolidine ring may bear a carbonyl only if the 5-position of said ring bears at least one non-H substituent; and 20 h) when n = 2, X = S(O), , the 4-position of the 1,3-thiazolidine ring bears a carbonyl group, R' is a substituted methyl group, and G is a phenyl group, then said phenyl group bears a secondary substituent; and pharmaceutically acceptable salts thereof. 25 3. A compound having the formula (T)t R AK ,R(G)g X N (Q)qR 2 (Q)q CnH2np (Q)qR 4 wherein R is 30 phenyl; or pyridyl; R' is alkyl of 1 - 10 carbons; 263 WO 00/42031 PCT/US99/29601 cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings; alkenyl of 2 - 10 carbons; or cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; R 2 , R3, and R 4 are independently selected from the group consisting of 5 H; alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; alkenyl of 2 - 10 carbons; and cycloalkenyl of 5 - 12 carbons; 10 X is 0 or S(O), ; wherein y is 0, 1, or 2; n is 2 or 3; p is the sum of non-H substituents R2, R3, and R 4 ; T is a substituent selected from the group consisting of 15 alkyl of 1 - 4 carbons; alkenyl of 2 - 4 carbons; NO 2 ; CN; and halogen; 20 tis 1 -5; provided that when substituent moiety T is alkyl of 1 - 4 carbons, or alkenyl of 2 - 4 carbons, then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; 25 alkoxy of 1 - 4 carbons; CO 2 R; wherein R' is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; 30 CO 2 H; C(O)N(R 6 )(R 7 ); wherein R is H or alkyl of 1 - 5 carbons; and R' is H or alkyl of 1 - 5 carbons; CHO; 35 OH; NO 2 ; CN; halogen; 264 WO 00/42031 PCT/US99/29601 S(O)yR; wherein R' is alkyl of 1 - 5 carbons; and =0; the number of said secondary substituents being 1 or 2 with the 5 exception of halogen, which may be employed up to the perhalo level; G is a substituent selected from the group consisting of halogen; alkyl of 1 - 4 carbons; alkenyl of 1 - 4 carbons; 10 cycloalkyl of 3 - 7 carbons; cycloalkenyl of 5 - 7 carbons; and aryl of 6 - 10 carbons; g is 0 - 4, with the exception of halogen, which may be employed up to the perhalo level; 15 provided that when substituent G is alkyl of 1 - 4 carbons, alkenyl of 1 - 4 carbons, cycloalkyl of 3 - 7 carbons, or cycloalkenyl of 5 - 7 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl, then G optionally may bear secondary substituents independently selected 20 from the group consisting of alkyl of 1 - 4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; 25 haloalkyl of 1 - 4 carbons; cycloalkyl of 3 - 8 carbons; alkoxy of 1 - 8 carbons; alkenyl of 2 - 5 carbons; cycloalkenyl of 5 - 8 carbons; and 30 halogen; qis0-4; and with the further provisos that: a) two of (Q)qR', (Q)qR 2 , (Q)qR 3 , and (Q)qR 4 may be joined, and taken 35 together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3 - 8 members containing 0 - 2 heteroatoms selected from the group consisting of N, 0, and S; b) when n = 2 or 3, at least one of R 2 , R3, and R4 is other than H; 265 WO 00/42031 PCT/US99/29601 c) when n = 2, and X = 0, if t = 1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3 oxazolidine ring must bear a substituent; d) when n = 3 and X = 0, if t is equal to or greater than 1, then at least 5 one T is selected from the list of substituents T above, excepting alkyl; e) when n = 2 or 3 and X = 0 or S, then the sum of non-hydrogen atoms in R', R2, R 3 , and R 4 is at least 5; and pharmaceutically acceptable salts thereof. 10 4. A compound of claim 1 selected, from the group consisting of: ( 4 S)- 2 -( 2 -methyl- 4 -nitrophenylimino)-3-isobutyl-4-isopropyl-1,3 thiazolidine; (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine; 15 (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(trifluoromethyl)-1,3 thiazolidine; ( 4 S)- 2 -( 2 -methyl-4-nitrophenylimino)-3-cyclopentyl-4-isobutyl- 1,3 thiazolidine; ( 4 S)- 2 -(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3 20 thiazolidine; ( 4 S)- 2 -( 2 -methyl-4-nitrophenylimino)-3-cyclopentyl-4-isopropyl-1,3 thiazolidine; (4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyltetrahydro-2H 1,3-thiazine; 25 (4S)-2-(4-nitro- 1 -naphthylimino)-3-cyclopentyl-4-((lR)- 1 -hydroxyethyl)- 1,3 thiazolidine; 2 -(4-cyano-2-methylphenylimino)- 1 -cyclopentyl-3-thia- 1 azaspiro[4.4]nonane; 2-(4-cyano-2-ethylphenylimino)- 1 -cyclopentyl-3-thia- 1 -azaspiro[4.4]nonane; 30 2-(4-cyanophenylimino)-1 -cyclopentyl-3-thia- 1 -azaspiro[4.4]nonane; 2 -( 4 -cyano-2-methylphenylimino)- 1 -isobutyl-3-thia- 1 -azaspiro[4.4]nonane; 2 -( 4 -cyano-2,3-dimethylphenylimino)- 1 -isobutyl-3-thia- 1 azaspiro[4.4]nonane; 2 -( 4 -cyano-2-methylphenylimino)- 1 -(1-ethyl-i -propyl)-3-thia- 1 35 azaspiro[4.4]nonane; 2-(4-cyano- 1 -naphthylimino)- 1 -isobutyl-3-thia- 1 -azaspiro[4.4]nonane; 2 -(2-methyl-4-nitrophenylimino)- 1 -(prop-2-en- 1 -yl)-3-thia- 1 azaspiro[4.4]nonane; 266 WO 00/42031 PCT/US99/29601 2-(2-methyl-4-nitrophenylimino)- 1 -isopropyl-3-thia- 1 -azaspiro[4.4]nonane; 2-(2-methyl-4-nitrophenylimino)- 1 -isobutyl-3-thia- 1 -azaspiro[4.4]nonane; 2-(2-methyl-4-nitrophenylimino)- 1 -cyclopentyl-3-thia- 1 -azaspiro[4.4]nonane; 2-(3-methyl-4-nitrophenylimino)- 1 -cyclopentyl-3-thia- 1 -azaspiro[4.4]nonane; 5 2-(2-methyl-4-nitrophenylimino)- 1 -cyclohexyl-3-thia- 1 -azaspiro[4.4]nonane; 2-(2,3-dimethyl-4-nitrophenylimino)- 1 -cyclopentyl-3-thia- 1 azaspiro[4.4]nonane; and 2-(4-cyano-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1 azaspiro[4.4]nonane. 10 5. A compound of claim 1 selected from the group consisting of: 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one; 2-(3-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one; 15 2-(3-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidin-4-one; 2-(3-methyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-(1 -cyclohexyl- 1-ethyl)- 1,3-thiazolidin-4 one; 20 2-(3-methyl-4-nitrophenylimino)-3-(1 -cyclohexyl- 1-ethyl)- 1,3-thiazolidin-4 one; 2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl-1-butyl)-1,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methylene-1,3-thiazolidin-4 one; and 25 2 -( 2 -methyl-4-nitrophenylimino)-3-isobutyl-5-methyl- 1,3-thiazolidin-4-one.
6. A compound of claim 1 selected from the group consisting of: 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-oxazolidine; 1 -cyclopentyl-2-(4-cyano-2-ethylphenylimino)-3-oxa-1 -azaspiro[4.4]nonane; 30 1 -cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1 -azaspiro[4.4]nonane; and 1 -cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa- 1 -azaspiro[4.4]nonane.
7. A pharmaceutical composition comprising a compound of claim 1, 2, 3, 4, 5 35 or 6, and a pharmaceutically acceptable carrier.
8. A method of treating a mammal by administering to said mammal an effective amount of a compound for: 267 WO 00/42031 PCT/US99/29601 Al) enhancement of bone formation in bone weakening diseases for the treatment or prevention of osteopenia or osteoporosis; A2) enhancement of fracture healing; B1) use as a female contragestive agent; 5 B2) prevention of endometrial implantation; B3) induction of labor; B4) treatment of luteal deficiency; B5) enhanced recognition and maintanence of pregnancy; B6) counteracting of preeclampsia, eclampsia of pregnancy, and preterm labor; 10 B7) treatment of infertility, including promotion of spermatogenesis, induction of the acrosome reaction, maturation of oocytes, or in vitro fertilization of oocytes; Cl) treatment of dysmenorrhea; C2) treatment of dysfunctional uterine bleeding; 15 C3) treatment of ovarian hyperandrogynism; C4) treatment of ovarian hyperaldosteronism; C5) alleviation of premenstral syndrome and of premenstral tension; C6) alleviation of perimenstrual behavior disorders; C7) treatment of climeracteric disturbance, including. menopause transition, mood 20 changes, sleep disturbance, and vaginal dryness; C8) enhancement of female sexual receptivity and male sexual receptivity; C9) treatment of post menopausal urinary incontinence; CI0) improvement of sensory and motor functions; ClI) improvement of short term memory; 25 C12) alleviation of postpartum depression; C13) treatment of genital atrophy; C14) prevention of postsurgical adhesion formation; C15) regulation of uterine immune function; C16) prevention of myocardial infarction; 30 DI) hormone replacement; El) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer, and endometrial cancer; E2) treatment of endometriosis; E3) treatment of uterine fibroids; 35 Fl) treatment of hirsutism; F2) inhibition of hair growth; G1) activity as a male contraceptive; G2) activity as an abortifacient; and 268 WO 00/42031 PCT/US99/29601 Hi) promotion of mylin repair; wherein said compound has the general formula (T)t R\ NK ,R(G)g X N (Q)qR 2 (Q)qR 3 (CnH 2 n-p- 2 s) (Q)qR 4 wherein 5 Ris aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S, with the proviso that R is other than benzofuran or benzothiophene; 10 R' is alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons and containing 1 - 3 rings; heterocycloalkyl of 4 - 7 carbons and containing 1 - 3 rings and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; 15 aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 rings and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or 20 alkynyl of 3 - 10 carbons; R2, R?, and R' are independently selected from the group consisting of H; alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; 25 alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons; aryl of 6 - 13 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; 30 C0 2 R ; wherein R' is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; 269 WO 00/42031 PCT/US99/29601 halogen; and =0 , representing two of the groups R 2 , R 3 , and R 4 ; X is 0 or S(O), ; wherein yis0, 1,or2; 5 nis2,3,4,or5; p is the sum of non-H substituents R 2 , R 3 , and R 4 ; s represents the number of double bonds in the ring, and is 0, 1, or 2; T is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; 10 alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; CO 2 H; CO 2 R; alkenyl of 2 - 4 carbons; 15 alkynyl of 2 - 4 carbons; C(O)C 6 H 5 ; C(O)N(R)(R 7 ) ;wherein R is H or alkyl of 1 - 5 carbons; and R' is H or alkyl of 1 - 5 carbons; 20 S(O),,R ; wherein y' is 1 or 2; and R' is alkyl of 1 - 5 carbons; SO 2 F; CHO; 25 OH; NO 2 ; CN; halogen; OCF 3 ; 30 N-oxide; O-C(R 9 ) 2 -0 , the oxygens being connected to adjacent positions on R; and wherein R' is H, halogen, or alkyl of 1 - 4 carbons; C(O)NHC(O) , the carbons being connected to adjacent positions on 35 R; and C(O)C 6 H 4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; tis 1 - 5; 270 WO 00/42031 PCT/US99/29601 provided that when substituent moiety T is alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; CO 2 R'; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C 6 HS; C(O)N(R 6 )(R 7 ); S(O),.R ; O-C(R!) 2 -0 , or C(O)C 6 H 4 , then T optionally may bear secondary 5 substituents selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; C0 2 R; CO 2 H; C(O)N(R 6 )(R 7 ); CHO; OH; NO 2 ; CN; halogen; S(O)yR; or =0, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level; 10 G is a substituent selected from the group consisting of halogen; OH; OR 5 ; =0 , representing two substituents G; 15 alkyl of 1 - 4 carbons; alkenyl of 1 - 4 carbons; cycloalkyl of 3 - 7 carbons; heterocycloalkyl of 3 - 5 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; 20 cycloalkenyl of 5 - 7 carbons; heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; CO 2 R'; C(O)N(R 6)(R7); 25 aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and 1 - 3 heteroatoms selected from the group consisting of N, 0, and S; NO 2 ; CN; 30 S(O),R; S0 3 R'; and SO 2 N(R 6 )(R 7 ); g is 0 - 4, with the exception of halogen, which may be employed up to the perhalo level; 35 provided that when substituent G is alkyl of 1 - 4 carbons, alkenyl of 1 - 4 carbons, cycloalkyl of 3 - 7 carbons, heterocycloalkyl of 3 - 5 carbons, cycloalkenyl of 5 - 7 carbons, or heterocycloalkenyl of 4 - 6 carbons, then G optionally may bear secondary substituents of halogen 271 WO 00/42031 PCT/US99/29601 up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the number of said secondary substituents being up to 3 for 5 alkyl moieties, and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; haloalkyl of 1 - 4 carbons; cycloalkyl of 3 - 8 carbons; 10 alkoxy of 1 - 8 carbons; alkenyl of 2 - 5 carbons; cycloalkenyl of 5 - 8 carbons; aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected 15 from the group consisting of N, 0, and S; C0 2 R =0 , representing two substituents Q; OH; halogen; 20 N(R)(R); S(O),R8; S0 3 R; and SO 2 N(R)(R'); q is 0 - 4 25 provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1 - 4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and 30 with the further proviso that two of (Q)qR', (Q)qR 2 , (Q)qR 3 , and (Q)qR 4 may be joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3 - 8 members containing 0 - 2 heteroatoms selected from the group consisting of N, 0, and S; 35 and pharmaceutically acceptable salts thereof.
9. The method of claim 8 wherein said mammal is a human. 272
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