WO2000042031A2 - 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
WO2000042031A2
WO2000042031A2 PCT/US1999/029601 US9929601W WO0042031A2 WO 2000042031 A2 WO2000042031 A2 WO 2000042031A2 US 9929601 W US9929601 W US 9929601W WO 0042031 A2 WO0042031 A2 WO 0042031A2
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Prior art keywords
carbons
methyl
alkyl
thiazolidine
nitrophenylimino
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PCT/US1999/029601
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French (fr)
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WO2000042031A3 (en
Inventor
Brian R. Dixon
Cedo M. Bagi
Catherine R. Brennan
David R. Brittelli
William H. Bullock
Jinshan Chen
William L. Collibee
Robert Dally
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 Corporation
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Priority to EP99968883A priority Critical patent/EP1144396A2/en
Application filed by Bayer Corporation filed Critical Bayer Corporation
Priority to KR1020017008891A priority patent/KR20010089831A/en
Priority to BR9916999-1A priority patent/BR9916999A/en
Priority to HU0105134A priority patent/HUP0105134A2/en
Priority to SK1003-2001A priority patent/SK10032001A3/en
Priority to CA002359562A priority patent/CA2359562A1/en
Priority to IL14403199A priority patent/IL144031A0/en
Priority to JP2000593599A priority patent/JP2002534517A/en
Priority to AU27087/00A priority patent/AU2708700A/en
Publication of WO2000042031A2 publication Critical patent/WO2000042031A2/en
Publication of WO2000042031A3 publication Critical patent/WO2000042031A3/en
Priority to NO20013318A priority patent/NO20013318L/en
Priority to BG105761A priority patent/BG105761A/en

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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
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • R 8 is alkyl of 1 - 5 carbons; SO 2 F; CHO; OH; NO 2 ;
  • R 2 , R 3 , and R 4 are more 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 O or S(O) y , wherein y is 0, 1 , or 2.
  • Chemical ionization mass spectra were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (lxlO "4 torr to 2.5x10 " “ 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.
  • 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 (3x100 mL), dried (MgSO 4 ), and treated with a IM HCl solution in ether (25 mL).
  • 1,3-thiazolidine (Method Clc; 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 concentrated under reduced pressure.
  • 2- oroet y ammon um c or e ntry 1 was reacte w t -met y - -n trop eny 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- nitrophenylimino)-3-(but-l-en-4-yl)-l,3-thiazolidine.
  • 2-Hydroxyethylamine was reacte w t enzy romi e 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.
  • (lS)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib.
  • the 2-hydroxyethylamine was converted to (25)- 4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2.
  • the alcohol was converted to N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride as described in Method B7c.

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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)

Abstract

This invention relates to 2-arylimino heterocycles, including 2-arylimino-1, 3-thiazolidines, 2-arylimino-2, 3, 4, 5-tetrahydro-1, 3-thiazines, 2-arylimino-1, 3-thiazolidin-4-ones, 2-arylimino-1, 3-thiazolidin-5-ones, and 2-arylimino-1, 3-oxazolidines, and their use in modulating progesterone receptor mediated processes, and pharmaceutical compositions for use in such therapies.

Description

Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents
FIELD: 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: 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., I, 302 (1994); Scheven, et al., Biochem. Biophys. Res. Commun., 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; A2) as an agent to enhance fracture healing;
Bl) 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, H, 285 (1995); Spitz et al, Adv. Contracept. 8, 1 (1992); Spitz et al., Annu. Rev. Pharmacol. Toxicol., 36, 47 (1996)); 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 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-Veriag, p. 27 (1995));
B5) to enhance recognition and maintanence of pregnancy (Bezer et al., In "Molecular and Cellular Aspects of Periimplantation Processes", Dey (Ed.),
Springer-Nerlag, p. 27 (1995)); 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 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)); CI) 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., 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)); 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)); 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); Backstrόm et al., Ciba Found. Symp., 121, 171 (1995)), mood changes (Backstrom et al., Ciba Found. Symp., 121, 171 (1995)), sleep disturbance (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (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 male sexual receptivity (Johnson et al., In "Essential Reproduction, 2nd ed.,
Blackwell Scientific Pub., London pl77 (1984)); C9) for treatment of post menopausal urinary incontinence (Makinen et al., Maturitas, 22, 233 (1995); Batra et al., J. Urology, 138, 1301 (1987)); CIO) to improve sensory and motor functions (Backstrom et al., Ciba Found.
Symp., 121, 171 (1995)); Cl l) to improve short term memory (Backstrom et al., Ciba Found. Symp., 121,
171 (1995)); C12) 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. 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)); Dl) 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 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. 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)); FI) for treatment of hirsutism (Orentreich et al., US 4684635; Azziz et al., J. Clin. Endocrinol. Metab., 80, 3406 (1995));
F2) for inhibition of hair growth (Houssay et al., Acta Physiol. Latinoam., 28, 11
(1978)); Gl) as a male contraceptive (Hargreave et al., Int. Congr., Symp. Semin. Ser., 12,
99 (1997); Meriggiola et al., J. Androl., 18, 240 (1997)); G2) as an abortifacient (Michna et al., Pharm. Ztg., Hi, 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, 268, 1500 (1995)). 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 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 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 (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 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: 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.
This invention relates to compounds having the formula (I)
Figure imgf000006_0001
wherein R is aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene; 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, O, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons; R2, R3, and R4 are independently selected from the group consisting of H; 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; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5 ; wherein
R5 is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; halogen; and
=O , representing two of the groups R2, R3, and R4; X is O or S(O)y ; wherein y is O, l, or 2; n is 2, 3, 4, or 5; p is the sum of non-H substituents R2, R3, and R4; 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;
CO2H; CO2R5; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C6H5; C(O)N(R6)(R7) ;wherein
R6 is H or alkyl of 1 - 5 carbons; and R7 is H or alkyl of 1 - 5 carbons;
S(O)y,R8 ; wherein y' is 1 or 2; and R8 is alkyl of 1 - 5 carbons; SO2F; CHO;
OH; NO2; CN; halogen; OCF3;
N-oxide;
O-C(R9)2-O , the oxygens being connected to adjacent positions on R; and wherein
R9 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)C6H4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; 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, CO2R5, alkenyl of 2 - 4 carbons, alkynyl of 2 - 4 carbons, C(O)C6H5, C(O)N(R6)(R7), S(O)y,R8, O-C(R9)2-O , or C(O)C6H4 , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; CO2R5; CO2H; C(O)N(R6)(R7);
CHO; OH; NO2; CN; halogen; S(O)yR8; or =O, 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;
OH; OR5; =O , representing two substituents G; 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, O, and S; cycloalkenyl of 5 - 7 carbons; heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5; C(O)N(R6)(R7); aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
NO2; CN;
S(O)yR8;
SO3R8; and
SO2N(R6)(R7); 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 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 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; 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; aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5 ;
=O , representing two substituents Q; OH; halogen; N(R6)(R7); S(O)yR8; SO3R8; and SO2N(R6)(R7); 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 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)qR2, (Q)qR3, and (Q)qR4 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, O, and S; b) when n = 2 or 3, at least one of R2, R3, and R4 is other than H; c) when n = 2, and X = O, 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 = O, 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 = O or S, then the sum of non-hydrogen atoms in R\ R2, R3, and R4 is at least 5; f) when n = 2, X = O, 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 = O, the 4-position of the 1,3 -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)y , the 4-position of the 1,3 -thiazolidine ring bears a carbonyl group, R1 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 CO2R5 , then R5 contains at least two carbons;
and pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutical compositions which include a compound of formula (I) as disclosed above, plus a pharmaceutically acceptable carrier.
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 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 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 or prevention of osteopenia or osteoporosis;
A2) enhancement of fracture healing;
B 1) activity as a female contragestive agent;
B2) prevention of endometrial implantation;
B 3 ) 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;
B7) treatment of infertility, including promotion of spermatogenesis, induction of the acrosome reaction, maturation of oocytes, or in vitro fertilization of oocytes;
C 1 ) treatment of dysmenorrhea;
C2) treatment of dysfunctional uterine bleeding;
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 changes, sleep disturbance, and vaginal dryness;
C8) enhancement of female sexual receptivity and male sexual receptivity;
C9) treatment of post menopausal urinary incontinence;
CIO) improvement of sensory and motor functions;
C 11 ) improvement of short term memory; C12) alleviation of postpartum depression;
C 13) treatment of genital atrophy;
C 14) prevention of postsurgical adhesion formation;
C 15) regulation of uterine immune function;
C 16) prevention of myocardial infarction; 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; FI) treatment of hirsutism;
F2) inhibition of hair growth;
Gl ) activity as a male contraceptive;
G2) activity as an abortifacient; and
HI) promotion of mylin repair; which comprises administering to said mammal an effective amount of a compound of the formula (II)
Figure imgf000012_0001
wherein
R is aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene; 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, O, and S; 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, O, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons; R2, R\ and R4 are independently selected from the group consisting of
H; 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; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5 ; wherein R5 is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; halogen; and
=O , representing two of the groups R2, R3, and R4; X is O or S(O)y ; wherein y is O, l, or 2; n is 2, 3, 4, or 5; p is the sum of non-H substituents R2, R3, and R4; 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; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; CO2H; CO2R5; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C6H5;
C(O)N(R6)(R7) ;wherein
R6 is H or alkyl of 1 - 5 carbons; and R7 is H or alkyl of 1 - 5 carbons; S(O)yR8 ; wherein y' is 1 or 2; and
R8 is alkyl of 1 - 5 carbons; SO2F; CHO; OH; NO2;
CN; halogen; OCF3; N-oxide; O-C(R9)2-O , the oxygens being connected to adjacent positions on R; and wherein
R9 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)C6H4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; t is l - 5; provided that when substituent moiety T is alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; CO2R5; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C6H5; C(O)N(R6)(R7); S(O)y,R8
; O-C(R9)2-O , or C(O)C6H4 , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; CO2R5; CO2H; C(O)N(R6)(R7); CHO; OH; NO2; CN; halogen; S(O)yR8; or =O, 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; OH;
OR5;
=O , representing two substituents G; 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, O, and S; cycloalkenyl of 5 - 7 carbons; heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5;
C(O)N(R6)(R7); aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
NO2;
CN;
S(O)yR8; SO3R8; and
SO2N(R6)(R7); 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 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 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; 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; aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5 ;
=O , representing two substituents Q; OH; halogen; N(R6)(R7); S(O)yR8;
SO3R8; and SO2N(R6)(R7); 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 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)αR2, (Q)qR3, and (Q)qR4 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, O, and S;
and pharmaceutically acceptable salts thereof.
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. R1 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. R1 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. R\ R3, and R4 are preferably H, alkyl of 1 - 10 carbons, cycloalkyl of 3 - 12 carbons, alkenyl of 2 - 10 carbons, cycloalkenyl of 5 - 12 carbons, or =O , in which the carbonyl represents two of the groups R2, R3, and R4. R2, R3, and R4 are more 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 O or S(O)y , wherein y is 0, 1 , or 2.
The subscript n, representing the number of carbons in the ring, is preferably 2 or 3.
The subscript p, representing the sum of non-H substituents R2, R3, and R4, 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, NO2, CN, and halogen. T is more preferably alkyl of 1 - 4 carbons, alkenyl of 2 - 4 carbons, NO2, 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, 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, CO2R5, CO2H, C(O)N(R6)(R7), CHO, OH, NO2, CN, halogen, S(O)yR8, and =O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level. 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 to the per-halo level.
G is preferably selected from the group consisting of halogen, OR5, 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 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, 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, CO2R5 , =O , OH, halogen,
N(R6)(R7), and S(O)yR8. Q is more preferably alkyl of 1 - 4 carbons, 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, or halogen.
The present invention also includes pharmaceutically acceptable salts of the compounds of Formula I. Suitable pharmaceutically acceptable salts are well known 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 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 peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine,
N.N-dimethylaminopyridine (DMAP), l,4-diazabicyclo[2.2.2]octane (DABCO), 1,5- diazabicyclo[4.3.0]non-5-ene (DBΝ) and l,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 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-l, 3-thiazolidines and ring expanded homologues of 2-imino- 1 ,3-thiazolidines of the invention are the following:
(¥S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-l,3-thiazolidine;
(4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-l,3-thiazolidine;
(¥S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(trifluoromethyl)-l,3- thiazolidine; (4S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isobutyl- 1 ,3-thiazolidine;
( S)-2-(2-methyl-4-nitrophenylimino)-3 -isobutyl-4-isopropyl- 1 ,3-thiazolidine;
(^S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isopropyl-l,3-thiazolidine;
(4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyltetrahydro-2H-l,3- thiazine; (4S)-2-(4-nitro- 1 -naphthylimino)-3-cyclopentyl-4-((l R)- 1 -hydroxyethyl)- 1 ,3- thiazolidine;
2-(4-cyano-2-methylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane;
2-(4-cyano-2-ethylphenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro [4.4]nonane; -(4-cyanophenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro [4.4]nonane; -(4-cyano-2-methylphenylimino)- 1 -isobutyl-3 -thia- 1 -azaspiro [4.4]nonane; -(4-cyano-2,3-dimethylphenylimino)-l-isobutyl-3-thia-l-azaspiro[4.4]nonane;
2-(4-cyano-2-methylphenylimino)- 1 -( 1 -ethyl- 1 -propyl)-3 -thia- 1 - 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)-l-isobutyl-3-thia-l-azaspiro[4.4]nonane; 2-(2-methyl-4-nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane;
2-(3-methyl-4-nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane;
2-(2-methyl-4-nitrophenylimino)-l-cyclohexyl-3-thia-l-azaspiro[4.4]nonane;
2-(2,3-dimethyl-4-nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane; and 2-(4-cyano-2,3-dimethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
The most preferred thiazolidin-4-ones of the invention are the following:
2-(2-methyl-4-nitrophenylimino)-3-isobutyl-l,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;
2-(3-methyl-4-nitrophenylimino)-3-benzyl-l,3-thiazolidin-4-one;
2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-l-butyl)-l,3-thiazolidin-4-one;
2-(3-methyl-4-nitrophenylimino)-3-(2-methyl- 1 -butyl)- 1 ,3-thiazolidin-4-one;
2-(2-methyl-4-nitropheny limino)-3 -( 1 -cyclohexyl- 1 -ethyl)- 1 ,3 -thiazolidin-4-one ; 2-(3-methyl-4-nitrophenylimino)-3-( 1 -cyclohexyl- 1 -ethyl)- 1 ,3-thiazolidin-4-one;
2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl-l-butyl)-l,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-l,3-thiazolidin-4-one.
The most preferred oxazolidines of the invention are the following:
2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4,4-dimethyl-l,3-oxazolidine; 1 -cyclopentyl-2-(4-cyano-2-ethylphenylimino)-3-oxa- 1 -azaspiro[4.4]nonane; l-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane; and l-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane.
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 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 therapy. When employed as in CI through C16, El through E3, or FI 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 Gl 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 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 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 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 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 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. 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 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. 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, 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 monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or /j-propyl, 7-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 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. 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 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 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, 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 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 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 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 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 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 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 or unsaturated C8-C18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C8-C18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, rc-butyl, .sec- butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric 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 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 C8-C18 fatty alcohols, saturated or unsaturated C8-C18 fatty acids, 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, amides, 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 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 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. 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 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, 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 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 conventional treatment tests.
The entire disclosures of all applications, patents and publications cited above and below are hereby incorporated by reference.
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 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.
LIST OF ABBREVIATIONS AND ACRYONYMS
As employed herein, the following terms have the indicated meanings.
AcOH acetic acid anh anhydrous
BOC tert-butoxycarbonyl cone concentrated dec decomposition
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DIBAL diisobutylaluminum hydride
DME 1 ,2-dimethoxyethane
DMF N, N-dimethylformamide
DMSO dimethylsulfoxide
EtOAc ethyl acetate
EtOH ethanol (100%)
Et2O diethyl ether
Et3N triethylamine
KMnO4 potassium permanganate
Magnosil® MgSiO3 xH2O rø-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C)
THF tetrahydrofuran
TFA trifluoroacetic acid
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 Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984). March. Advanced Organic Chemistry, 3rd 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 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 1991,40, 139; Dϋrr US Patent 4,079,144; Enders US Patent 4,148,799).
Scheme I o
CI Λ CI
ArNCO 2
ArNH2 s
U 1 CI^ I R1NH, A - ArNCS X... π π 3 4
As shown in Scheme II, thioureas react with α-haloketones, e.g. α- bromoketone 5, to afford, after dehydration, the thiazoline (6) (Hahn et al. Han'guk Nonghwa Hakhoechi 1991,40, 139; DUrr US Patent 4,079,144; Enders US Patent 4,148,799).
Scheme II
Figure imgf000026_0001
Similarly, thioureas react with α-haloacid halides (Giri et al. Asian J. Chem. 1992, 4, 785; Lakhan et al. Agric. Biol Chem. 1982,46, 557), α-haloacids (Dogan et al. Spectrosc. Lett. 1983, 16, 499; Seada et al. Indian J. Heterocycl. Chem. 1993, 3, 81), and α-haloesters (Seada et al. Indian J. Heterocycl. Chem. 1993, 5, 81) to afford 4-thiazolidinones (10).
Scheme III
Figure imgf000026_0002
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).
Scheme IV
ArSCN
NHR
^NHR1 HC C'
11 12
Figure imgf000027_0001
H+ H+ 11 ' kr^» N. Ar^κ N, S X^ N' RR1 S^N'R
Me . H.,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-l,3-heterocycle 19 (Jen et al. J.Med. Chem. 1975, 18, 90; 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 SOCl2 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).
Scheme V
A
Figure imgf000028_0001
20
A
Figure imgf000028_0002
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 affords the corresponding oxygen-containing heterocycle (Jen et al. J.Med. Chem. 1975, 18, 90; Ignatova et al. Khim. Geterotsikl Soedin. 1914, 354).
Scheme VI
A
Figure imgf000028_0003
18 1 ) Mel 22
2) OK
Chloroalkyl isothiocyanates have been reported to react with arylamines to afford the corresponding sulfur 2-phenylimino-l,3-heterocycle (Sagner et al. US Patent 3,651,053; Ibid US Patent 3,737,536).
Scheme VII
Ar-N
ArNH,
CI-(CH2)nNCS S^ H 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 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-l,3-heterocycle 30 (Wollweber US Patent 3,787,575; Ibid US Patent 3,686,199) and with 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
H AA CH-, Ar-NH so2cι2 Ar-
N
ArNH2 1 O^H SOC CI A C, I
Figure imgf000029_0001
Treatment of hydroxylamines with CS2 in the presence of base will generate the l,3-thiaza-2-thione (Scheme IX). It has been reported that thione 34 reacts with SOCl2 to give hydroscopically labile imidate 35, which on treatment with an aryl amine affords the sulfur-containing 2-imino-l,3-heterocycle (Hanefeld et al. Arch. Pharm. 1985, 318, 60; Ibid 1988, 321, 199).
Scheme IX
Figure imgf000029_0002
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-l,3-heterocycles with electrophiles, typically in the 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).
Scheme X
Figure imgf000030_0001
45
In addition, as shown in Scheme XI, sulfur-containing 2-imino-l,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).
Scheme XI
Figure imgf000030_0002
46 mCPBA 47 48
DETAILED EXPERIMENTAL PROCEDURES 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. 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 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 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 μm plates. Visualization of plates was effected by 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 chromatography (flash chromatography) was performed using 230-400 mesh EM
Science® silica gel. Rotary chromatography was performed using pre-cast SiO2 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. Fourier transform infrared sprectra were obtained using a Mattson 4020 Galaxy
Series spectrophotometer.
Proton (*H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (δ 0.00) or residual protonated solvent (CHC13 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (I3C) NMR spectra were measured with a General Electric GN-
Omega 300 (75 MHz) spectrometer with solvent (CDC13 δ 77.0; MeOD-d3; δ 49.0; DMSO-d6 δ 39.5) as standard.
Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were obtained as electron impact (El), chemical ionization (CI), or as fast atom 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 electron energy of 70 eV and a trap current of 300 μA. 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 methane or ammonia as the reagent gas (lxlO"4 torr to 2.5x10"" 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- 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 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 consistent 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.
A. Synthesis of Imine Precursors
Ala. General method of synthesis of anilines from nitrobenzenes. Synthesis of 4-cyano-2-methylaniline.
Figure imgf000032_0001
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 SnCl2 (9.6 g, 49.38 mmol) in cone. HCl (20 mL). After stirring for 3 h, the mixture was added carefully to a saturated NH4OH solution (120 mL) at 0 °C. The resulting mixture was extracted with EtOAc (4x30 mL). The combined organic layers were sequentially washed with H2O (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtO Ac/hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92%): TLC (30% EtOAc in hexane) R 0.23. This material was used without further purification.
A2a. General method for the synthesis of isothiocyanates. Synthesis of 4- nitro-2-w-propyI isothiocyanate.
Figure imgf000033_0001
Step 1
To a solution of 2-H-propylaniline (8.91 g, 66 mmol) and Et3N (14 mL, 106 mmol) in CH2C12 (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 CH2C12 (2x30 mL). The combined organic layers were sequentially washed with H2O (40 mL), a IN NaOH solution (40 mL), H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na^O,,), and concentrated under reduced pressure. The resulting powder was purified by crystalization ( EtOAc) to give 2-«-propylacetanilide as white needles (7.85 g, 67%). TLC (30% EtOAc/hex) R/0.37.
Figure imgf000033_0002
Step 2
To a solution of 2-«-propylacetanilide (1.15 g, 6.50 mmol) in TFA (20 mL) at
-5 °C was added NaNO2 (0.55 g, 6.50 mmol). The mixture was allowed to stir at -5
°C for 3 h, then was treated with H2O (30 mL). The resulting aqueous solution was extracted with EtOAc (3x20 mL). The combined organic layers were washed with a
IN NaOH solution (30 mL), H2O (30 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in a cone. 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 with a 50% NaOH solution. The basic mixture was extracted with EtOAc (4x30 mL).
The combined organic layers were sequentially washed with H2O (30 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc/hex) to give 2-«-propyl-4-nitroacetanilide as a yellow solid (0.56 g, 48%): TLC (20% EtOAc/hex)
Figure imgf000034_0001
Step 3 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, 95%): TLC (20% EtOAc/hex) R/0.82.
A2b. General method for the synthesis of isothiocyanates. Synthesis of 4-cyano- 2-ethylphenyl isothiocyanate.
Figure imgf000034_0002
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 concentrated under reduced pressure and the residue was treated with CH2C12 (600 L) and concentrated under reduced pressure to give 4-cyano-2-ethylphenyl isothiocyanate as a light tan crystalline solid (98 g, 100%): Η NMR (DMSO-d6) δ 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, IH); MS (CI-MS) m/z 189 ((M+H)+).
A2c. General method for the synthesis of isothiocyanates. Synthesis of 2,4- dimethyl-3-cyano-5-pyridyl isothiocyanate.
Figure imgf000034_0003
A suspension of 6-amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0.68 mmol) in CH2C12 (1 mL) was added to a vigorously stirred mixture of CaCO3 (0.41 g, 4.11 mmol) in a 1:2 water:CH2Cl2 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 CH2C12 (3 x 10 mL). The combined organic layers were washed with water (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 10% EtOAc/hex) to give 2,4-dimethyl-3-cyano-6-pyridyl isothiocyanate (0.12 g, 91%): CI-MS m/z 190 ((M+H)+).
A2d. General method for the synthesis of isothiocyanates. Synthesis of 2,3- dimethyl-4-nitrophenyl isothiocyanate.
Figure imgf000035_0001
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 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%): Η NMR (CDC13) δ 2.39 (s, 3H), 2.41 (s, 3H), 7.20 (d, J=8.4 Hz, IH); CI-MS m/z 200 ((M+H)+).
A2e. General method for the synthesis of isothiocyanates. Synthesis of 2,3- dimethyl-6-nitrophenyl isothiocyanate.
Figure imgf000035_0002
To a solution of 2,3-dimethyl-6-nitroaniline (3.0 g, 1.0 equiv.) in toluene (150 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%
CH2Cl2/hex) to afford 2,3-dimethyl-6-nitrophenyl isothiocyanate as a light yellow solid (3.63 g, 95%): Η NMR (CDC13) δ 2.39 (s, 3H), 2.40 (s, 3H), 7.17 (d, J=8.4 Hz, IH), 7.83 (d, J=8.7 Hz, IH). A3a. General method of synthesis of aryl isonitrile dichlorides. Synthesis of 4-cyano-2-ethylphenyl isocyanide dichloride.
Figure imgf000036_0001
Step 1 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 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 (CDClj) δ 1.13 (t, J=7.3 Hz, 3H), 2.48 (q, J=7.3 Hz, 2H), 7.65 (d, J=8.5 Hz, IH), 8 35 (d, J=8.5 Hz, IH), 8.37 (s, IH), 9.89 (br s, IH).
Figure imgf000036_0002
Step 2
To a solution of 4-cyano-2-ethylformanilide (167 g, 0.96 mol, 1.0 equiv.) in SOCl2 (525 mL, 6.05 mol, 6.3 equiv.) which had been cooled to 0 °C with an ice bath 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 CH2C12 (600 mL), and concentrated again under reduced pressure. The residue was dissolved in El^O (800 mL) and filtered through a pad of Magnosil® to give 4-cyano-2-ethylphenyl isocyanide dichloride as an oil (210 g, 96%): 'H NMR (CDC13) δ 1.13 (t, J=7.3 Hz,
3H), 2.49 (q, 2H, J = 7.3 Hz), 7.15 (d, J=8.2 Hz, IH), 8.35-8.40 (m, 2H).
A3b. General method of synthesis of aryl isonitrile dichlorides. Synthesis of 2-methyl-4-nitrophenyl isocyanide dichloride.
Figure imgf000037_0001
Step l
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 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- nitroformanilide as a light tan solid (295g, 100%): Η NMR (CDC13) δ 2.31 (s, 3H)
8.03 (m, 2H), 8.24 (d, J=8.8 Hz, IH), 8.39 (br s, IH), 9.94 (br s, IH).
Figure imgf000037_0002
Step 2
SOCl2 (525 mL, 6.05 mol, 6.3 equiv.) was added to 2-methyl-4- 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 with a 50% E^O/hex solution to yield 2-methyl-4-nitrophenyl isocyanide dichloride as a yellow solid (323 g, 85%): 'H NMR (CDC13) δ 2.19 (s, 3H), 7.20 (d, J=8.5Hz, IH), 8.15 (d, J=8.5Hz, IH), 8.2 (s, IH).
A4a. General method for the synthesis of nitroanilines from anilines. Synthesis of 2,3-dimethyl-6-nitroaniline and 2,3-dimethyl-4-nitroaniline.
Figure imgf000037_0003
Step l
To a solution of 2,3-dimethylaniline (1.1 mL, 1.00 equiv.) and Et3N (1.5 mL, 1.30 equiv.) in CH2C12 (15 mL) at 0 °C was added acetyl chloride (0.73 mL, 1.25 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 CH2C12 (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
NaHCO3 solution (2x25 mL) and a saturated NaCl solution (2x25 mL), dried
(Na2SO4), and concentrated under reduced pressure to give 2,3-dimethylacetanilide as a white solid (1.25 g, 93%): Η NMR (CDC13) δ 2.05 (s, 3H), 2.15 (s, 3H), 2.25 (s,
3H), 6.95 (d, J=7.5 Hz, IH) 7.02 (app t, J=7.5 Hz, IH), 7.35 (d, J=6.9 Hz, IH).
Figure imgf000038_0001
Step 2
To a solution of 2,3-dimethylacetanilide (14.0 g, 1.0 equiv.) in cone. H2SO4 (35 mL) at 0 °C was added HNO3 (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 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 (CDC13) δ 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, IH), 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, IH). This mixture was used in the next step without further purification.
Figure imgf000038_0002
Step 3
To a solution of the mixture of nitroacetanilides (16.0 g, 1.0 equiv.) was added a 60% H2SO4 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 (100 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with a saturated NaHCO3 solution (2x50 mL) and a saturated NaCl solution (2x50 mL), dried (NajSO.,), and concentrated under reduced pressure. The residue was purified by column chromatography (10% CH2Cl2/hex) to afford 2,3-dimethyl-6-nitroaniline (5.5 g, 43%), followed by 2,3- dimethyl-4-nitroaniline (1.5 g, 12%). 2,3-Dimethyl-6-nitroaniline (5.5 g, 43%): Η
NMR (CDC13) δ 2.05 (s, 3H), 2.20 (s, 3H), 6.15 (br s, 2H), 6.45 (d, J=8.7 Hz, IH), 7.63 (d, J=9.0 Hz, IH); Η NMR (DMSO-d6) δ 2.10 (s, 3H), 2.30 (s, 3H), 6.50 (d, J=8.7 Hz, IH), 7.15 (br s, 2H), 7.75 (d, J=9.0 Hz, IH). 2,3-Dimethyl-4-nitroaniline: Η NMR (CDC13) δ 2.10 (s, 3H), 2.45 (s, 3H), 4.05 (br s, 2H), 6.45 (d, J=9.0 Hz, IH), 7.65 (d, J=8.7 Hz, IH); Η NMR (DMSO-d6) δ 2.00 (s, 3H), 2.35 (s, 3H), 6.12 (br s, 2H), 6.53 (d, J=9.0 Hz, IH), 7.63 (d, J=9.0 Hz, IH).
A5a. General method for the synthesis of iodoanilines. Synthesis of 4-iodo-2-«- propylaniline.
Figure imgf000039_0001
To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of
NaHCO3 (5.0 g, 59.5 mmol) in H2O (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 H2O (30 mL) and extracted with EtOAc (4x40 mL). The combined organic layers were sequentially washed with a 5%
Figure imgf000039_0002
solution (30 mL) and a saturated NaHCO3 solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4- iodo-2-H-propylaniline (9.4 g, 98%): TLC (20% EtOAc/hex) R 0.43. This material was used in the next step without further purification.
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-l-
(hydroxymethyl)cyclohexane.
Figure imgf000039_0003
Step l
To a solution of 1-aminocyclohexane-l -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 of a IM NaOH solution as necessary. The resulting solution was washed with Et2O
(2x100 mL), then the aqueous layer was adjusted to pH 0 with a cone. 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- (benzyloxycarbonylamino)cyclohexane-l -carboxylic acid (17.3 g, 89%): TLC (25% EtOAc/hex) R 0.07.
Figure imgf000040_0001
Step 2 To a solution of l-(benzyloxycarbonylamino)cyclohexane-l -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 immediately by water (500 mL). The reaction was then warmed to 20 °C and stirred for 30 min. The reaction mixture was extracted with CH2C12 and concentrated under reduced pressure to yield l-(benzyloxycarbonylamino)-l-
(hydroxymethyl)cyclohexane (4.0 g, 100%): TLC (25% EtOAc/hex) R 0.11.
Figure imgf000040_0002
Step 3
A slurry of l-(benzyloxycarbonylamino)-l-(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- 1- (hydroxymethyl)cyclohexane.
Bib. General method for the synthesis of ethanolamines via reduction of amino acid derivatives. Synthesis of (lS)-l-(hydroxymethyl)-3- methylbutylamine.
Figure imgf000040_0003
Step l
To a suspension of (L)-leucine, (315 g, 2.4 mol) in MeOH (3.2 L) at -15 °C was added SOCl2 (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 reaction mixture was allowed to warm to room temp, and was stirred overnight. The resulting mixture was concentrated under reduced pressure and EtjO (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 a white crystalline solid (394 g, 86%): mp 147-149 °C; Η-NMR (CD3OD) δ 0.78- 0.98 (m, 6h), 1.58-1.72 (m, 3H), 3.76 (s, 3H), 3.92 (t, J=7.3 Hz, IH).
Figure imgf000041_0001
Step 2
To a mixture of (L)-leucine methyl ester HCl salt (254 g, 1.4 mol), NaHCO3, (118 g, 1.4 mol, 1.0 equiv.) and water (1.8 L) in EtOH (1.8 L) at 5°C was added
NaBH4, (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 NaBH4 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 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 IN NaOH solution (2x1 L). The aqueous layer was back-extracted with EtOAc (2x750 mL). The combined organics were dried (MgSO4) and concentrated under reduced pressure to yield (lS)-l-(hydroxymethyl)-3-methylbutylamine as a pale yellow oil (112 g, 65%): Η NMR (CDC13) δ 0.88-0.93 (m, 6H), 1.17 (t, J=7.7 Hz, 2H), 1.68-1.80 (m, 2H), 1.82 (br s, 2H), 2.86-2.91 (m, IH), 3.22 (dd, J=10.7, 8.1 Hz, IH), 3.56, (dd, J=10.3, 3.6 Hz, IH).
Blc. General method for the synthesis of ethanolamines via reduction of amino acid derivatives. Synthesis of l-hydroxymethylcyclopentanamine
Figure imgf000041_0002
Step 1
To a suspension of 1-aminocyclopentanecarboxylic acid, (675 g, 5.23 mol, 1.0 equiv.) in MeOH (6.5 L) held at - 15 °C with an ice/MeOH bath was added SOCl2
(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 pressure. The residue was treated with CH2C12 (1 L) and concentrated under reduced pressure to afford methyl 1-aminocyclopentanecarboxylate HCl salt as a white solid (938 g, 100%): 'H NMR (CD3OD) d 1.87-1.94 (m, 8H), 3.83 (s, 3H); NMR (DMSO- d6) δ 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 s 3H). This material was used in the next step without further purification.
Figure imgf000042_0001
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 NaHCO3 (145 g, 1.73 mol, 1.0 equiv.). The resulting mixture was then cooled to 5 °C with an ice bath and NaBH4 (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 NaBH4 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, 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 (MgSO4) and concentrated under reduced pressure to afford 1-hydroxymethylcyclopentanamine as a low melting wax (169 g, 85%): Η NMR (CDC13) δ 1.38-1.44 (m, 2H), 1.58-1.69 (m, 4H), 1.70-1.84 (m, 2H), 2.11 (br s, 3H), 3.36 (s, 2H). CI-MS m/z 116 ((M+H)+).
B2a. General method for the JV-alkylation of ethanolamines via substitution reactions. Synthesis of 2-(isobutylamino)-2-(hydroxymethyl)norbornane.
Figure imgf000042_0002
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 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 NaHCO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure to yield 2- (isobutylamino)-2-(hydroxymethyl)norbornane as a diastereomeric mixture (0.24 g, 55%): GC-MS m/z 197 (M+).
B2b. General method for the V-alkylation of ethanolamines via substitution reactions. Synthesis of ./V-hydroxyethyl-N-cyclohex-l-enylmethylamine.
Figure imgf000043_0001
Step l
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) dropwise. The mixture was allowed to stir at -78 °C for 4 h then treated with a saturated NaHCO3 solution (40 mL). The aqueous layer was extracted with EtOAc (4x20 mL) and the combined organic layers were washed with H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4),and concentrated under reduced pressure. The residual cyclohex-1-enylmethanol was used directly for the next step without purification: TLC (30% EtOAc/hex) R 0.44.
Step 2 TBr
To a solution of cyclohex-1-enylmethanol (3.58 g, 32 mmol) in CH2C12 (40 mL) at 0 °C was added PPh3 (36 mmol, 9.39 g) and CBr4 (39 mmol, 12.96 g). The 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-l-cyclohexene as an oil (3.25 g, 57% over two steps): TLC (30% EtOAc/hex) R 0.91.
Figure imgf000043_0002
Step 3
A solution of 1-bromomethyl-l-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 extracted with CH2C12 (4x20 mL) and the combined organic layers were washed with
H2O (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4) 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). B3a. General method for the N-alkylation of ethanolamines via reductive alkylation. Synthesis of (R)-Λ'-isobutylserine methyl ester HCl salt.
Figure imgf000044_0001
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 Et2O (100 mL) and a saturated NaHCO3 solution (100 mL). The organic layer was washed with a saturated NaHCO3 solution (3x100 mL), dried (MgSO4), and treated with a IM HCl 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-d6) δ 0.94 (dd, J=6.7, 3.0 Hz, 6H); 1.97-2.11 (m, IH); 2.76-2.9 l(m, IH); 3.76 (s, 3H); 3.86 (dd, J=12.1, 4.1 Hz, IH), 3.99 (dd, J=12.4, 3.2 Hz, IH), 4.13-4.21 (m, IH).
B4a. General method for the N-alkylation of ethanolamines via 2-alky 1-1,3- oxazolidine formation followed by reduction. Synthesis of 1- (cyclohexylamino)-l-(hydroxymethyl)cyclopentane.
Figure imgf000044_0002
Step 1
To a solution of 1 -amino- l-(hydroxymethyl)cyclopentane (Method Blc; 1.44 g, 12.54 mmol) in CH2C12 (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 with water (10 mL) and a saturated NaHCO3 solution (20 mL), dried (MgSO4), and concentrated under reduced pressure to give 14-aza-7-oxadispiro[4.2.5.1 Jtetradecane (2.38 g, 97%): GC-MS m/z 195 (M+).
Figure imgf000044_0003
Step 2 To a solution of LiAlH4 (0.93 g, 24.4 mmol) and A1C13 (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 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,O (200 mL). The organic layer was dried (NajSO and concentrated under reduced pressure to yield l-(cyclohexylamino)-l-(hydroxymethyl)cyclopentane 1.89 g (79%): GC-MS z l97 (M+).
B4b. General method for the V-alkylation of ethanolamines via 2-alk l,3- oxazolidine formation followed by reduction. Synthesis of V-cyclopentyI- (l,l-dimethyl-2-hydroxyethyl)amine.
Figure imgf000045_0001
Step 1
A mixture of 2-amino-2-methyl-l-propanol (15.0 g, 0.168 mol), cyclopentanone (14.9 mL, 0.168 mol, 1.0 equiv.) and /?-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 with EtOAc (500 mL), then washed with a saturated NaHCO3 (250 mL), dried
(Na^O^, and concentrated under reduced pressure to yield 4-aza-3, 3 -dimethyl- 1- oxaspiro[4.4]nonane as a pale yellow oil (15.5 g, 60%): Η NMR (CDC13) δ 1.12 (s, 6H), 1.65 (m, 5H), 1.80 (m, 2H), 1.97 (m, 2H), 3.45 (s, 2H).
Figure imgf000045_0002
Step 2
To a solution of 4-aza-3,3-dimethyl-l-oxaspiro[4.4]nonane (15.5 g, 0.10 mol) in EtOH (85 mL) at 0 °C was then added NaBH4 (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 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^ ,) and concentrated under reduced pressure to yield N-cyclopentyl-(l,l-dimethyl-2-hydroxyethyl)amine as a pale yellow oil (13.0 g, 83%): Η ΝMR (CDC13) δ 1.07 (s, 6H), 1.24 (m, 3H), 1.50 (m, 2H), 1.65 (m, 2H), 1.87 (m, 2H), 3.0 (m, IH), 3.22 (s, 2H); CI-MS m/z 158 ((M+H)+).
B4c. General method for the JV-alkylation of ethanolamines via 2-alk l,3- oxazolidine formation followed by reduction. Synthesis of (2S)-4-methyI- 2-(isobutylamino)pentan-l-ol.
Figure imgf000046_0001
Step l 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 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
ΝMR (CDC13) δ 0.88-0.99 (m, 12H), 1.18-1.35 (m, IH), 1.42-1.56 (m, IH), 1.61-
1.79 (m, 4H), 3.08 (t, J=7.4 Hz IH), 3.20-3.34 (m, IH), 3.85 (t, J=7.4 Hz, IH), 4.18
(dd, J = 7.3, 3.4 Hz, IH).
Figure imgf000046_0002
Step 2
To a solution of (4S)-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 ΝaBH4 (70.3 g,
1.82 mol) in portions at such a rate that the reaction temp, did not exceed 10 °C (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 (Na2SO4) and concentrated under reduced pressure to yield (2S)-4-methyl-2-(isobutylamino)pentan-l-ol as a viscous pale yellow oil (192 g,
85%): Η NMR (CDC13) δ 0.90-0.96 (m, 12H), 1.18-1.24 (m, IH), 1.32-1.39 (m, IH), 1.58-1.72 (m, 2H), 2.33 (dd, J=l l.l, 7.0 Hz, IH), 2.49 (dd, J=l l.l, 7.0 Hz, IH), 2.63-2.67 (m, IH), 3.19 (dd, J=10.3, 6.2 Hz, IH), 3.60 (dd, J=10.3, 6.2 Hz, IH).
B4d. General method for the iV-alkylation of ethanolamines via 2-aIkyl,3- oxazolidine formation followed by reduction. Synthesis of 1- (cyclopentylamino)-l-(hydroxymethyl)cyclopentane.
Figure imgf000047_0001
Step l.
A solution of 1-hydroxymethylcyclopentanamine (Method Blc; 263 g, 2.3 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, 100%) as a pale yellow oil: Η NMR (CDC13) δ 1.55-1.89 (m, 17H), 3.60 (s, 2H).
Figure imgf000047_0002
Step 2
To a solution of 6-aza-12-oxadispiro[4.1.4.2]tridecane (124 g, 0.69 mol) dissolved in EtOH (600 mL) held at -13 °C with an ice/MeOH bath was added
NaBH4 (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 EtOAc (1 L) and water (600 mL). The organic layer was dried (NajSO and concentrated under reduced pressure to yield l-(cyclopentylamino)-l- (hydroxymethyl)cyclopentane as a white powder (107 g, 85%): Η NMR (CDC13) δ 1.23-1.28 (m, 2H), 1.46-1.57 (m, 8H), 1.58-1.69 (m, 4H), 1.82-1.86 (m, 2H), 2.94- 3.06 (m, IH,), 3.30 (s, 2H).
B5a. General method for the synthesis of ethanolamines via reaction of amines with epoxides. Synthesis of JV-(hydroxyethyl)-iV-(2-butyI)amine. N— °H 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 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
Figure imgf000048_0001
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).
B6a. General method for the synthesis of propanolamines via Arndt Eisert homologation of amino acids followed by reduction. Synthesis of (R)-3- (te/tf-butylamino)-4-methylpentanol.
Figure imgf000048_0002
Step 1
To a solution of N-(tert-butoxycarbonyl)-(Z)-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. The filtrate was cooled to -10 °C, then treated with a solution of CH2Ν2 in E ,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 (SiO2, gradient from hexane to 30 % EtOAc/hex) to yield (S)-3-(tert-butoxycarbonylamino)-l-diazo-4-methylpentan-2- one (1.82 g, 38%): TLC (10% EtOAc/hex) R 0.11.
Figure imgf000049_0001
Step 2
A solution of (S)-3-(tert-butoxycarbonylamino)-l-diazo-4-methylpentan-2- one (1.83 g, 7.6 mmol) in MeOH (100 mL) was heated at the reflux temp, and a filtered solution of silver benzoate in Et3N (0.50 g silver benzoate in 5 mL Et3N, 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 pressure. The residue was dissolved in El^O (100 mL) and was sequentially washed with a IN HCl solution (100 mL), a saturated NaHCO3 solution (100 mL), and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure to give methyl (R)-3-(tert- butoxycarbonylamino)-4-methylpentanoate (1.63 g, 87%): TLC (10% EtOAc/hex) R/0.29.
Figure imgf000049_0002
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- butoxy carbonylamino)-4-methylpentanol (93%).
B7a. General method for the synthesis of chloroethylamines. Synthesis of (l_S)-l-(chloromethyl)-3-methylbutanammonium chloride.
Figure imgf000049_0003
A solution of (lS)-l-(hydroxymethyl)-3-methylbutylamine (Method Bib; 5.40g, 46.1 mmol) in CH2C12 (200 mL) was cooled over an ice bath and saturated with HCl gas. SOCl2 (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 Et2O to yield (lS)-l-(chloromethyl)-3- methylbutanammonium chloride (5.67 g, 71%): EI-MS m/z 136 ((M+H)+). B7b. General method for the synthesis of chloroethylamines. Synthesis of 1- (chloromethyl)-l-(cyclohexylamino)cyclopentane HCl salt.
Figure imgf000050_0001
A 4M HCl solution (p-dioxane, 40 mL) containing l-(cyclohexylamino)-l-
(hydroxymethyl)cyclopentane (Method B4a; 1.9 g, 9.6 mmol) and SOCl2 (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 HCl salt (2.84 g), which was used in the next step without further purification.
B7c. General method for the synthesis of chloroethylamines. Synthesis of 7V-(1- S)-(l-(chloromethyl)-3-methylbutyl)-iV-(isobutyl)amine HCl salt.
Figure imgf000050_0002
To a solution of (2S)-4-methyl-2-(isobutylamino)pentan-l-ol (Method B4c;
256 g, 1.5 mol) and toluene (2.5 L) was added SOCl2 (167 mL) over 15 min. After the addition of SOCl2 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 CH2C12 (2 L) and concentrated under reduced pressure. The red-brown residue was dissolved in Et2O (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-(l- S)-(l-(chloromethyl)-3-methylbutyl)-N-(isobutyl)amine HCl salt as a dark brown solid (276 g): 'H ΝMR (CDC13) δ 0.93-1.00 (m, 6H), 1.10-1.12 (m, 6H), 1.85 (m, 4H), 2.24-2.34 (m, 2H), 2.80-2.88 (m, IH), 2.90-3.02 (m, IH), 3.50-3.57 (m, IH),
3.96 (dd, J=12.9, 5.6 Hz, IH), 4.10 (dd, J=13.2, 3.6 Hz, IH).
B7d. General method for the synthesis of chloroethylamines. Synthesis of 1- (chloromethyl)-l-(cyclopentylamino)cyclopentane HCl salt.
Figure imgf000050_0003
To a solution of l-(cyclopentylamino)-l-(hydroxymethyl)cyclopentane (Method Blc; 140 g, 0.76 mol, 1.0 equiv.) in toluene (1.4 L). was added SOCl2 (84 mL) over a period of 15 min. After the addition of SOCl2 was complete the reaction mixture, which had already warmed to 40 °C, was heated at 60 °C overnight. The 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 Et2O and allowed stir for 4 h. The resulting precipitate was filtered and washed with EtjO (2x50 mL) to yield 1 -(chloromethyl)- 1-
(cyclopentylamino)cyclopentane HCl salt as an off-white powder (125 g, 70%): Η NMR (CDC13) δ 1.53-1.66 (m, 4H), 1.76-1.94 (m, 2H) 1.95-2.22 (m, 10H), 2.28-2.34 (m, 2H), 3.40 (s, 2H), 3.63-3.73 (m, IH).
B7e. General method for the synthesis of chloroethylamines. Synthesis of 1- chloromethylcyclopentanamine HCl salt
Figure imgf000051_0001
To a solution of 1-hydroxymethylcyclopentanamine HCl salt (Method Blc; 20 g, 0.17 mol) in anh. /?-dioxane (65 mL) was added HCl (4M in/p-dioxane; 65 mL, 0.26 mol). The resulting solution was stirred for 20 min. at room temp., then SOCl2
(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)+).
B8a. General method for the synthesis of 2-aminoethyIsulfonate esters.
Synthesis of (lR,2R)-l-(methanesuIfonyloxymethyl)-2-(ter/- butoxy)propaneammonium chloride.
Figure imgf000051_0002
Step l A solution of (L)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt (2.15 g, 4.4 mmol) in CH2C12 (50 mL) was treated with a solution of CH2Ν2 in EtjO until a yellow color persisted. The resulting solution was 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 (MgSO4), and concentrated under reduced pressure to yield (lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine methyl ester (1.44 g, 100%): TLC (25% EtOAc/hex) R 0.54.
Figure imgf000052_0001
Step 2
To a solution of (lS,2R)-N-(benzy loxy carbonyl)- O-tert-butylthreonine methyl ester (1.4 g, 4.4 mmol) in Et2O (20 mL) was added a saturated solution of LiBH4 in E^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 ΝaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure to yield (lR,2R)-N-(benzyloxycarbonyl)-l-(hydroxymethyl)-2-(tert- butoxy)propanamine (1.69 g, 99%): TLC (25% EtOAc/hex) R 0.20.
Figure imgf000052_0002
Step 3
To a solution of (lR,2R)-N-(benzyloxycarbonyl)-l-(hydroxymethyl)-2-(tert- butoxy)propanamine (1.6 g, 5.4 mmol) in anh. pyridine (30 mL) at 4 °C was added 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 (MgSO4) and concentrated under reduced pressure to yield (lR,2R)-N-(benzyloxy carbonyl)- 1- (methanesulfonyloxymethyl)-2-(tert-butoxy)propanamine as an oil (2.03 g, 100%): TLC (25% EtOAc/hex) R 0.31.
Figure imgf000052_0003
Step 4
To a solution of (lR,2R)-N-(benzyloxycarbonyl)-l-
(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% Pd/C (0.20 g). The resulting slurry was stirred under H2 (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%).
B8b. General method for the synthesis of 2-aminoethylsulfonate esters.
Synthesis of iV-(2-tosyloxyethyl)- 2-methylprop-2-en-l-ammonium trifluoroacetate.
Figure imgf000053_0001
Step l 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 (300 mL). The EtOAc solution was sequentially washed with water (4x500 mL) and a saturated ΝaCl solution (4x500 mL), dried (MgSO4), 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) R 0.51.
Figure imgf000053_0002
Step 2
A solution of N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert- butyl ester (0.26 g, 0.93 mmol) in Et2O (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 IN HCl was added dropwise until gas evolution stopped. The organic phase was washed with a saturated ΝaHCO3 solution (20 mL), dried
(MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 10% EtOAc/hex to 50% EtOAc/hex) to give N- (tert-butoxycarbonyl)-N-(2-hydroxyethyl)-l-amino-2-methylprop-2-ene (0.113 g, 57%): TLC (10% EtOAc/hex) R 0.66.
Figure imgf000054_0001
Step 3
To a solution of N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-l-amino-2- methylprop-2-ene (21.1 g, 98 mmol) in Et2O (800 mL) at -78 °C was slowly added potassium tert-butoxide (IM 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 treated with a solution of /?-toluenesulfonyl chloride (18.7 g, 98.0 mmol) in Et2O
(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 ΝaCl solution (800 mL), dried (MgSO4), and concentrated under reduced pressure to give N-(tert- butoxycarbonyl)-N-(2-tosyloxyethyl)-l-amino-2-methylprop-2-ene ( 36.4 g, 101%): TLC (25% EtOAc/hex) R/0.56.
Figure imgf000054_0002
Step 4
Solid N-(tert-butoxycarbonyl)-N-(2-tosyloxy ethyl)- 1 -amino-2-methylprop-2- ene (15 g, 55.7 mmol) was cooled to 0 °C and dissolved in TFA (200 mL). The reaction mixture was allowed to warm to room temp., then was concentrated under reduced pressure. The residual oil was crystallized using ΕX__0 (500 mL) to afford N-
(2-tosyloxyethyl)-2-methylprop-2-en-l -ammonium trifluoroacetate (16.7 g, 78%).
B9a. General method for the synthesis of 3-chloropropyl- and 4- chlorobutylamines. Synthesis of iV-isobutyl-3-chloropropylamine HCl salt.
Figure imgf000054_0003
Step l
To a solution of 3-aminopropanol (91 g, 65.4 mmol) in toluene (100 mL) was added isobutraldehyde (9.0 mL, 99.1 mmol, 1.5 equiv.) and MgSO4 (7.5 g) to generate an exotherm. The slurry was stirred for 30 min. and an additional portion of MgSO4 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-l,3-oxazine as a colorless oil (5.18 g, 61%): Η NMR (CDC13) δ 0.84-0.88 (m, 6H), 1.24-1.29 (m, IH), 1.51-1.66 (m, 3H), 2.77-2.87 (m,
IH), 3.07-3.13 (m, IH), 3.60-3.76 (m, 2H), 4.00-4.05 (m, IH).
HO HN J
Step 2
To a solution of 2-isopropyltetrahydro-l,3-oxazole (4.94 g, 38.2 mmol) in abs. EtOH (100 mL) at 0 °C was added NaBH4 (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 saturated NaCl solution. The combined aqueous layers were back-extracted with
EtOAc (150 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford N-isobutyl-3-hydroxypropylamine as a colorless oil (5.04 g, 100%): 'H ΝMR (CDC13) δ 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), 3.74 (dd, , J=5.5, 5.5 Hz, 2H); 13C ΝMR (CDC13) δ 20.5, 28.1, 30.6, 50.0, 57.8, 64.1.
C' "jΝ I HC.
Step 3
To a solution of N-isobutyl-3-hydroxypropylamine (1.01 g, 7.70 mmol) in toluene (100 mL) was added SOCl2 (1.37 g, 11.6 mmol, 1.5 equiv.) and the resulting 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: Η ΝMR (CDClj) δ 1.12 (s, 9H), 1.28 (t, J=7.0 Hz, 3H), 4.24 (q, J=7.0 Hz, 2H), 4.55 (s, IH), 5.00 (s, 2H); 13C ΝMR (CDC13) δ 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%).
BlOa. General method for the synthesis of 2-chlorothiazolidinium salts. Synthesis of ( _S)-2-chloro-3,4-diisobutyl-4,5-dihydro-l,3-thiazolinium chloride.
Figure imgf000056_0001
Step l
To a mixture of (2S)-4-methyl-2-(isobutylamino)pentan-l-ol HCl salt (Method B4c; 0.21 g, 1.0 mmol) and CS2 (0.30 mL, 5.0 mmol, 5.0 equiv.) in 2- butanone (20 mL) was added Cs2CO3 (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 absorbed onto SiO2 and purified by MPLC (Biotage 40 S silica gel column; 5%
EtOAc/hex) to give ( S)-3,4-diisobutyl-l,3-thiazolidin-2-thione as a yellow oil (0.11 g, 52%).
Figure imgf000056_0002
Step 2 A solution of ( S)-3,4-diisobutyl-l,3-thiazolidin-2-thione (5.0 g, 21.6 mmol) in SOCl2 (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 ( S)-2-chloro-3,4- diisobutyl-4,5-dihydro-l,3-thiazolinium chloride as a semisolid: 'H NMR δ 0.99- 1.10 (m, 12H), 1.59-1.67 (m, IH), 1.72-1.84 (m, IH), 2.00-2.10 (m, IH), 2.17-2.29 (br m, IH), 3.61-3.68 (m, IH), 3.86-3.95 (br m, 2H), 4.50-4.57 (m, IH), 4.97-5.06
(br m, IH). 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
Cla. General method for the synthesis of 2-imino-l, 3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S)- 2-(2-methyl-4-nitrophenylimino)-4-isobutyI-l,3-thiazolidine.
Figure imgf000057_0001
To a mixture of (lS)-l-(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 CH2C12 (15 mL) was added Et3N (1.08 mL, 7.78 mmol) via syringe. The resulting solution was stirred for 18 h at room temp. The reaction mixture was washed with a saturated NaHCO3 solution and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 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)
Clb. General method for the synthesis of 2-imino-l,3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (45)- 2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-l ,3-thiazolidine HCl salt.
Figure imgf000057_0002
To a solution of N-( 1 -S)-( 1 -(chloromethyl)-3 -methylbutyl)-N-(isobuty l)amine
HCl salt (Method B7c; 95 g, 0.41 mol, 1.08 equiv.) in CH2C12 (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 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 CH2C12 (500 mL), washed with a IN ΝaOH solution (3x500 mL), dried (MgSO4) and concentrated under reduced pressure. The residual dark oil (132 g) was dissolved in CH2C12 (50 mL) and filtered through a plug of silica gel (5 g SiO2/g 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 HCl solution (IM in Et2O, 500 mL) to give (4S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl- 1,3-thiazolidine HCl salt as a white solid (95 g, 66%): 'H NMR (CDC13) δ 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, IH), 2.82 (q, J=7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J=11.4, 7.7 Hz, IH), 4.18-4.25 (m, IH), 5.02 (dd, J=14.3, 8.1 Hz, IH), 7.32 (d, J=8.1 Hz IH), 7.51 (dd, 1H, J=8.1, 1.8 Hz, IH), 7.58 (d, J=1.8 Hz, IH).
Clc. General method for the synthesis of 2-imino-l, 3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (45)- 2-(2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl-l,3-thiazolidine.
Figure imgf000058_0001
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 CH2C12 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, 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%).
Cld. General method for the synthesis of 2-imino-l, 3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (45)- 2-(4-chloro-2-(trifluoromethyl)phenylimino)-3-isobutyI-l,3-thiazolidine.
Figure imgf000058_0002
N-(Hydroxyethyl)-N-isobutylamine was converted into N-(chloroethyl)-N- 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 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% CH3CN/79.9% water to 0.1% TFA/99.9% CH3CN) to furnish (4S)-2-(4-chloro-2-(trifluoromethyl)phenylimino)-3-isobutyl-l ,3-thiazolidine (0.020 g, 59%).
Cle. General method for the synthesis of 2-imino-l, 3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2-(2,4-dimethyl- 3-cyano-6-pyridylimino)-3-thia-l-azaspiro[4.4]nonane.
Figure imgf000059_0001
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 Et3N (1 mL) dropwise via syringe. The resulting mixture was heated at 50 °C overnight, then cooled to room temp., and treated with a saturated NaHCO3 solution. The resulting mixture was extracted with CH2C12 (3x25 mL). The combined organic layers were dried (NajSO and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 40% EtOAc/hex) to give 2-(2,4-dimethyl-3-cyano-6- pyridylimino)-3-thia-l-azaspiro[4.4]nonane (0.192 g, 51%): CI-MS m/z 287
((M+H)+).
Clf . General method for the synthesis of 2-imino-l, 3-thiazolidines via reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2-(3- quinolylimino)-3,5-diisobutyl-l ,3-thiazolidine.
Figure imgf000059_0002
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-(l-S)-(l- (chloromethyl)-3-methylbutyl)-N-(isobutyl)amine HCl salt (Method B7c; 0.113g, 0.54 mmol) in anh. CH2C12 (2 mL) was added diisopropylethylamine (0.208 g, 1.61 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 (SiO2, 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)+).
C2a. General method for the synthesis of 2-imino-l, 3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2-(2-methyl-4- nitrophenylimino)-3-thia-l-azaspiro [4.4] nonane.
Figure imgf000060_0001
To a solution of 1 -amino- l-(hydroxymethyl)cyclopentane (Method Blc; 20.7 g, 180 mmol) and HCl (4M in p-dio ane, 400 mL) was added SOCl2 (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- 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- nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane (38.3 g, 81%): TLC (25%
EtOAc/hex) Ry0.27.
C2b. General method for the synthesis of 2-imino-l, 3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of l-isobutyl-2-(2-methyl-4- nitrophenylimino)-3-thia-l-azaspiro[4.5]decane.
Figure imgf000061_0001
1 -Amino- l-(hydroxymethyl)cyclohexane (Method Bla) was dissolved in p- dioxane (80 mL) then treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2-(2-methyl-4- nitrophenylimino)-3-thia-l-azaspiro[4.5]decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield l-isobutyl-2-(2- methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.5]decane (0.026 g, 2%): TLC (20% EtOAc/hex) R/0.69.
C2c. General method for the synthesis of 2-imino-l, 3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2-(2-methyl-4- nitrophenylimino)-3-isobutylspiro[l,3-thiazoIidine-4,2'- bicyclo[2.2.1]heptane].
Figure imgf000061_0002
2-(Isobutylamino)-2-(hydroxymethyl)norbornane (Method B2a; 0.24 g, 1.2 mmol) was treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to yield 2-(2-methyl-4-nitrophenylimino)-3-(2- isobutylspiro[l,3-thiazolidine-4,2'-bicyclo[2.2.1]heptane] as an oil (0.022 g, 5%): TLC (25% EtOAc/hex) R 0.72.
C2d. General method for the synthesis of 2-imino-l, 3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 3-isobutyl-4-methyIene-2-(2- methyl-4-nitrophenylimino)-l,3-thiazolidin-5-one and (45)-3-isobutyI-4- carbomethoxy-2-(2-methyl-4-nitrophenylimino)-l,3-thiazolidine HCl salt.
Figure imgf000062_0001
(R)-N-Isobutylserine methyl ester HCl salt (Method B3a; 2.28 g, 10.8 mmol) was treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a. The resulting material was purified by column chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to give 3-isobutyl-
4-methylene-2-(2-methyl-4-nitrophenylimino)-l,3-thiazolidin-5-one (0.028 g, 10%) followed by (5)-3 -isobutyl-4-carborriethoxy-2-(2-methyl-4-nitrophenylimino)- 1,3- thiazolidine HCl salt (0.192 g, 56%). 3-Isobutyl-4-methylene-2-(2-methyl-4- nitrophenylimino)-l,3-thiazolidin-5-one: TLC (25% EtOAc/hex) Ry 0.40. (5)-3- isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-l,3-thiazolidine HCl salt:
TLC (free base, 25% EtOAc/hex) R/0.50.
C2e. General method for the synthesis of 2-imino-l, 3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of l-cyclohexyl-2-(2-methyl-4- nitrophenylimino)-3-thia-l-azaspiro [4.4] nonane.
Figure imgf000062_0002
l-(Cyclohexylamino)-l-(hydroxymethyl)cyclopentane (Method B4a; 1.89 g,
9.59 mmol) was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to yield l-cyclohexyl-2-(2- methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane (0.44 g, 17%): CI-MS m/z
374 ((M+H)+).
C2f. General method for the synthesis of 2-imino-l,3-thiazolidines via conversion of ethanolamines into 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2-(2-methyl-4- nitrophenylimino)-3-isobutyl-4,4-dimethyl-l,3-thiazolidine.
Figure imgf000063_0001
N-Isobutyl-l,l-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 saturation. SOCl2 (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 CHC13 (20 mL). To the resulting solution was added 2-methyl-4-nitro-phenyl isothiocyanate (1.94 g, 10 mmol), then a solution of Et3Ν (10 mmol) in CHC13 (10 mL) was added 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 (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (9% EtO Ac/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 El^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 Et2O (25 mL) followed by EtOAc
(25 mL).
C3a. General method for the synthesis of 2-imino-l,3-thiazolidine homologues via conversion of hydroxyalkylamines into chloroalkylamines followed by reaction with isothiocyanates. Synthesis of (R)-4-isopropyl-2-(2- methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-l,3-thiazine.
Figure imgf000063_0002
(R)-3-(tert- Butoxycarbonylamino)-4-methylpentanol (Method B6a) was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to afford (R)-4-isopropyl-2-(2-methyl-4- nitrophenylimino)-2,3,4,5-tetrahydro-l,3-thiazine (100%).
C4a. General method for the synthesis of 2-imino-l, 3-oxazolidines via reaction of 2-chloroethylamines with isocyanates. Synthesis of l-cyclohexyl-2-(2- methyl-4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane.
Figure imgf000064_0001
To a solution of 1 -(chloromethyl)- l-(cyclohexylamino)cyclopentane HCl salt (Method B7b; 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenyl isocyanate (0.75 g, 4.2 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 (SiO2, gradient from hexane to 10% EtOAc/hex) to yield l-cyclohexyl-2-(2-methyl- 4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane (0.021 g, 1.4%): CI-MS m/z 358 ((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)- 1,3-oxazolidine.
Figure imgf000064_0002
To a solution of N-(2-tosyloxyethyl)-2-methylprop-2-en-l -ammonium trifluoroacetate (Method B8b, Step 4; 0.21 g, 0.548 mmol) in -dioxane (5 mL) was added 2-methyl-4-nitrophenyl isocyanate (0.0955 g, 0.536 mmol), followed by Et3Ν (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 CH2C12 (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 CH2C12 (50 mL). The organic phase was dried (Na^O^ and concentrated under reduced pressure to give 2-(2-methyl-4- nitrophenylimino)-3-(2-methylprop-2-enyl)-l,3-oxazolidine as a yellow oil (0.020 g, 14%) CI-MS m/z 276 ((M+H)+).
C5b. General method for the synthesis of 2-iminoheterocycles via reaction of aminoethylsulfonate esters with isocyanates or isothiocyanates. Synthesis of (45)-4-(l(R)-terf-butoxyethyl)-3-isobutyl-2-(2-methyl-4- nitrophenylimino)-l,3-thiazolidine.
Figure imgf000065_0001
(1 R,2R)- 1 -(Methanesulfonyloxymethy l)-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 Cla to afford 4(S)- (l(R)-tert-butoxyethyl)-2-(2-methyl-4-nitrophenylimino)-l,3-thiazolidine (1.2 g, 67%). The (4S)-2-(2-methyl-4-nitrophenylimino)-4-(l(R)-tert-butoxyethyi -l,3- thiazolidine was reacted with isobutyl bromide in a manner analogous to Method
D2a to yield (4S)-4-(l(R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4- nitrophenylimino)- 1,3 -thiazolidine (0.26 g, 56%): TLC (25% EtOAc/hex) R 0.67.
C6a. General method for the synthesis of 2-imino-l,3-thiazolidines via conversion of chloroethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of (45)-2-(4-cyano-2- ethylphenylimino)-3,4-diisobutyl-l,3-thiazolidine HCl salt.
Figure imgf000065_0002
To a solution of sodium hydrogen sulfide (69 g, 1.2 mol, 2.2 equiv.) in water (500 mL) was added N-(l-5)-(l-(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 (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 K2CO3 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 pressure and the residue treated with EtOAc (2 L). The organic layer was washed with water (2x500 mL), dried (MgSO4) and concentrated under reduced pressure to give a dark oil (160 g). The oil was dissolved in CH2C12 (150 mL) and passed through a silica gel plug (3 g SiO2/l g crude product) with the aid of a 5% EtOAc/hex solution to afford an oil containing the desired product and some residual isocyanide dichloride (134 g). The oil was dissolved in EtOAc (500 mL) and treated with HCl (IN in E ,O, 500 mL). The resulting (4S)-2-(4-cyano-2-ethylphenylimino)- 3,4-diisobutyl-l,3-thiazolidine HCl salt was removed by filtration (147 g, 70%): Η NMR (CDC13) δ 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, IH), 2.82 (q, J=7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J=11.4 , 7.7 Hz, IH), 4.18-4.25 (m, IH), 5.02 (dd,
J=14.3, 8.1 Hz, IH), 7.32 (d, J=8.1 Hz, IH), 7.51 (dd, J=8.1, 1.8 Hz, IH), 7.58 ( d, J=1.8 Hz, IH).
C6b. General method for the synthesis of 2-imino-l,3-thiazolidines via conversion of chloroethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of l-cyclopentyl-2-(2- methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane HCl salt.
Figure imgf000066_0001
To a solution of sodium hydrogen sulfide (31 g, 0.55 mol, 2.2 equiv.) in water
(250 mL) was added 1 -(chloromethyl)- l-(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 reaction mixture was stirred at room temp, for 1 h, then a 3.6M K2CO3 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 organic layer was washed with water (2x200mL), dried (MgSO4) and concentrated under reduced pressure. The residual oil (86 g) was dissolved in CH2C12 (50 mL) and filtered through a plug of silica gel (3 g SiO2/l g crude product) with the aid of a 5% EtOAc/hex solution to afford an oil (34 g) containing the desired product and some residual isocyanide dichloride. This oil was dissolved in EtOAc (300 mL) and with
HCl (IN in EtjO, 1.5 L). The resulting solids were removed by filtration to give 1- cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane HCl salt as a white powder (36.8 g): Η NMR (CD3OD) δ 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, IH) 6.70 (br s, IH), 6.93 (d, J=8.4 Hz, IH), 7.96-8.04 (m, IH), 8.03 (d, J=3 Hz, IH).
C6c. General method for the synthesis of 2-imino-l, 3-thiazolidines via conversion of hydroxyethylamines into 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of l-cyclopentyI-2-(2- methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane.
Figure imgf000067_0001
Step l
To a 0 °C solution of Ph3P (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 equiv.) and l-cyclopentylamino-l-(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 with a IN HCl solution (5x125 mL). The combined aqueous layers were washed with
EtOAc (2x200 mL), neutralized with K2CO3 to pH 7.0-7.5, then extracted with EtOAc (5x200 mL). The organic layers were combined, dried (Na^O and concentrated under reduced pressure. The residue was dried in vacuo to afford 1- cyclopentylamino-l-(thioacetylmethyl)cyclopentane as a yellow oil (19.1 g): TLC (10% EtOAc/hexanes) R/0.16; Η NMR (CDC13) δ 1.20-1.87 (m, 16H), 2.34 (s, 3H),
2.92-3.02 (m, IH), 3.15 (s, 2H); 13C NMR (CDC13) δ 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%).
Figure imgf000068_0001
Step 2
A solution of l-cyclopentylamino-l-(thioacetylmethyl)cyclopentane (19.1 g) in a 0.33 M KOH solution in 9:1 MeOH:H2O (273 mL, 0.090 mol, 1.1 equiv.) was 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-l- (thiomethyl)cyclopentane as a yellow oil: TLC (10% EtOAc/hexanes) Rf 0.18 (streak); Η NMR (CD3OD) δ 1.32-1.71 (m, 14H), 1.87-1.94 (m, 2H), 2.67 (s, 2H), 3.07-3.14 (m, IH); FAB-LRMS m/z (rel abundance) 200 ((M+H)+, 19%). This material was used immediately in the next step without further purification
Figure imgf000068_0002
Step 3
A solution of crude l-cyclopentylamino-l-(thiomethyl)cyclopentane anh. CH2C12 (100 mL) at 0 °C was treated with a slurry of crude 2-methyl-4-nitrophenyl isocyanide dichloride (Method A3b; 19.1 g, 0.082 mol, 1.0 equiv. based on 1- cyclopentylamino-l-(thioacetylmethyl)cyclopentane) in CH2C12 (200 mL) followed by Et3N (30 mL, 0.215 mol, 2.6 equiv.), and the reaction mixture was allowed to warm to room temp, and stirred for 2 d. N,N-Dimethylethylenediamine (92 g, 0.023 mol, 0.3 equiv.) was added and the reaction mixture was stirred for 1 h. Silica gel (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 SiO2, 5% EtOAc/hex) to afford l-cyclopentyl-2-(2-methyl-4- nitrophenylimino)-3-thia-l -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; Η ΝMR (CDC13) δ 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, IH), 6.89 (d, J=8.5 Hz, IH), 7.95-8.03 (m, 2H); 13C ΝMR (CDC13) δ 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 C19H25Ν3O2S: C, 63.48; H, 7.01 ; N, 11.69. Found: C, 63.48; H, 6.89; N, 11.76. C7a. General method for the synthesis of 2-imino-l, 3-oxazolidines via reaction of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of 2- (4-cyano-2-ethylphenylimino)-3-cyclopentyl-4,4-dimethyl-l,3- oxazolidine.
Figure imgf000069_0001
A solution of N-cyclopentyl-(l,l-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 ΝaH (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 (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), H2O (20 mL) and a saturated ΝaCl solution (20 mL), dried (Νa^O.,) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 5% EtOAc/hex) to give 2-(4-cyano-
2-ethylphenylimino)-3-cyclopentyl-4,4-dimethyl-l,3-oxazolidine as a yellow solid (0.09 g, 43%): mp 112-114 °C; TLC (15% EtOAc/hex) R/0.60; Η ΝMR (CDC13) δ 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, IH), 3.97 (s, 2H), 7.04 (d, J=8.3 Hz, IH), 7.35 (dd, J=8.1, 1.8 Hz, IH), 7.40 (d, J=1.8 Hz, IH); CI-MS m/z (rel abundance) 312 ((M+H)+, 100%). HRMS Cacld for C17H23Ν3O3: 311.1998. Found: 311.1991.
C7b. General method for the synthesis of 2-imino-l, 3-oxazolidines via reaction of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of
( 5)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-l,3-oxazolidine.
Figure imgf000069_0002
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-l-ol (Method B4c; 0.26 g, 1.52 mmol) in THF (5 mL) was added Et3N (0.5 mL). The resulting mixture was stirred at room temp, for 1 h, then was treated with 2- (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-l,3-oxazolidine as a yellow oil (0.15 g): TLC (10% EtOAc/hex) R 0.35; Η NMR (CDC13) δ 0.81-1.00 (m, 12H), 1.14 (t, J=4.8Hz, 3H), 1.25-1.43 (m, 2H), 1.53-1.70 (m, 2H), 2.57 (sept, J=7.5 Hz, IH), 2.58
(q, J=7.5 Hz, 2H), 3.01 (dd, J=14.0, 6.3 Hz, IH), 3.33 (dd, J=13.6, 8.8 Hz, IH), 3.73- 3.83 (m, IH), 3.94 (app t, J=7.5 Hz, IH), 4.37 (app t, J=7.9 Hz, IH), 7.01 (d, J=8.1 Hz, IH), 7.33 (dd, J=8.1, 1.8 Hz, IH), 7.38 (d, J=1.8 Hz, IH); 13C NMR (CDC13) δ 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, 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- isobutyl-1 ,3-thiazolidin-4-one.
Figure imgf000070_0001
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 (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 layers were washed with a saturated ΝaCl solution (25 mL), dried (Νa2SO4) 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-l,3-thiazolidin-4-one as a pale yellow oil (0.52 g, 85%). C9a. General method for the synthesis of 2-imino-l,3-thiazolidines by reaction of hydroxyethylamines with isothiocyanates followed by acid catalyzed ring closure. Synthesis of 2-(2,6-dichlorophenylimino)-3- cyclohexyl-4,4-dimethyl-l,3-thiazolidine.
Figure imgf000071_0001
N-Cyclohexyl-l,l-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-l,l-dimethyl-2-hydroxyethanamine (l.Og, 6.0 mmol) in CH2C12 (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% ΝaOH solution. The resulting slurry was filtered, and the resulting solids were washed with water (20 mL), then recrystallized (EtOH) to yield 2-(2,6-dichlorophenylimino)-3-cyclohexyl-4,4-dimethyl-l,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 Et2O (50 mL) and treating this solution with a 2Ν ethereal HCl solution until no more solid precipitated. The resulting slurry was filtered and the resulting solids were washed with Et2O (25 mL) followed by EtOAc (25 mL).
ClOa. General method for the reaction of 2-chlorothiazoIinium salts with anilines. Synthesis of 2-(2-(7V-phenylcarbamoyl)phenylimino)-3,4- diisobutyI-l,3-thiazolidine.
Figure imgf000071_0002
A solution of 2-(N-phenylcarbamoyl)aniline (0.097 g, 0.36 mmol, 1.0 equiv.) and Et3Ν (0.5 mL, 3.6 mmol, 10 equiv.) in/?-dioxane (5 mL) was added to a solution of ( S)-2-chloro-3,4-diisobutyl-4,5-dihydro-l,3-thiazolinium chloride in dichloroethane (Method BlOa; 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) and a saturated NaCl solution (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was absorbed onto SiO2, 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%).
Clla. General method for synthesis of 2-imino-l,3-thiazolidin-5-ones via reaction of amino acid esters with isothiocyanates. Synthesis of 2-(2- methyl-4-nitrophenylimino)-3-isobutyl-l,3-thiazolidin-5-one.
Figure imgf000072_0001
A solution of N-isobutylglycine ethyl ester (0.41 g, 2.57 mmol) in water (5 mL) was treated with Et3Ν (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 (MgSO4) and concentrated under reduced pressure to afford 2-(2-methyl-4-nitrophenylimino)-3- isobutyl-l,3-thiazolidin-5-one (0.16 g, 88%): mp 152 °C.
D. General Methods for the Interconversion of Iminoheterocycles
Dla. General method for the neutralization of iminoheterocycle salts.
Synthesis of (45)-2-(4-cyano-2-ethyIphenylimino)-3,4-diisobutyl-l ,3- thiazolidine.
Figure imgf000072_0002
To a mixture of (45)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-l,3- thiazolidine HCl salt (Method C6a; 304 g, 0.8 mol), water (1 L) and EtOAc (1.4 L) was added NaHCO3 (150 g, 1.78 mol, 2.2 equiv.). The resulting mixture was stirred for 1 h. The organic layer was dried (MgSO4) 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, CH3OH); Η NMR (CDC13) δ 0.92-0.99 (m, 12H), 1.13 (t, J=7.4 Hz, 3H), 1.47-1.52 (m, IH), 1.58-1.67 (m, 2H), 2.07-2.11 (m, IH), 2.54 (q, J=7.4 Hz,
2H), 2.84-2.90 (m, 2H), 3.28 (dd, J=10.6, 6.6 Hz, IH), 3.68 (dd, J 3.6, 8.1, Hz, IH), 3.81-3.87 (m, IH), 6.85 (d, J=7.9 Hz, IH), 7.36-7.42 (m, 2H); CI-MS m/z 344 ((M+H)+).
Dlb. General method for the neutralization of iminoheterocycle salts.
Synthesis of l-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-l- azaspiro [4.4] nonane.
Figure imgf000073_0001
To 1 -cyclopenty l-2-(2-methyl-4-nitrophenylimino)-3 -thia- 1 - 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 NaHCO3 (15 g, 0.178 mol, 1.3 equiv.). The mixture was stirred for 1 h and the resulting organic layer was dried (MgSO4) concentrated under reduced pressure. The resulting light yellow solid was treated with EtOH (lOOmL), and concentrated under reduced pressure twice to give 1 -cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia- 1 -azaspiro[4.4]nonane
(46 g, 97%): mp 111-112 °C; Η NMR (CDC13) δ 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, IH), 6.87 (d, J=8.5 Hz, IH), 8.02 (m, 2H); CI-MS m/z 360 ((M+H)+).
D2a. General method for the ring-nitrogen alkylation of 2-imino heterocycles.
Synthesis of (45)-2-(2-methyI-4-nitrophenylimino)-3,4-diisobutyl-l ,3- thiazolidine HCl salt.
Figure imgf000074_0001
A slurry of (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-l,3-thiazolidine (Method Cla; 0.10 g, 0.34 mmol), isobutyl bromide (0.11 mL, 1.03 mmol) and Cs2CO3 (0.12 g, 0.38 mmol) in DMF (2 mL) was heated at 90 °C for 18 h, then cooled to 20 °C, diluted with EtOAc (50 mL) and washed with water (2x200 mL).
The organic phase was dried (MgSO4), concentrated under reduced pressure, and the residue was purified by chromatography (SiO2, gradient from 100% hex to 10% EtOAc/hex). The resulting material was dissolved in CH2C12 (10 mL), treated with an HCl solution (IM in Et2O, 2 mL), then concentrated under reduced pressure to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-l,3-thiazolidine HCl salt
(0.088 g, 68%): TLC (free base, 20% EtOAc/hex) R/0.74.
D2b. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of l-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-l- azaspiro [4.4] nonane.
Figure imgf000074_0002
A solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-l-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 stirred at 20-40 °C for 18 h, then cooled to 4 °C, and treated with water (1.5 L). A cone. 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 HCl solution (1 L), dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in CH2C12 (500 mL) and filtered through a pad of silica gel (9x4 cm). Hexane was added to the resulting solution and volatiles were slowly removed by partial vacuum until crystals formed. The solids were collected to yield l-cyclopentyl-2-(2-methyl- 4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane as yellow crystals (10.9 g, 26%): mp 118-9 °C; TLC (5% EtOAc/hex) R/0.34. 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-2 _F-l,3-thiazine.
Figure imgf000075_0001
(R)-4-Isopropyl-2-(2-methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-l,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-l,3-thiazine (0.081 g, 32%). TLC (33% EtOAc/hex) R 0.76.
D2d. General method for the ring-nitrogen alkylation of 2-imino heterocycles. 2-(2-Methyl-4-nitrophenylimino)-3-propanoyl-l,3-thiazolidine.
Figure imgf000075_0002
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 CH2C12 (5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and Et3N (0.049 mL, 0.35 mmol). The mixture was allowed to stir at room temp for 1 h, then was diluted with CH2C12 (40 mL). The resulting solution was sequentially washed with H2O (10 mL) and a saturated NaCl solution (10 mL), dried (Na^O , and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc/hex) to give 2-(2-methyl-4-nitrophenylimino)-3-propanoyl-l,3- thiazolidine (0.036 g, 35%): FAB-MS m/z 294 (( M+H)+).
D2e. General method for the ring-nitrogen alkylation of 2-imino heterocycles.
Synthesis of l-(cyclohexylmethyl)-2-(2-methyl-4-nitrophenylimino)-3- thia-l-azaspiro[4.4]nonane.
Figure imgf000076_0001
To a solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-l- 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 (aøprox. 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 (SiO2; 5% EtOAc/hex) to afford l-(cyclohexylmethyl)-2-(2-methyl- 4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane (0.042 g, 32%) mp 85-7 °C.
D2f. General method for the ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of (45)-2-(2-chloro-4-cyano-6-methylphenylimino)-3,4- diisobutyI-l,3-thiazo!idine trifluoroacetate salt.
Figure imgf000076_0002
To a solution of (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-4-isobutyl-
1,3-thiazolidine (Method Clc; 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 concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C-18 column, gradient from 0.1% TFA/20% CH3CN/79.9% water to 0.1% TFA/99.9% CH3CN) to furnish (4S)-2-(2-chloro-4-cyano-6- methylphenylimino)-3,4-diisobutyl-l,3-thiazolidine trifluoroacetate salt (0.030 g, 52% yield).
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)- 4,4-dimethyl-l,3-thiazolidine HBr salt.
Figure imgf000077_0001
2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-l ,3-thiazolidine was prepared in a manner analogous to that described in Method Cla. To a suspension of 2-(2- methyl-4-nitrophenylimino)-4,4-dimethyl- 1,3 -thiazolidine (1.5 mmol) in toluene (10 mL) was added 2-methylprop-2-en-l-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 CH2C12 (20 mL) to yield 2-(2-methyl-4- nitrophenylimino)-3-(2-methyl-prop-2-enyl)-4,4-dimethyl-l,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)-l-isobutyI-3-thia-l- azaspiro [4.4] nonane.
Figure imgf000077_0002
To a solution of 2-(2,4-dimethyl-3-cyano-6-pyridylimino)-3-thia-l- 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. 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 (SiO2, gradient from 20% EtOAc/hex to 100% CH2C12) to give 2-(2,4-dimethyl-3-cyano-6-pyridylimino)-l-isobutyl-3-thia-l- azasρiro[4.4]nonane (0.04 g, 17%): CI-MS m/z 343 ((M+H)+).
D3a. General method for the deprotection of te/tf-butoxycarbamoyl-protected alcohols. Synthesis of (45)-4-(l(R)-hydroxyethyl)-3-isobutyl-2-(2-methyl- 4-nitrophenylimino)-l,3-thiazolidine.
Figure imgf000078_0001
A solution of TFA (8 mL) was cooled to 4 °C and added to solid (4S)-4- (l(R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4-nitrophenylimino)-l,3-thiazolidine (Method C5b; 0.16 g, 0.42 mmol) via cannula. The resulting solution was warmed to 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^O (100 mL) and a saturated NaHCO3 solution (100 mL). The ether layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; gradient from hexane to 10% EtOAc/hex) to yield (4S)-4-(l(R)-hydroxyethyl)- 3-isobutyl-2-(2-methyl-4-nitrophenylimino)-l, 3-thiazolidine (0.13 g, 90%): TLC
(25% EtOAc/hex) R 0.13.
D4a. General method for the synthesis of 2-imino-l, 3-thiazolidine 3-oxides and 2-imino-l,3-thiazoIidine 3,3-dioxides via oxidation of 2-imino-l,3- thiazolidines. Synthesis of l-cyclopentyl-2-(2-methyl-4- nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane 3-oxide and 1- cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-l- azaspiro[4.4]nonane 3,3-dioxide.
Figure imgf000078_0002
A solution of l-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-l- 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 CH2C12 (5 mL) was stirred for 30 min., then washed with a saturated NaHCO3, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from hexane to 30% EtOAc/hex) to yield l-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-
3-thia-l-azaspiro[4.4]nonane 3,3-dioxide (0.030 g, 67%) followed by 1-cyclopentyl- 2-(2-methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane 3-oxide (0.011 g, 26%). l-Cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane 3,3-dioxide: TLC (25% EtOAc/hex) Rf 0.27. l-Cyclopentyl-2-(2-methyl-4- nitrophenylimino)-3 -thia- 1 -azaspiro [4.4]nonane 3-oxide: TLC (25% EtOAc/hex) Rf 0.10.
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)-l,3-thiazolidine.
Figure imgf000079_0001
2-(2-Methyl-4-nitrophenylimino)-l, 3-thiazolidine was prepared in a manner analogous to that described in method C2a and was alkylated with l-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)-l,3-thiazolidine. To a solution of 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2-oxobutyl)-l,3- thiazolidine (0.022 g, 0.065 mmol) in MeOH (2 mL) was added NaBH4 (0.0096 g, 0.26 mmol) in portions. The resulting mixture was stirred at room temp for 4 h, then was separated between EtOAc (10 mL) and H2O (5 mL) and the aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were sequentially washed with H2O (15 mL), a saturated NaCl solution (15 mL), dried (Na^O , and concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/hexane) to yield 2-(2-methyl-4-nitrophenylimino)-3-(3,3-dimethyl-2- hydroxybutyl)-l, 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 (45)-2-(4-carbamoyl-2-methylphenylimino)-3,4-diisobutyl- 1 ,3-thiazolidine.
Figure imgf000079_0002
Step l To a solution of (45)-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 H2O (1.5 mL) was added LiOH (0.016 g, 0.39 mmol). The resulting mixture was stirred for 2 d 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 H2O (15 mL), a saturated NaCl solution (15 mL), and dried (Na^O . Concentration under reduced pressure gave (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-l ,3-thiazolidine (0.034 g, 100%): TLC (40% EtOAc/hex) R 0.08. This material was used in the next step without further purification.
Figure imgf000080_0001
Step 2
To a solution of (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-l,3- thiazolidine (0.035 g, 0.10 mmol) in CH2C12 (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 NH3 (approximately 30 drops) was condensed into the solution at -78 °C. The resulting mixture was warmed to room temp, overnight, then treated with H2O (20 mL). The aqueous layer was extracted with CH2C12 (3x20 mL), sequentially washed with H2O (20 mL) and a saturated NaCl solution (20 mL), dried (Na^O^, 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.
D6b. General method for the interconversion of carboxylic acid derivatives. Synthesis of 2-(2-ethyl-4-(Λr-methylcarbamoyI)phenylimino)-l- cyclopentyl-3-thia-l -azaspiro [4.4] nonane.
Figure imgf000081_0001
To a solution of 2-(4-carboxy-2-ethylphenylimino)-l-cyclopentyl-3-thia-l- azaspiro[4.4]nonane (Method D9a; 0.58 g, 0.167 mmol) in CHC13 (5 mL) was added SOCl2 (0.06 mL, 0.83 mmol). The reaction mixture was heated at the reflux temp, for 3 h, then concentrated under reduced pressure. The residue was dissolved in CH2C12
(3 mL) and treated with methylamine (2.0M 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 CH2C12 (3x20 mL), and the combined organic layers were washed with a saturated NaCl solution (20 mL), dried (Na^O,,) and concentrated under reduced pressure. The residue was purified by preparative
TLC (50% EtOAc/hexane) to give 2-(2-ethyl-4-(N-methylcarbamoyl)phenylimino)- l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane (36 g, 56%): TLC (30% EtOAc/hex) Rf 0.44.
D7a. General method for the synthesis of cyanoarylimines from iodoarylimines. Synthesis of 2-(4-cyano-2-propylphenylimino)-3-thia-l- azaspiro [4.4] nonane.
Figure imgf000081_0002
4-Iodo-2-n-propylaniline was converted into 4-iodo-2-«-propylphenyl isothiocyanate in a manner analogous to Method A2b. Concurrently, 1 -amino- 1-
(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-l-azaspiro[4.4]nonane. A slurry of 2-(4-iodo-2- propylphenylimino)-3-thia-l -azaspiro [4.4]nonane (0.54 g, 1.35 mmol) and CuCΝ (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- propylphenylimino)-3-thia-l-azaspiro[4.4]nonane as a white solid (0.26 g, 65%): TLC (30% EtOAc/hex) R 0.37.
D8a. General method for the synthesis of phenylacetylenes. Synthesis of 2- (2,3-dimethyl-4-ethynylphenylimino)-l-isobutyl-3-thia-l- azaspiro [4.4] nonane.
Figure imgf000082_0001
Step l
4-Iodo-2,3-dimethylaniline was converted into 4-iodo-2,3-dimethylphenyl 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), Pd(PPh3)2Cl2 (0.005 g) and Cul (0.012 g, 0.063 mmol) in Et3N (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-l-ethynyl)phenylimino)- l-isobutyl-3-thia-l-azaspiro[4.4]nonane (0.005 g, 59%).
Figure imgf000082_0002
Step 2
A mixture of 2-(2,3-dimethyl-4-(2-trimethylsilyl-l-ethynyl)phenylimino)-l- isobutyl-3-thia-l-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 mixture was diluted with CH2C12 (20 mL), filtered, and the filtrate was concentrated under reduced pressure. Thre residue was purified by preparative TLC (2% EtO Ac/hex) to give 2-(2,3-dimethyl-4-ethynylphenylimino)-l-isobutyl-3-thia-l- azaspiro[4.4]nonane (0.003.2 g, 78%): TLC (20% EtOAc/hex) R 0.70.
D9a. General method for the synthesis of benzoic acids via hydrolysis of benzonitriles. Synthesis of 2-(4-carboxy-2-ethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Figure imgf000083_0001
2-(4-Cyano-2-ethylphenylimino)-3-thia-l-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)-l-cyclopentyl-3- thia-l-azaspiro[4.4]nonane. A solution of 2-(4-cyano-2-ethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane (0.32 g, 9.42 mmol) in cone. 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,, then extracted with CH2C12 (4x40 mL). The combined organic layers were sequentially washed with water (30 mL) and a saturated NaCl solution (30 mL), dried (Na^O^ and concentrated under reduced pressure, to give 2-(4-carboxy-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane as a white solid (0.34 g, 100%): mp 208-209 °C.
DlOa. General method for the conversion of carboxylic acids into ketones. Synthesis of 2-(4-acetyl-2-ethylphenylimino)-l-cyclopentyl-3-thia-l- azaspiro[4.4]nonane.
Figure imgf000083_0002
To a solution of the 2-(4-carboxy-2-ethylphenylimino)-l-cyclopentyl-3-thia- l-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 , 0.91 mL, 1.28 mmol). The reaction 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 NaHCO3 solution (10 mL). The resulting mixture was extracted with EtOAc (4x20 mL), and the combined organic layers were washed with a saturated NaCl solution (30 mL), dried (NajSO and concentrated under reduced pressure. The residue was purified by preparative TLC (10% EtOAc/hex) to give 2-(4-acetyl-2-ethylphenylimino)-l-cyclopentyl-3-thia-l- azaspiro[4.4]nonane as a white solid (0.032 g, 73%): mp 114 -115 °C.
Dlla. General method for the conversion of nitriles into aldehydes. Synthesis of 2-(2-ethyl-4-formyIphenylimino)-l-cyclopentyl-3-thia-l- azaspiro [4.4] nonane.
Figure imgf000084_0001
2-(4-Cyano-2-ethylphenylimino)-3-thia-l-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)-l-cyclopentyl-3- thia-l-azaspiro[4.4]nonane. To a solution of 2-(4-cyano-2-ethylphenylimino)-l- cyclopentyl-3 -thia- 1 -azaspiro [4.4]nonane (0.21 g, 0.60 mmol) in anh. toluene (20 mL) at -78C was added DIBAL (1.0M 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 residue was purified by preparative TLC (30% EtOAc/hex) to give 2-(2-ethyl-4- formylphenylimino)-l-cyclopentyl-3-thia-l-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. Synthesis of 2-(2-ethyl-4-((l_E)-2-ethoxycarbonylvinyl)phenyIimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Figure imgf000085_0001
To a solution of 2-(2-ethyl-4-formylphenylimino)-l-cyclopentyl-3-thia-l- azaspiro[4.4]nonane (Method Dl la; 0.053 g, 0.149 mmol) in CH3CN was added LiCl (0.0076 g, 0.182 mmol) followed by DBU (0.025 g, 0.167 mmol) and triethyl 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-((lE)-2- ethoxycarbonylvinyl)phenylimino)- 1 -cyclopenty 1-3 -thia- 1 -azaspiro[4.4]nonane as a colorless oil (0.029 g, 48%): TLC (30% ΕtOAc/hex) R 0.68.
D12b. General methods for the chain homologation of aldehydes or ketones. Synthesis of 2-(2-ethyl-4-((l_Ε)-2-nitrovinyl)phenylimino)-l-cyclopentyl- 3-thia-l-azaspiro[4.4]nonane.
Figure imgf000085_0002
To a solution of 2-(2-ethyl-4-formylphenylimino)-l -cyclopenty 1-3 -thia- 1- azaspiro[4.4]nonane (Method Dl la; 0.041 g, 0.115 mmol) in CH2C12 (10 mL) was added MeNO2 (2 drops) and piperidine (4 drops). The reaction mixture was heated at the reflux temp, overnight, thern cooled to room temp, and concentration under reduced pressure. The residue was purified by flash chromatography (3% EtOAc/hex) to give 2-(2-ethyl-4-((lE)-2-nitrovinyl)phenylimino)-l-cyclopentyl-3- thia-1 -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)-l-cyclopentyl-3- thia-l-azaspiro[4.4]nonane.
Figure imgf000086_0001
To a solution of 2-(2-ethyl-4-formylphenylimino)-l-cyclopentyl-3-thia-l- azaspiro[4.4]nonane (Method Dl la; 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 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.
D12d. General methods for the chain homologation of aldehydes or ketones.
Synthesis of 2-(2-ethyl-4-(2-cyanovinyl)phenylimino)-l-cyclopentyl-3-thia-l- azaspiro[4.4]nonane.
Figure imgf000086_0002
To a solution of KOH (0.024 g, 0.36 mmol) in CH3CN (20 ml) at the reflux temp. was added 2-(2-ethyl-4-formylphenylimino)-l-cyclopentyl-3-thia-l- azaspiro[4.4]nonane (Method Dl la; 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 CH2Cl2 (3xl5 mL). The combined organic layers were washed with a saturated NaCl solution and dried (Na^O,). The resulting material was purified by preparative TLC
(30% EtOAc/hex) to give 2-(2-ethyl-4-(2-cyanovinyl)phenylimino)-l -cyclopenty 1-3- thia-l-azaspiro[4.4]nonane as 1:3 cis/trans mixture of isomers (0.050 g): TLC (30% EtOAc/hex) R 0.56.
D13a. General method for the alkylation of chloromethyl side chains. Synthesis of 2-(2-methyI-4-nitrophenylimino)-4-(iV-methylaminomethyl)-l,3- thiazolidine.
Figure imgf000087_0001
To a solution of methylamine in methanol (2.0M, 5 mL) was added 2-(2- methyl-4-nitrophenylimino)-4-(chloromethyl)-l, 3-thiazolidine (prepared in a manner analogous to that described in Method C2a; 0.040 g, 0.140 mmol) and the 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/CH2Cl2) to give 2-(2-methyl-4-nitrophenylimino)-4-(N- methylaminomethyl)- 1,3 -thiazolidine as a solid (0.014 g, 35%).
D14a. Acid-catalyzed rearrangement of carbon-carbon double bonds.
Synthesis of 2-(4-nitrophenylimino)-3-(2-methylprop-l-en-l-yl)-l,3- thiazolidine.
Figure imgf000087_0002
2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give 2-(4-nitrophenyl)- 1,3 -thiazolidine.
The thiazolidine was reacted with l-bromo-2-methyl-2-propene according to Method
D2a to give 2-(4-nitrophenylimino)-3-(2-methylprop-2-en-l-yl)-l, 3-thiazolidine. A mixture of 2-(4-nitrophenylimino)-3-(2-methylprop-2-en-l-yl)-l, 3-thiazolidine (0.20 g) in poly(phosphoric acid) (0.4 mL) was heated at 80 °C for 5 h. The reaction 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 ΝaOH solution, then extracted with EtOAc (3 x 25 mL). The combined organic phases were dried (K2CO3) and concentrated under reduced pressure. The residue (0.21 g) was purified by preparative HPLC to afford 2-(4-nitrophenylimino)-3-(2-methylprop-l-en-l-yl)-l,3- thiazolidine.
SPECIFIC COMPOUND PREPARATIONS
Descriptions of the detailed preparative steps used to prepare the specific compounds listed in Tables 1-4 are provided below. Many of the compounds listed 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.
Entry 1
Figure imgf000088_0001
2-Chloroethylamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2-methyl-4-nitrophenylimino)- 1,3 -thiazolidine.
Entry 2
Figure imgf000088_0002
2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give 2-(4-nitrophenylimino)-l,3- thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2-(4-nitrophenylimino)-3-isobutyl- 1 ,3-thiazolidine.
Entry 3
Figure imgf000088_0003
2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 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
Figure imgf000088_0004
2-Chloroethylammonium chloride (Entry 1) was reacted with 2,3-dichlorophenyl isothiocyanate according to Method Cla to give 2-(2,3-dichlorophenylimino)-l,3- thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2-(2,3-dichlorophenylimino)-3-isobutyl-l ,3-thiazolidine.
Entry 5
Figure imgf000089_0001
N-Chloroethyl-N'-isobutylammonuim chloride (prepared as described in Method B7c) was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to method Cld to give 2-(2-methoxy-4-nitrophenylimino)-3 -isobutyl- 1, 3-thiazolidine.
Entry 6
Figure imgf000089_0002
N-Chloroethyl-N'-isobutylammonuimchloride (prepared as described in Method B7c) was reacted with 4-cyanophenyl isothiocyanate according to method Cld to give 2-(4-cyanophenylimino)-3 -isobutyl- 1 ,3 -thiazolidine .
Entry 7
Figure imgf000089_0003
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-l, 3-thiazolidine HCl salt.
Entry 8 ,>=N-^ -Cc N i-Bu Et
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.
Entry 9
Figure imgf000089_0004
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-l,3- thiazolidine.
Entry 10
Figure imgf000090_0001
2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with l-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.
Entry 11
Figure imgf000090_0002
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 l-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 ^N" "N°2
2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with l-bromo-2-methyl-2-propene according to Method D2a to give 2-(4- nitrophenylimino)-3-(2-methylprop-2-en- 1 -yl)- 1 ,3-thiazolidine.
Entry 13
Figure imgf000091_0001
2-Chloroethylammonium c o e ntry was reacte with 3,4-dichlorophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with l-bromo-2-methyl-2-propene according to Method D2a to give 2-(3,4- dichlorophenylimino)-3-(2-methylprop-2-en-l-yl)-l, 3-thiazolidine.
Entry 14
Figure imgf000091_0002
N-(2-Hydroxyethyl)-N-(2-methylbutyl)amine was reacted with SOCl2 according to 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-l- butyl)-l ,3-thiazolidine.
Entry 15
Figure imgf000091_0003
2- oroet y ammon um c or e ntry 1) was reacte w t -met y - -n trop eny 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- nitrophenylimino)-3-(but-l-en-4-yl)-l,3-thiazolidine.
Entry 16
2-Chloroethylammonium c
Figure imgf000091_0004
2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give the thiazolidine, which was reacted with l-bromobut-2-yne according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(but-2-yn-l-yl)-l,3-thiazolidine.
Entry 17
Figure imgf000092_0001
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- nitrophenylimino)-3 -(2-ethy 1- 1 -butyl)- 1 ,3 -thiazolidine .
Entry 18
Figure imgf000092_0002
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-methylbutyl bromide according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3 -(2 -methyl- 1 -butyl)- 1 ,3-thiazolidine.
Entry 19
Figure imgf000092_0003
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.
Entry 20
Figure imgf000092_0004
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 2,2-dimethylpropyl bromide according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(2,2-dimethylpropyl)-l,3-thiazolidine. Entry 21
Figure imgf000093_0001
2-Butylamine was converted to N-(2-hydroxyethyl)-N-(2-butyl)amine according to Method B5a. The amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(2-butyl)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-butyl)-l,3-thiazolidine.
Entry 22
Figure imgf000093_0002
3-Pentylamine was converted to N-(2-hydroxyethyl)-N-(3-pentyl)amine according to Method B5a. The amine was reacted with SOCl2 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 Cla to give to give 2-(2-methyl-4-nitrophenylimino)-3-(3-pentyl)-l, 3-thiazolidine.
Entry 23
Figure imgf000093_0003
2-Chloroethylammonium c or e ntry was reacte w t 2-methyl-4-nitrophenyl 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-(l-heptyl)-l,3-thiazolidine.
Entry 24
Figure imgf000093_0004
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-l-octene according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(oct- 1 -en-8-yl)- 1 ,3-thiazolidine. Entry 25
Figure imgf000094_0001
2-Propyl-l-hydroxypentane was converted to l-bromo-2-propylpentane according to 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 l-bromo-2-propylpentane according to Method D2a to give 2-(2-methyl-4-nitrophenylimino)-3-(2-propyl-l-pentyl)-l,3-thiazolidine.
Entry 26
Figure imgf000094_0002
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 l,l-dicyclopropylbut-l-en-4-yl bromide according to Method D2a to give 2-(2- methyl-4-nitrophenylimino)-3-(l , 1 -dicyclopropylbut- 1 -en-4-yl)- 1 ,3-thiazolidine.
Entry 27
amine followed (2,6-dichloro-4-
Figure imgf000094_0003
Entry 28
Figure imgf000094_0004
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)-l,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. The mixture was separated using preparative TLC to afford 2-(2-methyl-4- nitropheny limino)-3 -((Z)-bromoprop- 1 -en-3 -y 1)- 1 , 3 -thiazolidine .
Entry 29
Figure imgf000095_0001
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,3-dichloropropene according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3 -((E)-chloroprop- 1 -en-3 -yl)- 1 ,3 -thiazolidine .
Entry 30
Figure imgf000095_0002
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 3-chloro-l-propyne according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(prop-l-yn-3-yl)-l, 3-thiazolidine.
Entry 31
Figure imgf000095_0003
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)-l,3-dibromopropene according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(bromoprop-l-en-3-yl)-l, 3-thiazolidine as an E-/Z-mixture. The mixture was separated using preparative TLC to afford 2-(2-methyl-4- nitrophenylimino)-3-((E)-bromoprop-l-en-3-yl)-l,3-thiazolidine.
Entry 32
Figure imgf000095_0004
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-(l-ethoxycarbonyl-2-ethoxyprop-l-en-3-yl)-l,3- thiazolidine.
Entry 33
Figure imgf000096_0001
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 4-bromobutanoate according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(l-methoxycarbonyl-3-propyl)-l,3-thiazolidine.
Entry 34
Figure imgf000096_0002
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- nitropheny limino)-3 -(1 -methoxy carbonylmethyl)- 1 ,3 -thiazolidine .
Entry 35
Figure imgf000096_0003
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 α-chloroacetophenone according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(l-oxo-l-phenyl-2-ethyl)-l,3-thiazolidine. The ketone was reduced according to Method D5a to give 2-(2-methyl-4-nitrophenylimino)-3-(l- hydroxy- 1 -phenyl-2-ethyl)- 1 ,3-thiazolidine.
Entry 36
Figure imgf000097_0001
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 l-chloro-3,3-dimethyl-2-butanone according to Method D2a to give 2-(2- methyl-4-nitrophenylimino)-3-(2-oxo-3,3-dimethyl-l-butyl)-l, 3-thiazolidine.
Method 37
Figure imgf000097_0002
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 l-chloro-2 -butanone according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(2-oxo- 1 -butyl)- 1 ,3-thiazolidine.
Method 38
Figure imgf000097_0003
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 l-chloro-2-butanone according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(2-oxo-l-butyl)-l,3-thiazolidine. The ketone was reducded according to Method D5a to give 2-(2-methyl-4-nitrophenylimino)-3-(2-hydroxy-l- butyl)- 1 ,3-thiazolidine.
Method 39
Figure imgf000097_0004
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 l-chloro-3,3-dimethyl-2-butanone according to Method D2a to give 2-(2- 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- l-butyl)-l, 3-thiazolidine.
Entry 40
Figure imgf000098_0001
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 5-bromo-2-pentanone according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(2-oxo-5-pentanyl)- 1 ,3-thiazolidine.
Entry 41
Figure imgf000098_0002
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 1,1,3-trichloro-l-propene according to Method D2a to give 2-(2-methyl-4- nitrophenylimino)-3-(l , 1 -dichloroprop- 1 -en-3-yl)- 1 ,3-thiazolidine.
Entry 42
Figure imgf000098_0003
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-(l -oxo- 1 -propyl)- 1 ,3-thiazolidine.
Entry 43
Figure imgf000099_0001
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- methyl-4-nitrophenylimino)-3-((E)-5-methoxypent-2-en-l-yl)-l, 3-thiazolidine.
Entry 44
Figure imgf000099_0002
2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-l-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 SOCl2 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- nitroρhenylimino)-3-(cyclopentyl)-l,3-thiazolidine.
Entry 45
Figure imgf000099_0003
2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-l-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 SOCl2 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- nitrophenylimino)-3-(cyclopentyl)- 1 ,3-thiazolidine. Entry 46
Figure imgf000100_0001
2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-l-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 SOCl2 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.
Entry 47
Figure imgf000100_0002
Cyclohex-2-en-l-one was reduced according to Method B2b, Step 1 to afford cyclohex-2-en-l-ol. The alcohol was converted to the 3-bromo-l-cyclohexene according to Method B2b, Step 2. The halide was converted to N-(cyclohex-2-en-l- yl)-N-(2-hydroxyethyl)amine according to Method B2b, Step 3. The alcohol was reacted with SOCl2 according to Method B7a to afford N-(cyclohex-2-en-l-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- 4-nitrophenylimino)-3-(cyclohex-2-en- 1 -yl)- 1 ,3-thiazolidine.
Entry 48
Figure imgf000100_0003
2-Hydroxyethylamine and cyclohexanone were reacted according to Method B4a, Step 1 to afford 4-aza-l-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 SOCl2 according to Method B7c to afford N- cyclohexyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4- nitrophenyl isothiocyanate according to Method Cld to afford 2-(2-methyl-4- nitrophenylimino)-3-cyclohexyl-l,3-thiazolidine.
Entry 49
Figure imgf000101_0001
N-(2-Hydroxyethyl)aniline was reacted with SOCl2 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-l,3-thiazolidine.
Entry 50
Figure imgf000101_0002
2-Hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to give N-cycloheptyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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-l,3- thiazolidine.
Entry 51
Figure imgf000101_0003
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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-l,3- thiazolidine. Entry 52
Figure imgf000102_0001
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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-l,3- thiazolidine.
Entry 53
Figure imgf000102_0002
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 54
Figure imgf000102_0003
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3- (cyclopropylmethyl)- 1 ,3-thiazolidine.
Entry 55
Figure imgf000103_0001
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl- 4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-
(cyclopropylmethyl)- 1 ,3-thiazolidine.
Entry 56
Figure imgf000103_0002
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to
Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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- (cyclopropylmethyl)- 1 ,3-thiazolidine.
Entry 57
Figure imgf000103_0003
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4- dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3- (cyclopropylmethyl)- 1 ,3-thiazolidine.
Entry 58
Figure imgf000104_0001
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2- 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
Figure imgf000104_0002
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to
Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4- dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-
(cyclobutylmethyl)- 1 ,3-thiazolidine.
Entry 60
Figure imgf000104_0003
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to
Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4- dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3- (cyclobutylmethyl)- 1 ,3-thiazolidine.
Entry 61
Figure imgf000105_0001
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3- dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3-
(cyclobutylmethyl)-l, 3-thiazolidine.
Entry 62
Figure imgf000105_0002
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to
Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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- (cyclobutylmethyl)- 1 ,3-thiazolidine.
Entry 63
Figure imgf000105_0003
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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. Entry 64
Figure imgf000106_0001
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 65
Figure imgf000106_0002
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 66
Figure imgf000106_0003
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4- dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3- (cyclopentylmethyl)- 1 ,3-thiazolidine. Entry 67
Figure imgf000107_0001
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 68
Figure imgf000107_0002
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2- 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
Figure imgf000107_0003
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to
Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-
(cyclohexylmethyl)- 1 ,3-thiazolidine. Entry 70
Figure imgf000108_0001
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 71
Figure imgf000108_0002
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 72
Figure imgf000108_0003
1 -Cyclohexyl- 1-ethylamine was converte to N-(2- ydroxyethyl)-N-(l -cyclohexyl- 1- ethyl)amine according to Method B5a. The alcohol was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(l -cyclohexyl- 1- 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. Entry 73
Figure imgf000109_0001
give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 74
Figure imgf000109_0002
2-Hydroxyethylamine was reacte w t enzy romi e according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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-l,3-thiazolidine.
Entry 75
2-Hydroxyethylamine was
Figure imgf000109_0003
according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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- (2,4-dichlorophenylimino)-3 -benzyl- 1 ,3-thiazolidine.
Entry 76
Figure imgf000109_0004
2-Hydroxyethylamine was reacte w t enzy bromi e according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-benzyl-l ,3-thiazolidine.
Entry 77
2-Hydroxyethylamine was reacte
Figure imgf000110_0001
ide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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- (2,3-dichlorophenylimino)-3-benzyl-l ,3-thiazolidine.
Entry 78
Figure imgf000110_0002
2-Hydroxyethylamine was reacte w t 4-c orobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 79
Figure imgf000110_0003
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 with SOCl2 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)-! ,3-thiazolidine. Entry 80
Figure imgf000111_0001
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 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.
Entry 81
Figure imgf000111_0002
2-Hydroxyethylamine was reacted w t cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl-N-(2- 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
Figure imgf000111_0003
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3- dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-
(cycloheptylmethyl)-l, 3-thiazolidine.
Entry 83
Figure imgf000112_0001
2-Hydroxyethylamine was reacte w t cyc o eptylmet yl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl-N-(2- chloroethyl)ammonium chloride. The chloroethylamine was reacted with 4- cyanophenyl isothiocyanate to give 2-(4-cyanophenylimino)-3-(cycloheptylmethyl)- 1,3 -thiazolidine.
Entry 84
Figure imgf000112_0002
Methyl cyclodo ecanecar oxy ate was re uce accor ng 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- hydroxyethyl)-N-(cyclododecylmethyl)amine. The alcohol was reacted with SOCl2 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 Cla to give 2-(2-methyl-4- nitrophenylimino)-3-(cyclododecylmethyl)-l, 3-thiazolidine.
Entry 85
Figure imgf000112_0003
2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2-methyl-4-nitrophenylimino)- 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. Entry 86
Figure imgf000113_0001
2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl 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.
Entry 87
Figure imgf000113_0002
3-Aminoquinoline was converted to 3 -quinoline isothiocyanate according to Method A2c. (lS)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-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-(l S)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride as described in Method B7c. 3 -Quinoline isothiocyanate was reacted with N-(lS)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride according to Method Clf to give 2-(3-quinolylimino)- 3, 5-diisobutyl-l ,3-thiazolidine.
Entry 88
Figure imgf000113_0003
(lS)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (25)-
4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(l_S)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride as described in Method B7c. 4-Νitrophenyl isothiocyanate was reacted with N-(lS)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride according to Method Clf to give 2-(4- nitrophenylimino)-3 ,5-diisobutyl- 1 ,3-thiazolidine.
Entry 89
Figure imgf000114_0001
(lS)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (25)- 4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride as described in Method B7c. 4-Cyanophenyl isothiocyanate was reacted with N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride according to Method Clf to give 2-(4- cyanophenylimino)-3,5-diisobutyl-l, 3-thiazolidine.
Entry 90
Figure imgf000114_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was converted to (15)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( 5)-2-(2-methyl-
4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (45)-2-(2-methyl-4- nitrophenylimino)-3,4-diisobutyl-l, 3-thiazolidine HCl salt.
Entry 91
Figure imgf000114_0003
(15)-l-(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 (lR)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( R)-2-(2-methyl-
4-nitrophenylimino)-4-isobutyl-l,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( R)-2-(2-methyl-4- nitrophenylimino)-3,4-diisobutyl- 1,3 -thiazolidine HCl salt.
Entry 92
Figure imgf000115_0001
(lS)-l-(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 (lR)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( R)-2-(2-methyl- 5-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( R)-2-(2-methyl-5- nitrophenylimino)-3,4-diisobutyl- 1,3 -thiazolidine HCl salt.
Entry 93
Figure imgf000115_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was converted to (15)-1- (chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-5-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (45)-2-(2-methyl- 5-nitrophenylimino)-4-isobutyl-l,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( 5)-2-(2-methyl-5- nitrophenylimino)-3,4-diisobutyl-l, 3-thiazolidine HCl salt.
Entry 94
Figure imgf000115_0003
(15)-l-(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 (lR)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (¥R)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford ( R)-2-(2-methyl-4- nitrophenylimino)-4-isobutyl-3 -methyl- 1, 3-thiazolidine HCl salt.
Entry 95
Figure imgf000116_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was converted to (15)-1-
(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2-
Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( 5)-2-(2-methyl-
4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford ( 5)-2-(2-methyl-4- nitrophenylimino)-4-isobutyl-3-methyl-l, 3-thiazolidine HCl salt.
Entry 96
Figure imgf000116_0002
(1 )-l-(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 (lR)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( R)-2-(2-methyl-
5-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (¥R)-2-(2-methyl-5- nitrophenylimino)-4-isobutyl-3 -methyl- 1,3 -thiazolidine HCl salt.
Entry 97
Figure imgf000116_0003
(15)-l-(Hydroxymethyl)-3-methylbutylamine was converted to (15)-1-
(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-
Methyl-4-nitrophenyl isothiocyanate was reacted with (1 )-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( S)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with l-bromo-2-ethylbutane according to Method D2a to afford ( 5)-2-(2-methyl-4- nitrophenylimino)-4-isobutyl-3-(2-ethyl-l -butyl)- 1, 3-thiazolidine HCl salt.
Entry 98
Figure imgf000117_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( 5)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl- 1,3 -thiazolidine. The thiazolidine was reacted with l-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- thiazolidine.
Entry 99
Figure imgf000117_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2- Ethyl-4-cyanophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( S)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford ( 5)-2-(2-ethyl-4- cyanophenylimino)-4-isobutyl-3-(2-oxo-3,3-dimethyl-l-butyl)-l,3-thiazolidine.
Entry 100
Figure imgf000118_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (1 )-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (¥5)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2a to afford (45)-2-(2-methyl-4- nitrophenylimino)-4-isobutyl-3-(cyclopropylmethyl)-l,3-thiazolidine.
Entry 101
Figure imgf000118_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2-
Methyl -4-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( 5)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with cyclobutylmethyl bromide according to Method D2a to afford ( 5)-2-(2-methyl-4- nitrophenylimino)-4-isobutyl-3-(cyclobutylmethyl)- 1 ,3-thiazolidine.
Entry 102
Figure imgf000118_0003
(1 )-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (¥5)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with 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 ( 5)-2-(2- methyl-4-nitrophenylimino)-4-isobutyl-3-(3,3-dimethyl-2-hydroxy-l-butyl)-l,3- thiazolidine.
Entry 103
Figure imgf000119_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was converted to (15)-1- (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 (15)- l-(chloromethyl)-3 -methylbutanammonium chloride according to Method Cla to give (45)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-l,3- thiazolidine. The thiazolidine was reacted with isobutyl bromide according to
Method D2a to give (45)-2-(2,6-dimethyl-4-nitrophenylimino)-3,4-diisobutyl-l,3- thiazolidine HCl salt.
Entry 104
Figure imgf000119_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a.
2,3-Dichlorophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (45)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l,3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to give (45)-2-(2,3-dichlorophenylimino)- 4-isobutyl-3 -(3 -pentyl)- 1 ,3-thiazolidine.
Entry 105
Figure imgf000120_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (¥5)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give ( 5)-2-(2-methyl-4- nitropheny limino)-4-isobutyl-3 -(5 -heptyl)- 1 ,3 -thiazolidine .
Entry 106
Figure imgf000120_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a.
2,3-Dichlorophenyl isothiocyanate was reacted with (lS)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (¥5)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl- 1,3 -thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give ( 5)-2-(2,3- dichlorophenylimino)-3 ,4-diisobutyl- 1 ,3-thiazolidine.
Entry 107
Figure imgf000120_0003
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2- (Trifluoromethyl)-4-nitrophenyl isothiocyanate was reacted with (15)-1- (chloromethyl)-3 -methylbutanammonium chloride according to Method Clc to give ( 5)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-4-isobutyl- 1 ,3 -thiazolidine trifluoroacetate salt. Entry 108
Figure imgf000121_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2-
(Trifluoromethyl)-4-nitrophenyl isothiocyanate was reacted with (15)-1-
(chloromethyl)-3 -methylbutanammonium chloride according to Method Clc to give
(¥S)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-4-isobutyl- 1 ,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford
(45)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-3 ,4-diisobutyl- 1 ,3-thiazolidine trifluoroacetate salt.
Entry 109
Figure imgf000121_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 4-
Cyano-2-(trifluoromethyl)phenyl isothiocyanate was reacted with (1 )-1-
(chloromethyl)-3 -methylbutanammonium chloride according to Method Clc to give
( 5)-2-(4-cyano-2-(frifluoromethyl)phenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford
(45)-2-(4-cyano-2-(trifluoromethyl)phenylimino)-3,4-diisobutyl-l, 3-thiazolidine trifluoroacetate salt.
Entry 110
Figure imgf000121_0003
(1 )-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2- Chloro-4-cyano-6-methylphenyl isothiocyanate was reacted with (15)-1- (chloromethyl)-3 -methylbutanammonium chloride according to Method Clc to give (¥5)-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 (^5)-2-(2-chloro-4-cyano-6-methylphenylimino)-3,4-diisobutyl-l, 3-thiazolidine trifluoroacetate salt.
Entry 111
Figure imgf000122_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 4-
(Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (15)-1- (chloromethyl)-3 -methylbutanammonium chloride according to Method Cla to give ( 5)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl- 1 ,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (45)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3 ,4-diisobutyl- 1 ,3-thiazolidine.
Entry 112
Figure imgf000122_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(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 (1 )- l-(chloromethyl)-3 -methylbutanammonium chloride according to Method Cla to give ( 5)-2-(3,5-dimethyl-4-nitrophenylimino)-
4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (¥5)-2-(3,5-dimethyl-4-nitrophenylimino)-3 ,4- diisobutyl- 1 ,3-thiazolidine. Entry 113
Figure imgf000123_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4- (Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (15)-1- (chloromethyl)-3 -methylbutanammonium chloride according to Method Cla to give (45)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl- 1 ,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give
(45)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-l, 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- carbamoyl-2-methylphenylimino)-3 ,4-diisobutyl- 1, 3-thiazolidine.
Entry 114
Figure imgf000123_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 4- Fluoro-2-methylphenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2-(4-fluoro- 2-methylphenylimino)-4-isobutyl- 1,3 -thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give ( 5)-2-(4-fluoro-2- methylphenylimino)-3,4-diisobutyl-l,3-thiazolidine.
Entry 115
Figure imgf000123_0003
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (1 )- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 4- Chloro-2-methylphenyl isothiocyanate was reacted with (1 )-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (45)-2-(4-Chloro- 2-methylphenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give ( 5)-2-(4-chloro-2- methylphenylimino)-3 ,4-diisobutyl- 1 ,3-thiazolidine.
Entry 116
Figure imgf000124_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 4- Bromo-2-methylphenyl isothiocyanate was reacted with (15)-l-(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 with isobutyl bromide according to Method D2a to give ( 5)-2-(4-bromo-2- methylphenylimino)-3 ,4-diisobutyl- 1 ,3-thiazolidine.
Entry 117
Figure imgf000124_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was reacted with SOCl2 followed by 4- cyano-2-ethylphenyl isothiocyanate according to Method C2a to give (4S)-2-(4- cyano-2-ethylphenylimino)-4-isobutyl-l,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (45)-2-(4-cyano-2- ethylphenylimino)-3 ,4-diisobutyl- 1 ,3-thiazolidine.
Entry 118
Figure imgf000124_0003
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (25)- 4-methyl-2-(isobutylamino)pentan-l-ol as described in Method B4c. The resulting
2-hydroxyethylamine was converted to N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride according to Method B7c. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride to Method Clb to afford ( 5)-2-(2-methyl-4- nitrophenylimino)-3 ,4-diisobutyl- 1 ,3-thiazolidine.
Entry 119
Figure imgf000125_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (25)- 4-methyl-2-(isobutylamino)pentan-l-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(15)-l-(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-(1 )-l-(chloromethyl)-3-methylbutyl)- N-(isobutyl)ammonium chloride to Method Clb to afford ( 5)-2-(2-methyl-4- nitrophenylimino)-3 ,4-diisobutyl- 1 ,3-thiazolidine.
Entry 120
Figure imgf000125_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. 4-Νitro-l-naphthylamine was converted to 4-nitro-
1 -naphthyl isothiocyanate according to Method A2b. 4-Nitro-l -naphthyl isothiocyanate was reacted with (15)-l-(hydroxymethyl)-3-methylbutylamine to Method C2a to give (45)-2-(4-nitro-l-naphthylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (45)-2-(4-nitro-l-naphthylimino)-3,4-diisobutyl-l,3-thiazolidine.
Entry 121
Figure imgf000125_0003
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (25)-
4-methyl-2-(isobutylamino)pentan-l-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride according to Method B7c. 4-Νitrophenyl isothiocyanate was reacted with N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride to Method Clf to afford (¥5)-2-(4-nitrophenylimino)- 3,4-diisobutyl-l,3-thiazolidine.
Entry 122
Figure imgf000126_0001
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (25)-
4-methyl-2-(isobutylamino)pentan-l-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride according to Method B7c. 4-Cyanophenyl isothiocyanate was reacted with N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride to Method Clf to afford ( 5)-2-(4-cyanophenylimino)-
3,4-diisobutyl-l, 3-thiazolidine.
Entry 123
Figure imgf000126_0002
(15)-l-(Hydroxymethyl)-3-methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (25)- 4-methyl-2-(isobutylamino)pentan-l-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(15)-l-(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-(15)-l-(chloromethyl)-3-methylbutyl)- N-(isobutyl)ammonium chloride to Method Clb to afford (45)-2-(2-methyl-4- nitrophenylimino)-3,4-diisobutyl-l,3-thiazolidine. The thiazolidine was oxidized according to Method D4a to afford ( 5)-2-(2-methyl-4-nitrophenylimino)-3,4- diisobutyl- 1,3 -thiazolidine 1-oxide.
Entry 124
Figure imgf000127_0001
(lS,25)-l-(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 (lS,25)-l-(chloromethyl)-2- methylbutanammonium chloride according to Method Cla to give (¥5)-2-(2-methyl- 4-nitrophenylimino)-4-((25)-2 -butyl)- 1,3 -thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( 5)-2-(2-methyl-4- nitrophenylimino)- 4-((25)-2-butyl)-3-isobutyl-l, 3-thiazolidine HCl salt.
Entry 125
Figure imgf000127_0002
N-(tert-Butoxycarbamoyl)-( 1 S,2R)- 1 -(hydroxymethyl)-2-methylbutylamine was prepared from N-(tert-butoxycarbamoyl)-(Z)-allo-isoleucine as described in Method Bla, Step 2. The carbamate was converted to (lS,2R)-l-(chloromethyl)-2- methylbutanammonium chloride as described in Method B7b. 2-Methyl-4- nitrophenyl isothiocyanate was reacted with (lS,2R)-l-(chloromethyl)-2- methylbutanammonium chloride to Method Cle to give (¥5)-2-(2-methyl-4- nitrophenylimino)-4-((2R)-2-butyl)-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (¥5)-2-(2-methyl-4- nitrophenylimino)-4-((2R)-2-butyl)-3-isobutyl-l ,3-thiazolidine HCl salt.
Entry 126
Figure imgf000127_0003
N-(tert-Butoxycarbamoyl)-( 15)- 1 -cyclohexyl-2-hydroxyethylbutylamine was prepared from N-(tert-Butoxycarbamoyl)-(Z)- -cyclohexylglycine according to
Method Bla, Step 2. The carbamate was reacted with SOCl2 according to Method Bib, and the resulting material was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cla to give (¥5)-2-(2-methyl-4- nitrophenylimino)-4-cyclohexyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( 5)-2-(2-methyl-4- nitrophenylimino)-4-cyclohexyl-3 -isobutyl- 1 ,3-thiazolidine HCl salt. Entry 127
Figure imgf000128_0001
(15)-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4- Methoxycarbonyl-2-methylphenyl isothiocyanate was reacted with (1 )-1- (chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (4S)-2-(4- methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-l ,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( 5)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-3 -isobutyl- 1 ,3 - thiazolidine.
Entry 128
Figure imgf000128_0002
(15)-l-Isopropyl-2-hydroxyethylamine was converted to (15)-2-chloro-l- isopropylethylammonium chloride according to Method B7a. 2-Methyl-4- nitrophenyl isothiocyanate was reacted with (15)-2-chloro-l- isopropylethylammonium chloride according to Method Cla to give (4S)-2-(2- methyl-4-nitrophenylimino)-4-isopropyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (¥5)-2-(2-methyl- 4-nitrophenylimino)-4-isopropyl-3-isobutyl-l,3-thiazolidine HCl salt.
Entry 129
Figure imgf000128_0003
(1 )-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 5- Aminoindan-1-one was converted to l-oxo-5-indanyl isothiocyanate according to
Method A2a. The isothiocyanate was reacted with (15)-l-(chloromethyl)-2- methylbutanammonium chloride to Method Cla to give (4S)-2-(l-oxo-5- indanylimino)-4-(2-butyl)-l,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( 5)-2-(l-oxo-5-indanylimino)- 4-(2-butyl)-3-isobutyl- 1 ,3-thiazolidine.
Entry 130
Figure imgf000129_0001
(15)-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(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 (15)-l-(chloromethyl)-2- methylbutanammonium chloride according to Method Cla to give ( 5)-2-(4-chloro- 3-(trifluoromethyl)phenylimino)-4-(2-butyl)-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (45)-2-(4-chloro-3- (trifluoromethyl)phenylimino)-4-(2-butyl)-3 -isobutyl- 1 ,3-thiazolidine.
Entry 131
Figure imgf000129_0002
(15)-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4- Cyano-3-(trifluoromethyl)aniline was converted to 4-cyano-3- (trifluoromethyl)phenyl isothiocyanate according to A2a, Step 3. The isothiocyanate was reacted with (15)-l-(chloromethyl)-2-methylbutanammonium chloride according to Method Cla to give ( 5)-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 ( 5)-2-(4-cyano-3-(trifluoromethyl)phenylimino)-4-(2-butyl)- 3-isobutyl-l, 3-thiazolidine.
Entry 132
Figure imgf000130_0001
(15)-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4- Nitro- 1-naphthylamine was converted to 4-nitro-l -naphthyl isothiocyanate according to Method A2b. 4-Nitro-l -naphthyl isothiocyanate was reacted with (15)-1- (chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (4S)-2-(4- nitro-l-naphthylimino)-4-(2-butyl)- 1,3 -thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give ( 5)-2-(4-nitro-l- naphthylimino)-4-butyl-3-isobutyl- 1 ,3-thiazolidine.
Entry 133
Figure imgf000130_0002
(15)-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-
Cyano-2-ethylphenyl isothiocyanate was reacted with (1 )-l-(chloromethyl)-2- methylbutanammonium chloride to Method Cla to give ( 5)-2-(4-cyano-2- ethylphenylimino)-4-(2-butyl)-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give ( 5)-2-(4-cyano-2- ethylphenylimino)-4-butyl-3-isobutyl- 1 ,3-thiazolidine.
Entry 134
Figure imgf000130_0003
(15)-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(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 A2a, Step 3. 4-Cyano-2-methylphenyl isothiocyanate was reacted with (15)-1-
(chloromethyl)-2-methylbutanammonium chloride to Method Cla to give (4S)-2-(4- cyano-2-methylphenylimino)-4-(2 -butyl)- 1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give ( S)-2-(4-cyano-2- methylphenylimino)-4-butyl-3-isobutyl- 1 ,3-thiazolidine.
Entry 135
Figure imgf000131_0001
(15)-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 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 (15)-l-(chloromethyl)-2-methylbutanammonium chloride to Method Cla to give ( 5)-2-(4-cyano-2,5-dimethylphenylimino)-4-(2- butyl)- 1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (45)-2-(4-cyano-2,5-dimethylphenylimino)-4- butyl-3 -isobutyl- 1 ,3-thiazolidine.
Entry 136
Figure imgf000131_0002
(15)-l-(Hydroxymethyl)-2-methylbutylamine was made from (Z)-isoleucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2,5-methylaniline was converted to 2,5-dimethyl-4-nitrophenyl isothiocyanate according to Method A2a. 2,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (15)- l-(chloromethyl)-2 -methylbutanammonium chloride to Method Cla to give (^5)-2-(2,5-dimethyl-4-nitrophenylimino)-4-(2-butyl)-l,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give ( 5)-2-(2,5-dimethyl-4-nitrophenylimino)-4-butyl-3-isobutyl-l,3-thiazolidine.
Entry 137
Figure imgf000132_0001
(lR)-l-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2- Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2- methyl-4-nitrophenylimino)-4-isopropyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( R)-2-(2-methyl- 4-nitrophenylimino)-4-isopropyl-3 -isobutyl- 1 ,3-thiazolidine.
Entry 138
Figure imgf000132_0002
(15)-l-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2- methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2- methyl-4-nitrophenylimino)-4-isopropyl-l, 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-l, 3-thiazolidine.
Entry 139
Figure imgf000132_0003
(15)-l-Benzyl-2-hydroxyethylamine was converted to (15)-2-chloro-l- benzylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-2-chloro-l -benzylethylammonium chloride according to Method Cla to give (45)-2-(2-methyl-4-nitrophenylimino)-4-benzyl- 1,3 -thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (¥5)-2-(2-methyl-4-nitrophenylimino)-4-benzyl-3-isobutyl- 1, 3-thiazolidine HCl salt.
Entry 140
Figure imgf000133_0001
(15)-l-Phenyl-2-hydroxyethylamine was converted to (15)-2-chloro-l- phenylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-2-chloro-l -benzylethylammonium chloride according to Method Cla to give ( 5)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-
1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (¥5)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-3-isobutyl- 1,3 -thiazolidine HCl salt.
Entry 141
Figure imgf000133_0002
2-Piperidenemethanol was made from methyl pipecolinate as described in Method Bib. The 2-hydroxyethylamine was converted to 2-chloromethylpiperidinium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloromethylpiperidinium chloride according according to Method
Cla to give 9-(2-methyl-4-nitrophenylimino)-l-aza-8-thiabicyclo[4.3.0]nonane.
Entry 142
Figure imgf000133_0003
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- thiapyrrolizine.
Entry 143
Figure imgf000134_0001
(1 )-l-(4-Hydroxyphenylmethyl)-2-hydroxyethylamine was made from (Z)-tyrosine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4~(4-hydroxyphenylmethyl)-l,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((15)-l-(4- hydroxyphenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((15)-l-(4-hydroxyphenylmethyl)-2-chloroethyl)-N- isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-(( 15)- 1 -(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method Clb to give ( 5)-2-(2-ethyl-4-cyanophenylimino)-4-(4- hydroxyphenylmethyl)-3-isobutyl-l, 3-thiazolidine HCl salt.
Entry 144
Figure imgf000134_0002
(15)-l-(4-Chlorophenylmethyl)-2-hydroxyethylamine was made from (Z)-4- chlorophenylalanine methyl ester as described in Method Bib. The 2- hydroxyethylamine was converted to (45)-2-isopropyl-4~(4-chlorophenylmethyl)- 1,3 -oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((15)-l-(4-chlorophenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to
Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((15)-l-(4-chlorophenylmethyl)-2-chloroethyl)- N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((15)-l-(4-chlorophenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method Clb to give ( 5)-2-(2-ethyl-4-cyanophenylimino)-4-
(4-chlorophenylmethyl)-3 -isobutyl- 1,3 -thiazolidine HCl salt.
Entry 145
Figure imgf000135_0001
(15)-l-(Benzylthiomethyl)-2-hydroxyethylamine was made from (Z)-S- benzylcysteine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (45)-2-isopropyl-4~(benzylthiomethyl)-l,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((15)-l-
(benzylthiomethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((lS)-l-(benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((15)-l- (benzylthiomethyl)-2-chloroethyl)-N-isobutylammonium chloride according to
Method Clb to give ( 5)-2-(2-ethyl-4-cyanophenylimino)-4-(benzylthiomethyl)-3- isobutyl-1, 3-thiazolidine HCl salt.
Entry 146
Figure imgf000135_0002
(R)-N-isobutylserine methyl ester HCl salt was made from (Z))-serine methyl ester as described in Method B3a. The ester was reacted with SOCl2, followed by 2-methyl- 4-nitrophenyl isothiocyanate according to Method C2a to afford (45)-2-(2-methyl-4- nitrophenylimino)-4-(methoxycarbonyl)-3 -isobutyl- 1 ,3-thiazolidine HCl salt.
Entry 147
Figure imgf000135_0003
(5)-N-isobutylserine methyl ester HCl salt was made from (Z)-serine methyl ester as described in Method B3a. The ester was reacted with SOCl2, followed by 2-methyl- 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
Figure imgf000136_0001
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-0-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 afford (¥R)-2-(2-methyl-4-nitrophenylimino)-4-((lR)-l-tert- butoxyethyl)-3 -isobutyl- 1, 3-thiazolidine.
Entry 149
Figure imgf000136_0002
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-0-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 cyclopentyl bromide according to Method C5b to afford ( R)-2-(2-methyl-4-nitrophenylimino)-4-((lR)-l- tert-butoxyethyl)-3 -cyclopentyl- 1, 3-thiazolidine.
Entry 150
( 1 R,25)- 1 -Methanesulfonylo Jxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,25)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,25)-1- 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-((15)-l- tert-butoxyethyl)-3-cyclopentyl-l, 3-thiazolidine.
Entry 151
Figure imgf000137_0001
( 1 R,25)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,25)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,25)-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 (¥R)-2-(2-methyl-4-nitrophenylimino)-4-((15)-l-tert- butoxyethyl)-3-isobutyl-l, 3-thiazolidine.
Entry 152
Figure imgf000137_0002
( 1R,25)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,25)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,25)-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 ( R)-2-(4-cyano-2-methylphenylimino)-4-((15)- 1 -tert-butoxyethyl)-3-cyclopentyl- 1 ,3-thiazolidine.
Entry 153
Figure imgf000137_0003
( 1 R,25)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,25)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Νitro- 1-naphthylamine was converted to 4-nitro-l -naphthyl isothiocyanate according to Method A2b. (1R,25)-1- Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (¥R)-2-(4-nitro-l-naphthylimino)-4-((1 )-l-tert-butoxyethyl)- 3-isobutyl-l ,3-thiazolidine.
Entry 154
Figure imgf000138_0001
( 1 R,25)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(15,25)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Νitro- 1-naphthylamine was converted to 4-nitro-l -naphthyl isothiocyanate according to Method A2b. (1R,25)-1-
Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford ( R)-2-(4-nitro-l-naphthylimino)-4-((15)-l-tert-butoxyethyl)- 3 -cyclopentyl- 1 ,3-thiazolidine .
Entry 155
Figure imgf000138_0002
(lR,2R)-l-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. l-Amino-5,6,7,8- tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-l-yl isothiocyanate according to Method A2a. (lR,2R)-l-Methanesulfonyloxymethyl)-2- (tert-butoxy)propanammonium chloride was reacted with 4-nitro-5,6,7,8- tetrahydronaphth-1-yl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (^R)-2-(4-nitro-5,6,7,8-tetrahydronaphth-l-ylimino)-4-((lR)-l- tert-butoxyethyl)-3-cyclopentyl- 1 ,3-thiazolidine.
Entry 156
Figure imgf000139_0001
( 1 R,2R)- 1 -Methanesulfonylo Vxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. l-Amino-5,6,7,8- tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-l-yl isothiocyanate according to Method A2a. (lR,2R)-l-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 ( R)-2-(4-nitro-5,6,7,8-tetrahydronaphth-l-ylimino)-4-((lR)-l- tert-butoxyethyl)-3-isobutyl-l,3-thiazolidine.
Entry 157
Figure imgf000139_0002
(lR,2R)-l-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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. ( 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 (¥R)-2-(2-isopropyl-4- nitrophenylimino)-4-((lR)-l-tert-butoxyethyl)-3-isobutyl-l,3-thiazolidine.
Entry 158
Figure imgf000139_0003
( 1 R,2R)- 1 -Methanesulfony loxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-0-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 -Methanesulfony loxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford ( R)-2-(2-isopropyl-4- nitrophenylimino)-4-(( 1 R)- 1 -tert-butoxyethyl)-3 -cyclopentyl- 1 ,3-thiazolidine.
Entry 159
Figure imgf000140_0001
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-0-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
A2b. (lR,2R)-l-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 ( R)-2-(2,3-dimethyl-4- nitropheny limino)-4-(( 1 R)- 1 -tert-butoxyethy l)-3 -cyclopentyl- 1 ,3-thiazolidine .
Entry 160
Figure imgf000140_0002
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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 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 ( R)-2-(2,3-dimethyl-4- nitrophenylimino)-4-(( 1 R)- 1 -tert-butoxyethyl)-3 -isobutyl- 1 ,3-thiazolidine. Entry 161
Figure imgf000141_0001
(lR,2R)-l-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxy carbonyl)- 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 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 ( R)-2-(2,3-dimethyl-4- nitrophenylimino)-4-(( 1 R)- 1 -tert-butoxyethyl)-3-(2-ethyl- 1 -butyl)- 1 ,3-thiazolidine.
Entry 162
Figure imgf000141_0002
(lR,2R)-l-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. l-amino-4-cyano-5,6,7,8- tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (lR,2R)-l-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 ( R)-2-(4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((lR)-l- tert-butoxyethyl)-3 -cyclopentyl- 1 ,3-thiazolidine.
Entry 163
Figure imgf000142_0001
( 1 R,2R)- 1 -Methanesulfony loxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-0-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. l-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 -Methanesulfony loxymethyl)-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 ( R)-2-(4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((lR)-l- tert-butoxyethyl)-3 -isobutyl- 1 ,3-thiazolidine.
Entry 164
Figure imgf000142_0002
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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 ( R)-2-(2-methyl-4-nitrophenylimino)-4-((lR)-l-tert-butoxy)- 3-isobutyl-l,3-thiazolidine. The tert-butyl ether was deprotected according to
Method D3a to afford ( R)-2-(2-methyl-4-nitrophenylimino)-4-((lR)-l- hydroxyethyl)-3 -isobutyl- 1, 3-thiazolidine.
Entry 165
Figure imgf000142_0003
( 1 R,25)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)proρanammonium chloride was made from (Z)-(lS,25)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Νitro- 1-naphthylamine was converted to 4-nitro-l -naphthyl isothiocyanate according to Method A2b. (1R,25)-1- Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (^R)-2- 4-nitro-l-naphthylimino)-4-((15)-l-tert-butoxyethyl)- 3-cyclopentyl-l, 3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(4-nitro-l-naphthylimino)-4-((15)-l-hydroxyethyl)-3- cyclopentyl- 1 ,3 -thiazolidine.
Entry 166
Figure imgf000143_0001
( 1 R,25)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,25)-1- Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford ( R)-2-(2-methyl-4-nitrophenylimino)-4-((15)-l- tert-butoxyethyl)-3-cyclopentyl-l, 3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford ( R)-2-(2-methyl-4- nitrophenylimino)-4-(( 15)- 1 -hydroxy ethy l)-3 -cyclopentyl- 1 ,3-thiazolidine .
Entry 167
Figure imgf000143_0002
(lR,2R)-l-Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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 cyclopentyl bromide according to Method C5b to afford ( R)-2-(2-methyl-4-nitrophenylimino)-4-((lR)-l- tert-butoxyethyl)-3-cyclopentyl-l, 3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford ( R)-2-(2-methyl-4- nitrophenylimino)-4-((lR)-l-hydroxyethyl)-3-cyclopentyl-l,3-thiazolidine.
Entry 168
Figure imgf000144_0001
( 1 R,2S)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2S)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. (1R,25)-1- Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (¥R)-2-(2-methyl-4-nitrophenylimino)-4-((15)-l- tert-butoxyethyl)-3 -cyclopentyl- 1, 3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford ( R)-2-(2-methyl-4- nitrophenylimino)-4-((15)-l-hydroxyethyl)-3-cyclopentyl-l, 3-thiazolidine.
Entry 169
Figure imgf000144_0002
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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 bromide according to Method C5b to afford ( R)-2-(2-tert-butyl-4- cyanophenylimino)-4-(( 1 R)- 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-((lR)-l-hydroxyethyl)-3-cyclopentyl-l, 3-thiazolidine.
Entry 170
Figure imgf000144_0003
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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 bA2a. ( 1 R,2R)- 1 -Methanesulfony loxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2-tert-butyl-4-cyanophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford ( R)-2-(2-tert-butyl-4- cyanophenylimino)-4-((lR)-l-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-((lR)-l-hydroxyethyl)-3- isobutyl- 1, 3-thiazolidine.
Entry 171
Figure imgf000145_0001
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. 4-Νitro- 1-naphthylamine was converted to 4-nitro-l -naphthyl isothiocyanate according to Method A2b. (1R,2R)-1- Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (^R)-2-(4-nitro-l-naphthylimino)-4-((lR)-l-tert-butoxyethyl)- 3 -cyclopentyl- 1, 3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(4-nitro-l-naphthylimino)-4-((lR)-l-hydroxyethyl)-3- cyclopentyl- 1, 3-thiazolidine.
Entry 172
Figure imgf000145_0002
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. l-Amino-5,6,7,8- tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-l-yl isothiocyanate according to Method A2a. (lR,2R)-l-Methanesulfonyloxymethyl)-2- (tert-butoxy)propanammonium chloride was reacted with 4-nitro-5,6,7,8- tetrahydronaphth-1-yl isothiocyanate followed by cyclopentyl bromide according to
Method C5b to afford (^R)-2-(4-nitro-5,6,7,8-tetrahydronaphth-l-ylimino)-4-((lR)-l- tert-butoxyethyl)-3 -cyclopentyl- 1,3 -thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford ( R)-2-(4-nitro-5,6,7,8- tetrahydronaphth- 1 -ylimino)-4-(( 1 R)- 1 -hy droxyethyl)-3 -cyclopentyl- 1 ,3 -thiazolidine.
Entry 173
Figure imgf000146_0001
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. l-Amino-5,6,7,8- tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-l-yl isothiocyanate according to Method A2a. (1R,2R)-1 -Methanesulfony loxymethyl)-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 (^R)-2-(4-nitro-5,6,7,8-tetrahydronaphth-l-ylimino)-4-((lR)-l- tert-butoxyethyl)-3 -isobutyl- 1,3 -thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford ( R)-2-(4-nitro-5,6,7,8-tetrahydronaphth-l- ylimino)-4-((lR)-l -hydroxy ethyl)-3 -isobutyl- 1 ,3-thiazolidine.
Entry 174
Figure imgf000146_0002
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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. ( 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 (¥R)-2-(2-isopropyl-4- nitrophenylimino)-4-((lR)-l-tert-butoxyethyl)-3-isobutyl-l,3-thiazolidine. The tert- butyl ether was deprotected according to Method D3a to afford ( R)-2-(2-isopropyl- 4-nitrophenylimino)-4-((lR)-l-hydroxyethyl)-3 -isobutyl- 1, 3-thiazolidine.
Entry 175
Figure imgf000147_0001
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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.
( 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 ( R)-2-(2-isopropyl-4- nitrophenylimino)-4-(( 1 R)- 1 -tert-butoxyethyl)-3 -cyclopentyl- 1 ,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2- isopropyl-4-nitrophenylimino)-4-(( 1 R)- 1 -hydroxyethyl)-3 -cyclopentyl- 1 ,3- thiazolidine.
Entry 176
Figure imgf000147_0002
( 1 R,2R)- 1 -Methanesulfony loxymethy l)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-0-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 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 ( R)-2-(2,3-dimethyl-4- nitrophenylimino)-4-((lR)-l-tert-butoxyethyl)-3-(2-ethyl-l-butyl)-l,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2,3- dimethy l-4-nitrophenylimino)-4-(( 1 R)- 1 -hydroxyethyl)-3 -(2-ethy 1- 1 -butyl)- 1,3- thiazolidine.
Entry 177
Figure imgf000147_0003
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,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 A2b. (1R,2R)-1 -Methanesulfony loxymethyl)-2-(tert-butoxy)propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to afford (¥R)-2-(2,3-dimethyl-4- nitrophenylimino)-4-((lR)-l-tert-butoxyethyl)-3 -isobutyl- 1, 3-thiazolidine. The tert- butyl ether was deprotected according to Method D3a to afford (4R)-2-(2,3-dimethyl- 4-nitrophenylimino)-4-((lR)-l-hydroxyethyl)-3-isobutyl-l,3-thiazolidine.
Entry 178
Figure imgf000148_0001
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-0-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
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 ( R)-2-(2,3-dimethyl-4- nitrophenylimino)-4-(( 1 R)- 1 -tert-butoxyethyl)-3 -cyclopentyl- 1 ,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (4R)-2-(2,3- dimethyl-4-nitrophenylimino)-4-(( 1 R)- 1 -hydroxy ethyl)-3 -cyclopentyl- 1,3- thiazolidine.
Entry 179
Figure imgf000148_0002
( 1 R,2R)- 1 -Methanesulfonyloxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. l-amino-4-cyano-5, 6,7,8- tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (lR,2R)-l-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 ( R)-2-(4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((lR)-l- tert-butoxyethyl)-3-cyclopentyl-l,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (¥R)-2-(4-cyano-5, 6,7,8- tetrahydronaphthylimino)-4-((lR)-l-hydroxyethyl)-3-cyclopentyl-l, 3-thiazolidine.
Entry 180
Figure imgf000149_0001
( 1 R,2R)- 1 -Methanesulfony loxymethyl)-2-(tert-butoxy)propanammonium chloride was made from (Z)-(lS,2R)-N-(benzyloxycarbonyl)-O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a. l-amino-4-cyano-5,6,7,8- tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. (lR,2R)-l-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 (^R)-2-(4-cyano-5,6,7,8-tetrahydronaphthylimino)-4-((lR)-l- tert-butoxyethyl)-3-isobutyl-l,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to afford (¥R)-2-(4-cyano-5,6,7,8- tetrahydronaphthy limino)-4-(( 1 R)- 1 -hydroxy ethyl)-3 -isobutyl- 1 ,3 -thiazolidine.
Entry 181
Figure imgf000149_0002
2-Amino-l,3-propanediol was reacted with excess SOCl2 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4- nitrophenylimino)-4-(chloromethyl)-l, 3-thiazolidine. The thiazolidine was reacted with N-methylamine according to Method D13a to give 2-(2-methyl-4- nitrophenylimino)-4-(N-methylaminomethyl)-l, 3-thiazolidine, which was reacted 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
Figure imgf000150_0001
2-Amino-l,3-propanediol was reacted with excess SOCl2 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- 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)-l,3-thiazolidine.
Entry 183
Figure imgf000150_0002
(Z)-Histidinol was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (45)-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 (45)-2-(2-methyl-4-nitrophenylimino)-3 -isobutyl-4-( 1 -(isobutylimidazolyl)methyl)-
1 ,3-thiazolidine.
Entry 184
Figure imgf000150_0003
(Z)-Histidinol was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (45)-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 (45)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(3-(isobutylimidazolyl)methyl)- 1 ,3-thiazolidine. Entry 185
Figure imgf000151_0001
2-Hydroxypropylamine was converted to 2-chloropropylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloropropylammonium chloride according to Method Cla to give 2-(2-methyl-4- nitrophenylimino)-5-methyl-l, 3-thiazolidine. The thiazolidine was reacted with 2- methylprop-2-en-l-yl bromide according to Method D2g to afford 2-(2-methyl-4- nitrophenylimino)-3-(2-methylprop-2-en-l-yl)-5-methyl-l, 3-thiazolidine HBr salt.
Entry 186
Figure imgf000151_0002
2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-l,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2- hydroxyethylamine. The ethanolamine was reacted with SOCl2 followed by 2- chloro-4-(trifluoromethyl)phenyl isothiocyanate according to Method C2f to afford 2-(2-chloro-4-(trifluoromethyl)phenylimino)-3-isobutyl-5-phenyl-l,3-thiazolidine HCl salt.
Entry 187
Figure imgf000151_0003
2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-l,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2- hydroxyethylamine. The ethanolamine was reacted with SOCl2 followed by 2,3- dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3- dichlorophenylimino)-3-isobutyl-5-phenyl- 1 ,3-thiazolidine. Entry 188
Figure imgf000152_0001
HCI 3-Phenyl-2-hydroxypropylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-benzyl-l,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 SOCl2 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.
Entry 189
Figure imgf000152_0002
2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-l,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 SOCl2 followed by 2,6-dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,6-dichlorophenylimino)-3-cyclohexyl-5,5-dimethyl-l, 3-thiazolidine.
Entry 190
Figure imgf000152_0003
(1R)-1 -Cyclohexyl- 1-ethylamine was reacted with l,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- hydroxyethyl)amine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3- ((lR)-l-cyclohexyl-l-ethyl)-5,5-dimethyl-l,3-thiazolidine HCl salt. Entry 191
Figure imgf000153_0001
(15)- 1 -Cyclohexyl- 1-ethylamine was reacted with 1 ,2-epoxy-2-methylpropane according to Method B5b to give N-(( 15)- 1 -cyclohexyl- 1-ethy l)-N-(2,2-dimethyl-2- hydroxyethyl)amine. N-(( 15)- 1 -Cyclohexyl- 1 -ethyl)-N-(2,2-dimethyl-2- hydroxyethyl)amine was reacted with SOCl2 followed by 2,4-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,4-dichlorophenylimino)-3-
(( 15)- 1 -cyclohexyl- 1 -ethyl)-5 ,5-dimethyl- 1 ,3-thiazolidine HCl salt.
Entry 192
Figure imgf000153_0002
(15)- 1 -Cyclohexyl- 1-ethylamine was reacted with 1 ,2-epoxy-2-methylpropane according to Method B5b to give N-(( 15)- 1 -cyclohexyl- l-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl)amine. N-((1S)- 1 -Cyclohexyl- 1 -ethyl)-N-(2,2-dimethyl-2- hydroxyethyl)amine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3- ((15)-l-cyclohexyl-l-ethyl)-5,5-dimethyl-l,3-thiazolidine HCl salt.
Entry 193
Figure imgf000153_0003
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2,3- dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3- dichlorophenylimino)-5,5-dimethyl-l,3-thiazolidine. 2-(2,3-Dichlorophenylimino)- 5,5-dimethyl-l, 3-thiazolidine was reacted with ethylene oxide according to Method B5b to afford 2-(2,3-dichlorophenylimino)-5,5-dimethyl-l, 3-thiazolidine HCl salt.
Entry 194
Figure imgf000154_0001
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl-4- nitrophenylimino)-5,5-dimethyl-l, 3-thiazolidine.
Entry 195
Figure imgf000154_0002
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl-4- nitrophenylimino)-5,5-dimethyl-l, 3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-l-yl bromide according to Method D2g to afford 2-(2-methyl-4- nitrophenylimino)-3-(2-methylprop-2-en-l-yl)-5,5-dimethyl-l,3-thiazolidine HBr salt.
Entry 196
Figure imgf000154_0003
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2-methyl-4- nitrophenyl isothiocyanate according to Method Cla to afford 2-(2-methyl-4- nitrophenylimino)-5,5-dimethyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2-(2-methyl-4- nitrophenylimino)-3-isobutyl-5,5-dimethyl-l ,3-thiazolidine.
Entry 197
Figure imgf000155_0001
HCI 2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2,3- dichlorophenyl isothiocyanate according to Method Cla to afford 2-(2,3- dichlorophenylimino)-5,5-dimethyl-l, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2-(2,3- dichlorophenylimino)-3-isobutyl-5,5-dimethyl-l,3-thiazolidine.
Entry 198
Figure imgf000155_0002
2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-l,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 SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-cyclohexyl-5,5-dimethyl-l ,3-thiazolidine.
Entry 199
Figure imgf000155_0003
2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-l,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 SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2- (2,3-dichlorophenylimino)-3-cyclohexyl-5,5-dimethyl-l,3-thiazolidine.
Entry 200
Figure imgf000156_0001
(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- hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)- 3-((lR)-l-cyclohexyl-l-ethyl)-5,5-dimethyl-l,3-thiazolidine HCl salt.
Entry 201
Figure imgf000156_0002
(15)- 1 -Cyclohexyl- 1-ethylamine was reacted with 1 ,2-epoxy-2-methylpropane according to Method B5b to give N-(( 15)- 1 -cyclohexyl- l-ethyl)-N-(2,2-dimethyl-2- hydroxyethyl)amine. N-((1S)- 1 -Cyclohexyl- 1 -ethyl)-N-(2,2-dimethyl-2- hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-
3-((15)-l-cyclohexyl-l-ethyl)-5,5-dimethyl-l,3-thiazolidine HCl salt.
Entry 202
Figure imgf000156_0003
Isopropylamine was reacted with l,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 SOCl2 followed by 2-methyl- 4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4- nitrophenylimino)-3-isopropyl-5,5-dimethyl-l,3-thiazolidine.
Entry 203
Figure imgf000157_0001
Isopropylamine was reacted with l,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 SOCl2 followed by 2,3- dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3- dichlorophenylimino)-3 -isopropyl-5 , 5 -dimethyl- 1 ,3-thiazolidine .
Entry 204
Figure imgf000157_0002
HCI Isobutylamine was reacted with l,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 SOCl2 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.
Entry 205
Figure imgf000157_0003
l,l-Dimethyl-2-hydroxyamine was converted to l,l-dimethyl-2- chloroethylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with l,l-dimethyl-2-chloroethylammonium chloride according to Method Cla to give 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-l,3- thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-l-yl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-3- (2-methylprop-2-en-l-yl)-l, 3-thiazolidine HBr salt.
Entry 206
Figure imgf000157_0004
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 SOCl2 according to Method B7b, followed by 2-methyl-3-nitrophenyl isothiocyanate according to Method Cla to give 2-(2-methyl-4-nitrophenylimino)- 4,4-dimethyl-l, 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.
Entry 207
Figure imgf000158_0001
1 -Amino- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. l-(Cyclohexylamino)-l-hydroxymethylcyclopentane was synthesized as described in Method B4a. The 2-hydroxyethylamine was treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to afford 3-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-l-thia-3-azaspiro[4.4]nonane.
Entry 208
Figure imgf000158_0002
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 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 with SOCl2 according to Method B7a to give 1- amino-l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2- ethyl-4-nitrophenylimino)-l-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to afford 3-cyclopentyl- 2-(2-ethyl-4-nitrophenylimino)-l-thia-3-azaspiro[4.4]nonane.
Entry 209
Figure imgf000159_0001
2-H-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- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1 -amino- l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-«-propylphenyl isothiocyanate according to Method Cla to give 2-(4-iodo-2-w-propylphenylimino)- l-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-«- propylphenylimino)-l-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-«- propylphenylimino)- 1 -thia-3-azaspiro[4.4 Jnonane.
Entry 210
Figure imgf000159_0002
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- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1 -amino- 1 -(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-isopropylphenyl isothiocyanate according to Method Cla to give 2-(4-iodo-2-isopropylphenylimino)- l-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)-l-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- isopropylphenylimino)-l-thia-3-azaspiro[4.4]nonane.
Entry 211
Figure imgf000160_0001
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- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1 -amino- l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-tert-butylphenyl isothiocyanate according to Method Cla to give 2-(4-iodo-2-tert-butylphenylimino)- l-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)-l-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-tert- butylphenylimino)-l-thia-3-azaspiro[4.4]nonane.
Entry 212
Figure imgf000160_0002
1 -Amino- l-(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-l-methyl-6-oxodispiro[4.2.4.1]tridecane, which was reduced with NaBH4 according to Method B4a, Step 2 to afford l-(2- methylcyclopentyl)amino-l-(hydroxymethyl)cyclopentane. The 2- hydroxyethylamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to afford 3-(2-methylcyclopentyl)-2-(2- methyl-4-nitrophenylimino)- 1 -thia-3-azaspiro[4.4]nonane.
Entry 213
Figure imgf000161_0001
1 -Amino- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1 -amino- l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2-methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford l-isobutyl-2-(2- methyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane.
Entry 214
Figure imgf000161_0002
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 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 SOCl2 according to Method B7a to give 1- amino-l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2- ethyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford l-isobutyl-2-(2- ethyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane.
Entry 215
Figure imgf000161_0003
2-H-Propylaniline was converted to 2-«-propylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-«-propyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-«-propyl-4-nitroaniline. The aniline was converted to 2-«-propyl-4- nitrophenyl 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 SOCl2 according to Method B7a to give 1- amino-l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-«-propyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2- n-propyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford l-isobutyl-2-(2-«- propyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane.
Entry 216
Figure imgf000162_0001
2-Isoropylaniline was converted to 2-isopropylacetanilide according to Method A2a, 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 Blc. The 2- hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1- amino-l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate according to Method Cla to give 2-(2- isopropyl-4-nifrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford l-isobutyl-2-(2- isopropyl-4-nitrophenylimino)-3-thia- 1 -azaspiro[4.4]nonane.
Entry 217
Figure imgf000162_0002
2,3-Dimethyl-4-nitroaniline was synthesized as described in Method A4a. The aniline was converted into 2,3 -dimethyl -4-nitrophenyl isothiocyanate as described in method A2d. 1 -Amino- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1 -amino- l-(chloromethyl)cyclopentane HCl salt. The 2- chloroethylamine was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method Clc to give 2-(2,3-dimethyl-4-nitrophenylimino)-3-thia-l- azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford l-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-l- azaspiro[4.4]nonane.
Entry 218
Figure imgf000163_0001
3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1 -Amino- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with
SOCl2 according to Method B7a to give 1 -amino- l-(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-l-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford l-isobutyl-2-(3-methyl-4-nitrophenylimino)-3- thia- 1 -azaspiro[4.4]nonane.
Entry 219
Figure imgf000163_0002
l-Amino-5,6,7,8-tetrahydronaphthaline was converted to l-acetamino-5, 6,7,8- tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide was converted to l-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 l-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline was converted to 4-nitro-5,6,7,8-tetrahydro-l-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 SOCl2 according to Method B7a to give 1 -amino- l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-l-naphthyl isothiocyanate according to Method Cla to give 2-(4-nitro-5,6,7,8-tetrahydro-l- naphthylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford l-isobutyl-2-(4-nitro-5,6,7,8- tetrahydro- 1 -naphthylimino)-3-thia- 1 -azaspiro[4.4]nonane. Entry 220
Figure imgf000164_0001
1 -Amino- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1 -amino- l-(chloromethyl)cyclopentane HCl 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 l-isobutyl-2-(4- cyanophenylimino)-3-thia- 1 -azaspiro[4.4]nonane.
Entry 221
Figure imgf000164_0002
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- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl2 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)-l-thia-3- azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4-iodo-2-methylphenylimino)-l-thia-3- azaspiro[4.4]nonane.
Entry 222
Figure imgf000164_0003
1 -Amino- 1 -(hydroxymethyl)cyclopentane was synthesized as described in Method
Blc. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1 -amino- l-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method Cla to give 2-(4-cyano-2-methylphenylimino)-l-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)-l-thia-3-azaspiro[4.4]nonane.
Entry 223
Figure imgf000165_0001
1 -Amino- l-(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1 -amino- l-(chloromethyl)cyclopentane HCl salt. l-Amino-4-cyanonaphthalene was converted into 4-cyano-l -naphthyl isothiocyanate according to Method A2a, Step 3. The 2-chloroethylamine was reacted with 4-cyano-l -naphthyl isothiocyanate to Method Cla to give 2-(4-cyano-l-naphthylimino)-l-thia-3- azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4-cyano-l-naphthylimino)-l-thia-3- azaspiro[4.4]nonane.
Entry 224
Figure imgf000165_0002
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- 1- (hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2- hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1- amino- l-(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)-l-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-H-propylphenylimino)-l-thia-3-azaspiro[4.4]nonane. The phenyl iodide was 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
Figure imgf000166_0001
2,3-Dimethylaniline was onverted 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- 1- (hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2- hydroxyethylamine was reacted with SOCl2 folloowed by 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method C2a to give 2-(2,3-dimethyl-4- iodophenylimino)-l-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-«- propylphenylimino)-l-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)-l-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)-l-thia-3-azaspiro[4.4]nonane.
Entry 226
Figure imgf000166_0002
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- 1-
(hydroxymethyl)cyclopentane was synthesized as described in Method Blc. The 2- hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1- amino-l-(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)-l-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-«-propylphenylimino)-l-thia-3-azaspiro[4.4]nonane.
Entry 227
Figure imgf000166_0003
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- 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-l-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to afford 2-(2,3-dimethyl-6- nitrophenylimino)- 1 -isobutyl-3-thia- 1 -azaspiro[4.4]nonane.
Entry 228
Figure imgf000167_0001
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- 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-l- azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 2-(5-cyanothienylimino)-l-isobutyl-3-thia-l- azaspiro[4.4]nonane.
Entry 229
Figure imgf000167_0002
6-Amino-3-cyano-2,3-dimethylpyridine was converted to 3-cyano-2,3-dimethyl-6- 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 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-l-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.
Entry 230
Figure imgf000168_0001
l-(Hydroxymethyl)cyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4- nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4- nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with l-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.
Entry 231
Figure imgf000168_0002
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- cyano-2-ethylphenylimino)-3-thia-l-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.
Entry 232
Figure imgf000168_0003
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-nitrophenylimino)-3-thia-l-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.
Entry 233
Figure imgf000169_0001
1 -Hydroxymethylcyclopent 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-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with 3-bromo-2-methylpropene according to Method D2e to give 2-(2- methyl-4-nitrophenylimino)- 1 -(2-methy lprop- 1 -en-3 -yl)-3 -thia- 1 - azaspiro[4.4]nonane.
Entry 234
Figure imgf000169_0002
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-nitrophenylimino)-3-thia-l-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
Figure imgf000170_0001
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-nitrophenylimino)-3-thia-l-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.
Entry 236
Figure imgf000170_0002
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-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexylmethyl bromide according to Method D2e to give 2-(2- methyl-4-nitrophenylimino)-l-(cyclohexylmethyl)-3-thia-l-azaspiro[4.4]nonane.
Entry 237
Figure imgf000170_0003
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-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with 2-(bromomethyl)tetrahydro-2H-pyran according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)- 1 -(tetrahydro-2H-pyran-2-ylmethyl)-3-thia- 1 - azaspiro[4.4]nonane.
Entry 238
Figure imgf000171_0001
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-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with 2-(2-bromoethyl)-l,3-dioxane according to Method D2e to give 2-(2- methyl-4-nitrophenylimino)- 1 -(2-( 1 ,3 -dioxan-2-yl)ethyl)-3 -thia- 1 - azaspiro[4.4]nonane.
Entry 239
Figure imgf000171_0002
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-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclobutyl bromide according to Method D2e to give 2-(2-methyl-
4-nitrophenylimino)- 1 -cyclobuty 1-3 -thia- 1 -azaspiro[4.4]nonane.
Entry 240
Figure imgf000172_0001
l-(Hydroxymethyl)cyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4- nitrophenylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2-methyl-4- nitrophenylimino)- 1 -cyclopenty 1-3 -thia- 1 -azaspiro [4.4]nonane.
Entry 241
Figure imgf000172_0002
1 -Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was reacted with SOCl2 followed by with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4- nitrophenylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2-methyl-4- nitrophenylimino)-l-2-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was oxidized with -CPBA according to Method D4a to afford 2-(2-methyl-4- nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane 3-oxide.
Entry 242
Figure imgf000172_0003
1 -Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was reacted with SOCl2 followed by with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4- nitrophenylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2-methyl-4- nitrophenylimino)-l-2-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was oxidized with w-CPBA according to Method D4a to afford 2-(2-methyl-4- nitrophenylimino)- 1 -cyclopenty 1-3 -thia- 1 -azaspiro[4.4]nonane 3 ,3-dioxide.
Entry 243
Figure imgf000173_0001
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- 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-ethyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-(2- ethyl-4-nitrophenylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was 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
Figure imgf000173_0002
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 isothiocyanate according to Method Cle to give 2-(3-methyl-4-nitrophenylimino)-3- thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(3-methyl-4-nitrophenylimino)-l -cyclopentyl-3 - thia- 1 -azaspiro[4.4 Jnonane. Entry 245
Figure imgf000174_0001
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 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 Blc. The 2- hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1 -Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method Cle to give 2-
(2,3-dimethyl-4-nitrophenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2,3- dimethyl-4-nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Entry 246
Figure imgf000174_0002
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,- 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 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-l-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
Figure imgf000175_0001
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-iodophenyl isothiocyanate according to Method Cle to give 2-(4- iodophenylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodophenylimino)- l-2-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D2h to afford 2-(4-cyanophenylimino)-l -cyclopentyl-3 - thia-l-azaspiro[4.4]nonane.
Entry 248
Figure imgf000175_0002
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-
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-methylphenyl isothiocyanate according to Method Cle to give 2-(4- cyanophenylphenylimino)-3-thia-l-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
Figure imgf000175_0003
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- cyano-2-ethylphenylimino)-3-thia-l-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.
Entry 250
Figure imgf000176_0001
4-Iodo-2-H-propylaniline was converted to 4-iodo-2-«-propylphenyl isothiocyanate according to Method A2b. 1 -Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2-hydroxyethylamine was sequentially reacted with
SOCl2 and 4-iodo-2-n-propylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-«-propylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2- «-propylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2-«- propylphenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro[4.4]nonane.
Entry 251
Figure imgf000176_0002
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 SOCl2 and 4-iodo-2-isopropylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-isopropylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine 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)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Entry 252
Figure imgf000177_0001
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 reacted with SOCl2 and 4-iodo-2,3-dimethylphenyl isothiocyanate according to
Method C2a to give 2-(4-iodo-2,3-dimethylphenylimino)-3-thia-l- azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2,3-dimethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2,3-dimethylphenylimino)-l- cyclopentyl-3-thia- 1 -azaspiro[4.4]nonane.
Entry 253
Figure imgf000177_0002
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was hydrolyzed according to Method D9a to afford 2-(4-carboxy-2-ethylphenylimino)-l- cyclopenty 1-3 -thia- 1 -azaspiro[4.4]nonane.
Entry 254
Figure imgf000177_0003
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- 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-methylphenyl isothiocyanate according to Method Cle to give 2-(4- cyanophenylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- methylphenylimino)-l-cyclopentyl-3-thia-l-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 .
Entry 255
Figure imgf000178_0001
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l -cyclopentyl-3 -thia- 1 -azaspiro [4.4]nonane. The nitrile was hydrolyzed according to Method D9a to give 2-(4-carboxy-2-ethylphenylimino)-l-2- cyclopenty 1-3 -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 D 10a.
Entry 256
Figure imgf000178_0002
Methyl 4-amino-3-methylbenzoate was converted to 4-methoxycarbonyl-2- methylphenyl isothiocyanate according to Method A2b. 1- Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was sequentially reacted with SOCl2 and 4-methoxycarbonyl-2- methylphenyl isothiocyanate according to Method C2a to give 2-(4- methoxycarbonyl-2-methylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2h to give 2-(4-methoxy carbony 1-2-methylphenylimino)- 1 -cyclopentyl-3 -thia- 1 - azaspiro[4.4]nonane.
Entry 257
Figure imgf000179_0001
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was hydrolyzed according to Method D9a to give 2-(4-carboxy-2-ethylphenylimino)-l-2- cyclopentyl-3-thia-l-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.
Entry 258
Figure imgf000179_0002
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was hydrolyzed according to Method D9a to give 2-(4-carboxy-2-ethylphenylimino)-l-2- cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The benzoic acid was reacted with dimethylamine according to Method D6b to afford 2-(4-(N,N-dimethylcarbamoly)-2- ethylphenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro[4.4]nonane.
Entry 259
Figure imgf000180_0001
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 A3 a, 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 -(cyclopenty lamino)-l- (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to l-(cyclopentylamino)-l-(acetylthiomethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1-
(cyclopentylamino)-l-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 2,3-dichlorophenyl isocyanide dichloride according to Method C6c to afford 2- (2,3-dichlorophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Entry 260
Figure imgf000180_0002
2-(Trifluoromethyl)aniline was converted to the 2-(trifluoromethyl)formanilide according to Method A3 a, Step 1. The formanilide was converted to 2-
(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- 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 -(cyclopenty lamino)-l - (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to l-(cyclopentylamino)-l-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-l-(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.
Entry 261
Figure imgf000181_0001
4-(Trifluoromethyl)aniline was converted to the 4-(trifluoromethyl)formanilide according to Method A3 a, Step 1. The formanilide was converted to 4- (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- 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 l-(cyclopentylamino)-l- (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to l-(cyclopentylamino)-l-(thioacetylmethyl)cyclopentane according to Method C6c,
Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-l-(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 - azaspiro[4.4]nonane.
Entry 262
Figure imgf000181_0002
2-Chloro-3-methylaniline was converted to the 2-chloro-3-methylformanilide according to Method A3a, Step 1. The formanilide was converted to 2-chloro-3- methylphenyl isocyanide dichloride according to Method A3 a, 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 -(cyclopenty lamino)-l- (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to l-(cyclopentylamino)-l-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-l-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 2-chloro-3 -methylphenyl isocyanide dichloride according to Method C6c to afford 2-(2-chloro-3-methylphenylimino)- 1 -cyclopentyl-3 -thia- 1 - azaspiro [4.4]nonane .
Entry 263
Figure imgf000182_0001
3-(Trifluoromethyl)aniline was converted to the 3-(trifluoromethyl)formanilide according to Method A3 a, Step 1. The formanilide was converted to 3- (trifluoromethyl)phenyl isocyanide dichloride according to Method A3 a, 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 l-(cyclopentylamino)-l- (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to l-(cyclopentylamino)-l-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-l-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 3-(trifluoromethyl)phenyl isocyanide dichloride according to Method C6c to afford 2-(3-(trifluoromethyl)phenylimino)-l-cyclopentyl-3-thia-l- azaspiro[4.4]nonane.
Entry 265
Figure imgf000182_0002
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 A3 a, 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 l-(cyclopentylamino)-l- (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to 1 -(cyclopenty lamino)-l-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1-
(cyclopentylamino)-l-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 3-chloro-2-methylphenyl isocyanide dichloride according to Method C6c to afford 2-(3 -chloro-2-methy lpheny limino)- 1 -cyclopentyl-3 -thia- 1 - azaspiro[4.4]nonane.
Entry 265
Figure imgf000183_0001
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- methylphenyl isocyanide dichloride according to Method A3 a, 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 l-(cyclopentylamino)-l- (hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was converted to l-(cyclopentylamino)-l-(thioacetylmethyl)cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino)-l-(thiomethyl)cyclopentane. The 2-thioethylamine was reacted with 2,3-dichloro-4-methylphenyl isocyanide dichloride according to Method C6c to afford 2-(2,3-dichloro-4-methylphenylimino)- 1 -cyclopentyl-3 -thia- 1 - azaspiro [4.4] nonane .
Entry 266
Figure imgf000184_0001
1 -Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was sequentially reacted with SOCl2 and 4-bromo-2- methylphenyl isothiocyanate according to Method C2a to give 2-(4-bromo-2- methy lphenylimino)-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)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Entry 267
Figure imgf000184_0002
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dl la to give 2-(4-formyl-2-ethylphenylimino)-l- cyclopentyl-3-thia- 1 -azaspiro[4.4]nonane.
Entry 268
Figure imgf000184_0003
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dl la to give 2-(4-formyl-2-ethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a according to afford 2-(2-ethyl-4-((lE)- 2-ethoxycarbonylvinyl)phenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Entry 269
Figure imgf000185_0001
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dl la to give 2-(4-formyl-2-ethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The aldehyde was reacted with nitromethane according to Method D12b according to afford 2-(2-ethyl-4-((lE)-2- nitrovinyl)phenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Entry 270
Figure imgf000185_0002
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dl la to give 2-(4-formyl-2-ethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a according to afford 2-(2-ethyl-4-((lE)- 2-ethoxycarbonylvinyl)phenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The ester was saponified according to Method D6a to afford 2-(2-ethyl-4-((lE)-2- carboxyvinyl)phenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Entry 271
Figure imgf000186_0001
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dl la to give 2-(4-formyl-2-ethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The aldehyde was reacted with malononitrile according to Method D12c according to afford 2-(2-ethyl-4-(2,2- dicyanovinyl)pheny limino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro [4.4 ]nonane .
Entry 272
Figure imgf000186_0002
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dl la to give 2-(4-formyl-2-ethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The aldehyde was reacted with diethyl (2- oxopropyl)phosphonate according to Method D12a according to afford 2-(2-ethyl-4- ((7E)-2-acetylvinyl)phenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane.
Entry 273
Figure imgf000187_0001
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- cyano-2-ethylphenylimino)-3-thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2- ethylphenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The nitrile was reduced according to Method Dl la to give 2-(4-formyl-2-ethylphenylimino)-l- cyclopentyl-3-thia-l-azaspiro[4.4]nonane. The aldehyde was reacted with acetonitrile according to Method D12d according to afford 2-(2-ethyl-4-((7E)-2- cyanovinyl)phenylimino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro[4.4]nonane.
Entry 274
Figure imgf000187_0002
1 -Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3- thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-l-cyclohexyl-3- thia-1 -azaspiro[4.4]nonane.
Entry 275
Figure imgf000187_0003
1 -Hydroxymethylcyclopentanamine was prepared according to Method Blc. The 2- hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3- thia-l-azaspiro[4.4]nonane. The thiazolidine was reacted with cycloheptyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-l-cycloheptyl-3- thia-l-azaspiro[4.4]nonane.
Entry 276
Figure imgf000188_0001
1-Aminocyclohexane-l -carboxylic acid was protected as the benzyloxycarbonylamine according to Method Bla, Step 1. 1-
(Benzyloxycarbonylamino)cyclohexane-l -carboxylic acid was reduced to 1- (benzyloxycarbonylamino)-l-(hydroxymethyl)cyclohexane according to Method Bla, Step 2. The carbamate was deprotected according to Method Bla, Step 3 to give 1 -amino- l-(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-l- azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-l-isobutyl-3- thia-l-azaspiro[4.5]decane.
Entry 277
Figure imgf000188_0002
2-Methyl-4-nitroaniline was converted to the 2-methyl-4-nitroformanilide according to Method A3 a, 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 -carboxy late was reduced to 3-amino- 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-l-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- (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- 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
Figure imgf000189_0001
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 A3 a, Step 2. 4-Aminotetrahydro-2H- pyran-4-carboxylic acid was converted to the methyl ester according to Method Bib, Step 1. Methyl 4-aminotetrahydro-2H-pyran-4-carboxylate was reduced to 4-amino-
4-(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-l-aza-3,8-dioxaspiro[4.5]decane. The oxazolidine was reduced to 4-isobutylamino-4-(hydroxymethyl)tetrahydro-2H-pyran. The substituted 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- nitrophenylimino-l-isobutyl-l-aza-8-oxa-3-thiaspiro[4.5]decane.
Entry 279
Figure imgf000189_0002
2-Amino-2-norbornane-l -carboxylic acid as a mixture of isomers was converted to the N-benzyloxycarbonyl analogue according to Method Bla, Step 1. 1-
(Benzyloxycarbonylamino)-2-norbornane-l -carboxylic acid was reduced to 1- (benzyloxycarbonylamino)-l-(hydroxymethyl)-2-norbornane according to Method Bla, Step 2. The carbamate was deprotected according to Method Bla, Step 3 to give 1 -amino- l-(hydroxymethyl)-2-norbornane. The 2-hydroxyethylamine was alkylated with isobutyl bromide according to Method B2a to give N-isobutyl-1- amino-l-(hydroxymethyl)-2-norbornane. The alkylated 2-hydroxyethylamine was treated with SOCl2 according to Method B7a to give N-isobutyl-2-chloroethylamine ΗC1 salt. The chloroethylamine was treated with 2-methyl-4-nitrophenyl isothyiocyanate according to Method Cla to afford 2-(2-methyl-4-nitrophenylimino)- 3-isobutylspiro[ 1 ,3-thiazolidine-4,3'-bicyclo[3.2.1 Joctane] .
Entry 280
Figure imgf000190_0001
N-(tert-Butoxycarbonyl)-(Z)-valine was converted to (S)-3-(tert- butoxycarbonylamino)-l-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 ester was reduced according to Method B6a, Step 3 to give (R)-3-(tert- butoxycarbonylamino)-4-methylpentan-l-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 (4R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl- 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-l,3- thiazine HCl salt.
Entry 281
,>=Ν^ Νθ2 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 SOCl2 according to Method B9a, Step 3 to 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-l,3-thiazine.
Entry 282
Figure imgf000190_0002
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 SOCl2 according to Method B9a, Step 3 to give N-isobutyl-3 -chlorobutylamine HCl 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-l,3-thiazepine.
Entry 283
Figure imgf000191_0001
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.
Entry 284
Figure imgf000191_0002
3-Methyl-4-nitrophenyl isothiocyanate was reacted with benzylamine followed by chloroacetic acid according to Method C8a to afford 2-(3-methyl-4- nitrophenylimino)-3 -(phenylmethyl)- 1 ,3-thiazolidin-4-one.
Entry 285
Figure imgf000191_0003
3-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-l-butylamine 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
Figure imgf000192_0001
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.
Entry 287
Figure imgf000192_0002
2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4- nitrophenylimino)-3 -isobutyl- 1 ,3 -thiazolidin-4-one.
Entry 288
Figure imgf000192_0003
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-l-butylamine 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
Figure imgf000192_0004
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
Figure imgf000193_0001
2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by α-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4- nitrophenylimino)-3-isobutyl-5-methyl- 1 ,3-thiazolidin-4-one.
Entry 291
Figure imgf000193_0002
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- nitrophenylimino)-3-( 1 -cyclohexylethyl)- 1 ,3-thiazolidin-4-one.
Entry 292
Figure imgf000193_0003
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (lS)-l-amino-\- cyclohexylethane followed by chloroacetic acid according to Method C8a to afford
2-(2-methyl-4-nitrophenylimino)-3-((/5)-i-cyclohexylethyl)-l,3-thiazolidin-4-one.
Entry 293
Figure imgf000193_0004
2-Methyl-4-nitrophenyl isothiocyanate was reacted with ( R)-7-amino-l- cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((7R)-7-cyclohexylethyl)-l,3-thiazolidin-4-one.
Entry 294
Figure imgf000194_0001
2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by α-chloro-α-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4- nitrophenylimino)-3-isobutyl-5-phenyl- 1 ,3-thiazolidin-4-one.
Entry 295
Figure imgf000194_0002
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (7R)-7-amino-l- cyclohexylethane followed by α-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((7R)-7-cyclohexylethyl)-5-methyl-l ,3- thiazolidin-4-one.
Entry 296
Figure imgf000194_0003
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (7R)-7-amino-l- cyclohexylethane followed by α-chloro-α-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((7R)-7-cyclohexylethyl)-5-phenyl- 1 ,3-thiazolidin-4-one.
Entry 297
Figure imgf000194_0004
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (75)-7 -amino- 1- cyclohexylethane followed by α-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((75)-7-cyclohexylethyl)-5-methyl- 1 ,3- thiazolidin-4-one.
Entry 298
Figure imgf000195_0001
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (75)-7 -amino- 1- cyclohexylethane followed by α-chloro-α-phenylacetic acid according to Method
C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((75)-7-cyclohexylethyl)-5-phenyl- 1 ,3-thiazolidin-4-one.
Entry 299
Figure imgf000195_0002
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-l-butylamine followed by α-chloropropionic acid according to Method C8a to afford 2-(2-methyl- 4-nitrophenylimino)-3-(2-ethyl-l-butyl)-5-methyl-l,3-thiazolidin-4-one.
Entry 300
Figure imgf000195_0003
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.
Entry 301
Figure imgf000196_0001
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-l-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.
Entry 302
Figure imgf000196_0002
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methylbutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to afford 2- (2-methyl-4-nitrophenylimino)-3-(2-butyl)-5-isobutyl-l,3-thiazolidin-4-one.
Entry 303
Figure imgf000196_0003
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methylbutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2-(2- methyl-4-nitrophenylimino)-3-(2-butyl)-5-isopropyl-l,3-thiazolidin-4-one.
Entry 304
Figure imgf000196_0004
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-l,3-thiazolidin-4-one.
Entry 305
Figure imgf000197_0001
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (25)-2-methyl-l-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4- nitrophenylimino)-3-((25)-2-methyl-l-butyl)-l,3-thiazolidin-4-one.
Entry 306
Figure imgf000197_0002
2-Methyl-4-nitrophenyl isothiocyana ote was reacted with 2-ethyl-l-butylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2-(2- methyl-4-nitrophenylimino)-3-(2-ethyl-l-butyl)-5-isopropyl-l,3-thiazolidin-4-one.
Entry 307
Figure imgf000197_0003
(R)-N-isobutylserine methyl ester HCl salt was prepared from (Z))-serine methyl ester as described in Method B3a. The alcohol was reacted with SOCl2 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.
Entry 308
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)-l,3-thiazolidin-4-one. Entry 309
Figure imgf000198_0001
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
Figure imgf000198_0002
N-Isobutylglycine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method CI la to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-l,3- thiazolidin-5-one.
Entry 311
Figure imgf000198_0003
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-l-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.
Entry 312
Figure imgf000198_0004
N-Isobutylleucine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cl la to afford (45)-2-(2-methyl-4-nitrophenylimino)-3,4- diisobutyl- 1 ,3-thiazolidin-5-one.
Entry 313
Figure imgf000199_0001
N-Isobutylproline ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method Cl la to afford 4-(2-methyl-4-nitrophenylimino)-l- oxoperhydro-2-thiapyrrolizine.
Entry 314
Figure imgf000199_0002
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- (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)-l-amino-2- methylprop-2-ene. The alcohol was treated with ?-toluenesulfonyl chloride according to Method B8b, Step 3 to give N-(tert-butoxycarbonyl)-N-(2- tosyloxyethyl)-l-amino-2-methylprop-2-ene. The carbamate was deprotected according to Method B8b, Step 4 to give N-(2-tosyloxyethyl)-2-methylprop-2-en-l- 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.
Entry 315
Figure imgf000199_0003
(Z)-Valine methyl ester was reduced to (lS)-l-(hydroxymethyl)-2- methylpropylamine according to Method Bib, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (45)-2,4- diisopropyl- 1,3 -oxazolidine. The oxazolidine was reduced according to Method B4c,
Step 2 to give (15)-l-(hydroxymethyl)-N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (15)-l-(chloromethyl)-N-isobutyl-2-methylpropylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (¥5)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl- 1,3-oxazolidine.
Entry 316
Figure imgf000200_0001
(Z)-Leucine methyl ester was reduced to (15)-l-(hydroxymethyl)-3- methylbutylamine according to Method Bib, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (45)-2- isopropyl-4-isobutyl- 1,3 -oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (15)-l-(hydroxymethyl)-N-isobutyl-3-methylbutylamine.
The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (15)-l-(chloromethyl)-N-isobutyl-3-methylbutylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (¥5)-2-(2-methyl-4-nitrophenylimino)-3 ,4-diisobutyl- 1,3- oxazolidine.
Entry 317
Figure imgf000200_0002
(Z)-Leucine methyl ester was reduced to (15)-l-(hydroxymethyl)-3- methylbutylamine according to Method Bib, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (45)-2- isopropyl-4-isobutyl- 1,3 -oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (15)- l-(hydroxymethyl)-N-isobutyl-3 -methylbutylamine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOCl2 and SO2Cl2 according to Method A3 a, 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-l,3-oxazolidine.
Entry 318
Figure imgf000201_0001
2-Amino-2-methyl-l-propanol was reacted with cyclopentanone according to Method B4b, Step 1 to afford 4-aza-3,3-dimethyl-l-oxaspiro[4.4]nonane. The oxazolidine was reduced according to Method B4b, Step 2 to give N-cyclopentyl- (l,l-dimethyl-2-hydroxyethyl)amine. 2-Methyl-4-nitroaniline was converted to 2- methyl-4-nitroformanilide according to Method A3 a, Step 1. The formanilide was reacted with SOCl2 and SO2Cl2 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 afford 2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4,4-dimethyl- 1 ,3-oxazolidine.
Entry 319
Figure imgf000201_0002
2-Amino-2-methyl-l-propanol was reacted with cyclopentanone according to Method B4b, Step 1 to afford 4-aza-3,3-dimethyl-l-oxaspiro[4.4]nonane. The oxazolidine was reduced according to Method B4b, Step 2 to give N-cyclopentyl- (l,l-dimethyl-2-hydroxyethyl)amine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3 a, Step 1. The formanilide was reacted with SOCl2 and SO2Cl2 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 C7a to afford 2-(4-cyano-2-ethylphenylimino)-3-cyclopentyl-4,4-dimethyl-l,3-oxazolidine.
Entry 320
Figure imgf000202_0001
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 B4d, Step 2 to give 1 -(cyclopenty lamino)-l-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to l-(cyclopentylamino)-l-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford l-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane.
Entry 321
Figure imgf000202_0002
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 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 B4a, Step 2 to give l-(cyclobutylamino)-l-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to l-(cyclobutylamino)-l-(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-l-azaspiro[4.4]nonane.
Entry 322
Figure imgf000203_0001
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 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 l-(cyclohexylamino)-l-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to l-(cyclohexylamino)-l-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1- cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane.
Entry 323
Figure imgf000203_0002
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 B4d, Step 2 to give l-(cyclopentylamino)-l-(hydroxymethyl)cyclopentane. 4-
Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOCl2 and SO2Cl2 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 isocyanide dichloride according to Method C7a to afford l-cyclopentyl-2-(2-methyl-
4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane.
Entry 324
Figure imgf000204_0001
(15)- l-(Hydroxymethyl)-3 -methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (25)- 4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride as described in Method B7c. 4-Νitrophenyl isothiocyanate was reacted with N-(15)-l-(chloromethyl)-3-methylbutyl)-N- (isobutyl)ammonium chloride according to Method Clf to give 2-(4- nitrophenylthio)- 1 ,5-diisobutylimidazoline.
Entry 325
Figure imgf000204_0002
(15)- l-(Hydroxymethyl)-3 -methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-
Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( 5)-2-(2-methyl- 4-nitrophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give ( 5)-2-(N-(4-heptyl)-N-(2-methyl-5- nitrophenyl)amino)-4-isobutyl- 1 ,3-thiazoline.
Entry 326
Figure imgf000204_0003
(lR)-l-(Hydroxymethyl)-3 -methylbutylamine was made from (Z>)-leucine methyl ester according to Bib. The 2-hydroxyethylamine was converted to (1R)-1-
(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2- Methyl-5-nitrophenyl isothiocyanate was reacted with (lR)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give ( R)-2-(2-methyl- 5-nitrophenylimino)-4-isobutyl- 1,3 -thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford ( R)-2-(N-isobutyl-N-(2- methyl-5-nitrophenyl)amino)-4-isobutyl-l,3-thiazoline HCl salt.
Entry 327
Figure imgf000205_0001
(15)- l-(Hydroxymethyl)-3 -methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3 -methylbutanammonium chloride as described in Method B7a. 2- Methyl-4-nitrophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (¥5)-2-(2-methyl-
4-nitrophenylimino)-4-isobutyl-l, 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.
Entry 328
Figure imgf000205_0002
(1 )- l-(Hydroxymethyl)-3 -methylbutylamine was made from (Z)-leucine methyl ester as described in Method Bib. The 2-hydroxyethylamine was converted to (15)- l-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2,3-Dichlorophenyl isothiocyanate was reacted with (15)-l-(chloromethyl)-3- methylbutanammonium chloride according to Method Cla to give (4S)-2-(2,3- dichlorophenylimino)-4-isobutyl-l, 3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to afford ( S)-2-(N-(3-pentyl)-2-methyl-4- nitrophenylamino)-4-isobutyl- 1 ,3-thiazoline.
TABLES
The compounds listed in Tables 1-4 below were synthesized according to the methods described above.
Table 1.2-Imino-l,3-thiazoIidines and Ring Expanded Homologues
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
(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% CH3CN/water, Buffer B: 0.018% TF A/98% CH3CN/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.
(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% TF A/water, Buffer B: 0.5% TFA/CH3CN; 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 UN detector (210 nM) and a 4x125 mm Νucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H3PO4 /water, Buffer B: 0.01 mol% H3PO4 / CH3CΝ; 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.
(d) Ranin Dynamax HPLC equipped with UN-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% CH3CΝ; 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 UN-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% CH3CΝ; 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 UN-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% CH3CΝ; 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 UN-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% CH3CΝ; 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 UN-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% CH3CN; 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 UN-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% CH3CΝ; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min.
(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% CH3CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.
Table 2.2-Imino-l,3-thiazolidin-4-ones and 2-Imino-l,3-thiazolidin-5-ones
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
(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% CH3CN/water, Buffer B: 0.018% TF A/98% CH3CN/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.
(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% TF A/water, Buffer B: 0.5% TFA/CH3CN; 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) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H3PO4 /water, Buffer B: 0.01 mol% H3PO4 / CH3CN; 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.
(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% CH3CN; 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 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% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water,
Buffer B: 0.1% TFA 99.9% CH3CN; 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 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% CH3CN; gradient from 10% Buffer B to
100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min.
(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% CH3CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.
Table 3.2-Imino-l,3-oxazolidines
Figure imgf000247_0001
Figure imgf000248_0001
(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% CH3CN/water, Buffer B: 0.018% TF A/98% CH3CN/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.
(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% TF A/water, Buffer B: 0.5% TFA CH3CN; 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) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H3PO4 /water, Buffer B: 0.01 mol% H3PO4 / CH3CN; 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.
(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% CH3CN; 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 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% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water,
Buffer B: 0.1% TFA/99.9% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water,
Buffer B: 0.1% TFA 99.9% CH3CN; 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 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% CH3CN; gradient from 10% Buffer B to 100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min.
(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% CH3CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min. Table 4. Additional Examples
Figure imgf000250_0001
(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% CH3CN/water, Buffer B: 0.018% TF A/98% CH3CN/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.
(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% TF A/water, Buffer B: 0.5% TFA/CH3CN; 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) and a 4x125 mm Nucleosil 3 uM C-18 column; flow rate 2.0 mL/min.; Buffer A: 0.01 mol% H3PO4 /water, Buffer B: 0.01 mol% H3PO4 / CH3CN; 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.
(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% CH3CN; 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 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% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water,
Buffer B: 0.1% TFA/99.9% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; 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 column; flow rate 20 mL/min.; Buffer A: 0.1% TFA/99.9% water, Buffer B: 0.1% TFA/99.9% CH3CN; 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 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% CH3CN; gradient from 10% Buffer B to
100% Buffer B over 5 min., hold at 100% B 100% for 1.5 min.
(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% CH3CN; gradient from 20% Buffer B to 100% Buffer B over 30 min., hold at 100% B 100% for 7 min.
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 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, 150 mM NaCl, 5% Glycerol, 1% DMSO) containing various concentrations of a compound to be assayed, T47D cell cytosol (100 μL of a solution which will give at least 4000 cpm of binding) and 3H-progesterone (50 μL, 10 nM, NET-381). The mixture was incubated for 16 h at 4 °C, and treated with charcoal (250 μL of a 0.5% mixture of 0.05% dextran-coated charcoal which had been washed twice with 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 3H-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 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 3H-progesterone to the progesterone receptor at 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.
Table 5. Inhibitory Activity of Exemplifled Compounds
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
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.
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 claims.

Claims

We claim:
1. A compound having the formula
Figure imgf000258_0001
wherein
R is aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene;
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, O, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons; R2, R3, and R4 are independently selected from the group consisting of H; 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; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5 ; wherein
R5 is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; halogen; and =O , representing two of the groups R2, R3, and R4; X is O or S(O)y ; wherein y is 0, 1, or 2; n is 2, 3, 4, or 5; p is the sum of non-H substituents R2, R3, and R4; 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; CO2H; CO2R5; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C6H5;
C(O)N(R6)(R7) ;wherein R6 is H or alkyl of 1 - 5 carbons; and
R7 is H or alkyl of 1 - 5 carbons; S(O)y.R8 ; wherein y' is 1 or 2; and R8 is alkyl of 1 - 5 carbons; SO2F;
CHO; OH; NO2; CN; halogen;
OCF3; N-oxide;
O-C(R9)2-O , the oxygens being connected to adjacent positions on R; and wherein R9 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)C6H4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; 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, CO2R5, alkenyl of 2 - 4 carbons, alkynyl of 2 - 4 carbons, C(O)C6H5, C(O)N(R6)(R7), S(O)y,R8, O-C(R9)2-O , or C(O)C6H4 , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; CO2R5; CO2H; C(O)N(R6)(R7);
CHO; OH; NO2; CN; halogen; S(O)yR8; or =O, 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;
OH; OR5;
=O , representing two substituents G; 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, O, and S; cycloalkenyl of 5 - 7 carbons; heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5;
C(O)N(R6)(R7); aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S; NO2;
CN;
S(O)yR8;
SO3R8; and
SO2N(R6)(R7); 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 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 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; 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; aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5 ;
=O , representing two substituents Q; OH; halogen;
N(R6)(R7);
S(O)yR8;
SO3R8; and SO2N(R6)(R7); 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 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)qR2, (Q)qR3, and (Q)qR4 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, O, and S; b) when n = 2 or 3, at least one of R\ R3, and R4 is other than H; c) when n = 2, and X = O, 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 = O, 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 = O or S, then the sum of non-hydrogen atoms in R\ R2, R\ and R4 is at least 5; f) when n = 2, X = O, 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 = O, the 4-position of the 1,3-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)y , the 4-position of the 1, 3-thiazolidine ring bears a carbonyl group, R1 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 CO2R5 , then R5 contains at least two carbons;
and pharmaceutically acceptable salts thereof.
2. A compound having the formula
Figure imgf000262_0001
wherein R is phenyl; or pyridyl; R' is 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; R2, R3, and R4 are independently selected from the group consisting of H; alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons; and =O , representing two of the groups R2, R3, and R4; X is O or S(O)y ; wherein y is O, l, or 2; n is 2 or 3; p is the sum of non-H substituents R2, R3, and R4; T is a substituent 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; NO2; CN; and halogen; 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 alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; CO2R5; wherein
R5 is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons;
CO2H; C(O)N(R6)(R7); wherein
R6 is H or alkyl of 1 - 5 carbons; and R7 is H or alkyl of 1 - 5 carbons; CHO;
OH; NO2; CN; halogen; S(O)yR8; wherein
R8 is alkyl of 1 - 5 carbons; and
=O, representing two secondary substituents; 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; OR5; 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 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, 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 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; cycloalkyl of 3 - 8 carbons; alkoxy of 1 - 8 carbons; alkenyl of 2 - 5 carbons; cycloalkenyl of 5 - 8 carbons;
CO2R5 ; =O , representing two substituents Q;
OH; halogen;
N(R6)(R7); and
S(O)yR8; q is 0 - 4; and with the further provisos that: a) two of (Q)qR\ (Q)qR2, (Q)qR3, and (Q)qR4 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, O, and S; b) when n = 2 or 3, at least one of R2, R3, and R4 is other than H; c) when n = 2, and X = O, 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 = O, 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 = O or S, then the sum of non-hydrogen atoms in R1, R2, R3, and R4 is at least 5; f) when n = 2, X = O, 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 = O, the 4-position of the 1,3 -oxazolidine ring may bear a carbonyl only if the 5-position of said ring bears at least one non-H substituent; and h) when n = 2, X = S(O)y , the 4-position of the 1, 3-thiazolidine ring bears a carbonyl group, R1 is a substituted methyl group, and G is a phenyl group, then said phenyl group bears a secondary substituent;
and pharmaceutically acceptable salts thereof.
3. A compound having the formula
Figure imgf000265_0001
wherein R is phenyl; or
Pyridyl; R' is 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; R2, R3, and R4 are independently selected from the group consisting of H; alkyl of 1 - 10 carbons; cycloalkyl of 3 - 12 carbons; alkenyl of 2 - 10 carbons; and cycloalkenyl of 5 - 12 carbons; X is O or S(O)y ; wherein y is O, l, or 2; n is 2 or 3; p is the sum of non-H substituents R2, R3, and R4;
T is a substituent selected from the group consisting of alkyl of 1 - 4 carbons; alkenyl of 2 - 4 carbons;
NO2;
CN; and halogen; t is 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; alkoxy of 1 - 4 carbons;
CO2R5; wherein
R5 is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of
3 - 6 carbons; CO2H;
C(O)N(R6)(R7); wherein
R6 is H or alkyl of 1 - 5 carbons; and
R7 is H or alkyl of 1 - 5 carbons;
CHO; OH;
NO2;
CN; halogen; S(O)yR8; wherein
R8 is alkyl of 1 - 5 carbons; and =O; 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; alkyl of 1 - 4 carbons; alkenyl of 1 - 4 carbons; 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; 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 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; 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 halogen; q is 0 - 4; and with the further provisos that: a) two of (Q)qR', (Q)qR2, (Q)qR3, and (Q)qR4 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, O, and S; b) when n = 2 or 3, at least one of R2, R3, and R4 is other than H; c) when n = 2, and X = O, 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 = O, 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; e) when n = 2 or 3 and X = O or S, then the sum of non-hydrogen atoms in R1, R2, R\ and R4 is at least 5;
and pharmaceutically acceptable salts thereof.
4. A compound of claim 1 selected from the group consisting of:
( S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-l,3- thiazolidine; ( S)-2-(2-methyl-4-nitrophenylimino)-3 ,4-diisobutyl- 1, 3-thiazolidine; (^S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(trifluoromethyl)-l,3- thiazolidine; (4S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isobutyl-l,3- thiazolidine; (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-l,3- thiazolidine;
( S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isopropyl-l,3- thiazolidine; (4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyltetrahydro-2H- 1,3-thiazine; (4S)-2-(4-nitro- 1 -naphthylimino)-3 -cyclopenty l-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-ethy Iphenyhmino)- 1 -cyclopentyl-3 -thia- 1 -azaspiro [4.4]nonane ; 2-(4-cyanophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane;
2-(4-cyano-2-methylphenylimino)-l-isobutyl-3-thia-l-azaspiro[4.4]nonane; 2-(4-cyano-2,3-dimethylphenylimino)- 1 -isobutyl-3-thia- 1 - azaspiro[4.4]nonane; 2-(4-cyano-2-methy Ipheny mino)- 1 -( 1 -ethyl- 1 -propyl)-3 -thia- 1 - 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)-l-isobutyl-3-thia-l-azaspiro[4.4]nonane; 2-(2-methyl-4-nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane; 2-(3-methyl-4-nitrophenylimino)-l-cyclopentyl-3-thia-l-azaspiro[4.4]nonane; 2-(2-methyl-4-nitrophenylimino)- 1 -cyclohexy 1-3 -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.
5. A compound of claim 1 selected from the group consisting of: 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-l,3-thiazolidin-4-one; 2-(3-methyl-4-nitrophenylimino)-3-isobutyl-l,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-benzyl-l,3-thiazolidin-4-one; 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; 2-(3 -methy l-4-nitrophenylimino)-3 -(1 -cyclohexyl- 1 -ethyl)- 1 ,3 -thiazolidin-4- one; 2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl-l-butyl)-l,3-thiazolidin-4-one; 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methylene-l,3-thiazolidin-4- one; and 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; l-cyclopentyl-2-(4-cyano-2-ethylphenylimino)-3-oxa-l-azaspiro[4.4]nonane; l-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane; and l-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-l-azaspiro[4.4]nonane.
7. A pharmaceutical composition comprising a compound of claim 1, 2, 3, 4, 5 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: Al) enhancement of bone formation in bone weakening diseases for the treatment or prevention of osteopenia or osteoporosis;
A2) enhancement of fracture healing;
B 1 ) use as a female contragestive agent; B2) prevention of endometrial implantation;
B 3 ) 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; B7) treatment of infertility, including promotion of spermatogenesis, induction of the acrosome reaction, maturation of oocytes, or in vitro fertilization of oocytes;
C 1 ) treatment of dysmenorrhea;
C2) treatment of dysfunctional uterine bleeding; 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 changes, sleep disturbance, and vaginal dryness;
C8) enhancement of female sexual receptivity and male sexual receptivity;
C9) treatment of post menopausal urinary incontinence;
CIO) improvement of sensory and motor functions;
C 11 ) improvement of short term memory; C12) alleviation of postpartum depression;
C 13) treatment of genital atrophy;
C 14) prevention of postsurgical adhesion formation;
C 15) regulation of uterine immune function;
C 16) prevention of myocardial infarction; Dl) 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 ; FI) treatment of hirsutism;
F2) inhibition of hair growth;
Gl) activity as a male contraceptive;
G2) activity as an abortifacient; and promotion of mylin repair; wherein said compound has the general formula
Figure imgf000271_0001
wherein R is aryl of 6 - 14 carbons; or heteroaryl of 3 - 10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that
R is other than benzofuran or benzothiophene; R1 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, O, and S; 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, O, and S; alkenyl of 2 - 10 carbons; cycloalkenyl of 5 - 12 carbons and containing 1 - 3 rings; or alkynyl of 3 - 10 carbons;
R2, R3, and R4 are independently selected from the group consisting of
H; 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; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5 ; wherein
R5 is alkyl of 1 - 4 carbons, haloalkyl of 1 - 4 carbons, cycloalkyl of 3 - 6 carbons, or halocycloalkyl of 3 - 6 carbons; halogen; and
=O , representing two of the groups R2, R3, and R4; X is O or S(O)y ; wherein y is 0, 1, or 2; n is 2, 3, 4, or 5; p is the sum of non-H substituents R2, R3, and R4; 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; alkoxy of 1 - 4 carbons; aryl of 6 - 10 carbons; CO2H; CO2R5; alkenyl of 2 - 4 carbons; alkynyl of2 - 4 carbons;
C(O)C6H5; C(O)N(R6)(R7) ;wherein
R6 is H or alkyl of 1 - 5 carbons; and R7 is H or alkyl of 1 - 5 carbons; S(O)y.R8 ; wherein y' is 1 or 2; and R8 is alkyl of 1 - 5 carbons; SO2F; CHO; OH;
NO2; CN; halogen; OCF3; N-oxide;
O-C(R9)2-O , the oxygens being connected to adjacent positions on R; and wherein
R9 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)C6H4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R; 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; CO2R5; alkenyl of 2 - 4 carbons; alkynyl of 2 - 4 carbons; C(O)C6H5; C(O)N(R6)(R7); S(O)y,R8
; O-C(R9)2-O , or C(O)C6H4 , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; alkoxy of 1 - 4 carbons; CO2R5; CO2H; C(O)N(R6)(R7);
CHO; OH; NO2; CN; halogen; S(O)yR8; or =O, 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;
OH;
OR5;
=O , representing two substituents G; 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, O, and S; cycloalkenyl of 5 - 7 carbons; heterocycloalkenyl of 4 - 6 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5;
C(O)N(R6)(R7); aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
NO2;
CN; S(O)yR8;
SO3R8; and
SO2N(R6)(R7); 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 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 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; 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; aryl of 6 - 10 carbons; heteroaryl of 3 - 9 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S;
CO2R5
=O , representing two substituents Q;
OH; halogen; N(R6)(R7);
S(O)yR8;
SO3R8; and
SO2N(R6)(R7); 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 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)qR2, (Q)qR3, and (Q)qR4 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, O, and S;
and pharmaceutically acceptable salts thereof.
9. The method of claim 8 wherein said mammal is a human.
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Publication number Priority date Publication date Assignee Title
WO2001015679A2 (en) * 1999-08-31 2001-03-08 Jenapharm Gmbh & Co. Kg Mesoprogestins for the treatment and prevention of benign hormone dependent gynecological disorders
WO2001019807A1 (en) * 1999-09-14 2001-03-22 Shionogi & Co., Ltd. 2-imino-1,3-thiazine derivatives
WO2001072723A1 (en) * 2000-03-28 2001-10-04 Nippon Soda Co.,Ltd. Oxa(thia)zolidine derivative and anti-inflammatory drug
WO2002020526A2 (en) * 2000-09-07 2002-03-14 Bayer Pharmaceuticals Corporation Cyclic and acyclic amidines and pharmaceutical compositions containing them for use as progesterone receptor binding agents
WO2004110978A2 (en) * 2003-06-10 2004-12-23 Smithkline Beecham Corporation 1-aminonaphthalenes as modulators of androgen, glucocorticoid, mineralocorticoid and progesterone receptors
US6916806B2 (en) 2001-03-08 2005-07-12 Shionogi & Co., Ltd. Medicinal composition containing 1,3-thiazine derivative
US7115640B2 (en) 2001-12-21 2006-10-03 X-Ceptor Therapeutics, Inc. Heterocyclic modulators of nuclear receptors
US7189751B2 (en) 2001-06-25 2007-03-13 Nippon Soda Co., Ltd. Oxa(thia)zolidine compounds, process for preparation thereof and anti-inflammatory agents
US8193252B1 (en) 1999-08-31 2012-06-05 Bayer Pharma AG Mesoprogestins (progesterone receptor modulators) for the treatment and prevention of benign hormone dependent gynecological disorders
WO2021005082A1 (en) * 2019-07-10 2021-01-14 Bayer Aktiengesellschaft Process of preparing 2-(phenylimino)-1,3-thiazolidin-4-ones
CN114957288A (en) * 2022-06-07 2022-08-30 苏州华道生物药业股份有限公司 Synthesis method of tetramisole hydrochloride

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA75339C2 (en) * 1999-08-31 2006-04-17 Schering Ag Use of mesoprogestins (progesterone receptor modulators) as pharmaceutical components for manufacture of medicament for hormone replacement therapy (hrt)
CN103382158B (en) * 2013-07-29 2015-11-18 张家港市大伟助剂有限公司 A kind of preparation method of 2-clopentylamino ethanol
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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1510015A (en) * 1966-12-05 1968-01-19 Aquitaine Petrole Preparation of imino-thiazolidines
GB1140776A (en) * 1966-09-27 1969-01-22 Bayer Ag 2-phenylimino-2-oxazolidines and their production
FR2117337A5 (en) * 1970-12-04 1972-07-21 Eastman Kodak Co Merocyanine dye sensitisers - contg basic and acidic gps for silver halide emulsions
US3737536A (en) * 1968-04-27 1973-06-05 Bayer Ag Anaesthetic compositions for and use in animals
GB1342232A (en) * 1971-07-29 1974-01-03 Bayer Ag Aryliminothiazolidines a process for their preparation and their use as acaricides
US3787575A (en) * 1970-12-17 1974-01-22 Bayer Ag N-substituted-2-arylimino-oxazolidines used as acaricides
US4079144A (en) * 1975-05-07 1978-03-14 Ciba-Geigy Corporation Phenylimino-thiazolines and their use as acaricides
DE2658138A1 (en) * 1976-12-22 1978-07-06 Bayer Ag 2-Phenyl-imino-4-hydroxy-thiazolidine derivs. - useful as ectoparasiticides, esp. against acarids
EP0055458A2 (en) * 1980-12-30 1982-07-07 Hoechst Aktiengesellschaft Thiazoline derivatives, their preparation and use and pharmaceutical preparations containing them
US4346088A (en) * 1979-07-03 1982-08-24 Hoechst Aktiengesellschaft Thiazoline derivatives
DE3505432A1 (en) * 1985-02-16 1986-08-21 Hoechst Ag, 6230 Frankfurt Crop protection agents and pesticides based on thiazolidine derivatives, novel thiazolidine derivatives, and their preparation
EP0265162A1 (en) * 1986-10-17 1988-04-27 Stauffer Chemical Company Iminooxazolidines, process of preparation and method of use
EP0270138A1 (en) * 1986-11-04 1988-06-08 Duphar International Research B.V Substituted 2-phenylimino-oxazolidine compounds having herbicidal activity
US4806653A (en) * 1986-10-17 1989-02-21 Stauffer Chemical Company Process for preparation of iminooxazolidines
WO1989004595A2 (en) * 1987-11-19 1989-06-01 The Upjohn Company Ectoparasiticides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1963193A1 (en) * 1969-12-17 1971-06-24 Bayer Ag N-substituted 2-arylimino-oxazolidines, process for their preparation and their use as ectoparasiticides

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1140776A (en) * 1966-09-27 1969-01-22 Bayer Ag 2-phenylimino-2-oxazolidines and their production
FR1510015A (en) * 1966-12-05 1968-01-19 Aquitaine Petrole Preparation of imino-thiazolidines
US3737536A (en) * 1968-04-27 1973-06-05 Bayer Ag Anaesthetic compositions for and use in animals
FR2117337A5 (en) * 1970-12-04 1972-07-21 Eastman Kodak Co Merocyanine dye sensitisers - contg basic and acidic gps for silver halide emulsions
US3787575A (en) * 1970-12-17 1974-01-22 Bayer Ag N-substituted-2-arylimino-oxazolidines used as acaricides
GB1342232A (en) * 1971-07-29 1974-01-03 Bayer Ag Aryliminothiazolidines a process for their preparation and their use as acaricides
US4079144A (en) * 1975-05-07 1978-03-14 Ciba-Geigy Corporation Phenylimino-thiazolines and their use as acaricides
DE2658138A1 (en) * 1976-12-22 1978-07-06 Bayer Ag 2-Phenyl-imino-4-hydroxy-thiazolidine derivs. - useful as ectoparasiticides, esp. against acarids
US4346088A (en) * 1979-07-03 1982-08-24 Hoechst Aktiengesellschaft Thiazoline derivatives
EP0055458A2 (en) * 1980-12-30 1982-07-07 Hoechst Aktiengesellschaft Thiazoline derivatives, their preparation and use and pharmaceutical preparations containing them
DE3505432A1 (en) * 1985-02-16 1986-08-21 Hoechst Ag, 6230 Frankfurt Crop protection agents and pesticides based on thiazolidine derivatives, novel thiazolidine derivatives, and their preparation
EP0265162A1 (en) * 1986-10-17 1988-04-27 Stauffer Chemical Company Iminooxazolidines, process of preparation and method of use
US4806653A (en) * 1986-10-17 1989-02-21 Stauffer Chemical Company Process for preparation of iminooxazolidines
EP0270138A1 (en) * 1986-11-04 1988-06-08 Duphar International Research B.V Substituted 2-phenylimino-oxazolidine compounds having herbicidal activity
WO1989004595A2 (en) * 1987-11-19 1989-06-01 The Upjohn Company Ectoparasiticides

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8193252B1 (en) 1999-08-31 2012-06-05 Bayer Pharma AG Mesoprogestins (progesterone receptor modulators) for the treatment and prevention of benign hormone dependent gynecological disorders
WO2001015679A3 (en) * 1999-08-31 2001-11-22 Jenapharm Gmbh Mesoprogestins for the treatment and prevention of benign hormone dependent gynecological disorders
EA007854B1 (en) * 1999-08-31 2007-02-27 Шеринг Акциенгезельшафт Mesoprogestins (progesterone receptor modulators) for the treatment and prevention of benign hormone dependent gynecological disorders
WO2001015679A2 (en) * 1999-08-31 2001-03-08 Jenapharm Gmbh & Co. Kg Mesoprogestins for the treatment and prevention of benign hormone dependent gynecological disorders
WO2001019807A1 (en) * 1999-09-14 2001-03-22 Shionogi & Co., Ltd. 2-imino-1,3-thiazine derivatives
EP1219612A1 (en) * 1999-09-14 2002-07-03 Shionogi & Co., Ltd. 2-imino-1,3-thiazine derivatives
EP1219612A4 (en) * 1999-09-14 2002-10-16 Shionogi & Co 2-imino-1,3-thiazine derivatives
US6818640B1 (en) 1999-09-14 2004-11-16 Shionogi & Co., Ltd. 2-imino-1,3-thiazine derivatives
US7420053B2 (en) 1999-09-14 2008-09-02 Shionogi & Co., Ltd. 2-imino-1,3-thiazine derivatives
US7183275B2 (en) 1999-09-14 2007-02-27 Shionogi Co., Ltd. 2-imino-1,3-thiazine derivatives
WO2001072723A1 (en) * 2000-03-28 2001-10-04 Nippon Soda Co.,Ltd. Oxa(thia)zolidine derivative and anti-inflammatory drug
WO2002020526A2 (en) * 2000-09-07 2002-03-14 Bayer Pharmaceuticals Corporation Cyclic and acyclic amidines and pharmaceutical compositions containing them for use as progesterone receptor binding agents
WO2002020526A3 (en) * 2000-09-07 2002-05-30 Bayer Ag Cyclic and acyclic amidines and pharmaceutical compositions containing them for use as progesterone receptor binding agents
CN1301981C (en) * 2001-03-08 2007-02-28 盐野义制药株式会社 Medicinal composition containing 1,3-thiazine derivative
US6916806B2 (en) 2001-03-08 2005-07-12 Shionogi & Co., Ltd. Medicinal composition containing 1,3-thiazine derivative
US7189751B2 (en) 2001-06-25 2007-03-13 Nippon Soda Co., Ltd. Oxa(thia)zolidine compounds, process for preparation thereof and anti-inflammatory agents
US7115640B2 (en) 2001-12-21 2006-10-03 X-Ceptor Therapeutics, Inc. Heterocyclic modulators of nuclear receptors
WO2004110978A3 (en) * 2003-06-10 2005-04-28 Smithkline Beecham Corp 1-aminonaphthalenes as modulators of androgen, glucocorticoid, mineralocorticoid and progesterone receptors
WO2004110978A2 (en) * 2003-06-10 2004-12-23 Smithkline Beecham Corporation 1-aminonaphthalenes as modulators of androgen, glucocorticoid, mineralocorticoid and progesterone receptors
WO2021005082A1 (en) * 2019-07-10 2021-01-14 Bayer Aktiengesellschaft Process of preparing 2-(phenylimino)-1,3-thiazolidin-4-ones
CN114957288A (en) * 2022-06-07 2022-08-30 苏州华道生物药业股份有限公司 Synthesis method of tetramisole hydrochloride
CN114957288B (en) * 2022-06-07 2024-02-13 苏州华道生物药业股份有限公司 Synthesis method of tetramisole hydrochloride

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