SK10032001A3 - Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents - Google Patents

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-ARYLIMINOHETEROCYCLES AND THEIR CONTENTS, FOR USE AS A RECEPTOR BETWEEN PROGESTERONE

Technical field

The present invention relates to heterocyclic pharmaceuticals, in particular 2-aryliminoheterocycles, pharmaceutical compositions containing them, and their use in modulating progesterone receptor mediated processes.

BACKGROUND OF THE INVENTION

The agent that binds to the progesterone receptor can be used in a wide variety of indications, including those listed in the paragraphs marked below with the letters:

A1) to facilitate bone formation in bone debilitating diseases, to prevent and / or treat osteopenia or osteoporosis (Manzi et al., J. Soc. Gynecol. Invest., 1, 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 (ed.), 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 a fracture healing agent;

B1) as a female contraceptive (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Heikinheimo, Clin. Pharmacokinet., 33, 7 (1997); Li et al., Adv. Contracept., 11, 285 (1995); Spitz et al., Adv. Contracept., 8, 1 (1992); Spitz et al., Annu. Rev. Pharmacol. Toxicol., 36, 47 (1996));

B2) for preventing endometrial implantation (Cadepond et al., Annu. Rev. Med., 48, 129 (1997));

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)3) for induction of labor (Heikinheimo, Clin. Pharmacokinet., 33, 7 (1997); Karalis et al., Ann. NY Acad. Sci., 771, 551 (1995)), including the situation of foetus mortus (Heikinheimo, Clin. Pharmacokinet. 33, 7 (1997), Cadepond et al., Annu Rev. Med., 48, 129 (1997);

B4) for the treatment of luteal deficiency (Pretzsh et al., Zentralbl. Gynaekol., 119 (Suppl. 2), 25 (1997); Bezer et al. In "Molecular and Cellular Aspects of Periimplantation Processes", Dey (ed.) Springer-Verlag, p. 27 (1995));

B5) to facilitate recognition and maintenance of pregnancy (Bezer et al., In "Molecular and Cellular Aspects of Periimplantation Processes," Dey (ed.), Springer-Verlag, p. 27 (1995));

B6) to prevent preeclampsia, pregnancy eclampsia and premature labor (Yallampalli et al., WO 97/34 922);

B7) for the treatment of infertility, including by aid of spermatogenesis, induction of an acrosome response, 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. Signaling, 5, 531 (1993); Cork et al., Zygote 2, 289 (1994), Meizel, Biol Reprod., 56, 569 (1997));

C1) for the treatment of dysmenorrhoea (Coli Capdevila et al., Eur. J. Contracept. Reprod. Health Line, 2, 229 (1997); Adashi et al., Keio J. Med., 44, 124 (1995));

C2) for the treatment of dysfunctional uterine bleeding (Coli Capdevila et al., Eur. J. Contracept. Reprod. Health Lare, 2, 229 (1997); Adashi et al., Keio J. Med., 44, 124 (1995)) ;

C3) for the treatment of ovarian hyperandrogynism (Schaison et al., Androg. Excess Disord. Women, 715 (1997));

C4) for the treatment of ovarian hyperaldosteronism (Adashi et al., Keio J. Med., 44, 124 (1995));

C5) for the treatment of premenstrual syndrome and / or premenstrual tension (Mortola, Curr. Opin. Endocrinol. Diabetes, 2, 483 (1995)); Adashi et al., Keio

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J. Med., 44, 124 (1995));

C6) for the treatment of perimenstrual behavioral disorders (Constant et al., Hormone Res., 40, 141 (1993));

C7) for the treatment of climacterial disorders, i. menopausal passage (Adashi et al., Keio J. Med., 44, 124 (1995)) including hot flushes (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997); Bäckstrôm et al., Ciba Found. Symp., 121, 171 (1995)), mood changes (Backström et al., Ciba Found. Symp., 121, 171 (1995)), sleep disorders (Sarrel, Int. J. Fertil. Women's Med., 42 , 78 (1997)) and vaginal mucosal drying (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997));

C8) to facilitate female sexual sensitivity (Dei et al., Eur. J. Contracept. Reprod. Health Line, 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 sensitivity (Johnson et al., "Essential Reproduction", 2nd ed., Blackwell Scientific Pub., London, p. 177 (1984));

C9) for the treatment of postmenopausal urinary incontinence (Mäkinen et al., Maturitas, 22, 233 (1995); Batra et al., J. Urology, 138, 1301 (1987));

C10) to improve sensory and motor functions (Bäckstrôm et al., Ciba Found. Symp., 121, 171 (1995));

C11) to improve short-term memory (Bäckstrôm et al., Ciba Found. Symp., 121,171 (1995));

C12) for the treatment of postpartum depression (Dalton, Practitioner, 229, 507 (1985));

C13) for the treatment of genital atrophy (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997));

C14) to prevent the formation of post-surgical adhesions (Ustun, Gynecol. Obstet. Invest., 46, 202 (1998));

C15) for regulating uterine immune function (Hansen et al., J. Reprod. Fertil., 49 (Suppl.), 69 (1995));

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C16) for the prevention of myocardial infarction (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997));

D1) for hormone replacement therapy (Casper et al., J. Soc. Gynecol. Invest., 3, 225 (1996));

E1) for the treatment of cancers, including breast cancer (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Pike et al., Endocr. - Relat. Cancer, 4, 125 (1997); cancer uterus (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 the 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 the treatment of uterine fibroids (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Adashi et al., Keio J. Med., 44, 124 (1995));

F1) for the treatment of hirsutism (Orentreich et al., US Patent No. 4,684,635; Azziz et al., J. Clin. Endocrinol. Metab., 80, 3406 (1995));

F2) for inhibiting hair growth (Houssay et al., Acta Physiol. Latinoam., 28, 11 (1978));

G1) as a male contraceptive (Hargreave et al., Int. Congr., Symp. Semin. Ser., 12, 99 (1997); Meriggiola et al., J. Androl., 18, 240 (1997));

G2) as an abortive (Michna et al., Pharm. Ztg., 141, 11 (1996)); and

H1) to facilitate myelin recovery (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 gestagens alone or in combination with estrogens are clinically indicated: for contraception (Merck Manual; Merck &

(1992); for the treatment of gastrointestinal bleeding due to arterio-venous

757 / B malformations (Merck Manual; Merck & Co. (1992)); for the treatment of recurrent metatarsal stress fractures complicated by oligiomenorrhea or amenorrhea (Merck Manual, Merck & Co. (1992); for the treatment of premenstrual syndrome (PMS, premenstrual tension; Merck Manual; Merck & Co. (1992)); for postmenopausal hormone replacement therapy ( Merck Manual; Merck & Co. (1992)) for the treatment of hot flashes and subsequent insomnia and fatigue during menopause (Merck Manual; Merck & Co. (1992)); for the treatment of dysfunctional uterine bleeding when pregnancy is not desired ( Merck Manual; Merck & Co. (1992)) and for suppressing endometriosis (Merck Manual; Merck & Co. (1992)), breast cancer (Merck Manual; Merck & Co. (1992)), endometrial cancer (Merck Manual; Merck Manual; & Co. (1992)) or Luteal Insufficiency (Merck Manual; Merck & Co. (1992)) For example, medroxyprogesterone, which is a gestagen, alone or in combination with estragons, is indicated for the prevention of osteoporosis. and / or vaginal atrophy, treatment of moderate to severe vasomotor symptoms associated with menopause, treatment of secondary amenorrhoea, treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, to prevent pregnancy or as adjunctive treatment and palliative treatment of non-operable, endometrium or kidney (Merck Manual; Merck & Co. (1998)).

SUMMARY OF THE INVENTION

The present invention provides non-steroidal 2-arylimino- and 2-heteroaryliminoheterocyclic compounds that have affinity for the progesterone receptor and thus can act as progestogens and / or antigestagens and thereby modulate progesterone receptor mediated processes.

The present invention relates to compounds of formula (I):

757 / B (Q) q R '(T) t R (Q) q R ² (Q) q R ³

0) in which:

R is aryl of 6 to 14 carbon atoms or heteroaryl of 3 to 10 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, provided that R is not benzofuran or benzothiophene,

R ¹ is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms containing 1 to 3 rings, heterocycloalkyl of 4 to 7 carbon atoms and containing 1 to 3 rings and 1 to 3 heteroatoms selected from the group consisting of N, O and S, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms and containing 1 to 3 rings or alkynyl of 3 to 10 carbon atoms,

R ² , R ³ and R ⁴ are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms, aryl of 6 to 13 carbon atoms, heteroaryl of 3-9 carbon atoms and containing 1 to 3 heteroatoms selected from among N, O and s, the group CO 2 R ⁵ wherein R ⁵ is alkyl of 1 to 4 carbon atoms, haloalkyl of (C 1 -C 4), (C 3 -C 6) cycloalkyl or (C 3 -C 6) halocycloalkyl, halogen and = O, representing two of R ² , R ³ and R ⁴ ,

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 the substituents R ^2, R ³ and R ⁴ are not a hydrogen atom,

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T is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, CO ₂ H, CO ₂ R ⁵ , alkenyl of 2 to 4 carbon atoms , (C 2 -C 4) alkynyl, C (O) C 6 H 5, C (O) N (R ⁶ ) (R ⁷ ), wherein R ⁶ is hydrogen or C 1 -C 5 alkyl and R ⁷ is hydrogen or alkyl of 1 to 5 carbon atoms, S (O) y R ⁸ , wherein y 'is 1 or 2 and R ⁸ is alkyl of 1 to 5 carbon atoms, SO 2 F, CHO, OH, NO 2, CN, halogen, OCF 3, N-oxide, OC (R ⁹ ) 2 -O, wherein the oxygen atoms are attached at adjacent positions on R and wherein R ⁹ is hydrogen, halogen or C 1 -C 4 alkyl, C (O) NHC (O), wherein the carbon atoms are attached to adjacent positions on R and C (O) C 6 H _4, wherein the carbonyl carbon and the ring carbon ortho to the carbonyl carbon is attached t is 1 to 5, provided that when the substituent moiety T is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, a CO ₂ R group ^5, alkenyl of 2-4 carbon atoms, alkynyl of 2-4 carbon atoms, C (O) C6H5l C (O) N ^{(R6) R7),} s (O) y R ^8, OC (R ⁹ ) 2-O or C (O) C 6 H 4, then T may optionally carry secondary substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CO 2 R ⁵ , CO 2 H, C groups (O) N (R ⁶ ) (R ⁷ ), CHO, OH, NO ₂ , CN, halogen, S (O) _y R ⁸ or = O, the number of said secondary substituents being 1 or 2 except for a halogen atom which can be used up to the perhalogen level,

G is a substituent selected from the group consisting of halogen, OH, OR ^5, = 0, representing two substituents G, alkyl of 1 to 4 carbon atoms, alkenyl of 1-4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, (C 3 -C 5) heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, C 5 -C 7 cycloalkenyl, C 4 -C 6 heterocycloalkenyl and 1 to 3 heteroatoms selected from the group consisting of N, O and S groups

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CO ² R ⁵ , C (O) N (R ⁶ ) (R ⁷ ), C 6 -C 10 aryl, C 3 -C 9 heteroaryl and 1 to 3 heteroatoms selected from the group consisting of N, O and S, NO2, CN, S (O) y R ^8, the group SO 3 R ^8, and a group SO 2 N (R ⁶⁾ (R ^7), q is 0-4, except halogen, which may be employed up to the perhalo level, provided that when G is C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 5 heterocycloalkyl, C 5 -C 7 cycloalkenyl or C 4 -C 6 heterocycloalkenyl then G may optionally carry secondary halogen substituents up to the perhalogen level, and when G is aryl or heteroaryl, then G may optionally carry secondary substituents independently selected from the group consisting of C 1-4 alkyl and halogen, the number of said secondary substituents v is up to 3 for the alkyl moieties and up to the perhalogen level for halogen,

Q is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms, cycloalkenyl of C 5 -C 8 aryl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, CO ₂ R ⁵ , = O, two the substituents Q, OH, halogen, N (R ⁶⁾ (R ^7), of SOyR ^8, the group SO 3 R ^8, and a group SO ₂ N (R ⁶⁾ (R ^7), q is 0 to 4, provided that when Q is aryl or heteroaryl, then Q may optionally carry secondary substituents independently selected from the group consisting of alkyl of 1 to 4 carbon atoms and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties and up to the perhalogen level for halogen and beyond assuming that:

a) two of (Q) _q R ^1, (Q) q R ² (Q) q R ^3, and (Q) _q R ⁴ may be joined and conceived together with the atom (s) to which they are attached form a spiro or a non-spiral non-aromatic ring of 3 to 8 members containing 0 to 2 heteroatoms

757 / B selected from the group consisting of N, O and S,

b) when n = 2 or 3, at least one of R ² , R ³ and R ⁴ is not hydrogen,

c) when n = 2 and X = O, if t = 1, then T is selected from the list of substituents T above, except alkyl, wherein 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, except for alkyl and alkoxy,

e) when n = 2 or 3 and X = O or S, then the sum of the non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is at least 5,

f) when n = 2, X = O, the 4-position of the 1,3-oxazolidine ring carries a carbonyl group and R carries halogen at its 2 and 4 positions, then the 5-position of the R substituent carries a hydrogen atom,

g) when n = 2 and X = O, the 4-position of the 1,3-oxazolidine ring can carry a carbonyl only if the 5-position of said ring carries at least one non-hydrogen substituent,

h) when n = 2, X = S (O) _y , the 4-position of the 1,3-thiazolidine ring carries a carbonyl group, R ¹ is substituted with a methyl group and G is a phenyl group, then said phenyl group carries a secondary substituent,

i) when n = 4, X = S and G is a CO ² R ⁵ group, then R ⁵ contains at least two carbon atoms, and pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) described above and a pharmaceutically acceptable carrier:

Due to their affinity for the progesterone receptor and their resulting ability to act as gestagens and / or antigestagens and thereby modulate progesterone-mediated processes, the compounds of the present invention, as well as certain related compounds of the prior art, are considered useful for the purposes of " BACKGROUND OF THE INVENTION.

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It should be noted that the definition of the compound set for use in the claimed method of treatment (compounds of formula (II)) is broader than the compound of formula (I) as the method of treatment may utilize certain prior art compounds that have not been previously recognized. useful for this purpose. Accordingly, the present invention further relates to a method of treating a mammal to obtain an effect of:

(A1) facilitating bone formation in bone debilitating diseases for the treatment or prevention of osteopenia or osteoporosis;

A2) facilitating fracture healing,

B1) activity as a female contraceptive,

B2) prevention of endometrial implantation,

B3) induction of labor,

B4) treatment of luteal insufficiency,

B5) facilitating the recognition and maintenance of pregnancy,

B6) reversal of preeclampsia, pregnancy eclampsia and preterm labor,

B7) treatment of infertility, including by aid of spermatogenesis, induction of acrosome reaction, oocyte maturation or in vitro fertilization of oocytes,

C1) treatment of dysmenorrhea,

C2) treatment of dysfunctional uterine bleeding,

C3) treatment of ovarian hyperandrogynism,

C4) treatment of ovarian hyperaldosteronism,

C5) relieving premenstrual syndrome and premenstrual tension,

C6) alleviation of peri-menstrual behavioral disorders,

C7) treatment of climacterial disorders, including menopausal passage, mood changes, sleep disorders and vaginal mucosal drying;

C8) facilitation of female sexual sensitivity,

C9) treatment of postmenopausal urinary incontinence,

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C10) improvement of sensory and motor functions,

C11) improving short-term memory,

C12) treatment of postpartum depression,

013) treatment of genital atrophy,

C14) prevention of post-surgical adhesions

C15) regulation of uterine immune function,

C16) prevention of myocardial infarction,

D1) hormone replacement therapy,

E1) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer, and endometrial cancer,

E2) treatment of endometriosis,

E3) treatment of uterine fibroids,

F1) treatment of hirsutism,

F2) inhibition of hair growth,

G1) activity as a male contraceptive,

G2) activity as an abortive and H1) facilitating the recovery of myelin, comprising administering to said mammal an effective amount of a compound of formula (II):

(H)

757 / B in which:

R is aryl of 6 to 14 carbon atoms or heteroaryl of 3 to 10 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, provided that R is not benzofuran or benzothiophene,

R ¹ is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms containing 1 to 3 rings, heterocycloalkyl of 4 to 7 carbon atoms and containing 1 to 3 rings and 1 to 3 heteroatoms selected from the group consisting of N, O and S, aryl of 6 to 10 carbon atoms, heteroaryl of 3 to 9 carbon atoms and containing 1 to 3 rings and 1 to 3 heteroatoms selected from the group consisting of N, O and S, alkenyl of 2 to 10 carbon atoms, cycloalkenyl (C 5 -C 12) -containing 1 to 3 rings or (C 3 -C 10) alkynyl,

3 4

R, R and R are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms, aryl of 6 up to 13 carbon atoms, heteroaryl of 3 to 9 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, CO ₂ R ⁵ , wherein R ⁵ is C 1 -C 4 alkyl, haloalkyl of 1 (C 4-C 4) cycloalkyl, (C až-C cyk) cycloalkyl or (C až-C až) halocycloalkyl, halogen and = O, representing two of R ² , R ³ and R ⁴ ,

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 the non-hydrogen substituents R ² , R ³ and R ⁴ , s represents the number of double bonds in a is 0, 1 or 2,

T is a substituent selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 6 -C 10 aryl, ΟΟ ₂ Η, CO ₂ R ⁵ , C 2 -C 4 alkenyl

757 / B carbon, C 2 -C 4 alkynyl, C (O) C ₆ H ₅ , C (O) N (R ⁶ ) (R ⁷ ), wherein R ⁶ is hydrogen or C 1 -C 5 alkyl carbon atoms and R ⁷ is hydrogen or C 1 -C 5 alkyl, S (O) _y R ⁸ , where y 'is 1 or 2 and R ⁸ is C 1 -C 5 alkyl, SO 2 F, CHO , OH, NO 2, CN, halogen, OCF 3, N-oxide, OC (R ⁹⁾ 2 O, wherein the carbon atom attached to R at adjacent positions, and wherein R ⁹ is H, halogen or alkyl C 1 -C 4 alkyl, C (O) NHC (O), wherein the carbon atom attached to R at adjacent positions, and C (O) C 6 H _4, wherein the carbonyl carbon at the ortho position of the ring is attached to R in adjacent positions, t is 1 to 5, provided that when the substituent moiety T is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, CO ₂ R ⁵ , alkenyl 2 to 4 atoms amine, C 2 -C 4 alkynyl, C (O) C 6 H 5, C (O) N (R ⁶ ) (R ⁷ ), S (O) y R ⁸ , OC (R ⁹ ) 2 -O or C (O) CeH 4, then T may optionally carry secondary substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CO 2 R ⁵ , CO 2 H, C (O) N ( R ⁶ ) (R ⁷ ), CHO, OH, NO ₂ , CN, halogen, S (O) _y R ⁸ or = O, the number of said secondary substituents being 1 or 2 except for a halogen atom which can be used up to the perhalogen level,

G is a substituent selected from the group consisting of halogen, OH, OR ^5, = 0, representing two substituents G, alkyl of 1 to 4 carbon atoms, alkenyl of 1-4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, (C 3 -C 5) heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, C 5 -C 7 cycloalkenyl, C 4 -C 6 heterocycloalkenyl and 1 to 3 heteroatoms selected from the group consisting of N, O and S, CO ² R ⁵ , C (O) N (R ⁶ ) (R ⁷ ), C 6 -C 10 aryl, C 3 -C 9 heteroaryl and 1 to 3 heteroatoms selected from the group consisting of N, O and S groups, NO 2 groups, CN groups, S (O) _y R ⁸ groups, 31,757 / B groups

SO ₃ R ⁸ and SO ₂ N (R ⁶ ) (R ⁷ ) groups, g is 0 to 4, except for halogen, which may be used up to the perhalogen level, provided that G is C 1 -C 4 alkyl , C 1 -C 4 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 5 heterocycloalkyl, C 5 -C 7 cycloalkenyl or C 4 -C 6 heterocycloalkenyl, then G may optionally carry secondary halogen substituents up to to the perhalogen level and when G is aryl or heteroaryl, then G may optionally carry secondary substituents independently selected from the group consisting of alkyl of 1 to 4 carbon atoms and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties and up to perhalogen halogen levels,

Q is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms, cycloalkenyl of C 5 -C 8 aryl, C 6 -C 10 aryl, C 3 -C 9 heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, CO ₂ R ⁵ , = O, two the substituents Q, OH, halogen, N (R ⁶⁾ (R ⁷⁾ S (O) y R ^8, the group SO 3 R ^8, and a group SO ₂ N (R ⁶⁾ (R ^7), q is 0 to 4, provided that when Q is aryl or heteroaryl, Q may optionally carry secondary substituents independently selected from the group consisting of alkyl of 1 to 4 carbon atoms and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties and up to the perhalogen level for halogen; and provided that two (Q) _q R ¹ , (Q) q R ² , (Q) q R ³ and (Q) q R ⁴ may be joined and taken together with the atom (s) to which they are attached to form a 3- to 8-membered spiro- or non-spiro-non-aromatic ring containing 0 to 2 heteroatoms selected from the group consisting of N, O and S, and pharmaceutically acceptable salts thereof.

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DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula (I) are broadly defined in the above summary. The following preferred groups are present in the compounds of formula (I):

R is preferably phenyl or pyridyl.

R ¹ is preferably alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms and containing 1 to 3 rings, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms and containing 1 to 3 rings or alkynyl of C 3 -C 10 carbon atoms. More preferably, R ¹ is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms containing 1 to 3 rings, alkenyl of 2 to 10 carbon atoms or cycloalkenyl of 5 to 12 carbon atoms and containing 1 to 3 rings.

R ^2, R ³ and R ⁴ are preferably hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkenyl having 5 to 12 carbon atoms or the group = 0, wherein the carbonyl n < 5 / 10QA represents two of the groups R, R and R. R, R and R are more preferably hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, or cycloalkenyl of 5 to 12 carbon atoms.

Preferably X is O or S (O) _y , wherein y is 0, 1 or 2.

The subscript n, representing the number of carbon atoms in the ring, is preferably 2 or 3.

The subscript p, representing the sum of non-H substituents ^R2,. R ³ and R ⁴ are preferably 1 or 2.

T is preferably a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, NO ₂ , CN and halogen. More preferably, T is alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, NO ₂ , CN or halogen.

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The subscript t, representing the number of substituents T, is 1 to 5, more preferably up to 3.

When the substituent moiety T is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms, then T may optionally carry secondary substituents preferably selected from the group consisting of (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, CO ₂ R ⁵ , CO 2 H, C (O) N (R ⁶ ) (R ⁷ ), CHO, OH, NO ₂ , CN, halogen, S (O) _y R ^8, and = O, wherein the number of said secondary substituents is 1 or 2, in addition to halogen, which may be used up to the perhalogen level.

As used herein, the term "secondary substituent" means a substituent on a substituent, not a "secondary" as used to define the degree of substitution on carbon.

As used in this application, the terms "haloalkyl" and "halocycloalkyl" are used to refer to groups that may contain halogen atoms in any number up to the perhalogen level.

G is preferably selected from the group consisting of halogen, OR ⁵ , alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, aryl of 6 to 10 and CN. G is more preferably halogen, alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms or aryl of 6 to 10 carbon atoms.

The subscript g, representing the number of substituents G, is 0 to 4, more preferably 0 to 2, except for halogen which can be used up to the perhalogen level.

Q is preferably selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms, cycloalkenyl of C 5 -C 8 carbon atoms, CO ₂ R ⁵ groups

757 / B = O, OH, halogen, N (R ⁶ ) (R ⁷ ) and S (O) _y R ⁸ . More preferably Q is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms, cycloalkenyl of 5 to 8 carbon atoms 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, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfonic 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 inorganic base acid salts, such as those containing alkali metal cations (e.g., Li ⁺ , Na ⁺ or K ⁺ ), alkaline earth metal cations (e.g., Mg ²⁺ , Ca ^2+, or Ba ²⁺ ) , ammonium cation, as well as salts of organic bases, including aliphatic and aromatic substituted ammonium and quaternary ammonium cations such as salts derived from the protonation or peralkylation of triethylamine, N, N-diethylamine, Ν, Ν-dicyclohexylamine, - pyridine, N, Ndimethy ( DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

Many of the compounds of formula (I) have asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Methods for resolving enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention encompasses any racemically or optically active forms of the compounds of formula (I) that have progesterone receptor binding activity.

757 / B

The most preferred 2-imino-1,3-thiazolidines and 2-imino-1,3-thiazolidines extended ring homologues of the invention are as follows: (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- isopropyl-1,3-thiazolidine, (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine, (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (trifluoromethyl) -1,3-thiazolidine- ₁ (4S) -2- (2-methyl-4-nitrophenylimino) -3-cyclopentyl-4-isobutyl-1,3-thiazolidine, (4S) ) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1,3-thiazolidine, (4S) -2- (2-methyl-4-nitrophenylimino) -3-cyclopentyl-4- isopropyl-1,3-thiazolidine, (4R) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyltetrahydro-2H-1,3-thiazine, (4S) -2- (4-nitro) -1-naphthylimino) -3-cyclopentyl-4 - ((1R) -1-hydroxyethyl) -1,3-thiazolidine, 2- (4-cyano-2-methylphenylimino) -1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane, 2- (4-cyanophenylimino) -1-cyclopentyl-3-thia- 1-azaspiro [4.4] nonane, 2- (4-cyano-2-methylphenyl) limino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane, 2- (4-cyano-2,3-dimethylphenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane, 2 - (4-cyano-2-methylphenylimino) -1- (1-ethyl-1-propyl) -3-thiazaspiro [4.4] nonane, 2- (4-cyano-1-naphthylimino) -1-isobutyl -3-a-1-azaspiro [4.4] nonane, 2- (2-methyl-4-nitrophenylimino) -1- (prop-2-en-1-yl) -3-thia-1-azaspiro [4.4] nonane, 2- (2-methyl-4-nitrophenylimino) -1-isopropyl-3-thia-1-azaspiro [4.4] nonane, 2- (2-methyl-4-nitrophenylimino) -1-isobutyl-3-thia- 1-azaspiro [4.4] nonane, 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane, 2- (3-methyl-4-nitrophenylimino) -1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane, 2- (2-methyl-4-nitrophenylimino) -1-cyclohexyl-3-thia-1-azaspiro [4.4] nonane, 2- (2,3-dimethyl) -4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; and

757 / B

2- (4-cyano-2,3-Dimethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonan.

The most preferred thiazolidin-4-ones of the invention are the following compounds:

2- (2-methyl-4-nitro-phenylimino) -3-isobutyl-1,3-thiazolidine-4-one,

2- (3-methyl-4-nitro-phenylimino) -3-isobutyl-1,3-thiazolidine-4-one,

2- (2-methyl-4-nitro-phenylimino) ", 3-benzyl-1,3-thiazolidin-4-one,

2- (3-methyl-4-nitro-phenylimino) -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-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-1-ethyl) -1,3-thiazolidin-4-one,

2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1,3-thiazolidin-4-one,

2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-methylene-1,3-thiazolidin-4-one; and

2- (2-methyl-4-nitro-phenylimino) -3-isobutyl-5-methyl-1,3-thiazolidin-4-one.

The most preferred oxazolidines of the invention are the following compounds:

2- (2-methyl-4-nitro-phenylimino) -3-isobutyl-4,4-dimethyl-1,3-oxazolidine,

1-cyclopentyl-2- (4-cyano-2-etylfenylimino) -3-oxa-1-azaspiro [4.4] nonane,

1-Cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane; and

-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane.

The therapeutic agents of the invention may be used alone or in conjunction with other therapies. For example, when used as in A1 or A2, the agent may be used in combination with a calcium source, vitamin D or vitamin D analogs and / or antiresorptive therapies such as estrogen replacement fluoride source therapy, calcitonin or calcitonin analog treatment, or bisphosphonate treatment, such as alendronate. When used as in B1 to

757 / B

7, the agent may be used with therapies such as estrogen replacement therapy. When used as in C1 to C16, E1 to E3 or F1 or F2, the agent may be used concurrently with therapies such as estrogen replacement therapy and / or a gonadotropin releasing hormone agonist. When used as in G1 or G2, the agent may be used concurrently with therapies such as androgen.

The method of the invention is contemplated for use in treating conditions mediated by the progesterone receptor in both humans and other mammals.

The compounds may be administered orally, dermally, parenterally, injectable, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations. The term "administered by injection" includes intravenous, intra-articular, intramuscular, subcutaneous and parenteral injections, as well as the use of infusion techniques. Dermal administration may include topical administration or transdermal administration. Together with one or more non-toxic pharmaceutically acceptable carriers, and if desired, other active ingredients may be present in one or more compounds.

Compositions intended for oral administration may be prepared according to any suitable method known in the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of solvents, sweeteners, flavors, colorants and preservatives to provide palatable compositions.

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 solvents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid, and binders, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known methods to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a delaying onset of action, such as, may be used

757 / B glyceryl monostearate or glyceryl distearate. These compounds can also be prepared in solid, rapid release form.

Oral formulations may also be presented as solid gelatin capsules in which the active ingredient is mixed with an inert solid solvent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily environment, for example, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of carrier suspensions may also be used. Such excipients are suspending agents, for example, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; the dispersing or wetting agents may be naturally occurring phosphatides, for example lecithin, or the corresponding products of alkylene oxide with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycethanol or condensation products of ethylene oxide and ethylene oxide 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. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or η-propyl, phydroxybenzoate, 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 are exemplified above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present.

757 / B

The compounds may also be in the form of non-aqueous liquid compositions, 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, solid paraffin or cetyl alcohol. Sweetening agents such as those mentioned above and flavors may be added to provide palatable compositions. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums, for example acacia, tragacanth, naturally occurring phosphatides, for example soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of 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 demulsifier, a preservative and a flavoring and coloring agent.

The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. The compositions may 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 thus melts in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.

The compounds of the invention may also be administered transdermally using procedures known to those skilled in the art (see, for example, Chien, "Transdermal Controlled Systemic Medications", Marcel Dekker, Inc., 1987;

757 / B

Lipp et al., WO 94/04157 March 3, 1994). For example, a solution or suspension of a compound of formula (I) in a suitable volatile solvent optionally containing penetration enhancers may be combined with other ingredients known to those skilled in the art, such as matrix materials and a bactericide. After sterilization, the resulting mixture can be formulated according to known procedures into dosage forms. In addition, by treating with an emulsifying agent or water, a solution or suspension of the compound of formula (I) may be formulated into a lotion or balsam.

Suitable solvents for processing the transdermal delivery system 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 is hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, and halogenated hydrocarbons.

Suitable penetration enhancers 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 aliphatic alcohols having 8 to 18 carbon atoms such as lauryl or unsaturated fatty acids or cetyl alcohol, with 8 to 18 carbon atoms such as stearic acid, esters of saturated or unsaturated fatty acids with up to 24 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl- , tert-butyl or monoglycerine esters of acetic acid, caproic acid, lauric acid, myristinic acid, stearic acid or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with up to 24 carbon atoms in total, such as diisopropyl adipate, diisobutyl adipate, diisopropyl isisate, diisopropyl isisate, diisopropyl isisate fumarate. Next

The penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas, and derivatives thereof and ethers such as dimethylisosorbide and diethylene glycol monoethyl ether. Suitable penetration enhancers may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, C8-18 saturated or unsaturated aliphatic alcohols, C8-18 saturated or unsaturated fatty acids, saturated or unsaturated fatty acid esters with 24 carbon atoms, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbon atoms, phosphatidyl derivatives, terpenes, amides, ketones, ureas and derivatives and ethers thereof.

Suitable binder materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene copolymers, and natural and synthetic gums. Cellulose ethers, derivatized polyethylenes and silicates can also be used as matrix components. Other additives such as viscous resins or oils may also be added to increase the viscosity of the matrix.

For all modes of use described herein for compounds of Formula (I), the daily dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The daily dose for injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use in 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 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.

757 / B

One skilled in the art will recognize that the particular route of administration will depend on various factors, all of which are considered routine when administered. However, it will also be anticipated that the patient's specific dosage level will depend on various factors including the activity of the specific compound used, the patient's age, the patient's body weight, the general health of the patient, the patient's gender, diet, time of administration, route of administration, excretion, combination of drugs and severity of the condition being treated, but this is not limited thereto. One skilled in the art will further recognize that the optimal course of treatment, i. the method of treatment and the number of daily doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered over a defined number of days can be determined by those of ordinary skill in the art using conventional treatment tests.

All contents of all patent applications, patents and publications cited hereinbefore and hereinafter are incorporated herein by reference.

Compounds of formula (I) may be prepared using known chemical reactions and procedures from known compounds (or starting materials which, in turn, are obtainable from known compounds) using the preparation procedures below, as well as other reactions and procedures known to one skilled in the art. . However, the following general preparation procedures are presented in order to facilitate the synthesis of the compounds of the invention, with more detailed examples being presented in the experimental section. The examples are for illustration only and are not intended or to be construed as limiting the invention.

List of abbreviations and acronyms

As used herein, the following terms have the meanings indicated: AcOH and acetic acid anhydrous

BOC tert-butoxycarbonyl

757 / B

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DIBAL diizobutylaiumíniumhydrid DME 1,2-dimethoxyethane DMF N, N-dimethylformamide DMSO dimethyl sulfoxide EtOAc acetate EtOH ethanol (100%) Et ₂ O diethyl ether Et ₃ N triethylamine KMnO ₄ potassium permanganate Magnosil ^R MgSiO ₃ . x H ₂ O mCPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling point 30 to 60 ° C) THF tetrahydrofuran TFA trifluoroacetic acid

General methods of preparation

Arylamines, arylisocyanates, arylisothiocyanates, unsymmetrical arylthioureas, arylisocyanate dichlorides and 2-aryllimino-1,3-heterocycles can be synthesized using known methodology (Katritzky et al., Comprehensive Heterocyclic Chemistry, Pergamon Press, Oxford, UK (1984), March. Advanced Organic Chemistry, 3rd Ed., John Wiley, New York (1985)). For example, arylisocyanates (2) are available from the reaction of phosgene or phosgene equivalent, such as carbonyldiimidazole, diphosgene or triphosgene, and arylisothiocyanates (3) are available from the reaction of arylamine with thiophosgene or thiophosgene equivalent, such as thiocarbonyldiimidazole (Scheme I). So many

757 / B arylisocyanates and arylisothiocyanates are commercially available. Reaction of the aryl isothiocyanate with the primary amine then provides the thiourea 4 (Hahn et al., Han Guk Nonghwa Hakhoechi, 40, 139 (1997), Dirr, US Patent No. 4,079,144, Enders, US Patent No. 4,148,799).

Scheme I

ArNH ₂ o

Jl

Cl ^ Cl

ArNCO r ¹ nh ₂

ArNCS -3 ^al N ^ N ^R HH

As shown in Scheme II, thioureas react with α-haloketones, e.g. α-bromoketone 5 to obtain, after dehydration, thiazoline 6 (Hahn et al., Han Guk Nonghwa Hakhoechi, 40, 139 (1997); DOrr, US Patent No. 4,079,144; Enders, US Patent No. 4,148 799).

Scheme II

br ·

Ar ^ ^ΑΓ '· Ν ^Λ Ν -' HH

N

Λ R ¹ with n ' ^k ' K

757 / B

Similarly, thioureas react with α-halo acid halides (Giri et al., Asian J. Chem., 4, 785 (1992); Lakhan et al., Agric. Biol. Chem., 46, 557 (1982)), α- halogen acids (Dogam et al., Spectrosc. Lett., 16, 499 (1983), Seada et al., Indian J. Heterocycl. Chem., 3, 81 (1993)) and ahalogenesters (Seada et al., Indian J. Heterocycl Chem., 3, 81 (1993)) to give 4-thiazolidinones 10.

Scheme III

Arylisothiocyanates 3 also react with allylamines (Tsoi et al., Zh. Org. Khim., 19, 2605 (1983)) and propargylamines (Azerbaev et al., Khim. Geterotsikl. Soedin., 471 (1972)) to form the corresponding thioureas. , which upon acid treatment affords the thiazolidines substituted at the 5-position (Scheme IV).

757 / B

Scheme IV

ArSCN

S S ^and A, X..A ¹ Ar ^ _{ii iiZ} R ¹

HC ^ť

NN ^H J

H *

H ⁺

Ar \ 'N

A ..

N '

R ¹

Ar \

N _with A _n

-R ¹

my

HoC

Arylisothiocyanates can also be reacted with hydroxylamines 17 to form N-hydroxyalkylthiourea 18 (Scheme V). Acid treatment of the thiourea then affords the 2-imino-1,3-heterocycle 19 (Jen et al., J. Med. Chem., 18, 90 (1975); Tyukhteneva et al., Khim. Geterotsikl. Soedin., 12, 1629 ( 1985), Olszenko-Piontkowa et al., Org. Prep. Proced. Int., 3, 27 (1971)). Reaction of the hydroxyalkylthiourea 18 with SOCl ₂ gives a chloroalkyl analog 20 which, after base treatment, cyclizes to give the heterocycle 19 (Cherbuliez et al., Helv. Chim. Acta, 50, 331 (1967); Felix et al., US Patent No. 4,806) 653).

757 / B

Scheme V

ArSCN

R ¹ NH (CH _{2) n} OH ^N 'N ^ N ^{R H} be ^Ich ">

N (CH _{2) m}

R 1 NH (CH ₂ ) _n Cl

ArSCN -—3

H ⁺

^Ar ' _N A _N .R'

H ¹ c | x (CH ₂ ) _n 20 ^ΓΓΓ

A _R <

S N ' ^r (CH ₂ ) _n , 19

Alternatively, as shown in Scheme VI, treating the N-hydroxyalkylthiourea 18 with either HgO or an alkylating agent such as methyl iodide followed by a base gives the corresponding oxygen-containing heterocycle (Jen et al., J. Med. Chem., 18, 90 (1975)) , Ignatova et al., Khim. Geterotsikl. Soedin., 354 (1974).

Scheme VI

757 / B

ArSCN

R ¹ NH (CH _{2) n} OH

WITH

Ar · or

1) Me!

2) OH *

Chloroalkyl isothiocyanates have been reported to react with arylamines to provide the corresponding sulfur-containing 2-phenylimino-1,3-heterocycles (Sagner et al., U.S. Patent No. 3,651,053, ibid. U.S. Patent No. 3,737,536).

Scheme VII

CI- (CH ₂ ) _n NCS

With NH \ - / γη

Arylamines react with a formyl source such as formic anhydride to form formanilide 25, which can then be oxidized to the aryl isocyanide dichloride (Ferchland et al., DE 3 134 134; for review, see: Kuehle et al., Angew. Chem. 79, 663 (1967)]. Arylisocyanide dichlorides 26 react with hydroxylamines 27 to provide oxygen-containing 2-phenylimino-1,3-heterocycles (Wollweber US Patent No. 3,787,575, ibid. US Patent No. 3,686,199) and with hydroxylamide 28 to provide thiazolidinone 31. Additionally, for dichlorides arylisocyanides have been shown to react with aminomerocaptans 29 to provide sulfur-containing 2-phenylimino-1,3-heterocycles (Thibault, French Patent No. 1,510,015).

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Scheme VIII

Treatment of the hydroxylamines with CS ₂ in the presence of a base will result in formation

1,3-thiaza-2-thione (Scheme IX). There has been reports that thion 34 reacts with SOCl ₂ to provide a hygroscopically labile intermediate 35 which, upon arylamine treatment, yields a sulfur-containing 2-imino-1,3-heterocycle (Hanefeld et al., Pharm. Pharm., 318, 60 (1985)) ibid., 321, 199 (1988)).

Scheme IX

ArHO HN

M

CS _{2 s} Ä _N. R 'soc, _{2 s} A _n 4''N base

M '34

U

ArNH ₂ A r SN

M

757 / B

2-Imino-1,3-heterocycles containing both oxygen and sulfur can be further processed. Thus, for example, as shown in Scheme X, treatment of 2-phenylimino-1,3-heterocycles unsubstituted with N 3 electrophiles, typically in the presence of a base, provides the N 3 -substituted product (Ambartsumova et al., Chem. Heterocycle. Compd., 33, 475). (1997); Mizrakh et al., Khim. Geterotsikl. Soedin., 563 (1990); Olszenko-Piontkowa et al., Org, Prep. Proced. Int., 3, 27 (1971)).

Scheme X

R ¹ -Y

Y = halogen ^A %

Λ _R.

X N ^R (CH _{2) n} N ^Al

Λ

X NH ^V - (CH ₂ ) _n 37

X = O or S

CO ₂ Me 39

ABOUT

Λ,

R42

N

X

X NX ^ CO ₂ Me '- (CH 2),

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In addition, as shown in Scheme XI, sulfur-containing 2-imino-1,3-heterocycles can be oxidized to sulfoxide or sulfone (Chizhevskaya and

et al., Khim. Geterotsikl. Soedin., 96 (1971); Pandey et al., J. Indian Chem. Soc. 49, 171 (1972)). Scheme XI ^X N ^{Up to} N Λνη KMnO ₄ + + Xnh ° (CH ₂ ) _n (CH ₂ ) _n the sky 46 mCPBA 47 48

Detailed experimental procedures

Detailed procedures for preparing the compounds of this invention are provided in the following detailed synthetic procedures. In the tables of compounds that follow, the synthesis of each compound is performed by reference to these exemplary preparation steps.

DETAILED DESCRIPTION OF THE INVENTION

All reactions were carried out in flame-dried glass vessels or in an oven under dry argon or dry nitrogen pressure and agitated magnetically unless otherwise indicated. Sensitive liquids and solutions are transferred via syringe or cannula and introduced into reaction vessels through rubber trays. Commercial grade reagents and solvents were used without further purification.

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Unless otherwise indicated, the term "reduced pressure evaporation" refers to the use of a Buchi rotary evaporator at a pressure of about 2 kPa. Evaporation from flask to flask is performed with an Aldrich flask flask and in these cases temperatures refer to oven temperatures. All temperatures are in degrees Celsius (° C). Unless otherwise indicated, all parts and percentages are by volume.

Thin layer chromatography (TLC) was performed on 250 µm silica gel 60A F-254 plates on Whatman ^R -coated glass. The plates are visualized by one or more of the following: (a) ultraviolet irradiation, (b) iodine vapor exposure, (c) immersing the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersing the plate in cerium sulphate solution followed by by heating and / or (e) immersing the plate in an acidic ethanol solution of 2,4-di-nitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using silica gel with a particle size of 0.038-0.065 mm EM Science ^R. Rotary chromatography is performed using pre-cast silica plates (Alltech ^R ) from Harrison Research Chromatotron.

The melting points (m.p.) were determined using a Thomas-Hoover melting point apparatus or an Mettler FP66 automatic melting point apparatus and are untreated. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Sheri spectrophotometer.

Proton ( ¹ H) nuclear magnetic resonance (NMR) spectra are measured using a General Electric GN-Omega 300 (300 MHz) spectrometer using either Me4Si (δ 0.00) or residual protonated solvent (CHCl 3 δ 7.26; MeOH δ 3 , 30; DMSO δ 2.49) as standard. Carbon ( ¹³ C) NMR spectra are measured using a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl 3 δ 77.0; MeOD-d ₃ ; δ 49.0; DMSO-d ₆ δ 39.5) as standard.

757 / B

Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) are obtained as electron impact (EI), chemical ionization (Cl), or atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained using a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source is maintained at 250 ° C. Electron impact ionization is carried out with an electron energy of 70 eV and a capture current of 300 μΑ. Liquid cesium secondary ion mass spectra (FABMS), a newer version of fast atom bombardment, were obtained using a Kratos Concept 1H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reaction gas (1.33 x 10 ^-2 to 3.33 x 10 ^-4 Pa). Direct insertion desorption chemical ionization (DCI) probe (Vacumetrics, Inc.) is activated with 0 to 1.5 amps for 10 seconds and maintained at 10 amps until all traces of the sample have evaporated (approximately 1-2 minutes). Spectra are scanned from 50 to 800 amu in 2 seconds 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 capture mass spectrometer with electrospray ionization. Spectra are scanned from 120 to 800 amu using variable ion time according to the number of ions in the source. Gas chromatographic-ion selective mass spectra (GC-MS) were obtained using a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 mx 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization ionization). energy 70 eV).

Elemental analyzes were performed by Robertson Microlit Labs, Madison

NJ. NMR spectra, LRMS, elemental analyzes, and HRMS of the compounds were consistent with the assigned structures.

757 / B

Examples of the preparation of the compounds of this invention are provided in the following detailed synthetic procedures. In the tables of compounds that follow, the synthesis of each compound is performed by reference to these exemplary preparation steps.

A. Synthesis of imine precursors

A1a. General method for the synthesis of anilines from nitrobenzenes. Synthesis of 4-cyano-2-methylaniline.

NC

4-Cyano-2-methylaniline is synthesized as described above (J. Med. Chem., 34, 3295 (1991)). To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.34 mmol) in acetic acid (20 L) was added dropwise a solution of SnCl ₂ (9.6 g, 49.38 mmol) in concentrated hydrochloric acid ( 20 ml). After stirring for 3 hours, the mixture was carefully added to saturated ammonium hydroxide solution (120 mL) at 0 ° C. The resulting mixture was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc / hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92%).

TLC (30% EtOAc in hexane) R _f 0.23.

This material was used without further purification.

757 / B

2a. General method for the synthesis of isothiocyanates. Synthesis of 4-nitro-2-n-propylisothiocyanate.

Step 1

To a solution of 2-n-propylaniline (8.91 g, 66 mmol) and triethylamine (14 mL, 106 mmol) in dichloromethane (60 mL) was added dropwise acetic anhydride (10.9 mL, 99 mmol). The resulting mixture was allowed to stir at room temperature overnight and then treated with 1N hydrochloric acid solution (40 mL). The acidic mixture was extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed successively with water (40 mL), 1N sodium hydroxide solution (40 mL), water (40 mL) and saturated sodium chloride solution (40 mL), dried (sodium sulfate) and evaporated under reduced pressure. The resulting powder was purified by crystallization (EtOAc) to give 2-n-propyl acetanilide as white needles (7.85 g, 67%). TLC (30% EtOAc / hex) R _f 0.37.

NH ₂

757 / B

Step 2

To a solution of 2-n-propyl acetanilide (1.15 g, 6.50 mmol) in trifluoroacetic acid (20 mL) at -5 ° C was added sodium nitrite (0.55 g, 6.50 mmol). The mixture was allowed to stir at -5 ° C for 3 hours, then treated with water (30 mL). The resulting aqueous solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with 1N sodium hydroxide solution (30 ml), water (30 ml) and saturated sodium chloride solution (40 ml), dried (sodium sulfate) and evaporated under reduced pressure. The residue was dissolved in concentrated hydrochloric acid solution (30 mL) and heated at 100 ° C overnight. The resulting mixture was cooled to 0 ° C with an ice bath, then the pH was carefully adjusted to 10 with 50% sodium hydroxide solution. The basic mixture was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed successively with water (30 mL) and saturated sodium chloride solution (40 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc / hex) to give 2-n-propyl-4-nitroacetanilide as a yellow solid (0.56 g, 48%):

TLC (20% EtOAc / hex) R _f 0.47.

Ο, Ν

Step 3

To a solution of 2-n-propyl-4-nitroacetanilide (0.56 g, 0.31 mmol) in toluene (30 mL) was added dropwise thiophosgene (0.24 mL, 0.31 mmol). The mixture was heated at reflux overnight, then cooled to room temperature and evaporated under reduced pressure. The residue is purified by flash chromatography (1%).

757 / B

EtOAc / hex) to give 2-propyl-4-nitrophenylisothiocyanate as a yellow oil (0.65 g, 95%).

TLC (20% EtOAc / hex) _Rf 0.82.

A2B. General method for the synthesis of isothiocyanates. Synthesis of 4-cyano-2-ethylphenylisothiocyanate.

CN

et

C

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 using a syringe. A viscous suspension is formed over 5 minutes. The reaction mixture was heated to reflux and viscosity decreased. The reaction mixture was heated to reflux for 5 hours then allowed to cool to room temperature. The resulting mixture was evaporated under reduced pressure and the residue was treated with dichloromethane (600 mL) and evaporated under reduced pressure to give 4-cyano-2-ethylphenylisothiocyanate as a light brown crystalline solid (98 g, 100%).

¹ H NMR (DMSO-d 6): δ 1.18 (t, J = 7.4 Hz, 3H), 2.69 (q, J = 7.4 Hz, 2H), 7.55 (d, J = 7.0 Hz, 1H), 7.75 (d, J = 7.0 Hz, 2H), 7.84 (s, 1H).

MS (CI-MS) m / z 189 ((M + H) &lt; ^{+ &gt;} ).

A2c. General method for the synthesis of isothiocyanates. Synthesis of 2,4-dimethyl-3-cyano-5-pyridylisothiocyanate.

757 / B

Me

NC

,WITH

A suspension of 6-amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0.68 mmol) in dichloromethane (1 mL) was added to a vigorously stirred mixture of calcium carbonate (0.41 g, 4.11 mmol). in 1: 2 water: dichloromethane (9 mL total) at room temperature. 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 temperature and stirred overnight. The resulting aqueous layer was back-extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with water (10 mL), dried (magnesium sulfate) and evaporated under reduced pressure. The residue was purified by chromatography (silica, 10% EtOAc / hex) to give 2,4-dimethyl-3-cyano-6-pyridylisothiocyanate (0.12 g, 91%).

CI-MS m / z 190 ((M + H) &lt; ^{+ &gt;} ).

A2d. General method for the synthesis of isothiocyanates. Synthesis of 2,3-dimethyl-4-nitrophenylisothiocyanate.

Me, S

757 / B

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 stirred overnight heated to reflux. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography (25% CH ₂ Cl ₂ / hex) to give 2,3-dimethyl-4-nitrophenylisothiocyanate as a pale yellow solid (0.30 g, 48%).

¹ H NMR (CDCl ₃ ) δ 2.39 (s, 3H), 2.41 (s, 3H), 7.20 (d, J = 8.4 Hz, 1H).

CI-MS m / z 200 ((M + H) &lt; ^{+ &gt;} ).

A2E. General method for the synthesis of isothiocyanates. Synthesis of 2,3-dimethyl-6-nitrophenylisothiocyanate.

To a solution of 2,3-dimethyl-6-nitroaniline (3.0 g, 1.0 equiv) in toluene (150, 25 mL) was added thiophosgene (2.5 mL, 1.8 equiv) and the reaction mixture was stirred at room temperature. Heat to reflux overnight. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography (10% CH ₂ Cl ₂ / hex) to give 2,3-dimethyl-6-nitrophenyl isothiocyanate as a pale yellow solid (3.63 g, 95%).

¹ H NMR (CDCl 3) δ 2.39 (s, 3H), 2.40 (s, 3H), 7.17 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8) (7 Hz, 1H).

757 / B

A3a. General method for the synthesis of arylisonitrile dichlorides. Synthesis of 4-cyano-2-ethyl-phenyl-isocyanide dichloride.

NC.

et

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 hours . After the reaction mixture was cooled to room temperature, a solution of 4-amino-3-ethylbenzonitrile (140 g, 0.96 mol) in anhydrous tetrahydrofuran (700 mL) was added at a rate such that the reaction temperature did not exceed 45 ° C (approx. min). When the resulting solution was cooled to room temperature, evaporated under reduced pressure, treated with 100% ethanol (600 mL) and re-evaporated under reduced pressure to give 4-cyano-2-ethylformanilide as a light brown solid (167 g, 100%).

¹ H NMR (CDCl ₃ ) δ 1.13 (t, J = 7.3 Hz, 3H), 2.48 (q, J = 7.3 Hz, 2H), 7.65 (d, J = 8, 5 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H), 9.89 (broad s, 1H).

NC

et

757 / B

Step 2

To a solution of 4-cyano-2-ethylformanilide (167 g, 0.96 mol, 1.0 equiv) in SOCl ₂ (525 mL, 6.05 mol, 6.3 equiv) was cooled to 0 ° C using an ice bath, sulfuryl chloride (112 mL, 1.4 mol, 1.4 equiv) was added via syringe. Remove the cooling bath and heat the reaction at 50 ° C overnight. The resulting mixture was evaporated under reduced pressure, treated with dichloromethane (600 mL) and re-evaporated under reduced pressure. Dissolve the residue in diethyl ether (800 mL) and filter through a pad of Magnosil ^R to give 4-cyano-2-ethylphenylisocyanide dichloride as an oil (210 g, 96%).

¹ H NMR (CDCl 3) δ 1.13 (t, J = 7.3 Hz, 3H), 2.49 (q, J = 7.3 Hz, 2H), 7.15 (d, J = 8.2 Hz, 1H), 8.35-8.40 (m, 2H).

3b. General method for the synthesis of arylisonitrile dichlorides. Synthesis of 2-methyl-4-nitrophenylisocyanide dichloride.

Step 1

Acetic anhydride (400 mL, 4.26 mol, 2.6 equiv) was added to formic acid (200 mL, 5.25 mol, 3.2 equiv) and the resulting solution was heated to 60 ° C 2, 25 hours. After cooling to room temperature, a solution was added

Of 2-methyl-4-nitroaniline (152 g, 1.64 mol, 1.0 equiv) in anhydrous tetrahydrofuran (1.2 L) at a rate such that the reaction temperature does not exceed 45 ° C (approximately 30 ° C).

757 / B minutes). When the resulting solution was cooled to room temperature, it was evaporated under reduced pressure to half its volume and the reaction product was removed by filtration to give 2-methyl-4-nitropormanilide as a pale brown solid (295 g, 100%).

¹ H NMR (CDCl ₃ ) δ 2.31 (s, 3H), 8.03 (m, 2H), 8.24 (d, J = 8.8 Hz, 1H), 8.39 (broad s, 1H 9.94 (broad s, 1H).

Step 2

SOCl 3 (525 mL, 6.05 mol, 6.3 equiv) was added to 2-methyl-4-nitropormanilide (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 to 60 ° C for 4 hours then allowed to cool to room temperature overnight. The reaction mixture was evaporated to half volume under reduced pressure and the resulting suspension was filtered. The solids were washed with 50% Et ₂ O / hex solution to give 2-methyl-4-nitrophenylisocyanide dichloride as a yellow solid (323 g, 85%).

¹ H NMR (CDCl 3) δ 2.19 (s, 3H), 7.20 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8 2 (s, 1 H).

A4a. General method for the synthesis of nitroanilines from anilines. Synthesis of 2,3-dimethyl-6-nitroaniline and 2,3-dimethyl-4-nitroaniline.

757 / B

N Me H

Step 1

To a solution of 2,3-dimethylaniline (1.1 mL, 1.00 equiv) and triethylamine (1.5 mL,

1.30 equiv.) In dichloromethane (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 temperature then. The reaction was quenched with 2N hydrochloric acid (10 mL) and dichloromethane (25 mL). The resulting mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with 2N hydrochloric acid solution (2 x 25 mL), water (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL) and saturated sodium chloride solution (2 x 25 mL), dried (sodium sulfate) ) and evaporated under reduced pressure to give 2,3-dimethylacetanilide as a white solid (1.25 g, 93%).

¹ H NMR (CDCl 3) δ 2.05 (s, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 6.95 (d, J = 7.5 Hz,

H), 7.02 (apparent t, J = 7.5 Hz, 1H), 7.35 (d, J = 6.9 Hz, 1H).

Me

Me

NO ₂

N Me H

757 / B

Step 2

To a solution of 2,3-dimethylacetanilide (14.0 g, 1.0 equiv) in concentrated sulfuric acid (35 mL) at 0 ° C was added nitric acid (5.1 mL, 1.25 equiv) over 30 min. .). The resulting mixture was allowed to stir at room temperature for 15 minutes, then treated with ice water (500 mL) to form a yellow precipitate. The solids were removed and washed with water to give a 1 L mixture of 2,3-dimethyl-6-nitroacetanilide and 2,3-dimethyl-4-nitroacetanilide (16.0 g, 90%).

¹ H NMR (CDCl ₃ ) 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 (broad s, 1H), 7.15 (d, J = 8.7 Hz, 0.5H), 7.63 (d, J = 8) 7 Hz, 0.5H), 7.76 (d, J = 8.1 Hz, 1H).

This mixture was used in the next step without further purification.

Me

Me

NO _Z

Me NH ₂ NH ₂

Step 3

To a solution of the nitroacetanilide mixture (16.0 g, 1.0 equiv) was added 60% sulfuric acid solution (150 mL). The solution was refluxed for 1 hour, then cooled to room temperature and treated with 2N sodium hydroxide solution in ice water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (2 x 50 mL) and saturated sodium chloride solution (2 x 50 mL), dried (sodium sulfate) and evaporated under reduced pressure.

757 / B pressure. The residue was purified by column chromatography (10% CH ₂ Cl ₂ / hex) to give 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%):

¹ H NMR (CDCl ₃ ) δ 2.05 (s, 3H), 2.20 (s, 3H), 6.15 (broad s, 2H), 6.45 (d, J = 8.7 Hz, 1H ), 7.63 (d, J = 9.0 Hz, 1H), ¹ H NMR (DMSO-d ₆ ) δ 2.10 (s, 3H), 2.30 (s, 3H), 6.50 ( d, J = 8.7 Hz, 1H), 7.15 (broad s, 2H), 7.75 (d, J = 9.0 Hz, 1H).

2.3-Dimethyl-4-nitroaniline:

¹ H NMR (CDCl 3) δ 2.10 (s, 3H), 2.45 (s, 3H), 4.05 (broad s, 2H), 6.45 (d, J = 9.0 Hz, 1H) 7.65 (d, J = 8.7 Hz, 1H). ¹ H NMR (DMSO-d ₆ ) δ 2.00 (s, 3H), 2.35 (s, 3H), 6.12 (broad) s, 2H), 6.53 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H).

And 5a. General method for the synthesis of iodoanilines. Synthesis of 4-iodo-2-n-propylaniline.

NH,

To a solution of 2-n-propylaniline in methanol (25 mL) was added a solution of sodium bicarbonate (5.0 g, 59.5 mmol) in water (25 mL). Iodine (8.4 g, 33.3 mmol) was added portionwise over 70 minutes while maintaining the temperature at 10 ° C, then allowed to stir at 10 ° C for 30 minutes. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (4 x 40 mL). The combined organic layers were sequentially washed with 5% Na ₂ S ₂ O _{3 solution} (30 mL) and saturated sodium bicarbonate solution (30 mL), dried (sodium sulfate) and evaporated under reduced pressure to give 4-iodo-2-n-propylaniline (9.4

757 (B g, 98%).

TLC (20% EtOAc / hex) R _f 0.43.

This material was used in the next step without further purification.

B. Methods for Preparation of 2-Imino-Heterocyclic Precursors

B1a. General method of synthesis of ethanolamines by reduction of amino acid derivatives. Synthesis of 1-amino-1- (hydroxymethyl) -cyclohexane.

ABOUT

Step 1

To a solution of 1-aminocyclohexane-1-carboxylic acid (10.0 g, 70.0 mmol) in 1M sodium hydroxide solution (100 mL) was added benzyl chloroformate (12.0 mL, 84.0 mmol). The reaction mixture was stirred for 2 hours while maintaining the pH at 9 by adding 1M sodium hydroxide solution as needed. The resulting solution was washed with diethyl ether (2 x 100 mL), then the pH of the aqueous layer was adjusted to 0 with concentrated hydrochloric acid solution and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried (magnesium sulfate) and evaporated under reduced pressure to give (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid (17.3 g, 89%).

TLC (25% EtOAc / hex) _Rf 0.07.

757 / B

Step 2

To a solution of 1- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid (4.16 g, 15.0 mmol) and N-methylmorpholine (1.81 mL, 16.5 mmol) in 1,2-dimethoxyethane (15 mL) at 4 Isobutyl chloroformate (2.14 mL, 16.5 mmol) was added slowly at 0 ° C and the reaction stirred for 5 minutes then filtered into a pre-cooled (4 ° C) flask. Add sodium borohydride (0.85 g, 22.5 mmol) in water (7 mL) followed immediately by water (500 mL). The reaction mixture was then warmed to 20 ° C and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane and evaporated under reduced pressure to give 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) cyclohexane (4.0 g, 100%).

TLC (25% EtOAc / hex) R _f 0.11.

Ό

Step 3

A suspension of 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) cyclohexane (4.0 g, 15 mmol) and 10% Pd / C (0.40 g) in methanol (75 mL) was stirred under a hydrogen atmosphere (101.3 kPa). 1 hour, then worked up through Celite. The resulting mixture was filtered and evaporated under reduced pressure to give 1-amino-131,757 / B (hydroxymethyl) cyclohexane.

B1b. General method of synthesis of ethanolamines by reduction of amino acid derivatives. Synthesis of (1S) -1- (hydroxymethyl) -3-methylbutylamine.

_NH2 MeO

HCl

Step 1

To a suspension of (L) -leucine (315 g, 2.4 mol) in methanol (3.2 L) at -15 ° C was added dropwise SOCl ₂ (315 mL, 4.32 mol, 1.8 equiv.). ) at a rate such that the temperature of the reaction mixture does not exceed 5 ° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was evaporated under reduced pressure, diethyl ether (3 L) was slowly added to the residue to form a precipitate. The mixture is cooled with an ice bath, then treated relatively quickly with additional methanol (3 L). After 1 hour at 0 ° C, the crystals were collected and dried to give the (L) -leucine methyl ester hydrochloride salt as a white crystalline solid (394 g, 86%).

MP: Mp 147-149 ° C.

¹ H-NMR (CD 3 OD) δ 0.78-0.98 (m, 6H), 1.58-1.72 (m, 3H), 3.76 (s, 3H), 3.92 (t, J = 7.3 Hz, 1H).

HO NH ₂

757 / B

Step 2

To a mixture of (L) -leucine methyl ester hydrochloride (254 g, 1.4 mol) sodium bicarbonate (118 g, 1.4 mol, 1.0 equiv) and water (1.8 L) in ethanol (1.8 I) NaBH ₄ (159 g, 4.2 mol, 3.0 equiv) was added portionwise at 5 ° C at a rate such that the reaction temperature did not exceed 15 ° C (about 70 minutes). After the addition of NaBH ₄ was complete, the ice bath was removed and the reaction mixture was heated to reflux overnight. The resulting mixture was cooled to room temperature using an ice bath. The resulting suspension was filtered and the solids were washed with ethanol (750 mL). The combined organic filtrates were evaporated to a volume of approximately 950 ml under reduced pressure. The residue was diluted with ethyl acetate (2.5 L) and extracted with 1N sodium hydroxide solution (2 x 1 L). The aqueous layer was re-extracted with ethyl acetate (2 x 750 mL). The combined organic layers were dried (magnesium sulfate) and evaporated under reduced pressure to give (1S) -1 (hydroxymethyl) -3-methylbutylamine as a pale yellow oil (112 g, 65%).

¹ H-NMR (CDCl ₃ ) δ 0.88 - 0.93 (m, 6H), 1.17 (t, J = 7.7 Hz, 2H), 1.68 - 1.80 (m, 2H) 1.82 (broad s, 2H), 2.86-2.91 (m, 1H), 3.22 (dd, J = 10.7, 8.1 Hz, 1H), 3.56 (dd, J = 10.3, 3.6 Hz, 1H).

B1C. General method of synthesis of ethanolamines by reduction of amino acid derivatives. Synthesis of 1-hydroxymethylcyclopentanamine.

HCl

31757 / B

Step 1

To a suspension of 1-aminocyclopentanecarboxylic acid (675 g, 5.23 mol, 1.0 equiv) in methanol (6.5 L) maintained at -15 ° C using an ice / methanol bath was added SOCl 2 (687) dropwise. mL, 9.4 mol, 1.8 equiv) at a rate such that the reaction temperature did not exceed 7 ° C. After the addition was complete, the cooling was removed, the reaction mixture was allowed to stir overnight at room temperature, then evaporated under reduced pressure. The residue was treated with dichloromethane (1 L) and evaporated under reduced pressure to give methyl [1-aminocyclopentanecarboxylate hydrochloride salt] as a white solid (938 g, 100%).

¹ H-NMR (CD 3 OD) δ 1.87-1.94 (m, 8H), 3.83 (s, 3H).

¹ H-NMR (DMSO-d 6) 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 (broad s, 3H).

This material was used in the next step without further purification.

HO nh ₂

Step 2

A solution of methyl [1-aminocyclopentanecarboxylate] hydrochloride (310 g, 1.73 mol) in a solution of ethanol (12.5 L) and water (2.5 L) was treated with sodium bicarbonate (145 g, 1.73 mol, 1 L). , 0 equiv.). The resulting mixture was then cooled to 5 ° C with an ice bath and NaBH ₄ (196 g, 5.2 mol, 3.0 equiv.) Was added portionwise at a rate such that the reaction temperature did not exceed 15 ° C (about 75 minutes). . After the addition of NaBH ₄ was complete, the ice bath was removed and the reaction mixture was heated at room temperature overnight

757 / B reflux, cool to room temperature with an ice bath and filter. The resulting solids were washed with ethanol (750 mL) and the combined filtrates were evaporated under reduced pressure. The resulting suspension was then treated with ethyl acetate (2.5 L). The organic layer was washed with 1N sodium hydroxide solution (2 x 750 mL) and the aqueous layer was back extracted with ethyl acetate (2 x 500 mL). The combined organic layers were dried (magnesium sulfate) and evaporated under reduced pressure to give 1-hydroxymethylcyclopentanamine as a low melting wax (169 g, 85%).

¹ H-NMR (CDCl ₃ ) δ 1.38-1.44 (m, 2H), 1.58-1.69 (m, 4H), 1.70-1.84 (m, 2H), 2, 11 (broad s, 3H), 3.36 (s, 2H).

CI-MS m / z 116 ((M + H) &lt; ^{+ &gt;} ).

B2a. General method for alkylation of ethanolamines by substitution reactions. Synthesis of 2- (isobutylamino) -2- (hydroxymethyl) norborane.

NH OH

The 2-aminonorbornane-2-carboxylic acid is converted to 2-amino-2 (hydroxymethyl) norborane as a diastereomeric mixture in a manner analogous to Method B1a. A solution of the amino alcohol (0.31 g, 2.16 mmol) and isobutyl bromide (0.23 mL, 2.16 mol) in N, N-dimethylformamide (3 mL) was heated at 90 ° C for 92 hours, then cooled to room temperature and partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (100 mL). The organic layer was washed with saturated sodium chloride solution (50 mL), dried (magnesium sulfate) and evaporated under reduced pressure to afford (isobutylamino) -2 (hydroxymethyl) norborane as a diastereomeric mixture (0.24 g, 55%).

GC-MS m / z 197 (M &lt; ^{+ &gt;} ).

757 / B

B2b. General method of N-alkylation of ethanolamines by substitution reactions. Synthesis of N-hydroxyethyl-N-cyclohex-1-enyl-methylamine.

'OH

Step 1

To a stirred solution of methyl [cyclohex-1-enecarboxylate] (4.56 g, 32 mmol) in tetrahydrofuran (100 mL) at -78 ° C was added dropwise DIBAL (1M in tetrahydrofuran, 130 mmol, 130 mL). The mixture was allowed to stir at -78 ° C for 4 hours and then treated with saturated sodium bicarbonate solution (40 mL). The aqueous layer was extracted with ethyl acetate (4 x 20 mL), and the combined organic layers were washed with water (40 mL) and brine (40 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residual cyclohex-1-enylmethanol is used directly in the next step without purification.

TLC (30% EtOAc / hex) R _f 0.44.

br

757 / B

Step 2

To a solution of cyclohex-1-enylmethanol (3.58 g, 32 mmol) in dichloromethane (40 mL) at 0 ° C was added Pph ₃ (36 mmol, 9.39 g) and CBr ₄ (39 mmol, 12.96). g). The mixture was allowed to stir overnight at room temperature and then evaporated under reduced pressure. The residue was diluted with pentane (60 mL) and filtered. The filtrate was evaporated under reduced pressure and purified by column chromatography (5% EtOAc / hex) to give 1-bromomethyl-1-cyclohexene as an oil (3.25 g, 57% over two steps).

TLC (30% EtOAc / hex) R _f 0.91.

Step 3

A solution of 1-bromomethyl-1-cyclohexene (3.25 g) and 2-aminoethanol (6 ml) in trichlorethylene (40 ml) was heated at reflux for 3 days, cooled to room temperature and diluted with 1N sodium hydroxide solution (30 ml). ml). The aqueous layer was extracted with dichloromethane (4 x 20 mL) and the combined organic layers were washed with water (30 mL) and brine (30 mL), dried (sodium sulfate) and evaporated 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%).

Boiling point 92-94 ° C.

B3a. General method of N-alkylation of ethanolamines by reductive alkylation. Synthesis of (R) -N-isobutylserine hydrochloride salt.

757 / B

HO HN

HCl

CQ ₂ Me

To a suspension of (D) -serine methyl ester hydrochloride 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 temperature for 24 hours, then partitioned between diethyl ether (100 mL) and saturated sodium bicarbonate solution (100 mL). The organic layer was washed with saturated sodium bicarbonate solution (3 x 100 mL), dried (magnesium sulfate) and treated with 1M hydrochloric acid in ether (25 mL). The resulting mixture was evaporated under reduced pressure to give the hydrochloride salt of (R) -N-isobutylserine methyl ester (2.27 g, 79%).

Δ-NMR (DMSO-d ₆ ) δ 0.94 (dd, J = 6.7, 3.0 Hz, 6H), 1.97-2.11 (m, 1H), 2.76 2.91 ( m, 1H), 3.76 (s, 3H), 3.86 (dd, J = 12.1, 4.1 Hz, 1H), 3.99 (dd, J = 12.4,

3.2 Hz, 1H), 4.13-4.21 (m, 1H).

B4A. General method of N-alkylation of ethanolamines by formation of 2-alkyl-1,3-oxazolidine followed by reduction. Synthesis of 1- (cyclohexylamino) -1 (hydroxymethyl) cyclopentane.

757 / B

Step 1

To a solution of 1-amino-1- (hydroxymethyl) cyclopentane (Method B1c; 1.44 g, 12.54 mmol) in dichloromethane (10 mL) at 4 ° C was added trifluoroacetic acid (0.097 mL, 1.25 mmol). , cyclohexanone (1.30 mL, 12.54 mmol) and sodium sulfate (2 g), and the reaction mixture was warmed to 20 ° C. The reaction mixture was stirred for 72 hours and washed successively with water (10 mL) and saturated sodium bicarbonate solution (20 mL), dried (magnesium sulfate) and evaporated under reduced pressure to give 14-aza-7-oxadispiro [4.2.5.1] tetradecane (2.38 g, 97%).

GC-MS m / z 195 (MH +).

HO HN

IN.

Step 2

To a solution of LiAlH ₄ (0.93 g, 24.4 mmol) and AlCl ₃ (3.24 g, 24.4 mmol) in tetrahydrofuran at 4 ° C is added dropwise a solution of 14-aza-7-oxadispiro [4.2.5.1 ] tetradecane (2.38 g, 12.2 mmol) in tetrahydrofuran (15 mL). The resulting mixture was warmed to 20 ° C and stirred for 45 minutes then cooled to 4 ° C. Water (5 mL) was slowly added to quench the reaction and 1N sodium hydroxide solution (85 mL) was added to dissolve the resulting solids. The resulting solution was extracted with diethyl ether (200 mL). The organic layer was dried (sodium sulfate) and evaporated under reduced pressure to give 1- (cyclohexylamino) -1 (hydroxymethyl) cyclopentane (1.89 g, 79%).

GC-MS m / z 197 (M &lt; ^{+ &gt;} ).

757 / B

B4B. General method of N-alkylation of ethanolamines by formation of 2-alkyl-1,3-oxazolidine followed by reduction. Synthesis of N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine.

Q NH

Step 1

A mixture of 2-amino-2-methyl-1-propanol (15.0 g, 0.168 mol), cyclopentanone (14.9 mL, 0.168 mol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol, 0.05 equiv.) In toluene (300 mL) was stirred at reflux overnight. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (500 mL), then washed with saturated sodium bicarbonate solution (250 mL), dried (sodium sulfate) and evaporated under reduced pressure to give 4-aza-3,3-dimethyl-1. -oxaspiro [4.4] nonane as a light yellow oil (15.5 g, 60%).

¹ H NMR (CDCl ₃ ) δ 1.12 (s, 6H), 1.65 (m, 5H), 1.80 (m, 2H), 1.97 (m, 2H), 3.45 (s, 2H).

757 / B

Step 2

To a solution of 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane (15.5 g, 0.10 mol) in ethanol (85 mL) at 0 ° C was then added NaBH ₄ (5.47 g, 0.145 mol, 1.45 equiv) at a rate such that the reaction temperature did not exceed 10 ° C (about 1 hour). The reaction mixture was then allowed to warm to room temperature and stirred for 18 hours. The resulting mixture was treated with water (100 mL) and evaporated to a paste under reduced pressure. Methanol (100 mL) was added and the mixture was re-evaporated under reduced pressure. The residue was treated with ethyl acetate (300 mL) and water (150 mL). The organic layer was dried (sodium sulfate) and evaporated under reduced pressure to give N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine as a pale yellow oil (13.0 g, 83%).

¹ H NMR (CDCl 3) δ 1.07 (s, 6H), 1.24 (m, 3H), 1.50 (m, 2H), 1.65 (m, 2H), 1.87 (m, 2H) ), 3.0 (m, 1H), 3.22 (s, 2H).

CI-MS m / z 158 (M + H) &lt; ^{+ &gt;} ).

B4c. General method of N-alkylation of ethanolamines by formation of 2-alkyl-1,3-oxazolidine followed by reduction. Synthesis of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol.

About NH

Step 1

A solution of (1S) -1- (hydroxymethyl) -3-methylbutylamine (method B1b; 152 g, 1.3 mol) and isobutyraldehyde (118 mL, 1.3 mol, 1.0 equiv) in toluene (1.5 L) ) is heated to reflux while in a Dean-Stark trap

757 / B does not collect the theoretical amount of water (23.4 mL). The reaction mixture was evaporated by distillation to a volume of approximately 700 ml. The resulting mixture was cooled to room temperature and evaporated under reduced pressure to constant weight to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine as a pale yellow oil (223 g, 100%).

¹ H NMR (CDCl ₃ ) δ 0.88-0.99 (m, 12H), 1.18-1.35 (m, 1H), 1.42-1.56 (m, 1H), 1.61 1.79 (m, 4H), 3.08 (t, J = 7.4Hz, 1H), 3.20-3.34 (m, 1H), 3.85 (t, J = 7.4 Hz, 1H), 4.18 (dd, J = 7.3, 3.4 Hz, 1H).

Step 2

To a solution of (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine (223 g, 1.3 mol) in ethanol (1.1 L) cooled to -13 ° C using an ice / methanol bath NaBH ₄ (70.3 g, 1.82 mol) was added portionwise at a rate such that the reaction temperature did not exceed 10 ° C (about 2 hours). The reaction mixture was allowed to warm to room temperature, stirred overnight, then filtered through a thick sintered glass funnel. The resulting solids were washed with ethanol. The combined organic filtrate was evaporated under reduced pressure and the residue was treated with ethyl acetate (2 L) and water (1 L). The organic layer was dried (sodium sulfate) and evaporated under reduced pressure to give (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as a viscous pale yellow oil (192 g, 85%).

¹ H NMR (CDCl 3) δ 0.90 - 0.96 (m, 12H), 1.18 - 1.24 (m, 1H), 1.32 - 1.39 (m,

1H), 1.58-1.72 (m, 2H), 2.33 (dd, J = 11.1, 7.0 Hz, 1H), 2.49 (dd, J = 11.1, 7, 0

Hz, 1H), 2.63-2.67 (m, 1H), 3.19 (dd, J = 10.3, 6.2 Hz, 1H), 3.60 (dd, J = 10.3,

6.2 Hz, 1H).

757 / B

B4d. General method of N-alkylation of ethanolamines by formation of 2-alkyl-1,3-oxazolidine followed by reduction. Synthesis of 1- (cyclopentylamino) -1 (hydroxymethyl) cyclopentane.

About NH

Step 1

A solution of 1-hydroxymethylcyclopentanamine (Method B1c; 263 g, 2.3 mol) and cyclopentanone (220 mL, 1.3 mol, 1.1 equiv) in toluene (2.7 L) was heated to reflux with azeotropic removal. water until the theoretical amount of water (41.4 mL) was collected. Evaporate the reaction mixture to a volume of 700 mL by simple distillation, then cool to room temperature and evaporate to constant weight under reduced pressure to give 6-aza-12-oxadispiro [4.1.4.2] tridecane (414 g, 100%) as a light yellow oil.

¹ H NMR (CDCl 3) δ 1.55-1.89 (m, 17H), 3.60 (s, 2H).

HO

Step 2

To a solution of 6-aza-12-oxadispiro [4.1.4.2] tridecane (124 g, 0.69 mol) dissolved in ethanol (600 mL) and maintained at -13 ° C using an ice / methanol bath was added portionwise NaBH ₄ (38 g, 1.0 mol,

757 / B

1.45 equiv) at a rate such that the temperature did not exceed 10 ° C (about 30 minutes). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water (500 mL) and evaporated under reduced pressure. The resulting paste was partitioned between ethyl acetate (1 L) and water (600 mL). The organic layer was dried (sodium sulfate) and evaporated under reduced pressure to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane as a white powder (107 g, 85%).

Ή NMR (CDCl ₃ ) 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, 1H); 3.30 (s, 2H).

B5a. General process for the synthesis of ethanolamines by reaction of amines with epoxides. Synthesis of N- (hydroxyethyl) -N- (2-butyl) amine.

To a solution of sec-butylamine (60 mL, 0.60 mmol) in methanol (40 mL) at room temperature was added dropwise via cannula ethylene oxide (10 mL, 0.20 mmol). The mixture was stirred at room temperature for 4 hours and then evaporated 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%).

Boiling point: 109-112 ° C (799.8 Pa).

B5b. General process for the synthesis of ethanolamines by reaction of amines with epoxides. Synthesis of N- (3-phenyl-2-hydroxypropyl) -N-isobutylamine.

757 / B

2,3-epoxypropylbenzene (10 g, 74.5 mmol) and isobutylamine (5.4 g, 74.5 mmol) were combined and then treated with water (2 mL). The mixture was stirred overnight at 110 ° C, then distilled to give N- (3-phenyl-2-hydroxypropyl) -N-isobutylamine (6.5 g).

Boiling point 115-117 ° C (133.3 Pa).

B6a. General method for the synthesis of propanolamines by Arndt Eisert amino acid homology followed by reduction. Synthesis of (R) -3- (tert-butylamino) -4-methylpentanol.

Step 1

To a solution of N- (tert-butoxycarbonyl) - (L) -valine (4.32 g, 19.9 mmol) and N-methylmorpholine (2.3 mL, 20.9 mmol) in 1,2-dimethoxyethane (30 mL) at Isobutyl chloroformate (2.27 mL, 21.0 mmol) was added at -10 ° C. The resulting mixture was stirred at room temperature for 15 minutes, then filtered and the solids collected

757 / B were washed with cold 1,2-dimethoxyethane. The filtrate was cooled to -10 ° C, then treated with a solution of CH 2 N 2 in diethyl ether as long as the yellow color persisted, the resulting mixture was warmed to 20 ° C and stirred at this temperature for 45 minutes and then evaporated under reduced pressure. The residue was purified by chromatography (silica, gradient from hexane to 30% EtOAc / hex) to afford (S) -3- (tert-butoxycarbonylamino) -1-diazo-4-methylpentan-2-one (1.82 g, 38). %).

TLC (10% EtOAc / hex) R _f 0.11.

MeO

Step 2

A solution of (S) -3- (tert-butoxycarbonylamino) -1-diazo-4-methylpentan-2-one (1.83 g, 7.6 mmol) in methanol (100 mL) was heated to reflux and added. filtered solution of silver benzoate in triethylamine (0.50 g of silver benzoate in 5 ml of triethylamine, 0.5 ml). After the initial gas formation ceased (about 0.5 minutes), another silver solution (0.5 ml) was added. This process is repeated until the addition of the silver salt leads to further gas evolution. The resulting mixture was cooled to 20 ° C, treated with Celite, and filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in diethyl ether (100 ml) and washed successively with 1N hydrochloric acid (100 ml) and saturated sodium bicarbonate solution (100 ml) and saturated sodium chloride solution (50 ml), dried (magnesium sulfate) and evaporated under reduced pressure. to give methyl - [(R) -3- (tert-butoxycarbonylamino) -4-methylpentanoate] (1.63 g, 87%).

TLC (10% EtOAc / hex) R _f 0.29.

757 / B

OH

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 give (R) -3- ( tert-butoxycarbonylamino) -4-methylpentanol (93%).

B7. General method for the synthesis of chloroethylamines. Synthesis of (1S) -1- (chloromethyl) 3-methylbutanammonium chloride.

C 1 NH ₂ HCl

A solution of (1S) -1- (hydroxymethyl) -3-methylbutylamine (method B1b; 5.40 g, 46.1 mmol) in dichloromethane (200 mL) was cooled in an ice bath and saturated with hydrogen chloride gas. SOCl 2 (4.0 mL, 55.3 mmol) was added, the reaction mixture was heated to reflux for 2.5 hours, then cooled to room temperature and evaporated under reduced pressure. The residue was triturated with diethyl ether to give (1S) -1- (chloromethyl) -3-methylbutanammonium chloride (5.67 g, 71%). EI-MS m / z 136 ((M + H) &lt; ^{+ &gt;} ).

757 / B

B7b. General method for the synthesis of chloroethylamines. Synthesis of 1- (chloromethyl) -1- (cyclohexylamino) cyclopentane hydrochloride salt.

HCl

4M hydrochloric acid solution (p-dioxane, 40 mL) containing 1 (cyclohexylamino) -1- (hydroxymethyl) cyclopentane (Method B4a, 1.9 g, 9.6 mmol) and SOCl ₂ (0.84 mL, 11.5 mmol) was heated at 70 ° C for 18 hours. The resulting mixture was cooled to room temperature and evaporated under reduced pressure to give crude 1- (chloromethyl) -1- (cyclohexylamino) cyclopentane hydrochloride salt (2.84 g), which was used in the next step without further purification;

B7c. General method for the synthesis of chloroethylamines. Synthesis of N- (1S) - (1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) amine hydrochloride salt.

HCl

To a solution of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol (Method B4c, 256 g, 1.5 mol) and toluene (2.5 L) was added SOCl ₂ (167 L) over 15 minutes. ml). After the addition of SOCl ₂ was complete, the reaction mixture was heated at 90 ° C overnight.

757 / B

The reaction solution was then cooled to room temperature and evaporated under reduced pressure. The dark oil residue was dissolved in dichloromethane (2 L) and evaporated under reduced pressure. The red-brown residue was dissolved in diethyl ether (1 L) and hexane (750 mL) was added dropwise over 8 hours. The resulting suspension was stirred overnight, filtered and washed with 40% EtOAc / hex to give N- (1S) - (1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) amine hydrochloride salt as a dark brown solid (276 g).

¹ H NMR (CDCl ₃ ) 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, 1H), 2.90-3.02 (m, 1H), 3.50-3.57 (m, 1H), 3.96 (dd, J = 12.9, 5.6 Hz, 1H), 4.10 (dd, J = 13.2, 3.6 Hz, 1H).

B7d. General method for the synthesis of chloroethylamines. Synthesis of 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane hydrochloride salt.

To a solution of 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane (Method B1c, 140 g, 0.76 mol, 1.0 equiv) in toluene (1.4 L) was added SOCl ₂ (84 mL) over a period of 1 h. 15 minutes. After the addition of SOCl _{2 was} complete, the reaction mixture, which was already heated to 40 ° C, was heated at 60 ° C overnight. The resulting solution was cooled to room temperature and treated with hydrochloric acid (4N in p-dioxane, 100 mL) and the reaction mixture was heated to 60 ° C for 3 hours, then stirred at room temperature overnight. The resulting mixture was evaporated to half its original volume under reduced pressure, whereupon a precipitate formed. The resulting suspension was diluted with diethyl ether and allowed to stir for 4 hours. Filter the resulting precipitate a

Wash 757 / B with diethyl ether (2 x 50 mL) to give 1 (chloromethyl) -1- (cyclopentylamino) cyclopentane hydrochloride salt as an off-white powder (125 g, 70%).

¹ H NMR (CDCl ₃ ) 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, 1H).

B7e. General method for the synthesis of chloroethylamines. Synthesis of 1-chloromethylcyclopentanamine hydrochloride salt.

ci

NH ₂ HCl

To a solution of 1-hydroxymethylcyclopentanamine hydrochloride salt (Method B1c, 20 g, 0.17 mol) in anhydrous p-dioxane (65 mL) was added hydrochloric acid (4M in p-dioxane, 65 mL, 0.26 mol). The resulting solution was stirred at room temperature for 20 minutes, then SOCl ₂ (22.7 g, 0.19 mol) was added dropwise. The reaction mixture was heated at 80 ° C for 2 days, cooled to room temperature and evaporated under reduced pressure to give 1-chloromethyl-cyclopentanamine hydrochloride salt (29 g, 100%).

CI-MS m / z 171 ((M + H) &lt; ^{+ &gt;} ).

B8a. General process for the synthesis of 2-aminoethylsulfonate esters. Synthesis of (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride.

757 / B

Q k

Step 1

A solution of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -4-tert-butyltreonine dicyclohexylamine salt (2.15 g, 4.4 mmol) in dichloromethane (50 mL) was treated with a solution of CH 2 N 2 in diethyl ether until the yellow color persisted. . The resulting solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed successively with 1N hydrochloric acid solution (2 x 100 mL) and saturated sodium chloride solution (50 mL), dried (magnesium sulfate) and evaporated under reduced pressure to give the methyl ester (1S, 2R). 1) -N (Benzyloxycarbonyl) -O-tert-butyltreonine (1.44 g, 100%).

TLC (25% EtOAc / hex) R _f 0.54.

HO

ABOUT

Step 2

To a solution of (1S, 2R) -N- (Benzyloxycarbonyl) -O-tert-butyltreonine methyl ester (1.4 g, 4.4 mmol) in diethyl ether (20 mL) was added a saturated solution of LiBH ₄ in diethyl ether (9 mL), and the reaction mixture is heated to reflux 2

757 / B hours; then cooled to 20 ° C. To the resulting mixture was added water (5 mL), then 1N hydrochloric acid solution was added until no gas was formed. The ether layer was washed with saturated sodium chloride solution (50 mL), dried (magnesium sulfate) and evaporated under reduced pressure to give (1R, 2R) -N- (benzyloxycarbonyl) -1- (hydroxymethyl) -2- (tert-butoxy) propanamine (1.69 g, 99%).

TLC (25% EtOAc / hex) _Rf 0.20.

MsO ^H zM

λO

Step 3

To a solution of (1R, 2R) -N- (benzyloxycarbonyl) -1- (hydroxymethyl) -2- (t-butoxy) propanamine (1.6 g, 5.4 mmol) in anhydrous pyridine (30 mL) at 4 ° C was added dropwise methanesulfonyl chloride (0.75 mL, 9.7 mmol). The reaction mixture was stirred for 5.5 hours, then diluted with ethyl acetate (200 mL) and washed with 1N hydrochloric acid solution (4 x 200 mL). The combined organic layers were dried (magnesium sulfate) evaporated under reduced pressure to afford (1R, 2R) -N (benzyloxycarbonyl) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanamine as an oil (2.03 g, 100% ).

TLC (25% EtOAc / hex) R _f 0.31.

757 / B

Step 4

To a solution of (1R, 2R) -N- (benzyloxycarbonyl) -1- (methanesulfonyloxymethyl) -2 (tert-butoxy) propanamine (2.03 g, 5.5 mmol) in methanol (50 mL) was added a 4 M solution hydrochloric acid (dioxane, 1.5 mL, 6.0 mmol) and 10% Pd / C (0.20 g). The resulting suspension was stirred under a hydrogen atmosphere (101.3 kPa) for 2 hours, then treated with Celite, filtered and evaporated under reduced pressure to give (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride ( 1.6 g, 100%).

B8b. General process for the synthesis of 2-aminoethylsulfonate esters. Synthesis of N- (2-tosyloxyethyl) -2-methylprop-2-en-1-ammonium trifluoroacetate.

Step 1

To a solution of N- (tert-butoxycarbonyl) glycine tert -butyl ester (3.97 g, 17.2 mmol) in N, N-dimethylformamide (70 mL) at 0 ° C was added sodium hexamethyldisilazide (3.78 g, 20 mL). (6 mmol) and the resulting mixture was stirred for 25 minutes and then allowed to warm to room temperature. The resulting solution was treated with 3-bromo-2-methylpropene (2.60 mL, 25.7 mmol), stirred at room temperature for 10 minutes, and diluted with ethyl acetate (300 mL). The ethyl acetate solution was washed successively with water (4 x 500 ml) and saturated sodium chloride solution (4 x 500 ml), dried (magnesium sulfate) and evaporated under reduced pressure for

757 / B to provide N- (tert-butoxycarbonyl) -N- (2-methylprop-2-phenyl) glycine tert-butyl ester (4.03 g, 82%).

TLC (10% EtOAc / hex) R _f 0.51.

Step 2

A solution of N- (tert-butoxycarbonyl) -N- (2-methylprop-2-enyl) glycine tert-butyl ester (0.26 g, 0.93 mmol) in diethyl ether (3 mL) was treated with lithium borohydride (0.011 g) and then stir at room temperature overnight. To the resulting mixture was added water (2 mL), then 1N hydrochloric acid was added dropwise until gas evolution ceased. The organic phase was washed with saturated sodium bicarbonate solution (20 ml), dried (magnesium sulfate) and evaporated under reduced pressure. The residue is purified by chromatography (silica, gradient from 10% EtOAc / hex to 50% EtOAc / hex) to give N- (tert-butoxycarbonyl) N- (2-hydroxyethyl) -1-amino-2-methylprop-2-ene (0.113 g, 57%).

TLC (10% EtOAc / hex) R _f 0.66.

757 / B

Step 3

To the solution

N- (tert-butoxycarbonyl) -N- (2-hydroxyethyl) -1-amino-2-methylprop-2-ene (21.1 g, 98 mmol) in diethyl ether (800 mL) at -78 ° C is slowly added tert. potassium butoxide (1M in tert-butanol, 103 mL, 103 mmol). The reaction mixture was allowed to warm briefly to -45 ° C, then cooled to -78 ° C and treated with a solution of p-toluenesulfonyl chloride (18.7 g, 98.0 mmol) in diethyl ether (100 mL). The resulting mixture was then warmed to -45 ° C and treated with water (500 mL). The organic phase was washed with saturated sodium chloride solution (800 ml), dried (magnesium sulfate) and evaporated under reduced pressure to give N- (tert-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2-methylprop-2-ene (36.4 g, 101%).

TLC (25% EtOAc / hex) R _f 0.56.

TsO HN \ _t

CF ₃ CO ₂ H

Step 4

Solid N- (tert-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2-methylprop-2ene (15 g, 55.7 mmol) was cooled to 0 ° C and dissolved in trifluoroacetic acid (200 mL) ). The reaction mixture was allowed to warm to room temperature and then evaporated under reduced pressure. The resulting oil was crystallized using diethyl ether (500 mL) to give N- (2-tosyloxyethyl) -2-methylprop-2-en-1-ammonium trifluoroacetate (16.7 g, 78%).

757 / B

B9a. General method for the synthesis of 3-chloropropyl and 4-chlorobutylamines. Synthesis of N-isobutyl-3-chloropropylamine hydrochloride salt.

Step 1

To a solution of 3-aminopropanol (91 g, 65.4 mmol) in toluene (100 mL) was added isobutyraldehyde (9.0 mL, 99.1 mmol, 1.5 equiv) and magnesium sulfate (7.5 g) for creating an exotherm. The suspension was stirred for 30 minutes and another portion of magnesium sulfate (7.5 g) was added and the suspension was stirred overnight. The resulting mixture was filtered and evaporated under reduced pressure. The condensate was re-evaporated under reduced pressure and the two evaporators were combined to give 2-isopropyl-tetrahydro-1,3-oxazine as a colorless oil (5.18 g, 61%).

¹ H NMR (CDCl ₃ ) δ 0.84 - 0.88 (m, 6H), 1.24 - 1.29 (m, 1H), 1.51 -1.66 (m, 3H), 2.77 2.87 (m, 1H), 3.07-3.11 (m, 1H), 3.60-3.76 (m, 2H), 4.00-4.05 (m, 1H).

HO

HN

Step 2

To a solution of 2-isopropyl-tetrahydro-1,3-oxazole (4.94 g, 38.2 mmol) in absolute ethanol (100 mL) at 0 ° C was added NaBH ₄ (2.17 g, 57.4 mmol, 1 mL). , 5 equiv.) Over 15 minutes in small portions and the resulting mixture was added

The 757 / B was stirred at room temperature overnight. The resulting mixture was evaporated under reduced pressure, then treated with ethyl acetate (150 mL) and water (100 mL) (caution: gas evolution) and stirred at room temperature for 30 minutes. The resulting organic layer was washed with saturated sodium chloride solution. The combined organic layers were back-extracted with ethyl acetate (150 mL). The combined organic layers were dried (sodium sulfate) and evaporated under reduced pressure to give N-isobutyl-3-hydroxypropylamine as a colorless oil (5.04 g, 100%).

¹ H NMR (CDCl ₃ ) 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 (broad s, 2H), 3.74 (dd, J =

5.5, 5.5 Hz, 2H).

¹³ CNMR (CDCl ₃ ) δ 20.5, 28.1, 30.6, 50.0, 57.8, 64.1.

Cl HN

M

HCl

Step 3

To a solution of N-isobutyl-3-hydroxypropylamine (1.01 g, 7.70 mmol) in toluene (100 mL) was added SOCl ₂ (1.37 g, 11.6 mmol, 1.5 equiv) and the resulting mixture is stirred at room temperature for 4 hours. The resulting suspension was evaporated under reduced pressure to give the N-isobutyl-3-chloropropylamine hydrochloride salt.

¹ H NMR (CDCl ₃ ) δ 1.12 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H), 4.24 (q, J = 7.0 Hz, 2H), 4 55 (s, 1 H), 5.00 (s, 2 H).

¹³ C NMR (CDCl ₃ ) δ 13.9, 27.8, 38.2, 61.5, 67.1, 67.3, 117.0, 167.1, 180.7. CI-LRMS m / z (relative excess) 150 ((M + H) ⁺ , 100%).

757 / B

B10A. General process for the synthesis of 2-chlorothiazolidinium salts. Synthesis of (4S) -2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride.

WITH

Step 1

To a mixture of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol hydrochloride (Method B4c, 0.21 g, 1.0 mmol) and CS ₂ (0.30 mL, 5.0 mmol, 5.0 eq) in 2-butanone (20 mL) was added Cs ₂ CO 3 (0.72 g, 2.20 mmol, 2.2 eq) and the resulting mixture was heated to reflux overnight. The resulting orange solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate (25 mL). The residual solids were washed with ethyl acetate (25 mL) and the combined ethyl acetate phases were evaporated under reduced pressure. The residue is absorbed onto silica and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc / hex) to give (4S) 3,4-diisobutyl-1,3-thiazolidine-2-thione as a yellow oil (0.11 g). , 52%).

757 / B

Step 2

A solution of (4S) -3,4-diisobutyl-1,3-thiazolidin-2-thione (5.0 g, 21.6 mmol) in SOCl ₂ (31 mL, 0.43 mol) was heated to 70 ° C. 2.5 hours, then cooled to room temperature and evaporated under reduced pressure to give (4S) 2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride as a semi-solid.

¹ H NMR (CDCl 3) δ 0.99-1.10 (m, 12H), 1.59-1.67 (m, 1H), 1.72-1.84 (m, 1H), 2.00 - 2.10 (m, 1H), 2.17-2.29 (wide m, 1H), 3.61-3.68 (m, 1H), 3.86 3.95 (wide m, 2H), 4.50 - 4.57 (m, 1H), 4.97 - 5.06 (broad m, 1H).

This material was dissolved in dichloroethane (180 mL) to prepare a 0.12 M stock solution (quantitative conversion to thiazolidinium chloride is expected).

C. Methods for the synthesis of iminoheterocycles

C1a. General process for the synthesis of 2-imino-1,3-thiazolidines by reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine.

To a mixture of (1S) -1- (chloromethyl) -3-methylbutanammonium chloride (Method B7a,

1.14 g, 3.71 mmol) and 2-methyl-4-nitrophenylnyl isothiocyanate (0.72 g, 3.71 mmol) suspended in dichloromethane (15 mL) were added triethylamine (1.08) via syringe.

757 (B mL, 7.78 mmol). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated sodium bicarbonate solution and evaporated under reduced pressure. The residue is purified by chromatography (silica, gradient from 10% EtOAc / hex to 30% EtOAc / hex) to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine (0, 91 g, 47%).

TLC (25% EtOAc / hex) R _f 0.46.

C 1b. General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt.

To a solution of N- (1S) - (1- (chloromethyl) -3-methylbutyl) -N (isobutyl) amine hydrochloride salt (Method B7c, 95 g, 0.41 mol, 1.08 equiv.) In dichloromethane (1, 1 L) 4-cyano-2-ethylphenylisothiocyanate (Method A2b, 72 g, 0.38 mol) was added at 15 ° C followed by diisopropylethylamine (200 mL, 1.15 mol, 3.0 equiv.) To induce slight exotherm. When the reaction mixture was cooled back to room temperature, the ice bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with dichloromethane (500 mL), washed with 1N sodium hydroxide solution (3 x 500 mL), dried (magnesium sulfate) and evaporated under reduced pressure. The resulting dark oil (132 g) was dissolved in dichloromethane (50 mL) and filtered through a plug of silica gel (5 g silica)

757 / B per gram of crude product) with 5% EtOAc / hex to give an oil (120 g) which was dissolved in ethyl acetate (400 mL) and treated slowly with a solution of hydrochloric acid (1M in diethyl ether, 500 mL) to yield (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt as a white solid (95 g, 66%).

¹ H NMR (CDCl 3) 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 = 7.7Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J = 7, 7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J = 11.4, 7.7 Hz, 1H), 4.18-4.25 (m, 1H) 5.02 (dd, J = 14.3, 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.51 (dd, J = 8.1, 1.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H).

C1c. General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine.

To a suspension of 2-chloro-4-cyano-6-methylphenylisothiocyanate (0.10 g, 0.50 mmol) and poly (4-vinylpyridine) (0.030 g) in dichloromethane was added a solution of (1S) -1 (chloromethyl) - 3-methylbutanammonium chloride (method B7a, 0.086 g, 0.50 mol, 1.0 equiv) in N, N-dimethylformamide (2 mL) and the resulting mixture was stirred at 55 ° C for 16 hours and then evaporated 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%).

757 / B

C1d. General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) -2- (4-chloro-2- (trifluoromethyl) phenylimino) -3-isobutyl-1,3-thiazolidine.

Cl

N- (hydroxyethyl) -N-isobutylamine was converted to N- (chloroethyl) -N-isobutylammonium chloride in a manner analogous to Method B7c. To a suspension of N (chloroethyl) -N-isobutylammonium chloride (Ο, ΪΟ mmol, 0.10 M) and poly (4-vinylpyridine) (0.030 g) in N, N-dimethylformamide (1.0 mL) was added a solution of 4-chloro-2- ( trifluoromethyl) phenyl isothiocyanate (0.25 M in tetrahydrofuran, 0.40 mL, 0.1 mmol) and the resulting mixture was heated at 55 ° C for 16 hours in a sand bath. The resulting suspension is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by preparative reverse-phase HPLC (column C-18, gradient from 0.1% trifluoroacetic acid / 20% CH ₃ CN / 79.9% water to 0.10%). 1% trifluoroacetic acid (99.9% CH ₃ CN) to give (4S) -2- (4-chloro-2- (trifluoromethyl) phenylimino) -3-isobutyl-1,3-thiazolidine (0.020 g, 59%).

C1e. General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane.

757 / B

\ /

ABOUT

To a solution of 1-chloromethyl-cyclopentanamine hydrochloride (Method B7e, 0.25 g, 1.32 mmol) and 2,4-dimethyl-3-cyano-5-pyridylisothiocyanate (Method A2c, 0.23 g, 1.32 mmol) in triethylamine (1 mL) was added dropwise via anhydrous 1,2-dichloroethane (10 mL). The resulting mixture was heated at 50 ° C overnight, then cooled to room temperature and treated with saturated sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane (3 x 25 mL). The combined organic layers were dried (sodium sulfate) and evaporated under reduced pressure. The residue was purified by chromatography (silica, 40% EtOAc / hex) to give 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane (0.192 g, 51%) .

CI-MS m / z 287 ((M + H) &lt; ^{+ &gt;} ).

C1F. General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2- (3-quinolylimino) -3,5-diisobutyl-1,3-thiazolidine.

757 / B

3-Quinoline isothiocyanate was prepared in a manner analogous to A2c. To a solution of 3-quinoline isothiocyanate (0.1 g, 0.54 mmol) and N- (1S) - (1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) amine hydrochloride salt (Method B7c, 0.113 g, 0.54 mmol) in anhydrous dichloromethane (2 mL) was added dropwise diisopropylethylamine (0.208 g, 1.61 mmol). The resulting mixture was allowed to stir at room temperature overnight and then evaporated under reduced pressure. The residue was purified by chromatography (silica, 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) &lt; ^{+ &gt;} ).

C2a. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of ethanolamines to 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Me

N

To a solution of 1-amino-1- (hydroxymethyl) cyclopentane (method B1c, 20.7 g, 180 mmol) and hydrochloric acid (4M in p-dioxane, 400 mL) was added SOCl ₂ (15.7 mL, 216 mmol) and the resulting solution was heated at 100 ° C for 18 hours. The reaction mixture was evaporated under reduced pressure, then treated with 2-methyl-4-nitrophenylisothiocyanate (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 hours, cooled to room temperature and evaporated in vacuo

757 / B reduced pressure. The residue was treated with hot ethyl acetate, filtered and evaporated under reduced pressure. The residue was recrystallized (methanol) to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (38.3 g, 81%).

TLC (25% EtOAc / hex) R _f 0.27.

C2B. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of ethanolamines to 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.5] decane.

1-Amino-1- (hydroxymethyl) cyclohexane (Method B1a) is dissolved in pdioxane (80 mL) and then treated with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate in a manner analogous to Method C2a to give 2- (2-methyl-4-nitrophenylimino). 3-thia-1-azaspiro [4.5] decane (20%), which is reacted with isobutyl bromide in a manner analogous to Method D2a to give 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia- 1-azaspiro [4.5] decane (0.026 g, 2%).

TLC (20% EtOAc / hex) R _f 0.69.

C2c. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of ethanolamines to 2-chloroethylamines followed by reaction with isothiocyanates.

Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutylspiro [1,3-thiazolidin-4,2'-bicyclo [2.2.1] heptane],

757 / B

2- (isobutylamino) -2- (hydroxymethyl) norborane (Method B2a, 0.24 g, 1.2 mmol) is treated with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate in a manner analogous to Method C2a to give 2- (2- methyl 4-nitrophenylimino) -3- (2-isobutylspiro [1,3-thiazolidine-4,2'-bicyclo [2.2.1] heptarium] as an oil (0.022 g, 5%).

TLC (25% EtOAc / hex) R _f 0.72.

C2d. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of ethanolamines to 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 3-isobutyl-4-methylene-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidin-5-one and (4S) -3-isobutyl-4-carbomethoxy-2- (2- methyl-4-nitro-phenylimino) -1,3-thiazolidine.

757 / B

The (R) -N-isobutylserine hydrochloride salt (Method B3a, 2.28 g, 10.8 mmol) was treated with SOCl 3 followed by 2-methyl-4-nitrophenylisothiocyanate in a manner analogous to Method C2a. The resulting material was purified by column chromatography (silica, gradient from hexane to 10% EtOAc / hex) to give 3-isobutyl-4-methylene-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine-5- (0.028 g, 10%) followed by (S) -3-isobutyl-4-carbomethoxy-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine hydrochloride salt (0.192 g, 56%).

3-isobutyl-4-methylene-2- (2-methyl-4-nitro-phenylimino) -1,3-thiazolidin-5-one;

TLC (25% EtOAc / hex) _Rf 0.40.

(S) -3-Isobutyl-4-carbomethoxy-2- (2-methyl-4-nitrophenylimino) 1,3-thiazolidine hydrochloride:

TLC (free base, 25% EtOAc / hex) Rf 0.50.

C2E. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of ethanolamines to 2-chloroethylamines followed by reaction with isothiocyanates. Synthesis of 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

1- (cyclohexylamino) -1- (hydroxymethyl) cyclopentane (Method B4a, 1.89 g,

9.59 mmol) was reacted with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate in a manner analogous to Method C2a to give 131 757 / B cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] ] nonane (0.44 g, 17%) ·

CI-MS m / z 374 ((M + H) &lt; ^{+ &gt;} ).

C2F. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of ethanolamines to 2-chloroethylamines followed by reaction with isothiocyanate. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4,4-dimethyl-1,3-thiazole.

N-isobutyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a. A solution of N-isobutyl-1,1-dimethyl-2-hydroxyethanamine (1.45 g, 10 mmol) in toluene (20 mL) was bubbled into saturated hydrogen chloride. SOCl 3 (10 mmol) was added dropwise at room temperature, stirred at room temperature for 1 hour and at 50 ° C for 1 hour. The resulting mixture was evaporated under reduced pressure and the residue was dissolved in chloroform (20 mL). To the resulting solution was added 2-methyl-4-nitrophenylisothiocyanate (1.94 g, 10 mmol) then a solution of triethylamine (10 mmol) in chloroform (10 mL) was added dropwise at room temperature. The resulting mixture was heated to reflux for 3 hours and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and the resulting solution was washed successively with 10% aqueous sodium hydroxide solution (50 mL) and saturated sodium chloride solution (50 mL), dried (magnesium sulfate) and evaporated under reduced pressure. The residue is purified by chromatography (9% EtOAc / petroleum ether) and the resulting solids are recrystallized (petroleum ether) to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4,4-dimethyl-1,3-thiazolidine. nu (0.6

757 (B g, 63%). MP: 97 ° C. Where appropriate, the product is converted to the hydrochloride salt by dissolving the free base (5 mmol) in diethyl ether (50 mL) and treating this solution with 2N ethereal hydrochloric acid until no precipitate precipitates. The resulting suspension was filtered and the resulting solids were washed with diethyl ether (25 mL) followed by ethyl acetate (25 mL).

C3a. General method for the synthesis of 2-imino-1,3-thiazolidine homologs by homologous conversion of hydroxyalkylamines to chloroalkylamines followed by reaction with isothiocyanates. Synthesis of (R) -4-isopropyl-2- (2-methyl-4-nitrophenylimino) 2,3,4,5-tetrahydro-1,3-thiazine.

(R) -3- (tert-butoxycarbonylamino) -4-methylpentanol (Method B6a) is treated with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate in a manner analogous to Method C2a to provide (R) -4-isopropyl-2- ( 2-methyl-4-nitrophenyl-imino) -2,3,4,5-tetrahydro-1,3-thiazine (100%)

C4. General method for the synthesis of 2-imino-1,3-oxazolidines by reaction of 2-chloroethylamines with isocyanates. Synthesis of 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane.

757 / B

0 ₂ Ν

To a solution of 1- (chloromethyl) -1- (cyclohexylamino) cyclopentane hydrochloride (Method B7b, 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenylisocyanate (0.75 g, 4.2 10 mmol) in 1,2-dichloroethane (10 mL) was added N-methylmorpholine (0.92 mL, 8.4 mmol). The resulting mixture was heated at 50 ° C for 18 hours, then cooled to 20 ° C and evaporated under reduced pressure. The residue is purified by chromatography (silica, gradient from hexane to 10% EtOAc / hex) to give 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane (0.021 g) , 1.4%).

CI-MS m / z 358 ((M + H) &lt; ^{+ &gt;} ).

C5a. General process for the synthesis of 2-imino-heterocycles by reaction of aminoethylsulfonate esters with isocyanates or isothiocyanates. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -1,3-oxazolidine.

O ₂ N

Me

N

757 / B

To a solution of N- (2-tosyloxyethyl) -2-methylprop-2-ene-1-ammonium trifluoroacetate (Method B8b, Step 4, 0.21 g, 0.548 mmol) in p-dioxane (5 mL) was added 2-methyl- 4-nitrophenylisocyanate (0.0955 g, 0.536 mmol), followed by triethylamine (0.080 mL, 1.15 mmol). The resulting mixture was stirred overnight at 37 ° C, cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with water (50 mL). The organic layer was extracted with 2N hydrochloric acid solution. The aqueous layer was basified with 1N sodium hydroxide solution and extracted with dichloromethane (50 mL). The organic phase was dried (sodium sulfate) and evaporated under reduced pressure to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-prop-2-enyl) -1,3-oxazoidine as a yellow oil (0.020 g, 14 %).

CI-MS m / z 276 ((M + H) &lt; ^{+ &gt;} ).

757 / B

C5b. General method for the synthesis of 2-imino-heterocycles by reaction of aminoethylsulfonate esters with isocyanates or isothiocyanates. Synthesis of (4S) -4- (1 (R) tert -butoxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine.

_(L 1 R 2 R) -1- (methanesulfonyloxymethyl) -2- (terobutoxy) propánamóniumchlorid (Method B8a, 1.5 g, 5.5 mmol) was treated with 2-methyl-4nitrofenylizotiokyanátom a manner analogous to that described in the method for giving a C1a (4S) - (1 (R) -tert-butoxyethyl) -2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine (1.2 g, 67%). (4S) -2- (2-methyl-4-nitrophenylimino) 4- (1 (R) -t-butoxyethyl) -1,3-thiazolidine was reacted with isobutyl bromide in a manner analogous to Method D2a to afford (4S) -4- (1 (R) -tert-butoxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine (0.26 g, 56%).

TLC (25% EtOAc / hex) R _f 0.67.

C6. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of chloroethylamines to 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt.

757 / B

To a solution of sodium bisulfite (69 g, 1.2 mol, 2.2 equiv) in water (500 mL) was added N- (1S) - (1- (chloromethyl) -3-methylbutyl) -N (isobutyl) hydrochloride salt. of amine (Method B7c, 126 g, 0.55 mol, 1.0 equiv). The resulting mixture was stirred at room temperature for 8 hours, then 4-cyano-2-ethylphenylisocyanide 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 temperature for 1 hour, then 3.6 M potassium carbonate solution (305 mL, 2.0 equiv. 1.1 mol) was added and the mixture was stirred at room temperature overnight. The resulting organic layer was evaporated under reduced pressure and the residue was treated with ethyl acetate (2 L). The organic layer was washed with water (2 x 500 mL), dried (magnesium sulfate) and evaporated under reduced pressure to give a dark oil (160 g). Dissolve the oil in dichloromethane (150 mL) and pass through a plug of silica gel (3 g silica per 1 g crude product) with 5% EtOAc / hex to provide an oil containing the desired product and some residual isocyanide dichloride (134 g) . The oil was dissolved in ethyl acetate (500 mL) and treated with hydrochloric acid (1N in diethyl ether, 500 mL). The resulting (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt was removed by filtration (147 g, 70%).

¹ H NMR (CDCl 3) 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 = 7.7Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q J = 7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J = 11.4, 7.7 Hz, 1H), 4.18-4, 25 (m, 1H), 5.02 (dd, J = 14.3, 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.51 (dd, J) =

8.1, 1.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H).

757 / B

C6b. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of chloroethylamines to 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane hydrochloride salt.

To a solution of sodium bisulfite (31 g, 0.55 mol, 2.2 equiv) in water (250 mL) was added 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane hydrochloride (Method B7d, 60 g, 0, 25 mol, 1.0 equiv). The reaction mixture was stirred at room temperature for 8 hours, then 2-methyl-4-nitrophenylisocyanide 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 temperature for 1 hour and then 3.6 M dicalcium carbonate solution (305 mL, 2.0 eq., 0.5 mol) was added. The reaction mixture was stirred at room temperature overnight. The resulting upper organic layer was separated and evaporated under reduced pressure, and the residue was treated with ethyl acetate (1 L). The resulting organic layer was washed with water (2 x 200 mL), dried (magnesium sulfate) and evaporated under reduced pressure. The resulting oil (86 g) was dissolved in dichloromethane (50 mL) and filtered through a plug of silica gel (3 g silica per 1 g crude product) with 5% EtOAc / hex to give an oil (34 g) containing the desired product and some residual. isocyanide dichloride. This oil was dissolved in ethyl acetate (300 mL) and hydrochloric acid (1N in diethyl ether, 1.5 L). The resulting solids were removed by filtration to give the hydrochloride salt of 1-cyclopentyl-2- (2-methyl31,757 / B).

4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane as a white powder (36.8 g).

¹ H NMR (CD ₃ OD) 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, 1H), 6.70 (broad s, 1H 6.93 (d, J = 8.4 Hz, 1H), 7.96 - 8.04 (m, 1H), 8.03 (d, J = 3 Hz, 1H).

C6C. General method for the synthesis of 2-imino-1,3-thiazolidines by conversion of hydroxyethyl amines to 2-thioethylamines followed by reaction with isocyanide dichlorides. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Step 1

To a solution of Ph ₃ P (27.9 g, 0.107 mol, 1.3 equiv) at 0 ° C in anhydrous tetrahydrofuran (400 mL) was added diisopropylazodicarboxylate (21.5 g, 0.107 mol, 1.3 equiv.) Gradually. and 1-cyclopentylamino-1- (hydroxymethyl) cyclopentane (Method B4d, 15.0 g, 0.082 mol). The resulting suspension was stirred for 30 minutes and then treated with thiol acetic acid (7.6 mL, 0.107 mol, 1.3 equiv). The resulting yellow solution was stirred for 15 minutes and evaporated under reduced pressure to a volume of about 100 mL. The residue was dissolved in ethyl acetate (200 mL) and the resulting solution was extracted with 1N hydrochloric acid solution (5 x 125 mL). The combined organic layers were washed with ethyl acetate (2 x 200 mL), neutralized with potassium carbonate to pH 7.0 to 7.5, then extracted with ethyl acetate (5 x 200 mL). The organic layers were combined, dried (sodium sulfate) and evaporated under reduced pressure. The residue is dried under vacuum for

757 / B to provide 1-cyclopentylamino-1- (thioacetylmethyl) cyclopentane as a yellow oil (19.1 g).

TLC (10% ethyl acetate / hexanes) R _f 0.16.

1 H NMR (CDCl ₃ ) δ 1.20-1.87 (m, 16H), 2.34 (s, 3H), 2.92-3.02 (m, 1H), 3.15 (s, 2H) ).

¹³ C NMR (CDCl 3) δ 23.9, 25.2, 29.3, 36.4, 40.1, 55.8, 73.0, 169.8.

CI-LRMS m / z (relative excess) 242 ((M + H) ⁺ , 100%).

NH SH

Step 2

A solution of 1-cyclopentylamino-1- (thioacetylmethyl) cyclopentane (19.1 g) in 0.33 M potassium hydroxide in 9: 1 methanol: water (273 mL, 0.090 mol, 1.1 equiv) was stirred for 30 minutes . The reaction mixture was evaporated under reduced pressure and the residue was dried in vacuo to give crude 1-cyclopentylamino-1- (thiomethyl) cyclopentane as a yellow oil.

TLC (10% ethyl acetate / hexanes) R _f 0.18 (smudge).

¹ H NMR (CD ₃ OD) δ 1.32-1.71 (m, 14H), 1.87-1.94 (m, 2H), 2.67 (s, 2H), 3.07-3, 14 (m, 1 H).

FAB-LRMS m / z (relative excess) 200 ((M + H) ⁺ , 19%).

This material was used immediately in the next step without further purification.

757 / B

Ο ₂ Ν

Step 3

A solution of crude 1-cyclopentylamino-1- (thiomethyl) cyclopentane in anhydrous dichloromethane (100 mL) at 0 ° C was treated with a suspension of crude 2-methyl-4-nitrophenylisocyanide dichloride (Method A3b, 19.1 g, 0.082 mol, 1, 0 equiv based on 1-cyclopentylamino-1- (thioacetylmethyl) cyclopentane) in dichloromethane (200 mL) followed by triethylamine (30 mL, 0.215 mol, 2.5 equiv) and allowed to warm to room temperature and stir 2 days. N, N-dimethylethylenediamine (92 g, 0.023 mol, 0.3 equiv) was added and the reaction stirred for 1 hour. Silica gel (50 g) was added and the resulting mixture was evaporated under reduced pressure. The residue was dried in vacuo overnight and purified by flash chromatography (11 x 10 cm silica, 5% ethyl acetate / hex) to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1- azaspiro [4.4] nonane as a yellow granulated solid (17.8 g, 60% overall).

MP: Mp 120-121 ° C.

TLC (10% ethyl acetate / hexanes) R _f 0.45.

¹ H NMR (CDCl ₃ ) 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, 1H), 6.89 (d, J = 8.5 Hz, 1H), 7.95 - 8.03 (m, 2H).

¹³ C NMR (CDCl ₃ ) 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 (relative excess) 360 ((M + H) ⁺ , 100%).

Analytically for C ₁₉ H ₂₅ N ₃ O2S:

H, 7.01; N, 11.69

Found: C 63.48 H 6.89 N 11.76.

757 / B

C7a. General method for the synthesis of 2-imino-1,3-oxazolidines by reaction of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of 2- (4-cyano-2-ethylphenylimino) -3cyclopentyl-4,4-dimethyl-1,3-oxazolidine

NC

et

A solution of N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine (Method B4b, 0.12 g, 0.69 mmol) in tetrahydrofuran (2.5 mL) was added dropwise via syringe to a suspension of NaH (95%). , 0.05 g, 1.2 mmol) in tetrahydrofuran (5 mL) at room temperature. The reaction mixture was stirred for 15 minutes and then a solution of 4-cyano-2-ethylphenylisocyanate dichloride (Method A3a, 0.15 g, 0.63 mmol) in tetrahydrofuran (2.5 mL) was added dropwise via syringe. The resulting mixture was stirred overnight, then treated with 5% citric acid solution (10 mL) followed by ethyl acetate (25 mL). The organic phase was washed sequentially with 5% citric acid solution (20 ml), water (20 ml) and saturated sodium chloride solution (20 ml), dried (sodium sulfate) and evaporated under reduced pressure. The residue is purified by chromatography (silica, 5% ethyl acetate / hex) to give 2- (4-cyano-2-ethylphenylimino) -3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine as a yellow solid (0, 09 g, 43%).

MP: Mp 112-114 ° C.

TLC (15% EtOAc / hex) _Rf 0.60.

Ή NMR (CDCl ₃ ) 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, 1H), 3.97 (s, 2H), 7.04 (d, J = 8.3 Hz, 1H), 7.35 (dd, J) =

757 / B

8.1, 1.8, Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H).

CI-MS m / z (relative excess) 312 ((M + H ⁺ , 100%)).

HRMS calculated for C ₁₇ H ₂ 3 N ₃ O _3: 311.1998. Found: 311.1991.

C7b. General process for the synthesis of 2-imino-1,3-oxazolidines by reaction of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-oxazolidine.

To a solution of 4-cyano-2-ethylphenylisocyanide dichloride (Method A3a, 0.42 g, 1.83 mmol, 1.2 equiv) and (2S) -4-methyl-2- (isobutylamino) pentan-1-ol (Method B4c, 0.26 g, 1.52 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour and then treated with 2 (dimethylamino) ethylamine (0.5 mL). The mixture was stirred at room temperature for 1 hour and then evaporated under reduced pressure. The residue was purified by column chromatography (gradient from 5% ethyl acetate / hex to 10% ethyl acetate / hex) to afford (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-oxazolidine as yellow oil (0.15 g),

TLC (10% ethyl acetate / hex) R _f 0.35.

¹ H NMR (CDCl ₃ ) δ 0.81-1.00 (m, 12H), 1.14 (t, J = 4.8 Hz, 3H), 1.25-1.43 (m,

2H), 1.53-1.70 (m, 2H), 2.57 (sept, J = 7.5Hz, 1H), 2.58 (q, J = 7.5Hz, 2H),

3.01 (dd, J = 14.0, 6.3 Hz, 1H), 3.33 (dd, J = 13.6, 8.8 Hz, 1H), 3.73 - 3.83 (m .

H), 3.94 (apparent t, J = 7.5 Hz, 1 H), 4.37 (apparent t, J = 7.9 Hz, 1 H), 7.01 (d, J =

8.1 Hz, 1H), 7.33 (dd, J = 8.1, 1.8 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H).

757 / B ¹³ C NMR (CDCl ₃ ) 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%)).

-C 8. General method for synthesizing 2-imino-4-oxoheterocycle by reacting an isothiocyanate with an amine, followed by a reaction with a halonic acid halide. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-4-one.

To a solution of 2-methyl-4-nitrophenylisothiocyanate (0.190 g, 1.0 mmol) in N, N-dimethylformamide (5.3 mL) was added isobutylamine (0.4 M solution in N, N-dimethylformamide, 5.3 mL) and the reaction mixture. The mixture was allowed to stir for 4 hours, during which time TLC analysis (hexane: ethyl acetate 3: 1) indicated consumption of isothiocyanate. To the resulting mixture was added chloroacetic acid (0.8 M solution in N, N-dimethylformamide, 4.0 mL) followed by N-methylmorpholine (0.7 mL, 6.4 mmol). The reaction mixture was stirred at 80 ° C for 18 hours and then partitioned between water (10 mL) and ethyl acetate (25 mL). The aqueous phase is back extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (sodium sulfate) and evaporated under reduced pressure. The resulting residue was purified by MPLC (Biotage 40 S silica gel column, gradient from 5% ethyl acetate / hex to 33% ethyl acetate / hex) to afford 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-4. -one as a light yellow oil (0.52 g, 85%).

757 / B

100

C9a. General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of hydroxyethylamines with isothiocyanates, followed by acid-catalyzed ring closure. Synthesis of 2- (2,6-dichlorophenylimino) -3-cyclohexyl-4,4-dimethyl-1,3-thiazolidine.

CI

N-cyclohexyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a. A solution of 2,6-dichlorophenylisothiocyanate (1.2 g, 6.0 mmol) and N-cyclohexyl-1,1-dimethyl-2-hydroxyethanamine (1.0 g, 6.0 mmol) in dichloromethane (10 mL) was stirred. 20 hours at room temperature. The resulting mixture was evaporated under reduced pressure and then treated with a 33% hydrochloric acid solution (15 mL). The resulting mixture was heated to reflux for 1 hour, cooled to room temperature and neutralized with 45% sodium hydroxide solution. The resulting suspension is filtered and the resulting solids are washed with water (20 mL) and then recrystallized (ethanol) to give 2- (2,6-dichlorophenylimino) -3-cyclohexyl-4,4-dimethyl-1,3-thiazolidine ( 0.70 g, 33%).

MP: 134 ° C.

Where appropriate, the product is converted to the hydrochloride salt by dissolving the free base (5 mmol) in diethyl ether (50 mL) and treating the solution with 2 N ethereal hydrochloric acid until no precipitate precipitates. The resulting suspension was filtered and the resulting solids were washed with diethyl ether (25 mL) followed by ethyl acetate (25 mL).

757 / B

101

C10A. General method for reacting 2-chlorothiazolinium salts with anilines. Synthesis of 2- (2- (N-phenylcarbamoyl) phenylimino) -3,4-diisobutyl-1,3-thiazolidine.

A solution of 2- (N-phenylcarbamoyl) aniline (0.097 g, 0.36 mmol, 1.0 equiv.) And triethylamine (0.5 mL, 3.6 mmol, 10 equiv.) In p-dioxane (5 mL) was added. added to a solution of (4S) -2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride in dichloroethane (Method B10a, 0.12 M, 0.5 mL, 0.36 mmol). The resulting mixture was heated at 70 ° C overnight, then cooled to room temperature and diluted with ethyl acetate (25 mL). The ethyl acetate mixture was washed successively with water (2 x 25 mL) and saturated sodium chloride solution (25 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residue is absorbed onto silica and purified by MPLC (Biotage 40 S silica gel column, 5% ethyl acetate / hex) to give 2- (2- (N-phenylcarbamoyl) phenylimino) -3,4-diisobutyl-1,3-thiazolidine (0.090 g, 61%).

C11a. General method for the synthesis of 2-imino-1,3-thiazolidin-5-ones by reaction of amino acid esters with isothiocyanates. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-5-one.

757 / B

102

A solution of N-isobutylglycine ethyl ester (0.41 g, 2.57 mmol) in water (15 mL) was treated with triethylamine (0.71 mL, 5.15 mmol) followed by a solution of 2-methyl-4-nitrophenylisothiocyanate (0.50 g, 2.57 mmol) in acetone (5 mL). The resulting mixture was heated at 40 ° C for 2 hours, then cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between water (25 mL) and ethyl acetate (25 mL). The organic phase was dried (magnesium sulfate) and evaporated under reduced pressure to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-5-one (0.16 g, 88%).

MP: 152 [deg.] C.

D. General Methods for Interconversion of Iminoheterocycles

D1a. General method for neutralizing iminoheterocyclic salts. Synthesis of (4S) -2 (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

To a mixture of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt (Method C6a, 304 g, 0.8 mol), water (1 L) and ethyl acetate ( 1.4 L) was added sodium bicarbonate (150 g, 1.78 mol, 2.2 equiv). The resulting mixture was stirred for 1 hour. The organic layer was dried (magnesium sulfate) and evaporated under reduced pressure. The resulting viscous oil was treated with 100% ethanol and evaporated twice under reduced pressure to give (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine as a low melting solid (264). g, 96%).

757 / B

103

MP: Deň: 32 ° C.

[α] _D = + 2.4 (c 1.0, CH 3 OH).

¹ H NMR (CDCl 3) δ 0.92-0.99 (m, 12H), 1.13 (t, J = 7.4 Hz, 3H), 1.47-1.52 (m, 1H), 1 58-1.67 (m, 2H), 2.07-2.11 (m, 1H), 2.54 (q, J = 7.4 Hz, 2H), 2.84 2.90 (m, 2H), 3.28 (dd, J = 10.6, 6.6 Hz, 1H), 3.68 (dd, J = 13.6, 8.1 Hz, 1H),

3.81-3.87 (m, 1H), 6.85 (d, J = 7.9 Hz, 1H), 7.36-7.42 (m, 2H).

CI-MS m / z 344 ((M + H) &lt; ^{+ &gt;} ).

D1b. General method for neutralizing iminoheterocyclic salts. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

o ₂ n

Me

X-

To 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane hydrochloride salt (Method C 6b, 52.4 g, 0.132 mol) dissolved in a mixture of water (300 mL) and ethyl acetate (500 mL) was added sodium bicarbonate (15 g, 0.178 mol, 1.3 equiv). The mixture was stirred for 1 hour and the resulting organic layer was dried (magnesium sulfate) and evaporated under reduced pressure. The resulting pale yellow solid was treated with 100% ethanol (100 mL) and evaporated twice under reduced pressure to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (46). g, 97%).

MP: Mp 111-112 ° C.

¹ H NMR (CDCl 3) 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, 1H), 6.87 (d, J = 8.5 Hz, 1H), 8.02 (m,

757 / B

104

2Η).

CI-MS m / z 360 ((M + H) &lt; ^{+ &gt;} ).

D2a. General method of alkylation of nitrogen in the ring of 2-imino-heterocycles. Synthesis of (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt.

A suspension of (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine (Method C1a, 0.10 g, 0.34 mmol), isobutyl bromide (0.11 mL, 1 , 03 mmol) and CS 2 CO 3 (0.12 g, 0.38 mmol) in Ν, Ν-dimethylformamide (2 mL) was heated at 90 ° C for 18 hours, then cooled to 20 ° C, diluted with ethyl acetate (50 mL). ml) and washed with water (2 x 200 ml). The organic phase is dried (magnesium sulphate), evaporated under reduced pressure and the residue purified by chromatography (silica, gradient from 100% hex to 10% ethyl acetate / hex). The resulting material was dissolved in dichloromethane (10 mL), treated with a solution of hydrochloric acid (1M in diethyl ether, 2 mL) and then evaporated under reduced pressure to give the (4S) -2- (2-methyl-4-nitrophenylimino) hydrochloride salt. -3,4-diisobutyl-1,3-thiazolidine (0.088 g, 68%).

TLC (free base, 20% ethyl acetate / hex) R _f 0.74.

D2B. General method of alkylation of nitrogen in the ring of 2-imino-heterocycles. synthesis

1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

757 / B

105

A solution of 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (Method C2a, 33.2 g, 114 mmol) in N, N-dimethylformamide (1 L) was treated with sodium hydroxide. (690 g, 17.3 mol) and cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was stirred at 20 to 40 ° C for 18 hours, then cooled to 4 ° C and treated with water (1, 5 I). Concentrated hydrochloric acid solution was added to adjust the pH to 0 and the mixture was extracted with ethyl acetate (80 mL). The organic phase was washed with 1N hydrochloric acid solution (1 L), dried (magnesium sulfate) and evaporated under reduced pressure. The residue was dissolved in dichloromethane (500 mL) and filtered through a pad of silica gel (9 x 4 cm). Hexane was added to the resulting solution, and the volatiles were evaporated under partial vacuum until crystals formed. The solids were collected to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane as yellow crystals (10.9 g, 26%).

MP: Mp 118-119 ° C.

TLC (5% ethyl acetate / hex) R _f 0.34.

D2C. General method of alkylation of nitrogen in the ring of 2-imino-heterocycles. Synthesis of (4R) -3-isobutyl-4-isopropyl-2- (2-methyl-4-nitrophenylimino) tetrahydro-2H-1,3-thiazine.

757 / B

106

(R) -4-Isopropyl-2- (2-methyl-4-nitrophenylimino) -2,3,4,5-tetrahydro-1,3-thiazine (Method C3a) was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4R) -3-Isobutyl-4-isopropyl-2- (2-methyl-4-nitrophenylimino) tetrahydro-2H-1,3-thiazine (0.081 g, 32%).

TLC (33% ethyl acetate / hex) Rf 0.76.

D2d. General method of alkylation of nitrogen in the ring of 2-imino-heterocycles. 2- (2-methyl-4-nitrophenylimino) -3-propanoyl-1,3-thiazolidine.

To a solution of 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine (prepared in a manner analogous to that described in Method C1a, 0.084 g, 0.35 mmol) in dichloromethane (5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and triethylamine (0.049 mL, 0.35 mmol). The mixture was allowed to stir at room temperature for 1 hour and then diluted with dichloromethane (40 mL). The resulting solution was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residue is purified

757 / B

107 by preparative TLC (40% ethyl acetate / hex) to afford 2- (2-methyl-4-nitrophenylimino) -3-propanoyl-1,3-thiazolidine (0.036 g, 35%).

FAB-MS m / z 294 ((M + H) &lt; ^{+ &gt;} ).

D2E. General method of alkylation of nitrogen in the ring of 2-imino-heterocycles. Synthesis of 1- (cyclohexylmethyl) -2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

To a solution of 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (Method C2a, 0.10 g, 0.3432 mmol) and bromomethylcyclohexane (1.00 mL) in N, N-dimethylformamide (1.00 mL) was added sodium hydroxide (approximately 0.13 g). The resulting mixture was stirred at 45 ° C for 2 days, during which time it turned from purple red to bright orange. The reaction mixture was then cooled to room temperature, filtered and evaporated under reduced pressure. The residual oil is purified by chromatography (silica, 5% ethyl acetate / hex) to give 1- (cyclohexylmethyl) -2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (0.042 g, 32 %).

MP: Mp 85-87 ° C.

D2F. General method of alkylation of nitrogen in the ring of 2-imino-heterocycles. Synthesis of (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.

757 / B

108

NC

To a solution of (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine (Method C 1c, 0.050 g, 0.16 mmol) in N, N-dimethylformamide (1, 0 mL) was added NaH (0.0045 g, 1.1 equiv) and the resulting mixture was stirred at room temperature for 5 minutes. 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 and then evaporated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C-18 column, gradient from 0.1% trifluoroacetic acid / 20% CH ₃ CN / 79.9% water to 0.1% trifluoroacetic acid / 99.9% CH ₃ CN) to give the (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt (0.030 g, 52% yield).

T2G. General method of alkylation of nitrogen in the ring of 2-imino-heterocycles. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -4,4-dimethyl-1,3-thiazolidine hydrobromide salt.

Me

757 / B

109

2- (2-Methyl-4-nitrophenylimino) -4,4-dimethyl-1,3-thiazolidine was prepared in a manner analogous to that described in Method C1a. 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-1-yl bromide (4). (5 mmol) was added and the reaction mixture was heated to reflux for 3 hours, 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 dichloromethane (20 mL) to give the 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -4,4-dimethyl-1, hydrobromide salt. 3-thiazolidine (1.14 g, 77%).

MP: 229 ° C.

D2H. General method of alkylation of nitrogen in the ring of 2-imino-heterocycles. Synthesis of 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

Me

To a solution of 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane (Method C1e, 0.192 g, 0.669 mmol) and isobutyl bromide (0.5 mL) in NaH (95%, 0.62 g, 6.69 mmol) was added portionwise in anhydrous N, N-dimethylformamide (0.5 mL). The resulting mixture was heated at 50 ° C for 3 hours, then treated with methanol (approximately 0.5 mL) and evaporated under reduced pressure. The residue is purified by chromatography (silica, gradient from 20% ethyl acetate / hex to 100% dichloromethane) to give 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -1-isobutyl-3-thia-1-azaspiro [ 4.4] nonane (0.04 g, 17%).

757 / B

110

CI-MS m / z 343 ((M + H) &lt; ^{+ &gt;} ).

D3a. General method for removing a protecting group from tert-butoxycarbamoyl-protected alcohols. Synthesis of (4S) -4- (1- (R) -hydroxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine.

The trifluoroacetic acid solution (8 mL) was cooled to 4 ° C and solid (4S) -4- (1- (R) -tert-butoxyethyl) -3-isobutyl-2- (2-methyl-4-) was added via cannula. nitrophenylimino) -1,3-thiazolidine (Method C5b, 0.16 g, 0.42 mmol). The resulting solution was warmed to 20 ° C and stirred at 20 ° C for 1.5 hours. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between diethyl ether (100 mL) and saturated sodium bicarbonate solution (100 mL). The ether layer was dried (magnesium sulfate) and evaporated under reduced pressure. The residue is purified by chromatography (silica, gradient from hexane to 10% ethyl acetate / hex) to give (4S) -4- (1- (R) -hydroxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) ) 1,3-thiazolidine (0.13 g, 90%).

TLC (25% ethyl acetate / hex) R f 0.13.

D 4. General method for the synthesis of [2-imino-1,3-thiazolidine] -3-oxides and [2-imino-1,3-thiazolidine] -3,3-dioxide by oxidation of 2-imino-1,3-thiazolidines. Synthesis of [1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane] -3-oxide and [1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) - 3-thia-1-azaspiro [4.4] nonane] -3,3dioxidu.

757 / B

111

A solution of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (Method D2b, 0.041 g, 0.11 mmol) a. m-chloroperbenzoic acid (about 80%, 0.040 g, 0.19 mmol) in dichloromethane (5 mL) was stirred for 30 minutes, then washed with saturated sodium bicarbonate, dried (magnesium sulfate) and evaporated under reduced pressure. The residue is purified by chromatography (silica, gradient from hexane to 30% ethyl acetate / hex) to give [1-cyclopentyl-2- (2-methyl-4-nitrophenyl-imino) -3-thia-1-azaspiro [4.4] nonane] - 3,3-dioxide (0.030 g, 67%) followed by [1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-tha-1-azaspiro [4.4] nonane] -3-oxide (0.011 g, 26%).

[1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane] -3,3dioxid:

TLC (25% ethyl acetate / hex) R _f 0.27.

[1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane] -3-oxide: TLC (25% ethyl acetate / hex) Rf 0.10.

D5a. General method for reducing ketones or aldehydes containing heterocycles. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-hydroxybutyl) -1,3-thiazolidine.

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112

0 ₂ Ν

HO

2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine was prepared in a manner analogous to that described in Method C2a and alkylated with 1-bromo-3,3-dimethyl-2-butanonone in a manner analogous to that described in Method D2a to give 2 - (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-oxobutyl) -1,3tiazolidínu. To a solution of 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-oxobutyl) 1,3-thiazolidine (0.022 g, 0.065 mmol) in methanol (2 mL) was added portionwise NaBH ₄ (0.0096 g, 0.26 mmol). The resulting mixture was stirred at room temperature for 4 hours, then partitioned between ethyl acetate (10 mL) and water (5 mL) and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed successively with water (15 mL) and saturated sodium chloride solution (15 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residue was purified by preparative TLC (20% ethyl acetate / hexane) to give 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-hydroxybutyl) -1,3-thiazolidine (0.024 g, 92%) . FAB-MS 338 ((M + H) &lt; ^{+ &gt;} ).

D6a. General method of interconversion of carboxyl derivatives. Synthesis of (4S) 2- (4-carbamoyl-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

ABOUT

HO '

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113

Step 1

To a solution of (4S) -2- (4-methoxycarbonyl-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine (prepared in a manner analogous to that described in Method D2a, 0.035 g, 0.097 mmol) in a mixture of methanol (1.5 mL) and water (1.5 mL) were added lithium hydroxide (0.016 g, 0.39 mmol). The resulting mixture was stirred at room temperature for 2 days and then evaporated under reduced pressure. The residue was adjusted to pH 1 with 1% hydrochloric acid solution and then extracted with ethyl acetate (4 x 10 mL). The combined organic layers were washed successively with water (15 mL), saturated sodium chloride solution (15 mL), and dried (sodium sulfate). Evaporation under reduced pressure gave (4S) -2- (4-carboxy-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine (0.034 g, 100%).

TLC (40% ethyl acetate / hex) R f 0.08. This material was used in the next step without further purification.

Step 2

To a solution of (4S) -2- (4-carboxy-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine (0.035 g, 0.10 mmol) in dichloromethane (5 mL) was added carbonyldiimidazole (0.047 g, 0 mmol). , 29 mmol). The mixture was allowed to stir at room temperature for 2 hours, then anhydrous ammonia (approximately drops) precipitated into the solution at -78 ° C. The resulting mixture was warmed to room temperature overnight and then treated with water (20 mL). The aqueous layer was extracted

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114 dichloromethane (3 x 20 mL), washed successively with water (20 mL) and saturated sodium chloride solution (20 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residue was purified by flash chromatography (40% ethyl acetate / hexane) to afford (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 of interconversion of carboxyl derivatives. Synthesis of 2- (2-ethyl-4- (N-methylcarbamoyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

about

MeHN-

To a solution of 2- (4-carboxy-2-ethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D9a, 0.58 g, 0.167 mmol) in chloroform (5 mL) was added SOCI ₂ (0.06 mL, 0.83 mmol). The reaction mixture was refluxed for 3 hours and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and treated with ethylamine (2.0 M in tetrahydrofuran, 4 mL). The reaction mixture was stirred at room temperature for 2 hours and then treated with 1N sodium hydroxide solution (10 mL). The resulting mixture was extracted with dichloromethane (3 x 20 mL) and the combined organic layers were washed with brine (20 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residue was purified by preparative TLC (50% ethyl acetate / hexane) to give 2- (2-ethyl-4- (N-methylcarbamoyl) phenylimino) -1-cyclopentyl-3-thia-131 757 / B

115 azaspiro [4.4] nonane (36 g, 56%). TLC (30% ethyl acetate / hex) R _f 0.44.

D7a. General method for the synthesis of cyanoarylimines from iodarylimines. Synthesis of 2- (4-cyano-2-propylphenylimino) -3-thia-1-azaspiro [4.4] nonane.

4-Iodo-2-n-propylaniline is converted to 4-iodo-2-n-propylphenylisothiocyanate in a manner analogous to Method A2b. In parallel, 1-amino-1- (hydroxymethyl) cyclopentane is converted to the chloromethyl analog and then reacted with the isothiocyanate in a manner analogous to Method C2a to give 2- (4-iodo-2-propylphenylimino) -3-thia-1-azaspiro [4.4] nonane . A suspension of 2- (4-iodo-2-propylphenylimino) -3-thia-1-azaspiro [4.4] nonane (0.54 g, 1.35 mmol) and CuCN (0.24 g, 2.70 mmol) in Ν The Ν-dimethylformamide (4 mL) was heated at 140 ° C overnight. The resulting mixture was cooled to room temperature, evaporated under reduced pressure and purified by flash chromatography (10% ethyl acetate / hex) to afford 2- (4-cyano-2-propylphenylimino) -3-thia-1-azaspiro [4.4] nonane as a white solid. (0.26 g, 65%).

TLC (30% ethyl acetate / hex) R f 0.37.

D8a. General method for the synthesis of phenylacetylenes. Synthesis of 2- (2,3-dimethyl-4-ethynylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

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116

Me ₃ Si

Me

WITH

N

Λ

Step 1

4-Iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenylisothiocyanate in a manner analogous to Method A2b. 2- (2,3-dimethyl-4-iodophenylimino) -3-thia-1-azaspiro [4.4] nonane was prepared by a method analogous to that described in Method C2a, then alkylated with isobutyl bromide in a manner analogous to that described in Method D2a, iodophenyl compound (0.009) g, 0.021 mmol) of (trimethylsilyl) acetylene (30 mL, 0.21 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (0.005 g) and CuI (0.012 g, 0.063 mmol) in triethylamine (2 mL) were stirred at temperature room 18 hours. The resulting suspension is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by preparative TLC (2% ethyl acetate / hex) to give 2- (2,3-dimethyl-4- (2-trimethylsilyl-1-ethynyl) phenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4]. ] nonane (0.005 g, 59%).

H

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117

Step 2

A mixture of 2- (2,3-dimethyl-4- (2-trimethylsilyl-1-ethynyl) phenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane (0.005 g, 0.0125 mmol) and sodium hydroxide (0.006 g, 0.15 mmol) in methanol (2 mL) was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 mL), filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by preparative TLC (2% ethyl acetate / hex) to give 2- (2,3-dimethyl-4-ethynyl-phenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane (0.0032 g, 78 %).

TLC (20% ethyl acetate / hex) R _f 0.70.

D9a. General process for the synthesis of benzoic acids by hydrolysis of benzonitriles. Synthesis of 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

ABOUT

HO '

2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane is prepared by a method analogous to method C2a and the thiazolidine is alkylated by a method analogous to method D2b to give 2- (4-cyano-2-ethylphenylimino) A solution of 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.32 g, 9.42 mmol) ) in concentrated hydrochloric acid (15 mL) was heated at 100 ° C overnight and then cooled to room temperature to give a white precipitate.

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118 was adjusted to pH 6.5 with 1N sodium hydroxide solution and then extracted with dichloromethane (4 x 40 mL). The combined organic layers were washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried (sodium sulfate) and evaporated under reduced pressure to give 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia -1-azaspiro [4.4] nonane as a white solid (0.34 g, 100%).

MP: Mp 208-209 ° C.

D10a. General method for converting carboxylic acids to ketones. Synthesis of 2- (4-acetyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

To a solution of 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D9a, 0.046 g, 0.128 mmol) in tetrahydrofuran (10 mL) at -78 ° Methyl lithium (1.4 M in diethyl ether, 0.91 mL, 1.28 mmol) was added. The reaction mixture was allowed to gradually warm to room temperature and then stirred overnight. Trimethylsilyl chloride (0.5 ml) was added and the mixture was stirred at room temperature for 2 hours, then 1N hydrochloric acid solution (2 ml) was added. The mixture was stirred for 0.5 h and then treated with saturated sodium bicarbonate solution (10 mL). The resulting mixture was extracted with ethyl acetate (4 x 20 mL), and the combined organic layers were washed with brine (30 mL), dried (sodium sulfate) and evaporated under reduced pressure. The residue was purified by preparative TLC (10% ethyl acetate / hex) to afford 2- (4-acetyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane as a white solid

757 / B

119 (0.032 g, 73%). MP: Mp 114-115 ° C.

D11a. General process for the conversion of nitriles to aldehydes. Synthesis of 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane was prepared by a method analogous to method C2a and the thiazolidine was alkylated by a method analogous to method D2b to give 2- (4-cyano-2-ethylphenylimino) -1cyklopentyl-3-thia-1-azaspiro [4.4] nonane. To a solution of 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.21 g, 0.60 mmol) in anhydrous toluene (20 mL) at -78. DIBAL (1.0 M in toluene, 1.20 mL, 1.20 mmol) was added at 0 ° C. The reaction mixture was stirred at -78 ° C for 3 hours, then ethyl acetate (3 mL) was added at -78 ° C, stirring was continued for 0.5 hours, and wet silica gel (5% water, 2 g) was added. The reaction mixture was warmed to room temperature, stirred for 3 hours and then filtered through a pad of Celite. The filtrate was evaporated under reduced pressure and the residue was purified by preparative TLC (30% ethyl acetate / hex) to give 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-azaspiro [4.4] -nonane as a white solid (0.16 g, 7.5%).

MP: Mp 104-105 ° C.

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120

D12a. General methods of chain homologation of aldehydes or ketones. Synthesis of 2- (2-ethyl-4 - ((1E) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

To a solution of 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D11a, 0.053 g, 0.149 mmol) in CH ₃ CN was added lithium chloride (0.0076 g, 0.182 mmol) followed by DBU (0.025 g, 0.167 mmol) and triethylphosphonoacetate (0.041 g, 0.182 mmol). The reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue is purified by flash chromatography (3% ethyl acetate / hex) to give 2- (2-ethyl-4 - ((1 E) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] non-colorless oil (0.029 g, 48%).

TLC (30% ethyl acetate / hex) Rf 0.68.

D12b. General methods of chain homologation of aldehydes or ketones. Synthesis of 2- (2-ethyl-4 - ((1E) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

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121

To a solution of 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D11a, 0.041 g, 0.115 mmol) in dichloromethane (10 mL) MeNO ₂ (2 drops) and piperidine (4 drops) were added. The reaction mixture was heated at reflux overnight, then cooled to room temperature and evaporated under reduced pressure. The residue is purified by flash chromatography (3% ethyl acetate / hex) to give 2- (2-ethyl-1-4 - ((1 E) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane as a red solid (0.022 g, 48%) ·

MP: M.p. 141-142 ° C.

D12C. General methods of chain homologation of aldehydes or ketones. Synthesis of 2- (2-ethyl-4- (2,2-dicyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

NC

To a solution of 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D11a, 0.037 g, 0.104 mmol) in ethanol (10 mL) was added malononitrile (0.007). g, 0.104 mmol) and piperidine (4 drops). The reaction mixture was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residue was purified by preparative TLC (20% ethyl acetate / 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: Mp 135-136 ° C.

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122

D12D. General methods of chain homologation of aldehydes or ketones. Synthesis of 2- (2-ethyl-4- (2-cyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

To a solution of potassium hydroxide (0.024 g, 0.36 mmol) in CH ₃ CN (20 mL) at reflux temperature was added 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4]. ] nonane (Method D11a, 0.127 g, 0.36 mmol). The reaction mixture was heated to reflux for 4 hours, cooled to room temperature and evaporated under reduced pressure. The residue was diluted with water (15 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic layers were washed with saturated sodium chloride solution and dried (sodium sulfate). The resulting material was purified by preparative TLC (30% ethyl acetate / hex) to give 2- (2-ethyl-4- (2-cyano-vinyl) -phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane as a cis / trans mixture isomers in a ratio of 1: 3 (0; 050 g).

TLC (30% ethyl acetate / hex) Rf 0.56.

D13a. A general method for alkylating chloromethyl side chains. Synthesis of 2- (2-methyl-4-nitrophenylimino) -4- (N-methylaminomethyl) -1,3-thiazolidine.

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123 ο ₂ ν

Me

MeHN-

To a solution of methylamine in methanol (2.0 M, 5 mL) was added 2- (2-methyl-4-nitrophenylimino) -4- (chloromethyl) -1,3-thiazolidine (prepared in a manner analogous to that described in Method C2a, 0.040 g, 0.140 mmol) and the resulting mixture was stirred at room temperature for 72 hours. The mixture was evaporated under reduced pressure and the resulting residue was purified by flash chromatography (5% methanol / CH 2 Cl 2) for. to obtain 2- (2-methyl-4-nitrophenylimino) -4- (N-methylaminomethyl) -1,3-thiazolidine as a solid (0.014 g, 35%).

D14a. Acid catalyzed rearrangement of double bonds between carbon atoms. Synthesis of 2- (4-nitrophenylimino) -3- (2-methylprop-1-en-1-yl) -1,3-thiazolidine.

2-Chloroethylammonium chloride (Formula 1) is reacted with 4-nitrophenylisothiocyanate according to Method C1a to give 2- (4-nitrophenyl) -1,3-thiazolidine. Thiazolidine is reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,331 757 / B

124 thiazolidine. A mixture of 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine (0.20 g) in polyphosphoric acid (0.4 mL) was heated to 80 ° C. ° C 5 hours. The reaction mixture was then dissolved in water at 0 ° C (20 mL) by sonication. The pH of the aqueous mixture was adjusted to 12 with 1N sodium hydroxide solution, then extracted with ethyl acetate (3 x 25 mL). The combined organic phases were dried (potassium carbonate) and evaporated under reduced pressure. The residue (0.21 g) was purified by preparative HPLC to give 2- (4-nitrophenylimino) -3- (2-methylprop-1-en-1-yl) -1,3-thiazolidine.

Specific preparation of compounds

Descriptions of the detailed preparation steps used to prepare the specific compounds shown in Tables 1-4 are provided below. Many of the compounds listed in the tables can be synthesized in a variety of ways. Thus, the specific examples are provided by way of illustration and are not to be construed as limiting the scope of the invention in any way.

Item 1

Me

The 2-chloroethylamine hydrochloride salt is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine.

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125

Item 2

2-chloroethylammonium chloride (item 1) is reacted with 4-nitrophenylisothiocyanate according to Method C1a to give 2- (4-nitrophenylimino) -1,3-thiazolidine which is reacted with isobutyl bromide according to Method D2a to provide 2- (4-nitrophenylimino) 3-isobutyl-1,3tiazolidínu.

Item 3

2-Chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate which is treated with isobutyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine.

Item 4

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126

2-chloroethylammonium chloride (item 1) is reacted with 2,3-dichlorophenylisothiocyanate according to method C1a to give 2- (2,3-dichlorophenylimino) -1,3-thiazolidine which is reacted with isobutyl bromide according to method D2a to give 2- (2,3) -dichlórfenylimino) -3-isobutyl-1,3tiazolidínu.

Item 5

i-Bu MeO

N-chloroethyl-N'-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 2-methoxy-4-nitrophenylisothiocyanate according to Method C1d to give 2- (2-methoxy-4-nitrophenylimino) -3-isobutyl-1, 3tiazolidínu.

Item 6

CN i-Bu

Chloroethyl N'-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 4-cyanophenylisothiocyanate according to Method C1d to provide 2- (4-cyanophenylimino) -3-isobutyl-1,3-thiazolidine.

757 / B

127

Item 7

HCl no,; ’D,. i. /

-B at Me

2-Chloroethylammonium chloride (item 1) is reacted with 2-methyl-5-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with isobutyl bromide according to method D2a to give the hydrochloride salt of 2- (2-methyl-5-nitrophenylimino) -3- isobutyl-1,3-thiazolidine.

Item 8

//

et

CN i-Bu

N-chloroethyl-N'-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1d to give 2- (4-cyano-2-ethylphenylimino) -3-isobutyl-1, 3tiazolidínu.

Item 9

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128

N-chloroethyl-N'-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 4-chloro-2- (trifluoromethyl) phenyl isothiocyanate according to Method C1d to give 2- (4-chloro-2- (trifluoromethyl) phenylimino) - 3-isobutyl-1,3-thiazolidine.

Item 10

WITH.

2-chloroethylammonium chloride (item 1) is reacted with 4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1-bromo-2-methyl-2-propene according to method D2a to give 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine. 3-Allyl-1,3-thiazolidine is rearranged according to Method D14a to give 2- (4-nitrophenylimino) -3- (2-methylprop-1-en-1-yl) -1,3-thiazolidine.

Item 11

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1-bromo-2-methyl-2-propene according to method D2a to give 2- (2- methyl-4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine.

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129

Item 12

P

2-chloroethylammonium chloride (item 1) is reacted with 4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1-bromo-2-methyl-2-propene according to method D2a to give 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine.

Item 13

Cl

Cl

2-chloroethylammonium chloride (item 1) is reacted with 3,4-dichlorophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1-bromo-2-methyl-2-propene according to method D2a to give 2- (3,4-dichlorophenylimino) ) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine.

Item 14

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130

N- (2-hydroxyethyl) -N- (2-methylbutyl) amine is reacted with thionyl chloride according to Method B7a to provide N- (2-chloroethyl) -N- (2-methylbutyl) ammonium chloride. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl) -1,3-thiazolidine.

Item 15

WITH.

Me

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 4-bromobut-1-ene according to method D2a to give 2- (2-methyl-4-nitrophenylimino) - 3- (but-1-en-4-yl) -1,3-thiazolidinone.

Item 16

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1-bromobut-2-yne according to method D2a to give 2- (2-methyl-4-nitrophenylimino) - 3- (but-2-yn-1-yl) -1,3-thiazolidine.

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131

Item 17

Ο-.

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 2-ethylbutyl bromide according to method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- ethyl-1-butyl) -1,3-thiazolidine.

Item 18

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 2-methylbutyl bromide according to method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- ( 2-methyl-1-butyl) -1,3-thiazolidine.

Item 19

Me

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132

2-Chloroethyl ammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine which is reacted with 1-nonyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (1) (nonyl) -1,3-thiazolidine.

Item 20

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 2,2-dimethylpropyl bromide according to method D2a to give 2- (2-methyl-4-nitrophenylimino) - 3- (2,2-dimethylpropyl) -1,3-thiazolidine.

Item 21

The 2-butylamine is converted to N- (2-hydroxyethyl) -N- (2-butyl) amine according to Method B5a. The amine is reacted with thionyl chloride according to Method B7a to give N- (2-chloroethyl) -N- (2-butyl) ammonium chloride. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-butyl) -1,3-thiazolidine.

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133

Item 22

no ₂

3-Pentylamine is converted to N- (2-hydroxyethyl) -N- (3-pentyl) amine according to Method B5a. The amine is reacted with thionyl chloride according to Method B7a to give N- (2-chloroethyl) -N- (3-pentyl) ammonium chloride. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (3-pentyl) -1,3-thiazolidine.

Item 23

Me

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1-heptyl bromide according to method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (1) heptyl) -1,3-thiazolidine.

Item 24

757 / B

134

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine which is reacted with 8-bromo-1-octene according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) - 3- (oct-1-en-8-yl) -1,3-thiazolidine.

Item 25

The 2-propyl-1-hydroxypentane is converted to 1-bromo-2-propylpentane according to method B2b, step 2. 2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give the thiazolidine which is reacted with 1-bromo-2-propylpentane according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-propyl-1-pentyl) -1,3-thiazolidine.

Item 26

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1,1-dicyclopropylbut-1-en-4-yl bromide according to method D2a to give 2- (2) methyl-4-nitrophenylimino) -3- (1,1-dicyclopropylbut-1-en-4-yl) 1,3-thiazolidine.

757 / B

135

Item 27

2,6-Dichloro-4-nitrophenylisothiocyanate is reacted with 2-butylamine followed by chloroacetic acid according to Method C8a to give 2- (2,6-dichloro-4-nitrophenylimino) -3- (2-butyl) -1,3-thiazolidine -4-one.

Item 28

NO ₂

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with (E / Z) -1,3-dibromopropene according to method D2a to give 2- (2-methyl) -4-nitrophenylimino) -3- (bromoprop-1-en-3-yl) -1,3-thiazolidine as an E / Z mixture. The mixture was partitioned using preparative TLC to give 2- (2-methyl-4-nitrophenylimino) -3 - ((Z) -bromoprop-1-en-3-yl) -1,3-thiazolidinone.

Item 29

757 / B

136

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with (E) -1,3-dichloropropene according to method D2a to give 2 (2-methyl-4- nitrophenylimino) -3 - ((E) -chlórprop-1-en-3-yl) -1,3-thiazolidine.

Item 30

NO ₂

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 3-chloro-1-propyne according to method D2a to give 2- (2-methyl-4-nitrophenylimirio) - 3- (prop-1-yn-3-yl) -1,3-thiazolidine.

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with (E / Z) -1,3-dibromopropene according to method D2a to give 2- (2-methyl) -4-nitrophenylimino) -3- (bromoprop-1-en-3-yl) -1,3-thiazolidine as an E / Z mixture. The mixture was partitioned using preparative TLC to give 2- (2-methyl-4-nitrophenylimino) -3 - ((E) -bromoprop-1-en-3-yl) -1,3-thiazolidine.

757 / B

137

Item 32

Eto

Ô OEt

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with ethyl [(Z) -4-chloro-3-ethoxybut-2-enoate] according to method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-ethoxycarbonyl-2-ethoxyprop-1-en-3-yl) -1,3-thiazolidine.

Item 33

MeO

Me

2-Chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method Cla to give a thiazolidine which is reacted with methyl [4-bromobutanoate] according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) 3- (1-methoxycarbonyl-3-propyl) -1,3-thiazolidine.

Item 34

MeO N

Me

757 / B

138

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with methyl chloroacetate according to method D2a to give 2- (2-methyl-4-nitrophenylmethyl) methoxy- ) -1,3-thiazolidine.

Item 35

C

Ph N —I M e

HO

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with α-chloroacetophenone according to method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (1) oxo-1-phenyl-2-ethyl) -1,3-thiazolidine. The ketone is reduced according to Method D5a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-hydroxy-1-phenyl-2-ethyl) -1,3-thiazolidine.

Item 36

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate by method C1a to give thiazolidine, which is reacted with 1-chloro-3,3-dimethyl-2-butanone according to method D2a to afford 2 (2-methyl) -4-nitrophenylimino) -3- (2-oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine.

757 / B

139

Item 37

Q ^{> n} - CA ⁿ ° ^: > —I Me

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method 01a to give a thiazolidine which is reacted with 1-chloro-2-butanone according to method D2a to give 2- (2-methyl-4-nitrophenylimino) - 3- (2-oxo-1-butyl) -1,3-thiazolidine.

Item 38

no ₂

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1-chloro-2-butanone according to method D2a to give 2- (2-methyl-4-nitrophenylimino) - 3- (2-oxo-1-butyl) -1,3-thiazolidine. The ketone is reduced according to Method D5a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-hydroxy-1-butyl) -1,3-thiazolidine.

Item 39

757 / B

140

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1-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) -1,3tiazolidínu. The ketone is reduced according to Method D5a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-hydroxy-3,3-dimethyl-1-butyl) -1,3-thiazolidine.

Item 40

/ J

NO ₂

Me

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine which is 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.

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with 1,1,3-trichloro-1-propane according to method D2a to yield

2- (2-methyl-4-nitrophenylimino) -3- (1,1-dichloroprop-1-en-3-yl) -1,3-thiazolidine.

757 / B

141

Item 42

NO ₂

Me

ABOUT'

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine which is reacted with propionyl chloride according to method D2d to give 2- (2-methyl-4-nitrophenylimino) -3- (1-oxo) -1-propyl) -1,3-thiazolidine.

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine which is reacted with (E) -1-chloro-5-methoxy-2-pentene according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) -3 - ((E) -5-methoxy-pent-2-en-1-yl) -1,3-thiazolidine.

Item 44

757 / B

142

The 2-hydroxyethylamine and cyclopentanone are reacted according to Method B4b, Step 1 to give 4-aza-1-oxaspiro [4.4] nonane. Oxazolidine is reduced according to Method B4b, Step 2 to provide N-cyclopentyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclopentyl-N- (2-chloroethyl) amine. The amine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1d to provide 2- (2-methyl-4-nitrophenylimino) -3- (cyclopentyl) -1,3-thiazolidine.

Item 45

The 2-hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to provide 4-aza-1-oxaspiro [4.4] nonane. Oxazolidine is reduced according to Method B4b, Step 2 to provide N-cyclopentyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclopentyl-N- (2-chloroethyl) amine. The amine is reacted with 2-methoxy-4-nitrophenylisothiocyanate according to Method C1d to provide 2- (2-methoxy-4-nitrophenylimino) -3- (cyclopentyl) -1,3-thiazolidine.

Item 46

757 / B

143

The 2-hydroxyethylamine and cyclopentanone are reacted according to Method B4b, Step 1 to provide 4-aza-1-oxaspiro [4.4] nonane. The oxazolidine is reduced according to Method B4b, Step 2 to provide N-cyclopentyl-N- (2-hydroxyethyl) amine The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclopentyl-N- (2-chloroethyl) amine. 3-dichlorophenylisothiocyanate according to Method C1d to provide 2- (2,3-dichlorophenylimino) -3-cyclopentyl-1,3-thiazolidine.

Item 47

Cyclohex-2-en-1-one is reduced according to Method B2b, Step 1 to provide cyclohex-2-en-1-ol. The alcohol is converted to 3-bromo-1-cyclohexene according to Method B2b, Step 2, The halide is converted to N- (cyclohex-2-en-1-yl) -N (2-hydroxyethyl) amine according to Method B2b, Step 3. The alcohol is reacted with thionyl chloride according to Method B7a to provide N- (cyclohex-2-en-1-yl) N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclohex-2-en-1-yl) -1,3-thiazolidine.

Item 48

757 / B

144

The 2-hydroxyethylamine and cyclohexanone are reacted according to Method B4a, step 1 to provide 4-aza-1-oxaspiro [4.5] decane. The oxazolidine is reduced according to Method B4a, Step 2 to provide N-cyclohexyl-N- (2-hydroxyethyl) amine The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclohexyl-N- (2-chloroethyl) amine. with methoxy-4-nitrophenylisothiocyanate according to Method C1d to provide 2- (2-methyl-4-nitrophenylimino) -3-cyclohexyl-1,3-thiazolidine.

Item 49

-NO ₂

N- (2-hydroxyethyl) aniline is reacted with thionyl chloride according to Method B7a to give N- (2-chloroethyl) aniline chloride. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to provide 2- (2-methyl-4-nitrophenylimino) -3-phenyl-1,3-thiazolidine.

Item 50

2-Hydroxyethylamine is reacted with cycloheptyl bromide according to Method B2a to give N-cycloheptyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N31 757 / B

145 cycloheptyl-N- (2-chloroethyl) ammonium chloride. Chlorethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-cycloheptyl-1,3-thiazolidine.

Item 51

NO ₂

2-Hydroxyethylamine is reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give Ncyclooctyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with

2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-cyclooctyl-1,3-thiazolidine.

Item 52

2-Hydroxyethylamine is reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N -cyclooctyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2-methoxy-4-nitrophenylisothiocyanate to give 2- (2-methoxy-4-nitrophenylimino) -3-cyclooctyl-1,3-thiazolidine.

757 / B

146

Item 53

2-Hydroxyethylamine is reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give Ncyclooctyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,3-dichlorophenylisothiocyanate to give 2- (2,3-dichlorophenylimino) -3cyclooctyl-1,3-thiazolidine.

Item 54

2-Hydroxyethylamine is reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,3-dichlorophenylisothiocyanate to provide 2- (2,3-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine.

757 / B

147

Item 55

no ₂

2-Hydroxyethylamine is reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine.

Item 56

The 2-hydroxyethylamine is reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,4-dichlorophenylisothiocyanate to give 2- (2,4-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine.

Item 57

757 / B

148

2-Hydroxyethylamine is reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 3,4-dichlorophenylisothiocyanate to give 2- (3,4-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine.

Item 58

The 2-hydroxyethylamine is reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,2-dichlorophenylisothiocyanate to give 2- (2,2-dichlorophenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Item 59

Cl

757 / B

149

The 2-hydroxyethylamine is reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,4-dichlorophenylisothiocyanate to give 2- (2,4-dichlorophenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Item 60

The 2-hydroxyethylamine is reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 3,4-dichlorophenylisothiocyanate to give 2- (3,4-dichlorophenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Item 61

The 2-hydroxyethylamine is reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to yield N31 757 / B

150 cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,3-dimethylphenylisothiocyanate to give 2- (2,3-dimethylphenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Item 62

N

Me Cl

The 2-hydroxyethylamine is reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 3-chloro-2-methylphenylisothiocyanate to give 2- (3-chloro-2-methylphenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Item 63

2-Hydroxyethylamine is reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,3-dichlorophenylisothiocyanate to give 2- (2,3-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

757 / B

151

Item 64

Cl

The 2-hydroxyethylamine is reacted with cyclopentylmethyl bromide according to Method B2a to give N ^: cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 3,4-dichlorophenylisothiocyanate to give 2- (3,4-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Item 65

2-Hydroxyethylamine is reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl 3 according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. Chlorethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Item 66 _o '

757 / B

152

The 2-hydroxyethylamine is reacted with cyclopentylmethyl bromide according to method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl 3 according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,4-dichlorophenylisothiocyanate to give 2- (2,4-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Item 67

2-Hydroxyethylamine is reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. Chlorethylamine is reacted with 2,3-dimethylphenylisothiocyanate to give 2- (2,3-dimethylphenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Item 68

ci

757 / B

153

2-Hydroxyethylamine is reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. . The chloroethylamine is reacted with 3-chloro-2-methylphenylisothiocyanate to give 2- (3-chloro-2-methylphenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Item 69

Cl Cl

The 2-hydroxyethylamine is reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,3-dichlorophenylisothiocyanate to give 2- (2,3-dichlorophenylimino) -3- (cyclohexylmethyl) -1,3-thiazolidine.

Item 70

The 2-hydroxyethylamine is reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to give N31 757 / B

154 cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. Chlorethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclohexylmethyl) -1,3-thiazolidine.

The 2-hydroxyethylamine is reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl) amine. The alcohol is treated with SOCl 3 according to Method B7c to provide N-cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. Chlorethylamine is reacted with 2-methoxy-4-nitrophenylisothiocyanate to give 2- (2-methoxy-4-nitrophenylimino) -3- (cyclohexylmethyl) -1,3-thiazolidine.

Item 72

1-Cyclohexyl-1-ethylamine is converted to N- (2-hydroxyethyl) -N- (1-cyclohexyl-1-ethyl) amine according to Method B5a. The alcohol is reacted with SOCl 2 according to Method B7a to give N- (2-chloroethyl) -N- (1-cyclohexyl-1-ethyl) ammonium chloride. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-1-ethyl) -1,3-thiazolidine.

757 / B

155

Item 73

Rn Me Cl

2-Hydroxyethylamine is reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-benzyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 3-chloro-2-methylphenylisothiocyanate to give 2- (3-chloro-2-methylphenylimino) -3-benzyl-1,3-thiazolidine.

Item 74

Cl

Bn

2-Hydroxyethylamine is reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-benzyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 3,4-dichlorophenylisothiocyanate to give 2- (3,4-dichlorophenylimino) -3-benzyl-1,3-thiazolidine.

Item 75

757 / B

156

Bn Cl

Cl

2-Hydroxyethylamine is reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl 3 according to Method B7c to give N-benzyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,4-dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino) -3-benzyl-1,3-thiazolidine.

Item 76

Bn Me

2-Hydroxyethylamine is reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl 2 according to Method B7c to give N-benzyl-N- (2-chloroethyl) ammonium chloride. Chlorethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidine.

Item 77

757 / B

157

2-Hydroxyethylamine is reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-benzyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,3-dichlorophenylisothiocyanate to give 2- (2,3-dichlorophenylimino) -3-benzyl-1,3-thiazolidine.

Item 78

2-Hydroxyethylamine is reacted with 4-chlorobenzyl bromide according to Method B2a to give N- (4-chlorobenzyl) -N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N- (4-chlorobenzyl) -N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 4-cyano-2-ethylphenylisothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3- (4-chlorobenzyl) -1,3-thiazolidine.

Item 79

The 2-hydroxyethylamine is reacted with 4-chlorobenzyl bromide according to Method B2a to give N- (4-chlorobenzyl) -N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N- (431 757 / B).

158 chlorobenzyl) -N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2-chloro-4-cyanophenylisothiocyanate to give 2- (2-chloro-4-cyanophenylimino) -3- (4-chlorobenzyl) -1,3-thiazolidine.

Item 80

2-Hydroxyethylamine is reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. Chlorethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine.

Item 81

2-Hydroxyethylamine is reacted with cycloheptylmethyl bromide according to Method B. 2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is left

757 / B

159 to react with 2-methoxy-4-nitrophenylisothiocyanate to give 2- (2-methoxy-4-nitrophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine.

Item 82

2-Hydroxyethylamine is reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine is reacted with 2,3-dichlorophenylisothiocyanate to give 2- (2,3-dichlorophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine.

Item 83

2-Hydroxyethylamine is reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7c to provide N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine is reacted with 4-cyanophenylisothiocyanate to give 2- (4-cyanophenylimino) -331 757 / B

160 (cycloheptylmethyl) -1,3-thiazolidine.

Item 84

C _N / ^{c == N 1 H} C 1 ^{HNO 2} is Me

The methylcyclododecanecarboxylate is reduced according to Method B2b, Step 1 to obtain cyclododecylmethanol. The alcohol is converted to cyclododecylmethyl bromide according to method B2b, step 2. The halide is reacted with 2-hydroxyethylamine according to method B2b, step 3 to give N (2-hydroxyethyl) -N- (cyclododecylmethyl) amine. The alcohol is reacted with thionyl chloride according to Method B7a to give N- (2-chloroethyl) -N (cyclododecylmethyl) ammonium chloride. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclododecylmethyl) -1,3-thiazolidine.

Item 85

^M8 '

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine which is reacted with 3- (chloromethyl) -6,631,757 / B

161 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) - 1,3tiazolidínu.

Item 86

2-chloroethylammonium chloride (item 1) is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine which is 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.

Item 87 i-Bu

The 3-aminoquinoline is converted to the 3-quinoline isothiocyanate according to the method

A2c. (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, Steps 1-2.

The alcohol is converted to N- (1S) -1- (chloromethyl) -3- (methylbutyl) -N- (isobutyl) 31 757 / B

162 ammonium chloride as described in Method B7c. 3-Quinoline isothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3- (methylbutyl) -N- (isobutyl) ammonium chloride according to Method C1f to give 2- (3-quinolylimino) -3,5-diisobutyl- 1,3tiazolidínu.

Item 88

N 1 -Bu (1 S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, steps 1 to 2. The alcohol is converted to N- (1S) -1- (chloromethyl) -3- (methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. 4-Nitrophenylisothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3- (methylbutyl) -N- (isobutyl) ammonium chloride according to Method C1f to give 2- (4-nitrophenylimino) -3,5-diisobutyl- 1,3tiazolidínu.

Item 89 i-Bu (1S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, Steps 1-2.

757 / B

163

The alcohol is converted to N- (1S) -1- (chloromethyl) -3- (methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. 4-Cyanophenylisothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3- (methylbutyl) -N- (isobutyl) ammonium chloride according to Method C1f to give 2- (4-cyanophenylimino) -3,5-diisobutyl -1,3tiazolidínu.

Item 90

N y — v

1 H-Bu Me HCl (1 S) -1- (hydroxymethyl) -3-methylbutylamine is converted to (1 S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3 -tiazolidínu. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give the (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt.

Item 91

(1S) -1- (hydroxymethyl) -3-methylbutylamine is converted to (1R) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate was reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4R) -2- (231 757 / B).

164 methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide the (4R) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt.

Item 92

(1S) -1- (hydroxymethyl) -3-methylbutylamine is converted to (1R) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-5-nitrophenylisothiocyanate is reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4R) -2- (2-methyl-5-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give the (4R) -2- (2-methyl-5-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt.

Item 93

NO, i-Bu

Me ^HCl (1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in method B7a. 2-Methyl-5-nitrophenylisothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-5-nitrophenylimino) -4-isobutyl-1,3- thiazolidine. Thiazolidine is reacted with isobutyl bromide according to Method D2a to provide the hydrochloride salt

757 / B

165 (4S) -2- (2-methyl-5-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 94

Me Me

NO ₂

HCl (1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1R) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate was reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine . The thiazolidine is reacted with methyl iodide according to Method D2a to provide the (4R) 2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine hydrochloride salt.

Item 95 'N, Me Me

HCl (1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. The 2-methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with methyl iodide according to Method D2a to provide the (4S) -2 (2-methyl-4-nitrophenylimino) -4-isobutyl-3-methyl-1,3-thiazolidine hydrochloride salt.

757 / B

166

Item 96

NO ₂

(1S) -1- (hydroxymethyl) -3-methylbutylamine is converted to (1R) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-5-nitrophenylisothiocyanate is reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4R) -2- (2-methyl-5-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with methyl iodide according to Method D2a to give the (4R) -2 (2-methyl-5-nitrophenylimino) -4-isobutyl-3-methyl-1,3-thiazolidine hydrochloride salt.

Item 97

(1S) -1- (hydroxymethyl) -3-methylbutylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. Thiazolidine is reacted with 1-bromo-2-ethylbutane according to Method D2a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (2-ethyl-1-butyl) hydrochloride salt ) -1,3tiazolidínu.

757 / B

167

Item 98

Me

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to provide (4S) -2 (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (2-oxo-3). , 3-dimethyl-1-butyl) -1,3tiazolidínu.

Item 99

WITH.

N i-Bu Et '

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Ethyl-4-cyanophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (231 757 / B).

168 methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. Thiazolidine is reacted with isobutyl bromide according to Method D2f to provide (4S) -2- (2-ethyl-4-cyanophenylimino) -4-isobutyl-3- (2-oxo-3,3-dimethyl-1-butyl) -1,3 -tiazolidínu.

Item 100

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with cyclopropylmethyl bromide according to Method D2a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (cyclopropylmethyl) -1,3-thiazolidine.

Item 101

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -331 757 / B

169 of methylbutanammonium chloride according to Method C1a to afford (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with cyclobutylmethyl bromide according to Method D2a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (cyclobutylmethyl) -1,3-thiazolidine.

Item 102

WITH.

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. Thiazolidine is reacted with 2-chloro-3,3-dimethyl-2-butanone according to Method D2a to provide (4S) -2 (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (2-oxo-3). , 3-dimethyl-1-butyl) -1,3tiazolidínu. The ketone is reduced according to Method D5a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (3,3-dimethyl-2-hydroxy-1-butyl) -1,3-thiazolidine.

Item 103

Mei / ^N ° ² i-Bu Me HCl

757 / B

170 (1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2,6-Dimethyl-4-nitroaniline is converted to 2,6-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. 2,6-Dimethyl-4-nitrophenylisothiocyanate is reacted with (1S) -1 (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl -1,3-thiazolidine. Thiazolidine is. was reacted with isobutyl bromide according to Method D2a to provide (4S) -2- (2,6-dimethyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine hydrochloride salt.

Item 104

Cl Cl (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2,3-Dichlorophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with 3-bromopentane according to Method D2a to give (4S) -2- (2,3-dichlorophenylimino) -4-isobutyl-3- (3-pentyl) -1,3-thiazolidine.

Item 105

757 / B

171

(1S) -1- (hydroxymethyl) -3-methylbutylamine was. prepare leucine from methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3- thiazolidine. The thiazolidine is reacted with 5-iodoheptane according to Method D2a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (5-heptyl) -1,3-thiazolidine.

Item 106

Cl Cl

N

i-Bu (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2,3-Dichlorophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2,3-dichlorophenylimino) -3,4-diisobutyl-1,3-thiazolidine.

757 / B

172

Item 107

^F 3 ^C CF ₃ CO ₂ H (1 S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2- (Trifluoromethyl) nitrophenylisothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1c to give (4S) -2- (2- (trifluoromethyl) -4-nitrophenylimino) -4-isobutyl-1 trifluoroacetate salt. , 3tiazolidínu.

Item 108

NO ·

CF 3 CO 2 H (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2- (Trifluoromethyl) -4-nitrophenylisothiocyanate was reacted with (1S) -1- (chloromethyl) 3-methylbutanammonium chloride according to Method C1c to afford (4S) -2- (2 (Trifluoromethyl) -4-nitrophenylimino) -4-isobutyl -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2f to provide the (4S) -2- (2- (trifluoromethyl) -4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.

757 / B

173

Item 109 p

cf ₃ co ₂ h (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 4-Cyano2- (trifluoromethyl) phenyl isothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1c to give (4S) -2- (4-cyano-2- (trifluoromethyl) phenylimino) -4-isobutyl-1 , 3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2f to provide the (4S) -2- (4-cyano-2- (trifluoromethyl) phenylimino) -3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.

Item 110 ci

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Chloro-4-cyano-6-methylphenylisothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1c to afford (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -4-isobutyl -1,3-thiazolidine. Thiazolidine is reacted with isobutyl bromide according to Method D2f to provide

757 / B

174 (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.

Item 111

N) = N

//

P

OMe i-Bu Me (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 4- (methoxycarbonyl) -2-methylphenylisothiocyanate was reacted with (1S) -1 (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (4- (methoxycarbonyl) -2-methylphenylimino) -4 isobutyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4- (methoxycarbonyl) -2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 112

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. The 3,5-dimethyl-4-nitroaniline is converted to 3,5-dimethyl-4-nitrophenylisothiocyanate according to Method A2a, Step 3. The 3,5-dimethyl-4-nitrophenylisothiocyanate is reacted with

757 / B

175 (1S) -1- (Chloromethyl) -3-methylbutanammonium chloride according to Method C1a to afford (4S) -2- (3,5-dimethyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine.

The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (3,5-dimethyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 113

(1S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 4- (methoxycarbonyl) -2-methylphenylisothiocyanate was reacted with (1S) -1 (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to afford (4S) -2- (4- (methoxycarbonyl) -2-methylphenylimino) -4-isobutyl -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4- (methoxycarbonyl) -2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine. The thiazolidine is saponified according to Method D6a, Step 1 to afford (4S) -2- (4-carboxy-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine. The acid is condensed with ammonia as described in Method D6a, Step 2 to provide (4S) -2- (4-carbamoyl-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 114

b-Bu Me

757 / B

176 (1S) -1- (Hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 4-Fluoro-2-methylphenylisothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to afford (4S) -2- (4-fluoro-2-methylphenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-fluoro-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 115

Cl-Bu Me (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 4-Chloro-2-methylphenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (4-chloro-2-methylphenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-chloro-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 116

i-tiu Me

757 / B

ΧΠ (1S) -1- (Hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 4-Bromo-2-methylphenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (4-bromo-2-methylphenylimino) -4-isobutyl-1,3-thiazolidine . The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-bromo-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 117

1-Ethyl (1S) -1- (hydroxymethyl) -3-methylbutylamine is reacted with thionyl chloride followed by 4-cyano-2-ethylphenylisothiocyanate according to Method C2a to give (4S) -2- (4-cyano-2-ethylphenylimino) ) -4-isobutyl-1,3tiazolidínu. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 118

'' N

I-Bu Me (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -431,757 / B

178 methyl-2- (isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N (isobutyl) ammonium chloride according to Method B7c. 2-Methyl-4-nitrophenylisothiocyanate is reacted with N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride according to Method C1b to provide (4S) -2- (2-methyl) -4-nitrophenylimino) 3,4-diisobutyl-1,3-thiazolidinone.

Item 119 i-Bu Me (1S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N (isobutyl) ammonium chloride according to Method B7c. The 4-amino-3-methylpyridine is converted to 3-methyl-4-pyridylisocyanate according to Method A2b. 3-Methyl-4-pyridylisothiocyanate is reacted with N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N (isobutyl) ammonium chloride according to Method C1b to give (4S) -2- (2-methyl-4-nitrophenylimino) 3,4-diisobutyl-1,3-thiazolidine.

Item 120

757 / B

179 (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 4-nitro-1-naphthylamine is converted to 4-nitro-1-naphthylisothiocyanate according to Method A2b. 4-Nitro-1-naphthylisothiocyanate is reacted with (1S) -1- (hydroxymethyl) -3-methylbutylamine according to Method C2a to give (4S) -2- (4-nitro-1-naphthylimino) -4-isobutyl -1,3'tiazolidínu. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2 (4-nitro-1-naphthylimino) -3,4-diisobutyl-1,3-thiazolidine.

Item 121 (1S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as described in Method B4c: The resulting 2-hydroxyethylamine is converted to N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N (isobutyl) ammonium chloride according to Method B7c. The 4-nitrophenylisothiocyanate is reacted with N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride according to Method C1f to give (4S) -2- (4-nitrophenylimino) -3, 4-diizobutyl1,3-thiazolidine.

Item 122

CN i-Bu

757 / B

180 (1S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N (isobutyl) ammonium chloride according to Method B7c. 4-Cyanophenyl isothiocyanate is reacted with N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride according to Method C1f to give (4S) -2- (4-cyanophenylimino) -3, 4diizobutyl-1,3-thiazolidine.

Item 123 H-Bu Me (1 S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine is converted to N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N (isobutyl) ammonium chloride according to Method B7c. The 4-amino-3-methylpyridine is converted to 3-methyl-4-pyridylisocyanate according to Method A2b. 3-Methyl-4-pyridylisothiocyanate is reacted with N - ((1S) -1- (chloromethyl) -3-methylbutyl) -N (isobutyl) ammonium chloride according to Method C1b to provide (4S) -2- (2-methyl-4-nitrophenylimino) ) -3,4-diisobutyl-1,3-thiazolidine. Thiazolidine is oxidized according to Method D4a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine-1-oxide.

757 / B

181

Item 124

(1S, 2S) -1- (hydroxymethyl) -2-methylbutylamine was converted to (1S, 2S) -1 (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S, 2S) -1- (chloromethyl) -2-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4 - ((2S) -2-) butyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide the (4S) -2- (2-methyl-4-nitrophenylimino) -4 - ((2S) -2-butyl) -3-isobutyl-1,3-thiazolidine hydrochloride salt.

Item 125

N- (tert-butoxycarbamoyl) - (1S, 2R) -1- (hydroxymethyl) -2-methylbutylamine was prepared from N- (tert-butoxycarbamoyl) - (1 -) aloisoleucine as described in method B1a, step 2. The carbamate was converted to (1S, 2R) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7b. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S, 2R) -1- (chloromethyl) -2-methylbutanammonium chloride according to Method C1e to give (4S) -2- (2-methyl-4-nitrophenylimino) -4 - ((2R) -2-) butyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide

757 / B

182 (4S) -2- (2-methyl-4-nitrophenylimino) -4 - ((2R) -2-butyl) -3-isobutyl-1,3-thiazolidine hydrochloride salt.

Item 126

N- (tert-butoxycarbamoyl) - (1S) -1-cyclohexyl-2-hydroxyethylbutylamine was prepared from N- (tert-butoxycarbamoyl) - (L) -cyclohexylglycine according to method B1a, step 2. The carbamate was reacted with thionyl chloride according to method B1b and the resulting material is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4cyclohexyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide the (4S) -2- (2-methyl-4-nitrophenylimino) -4-cyclohexyl-3-isobutyl-1,3-thiazolidine hydrochloride salt.

Item 127

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 4-Methoxycarbonyl-2-methylphenylisothiocyanate is reacted with (1S) -1 (chloromethyl) -2-methylbutanammonium chloride according to Method C1a to give (4S) -2- (4-methoxycarbonyl-2-methylphenylimino) -4- (2-butyl) - 1,3-thiazolidine.

757 / B

183

The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4S) -2- (4-methoxycarbonyl-2-methylphenylimino) -4- (2-butyl) -3-isobutyl-1,3-thiazolidine.

Item 128

NO ₂ (1S) -1-isopropyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-isopropylethylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -2-chloro-1-isopropylethylammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4isopropyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-isobutyl-1,3-thiazolidine hydrochloride salt.

Item 129.0 (1S) -1- (hydroxymethyl) -2-methylbutylamine is prepared from isoleucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. The 5-aminoindan-1-one is converted to 1-oxo-5-indanylisothiocyanate according to Method A2a. The isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride according to Method C1a to give (4S) -2- (1-oxo-531,757 / B).

184 indanylimino) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4S) -2- (1-oxo-5-indanylimino) -4- (2-butyl) -3-isobutyl-1,3-thiazolidine.

Item 130

WITH.

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. The 4-chloro-3- (trifluoromethyl) aniline is converted to 4-chloro-3- (trifluoromethyl) phenyl isothiocyanate according to Method A2a, Step 3. 4-Chloro-3- (trifluoromethyl) phenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) ) -2-methylbutanammonium chloride according to Method C1a to give (4S) -2- (4-chloro-3- (trifluoromethyl) phenylimino) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4S) -2- (4-chloro-3- (trifluoromethyl) phenylimino) -4- (2-butyl) -3-isobutyl-1,3-thiazolidine.

Item 131

ABOUT

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 431,757 / B

185 cyano-3- (trifluoromethyl) aniline is converted to 4-cyano-3- (trifluoromethyl) phenyl isothiocyanate according to method A2a, step 3. The isothiocyanate is reacted with (1S) -1 (chloromethyl) -2-methylbutanammonium chloride according to method C1a to give (4S) -2- (4-cyano-3- (trifluoromethyl) phenylimino) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4S) -2- (4-cyano-3- (trifluoromethyl) phenylimino) -4- (2-butyl) -3-isobutyl-1,3-thiazolidine.

Item 132

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. The 4-nitro-1-naphthylamine is converted to 4-nitro-1-naphthylisothiocyanate according to Method A2b. 4-Nitro-1-naphthylisothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride according to Method C1a to give (4S) -2- (4-nitro-1-naphthylimino) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-nitro-1-naphthylimino) -4-butyl-3-isobutyl-1,3-thiazolidine.

Item 133

757 / B

186 (1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-2-ethyl-phenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methyl-butanammonium chloride according to Method C1a to give (4S) -2- (4-cyano-2-ethyl-phenyl-imino) -4- (2-butyl) -1,3 -tiazolidínu. The thiazolidine is reacted with isobutyl bromide according to method D 2a to give (4S) -2- (4-cyano-2-ethylphenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine.

Item 134

^from/

I-Bu Me

CN (1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from isoleucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-2-methylaniline is synthesized as described in Method A1a. The aniline is converted to 4-cyano-2-methylphenylisothiocyanate as described in Method A2a, Step 3. 4-Cyano-2-methylphenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride according to Method C1a to yield (4S). 2- (4-cyano-2-methylphenylimino) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4S) -2- (4-cyano-2-methylphenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine.

í Item 135 i

I

757 / B

187

CN (1 R) -1- (hydroxymethyl) -2-methylbutylamine was prepared from isoleucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (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 A1a. The aniline is converted to 4-cyano-2,5-dimethylphenylisothiocyanate as described in Method A2a, Step 3. The 4-cyano-2,5-dimethylphenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methyibutanammonium chloride according to Method C1a for (4S) -2- (4-cyano-2,5-dimethylphenylimino) -4- (2-butyl) -1,3-thiazolidine. was reacted with isobutyl bromide according to Method D2a due to (4S) -2- (4-cyano-2,5-dimethylphenylimino) -4-butyl-3-isobutyl-1,3-ziskam Thiazolidine to give thiazolidine.

Item 136

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) 1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 2,5-Methylaniline is converted to 2,5-dimethyl-4-nitrophenylisothiocyanate according to method

2a. 2,5-Dimethyl-4-nitrophenylisothiocyanate is reacted with (1S) -131 757 / B

188 (chloromethyl) -2-methylbutanammonium chloride according to Method C1a to afford (4S) -2- (2,5-dimethyl-4-nitrophenylimino) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2 (2,5-dimethyl-4-nitrophenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine.

Item 137 (1R) -1-isopropyl-2-hydroxyethylamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4R) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-isobutyl-1,3-thiazolidine.

Item 138

(1S) -1-isopropyl-2-hydroxyethylamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-1 , 3-thiazolidine. The thiazolidine is reacted with cyclopentyl bromide according to Method D2a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-cyclopentyl-1,3-thiazolidine.

757 / B

189

Item 139

(1S) -1-Benzyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-benzylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -2-chloro-1-benzylethylammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-benzyl-1,3-thiazolidine . The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide the (4S) -2- (2-methyl-4-nitrophenylimino) -4-benzyl-3-isobutyl-1,3-thiazolidirium hydrochloride salt.

Item 140

(1S) -1-phenyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-phenylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -2-chloro-1-benzylethylammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-phenyl-1,3 -thiazolidine.

The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide the (4S) -2- (2-methyl-4-nitrophenylimino) -4-phenyl-3-isobutyl-1,3-thiazolidine hydrochloride salt.

757 / B

190

Item 141

2-Piperidene-methanol is prepared from methylpipecolinate as described in Method B1b. The 2-hydroxyethylamine is converted to 2-chloromethylpiperidinium chloride according to Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-chloromethylpiperidinium chloride according to Method C1a to give 9- (2-methyl-4-nitrophenylimino) -1-aza-8-thiabicyclo [4.3.0] nonane.

Item 142

2-Pyrrolidine methanol is prepared from proline methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to 2-chloromethylpyrrolidinium chloride according to Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-chloromethylpyrrolidinium chloride according to Method C1a to give 3- (2-methyl-4-nitrophenylimino) -2,5,6,7,7a-pentahydro-2-thiapyrolysine.

Item 143 p

OH

757 / B

191 (1S) -1- (4-hydroxyphenylmethyl) -2-hydroxyethylamine was prepared from (L) -tyrosine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (4S) -2-isopropyl-4- (4-hydroxyphenylmethyl) -1,3-oxazolidine according to Method B4c, Step 1. Oxazolidine is reduced to N- (1S) -1- (4-hydroxyphenylmethyl) (2-hydroxyethyl) -N-isobutylamine according to method B4c, step 2. The resulting 2-hydroxyethylamine is treated with thionyl chloride according to method B7c to give N- (1S) -1- (4-hydroxyphenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride. 2-Ethyl-4-cyanophenylisothiocyanate is reacted with N- (1S) -1- (4-hydroxyphenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride according to Method C1b to give the hydrochloride salt of (4S) -2- (2-ethyl-4- cyanophenylimino) -4- (4-hydroxyphenylmethyl) -3-isobutyl-1,3-thiazolidine.

Item 144

(1S) -1- (4-chlorophenylmethyl) -2-hydroxyethylamine was prepared from (L) -4-chlorophenylalanine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (4S) -2-isopropyl-4- (4-chlorophenylmethyl) -1,3-oxazolidine according to Method B4c, Step 1. Oxazolidine is reduced to N- (1S) -1- (4-chlorophenylmethyl) (2-hydroxyethyl) -N-isobutylamine according to method B4c, step 2. The resulting 2-hydroxyethylamine was treated with thionyl chloride according to method B7c to give N - ((1S) -1- (4-chlorophenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride. 2-Ethyl-4-cyanophenylisothiocyanate is reacted with N - ((1S) -1- (4-chlorophenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride according to Method C1b to give the (4S) -2- (2-ethyl-4-) hydrochloride salt cyanophenylimino) -4- (4-chlorophenylmethyl) -331,757 / B

192 isobutyl-1,3-thiazolidine.

Item 145

(1S) -1- (Benzylthiomethyl) -2-hydroxyethylamine HCl was prepared from (L) S -benzylcysteine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (4S) -2-isopropyl-4- (benzylthiomethyl) -1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine is reduced to N- (1S) -1- (benzylthiomethyl) -2- hydroxyethyl) -Nisobutylamine according to method B4c, step 2. The resulting 2-hydroxyethylamine was treated with thionyl chloride according to method B7c to give N- (1S) -1 (benzylthiomethyl) -2-chloroethyl) -N-isobutylammonium chloride. 2-Ethyl-4-cyanophenylisothiocyanate is reacted with N- (1S) -1- (benzylthiomethyl) -2-chloroethyl) -Nisobutylammonium chloride according to Method C1b to give the (4S) -2- (2-ethyl-4-cyanophenylimino) hydrochloride salt ) -4- (benzylthiomethyl) -3-isobutyl-1,3tiazolidínu.

Item 146

MeO

NO ₂ i-Bu Me

HCl

The (R) -N-isobutylserine methyl ester hydrochloride salt is prepared from the (D) -serine methyl ester as described in Method B3a. The ester is reacted with thionyl chloride, followed by 2-methyl-4-nitrophenylisothiocyanate according to

757 / B

193 of Method C2a to provide the hydrochloride salt of (4S) -2- (2-methyl-4-nitrophenylimino) -4- (methoxycarbonyl) -3-isobutyl-1,3-thiazolidine.

Item 147

MeO

(S) -N-Isobutylserine methyl ester hydrochloride is prepared from (L) -serine methyl ester as described in Method B3a. The ester is reacted with thionyl chloride, followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give the hydrochloride salt of (4R) -2- (2-methyl-4-nitrophenylimino) -4- (methoxycarbonyl) -3-isobutyl-1,3- thiazolidine.

Item 148

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. (1R, 2R) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) -2- (2-methyl- 4-nitrophenyl 31,757 / B

194 imino) -4 - ((1 R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 149

Me

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. (1R, 2R) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to provide (4R) -2- (2-methyl-4- nitrophenylimino) -4 - ((1 R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 150

(1R, 2S) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. (1R, 2S) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is reacted with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl 31 757 / B

195 bromides according to Method C5b to provide (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 151

(1R, 2S) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. (1R, 2S) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b to provide (4R) -2- (2-methyl-4- nitrophenylimino) -4 - ((1 S) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 152

WITH.

CN (1R, 2S) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butyl-threonine according to of the description in method B8a. (1R, 2S) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-2-methylphenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (4-) cyano-231,757 / B

196 methylphenylimino) -4 - ((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 153

(1R, 2S) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from (L) - (1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butyl-threonine dicyclohexylamine salt as described in method B8a. 4-Nitro-1-naphthylamine is converted to 4-nitro-1-naphthylisothiocyanate according to Method A2b. (1R, 2S) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthylisothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) -2- (4-nitro-1-naphthylimino) -4 - ((1 S) -1-tercbutoxyetyl) -3-isobutyl-1,3-thiazolidine.

Item 154 '-

(1R, 2S) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2S) -N- (benzyloxycarbonyl) -D-tert-butyl-threonine according to of the description in method B8a. 4-Nitro-1-naphthylamine is converted to 4-nitro-1-naphthylisothiocyanate according to Method A2b. (1R, 2S) -131,757 / B

197 (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (4-nitro-1-naphthylimino) -4 - (( 1 S) -1térc-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 155

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyl-threonine according to of the description in method B8a. 1-Amino-5,6,7,8-tetrahydro-naphthalene is converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate according to Method A2a. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-nitro-5,6,7,8-tetrahydronaphthyl-isothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) ) -2- (4-nitro-5,6,7,8-1-yl-imino) -4 - ((1 R) -1-tercbutoxyetyl) -3-cyclopentyl-1,3-thiazolidine.

Item 156

757 / B

198 (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyl-threonine according to of the description in method B8a. 1-Amino-5,6,7,8-tetrahydro-naphthalene is converted to 4-nitro-5,6,7,8-tetrahydro-naphth-1-yl-1-isothiocyanate according to Method A2a. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is reacted with 4-nitro-5,6,7,8-tetrahydro-naphth-1-ylisothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) - 2 - (- 4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) 4 - ((1 R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 157

No ₂ (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in method B8a. 2-Isopropylaniline is converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a. (1R, 2R) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-isopropyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) -2- (2-isopropyl-4-nitrophenylimino) 4 - ((1 R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 158

757 / B

199 (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from (L) - (1S, 2R) -N (Benzyloxycarbonyl) -O-tert-butyltreonine dicyclohexylamine salt as described in method B8a. 2isopropylaniline was converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-isopropyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) 2- (2-isopropyl-4) -nitrophenylimino) -4 - ((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 159

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. The 2,3-dimethyl-4-nitroaniline is converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2, 2R) 3-dimethyl-4-nitrophenylimino) -4 - ((1 R) -1-tert-butoxyethyl) 3-cyclopentyl-1,3-thiazolidine.

Item 160

757 / B

200 (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine according to of the description in method B8a. The 2,3-dimethyl-4-nitroaniline is converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2 _{L of} 3-dimethyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) -2- (2,3) dimethyl-4nitrofenylimino) -4 - ((1 R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 161

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. The 2,3-dimethyl-4-nitroaniline is converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by 2-ethyl-1-butylbromide according to Method C5b to give (4R) -2 - (2,3-dimethyl-4-nitrophenylimino) -4 - ((1R) -1-tert-butoxyethyl) -3- (2-ethyl-1-butyl) -1,3-thiazolidine.

Item 162

757 / B

201 (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in method B8a. 1-Anilino-4-cyano-5,7,7,8-tetrahydronaphthalene is converted to 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate according to Method A2b. (1R, 2R) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is reacted with 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- ( 4-cyano-5,6,7,8-tetrahydronaphthylimino) -4 - ((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 163

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. 1-Amino-4-cyano-5,6,7,8-tetrahydronaphthalene is converted to 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate according to Method A2b. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-5,6,7,8-tetrahydro-naphthylisothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) -2- (4-cyano) -5,6,7,8-tetrahydronaftylimino) -4 - ((1 R) -1terc-butoxyethyl) -3-isobutyl-1,3-thiazolidine.

757 / B

202

Lot 164 p

^Μέυ? H (1 R, 2 R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propánamóniumchlorid is prepared from the dicyclohexylamine salt of (L) - (1 S, 2 R) -N- (benzyloxycarbonyl) -0-t-butyltreonínu as described in method B8a. (1R, 2R) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b to afford (4R) -2- (2-methyl-4- nitrophenylimino) 4 - ((1 R) -1-tert-butoxy) -3-isobutyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 165

(1R, 2S) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. 4-Nitro-1-naphthylamine is converted to 4-nitro-1-naphthylisothiocyanate according to Method A2b. (1R, 2S) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthylisothiocyanate followed by cyclopentyl bromide according to Method C5b to afford (4R) -2- (4-nitro-1-naphthylimino) -4 - ((1S) -1-tert -31,757 / B)

203 butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The t-butyl ether is deprotected according to Method D3a to provide (4R) -2- (4-nitro-1-naphthylimino) -4 ((1S) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 166

(1R, 2S) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine as described in Method B8a. '(1R, 2S) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2-) 4nitrofenylimino-methyl) -4 - ((1 S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1S) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 167

Me

WITH.

Me (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in method B8a. (1R, 2R) -131,757 / B

204 (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2-methyl-4-nitrophenylimino) -4- ((1 R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 168

(1R, 2S) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. (1R, 2S) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1S) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 169

757 / B

205 (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine according to of the description in method B8a. The 2-tert-butyl-4-cyanoaniline is converted to 2-tert-butyl-4-cyanophenylisothiocyanate according to Method A2b. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-tert-butyl-4-cyanophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2-) tert-butyl-4-kyanofenylimino) -4 - ((1 R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine.

The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2-tert-butyl-4-cyanophenylimino) -4 - ((1R) -1-hydroxyethyl) -3cyclopentyl-1,3-thiazolidine .

Item 170

with.

N, N-Bu-Bu (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in method B8a. 2-tert-Butyl-4-cyanoaniline is converted to 2-tert-butyl-4-cyanophenylisothiocyanate according to Method A2b. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-tert-butyl-4-cyanophenylisothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) -2- (2-) tert-butyl-4-cyanophenylimino) -4 - ((1 R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2-tert-butyl-4-cyanophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-isobutyl-1,3-thiazolidine.

757 / B

206

Item 171

Me

OH ^ ^S > NN · i-Bu

NO ₂ (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in method B8a. The 4-nitro-1-naphthylamine is converted to 4-nitro-1-naphthylisothiocyanate according to Method A2b. (1R, 2R) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (4-nitro-1-naphthylimino) -4 - ((1 R) -1terc-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (4-nitro-1-naphthylimino) -4 - ((1R) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 172

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O- tert -butyltreonine as described in the method B8a. 1-Amino-5,6,7,8-tetrahydronaphthalene is converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate according to Method A2a. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is reacted with 4-nitro-5,6,7,8-tetrahydronaphthal-131 757 / B

207 ylisothiocyanate followed by cyclopentyl bromide according to Method C5b to provide (4R) -2- (4-nitro-5,6,7,8; tetrahydronaphth-1-ylimino) -4 - ((1R) -1-tert-butoxyethyl) -3-cyclopentyl -1,3-thiazolidine. The t-butyl ether is deprotected according to Method D3a to provide (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4 - ((1R) -1-hydroxyethyl) -3 cyclopentyl-1,3-thiazolidine.

Item 173

Me (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in method B8a. 1-Amino-5,6,7,8-tetrahydronaphthalene is converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate according to Method A2a. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-nitro-5,6,7,8-tetrahydronaphthyl-isothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) ) -2- (4-nitro-5,6,7,8-1-yl-imino) -4 - ((1 R) -1-ŕercbutoxyetyl) -3-isobutyl-1,3-thiazolidine. The t-butyl ether is deprotected according to Method D3a to provide (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4 - ((1R) -1-hydroxyethyl) -3 isobutyl-1,3-thiazolidine.

Item 174

757 / B

208 (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine according to of the description in method B8a. 2-Isopropylaniline is converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a. (1R, 2R) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-isopropyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b to provide (4R) -2- (2-isopropyl-4-nitrophenylimino) ) -4 - ((1 R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2-isopropyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 175

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. 2-Isopropylaniline is converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a. (1R, 2R) -1 (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2-isopropyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2-isopropyl-4-nitrophenylimino) ) -4 - ((1 R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2-isopropyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

757 / B

209

Item 176

Me

(1R, 2R) -1- (Methanesulfopyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. The 2,3-dimethyl-4-nitroaniline is converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by 2-ethyl-1-butylbromide according to Method C5b to give (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1R) -1-tert-butoxyethyl) -3- (2-ethyl-1-butyl) -1,3-thiazolidine.

The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3- (2-ethyl-1- (butyl) -1,3-thiazolidinone.

Item 177

t-Bu Me Me (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is prepared from (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-dicyclohexylamine salt -butyltreonine as described in method B8a. The 2,3-dimethyl-4-nitroaniline is converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is reacted with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by

757 / B

210 of the isobutyl bromide of Method C5b to provide (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 178

(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in the method B8a. The 2,3-dimethyl-4-nitroaniline is converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2,3) (dimethyl-4-nitrophenylimino) -4 - ((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Item 179

Me

757 / B

211 (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyltreonine as described in method B8a. 1-Amino-4-cyano-5,6,7,8-tetrahydronaphthalene is converted to 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate according to Method A2b. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride is reacted with 4-cyano-5,6,7,8-tetrahydro-naphthylisothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (4-cyano) -2- (4-cyano) -5,6,7,8-tetrahydronaphthylimino) 4 - ((1 R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4 - ((1R) -1-hydroxyethyl) -3-cyclopentyl- 1,3-, thiazolidine.

Item 180

ÔH '' θ ^υ

CN (1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was prepared from the dicyclohexylamine salt of (L) - (1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butyitreonine as described in method B8a. 1-Amino-4-cyano-5,6,7,8-tetrahydronaphthalene is converted to 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate according to Method A2b. (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-5,6,7,8-tetrahydro-naphthylisothiocyanate followed by isobutyl bromide according to Method C5b to give (4R) -2- (4-cyano) -5,6,7,8-tetrahydronaftylímino) -4 - ((1 R) -1ŕerc-butoxyethyl) -3-isobutyl-1,3-thiazolidine. The tert-butyl ether is deprotected according to Method D3a to provide (4R) -2- (4-cyano) 757 / B

212

5,6,7,8-tetrahydronaphthylimino) -4 - ((1R) -1-hydroxyethyl) -3-isobutyl-1,3-thiazolidine.

Item 181 /

nu ₂

2-Amino-1,3-propanediol is reacted with an excess of thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -4- (chloromethyl) -1,3- thiazolidine. Thiazolidine is reacted with N-methylamine according to Method D13a to give 2- (2-methyl-4-nitrophenylimino) -4- (N-methylaminomethyl) -1,3-thiazolidine which is reacted with isobutyl bromide according to Method D2a to give 2- (2-methyl-4-nitro-phenylimino) -3-isobutyl-4- (N-isobutyl-N-methylaminomethyl) -1,3-thiazolidine.

Item 182

i-bu me

2-Amino-1,3-propanediol is reacted with an excess of thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -4- (chloromethyl) -1,3- thiazolidine. Thiazolidine is reacted with dimethylamine according to Method D13a to provide 2- (2-methyl-4-nitrophenylimino) -4- (N-isobutyl-N-methylaminomethyl) -1,3-thiazolidine which is reacted with isobutyl bromide according to Method D2a to provide 2 (2-methyl-4-nitro-phenylimino) -3-isobutyl-4- (N, N-dimethylaminomethyl) -1,3-thiazolidine.

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Item 183

i-Bu Me (L) -histidinol is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4- (1- (isobutylimidazolyl) methyl) - 1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4S) 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (1- (isobutylimidazolyl) methyl) -1,3-thiazolidine.

Item 184

(L) -histidinol is reacted with. thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give (4S) -2- (2-methyl-4-isrophenylimino) -4- (1- (isobutyl-limazolazolyl) methyl) -1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4S) 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (3- (isobutylimidazolyl) methyl) -1,3-thiazolidine.

Item 185

U

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214

The 2-hydroxypropylamine is converted to 2-chloropropylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-chloropropylammonium chloride according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -5-methyl-1,3-thiazolidine. Thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to provide the hydrobromide salt of 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -5-methyl -1,3-thiazolidine.

Item 186

i-Bu Cl HCl

2-Phenyl-2-hydroxyethylamine is reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. Oxazolidine is reduced according to Method B4c, Step 2 to obtain N-isobutyl-2-phenyl-2-hydroxyethylamine. Ethanolamine is reacted with thionyl chloride followed by 2-chloro-4- (trifluoromethyl) phenyl isothiocyanate according to Method C2f to provide 2- (2-chloro-4- (trifluoromethyl) phenylimino) -3-isobutyl-5-phenyl-1,3-thiazolidine hydrochloride salt yne.

Item 187 'N \ i-Bu Cl Cl

2-Phenyl-2-hydroxyethylamine is reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine.

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215

Oxazolidine is reduced according to Method B4c, Step 2 to obtain N-isobutyl-2-phenyl-2-hydroxyethylamine. Ethanolamine is reacted with thionyl chloride followed by 2,3-dichlorophenylisothiocyanate according to Method C2f to provide 2- (2,3-dichlorophenylimino) -3-isobutyl-5-phenyl-1,3-thiazolidine.

Item 188

3-Phenyl-2-hydroxypropylamine is reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-benzyl-1,3-oxazolidine. Oxazolidine is reduced according to Method B4c, Step 2 to obtain N-isobutyl-3-phenyl-2-hydroxypropylamine. The propanolamine is reacted with thionyl chloride followed by 2,3-dichlorophenylisothiocyanate according to Method C2f to provide 2- (2,3-dichlorophenylimino) -3-isobutyl-5-benzyl-1,3-thiazolidine hydrochloride salt.

Item 189

2-Methyl-2-hydroxypropylamine is reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. Oxazolidine is reduced according to Method B4c, Step 2 to give N-cyclohexyl-2-methyl-2-hydroxypropylamine. The propanolamine is reacted with thionyl chloride followed by 2,6-dichlorophenylisothiocyanate according to

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216 of Method C2f to provide 2- (2,6-dichlorophenylimino) -3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine.

Item 190 (1R) -1-cyclohexyl-1-ethylamine is 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 - ((1 R) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with thionyl chloride followed by 2,3dichlorophenylisothiocyanate according to Method C2f to provide the hydrochloride salt of 2- (2, 2-dimethylphenylisothiocyanate). 3-Dichloro-phenylimino) -3 - ((1 R) -1-cyclohexyl-1-ethyl) -5,5dimetyl-1,3-thiazolidine.

Item 191

(1S) -1-cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N - ((1S) -1-cyclohexyl-1-ethyl) -N (2,2 dimethyl-2-hydroxyethyl) amine. N - ((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with thionyl chloride followed by 2,4-dichlorophenylisothiocyanate according to Method C2f to provide the hydrochloride salt of 2- (2,4 (dichlorophenylimino) -3 - ((1S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazolidine.

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217

Item 192

Cl (1S) -1-cyclohexyl-1-ethylamine is reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N - ((1S) -1-cyclohexyl-1-ethyl) -N (2, 2-dimethyl-2-hydroxyethyl) amine. N - ((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with thionyl chloride followed by 2,3dichlorophenylisothiocyanate according to Method C2f to provide the hydrochloride salt of 2- (2,3 -dichlorophenylimino) -3 - ((1S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazolidine.

Item 193

HO.

Cl Cl HCl

2-Methyl-2-hydroxypropylamine is reacted with thionyl chloride followed by 2,3-dichlorophenylisothiocyanate according to Method C2f to provide 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1,3-thiazolidine. 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1,3-thiazolidine was reacted with ethylene oxide according to Method B5b to provide 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1,3 hydrochloride salt -tiazolidínu.

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Item 194

Me ⁷ / -NO

2-Methyl-2-hydroxypropylamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -5,5-dimethyl-1,3-thiazolidine.

Item 195

2-Methyl-2-hydroxypropylamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -5,5-dimethyl-1,3-thiazolidine. Thiazolidine is reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to provide the hydrobromide salt of 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -5 , 5-dimethyl-1,3-thiazolidine.

Item 196. ^ ^N- O- ^N ° 2 i-Bu Me

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219

2-Methyl-2-hydroxypropylamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -5,5-dimethyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2g to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5,5-dimethyl-1,3-thiazolidine.

Item 197

N

i-Bu Cl Cl HCl

2-Methyl-2-hydroxypropylamine is reacted with thionyl chloride followed by 2,3-dichlorophenylisothiocyanate according to Method C1a to provide 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2g to provide 2- (2,3-dichlorophenylimino) -3-isobutyl-5,5-dimethyl-1,3-thiazolidine.

Item 198

2-Methyl-2-hydroxypropylamine is reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. Oxazolidine is reduced according to Method B4c, Step 2 to give N-cyclohexyl-2-methyl-2-hydroxypropylamine. Propanolamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate

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220 according to Method C2f to provide 2- (2-methyl-4-nitrophenylimino) -3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine.

Item 199

Cl Cl

2-Methyl-2-hydroxypropylamine is reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. Oxazolidine is reduced according to Method B4c, Step 2 to give N-cyclohexyl-2-methyl-2-hydroxypropylamine. The propanolamine is reacted with thionyl chloride followed by 2,3-dichlorophenylisothiocyanate according to Method C2f to provide 2- (2,3-dichlorophenylimino) -3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine.

Item 200 (1R) -1-cyclohexyl-1-ethylamine is 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 is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2f to provide the hydrochloride salt of 2- (2 methyl-4-nitrophenylimino) -3 - ((1R) -1-cyclohexyl-1-ethyl) 5,5-dimethyl-1,3-thiazolidone.

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221

Item 201

(1S) -1-cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N - ((1S) -1-cyclohexyl-1-ethyl) -N (2,2 dimethyl-2-hydroxyethyl) amine. N - ((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2f to provide the hydrochloride salt of 2- (2 methyl-4-nitro-phenylimino) -3 - ((1 S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazolidine.

Item 202 'N, i-Pr Me

Isopropylamine is reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. The N-N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2f to give 2- (2-methyl-4-nitrophenylimino) -3-isopropyl- 5,5-dimethyl-1,3-thiazolidine.

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222

Item 203

Cl Cl

N i-Pr

Isopropylamine is reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. Nizopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with thionyl chloride followed by 2,3-dichlorophenylisothiocyanate according to Method C2f to provide 2- (2,3-dichlorophenylimino) -3-isopropyl-5,5- dimethyl 1,3tiazolidinu.

Item 204 i-Bu Cl

HCl

Isobutylamine is reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isobutyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. Nizobutyl N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with thionyl chloride followed by 2,4-dichlorophenylisothiocyanate according to Method C2f to provide the hydrochloride salt of 2- (2,4-dichlorophenylimino) -3-isobutyl-5, 5dimetyl-1,3-thiazolidine.

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223

Item 205

The 1,1-dimethyl-2-hydroxyamine was converted to 1,1-dimethyl-2-chloroethylammonium chloride according to Method B7a. The 2-methyl-4-nitrophenylisothiocyanate is reacted with 1,1-dimethyl-2-chloroethylammonium chloride according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-1,3-thiazolidine. The thiazolidine is reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to provide the hydrobromide salt of 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-3- (2-methylprop-2-ene). 1-yl) -1,3-thiazolidine.

Item 206

The methylaminoisobutyric acid is converted to the methylaminoisobutyrate hydrochloride salt according to Method B1c, Step 1. The ester is reduced to 3hydroxy-2-methyl-2-propylamine according to Method B1c, Step 2. The 2-hydroxyethylamine is treated with thionyl chloride according to Method B7b followed by 2-methyl- 3-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-3-isobutyl-1,3-thiazolidine.

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224

Item 207> N

1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. 1- (Cyclohexylamino) -1- (hydroxymethyl) cyclopentane was synthesized as described in Method B4a. The 2-hydroxyethylamine is treated with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to provide 3-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 208

The 2-ethylaniline is converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide is converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide is deprotected according to Method A2a, Step 3 to give 2- ethyl-4-nitroaniline. The aniline is converted to 2-ethyl-4-nitrophenylisothiocyanate according to Method A2a, Step 3. 1-Amino-1 (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a for the purpose of

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225 to obtain 1-amino-1- (chloromethyl) cyclopentane hydrochloride salt. 2-Chloroethylamine is reacted with 2-ethyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-ethyl-4-nitrophenylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to provide 3-cyclopentyl-2- (2-ethyl-4-nitrophenylimino) -1-thia-3azaspiro [4.4] nonane.

Item 209

The 2-n-propylaniline is converted to 4-iodo-2-n-propylaniline according to Method A5a. The aniline is converted to 4-iodo-2-n-propylphenylisothiocyanate according to Method A2b. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to provide the hydrochloride salt of 1-amino-1 (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 4-iodo-2-n-propylphenylisothiocyanate according to Method C1a to give 2- (4-iodo-2-n-propylphenylimino) -1-thia-3'azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to provide 3-cyclopentyl-2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro [4.4] nonane. The phenyl iodide is reacted with copper (I) cyanide according to Method D7a to provide 3-cyclopentyl-2- (4-cyano-2-n-propylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 210

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226

The 2-isopropylaniline is converted to 4-iodo-2-isopropylaniline according to Method A5a. The aniline is converted to 4-iodo-2-isopropylphenylisothiocyanate according to Method A2b. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to give the hydrochloride salt of 1-amino-1 (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 4-iodo-2-isopropylphenylisothiocyanate according to Method C1a to give 2- (4-iodo-2-isopropylphenylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2- (4-iodo-2-isopropylphenylimino) -1-thia-3-azaspiro [4.4] nonane. The phenyl iodide is reacted with copper (I) cyanide according to Method D7a to provide 3-cyclopentyl-2- (4-cyano-2-isopropylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 211

f-Bu

2-tert-Butylaniline is converted to 4-iodo-2-tert-butylaniline according to method

And 5a. The aniline is converted to 4-iodo-2-tert-butylphenylisothiocyanate according to method

A2B. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to

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227 of Method B7a to obtain the hydrochloride salt of 1-amino-1 (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 4-iodo-2-tert-butylphenylisothiocyanate according to Method C1a to give 2- (4-iodo-2-tert-butylphenylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to provide 3-cycliopentyl-2- (4-iodo-2-tert-butylphenylimino) -1-thia-3-azaspiro [4.4] nonane. The phenyl iodide is reacted with cuprous cyanide according to Method D7a to provide 3-cyclopentyl-2- (4-cyano-2-tert-butylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 212

1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The aminoalcohol is reacted with 2-methylcyclopentanone according to Method B4a, step 1 to give 13-aza-1-methyl-6-oxodispiro [4.2.4.1] Tridecane that is reduced with NaBH ₄ according to Method B4a, step 2 to provide 1- ( 2-methylcyclopentyl) amino-1- (hydroxymethyl) cyclopentane. 2hydroxyethylamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to method C2a to give 3- (2-methylcyclopentyl) -2- (2-methyl-4-nitrophenylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 213

t-ti Me

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228

1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to give the hydrochloride salt of 1-amino-1 (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Item 214

The 2-ethylaniline is converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide is converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide is deprotected according to Method A2a, Step 3 to give 2- ethyl-4-nitroaniline. The aniline is converted to 2-ethyl-4-nitrophenylisothiocyanate according to Method A2a, Step 3. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to give the hydrochloride salt of 1-amino-1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 2-ethyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-ethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2b to provide 1-isobutyl-2- (2-ethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Item 215

757 / B

229 i-Bu n-Pr

The 2-n-propylaniline is converted to the 2-n-propyl acetanilide according to Method A2a, Step 1. The acetanilide is converted to the 2-n-propyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide is deprotected according to Method A2a, step 3 to obtain 2-n-propyl-4-nitroaniline. The aniline is converted to 2-n-propyl-4-nitrophenylisothiocyanate according to Method A2a, Step 3. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to give the hydrochloride salt of 1-amino-1- (chloromethyl) cyclopentane. n-propyl-4-nitrophenylimino) -3-thia-1azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide 1-isobutyl-2- (2-n-propyl-4-nitrophenylimino) -3-thiazolazio [4.4] nonane.

Item 216

2-Isopropylaninine is converted to 2-isopropylacetanilide according to the method

A2a, step 1. The acetanilide is converted to 2-isopropyl-4-nitroacetanilide according to method A2a, step 2. The acetanilide is deprotected according to method A2a, step 3 to give 2-isopropyl-4-nitroaniline. The aniline is converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a, Step 3. 1-Amino-1 (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. 231,757 / B

230 hydroxyethylamine is reacted with thionyl chloride according to method B7a to provide the 1-amino-1- (chloromethyl) cyclopentane hydrochloride salt. 2-Chloroethylamine is reacted with 2-isopropyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-isopropyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-isopropyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Item 217

2,3-dimethyl-4-nitroaniline was synthesized as described in Method A4a. The aniline is converted to 2,3-dimethyl-4-nitrophenylisothiocyanate as described in Method A2d. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7e to give the hydrochloride salt of 1-amino-1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method C1c to give 2- (2,3-dimethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide 1-isobutyl-2- (2-isopropyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Item 218

i-Bu

Me

757 / B

231

3-Methyl-4-nitroaniline is converted to 3-methyl-4-nitrophenylisothiocyanate according to Method A2a, Step 3. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to give the hydrochloride salt of 1-amino-1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 3-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide 1-isobutyl-2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

The 1-amino-5,6,7,8-tetrahydronaphthaline is converted to 1-acetamino-5,6,7,8-tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide is converted to 1acetamino-4-nitro-5,6,7, 8-Tetrahydronaphthaline according to Method A2a, Step 2. The acetanilide is deprotected according to Method A2a, Step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline is converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthylisothiocyanate according to Method A2a, Step 3. 1 Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to give the hydrochloride salt of 1-amino-1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthylisothiocyanate according to Method C1a to give 2- (4-nitro-5,6,7,8-tetrahydro-1-naphthylimino) -3-thia-1 azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide 1-isobutyl-2 (4-nitro-5,6,7,8-tetrahydro-1-naphthylimino) -3-thia-1-azaspiro [4.4] nonane.

757 / B

232

Item 220

CN

1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7e to provide the hydrochloride salt of 1-amino-1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 4-cyanophenylisothiocyanate according to Method C1a to give 2- (4-cyanophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide 1-isobutyl-2- (4-cyanophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Item 221

4-Cyano-2-methylaniline is synthesized as described in Method A1a. The aniline is converted to 4-cyano-2-methylphenylisothiocyanate according to Method A2a, Step 3. 1 Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to provide the hydrochloride salt of 1-amino-1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 4-cyano-2-methylphenylisothiocyanate according to Method C1a to give 2- (4-cyano-2-methylphenylimino) -1-thia-3azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to

757 / B

233 of Method D2b to provide 3-isobutyl-2- (4-iodo-2-methylphenylimino) -1-thia-3azaspiro [4.4] nonane.

Item 222

CN

1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to give the hydrochloride salt of 1-amino-1 (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 4-cyano-2-methylphenylisothiocyanate according to Method C1a to give 2- (4-cyano-2-methylphenylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2b to provide 3-isobutyl-2- (4-cyano-2-methylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 223

1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7a to give 1-amino-1 (chloromethyl) cyclopentane hydrochloride salt; 1-Amino-4-cyanaphthalene is converted to 4-cyano-1-naphthylisothiocyanate according to Method A2a, Step 3. 2-Chloroethylamine is reacted with 4-cyano-1-naphthylisothiocyanate according to Method C1a to yield

757 / B

234

2- (4-cyano-1-naphthylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-cyano-1-naphthylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 224

The 2,3-dimethylaniline is converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline is converted to 2,3-dimethyl-4-iodophenylisothiocyanate according to Method A2a, Step 3. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chioride according to method B7e to give the hydrochloride salt of 1-amino-1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 2,3-dimethyl-4-iodophenylisothiocyanate according to Method C1e to give 2- (2,3-dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro [4.4] nonane. The phenyl iodide is reacted with copper (I) cyanide according to Method D7a to provide 3-isobutyl-2- (2,3-dimethyl-4-cyanophenylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 225

N i-Bu. Me

Me

757 / B

235

The 2,3-dimethylaniline is converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline is converted to 2,3-dimethyl-4-iodophenylisothiocyanate according to Method A2a, Step 3. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. 2-Hydroxyethylamine is reacted with thionyl chloride followed by 2,3-dimethyl-4-iodophenylisothiocyanate according to Method C2a to give 2- (2,3-dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide 3-isobutyl-2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro (4.4) nonane. The phenyl iodide is reacted with trimethylsilylacetylene according to Method D8a, Step 1 to give 3-isobutyl-2- (2,3-dimethyl-4- (2-trimethylsilyletinyl) phenylimino) -1-thia-3azaspiro [4.4] nonane. The silyl acetylene is deprotected according to Method D8a, Step 2 to provide 3-isobutyl-2- (2,3-dimethyl-4-ethynylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

Item 226

The 2,3-dimethylaniline is converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline is converted to 2,3-dimethyl-4-iodophenylisothiocyanate according to Method A2a, Step 3. 1-Amino-1- (hydroxymethyl) cyclopentane is synthesized as described in Method B1c. The 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7e to give the hydrochloride salt of 1-amino-1 (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 2,3-dimethyl-4-iodophenylisothiocyanate according to Method C1e to give 2- (2,3-dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

757 / B

236

Item 227

i-bu me me

The 2,3-dimethylaniline is converted to 2,3-dimethyl-6-nitroaniline according to Method A4a. The aniline is converted to 2,3-dimethyl-6-nitrophenylisothiocyanate according to Method A2d. 1- (hydroxymethyl) cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2,3-dimethyl-6-nitrophenylisothiocyanate according to Method C1e to give 2- (2,3-dimethyl-6-nitrophenylamino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2b to provide 2- (2,3-dimethyl-6-nitrophenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

Item 228

2-Cyano-5-nitrothiophene is reduced to 2-amino-5-cyanothiophene according to Method A1a. The aminothiophene is converted to 6-cyano-1-thiophenisothiocyanate according to Method A2b. 1- (hydroxymethyl) cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 5-cyano-1-thiophenisothiocyanate according to Method B1e to give 2- (5-cyanothienylimino) 31,757 / B

237

3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give 2- (5-cyanothienylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

Item 229

6-Amino-3-cyano-2,3-dimethylpyridine is converted to 3-cyano-2,3-dimethyl-6-pyridylisothiocyanate according to Method A2c. 1- (hydroxymethyl) cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethylcyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 3-cyano-2,3-dimethyl-6-pyridylisothiocyanate according to Method C1e to give 2- (3-cyano-2,3-dimethyl-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane . Thiazolidine is reacted with isobutyl bromide according to Method D2h to give 2- (5-bromothienylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

Item 230

1- (hydroxymethyl) cyclopentanamine was prepared according to Method B1c. 2hydroxyethylamine is sequentially treated with thionyl chloride and 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with 131 757 / B

238 bromo-2-ethylbutane according to Method D2a to provide 2- (2-methyl-4-nitrophenylimino) -1- (2-ethyl-1-butyl) -3-thia-1-azaspiro [4.4] nonane.

Item 231

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with 3-bromopentane according to Method D2b to give 2- (4-cyano-2-ethyl-phenyl-amino) -1- (3-pentyl) -3-thia-1-azaspiro [4.4] nonane.

Item 232

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with isopropyl bromide according to Method D2e for

757 / B

239 obtaining 2- (2-ηΊβίγΙ-4-ηίίΓθίθηγΙίΓηίηο) -1- (2-ρΓοργΙ) -3-β-3-3-3Ζ35ρΪΓθ [4.4] ηοηέηυ.

Item 233

r

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with 3-bromo-2-methylpropene according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (2-methylprop-1-en-3-yl) -3-thia-1-azaspiro [4.4] nonane.

Item 234

Me

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with allyl bromide according to Method D2e to yield

757 / B

240

2- (2-methyl-4-nitrophenylimino) -1- (1-prop-1-en-3-yl) -3-thia-1-azaspiro [4.4] nonane.

Item 235

1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

The thiazolidine is reacted with cyclopropylmethyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (cyclopropylmethyl) -3-thia-1-azaspiro [4.4] nonane.

Item 236

1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclohexylmethyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (cyclohexylmethyl) -3-thia-1-azaspiro [4.4] nonane.

757 / B

241

Item 237

C

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is 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.

Item 238

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with 2- (2-bromomethyl) -1,3-dioxane according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (2- (1,3-dioxan-2-yl) (1-ethyl) -3-thiazole 757 / B

242

azaspiro [4.4] nonane.

Item 239 ^S ) = NN ° 2

ABOUT

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclobutyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1-cyclobutyl-3-thia-1-azaspiro [4.4] nonane.

Item 240

1- (hydroxymethyl) cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is treated with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

757 / B

243

Item 241

1-Hydroxymethylcyclopentanamine is prepared according to Method Bi c. 2hydroxyethylamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to method C2a to give 2- (2-methyl-4-nitrophenylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Thiazolidine is oxidized with 3-chloroperoxybenzoic acid according to Method D4a to give 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane-3-oxide.

Item 242

NO ₂

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. 2hydroxyethylamine is reacted with thionyl chloride followed by 2-methyl-4-nitrophenylisothiocyanate according to method C2a to give 2- (2-methyl-4-nitrophenylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Thiazolidine is oxidized with 3-chloroperoxybenzoic acid according to Method D4a to provide 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] 31,757 / B

244 nonane-3,3-dioxide.

Item 243

The 2-ethylaniline is protected as 2-ethylacetanilide according to method A2a, step 1. The acetamide is converted to 2-ethyl-4-nitroaniline, then the protecting group is removed according to method A2a, step 2. The aniline is converted to 2-ethyl-4-nitrophenylisothiocyanate according to of Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethylcyclopentanamine hydrochloride salt according to Method B7e. The 1-chloromethylcyclopentanamine hydrochloride salt is reacted with

2-ethyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-ethyl-4-nitrophenylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (2-ethyl-4-nitrophenylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 244

// no ₂

Me

3-Methyl-4-nitroaniline is converted to 3-methyl-4-nitrophenylisothiocyanate according to Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. Hydrochloride salt 131 757 / B

245 chloromethylcyclopentanamine was reacted with 3-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (3-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 245

The 2,3-dimethylaniline is protected as the 2,3-dimethylacetanilide according to method A2a, step 1. The acetamide is converted to 2,3-dimethyl-4-nitroaniline, then the protecting group is removed according to method A2a, step 2. The aniline is converted to 2,3dimethyl-4-nitrophenylisothiocyanate according to Method A2a, Step 3. 1 (Hydroxymethyl) cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2,3-dimethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (2,3-dimethyl-4-nitrophenylirino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 246

757 / B

246

The 2,3-dimethylaniline is protected as the 2,3-dimethylacetanilide according to method A2a, step 1. The acetamide is converted to 2,3-dimethyl-6-nitroaniline, then the protecting group is removed according to method A2a, step 2. The aniline is converted to 2,3-dimethyl-6-nitrophenylisothiocyanate according to Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethylcyclopentanamine hydrochloride salt according to Method B7e. The 1-chloromethylcyclopentanamine hydrochloride salt is reacted with

2,3-dimethyl-6-nitrophenylisothiocyanate according to Method C1e to give 2- (2,3-dimethyl-6-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is 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.

Item 247

CN

1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 4-iodophenylisothiocyanate according to Method C1e to give 2- (4-iodophenylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodophenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide is reacted with copper (I) cyanide according to Method D2h to provide 2- (4-cyanophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

757 / B

247

Item 248

4-Cyano-2-methylaniline was prepared according to Method A1a. The aniline is converted to 4-cyano-2-methylphenylisothiocyanate according to Method A2b, 1-hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethylcyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopehthanamine hydrochloride is reacted with 4-cyano-2-methylphenylisothiocyanate according to Method C1e to give 2- (4-cyanophenylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 249

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-231 757 / B).

248 Ethylphenylamino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 250

C

4-Iodo-2-n-propylaniline is converted to 4-iodo-2-n-propylphenylisothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is sequentially treated with thionyl chloride and 4-iodo-2-n-propylphenylisothiocyanate according to Method C2a to give 2- (4-iodo-2-n-propylphenylimino) -3'-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2-n-propylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide is reacted with copper (I) cyanide according to Method D7a to provide 2- (4-cyano-2-n-propylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 251

4-Iodo-2-isopropylaniline is converted to 4-iodo-2-isopropylphenylisothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is sequentially treated with thionyl chloride and 4-iodo-2-isopropylphenylisothiocyanate according to Method C2a to give 2- (4-iodo-2-isopropylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-231 757 / B).

I

249 isopropylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide is reacted with cuprous cyanide according to Method D7a to provide 2- (4-cyano-2-isopropylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 252

4-Iodo-2,3-dimethylaniline is converted to 4-iodo-2,3-dimethylphenylisothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is sequentially treated with thionyl chloride and 4-iodo-2,3-dimethylphenylisothiocyanate according to Method C2a to give 2- (4-iodo-2,3-dimethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2,3-dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide is reacted with cuprous cyanide according to Method D7a to provide 2- (4-cyano-2,3-dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 253

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e

757 / B

250 to obtain 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is hydrolyzed according to Method D9a to provide 2- (4-carboxy-2-ethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 254

4-Cyano-2-methylaniline was prepared according to Method A1a. The aniline is converted to 4-cyano-2-methylphenylisothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethylcyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 4-cyano-2-methyl-phenylisothiocyanate according to Method C1e to give 2- (4-cyanophenyl-phenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is hydrolyzed according to Method D9a to provide 2- (4-carboxy-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 255

757 / B

251

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The benzoic acid was converted to 2- (4-acetyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane according to Method D10a.

Item 256

Methyl [4-amino-3-methylbenzoate] was converted to 4-methoxycarbonyl-2-methylphenylisothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is sequentially reacted with thionyl chloride and 4-methoxycarbonyl-2-methylphenylisothiocyanate according to Method C2a to give 2- (4-methoxycarbonyl-2-methylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2h to give 2- (4-methoxycarbonyl-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

757 / B

252

Item 257

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Benzoic acid is reacted with methylamine according to Method D6b to give 2- (4- (N-methylcarbamoyl) -2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 258

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] 31 757 / B

253 nonan. The nitrile is hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Benzoic acid is reacted with dimethylamine according to method D6b to provide 2- (4 (N, N-dimethylcarbamoyl) -2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 259

WITH,

The 2,3-dichloroaniline is converted to 2,3-dichloroformanilide according to Method A3a, Step 1. Formanilide is converted to 2,3-dichlorophenylisocyanide dichloride according to Method A3a, Step 2. The 1-hydroxymethylcyclopentanamine hydrochloride salt is synthesized according to Method B1c. The 2-hydroxyethylamine is converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to method B4d, step 1. The oxazolidine is opened by reduction according to method B4d, step 2 to give 1- (cycliopentylamino) -1 (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine is converted to 1- (cyclopentylamino) -1- (acetylthiomethyl) cyclopentane according to method C6c, step 1. The thioacetate is hydrolyzed according to method C6c, step 2 to give 1 (cyclopentylamino) -1- (thiomethyl) cyclopentane. 2-Thioethylamine is reacted with 2,3-dichlorophenylisocyanide dichloride according to Method C6c to provide 2- (2,3-dichlorophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 260

757 / B

254

2- (trifluoromethyl) aniline was converted to 2- (trifluoromethyl) formanilide according to Method A3a, Step 1. Formanilide was converted to 2- (trifluoromethyl) phenylisocyanide dichloride according to Method A3a, Step 2. 1- (Hydroxymethyl) cyclopentanamine hydrochloride salt synthesized according to Method B1c. The 2-hydroxyethylamine is converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to method B4d, step 1. The oxazolidine is reductively opened according to method B4d, step 2 to give 1 (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine is converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to method C6c, step 1. The thioacetate is hydrolyzed according to method C6c, step 2 to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. The 2-thioethylamine is reacted with 2- (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c to provide 2- (2- (trifluoromethyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 261

The 4- (trifluoromethyl) aniline was converted to 4- (trifluoromethyl) formanilide according to Method A3a, Step 1. The formanilide was converted to 4- (trifluoromethyl) phenyl isocyanide dichloride according to Method A3a, Step 2. The 1-hydroxymethylcyclopentanamine hydrochloride salt was synthesized according to Method B1c . The 2-hydroxyethylamine is converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to method B4d, step 1. The oxazolidine is reductively opened according to method B4d, step 2 to give 1 (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine is converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to method C6c, step 1. The thioacetate is hydrolyzed according to method C6c, step 2 to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. 2-Thioethylamine is reacted with 4- (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c for

757 / B

255 to give 2- (4- (trifluoromethyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 262

2-Chloro-3-methylaniline is converted to 2-Chloro-3-methylformanilide according to Method A3a, Step 1. Formanilide is converted to 2-Chloro-3-methylphenylisocyanide dichloride according to Method A3a, Step 2. The 1 (hydroxymethyl) cyclopentanamine hydrochloride salt is synthesized. according to method B1c. The 2-hydroxyethylamine is converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to method B4d, step 1. The oxazolidine is reductively opened according to method B4d, step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine is converted to 1- (cyclopentylamino) -1 (thioacetylmethyl) cyclopentane according to method C6c, step 1. The thioacetate is hydrolyzed according to method C6c, step 2 to give 1- (cyclopentylamino) -1 (thiomethyl) cyclopentane. 2-Thioethylamine is reacted with 2-chloro-3-methylphenylisocyanide dichloride according to Method C6c to provide 2- (2-chloro-3-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 263

The 3- (trifluoromethyl) aniline is converted to the 3- (trifluoromethyl) formanilide according to

757 / B

256 of Method A3a, Step 1. Formanilide is converted to 3- (trifluoromethyl) phenylisocyanide dichloride according to Method A3a, Step 2. 1-Hydroxymethylcyclopentanamine hydrochloride salt is synthesized according to Method B1c. The 2-hydroxyethylamine is converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to method B4d, step 1. The oxazolidine is reductively opened according to method B4d, step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine is converted to 1- (cyclopentylamino) -1 (thioacetylmethyl) cyclopentane according to method C6c, step 1. The thioacetate is hydrolyzed according to method C6c, step 2 to give 1- (cyclopentylamino) -1 (thiomethyl) cyclopentane. 2-Thioethylamine is reacted with 3 (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c to provide 2- (3 (trifluoromethyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 264

3-Chloro-2-methylaniline is converted to 3-Chloro-2-methylformanilide according to Method A3a, Step 1. Formanilide is converted to 3-Chloro-2-methylphenylisocyanide dichloride according to Method A3a, Step 2. The 1-hydroxymethylcyclopentanamine hydrochloride salt is synthesized according to Method B1. The 2-hydroxyethylamine is converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to method B4d, step 1. The oxazolidine is reductively opened according to method B4d, step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine is converted to 1- (cyclopentylamino) -1 (thioacetylmethyl) cyclopentane according to method C6c, step 1. The thioacetate is hydrolyzed according to method C6c, step 2 to give 1- (cyclopentylamino) -1 (thiomethyl) cyclopentane. 2-Thioethylamine is reacted with 3-chloro-2-methylphenylisocyanide dichloride according to Method C6c to provide 2- (3-chloro-231 757 / B).

257 methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 265

The 2,3-dichloro-4-methylaniline is converted to 2 _{L of} 3-dichloro-4-methylformanilide according to Method A3a, Step 1. Formanilide is converted to the 2,3-dichloro-4-methylphenylisocyanide dichloride according to Method A3a, Step 2. 1 Hydroxymethylcyclopentanamine hydrochloride salt is synthesized according to Method B1c. The 2-hydroxyethylamine is converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to method B4d, step 1. The oxazolidine is reductively opened according to method B4d, step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane.

The substituted 2-hydroxyethylamine is converted to 1- (cyclopentylamino) -1 (thioacetylmethyl) cyclopentane according to the method. C6c, step 1. The thioacetate is hydrolyzed according to Method C6c, step 2 to give 1- (cyclopentylamino) -1 (thiomethyl) cyclopentane. 2-Thioethylamine is reacted with 2,3dichloro-4-methylphenylisocyanide dichloride according to Method C6c to provide 2- (2,3dichloro-4-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. 2hydroxyethylamine is sequentially treated with thionyl chloride and 4-bromo-2-methylphenylisothiocyanate according to Method C2a to give 2- (4-bromo-2-methylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with

757 / B

258 with cyclopentyl bromide according to Method D2b to provide 2- (4-bromo-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 267

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] thionane. The nitrile is reduced according to Method D11a to give 2- (4-formyl-2-ethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 268

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro 31,757 / B

259 [4.4] nonane. The nitrile is reduced according to Method D11a to give 2- (4-formyl-2-ethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with triethylphosphonoacetate according to Method D12a to provide 2- (2-methyl-4 - ((1E) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 269

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethyl-cyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is reduced according to Method D11a to give 2- (4-formyl-2-ethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with nitromethane according to Method D12b to provide 2- (2-ethyl-4 - ((1E) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 270

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. 231,757 / B

260 hydroxyethylamine was converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is reduced according to Method D11a to give 2- (4-formyl-2-ethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with triethylphosphonoacetate according to Method D12a to provide 2- (2-ethyl-4 - ((1E) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The ester is saponified according to Method D6a to provide 2- (2-ethyl-4 ((1 E) -2-carboxyvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 271

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is reduced according to Method D11a to give 2- (4-formyl-2-ethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with the mononitrile according to Method D12c to provide 2- (2-ethyl-4- (2,2-dicyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

757 / B

261

Item 272

C

1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is reduced according to Method D11a to give 2- (4-form I-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with diethyl (2-oxopropyl) phosphonate according to Method D12a to provide 2- (2-ethyl-4 - ((1E) -2-acetylvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] ] nonane.

Heading 273 _ς

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. The 2-hydroxyethylamine is converted to the 1-chloromethyl-cyclopentanamine hydrochloride salt according to Method B7e. 1-Chloromethylcyclopentanamine hydrochloride is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclopentyl bromide according to Method D2b for

757 / B

262 to obtain 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile is reduced according to Method D11a to give 2- (4-formyl-2-ethyl-phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with acetonitrile according to Method D12d to provide 2- (2-ethyl-4 ((1E) -2-cyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Item 274

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. 2hydroxyethylamine is sequentially treated with thionyl chloride and 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cyclohexyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1-cyclohexyl-3-thia-1-azaspiro [4.4] nonane.

Item 275

1-Hydroxymethylcyclopentanamine is prepared according to Method B1c. 2hydroxyethylamine is sequentially treated with thionyl chloride and 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine is reacted with cycloheptyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1-cycloheptyl-3-thia-1-azaspiro [4.4] nonane.

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263

Item 276

1-Aminocyclohexane-1-carboxylic acid is protected as benzyloxycarbonylamine according to Method B1a, Step 1 1- (Benzyloxycarbonylamino) cyclohexane-1-carboxylic acid is reduced to 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) cyclohexane according to Method B1a, Step 2 The carbamate is deprotected according to Method B1a, Step 3 to give 1-amino-1- (hydroxymethyl) cyclohexane. The 2-hydroxyethylamine is sequentially treated with thionyl chloride and 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-13-azaspiro [4.5] decane. The thiazolidine is alkylated with isobutyl bromide according to Method D2b to provide 2- (2-methyl-4-nitrophenylimino) -1-isobutyl-3-thia-1-azaspiro [4.5] decane.

Item 277

2-Methyl-4-nitroaniline is converted to 2-methyl-4-nitropormanilide according to Method A3a, Step 1. Formanilide is converted to 2-methyl-4-nitrophenylisocyanide dichloride according to Method A3a, Step 2. 3-Aminotetrahydro-2H-pyran-3- acid The carboxylic acid is converted to the methyl ester according to Method B1b, Step 1. The methyl [3-aminotetrahydro-2H-pyran-3-carboxylate] is reduced to 3-amino (hydroxymethyl) tetrahydro-2H-pyran according to Method B1b, Step 2. 2-Hydroxyethylamine reacted with isobutyraldehyde according to Method B4c, Step 1 to provide 2-isopropyl-1-aza-3,7-dioxaspiro [4.5] decane. The oxazolidine is reduced to 3-isobutylamino-3- (hydroxymethyl) tetrahydro-2H-pyran. The substituted 2-hydroxyethylamine is converted to 3-isobutylamino-3 (acetyithiomethyl) tetrahydro-2H-pyran according to method C6c, step 1. The thioacetate is saponified according to method C6c, step 2 to give 3-isobutylamino-331 757 / B

264 (thiomethyl) tetrahydro-2H-pyran. 2-Thioethylamine is reacted with dichloride

2-methyl-4-nitrophenylisocyanide to provide 2- (2-methyl-4-nitrophenylimino) -1-isobutyl-1-aza-7-oxa-3-thiaspiro [4.5] decane.

Item 278

2-Methyl-4-nitroaniline is converted to 2-methyl-4-nitropormanilide according to Method A3a, Step 1. Formanilide is converted to 2-methyl-4-nitrophenylisocyanide dichloride according to Method A3a, Step 2. 4-Aminotetrahydro-2H-pyran-4- acid The carboxylic acid is converted to the methyl ester according to Method B1b, Step 1. The methyl [4-aminotetrahydro-2H-pyran-4-carboxylate] is reduced to 4-amino-4- (hydroxymethyl) tetrahydro-2H-pyran according to Method B1b, Step 2. 2hydroxyethylamine is reacted with isobutyraldehyde according to Method B4c, Step 1 to provide 2-isopropyl-1-aza-3,8-dioxaspiro [4.5] decane. The oxazolidine is reduced to 4-isobutylamino-4- (hydroxymethyl) tetrahydro-2H-pyran. The substituted 2-hydroxyethylamine is converted to 4-isobutylamino-4- (acetylthiomethyl) tetrahydro-2H-pyran according to method C6c, step 1. The thioacetate is saponified according to method C6c, step 2 to give 4-isobutylamino-4 (thiomethyl) tetrahydro-2H- pyran. 2-Thioethylamine is reacted with dichloride

2-methyl-4-nitrophenylisocyanide to provide 2- (2-methyl-4-nitrophenylimino) -1-isobutyl-1-aza-8-oxa-3-thiaspiro [4.5] decane.

Item 279

The 2-amino-2-norborane-1-carboxylic acid isomer mixture is converted to the N-benzyloxycarbonyl analogue according to Method B1a, Step 1.

1- (Benzyloxycarbonylamino) -2-norborane-1-carboxylic acid is reduced

757 / B

265 to 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) -2-norbomane according to method B1a, step 2. The carbamate is deprotected according to method B1a, step 3 to give 1-amino-1- (hydroxymethyl) -2- norbornane. The 2-hydroxyethylamine is alkylated with isobutyl bromide according to Method B2a to give N-isobutyl-1-amino-1- (hydroxymethyl) -2-norbomane. The alkylated 2-hydroxyethylamine is treated with thionyl chloride according to Method B7a to give the hydrochloride salt of N-isobutyl-2-chloroethylamine. The chloroethylamine is treated with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutylspiro [1,3-thiazolidine-4,3'-bicyclo [3.2.1] octane].

Item 280

Λ-ΝΟζ

HCl

N- (tert-butoxycarbonyl) - (L) -valine was converted to (S) -3- (tert-butoxycarbonylamino) -1-diazo-4-methylpentan-2-one according to Method B6a, step 1. The diazo compound was converted to methyl- [(R) -3- (tert-butoxycarbonylamino) -4-methylpentanoate] according to method B6a, step 2. The ester is reduced according to method B6a, step 3 to give (R) -3- (tert-butoxycarbonylamino) -4-methylpentan-1-ol . The carbamate is deprotected and converted to (R) -3-amino-1-chloro-4-methylpentane according to Method B7e. 3-Chloropropylamine is treated with 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-1,3-thiazine. Thiazine is alkylated with isobutyl bromide according to Method D2a to provide (4R) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1,3-thiazine hydrochloride salt.

Item 281

The 3-aminopropanol is reacted with butyraldehyde according to the method

757 / B

266

B9a, step 1 to provide 2-isopropyltetrahydro-1,3-oxazine. Oxazine is reduced according to Method B9a, Step 2 to obtain N-isobutyl-3-hydroxypropylamine. The 1-hydroxypropylamine is reacted with thionyl chloride according to Method B9a, Step 3 to give the hydrochloride salt of N-isobutyl-3-chloropropylamine. 3-Chloropropylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyltetrahydro-1,3-thiazine.

Item 282

N) 'J-Bu Me

no ₂

4-Aminobutanol is reacted with butyraldehyde according to Method B9a, Step 1 to provide 2-isopropyltetrahydro-1,3-oxazepine. 1,3-Oxazepine is reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxybutylamine. The 1-hydroxybutylamine is reacted with thionyl chloride according to Method B9a, step 3 to give the hydrochloride salt of N-isobutyl-3-chlorobutylamine. 3-Chlorobutylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyltetrahydro-1,3-thiazepine.

Item 283

i-Bu //

NO ₂

Me

3-Methyl-4-nitrophenylisothiocyanate is reacted with isobutylamine followed by chloroacetic acid according to Method C8a to give 2- (3-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-4-one.

Item 284

757 / B

267

3-Methyl-4-nitrophenylisothiocyanate is reacted with benzylamine followed by chloroacetic acid according to Method C8a to give 2- (3-methyl-4-nitrophenylimino) -3- (phenylmethyl) -1,3-thiazolidin-4-one.

Item 285

3-Methyl-4-nitrophenylisothiocyanate is reacted with 2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to give 2- (3-methyl-4-nitrophenylimino) -3- (2-methylbutyl) -1,3-thiazolidine- 4-one.

Item 286

no ₂

3-Methyl-4-nitrophenylisothiocyanate is reacted with 1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to give 2- (3-methyl-4-nitrophenylimino) -3- (1-cyclohexylethyl) -1,3-thiazolidine-4- one.

Item 287

no ₂

2-Methyl-4-nitrophenylisothiocyanate is reacted with isobutylamine followed by chloroacetic acid according to Method C8a to provide 231 757 / B

268 (2-Methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-4-one.

Item 288

no ₂

2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methylbutyl) -1,3-thiazolidine- 4-one.

Item 289

2-Methyl-4-nitrophenylisothiocyanate is reacted with benzylamine followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3- (phenylmethyl) -1,3-thiazolidin-4-one.

Item 290

NO ₂ i-Bu Me

2-methyl-4-Nitrophenyl isothiocyanate was reacted with isobutylamine followed by α-chloropropionic acid according to Method C8a for giving a 2- (2-methyl-4-nitro-phenylimino) _{-3-isobutyl-5-methyl-1-I,} 3-thiazolidine-4- one.

757 / B

269

Item 291

2-Methyl-4-nitrophenylisothiocyanate is reacted with 1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-cyclohexylethyl) -1,3-thiazolidine-4- one.

Item 292

2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1-amino-1-cyclohexylethan followed by chloroacetic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3 - ((1S) -1-cyclohexylethyl) ) -1,3-thiazolidin-4-one.

Item 293

2-Methyl-4-nitrophenylisothiocyanate is reacted with (1R) -1-amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3 - ((1R) -1- cyclohexylethyl) -1,3-thiazolidin-4-one.

757 / B

270

2-Methyl-4-nitrophenylisothiocyanate is reacted with isobutylamine followed by α-chloro-α-phenylacetic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-phenyl-1,3- thiazolidin-4-one.

Item 295

2-Methyl-4-nitrophenylisothiocyanate is reacted with (1R) -1-amino-1-cyclohexylethane followed by α-chloropropionic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3 - ((1R) -1 cyclohexylethyl) -5-methyl-1,3-thiazolidin-4-one.

2-Methyl-4-nitrophenylisothiocyanate is reacted with (1R) -1-amino-1-cyclohexylethan followed by α-chloro-α-phenylacetic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3 - ((( 1 R) -1cyklohexyletyl) -5-phenyl-1,3-thiazolidin-4-one.

757 / B

271

Item 297

2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1-amino-1-cyclohexylethan followed by α-chloropropionic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3 - ((1S) -1 cyclohexylethyl) -5-methyl-1,3-thiazolidin-4-one.

Item 298

2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1-amino-1-cyclohexylethane followed by α-chloro-α-phenylacetic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3 - ((( 1 S) -1cyklohexyletyl) -5-phenyl-1,3-thiazolidin-4-one.

2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-ethyl-1-butylamine followed by α-chloropropionic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) - 5-methyl-1,3tiazolidín-4-one.

757 / B

272

Item 300

I / Bu Bu

NO ₂

2-Methyl-4-nitrophenylisothiocyanate is reacted with isobutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-isobutyl-1,3- thiazolidin-4-one.

Heading 301 _ς

i-Bu Me) = N

N

2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-ethyl-1-butylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5- (2 -etyl1-butyl) -1,3-thiazolidin-4-one.

Item 302

2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-methylbutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-butyl) -5-isobutyl-1, 3-thiazolidin-4-one.

Item 303

757 / B

273

2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-methylbutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3- (2-butyl) -5-isopropyl-1, 3-thiazolidin-4-one.

2-Methyl-4-nitrophenylisothiocyanate is reacted with isobutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-isopropyl-1,3- thiazolidin-4-one.

Item 305

2-Methyl-4-nitrophenylisothiocyanate is reacted with (2S) -2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3 - ((2- (2-methyl) 1-butyl) -1,3-thiazolidin-4-one.

Item 306

757 / B

274 no ₂

I Me

C

2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-ethyl-1-butylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1). butyl) -Sizopropyl-1,3-thiazolidin-4-one.

Item 307

I i-Bu Me

The (R) -N-isobutylserine methyl ester hydrochloride salt is prepared from the (D) -serine methyl ester as described in Method B3a. The alcohol is reacted with thionyl chloride according to Method B7b, followed by reaction with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-methylene-1,3-thiazolidin-5-one .

Item 308

2,4,6-Trichlorophenylisothiocyanate is reacted with 2-butylamine followed by chloroacetic acid according to Method C8a to give 2 (2,4 _L 6-trichlorophenylimino) -3- (2-butyl) -1,3-thiazolidin-4-one .

Item 309

Cl

757 / B

275

3,4-dichlorophenyl isothiocyanate was treated with 2-methylbutylamine followed by chloroacetic acid according to Method C8a for giving a 2- (3,4-Dichloro-phenylimino) -3- (2-butyl) _-1-I, 3-thiazolidin-4-one.

Item 310

no ₂

N-isobutylglycine ethyl ester is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C11a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-5-one.

Item 311

2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-ethyl-1-butylamine followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1, 3-thiazolidin-4-one.

Item 312

ABOUT.

NO ₂ i-Bu Me

N-isobutylleucine ethyl ester is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C11a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidin-5-one.

757 / B

276

Item 313

no ₂

N-isobutylproline ethyl ester is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C11a to give 4- (2-methyl-4-nitrophenylimino) -1-oxoperhydro-2-thiapyrolysine.

Item 314

N- (tert-butoxycarbonyl) glycine tert -butyl ester is 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 is reduced according to Method B8b, Step 2 to give N- (tert-butoxycarbonyl) -N (2-hydroxyethyl) -1-amino-2-methylprop-2-ene. The alcohol is treated with ptoluenesulfonyl chloride according to Method B8b, Step 3 to give N- (tert-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2-methylprop-2-ene. The carbamate is deprotected according to Method B8b, step 4 to afford N- (2-tosyloxyethyl) -2-methylprop-2-ene-1-ammonium trifluoroacetate. The tosylate is reacted with 2-methyl-4-nitrophenylisocyanate according to Method C5a to provide 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -1,3-oxazolidine.

Item 315

757 / B

277

(L) -valine methyl ester is reduced to (1S) -1- (hydroxymethyl) -2-methylpropylamine according to method B1b, step 2. 2-hydroxyethylamine is reacted with isobutyraldehyde according to method B4c, step 1 to give (4S) -2.4 diisopropyl-1,3-oxazolidine. Oxazolidine is reduced according to Method B4c, Step 2 to give (1S) -1- (hydroxymethyl) -N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7b to give (1S) -1- (chloromethyl) -N-isobutyl-2-methylpropylamine. The chloroethylamine is reacted with 2-methyl-4-nitrophenylisocyanate according to Method C4a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1,3-oxazolidine.

Item 316

₂ i-Bu Me

(L) -leucine methyl ester is reduced to (1S) -1- (hydroxymethyl) -3-methylbutylamine according to method B1b, step 2. 2-hydroxyethylamine is reacted with isobutyraldehyde according to method B4c, step 1 to provide (4S) -2-isopropyl -4-isobutyl-1,3-oxazolidine. Oxazolidine is reduced according to Method B4c, Step 2 to obtain (1S) -1- (hydroxymethyl) -N-isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7b to give (1S) -1- (chloromethyl) -Nisobutyl-3-methylbutylamine. Chlorethylamine is reacted with 2-methyl-4-nitrophenylisocyanate according to Method C4a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-oxazolidine:

Item 317

757 / B

278

(L) -leucine methyl ester is reduced to (1S) -1- (hydroxymethyl) -3-methylbutylamine according to method B1b, step 2. 2-hydroxyethylamine is reacted with isobutyraldehyde according to method B4c, step 1 to provide (4S) -2-isopropyl -4-isobutyl-1,3-oxazolidine. Oxazolidine is reduced according to Method B4c, Step 2 to obtain (1S) -1- (hydroxymethyl) -N-isobutyl-3-methylbutylamine. The 4-amino-3-ethylbenzonitrile is converted to 4-cyano-2-ethyl-formmanilide according to method A3a, step 1. Formanilide is reacted with thionyl chloride and SO 2 Cl 2 according to method A3a, step 2 to give 4-cyano-2-ethylphenylisocyanide dichloride. The substituted 2-hydroxyethylamine is reacted with 4-cyano-2-ethylphenylisocyanide dichloride according to Method C7b to provide (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-oxazolidine.

Item 318 _Λ

2-Amino-2-methyl-1-propanol is reacted with cyclopentanone according to Method B4b, Step 1 to provide 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane. Oxazolidine is reduced according to Method B4b, Step 2 to give N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine. The 2-methyl-4-nitroaniline is converted to 2-methyl-4-nitropormanilide according to Method A3a, Step 1. Formanilide is reacted with thionyl chloride and SO ₂ Cl ₂ according to Method A3a, Step 2 to give 2-methyl-4- dichloride nitrofenylizokyanidu. The substituted 2-hydroxyethylamine is reacted with 2-methyl-4-nitrophenylisocyanide dichloride according to Method C7a to provide 2- (2-methyl-4-nitrophenylimino) -3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine.

Item 319

757 / B

279

2-Amino-2-methyl-1-propanol is reacted with cyclopentanone according to Method B4b, Step 1 to provide 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane. Oxazolidine is reduced according to Method B4b, Step 2 to give N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine. 4-Amino-3-ethylbenzonitrile is converted to 4-cyano-2-ethylformanilide according to Method A3a, Step

1. Formanilide is reacted with thionyl chloride and SO 2 Cl 2 according to Method A3a, Step 2 to obtain 4-cyano-2-ethylphenylisocyanide dichloride. The substituted 2-hydroxyethylamine is reacted with 4-cyano-2-ethylphenylisocyanide dichloride according to Method C7a to provide 2- (4-cyano-2-ethylphenylimino) -3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine.

Item 320 _Λ . .

The 1-aminocyclopentanecarboxylic acid is converted to the methyl ester according to method B1c, step 1. The ester is reduced to 1-hydroxymethylcyclopentanamine according to method B1c, step 2. The hydroxyethylamine is reacted with the cyclopentanone according to method B4d, step 1 to give 6-aza-4-oxo [12a] , 1,4,2] tridecane. Oxazolidine is reduced according to Method B4d, Step 2 to obtain 1- (cyclopentylamino) - (1-hydroxymethyl) cyclopentane.

The substituted 2-hydroxyethylamine is reacted with thionyl chloride according to Method B7b to give 1- (cyclopentylamino) -1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 2-methyl-4-nitrophenylisocyanate according to Method C4a to provide 1-cyclopentyl 2- (2-methyl-4-nitrophenylimino) -3oxa-1-azaspiro [4.4] nonane.

Item 321

757 / B

280

The 1-aminocyclopentanecarboxylic acid is converted to the methyl ester according to method B1c, step 1. The ester is reduced to 1hydroxymethylcyclopentanamine according to method B1c, step 2. The hydroxyethylamine is reacted with cyclobutanone according to method B4a, step 1 to obtain 5-piperis-12-oxadis , 4,2] dodecane. Oxazolidine is reduced according to Method B4a, Step 2 to give 1- (cyclobutylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine is reacted with thionyl chloride according to method B7b to give 1- (cyclobutylamino) -1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 2-methyl-4-nitrophenylisocyanate according to Method C4a to provide 1-cyclobutyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-azaspiro [4.4] nonane.

Item 322

The 1-aminocyclopentanecarboxylic acid is converted to the methyl ester according to method B1c, step 1. The ester is reduced to 1-hydroxymethylcyclopentanamine according to method B1c, step 2. The hydroxyethylamine is reacted with cyclohexanone according to method B4a, step 1 to give 6-aza-13-oxis , 1,5,2] tetradecane. Oxazolidine is reduced according to Method B4a, Step 2 to give 1- (cyclohexylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine is reacted with thionyl chloride according to method B7b to give 1- (cyclohexylamino) -1- (chloromethyl) cyclopentane. 2-Chloroethylamine is reacted with 2-methyl-4-nitrophenylisocyanate according to Method G4a to give 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-azaspiro [4.4] nonane.

Item 323

757 / B

281

ABOUT

et

CN

The 1-aminocyclopentanecarboxylic acid is converted to the methyl ester according to method B1c, step 1. The ester is reduced to 1-hydroxymethylcyclopentanamine according to method B1c, step 2. The hydroxyethylamine is reacted with the cyclopentanone according to method B4d, step 1 to give 6-aza-4-oxo [12a] , 1,4,2] tridecane. Oxazolidine is reduced according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. 4-Amino-3-ethylbenzonitrile is converted to 4-cyano-2-ethylformanilide according to Method A3a, Step

1. Formanilide is reacted with thionyl chloride and SO 2 Cl 2 according to Method A3a, Step 2 to obtain 4-cyano-2-ethylphenylisocyanide dichloride. The substituted 2-hydroxyethylamine is reacted with 2-methyl-4-nitrophenylisocyanide dichloride according to Method C7a to provide 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane.

Item 324

N

N,

i-Bu (1S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, steps 1 to 2. The alcohol is converted to N- (1S) -1- (chloromethyl) -3-methylbutyl) - N- (isobutyl) ammonium chloride as described in Method B7c. 4-Nitrophenylisothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride according to Method C1f to give 2- (4-nitrophenylthio) -1,5-diisobutylimidazoline.

757 / B

282

Item 325

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (48) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with 5-iodo-heptane according to Method D2a to give (4S) -2- (N- (4-heptyl) -N- (2-methyl-5-nitrophenyl) amino) -4-isobutyl-1,3-thiazoline.

(1R) -1- (hydroxymethyl) -3-methylbutylamine is prepared from leucine methyl ester (D) as described in method B1b. The 2-hydroxyethylamine is converted to (1R) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-5-nitrophenylisothiocyanate is reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4R) -2- (2-methyl-5-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with isobutyl bromide according to Method D2a to provide (4R) -2- (N-isobutyl-N- (2-methyl-5-nitrophenyl) amino) -4-isobutyl-1,3-thiazoline hydrochloride salt.

757 / B

283 (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from leucine methyl ester (L) as described in method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with neopentyl bromide according to Method D2a to provide (4S) -2- (N- (2,2-dimethylpropyl) -2-methyl-4-nitrophenylamino) -4-isobutyl-1,3-thiazoline.

Item 328

(1S) -1- (hydroxymethyl) -3-methylbutylamine is prepared from (L) leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine is converted to (1S) -1 (chloromethyl) -3-methylbutanammonium chloride as described in Method B7ä. 2,3-Dichlorophenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride according to Method C1a to give (4S) -2- (2,3-Dichlorophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine is reacted with 3-bromopentane according to Method D2a to provide (4S) -2- (N- (3-pentyl) -2-methyl-4-nitrophenylamino) -4-isobutyl-1,3-thiazoline.

The compounds presented in Tables 1-4 below are synthesized according to the procedures described above.

757 / B

284

Table 1

2-imino-1,3-thiazolidines and extended ring homologs

Polož- ka compound mp (° C) HPLC (Min) TLC Rf System solvent for TLC Mass Spec (source) process synthesis 1 C _n ^ ^{= n_} 0 ~ ⁿ ° ^{2 H} m / 90- 92 0.36 30% EtOAc / hex 238 (M + H) + [FAB] Cla 2 i-Bu 0.49 20% EtOAc / pentane 280 (M + H) + [CI] duties D2a 3 C _n ^ ^n_ O ^ ⁿ ° ^! i-bu me 0.52 20% EtOAc / pentane 294 (M + H) + [CI] duties D2a 4 i-Bu Cl Cl 0.78 20% EtOAc / pentane 303 (M + H) + [CI] duties D2a 5 C _N > ^N ^ p ^ ^N ° ² i-Bu MeO 11.9 (H) 310 (M + H) + [HPLC ES-MS] cld 6 C _N ^ ^{N =} O- ^CN i-Bu 9.9 (H) 260 (M + H) + [HPLC ES-MS] cld 7 HCl NO ₂ i-Bu Me 0.50 20% EtOAc / hex duties D2a 8 _{N n} ' ^{== n} C C ^ ^cn i-Bu Et 25.0 (H) 288 (M + H) + [HPLC ES-MS] cld

757 / B

285

9 C> = ^Ν -0 ~ ^α i-Bu F3C 32.0 (H) 337 (M-H) + [HPLC ES-MS] cld 10 ί / ^{Ν_Η Ο Ν} ° ~ ^2/1 0.23 20% EtOAc / pentane 278 (M + H) +  [CI] duties D2a, D14a 11 C ^ PZP ** ⁰² ^ r — 1 Me 0.49 20% EtOAc / pentane 292 (M + H) + [CI] duties D2a 12 c _n > = ⁿ P> ⁿ ° ² P 0.33 20% EtOAc / pentane 278 (M + H) + [CI] duties D2a 13 C &^gt; ^N ^ ^c 'p ^ci 0.43 11% EtOAc / pentane 301 (M + H) + [CI] duties D2a 14 C _n / ^{c = n} ~ CD ^{> _no2} -1 Me 0.77 30% EtOAc / hex 308 (M + H) + [FAB] B2b steps 1-3. B7, Cla , 15 C ^ O ^{- "network 02} ^ -1 ^Z Me 69- 70 0.78 30% EtOAc / hex 292 (M + H) + [FAB] duties D2a 16 C _N ^ ^{= N} PP ^N ° ² - == - 1 Me 108- 109 0/78 30% EtOAc / hex 290 (M-rH) -t [FAB] duties D2a 17 C _N ⁷ C ^{== NH) H} 2 ^{NO 2} ^) - ¹ Me 0.77 30% EtOAc / hex 322 (M + H) + [FAB] duties D2a 18 C _n ^ ^N X ZX ^N ° ^{2 -} 1 Me 0.77 30% EtOAc / hex 308 (M + H) + [FAB] duties D2a

757 / B

286

19 c> ⁿ 5> ⁿ ° ² —1 Me 0.72 40% EtOAc / hex 364 (M + H) + [FAB] duties D2a 20 C _n / ^{= n_} CD ^ ^{no2 -} 1 Me ' 0.67 30% EtOAc / hex 308 (M + H) + [FAB] duties D2a 21 C _N A ^N -T i ^ ^NO 2 <A ^Me 0.71 40% EtOAc / hex 294 (M + H) + [FAB] B5a. B7, Cla 22 C _n / ^{N =} H ^ ^_n ° ² Me 0.71 40% EtOAc / hex 308 (M + H) + [FAB] B5a. B7, Cla 23 ) Ί _Ν / ^{Ν =} ~ ^ζ3 ΗΝ ² ° -1 Me 0.72 40% EtOAc / hex 336 (M + H) + [FAB] duties D2a 24 (^ C2 ^{= N} -Cfy- ^N ° ^{2 -} 1 Me 0.71 40% EtOAc / hex 348 (M + H) + [FAB] duties D2a 25 \ ί ^{> Ν} -ρ- ^Ν ° ² \ -1 Me 0.71 40% EtOAc / hex 350 (M + H) + [FAB] B2b, step 2, Customs, D2a 26 0.68 30% EtOAc / hex 372 (M + H) + [FAB] duties D2a 28 _Br c> ⁿ - €> ⁿ ° ^{2 Μ} θ 0.74 40% EtOAc / hex 356 (M + H) + [FAB] duties D2a 29 1 ) Me 0.74 40% EtOAc / hex 312 (M + H) + [FAB] duties D2a 30 » ^> ⁿ ~ O- ⁿ ° ² ΞΞ — í M e 129- 131 276 (M + H) + [FAB] duties D2a

757 / B

287

31 ° ^N ° 2) Me ' 112- 113 356 (M + H) + [FAB] duties D2A 32 C _n > ^{= n_} 0 ~ ⁿ ° ^{2 Me} TX _t 394 (M + H) + [FAB] duties D2a 33 ^O - ^N --CH ² 'MeCr 4 - ¹ Me 0.40 40% EtOAc / hex 238 (M + H) + [FAB] duties D2a 34 ° ⁿ ° 2 MeO yj Me ^Z O 0.63 40% EtOAc / hex 309 (M &lt; + &gt;) [EI] duties D2a 35 Γ ⁵ > = Ν- / ~ Υ-ΝΟ _{2 Ph} 'M —I Me HO 358 (M + H) + [FAB] duties D2a, D5a 36 ₀ C _t = ^N - p - ^ 1 Me ^z 0.65 40% EtOAc / hex 336 (M + H) + [FAB] duties D2a 37 _o c _n ^{> nh} P ^ ⁿ ° ² y — 1 Me ^Z 0.63 40% EtOAc / hex 308 (M + H) + [FAB] duties D2a 38 r ^s > = _N V ~ V _N o ₂ ho ^ n \ -1 Me 310 (M + H) + [FAB] duties D2a, D5a 39 HO N y — 1 Me ^Z 338 [FAB] duties D2a, D5a 40 0.65 40% EtOAc / hex 321 (M-rH) + [FAB] duties D2a

757 / B

288

41- C> ^N 2 O- ^NO 2 ci ny / c, X> ^Me 0.74 40% EtOAc / hex 346 (M + H) + [FAB] duties D2a 42 C _t ^{= N-} O- ^{NO 2} ( ^Me ) ^Me . 0.63 40% EtOAc / hex 394 (M + H) + [FAB] duties d2d 43 ^Me X) Me 0.40 40% EtOAc / hex 335 (M + H) + [FAB] duties D2a 44 C _n x ^{= n} X 3 ~ ⁿ ° ² · · 14 _y 9 (f) 306 (M + H) + [HPLC ES-MS] B4B, B7c. cld 45 C _n ' ^{, = n-} O- ^{NO 2 MeCO 3} 14.4 (H) 322 (M + H) + [HPLC ES-MS] B4B, B7c. cld 46 C> ^N -p ^ X ^ cr ci 15.6 (F) 315 (M + H) + [HPLC ES-MS] B4B, B7c. cld 47 C _n ^{= n_ 0_n} ° ² δ 0.77 30% EtOAc / hex 318 (M + H) + [FAB] B2b steps 1-3. B7, Cla 48 _Cn ^{= n-} O- ⁿ ° ² δ 320 (M + H) + [HPLC ES-MS] B4A, B7c. cld 49 C _n ^ ^{= n} XZX ⁿ ° ² ó ' 119- 121 0.37 20% EtOAc / hex 314 (M + H) + [HPLC ES-MS] B7, Cla

757 / B

289

50 Γ ⁵ > Ν- / ~ Λ- ^Ν ° 2 y— & 15.4 (H) 334 (M + H) + [HPLC ES-MS] B2a, B7c. cld 51 C _n ^ ^{= n EN} } ^_no2 Ο 19.1 (H) 348 (M + H) + [HPLC ES-MS] B2a, B7c. cld 52 ^ X ^ MeO ^Z 16.9 (H) 364 (M + H) + [HPLC ES-MS] B2a, B7c. cld 53 c> - "Q Oh. Cl Cl 99 1 ~ h (h) 357 (M + H) + [HPLC ES-MS] B2a, B 7c, cld 54 Φ “ ^- Q y ° ° 2.63 (I) 301 (M + H) + [HPLC ES-MS] B2a, B7c. cld 55 C _n Nn- <O- ^{NO 2} Y "' 2.31 (I) 292 ' (M + H) + [HPLC ES-MS] B2a, · B7c. cld 56 ^Cl 2.78 (I) 301 (M + H) + [HPLC ES-MS] B2a, B7c. cld 57 ^ Q = ⁿ &^lt; ^ ^ci 2.95 (I) 301 (M + H) + [HPLC ES-MS] B2a, B7c. cld

757 / B

290

58 PC .in --- L 3.18 (I) 315 (M + H) + [HPLC ES-MS] B2a. B7c. cld 59 ï 3.29 (I) 315 (M + H) + [HPLC ES-MS] B2a, B7c. cld 60 C> = ^Ν “Ο ^ει P ° 3.48 (I) 315 (M + H) + [HPLC ES-MS] B2a. B7c. cld 61 c> ^N -p r ~ - ^ Μβ Μβ 3.18 (I) 275 (M + H) + [HPLC ES-MS] B2a. B7c cld 62 Me Cl 3.23 (I) 295 (M + H) + [HPLC ES-MS] B2a. B 7c, cld 63 and I T 1 c> - p ï ° 3.99 G) 329 (M + H) + [HPLC ES-MS] B2a, B7t. cld 64th ï ° 4.13 (I) 329 (M + H) + [HPLC ES-MS] B2a. B7c. cld 65 C> ^{N -} O - j Me Q 3.60 (0 320 (M + H) + [HPLC ES-MS] B2a. B7c. cld 66 C ^ ⁿ ~ O ^or d ° 4.8 (I) 329 (M + H) + [HPLC ES-MS] B2a, ti 7c cld

210

757 / B

291

67 stork j Me Me σ 3.99 (I) 289 (M + H) + [HPLC ES-MS] B2a, B7c. cld 68 cp-p J Me ⁷ Cl d 4.05 (I) 309 (M + H) + [HPLC ES-MS] B2a, B7c. cld 69 Cp ^ p ï ” 17.0 (F) 343 (M + H) 4- [HPLC ES-MS] B2a, B7c. cld 70 ï 16.7 (F) 334 (M + H) + [HPLC ES-MS] B2a, B7c. cld 71 CppP ⁰ * j MeO O 16.3 (F) 350 (M + H) + [HPLC ES-MS] B2a, B7c. cld 72 cppp ° ² CP ' 125- 126 0.77 30% EtOAc / hex 348 (M + H) + [FAB] B5a. B7, Cla 73 No-P Bn Me ⁷ Cl 3.40 G) 317 (M + H) + [HPLC ES-MS] B2a, B7c. cld 74 cp-Q- ^or Bn Cl 3.63 (I) 337 (M + H) + [HPLC ES-MS] B2a, B7c ^ cld 75 p ^N pP Bn Cl 3.68 (I) 337 (M + H) + [HPLC ES-MS] B2a, B7c. cld

757 / B

292

76 Bn Me 3.45 (I) 328 (M + H) + [HPLC ES-MS] B2a, B7c. cld 77 Bn Cl Cl 3 _y 66 (0 337 (M + H) + [HPLC ES-MS] B2a, B7c. cld 78 C / O ™ ABOUT ' 13.9 (G) 356 (M + H) + [HPLC ES-MS] B2a, B7c. cld 79 O'O 'i 7 XJ Cl 15.3 (G) 362 (M + H) + [HPLC ES-MS] B2a, B7c. cld 80 c _r > ^N -CO ^N02 honors “· 19.6 (H) 348 (M + H) + [HPLC ES-MS] B2a, B7c. cld 81 c> ⁿ - € 0 ° ² θ> ^Me ° 18.1 (H) 364 (M + H) + [HPLC ES-MS] B2a, B7c. cld 82 cy ^{1 Cl Cl} 18.7 (H) 357 (M + H) + [HPLC ES-MS] B2a, B7c. cld 83 c> -O ™ honor 15.4 (F) 314 (M + H) + [HPLC ES-MS] B2a, B7c. cld

757 / B

293

84 About Α ^ν -Ο- ^Ν0 · A 0.68 30% EtOAc / hex '404 (M + H) + [FAB] B2b steps 1-3. B7, Cla 85 ι (/ “Ό ·“ ^{1 Me.)} 0.68 30% EtOAc / hex 372 (M + H) + [FAB] duties D2a 86 C _N > ^{= N_} {A ^{N02 is} "· 0.71 40% EtOAc / hex 344 (M + H) + [FAB] duties D2a 87 > XYXX i-Bu \ z = / 0.38 30% EtOAc / hex 342 (M + H) + [HPLC ES-MS] A2c, blb, b4c. B7c. CLF 88 ' ^s Oc _n > ⁿ X 3 ^{h n} ° ² i-Bu 0.78 30% EtOAc / hex 336 (M + H) + [HPLC ES-MS] blb, b4c. B7c. CLF 89 i-Bu 0.79 1 30% EtOAc / hex 316 (M + H) + [HPLC ES-MS] blb, b4c. B7c. CLF 90 i-Bu Me HCl 0.74 20% EtOAc / hex B7, duties D2a 91 % X ^{> nh} Q ^no2 i-Bu Me HCl 7.85 (B) 0.74 20% EtOAc / hex 350 (M + H) + [FAB] B7, duties D2a 92 no ₂ Λ.ΧΗ-0 i-Bu _Me / «Cl 0.77 1 20% EtOAc / hex B7, duties D2a

757 / B

294

93 No ₂ i-Bu Me NCI 0.76 20% EtOAc / hex B7, duties D2a 94 Me Me HCl 0.50 20% EtOAc / hex B7, duties D2a 95 and X> ^ ° ² Me Me HCl 00:50 20% EtOAc / hex B7, duties D2a 96 ₂ Me Me HCl 00:52 20% EtOAc / hex B7, duties D2a 97 Me \ y \ y hci 0.79 20% EtOAc / hex B7, duties D2a 98 Me _x C _n ^{> = n} P 2 ^{NO 2} 0.70 30% EtOAc / hex 391 (M +) [El] blb, B7, duties D2a ⁹⁹ i-Bu Et 46- 49 0.65 10% EtOAc / hex 344 (M + H) + [HPLC ES-MS] blb, B7, duties D2F 100 V ^ue 347 (M +) [El] blb, B7, duties D2a 101 AóÓ'Óó ^-0 'cf' 0.63 30% EtOAc / hex 361 (M +) [FAB} blb, B7, duties D2a

757 / B

295

102 • J Me ^Z 0.63 30% EtOAc / hex '394 (M + H) + [FAB] blb, B7, duties D2a, D5a 103 Me i-Bu Me HCl 7.67 (B) 363 (M +) [EI] A2B, B7, duties D2a 104 Cl Cl 0.74 and 30% EtOAc / hex 387 (M + H) + [FAB] blb, B7, duties D2a 105 Me 0.81 30% EtOAc / hex 392 (M + H) + [FAB] blb, B7, duties D2a 106 Cl Cl λΧ ^{> ν} ~ ο i-Bu 53- 55 360 (M + H) + [FAB] blb, B7, duties D2a 107 λΧ> -} νο> ^{νο! H} F3C cf ₃ every ₂ h 17.5 (D) 348 (M + H) + [HPLC ES-MS] blb, B7, CIC 108 β-Bu F ₃ C _{CF 3 CO 2 H} 28.9 (D) 404 (M + H) + [HPLC ES-MS] blb, B7, CIC D2F 109 > j ^> ^{= n} -Q ^{-cn μΒϋ F} ' ^C CF 3 CO 3 H 23.7 (E) 383 (M + H) + [HPLC ES-MS] blb, B7, CIC D2F 110 ^C, V-Bu Me _{CF; CO 2 H} 23.8 (D) 364 (M + H) + [HPLC ES-MS] blb, B7, CIC D2F

757 / B

296

111 in £ ^S > -HJK ^P -y OMe i-Bu Me 36 0? 30% EtOAc / hex 363 (M + H) + [FAB] blb, B7, duties D2a 112 Me kBu Me 0.79 30% EtOAc / hex 364 (M + H) + [CI] A2a, step 3, Bbl, B7a, Cla, D2a 113 i-bu me 130- 131 348 (M + H) + [CI] blb, B7, duties D2a, D6a 114 Λ ^ ν ^{> Ν} >> ^Ρ i-Bu M e 0.74 1 30% EtOAc / hex 323 (M + H) + [FAB] blb, B7, duties D2a 115 i-bu me 0.74 1 30% EtOAc / hex 338 (M +) [EI] blb, B7, duties D2a 116 i-bu me 0.74 and 30% EtOAc / hex 383 (M + H) + [FAB] blb, B7, duties D2a 117 _z x ^ Xn ^{> = n} '0 ^-cn i-Bu Et 0.54 50% EtOAc / hex C2a, D2a 118 λΧ ^{> ν} ^ ζ> ^ν ° ³ i-Bu Me ^Z 00:44 5% EtOAc / hex 350 (M + H) + [CI] blb, b4c. B7c. Clb 119 aX ^{> n} -P i-Bu Me 00:50 80% EtOAc / hex 306 (M + H) + [CI] A2B, blb, b4c.

757 / B

297

B7c. Clb 120 i-Bu <<_J> 124- 126 0.43 10% EtOAc / hex A2B, blb, C2a, D2a 121 i-Bu 0.80 30% EtOAc / hex 336 (M + H) + [HPLC ES-MS] blb, b4c. B7c. CLF 122 j ^ C ^{> n_} CX ^cn i-Bu 0.85 30% EtOAc / hex 316 (M + H) + [HPLC ES-MS] blb, b4c. B7c. CLF 123 aX ^{> nh} P i-Bu Me 00:26 100% EtOAc 322 (M + H) + [HPLC ES-MS] A2B, blb, b4c. B7c. Clb, D 4 124 iX / CH 2 ( ¹⁰² L) i-Bu Me HCl 00:51 10% EtOAc / hex B7, duties D2a 125 L-Bu Me HCl 8.83 (B) 350 (M + H) + [CI] Bla Step 2, B7b, Cle. D2a 126 Γ> = ^N —Ο “ ^Ν ° 2 θί-έυ m / HCl 00:50 10% EtOAc / hex Bla Step 2, Blb, duties D2a 127 I and ^{the> NH} CH <X ^ N-'J characterized OMe 1 i-Bu Me HCI 00:36 30% EtOAc / hex 362 (M + H) -? [EI] blb, B7, duties D2a

757 / B

298

128 l-Bu Me 0.80 s 25% EtOAc / hex B7, duties D2a 129 62- 64 345 (M + H) + [FAB] A2a, B7, duties D2a 130 1 i-Bu CF ₃ 0 _} 91 30% EtOAc / hex 393 (M + H) + [FAB] A2a, Step 3, Blb, B7, duties D2a 131 iX> ^N -Cr ^{cN 11} i-Bu CF ₃ 0.70 30% EtOAc / hex 384 (M + H) + [FAB] A2a step 3, Bbl, B7a, Cla, D2a 132 iX'r ^N ^>^NO; i j-Bu 4 p 386 (M + H) + [FAB] A2B, blb, B7, duties D2a 133 q ^ ^{> n} ^ O- ^{cn II} -Bu Et 0.72 20% EtOAc / hex 343 (M +) [El] blb, B7, duties D2a 134 iX> ⁿ <> ^cn 2 i-Bu Me ^Z 0.70 30% EtOAc / hex 330 (M + H) + [FAB] Ala, A2a step 3, Bla, B7, D2a 135 Me uQ = ^N- p ^ ^{cN 11} -Bu Me 0.70 30% EtOAc / hex 344 (M + H) + [FAB] Ala, A2a step 3,

757 / B

299

blah, B7, D2A 136 Me 2 i-Bu Me 0.74 30% EtOAc / hex 364 (M + H) + [FAB] A2a, blb, B7, duties D2a 137 2 i-Bu Me 8.18 (B) 336 (M + H) + [FAB] C2a, D2a 138 u> -o- ⁿ ° ² 1 i Me “ 7.91 (B) 0.73 25% EtOAc / hex C2a, D2a 139 X '^^ ZX' ⁴⁰² (iBu Me Li) ^hci 0.82 33% EtOAc / hex B7b. duties D2a 140 t-Bu Me HCl 0.80 33% EtOAc / hex B7b. duties D2a 141 Χ _ν ^{> = νη} Ο ^ην ° ² Me ' 00:59 50% EtOAc / hex 292 (M + H) + [CI] blb, B7, Cla 142 Xn ^{> N} 4 ^{H N} ° ² in J Me 00:49 50% EtOAc / hex 278 (M + H) + [FAB] blb, B7, Cla 143 i-Bu Et M HCl OH 00:24 20% EtOAc / hex 394 (M + H) -R [HPLC ES-MS] blb, b4c. B7c. Clb

757 / B

300

144 ^cn 1-Bu Et Lj HCl Cl 00:43 ) 10% EtOAc / hex 412 (M + H) + [HPLC ES-MS] blb, b4c. B7c. Clb 145 Xh> = ⁿ ^ P ^ ^gn I-Bu Et ô ” 88- 90 0 ^ 0 10% EtOAc / hex 424 (M + H) + [HPLC ES-MS] blb, b4c. B7c. Clb 146 Γ) = N-Z ~ _W-NO2 MeO ^ yl ^ N 0 ^{Me μέυ} HCl 0.40 25% EtOAc / hex B3a, C2a 147 Γ / ^ N — ζ ~ / - NO ₂ MeO ^ - <N J- # 0 ^{μέυ Me} HCl 0.40 25% EtOAc / hex B3a, C2a 148 Me ^ X ^ -Q- ⁰² x i-Bu Me r 8.79 1 (B) B8a. C5b 149 Me ^ X ^ ^N O ' ^N ° ² > r ⁴ o' 9.11 (B) 406 (M + H) + [C] B8a. C5b 150 Μβ _ν ^ Ν ^{> = Ν} ^^ ^Νθ2 r ó ' 8.84 (B) 406 (M + H) + [C] B8a. C5b 151 Ah-Bu Me > r 8.63 (B) 394 (M + H) + [CI] B 8a, C5b 152 r5 " 4.05 (A) 385 (M + H) + [HPLC ES-MS] B8a. C5b

757 / B »

301

153 Γ ^ ^{= ν} ~ 4 ~ /> ^νο 2 ^μέυ Ο 5.26 (A) 430 (M + H) + [HPLC ES-MS] A2B, B8a. C5b 154 ^Γ δ> = ^{Ν_ <θ} "2 ^Ν0 Me-sy ^ Ύ N ~ \> R ° ^O 5:44 (A) 442 (M + H) + [HPLC ES-MS] A2B, B8a. CSB 155 Υό θ 4.19 (A) 446 (M + H) + [HPLC ES-MS] A2a, B8a. C5b 156 ,, _e Pp-Q- ^NO ; \ ^ θ '^ ^υ \ _ / 4.80 (A) 434 (M + H) + [HPLC ES-MS] A2a, B8a. C5b 157 Me ^ N ^{> N} p ^ ^NO2 -i-Bu i-Pr> r 3.98 (A) 422 (M + H) + [HPLC ES-MS] A2a, B8a. C5b 158 Me ^ GB ^N “O“ ^N ° ^! 7 ό ^m 6.12 (A) 434 (M + H) + [HPLC ES-MS] A2a, B8a. C5b 159 I X Me Me > r ô. 5.74 (A) 420 (M + H) + [HPLC ES-MS] A2B, B8a. C5b 160 Me ^ j ^{> N_} P ^N ° ² Á-Bu Me Me Ύ 5:40 (A) 408 (M + H) + [HPLC ES-MS] A2B, B8a. C5b 161 MeP J = ^N- O ^NO > ϊ Me Me V p 3.65 (A) 436 (M + H) + [HPLC ES-MS] A2B, B8a. C5b

757 / B

302

162 '  s Me ^^ N V- / Zó ° 5.07 (A) 426 (M + H) + [HPLC ES-MS] A2B, B8a. C5b 163 Me ^ N ^{> N_} P ^ ^CN O 5:00 (A) 414 (M + H) + [HPLC ES-MS] A2B, B8a. C5b 164 i-bu me 00:13 25% - EtOAc / hex B8a. C5b, D3a 165 r ^s > Nn- ^N ° 2 Me- ^ χ''Ν VY HH ^ p 4.75 (A) 386 (M + H) + [HPLC ES-MS] A2B, B8a. C5b, D3a 166 Q1, i-Bu Me 7.29 (B) 338 (M + H) + [CI] B8a. C5b, D3a 167 Oh ^ Z ^ ^Me ' 00:16 25% EtOAc / hex B 8a, C5b D3a 168 MeV / pVO ^{2 OH} 6 ^Me 7.18 (B) 350 (M + H) + [CI] B 8a, C5b D3a 169 McJ ^ PpZ ^{02 f} ' ^Bu 5.07 (A) 372 (M + H) + [HPLC ES-MS] A2B, B8a. C5b, D3b 170 i-Bu t-Bu 4.75 (A) 360 (M + H) + [HPLC ES-MS] A2B, B8a. C5b, D3b 171 Γ> = n ^ C ^ -no ₂ Me ^ / ^ N p_y ÔH ^! - ^Bu p_ / 4.68 (A) 374 (M + H) + [HPLC ES-MS] A2B, B8a. C5b, D3b

757 / B

303

172 Ij ^S ^ ^{= N} ^ C ^ ^NNO 2 Me ^ ZN 'y - / ^OH 0 ° 2.5 (A) F 390. (M + H) + [HPLC ES-MS] A2a, B8a. C5b, D3b 173 óh ^μέυ {_} 4:55 (A) 378 (M + H) + [HPLC ES-MS] A2a, B 8a, C5b D3b 174 ^{ÔH μέυ!} ' ^Pr 5.86 (A) 366 (M + H) + [HPLC ES-MS] A2a, B8a. C5b, D3b 175 MeJ ^ ^{> N} ^ pP ^N ° ^{2 ÔH} '* ^Pl 6:00 (A) 378 (M + H) + [HPLC ES-MS] A2a, B8a. C5b, D3b 176 Me.X ^{> N} ^ Q · ⁰² ÔH k ^{e e Me} 0.89 (A) 380 (M + H) + [HPLC ES-MS] A2B, B8a. C5b, D3b 177 Μ ^ Ν ^ -Ρ ^ ⁰² i-Bu Me Me 5:42 (A) 352 (M + H) + [HPLC ES-MS] A2B, B8a. C5b, D3b 178 Μβ ^ Ν ^{) = Ν_} Ρ ^Ν ° ^{2 ÔH Μβ M} ® 5.64 (A) 364 (M + H) + [HPLC ES-MS] A2B, B 8a, C5b D3b 179 _{Μ θ} ^ ^{Ν> Ν CN} O * ά θ 4.26 (A) 370 (M + H) + [HPLC ES-MS] A2B, B8a. C5b, D3b 180 ^{ÔH μΒυ} \ _ / 3.94 (A) 358 (M + H) + [HPLC ES-MS] A2B, B8a. C5b, D3b

757 / B

304

181 ί-Bu Me 8:46 (B) C2a, D13a, D2a 182 i-bu me 0.82 5% MeOH / CH2C12 C2a, D13a, D2a. 183 / xXA'-CA ⁰² N. ',. / hBu Me 0 15 25% EtOAc / CH2C12 C2a, D2a 184 ΓκΑΑ ^ν Α> ^ν ° ² N - Λ 0.04 25% EtOAc / CH2C12 C2a, D2a 185 ^x C _N '^{> = n} X Z 2 ^{nc> 2} Me T ^HBr 211 0.78 10% MeQH / 90% CH2C12 B7, duties T2G 186 θΆ _Ν ό = ^Ν-C) - = ^cf, .i-Bu Cl HCl 159 078 10% EtOAc / 90% pet. ether b4c. C2F 187 i-Bu Cl Cl 00:26 1 10% EtOAc / 90% pet. ether b4c. C2F 188 O = ^n- Q i-Bu Cl Cl HCl 177 024 10% EtOAc / 90% pet. ether b4c. C2F 189 and-A about 134 C2F

757 / B

305

190 o ¹ · - ° no 209 B5b. C2F 191 qA ^Cl - 162 B5b. C2F 192 <Y ^ Me ^C 'θ' U 209 B5b. C2F 193 HO ^ J Cl Cl HCl 164 C2F. B5b 194 ^H m / 178 0.80 10% MeOH / 90% CH2C12 C2F 195 IN 181 duties T2G 196 i-bu me 97 duties T2G 197 i-Bu Cl Cl HCl 154 duties T2G 198 Α> ^Ν - <λ ^Νθ2 “' 156 b4c. C2F

757 / B

306

199 ABOUT" " 154 b4c. C2F 200 <A, “θ U ^HCl 196 B5b. C2F 201 Y _N ^{= N} pP ^N ° ² U ^hci 188 190 0.28 10% EtOAc / 90% pet. ether B5b. C2F 202 Y _N ^{2 = N} pP ^N ° ² i-Pr Me 10S 0.16 10% EtOAc / 90% pet. ether B5b. C2F 203 i-Pr Cl Cl 63 0.26 10% EtOAc / 90% pet. ether B5b. C2F 204 ύ / 'φ- i-Bu Cl HCl 95- 97 00:34 10% EtOAc / 90% pet. ether B5b. C2F 205 PppŽP ° ² Y · »' 229 B7, duties T2G 206 ppp ^{> N} ° ² i-Bu Me 7.83 (B) 321 (M + H) + [EI] BLC, B7b. duties D2a

757 / B

307

207 Q > = ^N - <\ // “ ^N ° 2 nv — v o 8:59, (B) • 374 (M + H) &lt; + &gt; [CI] BLC, B4A C2a 208 q ^ _n ^ ^{n- (} O- ^{nO 2} δ) 0.64 / 30% EtOAc / hex 374 (M + H) + [CI] A2a, BLC, B7, duties d2b 209 C A f = \ / = N - G // - CN about··" 0.74 20% EtOAc / hex 368 (M + H) + [CI] and 5a, A2B, BLC, B7, duties d2b, D7a 210 C . ₇ ^n- C7 ™ 6 0.74 20% EtOAc / hex 368 (M + H) + [CI] and 5a, A2B, BLC, B7, duties d2b, D7a 211 C \ = - / "V / = ^N - (\ /) - CN ó ' 200 201 0.74 20% EtOAc / hex 382 (M + H) + [CI], and 5a, A2B, BLC, B7, duties d2b, D7a 212 about - ^with \ / = \. / ^N \\ # ~ ^N0 2 ny— / ó “· 8.65 (B) 374 (M + H) + [CI] BLC, B4A, C2a

757 / B

308

213 Ό > = N— (v ... r - NO ₂ N y ~ 7f i-Bu Me 0.82 25% EtOAc / hex BLC, B7, Cle. D2a 214 D ^ A ^N ° ^! i-Bu Et 0 1 _l 86 30% EtOAc / hex 362 (M + H) + [FAB] A2a, BLC, B7, duties D2a 215 D > = ⁿ - (D ^-no 2 h JJ i-Bu n-Pr 0.80 1 30% EtOAc / hex 376 (M + H) + [FAB] A2a, BLC, B7, duties D2a 216 D ζ> ^Ν Αλ ^Ν ° ² i-Bu i-Pr 0.86 30% EtOAc / hex 376 (M + H) + [FAB] A2a, BLC, B7, duties D2a 217 D > nA 3 -n ^o 2 -n i-Bu Me Me 0.83 1 30% EtOAc / hex 362 (M + H) + [C] A4a. A2d. BLC, B7e. CIC D2a 218 C ^S ) t = _N - / - d - _N O ₂ h Mi-Bu Me 68- 70 348 (M + H) + [C] A2a BLC, B7, duties D2a 219 C y x 0.64 30% EtOAc / hex 383 (M &lt; + &gt;) [EI] A2a, BLC, B7, duties D2a

757 / B

309

220 C 'd ^N -Cr ^CN i-Bu 71- 72 BLC, B7e. duties D2a 221 Ό d ^{= N -} C ^y y ^CN 'N i-Bu Me. 98- 100 327 (M +) [EI] Ala, A2a, step 3, Blc, B7a, Cla d2b 222 i-Bu Et 26.5 G) 342 (M + H) f [HPLC ES-MS] Blc, B7a,. duties d2b 223 D < ^S x / = \> = N— ( _x /> - CN N V p i-Bu 0.73 20% EtOAc / hex 364 (M + H) + [FAB] A2a step 3, Blc, B7a, Cla, d2b 224 Ό -N ^{> = N} P ^-CN i -Bu Me Me 00:16 50% CH2C12 / hex 342 (M + H) + [CI] and 5a, A2a Step 3, Blc, B7e Cle. D2H, D7a 225 cfô'óf- ^N i-Bu Me Me 0.70 20% EtOAc / hex and 5a, A2a step 3, Blc, C2a, D2a DSA

757 / B

310

226 C N / Λ ^J i-Bu Me Me 0.39 50% CH2C12 / hex 443 (M + H) + [CI] and 5a, A2a Step 3, Blc, B7e. Cle. D2H 227 C by ₂ n i-Bu Me Me 362 (M + H) + [CI] A4a. A2d. BLC, B7e. Cle. d2b 228 C s- / ^{CN -} 0Ό ^{J J} -Bu 58- 60 320 (M + H) + [C] Ala, A2B, BLC, B7e. Cle. D2a 229 D Me N = Z O m- ^cn i-Bu Me 140 143 0.68 30% EtOAc / hex 343 (M + H) + [CI-MS] A2c, BLC, B7e. Cle. D2H 230 D ^ _N ^ ^N ^ ZX ^{No. 2} I Me '\ - \ HCl 0.83 25% EtOAc / hex BLC, C2a, D2a 231 D > ⁿ -O ^ ^cn y 86- 88 0.74 1 20% EtOAc / hex 356 (M + H) + [CI] BLC, B7e. Cle. d2b 232 D - _N ' ^{= N_O> _NO 2} A, ^Me 135 137 BLC, B7e. Cle. D2E

757 / B

311

233 € -Ρ ^Ν- νΡ ^Ν0ζ v 95- 97 BLC, B7e. Cle. D2E 234 C d = ^Me 0 _} 28 40% EtOAc / hex BLC, B7e. Cle. D2H 235 D IN" 100 102 BLC, B7e. Cle. D2E 236 about (Me ABOUT 85- 87 BLC, B7e. Cle. D2E 237 D - ^_C> pd ^{N_ No. 2} k5 96- 98 BLC, B7e. Cle. D2E 238 DHR · about 4.81 (A) 406 (M + H) + [HPLC ES-MS] BLC, B7e. Cle. D2E 239 C -pPP ⁰ 'ó · 5.29 (A) 346 (M + H) + [HPLC- ES-MS] BLC, B7e. Cle. D2E 240 0 - _ν ^{> = ν_} ^ ^ην ° ² ° 120 121 00:45 10% EtOAc / hex BLC, C2a, d2b

757 / B

312

241 0 about n about "· 126- 128 00:10 25% EtOAc / hex BLC, C2a, d2b, D4a. 242 D ° s', o / =>. X ^{> = N} "y / ^_N ° ² · · 181 DEC 0.27 25% EtOAc / hex BLC, C2a, d2b, D 4 243 D ^ = N— / j — NO ₂ 0 ^ 0.86 30% EtOAc / hex 374 (M + H) + [CI] A2a, BLC, B7e. Cle. d2b 244 D about " 136- 137 360 (M + H) + [FAB] A2a step 3, BLC, B7e. Cle. d2b 245 D -N X Me Me 83- 84 374 (M + H) + [CI] A2a, BLC, B7e. Cle. d2b 246 o ₂ n 374 (M + H) + [CI] A2a, BLC, B7e. Cle. d2b 247 € about 158- 159 BLC, B7e. Cle. d2b D2H

757 / B

313

248 Me CN 106- 107 0.73 30% EtOAc / hex 340 (M + H) + [CI] Ala, A2B, BLC, B7e. Cle. d2b 249 C 7 '-Το CN 18.1 (J) 0.66 20% EtOAc / hex 354 (M + H) + [HPLC ES-MS] Ala, A2B, B7, D2F 250 C 0 "ΆΓ about" CN 0.74 20% EtOAc / hex 368 (M + H) + [CI] BLC, B7e. Cle. d2b 251 C ABOUT CN 0.74 20% EtOAc / hex 368 (M + H) + [CI] A2B, BLC, C2a, d2b, D7a 252 C Me Me CN 0.18 50% CH2C12 / hex 354 (M + H) + . [CI] A2B, BLC, C2a, d2b, D7a 253 D and 208- 209 BLC, B7e. C2E. d2b, D9a 254 D ό " C 228- 229 Ala, A2B, BLC, B7e. Cle. d2b, D9a

757 / B

314

. 255 C N 7-7 Me about " 114- 115 BLC, B7e. C2E. d2b, D9a dioate 256 D s ^ p-L about · 0 _f 63 30% EtOAc / hex A2B, BLC, C2a, D2H 257 D --S / = \ P N 7-7 NHMe about " 0.44 30% EtOAc / hex BLC, B7e. Cle. d2b, D9a. d6b 258 D N 7-7 NMe ₂ ύ “ 0.44 30% EtOAc / hex BLC, B7e. Cle. d2b, D9a. d6b 259 C fy ™ ^ '-' cf ₃ every ₂ h 0.71 10% EtOAc / hex 369 (M + H) + [CI] A3a, BLC, b4d. C6c 260 ^and ó ^w 0.62 10% EtOAc / hex 369 (M + H) + [CI] A3a, BLC, b4d. C6c 261 C '7d ^c ·· ô 0.78 1 10% EtOAc / hex 369 (M + H) + [CI] A3a, BLC, b4d. C6c

757 / B

315

262 D > 57 / to Cl Me <7 CF ₃ CO ₂ H 0.84 10% · EtOAc / hex '349 (M + H) + [CI] A3a, BLC, b4d. C6c 263 about 0.80 1 10% EtOAc / hex 369 (M + H) + [CI] A3a, BLC, b4d. C6c 264 D r ^s v_ ΛΛ L d = ^N - <zd ^cl N / \ Me Cl - / CF ₃ CO ₂ H 00:44 1 2% EtOAc / hex 383 (M + H) + [CI] A3a, BLC, b4d. C6c 265 C d ^{> N} d) / L Me Cl - CF ₃ CO ₂ H. 0.65 2% EtOAc / hex 349 (M + H) + [CI] A3a, BLC, b4d. C6c 266 D :> - P ^ about " 0.71 20% EtOAc / hex C2a, D2a 267 D ^s > ⁿ O- / ° NH ó · ' 104- 105 00:16 10% EtOAc / hex BLC, B7e, Cle, d2b, DLLA 268 D «OEt 0.68 30% EtOAc / hex BLC, B7e. Cle. d2b, DLLA D12a 269 C -Z ^N Q ^ V _NO! ó ^E ' 141- 142 0.61 20% EtOAc / hex BLC, B / E, Cle. d2b, DLLA D12b

757 / B

316

270 D ^{> S} \> = ^{n -} Λλ / P Í82- 183 BLC, B7e. ' Cle. d2b, DLLA D 12a D6a 271 D Et NC 135- 136 2 0? 20% EtOAc / hex BLC, B7e. Cle. d2b, DLLA D12C 272 Et Me 0.68 30% EtOAc / hex BLC, B7e. Cle. d2b, DLLA D12a 273 D ό 00:56 30% EtOAc / hex BLC, B7e. Cle. d2b, DLLA D12D 274 C - _n ^{> n} ^ G ^ ⁿ ° ² δ 155- 157 BLC, C2a, D2E 275 € about 159- 162 BLC, C2a, D2E 276 C -d ^N d ^ ^N ° ² 2 -Bu Me ' 0.69 1 20% EtOAc / hex blah, C2a, d2b

757 / B

317

277 ^: D -N ^ ^{N (} P) ^ ^NO2 kBu Me 101- 104 00:15 10% EtOAc / hex 364 (M + H) + [HPLC ES-MS] A3a, blb, b4c. C6c 278 ^> ^N- p- ^N °> i-Bu Me 102- 105 00:29 10% EtOAc / hex 364 (M + H) + [HPLC ES-MS] A3a, blb, b4c. C6c 279 A? Fp ^N - <> ^{NO 2} VjX i-Bu Me 0.72 25% EtOAc / hex blah, B2a, B7, Cla 280 ^ C ^ ^{n_ No. 2} - / i-Bu Me HCI 0.76 33% EtOAc / hex B6a. B7e. C2a, D2a 281 O ⁿ ->> ² i-Bu Me 00:53 20% EtOAc / hex 308 (M + H) + [HPLC ES-MS] b9a. Cla 282 i-bu me 00:51 . 20% EtOAc / hex 322 (M + H) + [HPLC ES-MS] b9a. Cla

757 / B

318

(a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2 x 300 mm Phenomenex 3 μΜ C-18 column; flow rate 1.0 ml / min; buffer A: 0.02% trifluoroacetic acid / 2% CH 3 CN / water, buffer B: 0.018% trifluoroacetic acid / 98% CH ₃ CN / water; maintained at 100% buffer A for 1 minute, gradient from 100% buffer A to 100% buffer B over 3 minutes, held at 100% buffer B for 1 minute, gradient from 100% buffer B to 100% buffer A over 0.5 minutes, held at 100% buffer A for 1.5 minutes.

(b) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 4 x 100 mm Dynamax 3 μΜ C-18 column, flow rate 1,5 ml / minute; buffer A: 0.5% trifluoroacetic acid / water, buffer B: 0.5% trifluoroacetic acid / CH ₃ CN; gradient from 100% buffer A to 100% buffer B over 10 minutes, maintained at 100% buffer B for 5 minutes.

(c) Hewlett Packard 1090 HPLC equipped with a UV detector (210 nM) and a 4 x 125 mm Nucleosil 3 μΜ C-18 column; flow rate 2.0 ml / min; buffer A: 0.01% molar phosphoric acid / water, buffer B: 0.01% molar phosphoric acid / CH ₃ CN; 10% buffer B over 1 minute, gradient from 10% buffer B to 90% buffer B over 8 minutes, gradient from 90% buffer B to 10% buffer B over 4 minutes.

(d) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 μΜ C-18 column; flow rate 18 ml / min; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, held at 100% buffer B for 30 minutes.

(e) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 μΜ C-18 column; flow rate 18 ml / min; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 50% buffer B to 60% buffer B in 25 minutes, gradient from 60% to 100% in 32 minutes.

(f) Ranin Dynamax HPLC equipped with a dual wavelength detector

757 / B

319

UV-DII (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, maintained at 100% buffer B for 100% 30 minutes.

(g) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 50% buffer B to 100% buffer B over 25 minutes, maintained at 100% buffer B 100% for 7 minutes.

(h) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 30 minutes, maintained at 100% buffer B 100% for 7 minutes.

(i) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 4,6 x 100 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 5 minutes, maintained at 100% buffer B 100% for 1.5 minutes.

(j) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 20% buffer B to 100% buffer B over 30 minutes, maintained at 100% buffer B 100% for 7 minutes.

757 / B

320

Table 2

2-imino-1,3-thiazolidin-4-ones and 2-imino-1,3-thiazolidin-5-ones

Polož- ka compound mp (° C) HPL (min) TLC ^R < The system dissolves. dei for TLC Materials. Spec (source) cause synthesis 283 i-bu me 3.8 (C) 00:44 100% CH2C12 307 (M &lt; + &gt;) [EI] C8a 284 about .. 7.98 (C) 00:20 / 100% CH2C12 341 (M &lt; + &gt;) [EI] C8a 285 ₀ ΧΑ ^Ν ΑΖ ^ ^Ν ° ² Α - χ ^Me 8:46 (C) 00:26 I 100% CH2C12 321 (M &lt; + &gt;) [EI] C8a 286 θΑ, Α'ΑΖ ^ ^{03 Me} 9:46 (C) 00:30 I 100% CH2C12 361 (M &lt; + &gt;) [EI] C8a

757 / B

321

287 Γ> = n-LL-no ₂ -Bu Me 8.03 (C) _about 1 o ° 100% CH2C12 307 (M &lt; + &gt;) [EI] C8a 288 ₀ /> ^N p> ^N ° ² Ϊ Me 8.45 (C) 0.62 100% CH2C12 321 (M &lt; + &gt;) [EI] C8a 289 M ^δ > = ^Ν - <θ- ^Ν 2 M L Me D 8.02 (C) 0.61 100% CH2C12 341 (M &lt; + &gt;) [EI] C8a 290 _rf Xn ^{> = N} pZP ^{NO 2} i -Bu Me 8.53 (C), 0.67 100% CH2C12 321 (M &lt; + &gt;) [EI] C8a 291 Λ> -ρ- θχ-k ^Me 9.37 (C) 0.62 100% CH2C12 361 (M &lt; + &gt;) [EI] C8a 292 _the Xpp> ^{No. 2 Me} Q p 9.35 (C) 0.76 100% CH2C12 361 (M &lt; + &gt;) [EI] C8a 293 _o XppP ° ² J ... Me ⁷ Cr 98 9.36 (C) 0.76 100% CH2C12 361 (M &lt; + &gt;) [EI] C8a 294 θχρρρ ° ² i-Bu Me ⁷ 1.9 (C) 0.78 100% CH2C12 383 (M &lt; + &gt;) [EI] C8a 295 M ^e s_ ^ S z = \ _o X _ti ^{> N} XX ^N0 'Me ⁷ U' 63- 67 9.78 (C) 0/73 100% CH2C12 375 (M &lt; + &gt;) [EI] C8a

757 / B

322

296 NO ₂ AÄ 62- 63 10.1 1 (c) 0.86 100% CH2C12 437 (M &lt; + &gt;) [EI] C8a 297 ^Μ θ 68- 71 9.77 (C) 0.74 T 100% CH2C12 375 (M +) C8a 298 θΧΡ ^Ν -Ο- ^Ν ° ² θΑ. ^Me 69- 71 10.0 0 (c) 0.91 100% CH2C12 437 (M &lt; + &gt;) [EI] C8a 299 Me. _s A # ⁰ * í Me V 9.23 (C) 0.70 100% CH2C12 349 (M &lt; + &gt;) [EI] C8a 300 Iχλ · ^Νθ2 i-Bu Me 9.47 (C) 0.79 100% CH2C12 363 (M &lt; + &gt;) [EI] C8a 301 P ^ Xp ~ CP ⁰ 'i-Bu M e 10.2 0 (c) 0.86 100% CH2Cl2 391 (M &lt; + &gt;) [EI] C8a 302 Me 9.83 (C) 0.82 100% CH2C12 377 (M &lt; + &gt;) [EI] C8a 303 Me ^ν Α ^ ^ν ° ² AA Me 9.61 T (C) 00:34 50% CH2C12 / cyclohex 363 (M &lt; + &gt;) [EI] C8a 304 XP ⁿ -O ~ ⁿ ° ² i-Bu Me 9.23 (C) 00:32 50% CH2Cl2 / cyclohex 349 (M &lt; + &gt;) [EI] C8a

757 / B

323

305 < ^s / = \ Γ> = N - \\ zNO ₂ cA M JM e 8:37 (C) 00:55 100% CH2C12 321 (M &lt; + &gt;) [EI] C8a 306 L Me C 9.90 (C) 0.78 100% CH2C12 377 (M &lt; + &gt;) [EI] C8a 307 i-bu me 00:50 25% EtOAc / hex B3a, B7b. C2a 27 O = ^{n -} 0 ~ ⁿ ° * —1 ci 8.97 (C) 00:40 30% EtOAc / hex 362 (M + H) + [FAB] C8a 308 ₀ X>X> ^and AJ ^Cl 1 7.95 (C) 00:35 10% EtOAc / hex 365 (M + H) + [FAB] C8a 309 _O X> A ^C 'AJ' ^Cl 7.95 (C) 00:35 10% EtOAc / hex 635 (M + H) + [FAB] C8a 310 i-3u Me 152 7.28 (C) 307 (M &lt; + &gt;) [EI] Clla 311 _o x> -A ^noj <Ai ^e 8.79 (C) 0.66 100% CH2C12 335 (M &lt; + &gt;) [EI] C8a 312 i-bu me 8.66 (C) 00:17 100% CH2C12 363 (M &lt; + &gt;) [EI] Clla

757 / B

324

(a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2 x 300 mm Phenomenex 3 μΜ C-18 column; flow rate 1.0 ml / min; buffer A: 0.02% trifluoroacetic acid / 2% CH ₃ CN / water, buffer B: 0.018% trifluoroacetic acid / 98% CH ₃ CN / water; maintained at 100% buffer A for 1 minute, gradient from 100% buffer A to 100% buffer B over 3 minutes, held at 100% buffer B for 1 minute, gradient from 100% buffer B to 100% buffer A over 0.5 minutes, held at 100% buffer A 'for 1.5 minutes.

(b) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 4 x 100 mm Dynamax 3 μΜ C-18 column, flow rate 1,5 ml / minute; buffer A: 0.5% trifluoroacetic acid / water, buffer B: 0.5% trifluoroacetic acid / CH ₃ CN; gradient from 100% buffer A to 100% buffer B over 10 minutes, maintained at 100% buffer B for 5 minutes

(c) Hewlett Packard 1090 HPLC equipped with a UV detector (210 nM) and a 4 x 125 mm Nucleosil 3 μΜ C-18 column; flow rate 2.0 ml / min; buffer A: 0.01 mol% phosphoric acid / water, buffer B: 0.01 mol% phosphoric acid / CH ₃ CN; 10% buffer B over 1 minute, gradient from 10% buffer B to 90% buffer B over 8 minutes, gradient from 90% buffer B to 10% buffer B over 4 minutes.

(d) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 μΜ C-18 column; flow rate 18 ml / min; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, held at 100% buffer B for 30 minutes.

(e) Ranin Dynamax HPLC equipped with a dual wavelength detector

757 / B

325

UV-DII (254 and 220 nm) and a 2500 mm Dynamax 8 μΜ C-18 column; flow rate 18 ml / min; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 50% buffer B to 60% buffer B in 25 minutes, gradient from 60% to 100% in 32 minutes.

(f) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, maintained at 100% buffer B for 100% 30 minutes.

(g) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 50% buffer B to 100% buffer B over 25 minutes, maintained at 100% buffer B 100% for 7 minutes.

(h) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 30 minutes, maintained at 100% buffer B 100% for 7 minutes.

(i) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 4,6 x 100 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 5 minutes, maintained at 100% buffer B 100% for 1.5 minutes.

(j) Ranin Dynamax HPLC equipped with a dual wavelength detector

757 / B

326

UV-DII (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 20% buffer B to 100% buffer B over 30 minutes, maintained at 100% buffer B 100% for 7 minutes.

Table 3

2-imino-1,3-oxazolidine

Polož- <a compound (° C) HPLC (Min) TLC ^R r ´yseem dissolves'for TLC. Materials. spe: (source) ¢. Process synthesis 314 ^{> Hn hn} ° Me ² Me 0.30 30% EtOAc / hex 276 (M + H) + [CI] B8a C5a 315 Pn ^{> = n} ' ^h P ^h - ⁿ⁰² l-Bu Me 6.77 (C) 0.30 20% EtOAc / hex 319 (M +) [EI] Τ3-5 ^- B4c B 7b C4a ³¹⁶ i-bu me 7.42 (C) 0 _; 25 30% EtOAc / hex 334 (M + H) + [CI] BT5 ~ ~ b4c B7b C4 317 i-Bu Et op 10% EtOAc / hex 328 (M + H) + [HPLC ES-MS] A3a Blb b4c C7b 318 about · . J 134- 136 00:55 / 15% EtOAc / hex 318 (M + H) + [CI] A3a b4c C7a

757 / B

327

319 O / ~ 'X _n ^{> = n_} O' ^cn 6 112- 114 • 0.60 15% EtOAc / hex 312 (M + H) + [CI] A3a, b4c. C7a 320 about " 8 _; 25 b 344 (M + H) + [CI] BLC, b4d. B7b. C4 321 č · 7.83 (B) BLC, B4A, B7b. C4 BLC, B4A, B7b. C4 322 about 8.30 (B) 358 (M + H) + [CI] 323 about 0 ₍ 38 10% EtOAc / hex 338th (M + H) + [FAB] A3a, BLC, b4d. C7a

(a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2 x 300 mm Phenomenex 3 μΜ C-18 column; flow rate 1.0 ml / min; buffer A: 0.02% trifluoroacetic acid / 2% CH ₃ CN / water, buffer B: 0.018% trifluoroacetic acid / 98% CH ₃ CN / water; maintained at 100% buffer A for 1 minute, gradient from 100% buffer A to 100% buffer B over 3 minutes, held at 100% buffer B for 1 minute, gradient from 100% buffer B to 100% buffer A over 0.5 min, held at 100% buffer A

1.5 minutes.

(b) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 4 x 100 mm Dynamax 3 μΜ C-18 column, flow rate 1,5 ml / minute; buffer A: 0.5% trifluoroacetic acid / water, buffer B: 0.5% trifluoroacetic acid / CH ₃ CN; gradient from 100% buffer A to 100% buffer B over 10 minutes, held at 100% buffer B for 5 minutes.

(c) Hewlett Packard 1090 HPLC equipped with a UV detector (210 nM);

757 / B

328 column 4 x 125 mm Nucleosil 3 μΜ C-18; flow rate 2.0 ml / min; buffer A: 0.01 mol% phosphoric acid / water, buffer B: 0.01 mol% phosphoric acid / CH ₃ CN; 10% buffer B over 1 minute, gradient from 10% buffer B to 90% buffer B over 8 minutes, gradient from 90% buffer B to 10% buffer B over 4 minutes.

(d) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 μΜ C-18 column; flow rate 18 ml / min; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid // 99.9 CH ₃ CN; gradient from 30% buffer B to 100% buffer over 25 minutes, maintained at 100% buffer B for 30 minutes.

(e) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 μΜ C-18 column; flow rate 18 ml / min; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 50% buffer B to 60% buffer B in 25 minutes, gradient from 60% to 100% in 32 minutes

(f) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, maintained at 100% buffer B for 100% 30 minutes.

(g) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 50% buffer B to 100% buffer B over 25 minutes, maintained at 100% buffer B 100% for 7 minutes.

(h) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; speed

757 / B

329 flow rate 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 30 minutes, maintained at 100% buffer B 100% for 7 minutes.

(i) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 4,6 x 100 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 5 minutes, maintained at 100% buffer B 100% for 1.5 minutes.

(j) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 20% buffer B to 100% buffer B over 30 minutes, maintained at 100% buffer B 100% for 7 minutes.

Table 4

Other examples

Polož- compound mp CC) HPLC (Min) TLC Rf System of solvents for TLC -Imot.spek. (source) process synthesis to and 324 i-Bu 0.67 30% EtOAc / hex 336 (M + H) + [HPLC ES-MS] blb, B4c. ' B7c. CLF 325 Me 0.81 30% EtOAc / hex 392 (M + H) + [FAB] B7, duties D2a 326 Me HCI \ 7.99 (B) 00:59 T 20% EtOAc / hex 350 (M + H) + [FAB] Blb B7, duties D2a

757 / B

330

327 X ^Me 0.81 30% EtOAc / hex 364 (M + H) + [FAB] B7, duties D2a 328 Cl Cl 74 30% EtOAc / hex 387 (M + H) + [FAB] B7, duties D2a

(a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2 x 300 mm Phenomenex 3 μΜ C-18 column; flow rate 1.0 ml / min; buffer A: 0.02% trifluoroacetic acid / 2% CH ₃ CN / water, buffer B: 0.018% trifluoroacetic acid / 98% CH ₃ CN / water; maintained at 100% buffer A for 1 minute, gradient from 100% buffer A to 100% buffer B over 3 minutes, held at 100% buffer B for 1 minute, gradient from 100% buffer B to 100% buffer A over 0.5 min, held at 100% buffer A

1.5 minutes.

(b) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 4 X 100 mm Dynamax 3 μΜ C-18 column, at a flow rate of 1,5 ml / minute; buffer A: 0.5% trifluoroacetic acid / water, buffer B: 0.5% trifluoroacetic acid / CH ₃ CN; gradient from 100% buffer A to 100% buffer B over 10 minutes, held at 100% buffer B for 5 minutes.

(c) Hewlett Packard 1090 HPLC equipped with a UV detector (210 nM) and a 4 x 125 mm Nucleosil 3 μΜ C-18 column; flow rate 2.0 ml / min; buffer A: 0.01 mol% phosphoric acid / water, buffer B: 0.01 mol% phosphoric acid / CH ₃ CN; 10% buffer B over 1 minute, gradient from 10% buffer B to 90% buffer B over 8 minutes, gradient from 90% buffer B to 10% buffer B over 4 minutes.

(d) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 μΜ C-18 column; flow rate 18 ml / min; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid // 99.9 CH ₃ CN; gradient from 30% buffer B to 100% buffer over 25 minutes, maintained at 100% buffer B for 30 minutes.

757 / B

331

(e) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 2500 mm Dynamax 8 μΜ C-18 column; flow rate 18 ml / min; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 50% buffer B to 60% buffer B in 25 minutes, gradient from 60% to 100% in 32 minutes.

(f) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, maintained at 100% buffer B 100% 30 minutes

(g) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 50% buffer B to 100% buffer B over 25 minutes, maintained at 100% buffer B 100% for 7 minutes

(h) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 30 minutes, maintained at 100% buffer B 100% for 7 minutes.

(i) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 4,6 x 100 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 5 minutes, maintained at 100% buffer B 100% for 1.5 minutes.

757 / B

332

(j) Ranin Dynamax HPLC equipped with a UV-DII dual wavelength detector (254 and 220 nm) and a 21 x 2500 mm Microsorb 5 μΜ C-18 column; flow rate of 20 ml / minute; buffer A: 0.1% trifluoroacetic acid / 99.9% water, buffer B: 0.1% trifluoroacetic acid / 99.9% CH ₃ CN: gradient from 20% buffer B to 100% buffer B in 30 minutes, held at 100% buffer B for 100% for 7 minutes.

Biological protocol

Progesterone receptor binding activity of a compound can be determined routinely according to the procedure described below. This procedure was used to determine the progesterone binding activities of the compounds of the invention.

Progesterone receptor binding assay

Binding buffer (100 ml, 50 mM Tris, pH 7.4, 10 mM molybdic acid, 2 mM EDTA, 150 mM NaCl, 5% glycerol, 1% DMSO) was added to siliconized water bath cooled tubes. of the compound to be tested, cell cytosol T47D (100 μΙ of solution giving at least 4000cpm binding) and ³ H-progesterone (50 μΙ, 10 nM, NET-381). The mixture was incubated for 16 hours at 4 ° C and treated with activated carbon (250 μΙ and 0.5% 0.05% dextran coated charcoal, which was washed twice with binding buffer). The resulting mixture was incubated at 4 ° C for 10 minutes. Centrifuge the tubes (20 minutes at 2800 xg) at 4 ° C. The supernatant was transferred to scintillation vials containing scintillation fluid (4 mL). The remaining ³ H-progesterone is determined using a Packard 1900 TR beta counter. Each determination shall include the following control groups:

1. Total binding group (without compound)

2. Non-specific binding group (with 400 nM progesterone); and

3. a positive control group (with 2 nM progesterone or known inhibitor).

757 / B

333

The compounds of the present invention have been found to cause β

inhibition of H-progesterone binding to the progesterone receptor greater than or equal to 30% at a compound concentration of 200 nM. The ranges of activities of the compounds of the invention in determining the progesterone receptor binding at a compound concentration of 200 nM are shown in Table 5.

Table 5

Inhibitory activity of the compounds exemplified

Compounding agent 30 - 59% inhibition at 200 nM (entry number) Compounding agent 60-79% inhibition at 200 nM (entry number) Compound causing 80-100% inhibition at 200 nM (entry number) 1 2 3 5 4 8 6 9 11 7 15 14 10 16 17 12 19 18 13 26 20 27 29 21 34 30 22 43 31 23 45 . 32 24 48 35 25 49 36 28 56 37 33 57 38 40 59 39 41 61 42 44 64 46 47 66 54 50 67 60 51 74 63 52

757 / B

334

Compounding agent 30 - 59% inhibition at 200 nM (entry number) Compounding agent 60-79% inhibition at 200 nM (entry number) Compound causing 80-100% inhibition at 200 nM (entry number) 79 73 55 83 77 58 84 78 62 87 81 65 89 82 68 92 86 69 94 88 70 96 95 72 108 103 ⁷⁶ 113 106 80 120 110 85 123 112 90 129 114 91 130 119 93 131 134 97 135 144 99 136 149 102 141 150 104 143 153 105 146 154 107 147 155 109 148 160 111 151 162 115 152 164 116 156 166 117 157 170 118 158 174 121 159 180 122 161 188 125 163 193 126

757 / B

335

Compounding agent 30 - 59% inhibition at 200 nM (entry number) Compounding agent 60-79% inhibition at 200 nM (entry number) Compound causing 80-100% inhibition at 200 nM (entry number) 169 198 127 ¹⁷⁵ 200 128 181 201 132 182 210 133 183 211 137 184 T 212 138 185 225 139 186 236 140 187 241 145 189 242 165 190 246 167 191 258 168 192 260 171 194 261 172 195 269 173 199 277 176 202 279 177 203 290 178 204 294 179 205 296 196 207 297 197 226 300 206 227 301 208 228 317 209 229 213 238 215 254 218 257 219 262 220 263 221

757 / B

336

Compounding agent 30 - 59% inhibition at 200 nM (entry number) Compounding agent 60-79% inhibition at 200 nM (entry number) Compound causing 80-100% inhibition at 200 nM (entry number) 264 223 265 224 266 230 270 231 272 232 273 233 308 234 309 235 310 237 312 240 313 243 314 244 321 245 324 247 326 248 327 249 328 250 251 252 253 255 256 259 267 268 271 274 275 276 278

757 / B

337

Compounding agent 30 - 59% inhibition at 200 nM (entry number) Compounding agent 60-79% inhibition at 200 nM (entry number) Compound causing 80-100% inhibition at 200 nM (entry number) 280 281 282 283 284 285 286 287 288 289 291 292 293 295 298 299 302 303 304 305 306 307 311 315 316 318 319 320 322 323

757 / B

338

Compounding agent 30 - 59% inhibition at 200 nM (entry number) Compounding agent 60-79% inhibition at 200 nM (entry number) Compound causing 80-100% inhibition at 200 nM (entry number) 325

The foregoing examples may be repeated with similar success by replacing the reactants and / or process conditions of the invention used in the previous examples with the generally or specifically described reactants and / or process conditions of the invention.

Other embodiments of the invention will be apparent to those skilled in the art from the teachings of this disclosure or from the embodiments of the invention described herein. It is intended that the description and examples be given by way of example only, with the true scope and spirit of the present invention being indicated by the following claims.

Claims (9)

PATENT CLAIMS 1. A compound of the general formula: N, Λ x MX ^y Nk (O) q R (t) _t R (Q) qR ² '(Q) qR ³ wherein: R is aryl of 6 to 14 carbon atoms or heteroaryl of 3 to 10 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, provided that R is not benzofuran or benzothiophene, R ¹ is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms containing 1 to 3 rings, heterocycloalkyl of 4 to 7 carbon atoms and containing 1 to 3 rings and 1 to 3 heteroatoms selected from the group consisting of N, O and S, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms and containing 1 to 3 rings or alkynyl of 3 to 10 carbon atoms, R ² , R ³ and R ⁴ are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms, 31,757 / B 340 aryl of 6 to 13 carbon atoms, heteroaryl of 3 to 9 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, CO ₂ R ⁵ , wherein R ⁵ is C 1 -C 4 alkyl , haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or halocycloalkyl having 3 to 6 carbon atoms, halogen and = 0, representing two of the groups R ^2, R ³ and R ^4, 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 the substituents R ² , R ³ and R ⁴ which are not hydrogen, T is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, CO ₂ H, CO ₂ R ⁵ , alkenyl of 2 to 4 carbon atoms . I (C 2 -C 4) alkynyl, C (O) C ₆ H ₅ , C (O) N (R ⁶ ) (R ⁷ ), wherein R ⁶ is hydrogen or C 1 -C 5 alkyl and R 6 ⁷ is hydrogen or (C 1 -C 5) alkyl, S (O) _y R ⁸ , wherein y 'is 1 or 2, and R ⁸ is C 1 -C 5 alkyl, SO ₂ F, CHO, 31,757 / B 341 OH, NO ₂ , CN, halogen, OCF ₃ , N-oxide, OC (R ⁹ ) ₂ -O, wherein the oxygen atoms are attached at adjacent positions on R and wherein R ⁹ is hydrogen, halogen or C 1 -C 4 alkyl, C (O) NHC (O) ) wherein the carbon atoms are attached to adjacent positions on R and C (O) C 6 H _4, wherein the carbonyl carbon and the ring carbon ortho to the carbonyl carbon are attached to adjacent positions on R; t is 1 to 5, provided that when the substituent moiety T is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, CO ₂ R ⁵ , alkenyl of 2 to 4 carbon atoms, alkynyl of 2 up to 4 atoms. alkyl, C (O) C6H5, C (O) N ^{(R6) (R7),} S (O) y R ^8, OC (R ⁹⁾ 2-O or C (O) CeH4 then T may optionally carry secondary substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CO 2 R ⁵ , CO 2 H groups, C (O) N (R ⁶ ) (R ⁷ ), CHO, OH, NO ₂₎ of CN, halogen, S (O) _y R ⁸ or = O, the number of said secondary substituents being 1 or 2 except for a halogen atom which may be used up to the perhalogen level, G is a substituent selected from the group consisting of 31,757 / B 342 halogen, OH, OR ^5, = 0, representing two substituents G, alkyl of 1 to 4 carbon atoms, alkenyl of 1-4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, heterocycloalkyl of 3 to 5 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of N, O and S, cycloalkenyl of 5 to 7 carbon atoms, heterocycloalkenyl of 4 to 6 carbon atoms, and 1 to 3 heteroatoms selected from the group consisting of N, O and S, CO ₂ R ⁵ , C (O) N (R ⁶ ) (R ⁷ ), C 6 -C 10 aryl, C 3 -C 9 heteroaryl and 1 to 3 heteroatoms selected from the group consisting of N, O and S, NO _2, CN, S (O) _s R ^8, the group SO 3 R ^8, and a group SO ₂ N (R ⁶⁾ (R ^7), q is 0-4, except halogen, which may be employed up to the perhalo level, provided that when G is C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 3 -C 7 cycloalkyl, and t Mom atoms, 31,757 / B 343 heterocycloalkyl of 3 to 5 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms or heterocycloalkenyl of 4 to 6 carbon atoms, then G may optionally carry secondary halogen substituents up to the perhalogen level and when G is aryl or heteroaryl, then G may optionally carry secondary substituents independently selected from the group consisting of alkyl of 1 to 4 carbon atoms and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties and up to the perhalogen level for halogen, Q is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms; (C 8-C) cycloalkyl, (C až-C alko) alkoxy, (C až-C alk) alkenyl, (C až-C 8) cycloalkenyl, (C až-Cry) aryl, (C až-C hetero) heteroaryl up to 3 heteroatoms selected from the group consisting of N, O and S, CO ₂ R ⁵ , = O, representing two substituents Q, OH, halogen, N (R ⁶ ) (R ⁷ ), SO _and R ⁸ , SO ₃ R ⁸ and SO ₂ N (R ⁶ ) (R ⁷ ), q is 0 to 4, provided that when Q is aryl or heteroaryl, 31,757 / B 344 then Q may optionally carry secondary substituents independently selected from the group consisting of alkyl of 1 to 4 carbon atoms and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties and up to the perhalogen level for the halogen and provided that: (a) two of (Q) _q R ¹ , (Q) q R ² , (Q) q R ³ and (Q) _q R ⁴ may be joined and taken together with the atom (s) to which they are attached to form a spiro; or a 3- to 8-membered non-aromatic non-aromatic ring containing 0 to 2 heteroatoms selected from the group consisting of N, O and S, b) when n = 2 or 3, at least one of R ² , R ³ and R ⁴ is not hydrogen, c) when n = 2 and X = O, if t = 1, then T is selected from the list of substituents T above, except alkyl, wherein 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, except for alkyl and alkoxy; e) when n = 2 or 3 and X = O or S, then the sum of the non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is at least 5, f) when n = 2, X = O, the 4-position of the 1,3-oxazolidine ring carries a carbonyl group and R carries halogen at its 2 and 4 positions, then the 5-position of the R substituent carries a hydrogen atom, g) when n = 2 and X = O, the 4-position of the 1,3-oxazolidine ring can carry a carbonyl only if the 5-position of said ring carries at least one non-hydrogen substituent, h) when n = 2, X = S (O) _y , the 4-position of the 1,3-thiazolidine ring carries a carbonyl group, R ¹ is substituted with a methyl group and G is a phenyl group, then said phenyl group carries a secondary substituent, 31,757 / B 345 i) when n = 4, X = S and G is a CO ² R ⁵ group, then R ⁵ contains at least two carbon atoms, and pharmaceutically acceptable salts thereof. 2. Compound of general formula: in which: R is phenyl or pyridyl, R ¹ is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms and containing 1 to 3 rings, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms and containing 1 to 3 rings or alkynyl of 3 up to 10 carbon atoms, R ² , R ³ and R ⁴ are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms, 31,757 / B 346 of = 0, representing two of the groups R ^2, R ³ and R ^4, X is O or S (O) _y , wherein y is 0,1 or 2, n is 2 or 3, p is the sum of the substituents R ² , R ³ and R ⁴ which are not hydrogen, T is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, NO ₂ , CN and halogen; is 1 to 5, provided that when the substituent moiety T is alkyl of 1 to 4. carbon atoms, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, then T may optionally carry secondary substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 alkoxy to 4 carbon atoms, CO 2 R ⁵ wherein R ⁵ is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or halocycloalkyl having 3 to 6 carbon atoms, CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ), wherein R ⁶ is hydrogen or C 1 -C 5 alkyl and R ⁷ is hydrogen or (C 1 -C 5) alkyl, CHO, 31,757 / B 347 OH, NO ₂ , CN, halogen, S (O) _y R ⁸ , where R ⁸ is C 1 -C 5 alkyl, and = O, representing two secondary substituents, the number of said secondary substituents is 1 or 2 in addition to a halogen atom which may be used up to the perhalogen level, G is a substituent selected from the group consisting of halogen, OR ⁵ , C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, C 6 -C 7 aryl And 10 CN atoms. g is 0 to 4, except for halogen which may be used up to the perhalogen level, provided that G is C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 3 -C 7 cycloalkyl or cycloalkenyl having 5 to 7 carbon atoms, then G may optionally carry secondary halogen substituents up to the perhalogen level and, when G is aryl, then G may optionally carry secondary substituents independently selected from the group consisting of C1-C4 alkyl and halogen, wherein the number of said secondary substituents is up to 3 for the alkyl moieties and up to the perhalogen level 31,757 / B 348 for halogen, Q is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms, cycloalkenyl of 5 to 8 carbon atoms, CO 2 R ⁵ , = O, representing two substituents Q, OH, halogen, N (R ⁶ ) (R ⁷ ) and SO _y R ⁸ , q is 0 to 4, and among others provided that: a) two of (Q) _q R ^1, (Q) q R ² (Q) q R ^3, and (Q) _q R ⁴ may be joined and conceived together with the atom (s) to which they are attached form a spiro or a non-spiral non-aromatic ring of 3 to 8 members containing 0 to 2 heteroatoms selected from the group consisting of N, O and S, b) when n = 2 or 3, at least one of R ² , R ³ and R ⁴ is not hydrogen, c) when n = 2 and X = O, if t = 1, then T is selected from the list of substituents T above, except alkyl, wherein 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 T substituents of said 31,757 / B 349 above, except alkyl and alkoxy, e) when n = 2 or 3 and X = O or S, then the sum of the non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is at least 5, f) when n = 2, X = O, the 4-position of the 1,3-oxazolidine ring carries a carbonyl group and R carries halogen at its 2 and 4 positions, then the 5-position of the R substituent carries a hydrogen atom, g) when n = 2 and X = O, the 4-position of the 1,3-oxazolidine ring can carry a carbonyl only if the 5-position of said ring carries at least one non-hydrogen substituent, h) when n = 2, X = S (O) _y , the 4-position of the 1,3-thiazolidine ring carries a carbonyl group, R ¹ is substituted with a methyl group and G is a phenyl group, then said phenyl group carries a secondary substituent, and its pharmaceutical acceptable salts. 3. Compound of general formula: in which: R is phenyl or pyridyl, R ¹ is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms and containing 1 to 3 rings, 31,757 / B 350 alkenyl of 2 to 10 carbon atoms or cycloalkenyl of 5 to 12 carbon atoms and containing 1 to 3 rings, R ² , R ³ and R ⁴ are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, and cycloalkenyl of 5 to 12 carbon atoms, X is O or S (O) _y , wherein y is 0, 1 or 2, n is 2 or 3, p is the sum of the substituents R ² , R ³ and R ⁴ which are not hydrogen, T is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, NO ₂ , CN and halogen, t is 1 to 5, provided that when the substituent moiety T is alkyl with C 1 -C 4 or C 2 -C 4 alkenyl, then T may optionally carry secondary substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CO ₂ R ⁵ , wherein: R ⁵ is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 halocycloalkyl, CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ) wherein R ⁶ is hydrogen or alkyl having 1 31,757 / B 351 to 5 carbon atoms and R ⁷ is hydrogen or C 1 -C 5 alkyl, CHO, OH, NO ₂ , CN, halogen, S (O) _y R ⁸ , wherein R ⁸ is C 1 -C 5 alkyl carbon, and group = 0, wherein the number of said secondary substituents is 1 or 2, except for a halogen atom which may be used up to the perhalogen level, G is a substituent selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkenyl, (C3-C7) cycloalkyl, (C6-C7) cycloalkenyl, (C6-C10) aryl, g is 0 to 4, except for halogen which may be used up to the perhalogen level, provided that G is C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 3 -C 7 cycloalkyl or cycloalkenyl having 5 to 7 carbon atoms, then G may optionally carry secondary halogen substituents up to the perhalogen level and, when G is aryl, then G may optionally carry secondary substituents independently selected from the group consisting of C1-C4 alkyl and halogen, wherein number of secondary 31,757 / B 352 substituents are up to 3 for the alkyl moieties and up to the perhalogen level for the halogen, Q is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms, cycloalkenyl of From 5 to 8 carbon and halogen atoms, q is 0 to 4, and provided that: (a) two of (Q) _q R ¹ , (Q) q R ² , (Q) q R ³ and (Q) _q R ⁴ may be joined and taken together with the atom (s) to which they are attached to form a spiro; or a 3- to 8-membered non-aromatic non-aromatic ring containing 0 to 2 heteroatoms selected from the group consisting of N, O and S, b) when n = 2 or 3, at least one of R ² , R ³ and R ⁴ is not hydrogen, c) when n = 2 and X = O, if t = 1, then T is selected from the list of substituents T above, except alkyl, wherein 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 except alkyl; e) when n = 2 or 3 and X = O or S, then the sum of the non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is at least 5, and pharmaceutically acceptable salts thereof. 31,757 / B 353 A compound according to claim 1 selected from the group consisting of: (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1,3-thiazolidine, (4S) -2- (2- methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine, (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (trifluoromethyl) -1,3- thiazolidine, (4S) -2- (2-methyl-4-nitrophenylimino) -3-cyclopehtyl-4-isobutyl-1,3-thiazolidine, (4S) -2- (2-methyl-4-nitrophenylimino) -3- isobutyl-4-isopropyl-1,3-thiazolidine, (4S) -2- (2-methyl-4-nitrophenylimino) -3-cyclopentyl-4-isopropyl-1,3-thiazolidine, (4R) -2- (2R) -methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyltetrahydro-2H-1,3-thiazine, (4S) -2- (4-nitro-1-naphthylimino) -3-cyclopentyl-4 - ((1R) -1-hydroxyethyl) -1,3-thiazolidine, 2- (4-cyano-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane, 2- (4-cyanophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane, 2- (4-cyano-2) -methylphenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane, 2- (4-cyano-2,3-dimethylphenyl) mino) -1-isobutyl-3-thia-1-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) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane, 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane, 2- (3-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane, 2- (2-methyl-4-nitrophenylimino) -1-cyclohexyl-3 -thia-1-azaspiro [4.4] nonane, 2- (2,3-dimethyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane, and 31 757/8 354 2- (4-cyano-2,3-dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. A compound according to claim 1 selected from the group consisting of: 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-4-one, 2- (3-methyl-4-nitrophenylimino) -3 -isobutyl-1,3-thiazolidin-4-one, 2- (2-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidin-4-one, 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-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-1-ethyl) -1,3-thiazolidinyl- 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1,3-thiazolidin-4-one, 2- (2-methyl-4-nitrophenylimino) - 3-isobutyl-5-methylene-1,3-thiazolidin-4-one; and 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-methyl-1,3-thiazolidin-4-one. A compound according to claim 1 selected from the group consisting of: 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4,4-dimethyl-1,3-oxazolidine, 1-cyclopentyl-2- (4-cyano- 2-etylfenylimino) -3-oxa-1-azaspiro [4.4] nonane, 1-Cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane and 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1- azaspiro [4.4] nonane. A pharmaceutical composition comprising a compound according to claim 1, 2, 3, 4, 5 or 6 and a pharmaceutically acceptable carrier. 8. A method of treating a mammal comprising administering to said mammal an effective amount of a compound for: (A1) facilitating bone formation in bone debilitating diseases for treatment; or 31,757 / B 355 prevention of osteopenia or osteoporosis, A2) facilitating fracture healing, B1) use as female contraceptive, B2) prevention of endometrial implantation, B3) induction of labor, B4) treatment of luteal insufficiency, B5) facilitating the recognition and maintenance of pregnancy, B6) reversal of preeclampsia, pregnancy eclampsia and preterm labor, B7) treatment of infertility, including by aid of spermatogenesis, induction of acrosome response, oocyte maturation or in vitro fertilization of oocytes, C1) treatment of dysmenorrhea, C2) treatment of dysfunctional uterine bleeding, C3) treatment of ovarian hyperandrogynism, C4) treatment of ovarian hyperaldosteronism, C5) relieving premenstrual syndrome and premenstrual tension, C6) alleviation of peri-menstrual behavioral disorders, C7) treatment of climacterial disorders, including menopausal passage, mood changes, sleep disorders and vaginal mucosal drying; C8) facilitation of female sexual sensitivity, C9) treatment of postmenopausal urinary incontinence, C10) improvement of sensory and motor functions, C11) improving short-term memory, C12) treatment of postpartum depression, C13) treatment of genital atrophy, C14) prevention of the formation of post-surgical adhesions, 31,757 / B 356 C15) regulation of uterine immune function, C16) preventing myocardial infarction, D1) hormone replacement therapy, E1) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer, and endometrial cancer, E2) treatment of endometriosis, E3) treatment of uterine fibroids, F1) treatment of hirsutism, F2) inhibiting hair growth, G1) activity as a male contraceptive, G2) Abortive activity a H1) facilitating the recovery of myelin, wherein said compound has the general formula: in which: R is aryl of 6 to 14 carbon atoms or heteroaryl of 3 to 10 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, provided that R is not benzofuran or benzothiophene, R ¹ is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms and containing 1 to 3 rings, 31,757 / B I 357 heterocycloalkyl of 4 to 7 carbon atoms containing 1 to 3 rings and 1 to 3 heteroatoms selected from the group consisting of N, O and S, aryl of 6 to 10 carbon atoms, heteroaryl of 3 to 9 carbon atoms and containing 1 to 3 rings and 1 to 3 heteroatoms selected from the group consisting of N, O and S, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms and containing 1 to 3 rings or alkynyl of 3 to 10 carbon atoms, R ² , R ³ and R ⁴ are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkenyl of 5 to 12 carbon atoms, aryl of 6 to 13 carbon atoms, heteroaryl of 3-9 carbon atoms and containing 1 to 3 heteroatoms selected from among N, O and s, CO ₂ R ⁵ wherein R ⁵ is alkyl of 1 to 4 carbon atoms, (C 1 -C 4) haloalkyl, (C 3 -C 6) cycloalkyl or (C 3 -C 6) halocycloalkyl, halogen and = O, representing two of R ² , R ³ and R ⁴ , 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 the non-hydrogen substituents R ² , R ³ and R ⁴ , s represents the number of double bonds in a is 0, 1, or 2, 31,757 / B 358 T is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, CO 2 H, CO ₂ R ⁵ , alkenyl of 2 to 4 carbon atoms, alkynyl C 2 O 4, C (O) C ₆ H ₅ , C (O) N (R ⁶ ) (R ⁷ ), wherein R ⁶ is hydrogen or C 1 -C 5 alkyl and R ⁷ is a hydrogen atom or a (C 1 -C 5) alkyl group of S (O) _y R ⁸ where y 'is 1 or 2 and R ⁸ is (C 1 -C 5) alkyl, SO ₂ F, CHO, OH, NO2, CN, halogen, OCF ₃ , N-oxide, OC (R ⁹ ) ₂ -O, wherein the carbon atoms are attached to R at adjacent positions and wherein R ⁹ is hydrogen, halogen or C 1 -C 4 alkyl, C (O) NHC (O) ), wherein the carbon atoms are attached to R at adjacent positions and 31,757 / B 359 of a C (O) C ₆ H _{4 group} wherein the carbonyl carbon atom in the ortho ring position is attached to R at adjacent positions, t is 1 to 5, provided that when the substituent moiety T is alkyl of 1 to 4 carbon atoms , C 1 -C 4 alkoxy, C 6 -C 10 aryl, CO ₂ R ⁵ , C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C (O) C 6 H ⁵ , C (O) ) N (R ⁶ ) (R ⁷ ), S (O) y R ⁸ , OC (R ⁹ ) 2 -O or C (O) C 6 H 4, then T may optionally carry secondary substituents selected from the group consisting of alkyl (C 1 -C 4), (C 1 -C 4) alkoxy, CO 2 R ⁵ , CO 2 H, C (O) N (R ⁶ ) (R ⁷ ), CHO, OH, NO ₂ , CN, halogen, S (O) _y R ⁸ or = O, the number of said secondary substituents being 1 or 2 except for halogen which can be used up to the perhalogen level, G is a substituent selected from the group consisting of halogen, OH, OR ^5, = 0, representing two substituents G, alkyl of 1 to 4 carbon atoms, alkenyl of 1-4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, (C 3 -C 5) heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, C 5 -C 7 cycloalkenyl, C 4 -C 6 heterocycloalkenyl and 1 to 3 heteroatoms selected from the group consisting of N, O and S, CO ₂ R ⁵ groups, 31,757 / B 360 of the C (O) N (R ⁶ ) (R ⁷ ), aryl of 6 to 10 carbon atoms, heteroaryl of 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of N, O and S, NO 2, CN, S (O) _s R ^8, the group SO 3 R ^8, and a group SO ₂ N (R ⁶⁾ (R ^7), q is 0-4, except halogen, which may be employed up to the perhalo level, provided that when G is C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 5 heterocycloalkyl, C 5 -C 7 cycloalkenyl or C 4 -C 6 heterocycloalkenyl carbon atoms, then G may optionally carry secondary halogen substituents up to the perhalogen level, and when G is aryl or heteroaryl, G may optionally carry secondary substituents independently selected from the group consisting of C 1-4 alkyl and halogen, the number of said secondary substitues nt is up to 3 for the alkyl moieties and up to the perhalogen level for the halogen, Q is a substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms, cycloalkenyl of 5 to 8 carbon atoms, 31,757 / B 361 aryl of 6 to 10 carbon atoms, heteroaryl of 3 to 9 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, CO ₂ R ⁵ , = O, two substituents Q, OH , halogen, N (R ⁶ ) (R ⁷ ), S (O) _y R ⁸ , SO ₃ R ^8, and SO ₂ N (R ⁶ ) (R ⁷ ) groups, q is 0 to 4, provided that: that when Q is aryl or heteroaryl, Q may optionally carry secondary substituents independently selected from the group consisting of alkyl of 1 to 4 carbon atoms and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties and up to the perhalogen level for halogen; and provided that two (Q) _q R ¹ , (Q) q R ² , (Q) q R ³ and (Q) q R ⁴ may be joined and taken together with the atom (s) to which they are attached to form a 3- to 8-membered spiro- or non-spiro-non-aromatic ring containing 0 to 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.