KR20010089831A - Substituted 2-Arylimino Heterocycles and Compositions Containing Them, for Use as Progesterone Receptor Binding Agents - Google Patents

Abstract

2-arylimino-1,3-thiazolidine, 2-arylimino-2,3,4,5-tetrahydro-1,3-thiazine, 2-arylimino-1,3 2-arylimino heterocycles including thiazolidin-4-one, 2-arylamino-1,3-thiazolidin-5-one, 2-arylimino-1,3-oxazolidine and the like , To their use in the regulation of progesterone receptor mediated processes, and to pharmaceutical compositions for use in therapy.

Description

Substituted 2-Arylimino Heterocycles and Compositions Containing Them, for Use as Progesterone Receptor Binding Agents}

Agents that bind to progesterone receptors can be used in a variety of applications, including those described in the following paragraphs.

A1) Osteoporosis or osteoporosis including corticosteroid-induced osteoporosis (Picardo, et al., Drug Safety 15, 347 (1996)), postmenopausal osteoporosis or Paget's disease (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 (Eds.), CRC Press, 207 (1996); Scheven et al., Biochem. Biophys. Res. Commun., 186, 54 (1992)) For the prevention and / or treatment of, promoting bone production in bone weakness diseases,

A2) agents that promote fracture healing,

B1) Women with Congestive Diseases (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) Prevention of endometrial implantation (Cadepond et al., Annu. Rev. Med., 48, 129 (1997)),

B3) induction of labor, including in the case of foetus mortus (Heikinheimo, Clin. Pharmacokinet., 33,7 (1997); Cadepond et al., Annu. Rev. Med., 48,129 (1997)) Heikinheimo Clin.Pharmacokinet., 33, 7 (1997); Karalis et al., Ann. NY Acad. Sci., 771, 551 (1995)),

B4) Treatment of Progesterone 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) Increased awareness and maintenance of pregnancy (Bezer et al., In "Molecular and Cellular Aspects of Periimplantation Processes", Dey (Ed.), Springer-Verlag, p.27 (1995)),

B6) alleviation of preeclampsia, preeclampsia and early delivery (Yallampalli et al., WO 97 / 34,922),

B7) treatment of infertility, including the promotion of sperm production, induction of acrosome reactions, oocyte maturation and in vitro fertilization (Baldi et al., J. Steroid Biochem. Mol. Biol., 53, 199 (1995); Baldi et al. 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) Treatment of menstrual irregularities (Coll Capdevila et al., Eur. J. Contracept. Reprod. Health Care, 2, 229 (1997); Adashi et al., Keio J. Med., 44, 124 (1995)),

C2) Treatment of dysfunctional uterine bleeding (Coll Capdevila et al., Eur. J. Contracept. Reprod. Health Care, 2, 229 (1997); Adashi et al., Keio J. Med., 44,124 (1995)) ,

C3) treatment of androgen hyperplasia of the ovary (Schaison et al., Androg. Excess Disord. Women, 715 (1997)),

C4) treatment of aldosterone hyperplasia of the ovary (Adashi et al., Keio J. Med., 44, 124 (1995)),

C5) treatment of premenstrual syndrome and / or premenstrual strain (Mortola, Curr. Opin. Endocrinol. Diabetes, 2, 483 (1995)); Adashi et al., Keio J. Med., 44,124 (1995)),

C6) treatment of premenstrual behavioral disorders (Constant et al., Hormone Res., 40, 141 (1993)),

C7) Menopausal Disorder, Sarrel, Int. J. Fertil. Women's Med., 42,78 (1997); Baeckstroem et al., Ciba Found. Symp., 121, 171 (1995)), Emotional changes ( Backstrom et al., Ciba Found.Symp., 121, 171 (1995)), sleep disorders (Sarrel, Int. J. Fertil. Women's Med., 42,78 (1997)) and vaginal dryness (Sarrel, Int. J) Treatment of menopausal changes (Adashi et al., Keio J. Med., 44, 124 (1995)), including Fertil.Women's Med., 42,78 (1997)),

C8) Sexual Acceptance of Women (Dei et al., Eur. J. Contracept.Reprod. Health Care, 2 (4), 253 (1997); McCarthy et al., Trends Endocrinol. Metab., 7, 327-333 ( Mani et al., Horm. Behav., 31,244 (1997)) and sexual acceptability in men (Johnson et al., In "Essential Reproduction, 2 ^nd ed., Blackwell Scientific Pub., London pl77 (1984)) increase,

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

C10) improvement of sensory and motor functions (Baeckstroem et al., Ciba Found. Symp., 121, 171 (1995)),

C11) improvement of short-term memory (Baeckstroem et al., Ciba Found. Symp., 121, 171 (1995)),

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

C13) Treatment of genital atrophy (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997)),

C14) prevention of postoperative adhesion formation (Ustun, Gynecol. Obstet. Invest., 46, 202 (1998)),

C15) modulation of uterine immune function (Hansen et al., J. Reprod. Fertil., 49 (Suppl.), 69 (1995)),

C16) Prevention of myocardial incomplete fractures (Sarrel, Int. J. Fertil. Women's Med., 42, 78 (1997)),

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

E1) breast cancer (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Pike et al., Endocr.-Relat. Cancer, 4,125 (1997)), uterine cancer (Heikinheimo Clin. Pharmacokinet., 33 , 7 (1997)), ovarian cancer (Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997); Hughes, WO 98 / 10,771) and endometrial cancer (Satyaswaroop, Contrib. Oncol., 50, 258 (1995); treatment of cancer, including Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997),

E2) 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) treatment of uterine fibrosis (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); Adashi et al., Keio J. Med., 44, 124 (1995)),

F1) treatment of hirsutism (Orentreich et al., US Pat. No. 4,46,635; Azziz et al., J. Clin. Endocrinol. Metab., 80, 3406 (1995)),

F2) inhibition of hair growth (Houssay et al., Acta Physiol. Latinoam., 28, 11 (1978)),

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

G2) abortions (Michna et al., Pharm. Ztg., 141, 11 (1996)), and

H1) Promoting myelin repair (Baulieu et al., Cell. Mol. Neurobiol., 16, 143 (1996); Baulieu et al., Mult. Scler., 3, 105 (1997); Schumaker et al., Dev. Neurosci., 18, 6 (1996); Koenig et al., Science, 268, 1500 (1995)).

Currently, progesterone or progestin is used alone or in combination with estrogen (Merck Manual; Merck & Co. (1992)), for the treatment of gastrointestinal bleeding due to arteriovenous malformations (Merck Manual; Merck & Co. (1992)), rare month Treatment of recurrent ulnar stress fractures combined with mild or amenorrhea (Merck Manual; Merck & Co. (1992)), premenstrual syndrome (PMS, premenstrual strain; Merck Manual; Merck & Co. (1992)), postmenopausal Hormone replacement therapy (Merck Manual; Merck & Co. (1992)), hot flashes during menopause and subsequent insomnia and fatigue (Merck Manual; Merck & Co. (1992)), dysfunctional uterus if pregnancy is undesirable Treatment of bleeding (Merck Manual; Merck & Co. (1992)), and endometriosis (Merck Manual; Merck & Co. (1992)), breast cancer (Merck Manual; Merck & Co. (1992)), endometrial cancer ( Merck Manual; Merck & Co. (1992) or Merck Manual; Merck & Co. (1992). For example, methoxyprogesterone, a type of progestin, alone or in combination with estrogen, can be used to prevent osteoporosis, to treat vulva and / or vaginal atrophy, to treat intermediate to severe angiomotor symptoms associated with menopause, to treat secondary amenorrhea, Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, prevention of pregnancy, or adjuvant therapy and alleviation of inoperable, recurrent and metastatic endometrial or kidney cancer (Merck Manual; Merck & Co. (1998)) It is used in therapy.

Summary of the Invention

The present invention is a nonsteroidal 2-arylimino- and 2-heteroarylimino-hetero that has affinity for progesterone receptors and thus can act as progestins and / or antiprogestins to regulate the process mediated by progesterone receptors. Provided are cyclic compounds.

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.

Where

R is aryl having 6 to 14 carbon atoms; Or heteroaryl having 3 to 10 carbon atoms 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 having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms containing 1 to 3 rings; Heterocycloalkyl containing 4 to 7 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms containing 1 to 3 rings; Or alkynyl having 3 to 10 carbon atoms,

R ² , R ³ and R ⁴ are independently H; Alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms; Aryl having 6 to 13 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; CO ₂ R ⁵ (R ⁵ is alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or halocycloalkyl having 3 to 6 carbon atoms); halogen; And ═O (which represents two groups of R ² , R ³ and R ⁴ ),

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

n is 2, 3, 4 or 5,

p is the sum of the R ² , R ³ and R ⁴ substituents but not hydrogen,

T is alkyl having 1 to 4 carbon atoms; Alkoxy having 1 to 4 carbon atoms; Aryl having 6 to 10 carbon atoms; CO ₂ H; CO ₂ R ⁵ ; Alkenyl having 2 to 4 carbon atoms; Alkynyl having 2 to 4 carbon atoms; C (O) C ₆ H ₅ ; C (O) N (R ⁶ ) (R ⁷ ) (R ⁶ is H or alkyl of 1 to 5 carbon atoms, R ⁷ is H or alkyl of 1 to 5 carbon atoms); S (O) _{y '} R ⁸ (y' is 1 or 2, R ⁸ is alkyl of 1 to 5 carbon atoms); SO ₂ F; CHO; OH; NO ₂ ; CN; halogen; OCF ₃ ; N-oxides; OC (R ⁹ ) ₂ -O (oxygen is bonded to an adjacent position on R and R ⁹ is H, halogen or alkyl of 1 to 4 carbon atoms); C (O) NHC (O) (carbon is bonded to an adjacent position on R); And C (O) C ₆ H ₄ (carbonyl carbon and ring carbon in the ortho position on carbonyl are bonded to adjacent positions on R),

t is 1 to 5,

Provided that the substituent residue T is alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, aryl having 6 to 10 carbon atoms, CO ₂ R ⁵ , alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, 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 , T Is optionally alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, CO ₂ R ⁵ , CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ), CHO, OH, NO ₂ , CN, halogen, May include a second substituent selected from the group consisting of S (O) _y R ⁸ or ═O, wherein the number of second substituents is 1 or 2, except for halogen, which may be used up to the perhalo level,

G is halogen; OH; OR ⁵ ; = 0 (indicates two substituents G); Alkyl having 1 to 4 carbon atoms; Alkenyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 7 carbon atoms; Heterocycloalkyl having 3 to 5 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Cycloalkenyl having 5 to 7 carbon atoms; Heterocycloalkenyl having 4 to 6 carbon atoms containing 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 ); Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; NO ₂ ; CN; S (O) _y R ⁸ ; SO ₃ R ⁸ ; And it is a substituent selected from the group consisting of SO ₂ N (R ⁶ ) (R ⁷ ),

g is 0 to 4, except for halogen, which may be used up to the perhalo level,

Provided that substituent G is alkyl having 1 to 4 carbons, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heterocycloalkyl having 3 to 5 carbon atoms, cycloalkenyl having 5 to 7 carbon atoms or 4 to 6 carbon atoms If is heterocycloalkenyl, G may comprise a second substituent, which is a halogen, optionally used up to the perhalo level; If substituent G is aryl or heteroaryl, G may optionally comprise a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, said second substituent being 3 or less for an alkyl moiety For halogen up to the perhalo level,

Q is alkyl having 1 to 4 carbon atoms; Haloalkyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 8 carbon atoms; Alkoxy having 1 to 8 carbon atoms; Alkenyl having 2 to 5 carbon atoms; Cycloalkenyl having 5 to 8 carbon atoms; Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; CO ₂ R ⁵ ; = 0 (indicates two substituents Q); OH; halogen; N (R ⁶ ) (R ⁷ ), S (O) _y R ⁸ ; SO ₃ R ⁸ ; And it is a substituent selected from the group consisting of SO ₂ N (R ⁶ ) (R ⁷ ),

q is 0 to 4,

Provided that when substituent Q is aryl or heteroaryl, Q may optionally include a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, wherein the second substituent is 3 or less for an alkyl moiety And up to the perhalo level for halogen,

Also,

a) two of (Q) _q R ¹ , (Q) _q R ² , (Q) _q R ³ and (Q) _q R ⁴ are bonded to N, O and S together with the atom (s) to which they are attached Can form a 3-8 membered non-aromatic ring of spiro or bispyro containing 0 to 2 heteroatoms selected from the group consisting of

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

c) when n is 2 and X is O, when t is 1, T is selected from the list of substituents of T except for alkyl, and the 4-position of the 1,3-oxazolidine ring must comprise substituents,

d) when n is 3 and X is O, when t is at least 1, at least one T is selected from the list of substituents of T except for alkyl and alkoxy,

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

f) 5-position of R when n is 2, X is O, and the 4-position of the 1,3-oxazolidine ring comprises a carbonyl group and R comprises a halogen in 2- and 4-positions Contains H,

g) when n is 2 and X is O, the 4-position of the ring may comprise carbonyl only if the 5-position of the 1,3-oxazolidine ring contains at least one non-H substituent; ,

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

i) when n is 4, X is S and G is CO ₂ R ^5, then R ⁵ contains at least two carbons;

The invention also relates to a pharmaceutical composition comprising a compound of formula (I) as described above and a pharmaceutically acceptable carrier.

Compounds of the invention and certain related compounds of the prior art are described in the Background section because they can modulate the affinity of the compound to progesterone receptors and thus act as progestin and / or antiprogestin to mediate the process of progesterone receptors. It is believed to be useful for the purposes described.

Since certain compounds of the prior art that have not been recognized as useful for therapeutic purposes are used in the methods of treatment of the present invention, the definition of a set of compounds used in the claimed methods of treatment (Formula II) is less than the set of compounds defined by Formula (I). It should be understood that it is extensive. Accordingly, the present invention further relates to a method of treating a mammal comprising administering to the mammal an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof to achieve the following effects:

A1) promoting bone production for the treatment or prevention of osteopenia or osteoporosis in bone weakness diseases,

A2) promoting fracture healing,

B1) activity as a therapeutic agent for female congestive diseases,

B2) prevention of endometrial implantation,

B3) induction of labor,

B4) treatment of progesterone deficiency,

B5) increase awareness and maintenance of pregnancy,

B6) alleviation of preeclampsia, preeclampsia and early delivery,

B7) treatment of infertility, including the promotion of sperm production, induction of acrosome reactions, oocyte maturation or in vitro fertilization of oocytes,

C1) treatment of menstrual irregularities,

C2) treatment of dysfunctional uterine bleeding,

C3) treatment of androgen hyperplasia of the ovary,

C4) treatment of aldosterone hyperplasia of the ovary,

C5) relief of premenstrual syndrome and premenstrual tension,

C6) alleviation of premenstrual behavioral disorders,

C7) treatment of menopausal disorders, including menopausal changes, emotional changes, sleep disorders and vaginal dryness,

C8) promoting female sexual acceptability and male sexual acceptability,

C9) treatment of postmenopausal incontinence,

C10) improvement of sensory and motor functions,

C11) improvement of short-term memory,

C12) alleviation of postpartum depression,

C13) treatment of genital atrophy,

C14) prevention of postoperative adhesions,

C15) regulation of uterine immune function,

C16) prevention of myocardial incomplete fractures,

D1) hormone replacement therapy,

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

E2) treatment of endometriosis,

E3) treatment of uterine fibrosis,

F1) the treatment of hirsutism,

F2) inhibition of hair growth,

G1) activity as a male contraceptive,

G2) activity as an abortion drug, and

H1) Promoting Myelin Recovery.

Where

R is aryl having 6 to 14 carbon atoms; Or heteroaryl having 3 to 10 carbon atoms 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 having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms containing 1 to 3 rings; Heterocycloalkyl containing 4 to 7 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 rings and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms containing 1 to 3 rings; Or alkynyl having 3 to 10 carbon atoms,

R ² , R ³ and R ⁴ are independently H; Alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms; Aryl having 6 to 13 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; CO ₂ R ⁵ (R ⁵ is alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or halocycloalkyl having 3 to 6 carbon atoms); halogen; And ═O (which represents two groups of R ² , R ³ and R ⁴ ),

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

n is 2, 3, 4 or 5,

p is the sum of the R ² , R ³ and R ⁴ substituents but not hydrogen,

s is 0, 1 or 2 as the number of double bonds in the ring,

T is alkyl having 1 to 4 carbon atoms; Alkoxy having 1 to 4 carbon atoms; Aryl having 6 to 10 carbon atoms; CO ₂ H; CO ₂ R ⁵ ; Alkenyl having 2 to 4 carbon atoms; Alkynyl having 2 to 4 carbon atoms; C (O) C ₆ H ₅ ; C (O) N (R ⁶ ) (R ⁷ ) (R ⁶ is H or alkyl of 1 to 5 carbon atoms, R ⁷ is H or alkyl of 1 to 5 carbon atoms); S (O) _{y '} R ⁸ (y' is 1 or 2, R ⁸ is alkyl of 1 to 5 carbon atoms); SO ₂ F; CHO; OH; NO ₂ ; CN; halogen; OCF ₃ ; N-oxides; OC (R ⁹ ) ₂ -O (oxygen is bonded to an adjacent position on R and R ⁹ is H, halogen or alkyl of 1 to 4 carbon atoms); C (O) NHC (O) (carbon is bonded to an adjacent position on R); And C (O) C ₆ H ₄ (carbonyl carbon and ring carbon in the ortho position on carbonyl are bonded to adjacent positions on R),

t is 1 to 5,

Provided that the substituent residue T is alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, aryl having 6 to 10 carbon atoms, CO ₂ R ⁵ , alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, 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 , T Is optionally alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, CO ₂ R ⁵ , CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ), CHO, OH, NO ₂ , CN, halogen, May include a second substituent selected from the group consisting of S (O) _y R ⁸ or ═O, wherein the number of second substituents is 1 or 2, except for halogen, which may be used up to the perhalo level,

G is halogen; OH; OR ⁵ ; = 0 (indicates two substituents G); Alkyl having 1 to 4 carbon atoms; Alkenyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 7 carbon atoms; Heterocycloalkyl having 3 to 5 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Cycloalkenyl having 5 to 7 carbon atoms; Heterocycloalkenyl having 4 to 6 carbon atoms containing 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 ); Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; NO ₂ ; CN; S (O) _y R ⁸ ; SO ₃ R ⁸ ; And it is a substituent selected from the group consisting of SO ₂ N (R ⁶ ) (R ⁷ ),

g is 0 to 4, except for halogen, which may be used up to the perhalo level,

Provided that substituent G is alkyl having 1 to 4 carbons, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heterocycloalkyl having 3 to 5 carbon atoms, cycloalkenyl having 5 to 7 carbon atoms or 4 to 6 carbon atoms If is heterocycloalkenyl, G may comprise a second substituent, which is a halogen, optionally used up to the perhalo level; If substituent G is aryl or heteroaryl, G may optionally comprise a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, said second substituent being 3 or less for an alkyl moiety For halogen up to the perhalo level,

Q is alkyl having 1 to 4 carbon atoms; Haloalkyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 8 carbon atoms; Alkoxy having 1 to 8 carbon atoms; Alkenyl having 2 to 5 carbon atoms; Cycloalkenyl having 5 to 8 carbon atoms; Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; CO ₂ R ⁵ ; = 0 (indicates two substituents Q); OH; halogen; N (R ⁶ ) (R ⁷ ), S (O) _y R ⁸ ; SO ₃ R ⁸ ; And it is a substituent selected from the group consisting of SO ₂ N (R ⁶ ) (R ⁷ ),

q is 0 to 4,

Provided that when substituent Q is aryl or heteroaryl, Q may optionally include a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, wherein the second substituent is 3 or less for an alkyl moiety And up to the perhalo level for halogen,

In addition, two of (Q) _q R ¹ , (Q) _q R ² , (Q) _q R ³ and (Q) _q R ⁴ are bonded to N, O and S together with the atom (s) to which they are attached It is possible to form 3-8 membered non-aromatic rings of spiro or bispyro containing 0 to 2 heteroatoms selected from the group consisting of:

FIELD OF THE INVENTION The present invention relates to heterocyclic medicaments, and more specifically to 2-arylimino heterocycle compounds, pharmaceutical compositions comprising them and their use in the regulation of progesterone receptor mediated processes.

Compounds of formula (I) have been broadly defined in the Summary section of this invention. In the formula (I), the following groups are preferably used.

Preferably R is phenyl or pyridyl,

Preferably, R ¹ is alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 12 carbon atoms containing 1 to 3 rings, alkenyl having 2 to 10 carbon atoms, and having 5 to 12 carbon atoms containing 1 to 3 rings. Cycloalkenyl or alkynyl having 3 to 10 carbon atoms. More preferably, R ¹ is alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 12 carbon atoms containing 1 to 3 rings, alkenyl having 2 to 10 carbon atoms or 5 to 12 carbon atoms containing 1 to 3 rings. Cycloalkenyl.

Preferably, R ² , R ³ and R ⁴ are H, 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, or Bonyl represents two groups of R ² , R ³ and R ⁴ ). More preferably, R ² , R ³ and R ⁴ are H, alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 12 carbon atoms, alkenyl having 2 to 10 carbon atoms or cycloalkenyl having 5 to 12 carbon atoms.

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

Preferably, n which represents carbon number of a ring is 2 or 3.

Preferably p is 1 or 2 which represents the sum of the R ² , R ³ and R ⁴ substituents but not hydrogen.

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

T which represents the number of substituents T is 1-5, More preferably, it is 1-3.

If substituent residue 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, T is optionally alkyl of 1 to 4 carbon atoms, of 1 to 4 carbon atoms From the group consisting of 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 And may include a second substituent selected, wherein the number of second substituents is 1 or 2, except for halogen, which may be used up to the perhalo level.

As used herein, the term "second substituent" refers to a substituent on a substituent, and therefore "second" is not used to limit the degree of substitution of carbon.

As used herein, the terms "haloalkyl" and "halocycloalkyl" refer to groups that may contain any number of halogens up to the perhalo level.

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

G, which represents the number of substituents G, is 0 to 4, more preferably 0 to 2, except for halogen, which may be used up to the perhalo level.

Preferably, Q is alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, alkenyl having 2 to 5 carbon atoms, cycloal having 5 to 8 carbon atoms. Kenyl, CO ₂ R ⁵ , ═O, OH, halogen, N (R ⁶ ) (R ⁷ ) and S (O) _y R ⁸ . More preferably, Q is alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, alkenyl having 2 to 5 carbon atoms, cyclo having 5 to 8 carbon atoms. Alkenyl or halogen.

The present invention also includes pharmaceutically acceptable salts of compounds of formula (I). Suitable pharmaceutically acceptable salts are well known to those skilled in the art, including 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, Basic salts of inorganic and organic acids such as oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. Pharmaceutically acceptable salts also include alkali metal cations (e.g. Li ⁺ , Na ⁺ or K ⁺ ), alkaline earth metal cations (e.g. Mg ⁺² , Ca ⁺² or Ba ⁺² ), ammonium cations Triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4, as well as acid salts of inorganic bases such as salts containing Diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene Acid salts of organic bases, including aliphatic and aromatic substituted ammonium and quaternary ammonium cations such as resulting from quantization or peralkylation of (DBU).

Many compounds of formula (I) have asymmetric carbons and therefore may exist in racemate and optically active forms. Methods of separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention includes any racemate or optically active form of a compound described in formula (I) that has progesterone receptor binding activity.

Most preferred 2-imino-1,3-thiazolidine and the ring extended homologues of the 2-imino-1,3-thiazolidine of the present invention include

(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-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-methylphenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane,

2- (4-cyano-2,3-dimethylphenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane,

2- (4-cyano-2-methylphenylimino) -1- (1-ethyl-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

2- (4-cyano-2,3-dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Most preferred thiazolidin-4-ones of the present invention

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-thiazolidin-4-one,

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

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

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

Most preferred oxazolidines of the present invention

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

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

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

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

The therapeutic agents of the invention may be used alone or in combination with other therapies. For example, when used in A1 or A2, the agent may be a calcium source, an analog of vitamin D or vitamin D, and / or an estrogen replacement therapy, treatment with a fluoride source, treatment with a calcitonin or calcitonin analog or bisphosphonates (eg For example, it may be used in combination with anti-osteoabsorbent therapy such as treatment with Alendronate). When used in B1 to B7, the medicament may be used in combination with a therapy such as estrogen replacement therapy. When used in C1 to C16, E1 to E3, or F1 or F2, the medicament may be combined with treatments such as estrogen replacement therapy and / or gonadotropin-releasing hormone agonist therapy. When used for G1 or G2, the medicament may be combined with a therapy such as androgen therapy.

The methods of the present invention are intended for use in treating progesterone receptor mediated symptoms in humans and other mammals.

The compounds of the present invention may be oral, dermal, parenteral, injectable, inhaled or sprayed, or sublingually, rectally or vaginally in unit dosage form. The term "administered by injection" includes the use of irrigation techniques as well as intravenous, intraarterial, intramuscular, subcutaneous and parenteral injection. Skin administration can include topical or transdermal administration. One or more compounds may be present in combination with one or more pharmaceutically acceptable non-toxic carriers and, if necessary, with other active ingredients.

Compositions for oral administration may be prepared according to any suitable method known in the art of pharmaceutical composition manufacture. The composition may comprise one or more adjuvants selected from the group consisting of diluents, sweeteners, flavors, colorants and preservatives to provide a tasty formulation.

Tablets include the active ingredient in combination with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. Such excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agents such as corn starch or alginic acid; And binders such as magnesium stearate, stearic acid or talc. Tablets may not be coated or may be coated by known techniques for delaying disintegration and absorption in the gastrointestinal tract to provide long lasting activity. For example, release delaying materials such as glyceryl monostearate or glyceryl distearate can be used. The compound may also be prepared as an immediate release solid.

In addition, oral compositions are hard gelatin capsules in which the active ingredient is combined with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or soft in combination with water or an oil medium such as peanut oil, liquid paraffin or olive oil. May be present as gelatin capsules.

In addition, an aqueous suspending agent can be used comprising the active substance in combination with excipients suitable for the manufacture of aqueous suspending agents. Suitable excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia rubber, and dispersing or wetting agents Natural phospholipids such as lecithin, condensation products of fatty acids such as polyoxyethylene stearate with alkylene oxides, condensation products of long chain aliphatic alcohols such as heptadecaethyleneoxycetanol with ethylene oxide, polyoxyethylene sorbitol monoole Condensation products of partial esters derived from hexitol and fatty acids such as ates with ethylene oxide, or condensation products of ethylene oxide with partial esters derived from hexitol anhydrides and fatty acids such as polyethylene sorbitan monooleate have. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. have.

Dispersible powders and granules suitable for the preparation of aqueous suspending agents by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are already exemplified above. For example, additional excipients may be present, such as sweetening, flavoring and coloring agents.

The compounds of the invention are also non-aqueous suspensions, such as oily suspensions, which can be formulated by suspending the active ingredient in vegetable oils such as arachis oil, olive oil, sesame oil or peanut oil or mineral oils such as liquid paraffin. It may be in the form of a liquid formulation. Oily suspensions may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as described above may be added for tasty oral formulations. Such compositions can be stored with the addition of an antioxidant such as ascorbic acid.

In addition, the pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers are natural rubbers such as acacia rubber or tragacanth rubber, natural phospholipids such as soybean, lecithin and esters or partial esters (derived from hexitol anhydrides and fatty acids such as sorbitan monooleate), and polyoxyethylene sorbents. Condensation products of ethylene oxide, such as non-elastic monooleate, with the partial esters. Emulsifiers may also include sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. The formulation may also include analgesics, preservatives, flavors and coloring agents.

In addition, the compounds of the present invention may be administered in the form of suppositories for rectal or vaginal administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and therefore will melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.

In addition, the compounds of the present invention can be administered transdermally using methods known to those of skill in the art (Chien; “Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc .; 1987. Lipp et al. WO 94/04157 5 1994 March 3). For example, solutions or suspensions of compounds of formula (I) in suitable volatile solvents, optionally including penetration promoters, may be combined with additional additives known to those skilled in the art, such as matrix materials and fungicides. After sterilization, the resulting mixture may be formulated in dosage form according to the procedures known below. Emulsifiers and water can also be treated to formulate solutions or suspensions of compounds of formula (I) into lotions or ointments.

Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, including lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran Lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons and halogenated hydrocarbons.

Penetration promoting substances suitable for transdermal delivery systems are known to those skilled in the art and include saturated or unsaturated C ₈ -C ₁₈ such as monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, lauryl alcohol or cetyl alcohol. Fatty alcohols, methyl, ethyl, propyl, isopropyl, n-butyl, sec of saturated or unsaturated C ₈ -C ₁₈ fatty acids such as stearic acid, acetic acid, caproic acid, lauric acid, myristic acid, stearic acid or palmitic acid Saturated or unsaturated fatty acid esters having up to 24 carbon atoms, such as -butyl, isobutyl, tert-butyl or monoglycerine esters, or diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate or Diesters of saturated or unsaturated dicarboxylic acids having up to 24 carbon atoms, such as diisopropyl fumarate, Included. Additional penetration promoting materials include phospholipid derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and derivatives thereof, and ethers such as dimethyl isosorbide and diethylene glycol monoethyl ether. Suitable penetration enhancers also include monohydroxy or polyhydroxy alcohols, saturated or unsaturated C ₈ -C ₁₈ fatty alcohols, saturated or unsaturated C ₈ -C ₁₈ fatty acids, saturated or unsaturated fatty acids of 24 or less carbon atoms, total carbon of 24 or less One or more mixtures selected from diesters of saturated or unsaturated dicarboxylic acids, phospholipid derivatives, terpenes, amides, ketones, ureas and derivatives thereof, and ethers.

Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene copolymers, and natural and synthetic rubbers. In addition, cellulose ethers, derivatized polyethylenes and silicates may be used as the matrix component. Additional additives such as viscous resins or oils may be added to increase the viscosity of the matrix.

For all dosages of the compound of formula (I) disclosed herein, a daily oral dosage of 0.01 to 200 mg per kg of total body weight will be preferred. Daily dosages of injections, including intravenous, intramuscular subcutaneous and parenteral injections, and administration using irrigation techniques, preferably from 0.01 to 200 mg / kg total body weight. The daily rectal dosage will preferably be between 0.01 and 200 mg / kg total body weight. The daily vaginal dosage will preferably be between 0.01 and 200 mg / kg total body weight. Daily topical dosages of 0.1 to 200 mg will preferably be administered between 1 and 4 times a day. Transdermal administration concentrations will preferably be such that the daily dosage is maintained at 0.01 to 200 mg / kg. The daily inhalation dose will preferably be between 0.01 and 10 mg / kg total body weight.

Those skilled in the art will appreciate that the method of administration will vary depending upon the various factors typically considered in the dosage regimen. However, the specific dosage for any given patient depends on the activity of the specific compound used, the patient's age, the patient's weight, the general health of the patient, the patient's gender, the patient's eating habits, the time of administration, the route of administration, the rate of excretion, It is to be understood that this will depend upon various factors including but not limited to drug combination and severity of the condition being treated. In addition, those skilled in the art will appreciate that the optimal course of treatment, i.e., the mode of treatment and the number of daily doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a given period of time, can be ascertained by those skilled in the art using conventional therapeutic tests.

The entire disclosures of all applications, patents, and documents cited above and below are hereby incorporated by reference.

Compounds of formula (I) are prepared from known compounds (or starting materials that can be prepared from known compounds) using known chemical reactions and processes, and other reactions and procedures known to those skilled in the art, through the preparation methods described below. It can manufacture. Nevertheless, the following general methods of preparation have been described to assist those skilled in the art in synthesizing the compounds of the present invention with reference to certain more detailed examples described in the experimental section. The examples are described solely for the purpose of illustrating the invention and are not intended to limit the invention in any way and should not be so interpreted.

<List of abbreviations and acronyms>

As used herein, the following terms have the meaning given.

AcOH acetic acid

anh anhydrous (water)

BOC tert-butoxycarbonyl

conc concentrated

dec decomposition

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

DIBAL diisobutylaluminum hydride

DME 1,2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

EtOH Ethanol (100%)

Et ₂ O diethyl ether

Et ₃ N triethylamine

KMnO ₄ Potassium Permanganate

Magnosil (registered trademark) MgSiO ₃ · xH ₂ O

m-CPBA 3-chloroperoxybenzoic acid

MeOH Methanol

pet. ether petroleum ether (melting point 30-60 ° C)

THF tetrahydrofuran

TFA trifluoroacetic acid

General manufacturing method

Aryl amines, aryl isocyanates, aryl isothiocyanates, asymmetric aryl thioureas, aryl isocyanate dichlorides and 2-arylimino-1,3-heterocycles can be synthesized using known methods (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984) .March. Advanced Organic Chemistry, 3 ^rd Ed .; John Wiley: New York (1985)). For example, aryl isocyanates (2) are available from the reaction of phosgene or phosgene equivalents such as carbonyl diimidazole, diphosgene or triphosgene, and aryl isothiocyanates (3) are aryl amines with thiophosgene or thio Available from the reaction of phosgene equivalents (thiocarbonyl diimidazole of Scheme I). In addition, many aryl isocyanates and aryl isothiocyanates are commercially available. Reaction of aryl isothiocyanates with primary amines affords thiourea (4) (Hahn et al. Han'guk Nonghwa Hakhoechi 1997, 40, 139; Duerr, US Pat. No. 4,079,144; Enders, US Pat. No. 4,148,799) ).

As described in Scheme II, thiourea is reacted with an α-haloketone, such as α-bromoketone (5), followed by dehydration to give thiazoline (6) (Hahn et al. Han'guk Nonghwa Hakhoechi 1997, 40 , 139; Duerr, US Pat. No. 4,079,144; Enders, US Pat. No. 4,148,799).

Similarly, thiourea can be converted to α-haloacid halides (Giri et al. Asian J. Chem. 1992, 4, 785; Lakhan et al. Agric. Biol. Chem. 1982, 46, 557), α-halosan (Dogan et al. Spectrosc. Lett. 1983, 16, 499; Seada et al Indian J. Heterocycl. Chem. 1993, 3, 81) or α-haloesters (Seada et al Indian J. Heterocycl. Chem. 1993, 3 , 81) to give 4-thiazolidinone (10).

The aryl isothiocyanate (3) may also be allylamine (Tsoi et al. Zh. Org. Khim. 1983, 19, 2605) or propargylamine (Azerbaev et al. Khim. Geterotsikl. Soedin. 1972, 471). To form the corresponding thiourea, which is then treated with acid to give 5-substituted thiazolidine (Scheme IV).

Aryl isothiocyanate is also reacted with hydroxylamine (17) to produce N-hydroxyalkylthiourea (18) (Scheme V). Thiourea is treated with acid to give 2-imino-1,3-heterocycle (19) (Jen et al. J. Med. Chem. 1975, 18, 90; Tyukhteneva et al. Khim. Geterotsikl. Soedin. 1985, 12, 1629; Olszenko-Piontkowa et al. Org.Prep.Proced.Int. 11971, 3, 27). Hydroxyalkylthiourea (18) is reacted with SOCl ₂ to obtain chloroalkyl homologue (20) and then cyclized by treatment with base to obtain heterocycle (19) (Cherbuliez et al. Helv. Chim. Acta 1967, 50, 331; Felix et al. US Pat. No. 4,806,653).

Alternatively, N-hydroxyalkylthiourea (18) is treated with HgO or an alkylating agent (e.g. methyl iodide) as described in Scheme VI, followed by treatment with base to obtain the corresponding oxygen-containing heterocycle ( Jen et al. J. Med. Chem. 1975, 18, 90; Ignatova et al. Khim. Geterotsikl. Soedin. 1974, 354).

It is reported that chloroalkyl isothiocyanates react with arylamines to produce the corresponding sulfur 2-phenylimino-1,3-heterocycles (Sagner et al. US Pat. No. 3,651,053; Ibid US Pat. No. 3,737,536). ).

The aryl amine is reacted with a formylating agent such as form acetic anhydride to produce formanilide (25) which is then oxidatively converted to aryl isocyanide dichloride (Ferchland et al. DE 3,134,134; Kuehle for comment) et al. Angew. Chem. 1967, 79, 663). Aryl asocyanide dichloride (26) is reacted with hydroxylamine (27) to obtain an oxygen-containing 2-phenylimino-1,3-heterocycle (30) (Wollweber US Patent No. 3,787,575; Ibid USA Patent 3,686,199) and hydroxylamide (28) to obtain thiazolidinone (31). Aryl isocyanide dichloride has also been shown to react with aminomercaptans 29 to produce sulfur-containing 2-phenylimino-1,3-heterocycle 32 (Thibault French Patent No. 1,510,015). .

Reacting hydroxylamine in the presence of CS ₂ with a base will give 1,3-thiaza-2-thione (Scheme VII). It is reported that thion 34 reacts with SOCl ₂ to produce imidate 35 which is unstable to water absorption, and treatment with aryl amine produces sulfur-containing 2-imino-1,3-heterocycle. (Hanefeld et al. Arch. Pharm. 1985, 318, 60; Ibid 1988, 321, 199).

Oxygen-containing and sulfur-containing 2-imino-1,3-heterocycles can be further processed. Thus, for example, as described in Scheme V, N3-unsubstituted 2-phenylimino-1,3-heterocycle is usually treated with an electrophile in the presence of a base to obtain an N3-substituted product (Ambartsumova et al. Chem.Heterocycl.Compd. 1997, 33, 475; Mizrakh et al.Khim.Geterotsikl.Soedin. 1990, 563; Olszenko-Piontkowa et al.Org.Prep.Proced.Int. 11971, 3, 27).

In addition, sulfur-containing 2-imino-1,3-heterocycles can be oxidized to sulfoxides or sulfones as described in Scheme XI (Chizhevskaya et al. Khim. Geterotsikl. Soedin. 1971, 96; Pandey et al. J. Indian Chem. Soc. 1972, 49, 171).

Detailed Experiment Process

Detailed examples of the preparation of the compounds of the present invention are described in the detailed synthesis procedures below. In the table of compounds below, the synthesis of each compound is referred to their exemplary preparation steps.

All reactions were carried out in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen and stirred using a magnetic field unless otherwise noted. Unstable liquids and solutions were transferred via syringe or cannula and introduced into the reaction vessel through the rubber septum. Commercial grade reagents and solvents were used without further purification.

Unless stated otherwise, the term 'concentration under reduced pressure' means using a Buchi rotary evaporator at about 15 mm Hg. Bulb-to-bulb concentration was carried out using an Aldrich Kugelrohr apparatus, in which case the temperature was oven temperature. All temperatures were recorded in uncorrected degrees Celsius (° C). Unless otherwise stated, all parts and percentages are by volume.

Thin layer chromatography (TLC) was performed on Whatman® pre-coated glass-supported silica gel 60A F-254 250 μm plates. (a) ultraviolet irradiation, (b) exposure to iodine vapor, (c) immersing the plate in a 10% solution of phosphomolybdic acid in ethanol and heating, (d) immersing the plate in cerium sulfate and then heating, and (Or) (e) The plates were immersed in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by visualization of the plates by one or more techniques during heating. Column chromatography (flash chromatography) was carried out using 230-400 mesh EM Science® silica gel. Rotation chromatography was performed using a precast SiO ₂ plate (Alltech) from Harrison Research Chromatotron.

Melting points (mp) were measured using a Thomas-Hoover melting point meter or a Mettler FP66 automatic melting point meter and were not calibrated. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrometer.

Proton ( ¹ H) nuclear magnetic resonance (NMR) spectra were obtained using General Electric (Me ₄ Si (δ0.00) or residual quantization solvent (CHCl ₃ δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. It was measured with a GN-Omega 300 (300MHz) spectrometer of General Electric.

Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were obtained as electron collision (EI), chemical ionization (CI), or high speed atomic bombardment (FAB) mass spectra. Residue impingement mass spectra (EI-MS) were obtained using a Hewlett Packad 5989A mass spectrometer equipped with a vacuum desorption chemical ionization probe for sample introduction. The ion source was kept at 250 ° C. Electron collision ionization was performed with electron energy of 70 eV and capture current of 300 μA. Liquid cesium secondary ion mass spectra (FAB-MS), an updated version of the high-speed electron bombardment, were obtained using a Kreptos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using Hewlett Packard MS-engine (5989A) with methane or ammonia as reagent gas (1 × 10 ⁴ torr to 2.5 × 10 ⁴ torr). Direct insertion desorption chemical ionization (DCI) probes (Vaccumetrics, Inc.) were ramped from 0 to 1.5 amps for 10 seconds and held at 10 amps until all sample traces disappeared (about 1 to 2 minutes). Spectra were scanned at 50-800 amu in 2 sec / scan. HPLC-electrospray mass spectra (HPLC ES-MS) using Hewlett Packard 1100 HPLC equipped with a four-part pump, variable wavelength detector, C-18 column, and an electrospray ionized Finnigan LCQ ion capture mass spectrometer Obtained. The spectra were scanned from 120 to 800 amu using variable ion times depending on the number of ions in the light source. Gas chromatography-ion selective mass spectra (GC-MS) were obtained from HP-1 methyl silicon column (0.33 mM coating; 25 m × 0.2 mm). And Hewlett Packard 5890 gas chromatography equipped with a Hewlett Packard 5971 mass selection detector (ionization energy 70 eV).

Elemental analysis was performed at Robertson Microlit Labs, Madison NJ. NMR spectra, LRMS, elemental analysis and HRMS for the compounds were consistent with the designated structures.

Preparation examples for the compounds of the present invention are described in the following detailed synthetic methods. In the table of compounds below, the synthesis of each compound is referred to their exemplary preparation steps.

A. Synthesis of Imine Precursors

A1a. General method for the synthesis of aniline from nitrobenzene. Synthesis of 4-cyano-2-methylaniline

4-Cyano-2-methylaniline was synthesized as described above (J. Med. Chem. (1991), 34, 3295): 3-methyl-4-nitrobenzonitrile (2.0 g, in acetic acid (20 L) 12.34 mmol) was added dropwise a solution of SnCl ₂ (9.6 g, 49.38 mmol) in concentrated HCl (20 mL). After stirring for 3 hours, the mixture was added carefully to saturated NH ₄ OH solution (120 mL) at 0 ° C. The resulting mixture was extracted with EtOAc (4 × 30 mL). The combined organic layers were washed sequentially with H ₂ O (30 mL) and saturated NaCl solution (30 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc / hexanes) to give 4-cyano-2-methylaniline (1.48 g, 92%) as a white solid: TLC (30% EtOAc in hexane) Rf 0.23. This material was used without further purification.

A2a. General method for isothiocyanate synthesis. Synthesis of 4-nitro-2-n-propyl isothiocyanate

<Step 1>

Acetic anhydride (10.9 mL, 99 mmol) was added dropwise to a solution of 2-n-propylaniline (8.91 g, 66 mmol) and Et ₃ N (14 mL, 106 mmol) in CH ₂ Cl ₂ (60 mL). The resulting mixture was stirred at room temperature overnight and then treated with 1N HCl solution (40 mL). The acidic mixture was extracted with CH ₂ Cl ₂ (2 × 30 mL). The combined organic layers were washed sequentially with H ₂ O (40 mL), 1N NaOH solution (40 mL), H ₂ O (40 mL) and saturated NaCl solution (40 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. . The resulting powder was purified by crystallization (EtOAc) to give 2-n-propylacetanilide (7.85 g, 67%) as white needle crystals. TLC (30% EtOAc / hexanes) Rf 0.37.

<Step 2>

NaNO ₂ (0.55 g, 6.50 mmol) was added to a solution of 2-n-propylacetanilide (1.15 g, 6.50 mmol) in TFA (20 mL) at −5 ° C. The mixture was stirred at 0 ° C. for 3 h and then treated with H ₂ O (30 mL). The resulting aqueous solution was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with 1N NaOH solution (30 mL), H ₂ O (30 mL) and saturated NaCl solution (40 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was dissolved in concentrated HCl solution (30 mL) and heated at 100 ° C. overnight. The resulting mixture was cooled to 0 ° C. in an ice bath, then the pH was carefully adjusted to 10 using 50% NaOH solution. The basic mixture was extracted with EtOAc (4 times 30 mL). The combined organic layers were washed sequentially with H ₂ O (30 mL) and saturated NaCl solution (40 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc / hexanes) to give 2-n-propyl-4-nitroacetanilide (0.56 g, 48%) as a yellow solid: TLC (20% EtOAc / hexanes) Rf 0.47.

<Step 3>

Thiophosgene (0.24 mL, 0.31 mmol) was added dropwise to a solution of 2-propyl-4-nitroacetanilide (0.56 g, 0.31 mmol) in toluene (30 mL). The mixture was heated at reflux overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (1% EtOAc / hexanes) to give 2-propyl-4-nitrophenyl isothiocyanate (0.65 g, 95%) as a yellow oil: TLC (20% EtOAc / hexanes) Rf 0.82 .

A2b. General method for isothiocyanate synthesis. Synthesis of 4-cyano-2-ethylphenyl isothiocyanate

Thiophosgene (43 mL, 0.56 mol, 1.1 equiv) was slowly added dropwise through a syringe to a solution of 4-amino-3-ethylbenzonitrile (75 g, 0.51 mol) in toluene (1 L). Within 5 minutes a viscous slurry was produced. The reaction mixture was heated at reflux for 5 hours and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure, then treated with CH ₂ Cl ₂ (600 mL) and concentrated under reduced pressure to give 4-cyano-2-ethylphenyl isothiocyanate (98 g, 100%) as a light tan crystalline solid. : 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) ⁺ ).

A2c. General method for isothiocyanate synthesis. Synthesis of 2,4-dimethyl-3-cyano-5-pyridyl isothiocyanate

A suspension of 6-amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0.68 mmol) in CH ₂ Cl ₂ (1 mL) was added to a water: CH ₂ Cl ₂ (1: 2) mixture (9 mL total). To a thoroughly stirred CaCO ₃ (0.41 g, 4.11 mmol) mixture at room temperature. The reaction mixture was cooled to 0 ° C. and thiophosgen (0.09 g, 0.78 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. The resulting aqueous layer was back-extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic layers were washed with water (10 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , 10% EtOAc / hexanes) to give 2,4-dimethyl-3-cyano-6-pyridyl isothiocyanate (0.12 g, 91%): CI-MS m / z 190 ((M + H) &lt; + &gt;).

A2d. General method for isothiocyanate synthesis. Synthesis of 2,3-dimethyl-4-nitrophenyl isothiocyanate

Thiophosgen (0.3 mL, 1.3 equiv) was added to a solution of 2,3-dimethyl-4-nitroaniline (0.5 g, 1.0 equiv) in toluene (50 mL) and the reaction mixture was heated at reflux overnight. Was concentrated under reduced pressure, and the residue was purified by column chromatography (25% CH ₂ Cl ₂ / hexane) to give 2,3-dimethyl-4-nitrophenyl isothiocyanate (0.30 g, 48%) as a light yellow solid. Obtained: 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) ⁺ ).

A2e. General method for isothiocyanate synthesis. Synthesis of 2,3-dimethyl-6-nitrophenyl isothiocyanate

Thiophosgen (2.5 mL, 1.8 equiv) was added to a solution of 2,3-dimethyl-6-nitroaniline (3.0 g, 1.0 equiv) in toluene (150 mL) and the reaction mixture was heated at reflux overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (10% CH ₂ Cl ₂ / hexanes) to give 2,3-dimethyl-6-nitrophenyl isothiocyanate (3.63 g, 95 as a pale yellow solid). %) Were obtained: 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) .

A3a. General method for aryl isonitrile dichloride synthesis. Synthesis of 4-cyano-2-ethylphenyl isocyanide dichloride

<Step 1>

Acetic anhydride (235 mL, 2.5 mol, 2.6 equiv) was added to formic acid (118 mL, 3.1 mol, 3.2 equiv) and the resulting solution was heated at 60 ° C. for 2 h. After the reaction was cooled to room temperature, a solution of 4-amino-3-ethylbenzonitrile (140 g, 0.96 mol) in dry THF (700 mL) was added at a rate (about 20 minutes) at which the reaction temperature did not exceed 45 ° C. When the resulting solution was cooled to room temperature, it was concentrated under reduced pressure, treated with EtOH (600 mL), and then again under reduced pressure to afford 4-cyano-2-ethylformanilide (167 g, 100%) as a light tan solid. Obtained: 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, 1 H), 8.37 (s, 1 H), 9.89 (br s, 1 H).

<Step 2>

Sulfuryl chloride (112 mL, via syringe) in 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) cooled to 0 ° C. in an ice bath. 1.4 mol, 1.4 equivalents) was added. The cooling bath was removed and the reaction heated at 50 ° C. overnight. The resulting mixture was concentrated under reduced pressure, treated with CH ₂ Cl ₂ (600 mL) and then again under reduced pressure. The residue was dissolved in Et ₂ O (800 mL) and filtered through a pad of Magnosil® Magnosil to afford 4-cyano-2-ethylphenyl isocyanide dichloride (210 g, 96%) as an oil. : ¹ H NMR (CDCl ₃ ) δ 1.13 (t, J = 7.3 Hz, 3H), 2.49 (q, 2H, J = 7.3 Hz), 7.15 (d, J = 8.2 Hz, 1H), 8.35-8.40 (m , 2H).

A3b. General method for aryl isonitrile dichloride synthesis. Synthesis of 2-methyl-4-nitrophenyl isocyanide 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 at 60 ° C. for 2.5 h. After cooling to room temperature, a solution of 2-methyl-4-nitroaniline (152 g, 1.64 mol, 1.0 equivalent) in dry THF (1.2 L) was added at a rate (about 30 minutes) at which the reaction temperature did not exceed 45 ° C. . When the resulting solution was cooled to room temperature, it was concentrated to half volume under reduced pressure, and the reaction product was isolated by filtration to give 2-methyl-4 nitroformanilide (295 g, 100%) as a light tan solid: ¹ H NMR (CDCl ₃ ) δ 2.31 (s, 3H) 8.03 (m, 2H), 8.24 (d, J = 8.8 Hz, 1H), 8.39 (br s, 1H), 9.94 (br s, 1H).

<Step 2>

SOCl ₂ (525 mL, 6.05 mol, 6.3 equiv) was added to 2-methyl-4nitroformanilide (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 then heated at 60 ° C. for 4 hours and then left to cool to room temperature. The reaction mixture was concentrated to half volume under reduced pressure and the resulting slurry was filtered. This solid was washed with 50% Et ₂ O / hexane solution to give 2-methyl-4-nitrophenyl isocyanide dichloride (323 g, 85%) as a yellow solid: 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, 1H).

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

<Step 1>

To a solution of 2,3-dimethylaniline (1.1 mL, 1.00 equiv) and Et ₃ N (1.5 mL, 1.30 equiv) in CH ₂ Cl ₂ (15 mL) at 0 ° C. add acetyl chloride (0.73 mL, 1.25 equiv) for 30 min. Was added over. The reaction mixture was stirred at room temperature overnight and then treated with 2N HCl solution (10 mL) and CH ₂ Cl ₂ (25 mL). The resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organics were washed with 2N HCl solution (2 times 25 mL), water (2 times 25 mL), saturated NaHCO ₃ solution (2 times 25 mL) and saturated NaCl solution (2 times 25 mL) and dried (Na ₂ SO ₄ ), then concentrated under reduced pressure to give 2,3-dimethylacetanilide (1.25 g, 93%) as a white solid: 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, 1H) 7.02 (app t, J = 7.5 Hz, 1H), 7.35 (d, J = 6.9 Hz, 1H).

<Step 2>

To a solution of 2,3-dimethylacetanilide (14.0 g, 1.0 equiv) in concentrated H ₂ SO ₄ (35 mL) at 0 ° C. was added HNO ₃ (5.1 mL, 1.25 equiv) over 30 minutes. The resulting mixture was left to cool to room temperature for 15 minutes and then treated with ice water (500 mL) to give a yellow precipitate. This solid was separated and washed with water to give a 1: 1 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 (br s, 1H ), 7.15 (d, J = 8.7 Hz, 0.5H), 7.63 (d, J = 8.7 Hz, 0.5H), 7.76 (d, J = 8.1 Hz, 1H). This mixture was used for the next step without further purification.

<Step 3>

To a solution of nitroacetanilide mixture (16.0 g, 1.0 equiv) was added 60% H ₂ SO ₄ solution (150 mL). The solution was heated at reflux for 1 h, then cooled to room temperature and treated with a 2N NaOH solution in ice water (100 mL). The resulting mixture was extracted with EtOAc (3 times 50 mL). The combined organic layers were washed with saturated NaHCO ₃ solution (2 times 50 mL) and saturated NaCl solution (2 times 50 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (10% CH ₂ Cl ₂ / hexanes) to give 2,3-dimethyl-6-nitroaniline (5.5 g, 43%), followed by 2,3-dimethyl-4-nitroaniline (1.5 g, 12%) was obtained. 2,3-dimethyl-6-nitroaniline (5.5 g, 43%): ¹ H NMR (CDCl ₃ ) δ2.05 (s, 3H), 2.20 (s, 3H), 6.15 (br 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 (br 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 (br 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 (br s, 2H), 6.53 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H).

A5a. General method for iodoaniline synthesis. Synthesis of 4-iodo-2-n-propylaniline

To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHCO ₃ (5.0 g, 59.5 mmol) in H ₂ O (25 mL). Iodine (8.4 g, 33.3 mmol) was added in portions over 70 minutes while maintaining the temperature at 10 ° C., and then the mixture was stirred at 10 ° C. for 30 minutes. The resulting mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (4 × 40 mL). The combined organic layers were washed sequentially with 5% Na ₂ S ₂ O ₃ solution (30 mL) and saturated NaHCO ₃ solution (30 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to yield 4-iodo-2-. n-propylaniline (9.4 g, 98%) was obtained: TLC (20% EtOAc / hexanes) Rf 0.43. This material was used in the next step without further purification.

B. Method of Producing 2-Iminoheterocycle Precursors

B1a. General method for the synthesis of ethanolamine via reduction of amino acid derivatives. Synthesis of 1-amino-1- (hydroxymethyl) cyclohexane

<Step 1>

Benzyl chloroformate (12.0 mL, 84.0 mmol) was added to a solution of 1-aminocyclohexane-1-carboxylic acid (10.0 g, 70.0 mmol) in 1 M NaOH solution (100 mL). The reaction mixture was stirred for 2 hours while maintaining the pH at 9 by adding 1M NaOH solution if necessary. The resulting solution was washed with Et ₂ O (2 × 100 mL), then the pH of the aqueous layer was adjusted to 0 with concentrated HCl solution and the solution extracted with EtOAc (3 × 150 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to give 1- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid (17.3 g, 89%): TLC (25% EtOAc / hexane) Rf 0.07.

<Step 2>

Isobutyl in a solution of 1- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid (4.16 g, 15.0 mmol) and N-methylmorpholine (1.81 mL, 16.5 mmol) in DME (15 mL) at 4 ° C. Chloroformate (2.14 mL, 16.5 mmol) was added slowly and the reaction mixture was stirred for 5 minutes and then filtered into a pre-cooled (4 ° C.) flask. Sodium borohydride (0.85 g, 22.5 mmol) in water (7 mL) was added and water (500 mL) was added immediately. The reaction was warmed to 20 ° C. and stirred for 30 minutes. The reaction mixture was extracted with CH ₂ Cl ₂ and concentrated under reduced pressure to give 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) cyclohexane (4.0 g, 100%): TLC (25% EtOAc / hexane ) Rf 0.11.

<Step 3>

Slurry of 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) cyclohexane (4.0 g, 15 mmol) and 10% Pd / C (0.40 g) in MeOH (75 mL) under H ₂ (1 atm) After stirring for 1 hour, the mixture was treated with Celite. The reaction mixture was filtered and concentrated under reduced pressure to give 1-amino-1 (hydroxymethyl) cyclohexane.

B1b. General method for the synthesis of ethanolamine via reduction of amino acid derivatives. Synthesis of (1S) -1- (hydroxymethyl) -3-methylbutylamine

<Step 1>

To a suspension of (L) -leucine (315 g, 2.4 mol) in MeOH (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 did not exceed 5 ° C. . After complete addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated under reduced pressure and Et ₂ O (3 L) was slowly added to the residue to give a precipitate. The mixture was cooled in an ice bath and then quickly treated with additional MeOH (3 L) respectively. After 1 hour at 0 ° C., the crystals were collected and dried to give (L) -leucine methyl ester HCl salt (394 g, 86%) as a white crystalline solid: 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).

<Step 2>

NaBH ₄ (159 g) in a mixture of (L) -leucine methyl ester HCl salt (254 g, 1.4 mol), NaHCO ₃ (118 g, 1.4 mol, 1.0 equiv) and water (1.8 L) in EtOH (1.8 L) at 5 ° C. , 4.2 mol, 3.0 equivalents) were added in portions at a rate (about 70 minutes) at which the reaction temperature did not exceed 15 ° C. After complete addition of NaBH ₄ , the ice bath was removed and the reaction was heated to reflux overnight. The resulting mixture was cooled to room temperature with the aid of an ice bath. The resulting slurry was filtered and the solid was washed with EtOH (750 mL). The combined filtrates were concentrated to about 950 mL under reduced pressure. The residue was diluted with EtOAc (2.5 L) and extracted with 1N NaOH solution (2 × 1 L). The aqueous layer was back extracted with EtOAc (2 × 750 mL). The combined organics were dried (MgSO ₄ ) and concentrated under reduced pressure to give (1S) -1- (hydroxymethyl) -3-methylbutylamine (112 g, 65%) as a pale yellow oil: ¹ H NMR (CDCl ₃₎ ) δ0.88-0.93 (m, 6H), 1.17 (t, J = 7.7 Hz, 2H), 1.68-1.80 (m, 2H), 1.82 (br s, 2H), 2.86-2.91 (m, 1H), 3.22 (dd, J = 10.7, 8.1 Hz, 1H), 3.56 (dd, J = 10.3, 3.6 Hz, 1H).

B1c. General method for the synthesis of ethanolamine via reduction of amino acid derivatives. Synthesis of 1-hydroxymethylcyclopentanamine

<Step 1>

React SOCl ₂ (687 mL, 9.4 mol, 1.8 equiv) while maintaining a suspension of 1-aminocyclopentanecarboxylic acid (675 g, 5.23 mol, 1.0 equiv) in MeOH (6.5 L) at −15 ° C. in an ice / MeOH bath. The temperature was added dropwise at a rate not exceeding 7 ° C. After complete addition, the cooling device was removed and the reaction stirred overnight at room temperature and then concentrated under reduced pressure. The residue was treated with CH ₂ Cl ₂ (1 L) and concentrated under reduced pressure to afford methyl 1-aminocyclopentanecarboxylate HCl salt (938 g, 100%) as a white solid. ¹ H NMR (CD ₃ OD) d 1.87-1.94 (m, 8H), 3.83 (s, 3H); 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 (br s 3H). This material was used in the next step without further purification.

<Step 2>

A solution of methyl 1-aminocyclopentanecarboxylate HCl salt (310 g, 1.73 mol) in EtOH (12.5 L) and water (12.5 l) was treated with NaHCO ₃ (145 g, 1.73 mol, 1.0 equiv). The resulting mixture was cooled to 5 ° C. in an ice bath and NaBH ₄ (196 g, 5.2 mol, 3.0 equiv) was added in portions at a rate (about 75 minutes) at which the reaction temperature did not exceed 15 ° C. After complete addition of NaBH ₄ , the ice bath was removed and the reaction was heated at reflux overnight, then cooled to room temperature with the help of an ice bath and filtered. The resulting solid was washed with EtOH (750 mL) and the combined filtrates were concentrated under reduced pressure. The resulting slurry was treated with EtOAc (2.5 L). The organic layer was washed with 1N NaOH solution (2 × 750 mL) and the aqueous layer was back extracted with EtOAc (2 × 500mL). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to give 1-hydroxymethylcyclopetanamine (169 g, 85%) as low temperature melt wax: 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 (br s, 3H), 3.36 (s, 2H). CI-MS m / z 116 ((M + H) ⁺ ).

B2a. General method for N-alkylation of ethanolamine via substitution reaction. Synthesis of 2- (isobutylamino) -2- (hydroxymethyl) norbornane

In a similar manner to Method Bla, 2-aminonorbornane-2-carboxylic acid was converted to 2-amino-2- (hydroxymethyl) norbornane as a stereoisomer mixture. A solution of amino alcohol (0.31 g, 2.16 mmol) and isobutyl bromide (0.23 mL, 2.16 mL) in DMF (3 mL) was heated at 90 ° C. for 92 h, then cooled to room temperature, EtOAc (100 mL) and saturated NaHCO ₃ Partition between solutions (100 mL). The organic layer was washed with saturated NaCl solution (50 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to afford 2- (isobutylamino) -2- (hydroxymethyl) norbornane (0.24 g, 55 as stereoisomer mixture). %) Was obtained: GC-MS m / z 197 (M ⁺ ).

B2b. General method for N-alkylation of ethanolamine via substitution reaction. Synthesis of N-hydroxyethyl-N-cyclohex-1-enylmethylamine

<Step 1>

To a stirred solution of methyl cyclohex-1-enecarboxylate (4.56 g, 32 mmol) in THF (100 mL) at −78 ° C. was added dropwise DIBAL (1M in THF, 130 mmol, 130 mL). The mixture was stirred at -78 ° C for 4 h and then treated with saturated NaHCO ₃ solution (40 mL). The aqueous layer was extracted with EtOAc (4 times 20 mL) and the combined organic layers were washed with H ₂ O (40 mL) and saturated NaCl solution (40 mL), then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The remaining cyclohex-1-enylmethanol was used directly in the next step without purification: TLC (30% EtOAc / hexanes) Rf 0.44.

<Step 2>

To a solution of cyclohex-1-enylmethanol (3.58 g, 32 mmol) in CH ₂ Cl ₂ (40 mL) at 0 ° C. was added PPh ₃ (36 mmol, 9.39 g) and CBr ₄ (39 mmol, 12.96 g). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was diluted with pentane (60 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (5% EtOAc / hexanes) to give 1-bromomethyl-1-cyclohexene (3.25 g, 57% 2 steps) as an oil: TLC (30% EtOAc / hexanes) ) Rf 0.91.

<Step 3>

Solutions of 1-bromomethyl-1-cyclohexene (3.25 g) and 2-aminoethanol (6 mL) in trichloroethylene (40 mL) were heated at reflux for 3 days and cooled to room temperature, followed by 1NNaOH solution (30 mL). Diluted with. The aqueous layer was extracted with CH ₂ Cl ₂ (4 × 20 mL) and the combined organic layers were washed with H ₂ O (30 mL) and saturated NaCl solution (30 mL), then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. . The residue was purified by vacuum distillation to give N-hydroxyethyl-N-cyclohex-1-enylmethylamine (1.78 g, 62%) as a colorless oil: bp 92-94 ° C. (6 mmHg).

B3a. General method for N-alkylation of ethanolamine via reductive alkylation. Synthesis of (R) -N-isobutylserine Methyl Ester HCl Salt

Isobutylaldehyde (1.5 mL, 16.4 mmol) and sodium triacetoxyborohydride (4.3 g, 20.5 mmol) in a suspension of (D) -serine methyl ester HCl salt (2.13 g, 13.7 mmol) in 1,2-dichloroethane. ) Was added. The reaction mixture was stirred at room temperature for 24 hours and then partitioned between Et ₂ O (100 mL) and saturated NaHCO ₃ solution (100 mL). The organic layer was washed with saturated NaHCO ₃ solution (3 × 100 mL), dried (MgSO ₄ ) and treated with 1M HCl solution in ether (25 mL). The resulting mixture was concentrated under reduced pressure to give (R) -N-isobutylserine methyl ester HCl salt (2.27 g, 79%): NMR (DMSO-d ₆ ) δ0.94 (dd, J = 6.7, 3.0 Hz , 6H); 1.97-2. 11 (m, 1 H); 2.76-2.91 (m, 1 H); 3.76 (s, 3 H); 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 for the N-alkylation of ethanolamine via reduction after 2-alkyl-1,3-oxazolidine formation. Synthesis of 1- (cyclohexylamino) -1- (hydroxymethyl) -cyclopentane

<Step 1>

To a solution of 1-amino-1- (hydroxymethyl) cyclopentane (method B1c; 1.44 g, 12.54 mmol) in CH ₂ Cl ₂ (10 mL) at 4 ° C., TFA (0.097 mL, 1.25 mmol), cyclohexanone ( 1.30 mL, 12.54 mmol) and sodium sulfate (2 g) were added and the reaction was warmed to 20 ° C. The reaction was stirred for 72 h, washed sequentially with water (10 mL) and saturated NaHCO ₃ solution (20 mL), then dried (MgSO ₄ ) and concentrated under reduced pressure to give 14-aza-7-oxadispiro [4.2.5.1] Tetradecane (2.38 g, 97%) was obtained: GC-MS m / z 195 (M ⁺ ).

<Step 2>

In a solution of LiAlH ₄ (0.93 g, 24.4 mmol) and AlCl ₃ (3.24 g, 24.4 mmol) in THF at 4 ° C., 14-aza-7-oxadispiro [4.2.5.1] tetradecane (2.38) in THF (15 mL). g, 12.2 mmol) was added dropwise. The resulting mixture was warmed to 20 ° C. and stirred for 45 minutes and then cooled to 4 ° C. Water (5 mL) was added slowly to stop the reaction, and 1N NaOH solution (85 mL) was added to dissolve the resulting solid. The resulting solution was extracted with Et ₂ O (200 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1- (cyclohexylamino) -1- (hydroxymethyl) cyclopentane (1.89 g, 79%): GC-MS m / z 197 (M ⁺ ).

B4b. General method for N-alkylation of ethanolamine via reduction after 2-alkyl-1,3-oxazolidine formation. Synthesis of N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine

<Step 1>

2-amino-2-methyl-1-propanol (15.0 g, 0.168 mol), cyclopentanone (14.9 mL, 0.168 mol, 1.0 equivalent) and p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol) in toluene (300 mL) , 0.05 equiv) was stirred at reflux overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc (500 mL), washed with saturated NaHCO ₃ (250 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to 4-a-3 as a pale yellow oil. , 3-dimethyl-1-oxaspiro [4.4] nonane (15.5 g, 60%) was obtained: ¹ H NMR (CDCl ₃ ) δ1.12 (s, 6H), 1.65 (m, 5H), 1.80 (m, 2H), 1.97 (m, 2H), 3.45 (s, 2H).

<Step 2>

Reaction of NaBH ₄ (5.47 g, 0.145 mol, 1.45 equiv) to a solution of 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane (15.5 g, 0.10 mol) in EtOH (85 mL) at 0 ° C The temperature was added at a rate (about 1 hour) not to exceed 10 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The resulting mixture was treated with water (100 mL) and concentrated to paste under reduced pressure. MeOH (100 mL) was added and the mixture was concentrated again under reduced pressure. The residue was treated with EtOAc (300 mL) and water (150 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine (13.0 g, 83%) as a pale yellow oil: ¹ H NMR (CDCl ₃ ) δ1.07 (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 mlz 158 ((M + H) ⁺ ).

B4c. General method for N-alkylation of ethanolamine via reduction after 2-alkyl-1,3-oxazolidine formation. Synthesis of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol

<Step 1>

A solution of (1S) -1- (hydroxymethyl) -3-methylbutylamine (method B1b; 152 g, 1.3 mol) and isobutylaldehyde (118 mL, 1.3 mol, 1.0 equiv) in toluene (1.5 L) was theoretically Heat at reflux temperature until phosphorus water was collected (23.4 mL) in Dean-Stark trap. The reaction mixture was concentrated to about 700 mL by distillation. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to a constant weight to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine (223 g, 100%) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 0.98-0.99 (m, 12H), 1.18-1.35 (m, 1H), 1.42-1.56 (m, 1H), 1.61-1.79 (m, 4H), 3.08 (t, J = 7.4 Hz 1H), 3.20-3.34 (m, 1H), 3.85 (t, J = 7.4 Hz, 1H), 4.18 (dd, J = 7.3, 3.4 Hz, 1H).

<Step 2>

NaBH in 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 / MeOH bath. ₄ (70.3 g, 1.82 mol) was added in portions at a rate (about 2 hours) at which the reaction temperature did not exceed 10 ° C. The reaction mixture was allowed to warm to room temperature and stirred overnight, then filtered through a coarse sintered glass funnel. The resulting solid was washed with EtOH. The combined filtrates were concentrated under reduced pressure and the residue was treated with EtOAc (2 L) and water (1 L). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford (2S) -4-methyl-2- (isobutylamino) pentan-1-ol (192 g, 85%) as a pale yellow viscous oil: 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).

B4d. General method for N-alkylation of ethanolamine via reduction after 2-alkyl-1,3-oxazolidine formation. Synthesis of 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane

<Step 1>

A theoretical amount of water was added while heating 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) at reflux. The water was azeotropically distilled until collected (41.4 mL). The reaction mixture was concentrated to 700 mL by simple distillation, then cooled to room temperature and concentrated to constant weight 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).

<Step 2>

In a solution of 6-aza-12-oxadispiro [4.1.4.2] tridecane (124 g, 0.69 mol) dissolved in EtOH (600 mL) maintained at -13 ° C using an ice / MeOH bath, NaBH ₄ (38 g, 1.0 mol, 1.45 equiv) was added in portions at a rate (about 30 minutes) at which the reaction temperature did not exceed 10 ° C. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (500 mL) and concentrated under reduced pressure. The remaining paste was partitioned between EtOAc (1 L) and water (600 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane (107 g, 85%) as a white powder: ¹ H 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 method for the synthesis of ethanolamine through the reaction of amines with epoxides. Synthesis of N- (hydroxyethyl) -N- (2-butyl) amine

Ethylene oxide (10 mL, 0.20 mmol) was added dropwise via cannula to a solution of sec-butylamine (60 mL, 0.60 mmol) in MeOH (40 mL) at room temperature. The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was purified by vacuum distillation to give N- (hydroxyethyl) -N- (2-butyl) amine (16.4 g, 70%) as a colorless oil: bp 109-112 ° C. (6 mmHg).

B5b. General method for the synthesis of ethanolamine through the reaction of amines with epoxides. Synthesis of N- (3-phenyl-2-hydroxypropyl) -N-isobutylamine

2,3-Epoxypropyl benzene (10 g, 74.5 mmol) and isobutylamine (5.4 g, 74.5 mmol) were mixed and then treated with water (2 mL). The mixture was stirred at 110 ° C. overnight and then distilled to give N- (3-phenyl-2-hydroxypropyl) -N-isobutylamine (6.5 g): bp 115-117 ° C. (1 mmHg).

B6a. General method for the synthesis of propanolamine via reduction after Arndt Eisert homogenization of amino acids. Synthesis of (R) -3- (tert-butylamino) -4-methylpentanol

<Step 1>

Isobutyl in a solution of N- (tert-butoxycarbonyl)-(L) -valine (4.32 g, 19.9 mmol) and N-methylmorpholine (2.3 mL, 20.9 mmol) in DME (30 mL) at −10 ° C. Chloroformate (2.27 mL, 21.0 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, then filtered and the solid washed with cold DME. After cooling the filtrate to −10 ° C., the solution was treated with a solution of CH ₂ N ₂ in Et ₂ O until yellow remained, the resulting mixture was warmed to 20 ° C. and stirred at that temperature for 45 minutes, then the mixture The residue was purified by chromatography (SiO ₂ , gradient from hexane to 30% EtOAc / hexanes) to give (S) -3- (tert-butoxycarbonylamino) -1-diazo-4 -Methylpentan-2-one (1.82 g, 38%) was obtained: TLC (10% EtOAc / hexanes) Rf 0.11.

<Step 2>

A solution of (S) -3- (tert-butoxycarbonylamino) -1-diazo-4-methylpentan-2-one (1.83 g, 7.6 mmol) in MeOH (100 mL) was heated to reflux temperature, A solution of silver benzoic acid (0.50 g silver benzoic acid in 5 mL Et ₃ N, 0.5 mL) in filtered Et ₃ N was added. After the initial gas evolution had stopped (about 0.5 minutes), additional silver solution (0.5 mL) was added. This process was repeated until no gas was released even with the addition of silver salt. The resulting mixture was cooled to 20 ° C., treated with Celite (R) and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in Et ₂ O (100 mL), washed sequentially with 1N HCl solution (100 mL), saturated NaHCO ₃ solution (100 mL) and saturated NaCl solution (50 mL), then dried (MgSO ₄ ) and concentrated under reduced pressure to methyl (R) -3- (tert-butoxycarbonylamino) -4-methylpentanoate (1.63 g, 87%) was obtained: TLC (10% EtOAc / hexanes) Rf 0.29.

<Step 3>

In a similar manner to step 2 of Method B8a, methyl (R) -3- (tert-butoxycarbonylamino) -4-methylpentanoate (1.62 g, 6.6 mmol) was treated with lithium borohydride (R) 3- (tert-butoxycarbonylamino) -4-methylpentanol (93%) was obtained.

B7a. General method for the synthesis of chloroethylamine. Synthesis of (1S) -1- (chloromethyl) -3-methylbutanammonium chloride

A solution of (1S) -1- (hydroxymethyl) -3-methylbutylamine (method B1b; 5.40 g, 46.1 mmol) in CH ₂ Cl ₂ (200 mL) was cooled in an ice bath and saturated HCl gas. SOCl ₂ (4.0 mL, 55.3 mmol) was added and the reaction was heated at reflux for 2.5 h, then cooled to room temperature and concentrated under reduced pressure. The residue was triturated with Et ₂ O to give (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride (5.67 g, 71%): EI-MS m / z 136 ((M + H) ⁺ ) .

B7b. General method for the synthesis of chloroethylamine. Synthesis of 1- (chloromethyl) -1- (cyclohexylamino) cyclopentane HCl Salt

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

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

To a solution of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol (method B4c; 256 g, 1.5 mol) and toluene (2.5 L) was added SOCl ₂ (167 mL) over 15 minutes. . After complete addition of SOCl ₂ , the reaction was heated at 90 ° C. overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The reddish brown residue was dissolved in Et ₂ O (1 L), and hexane (750 mL) was added dropwise over 8 hours. The resulting slurry was stirred overnight, filtered and washed with 40% EtOAc / hexane solution to give N- (1S)-(1- (chloromethyl) -3-methylbutyl) -N (isobutyl) amine as a dark brown solid. HCl salt (276 g) was obtained: 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 chloroethylamine. Synthesis of 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane HCl 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 15 minutes. . SOCl ₂ , previously heated to 40 ° C., was completely added and then heated at 60 ° C. overnight. The resulting solution was cooled to room temperature and treated with HCl (4N in p-dioxane, 100 mL), then the reaction was heated at 60 ° C. for 3 hours and stirred at room temperature overnight. The resulting mixture was concentrated to half of the original volume under reduced pressure, at which time a precipitate began to form. The resulting slurry was diluted with Et ₂ O and stirred for 4 hours. The resulting precipitate was filtered and washed with Et ₂ O (2 × 50 mL) to give 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane HCl salt (125 g, 70%) as off-white powder: ¹ H NMR (CDCl ₃ ) δ1.53-1.66 (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, 1 H).

B7e. General method for the synthesis of chloroethylamine. Synthesis of 1-chloromethylcyclopentanamine HCl Salt

To a solution of 1-hydroxymethylcyclopentanamine HCl salt (method B1c; 20 g, 0.17 mol) in p-dioxane anhydrous (65 mL) was added HCl (4M in p-dioxane; 65 mL, 0.26 mol). The resulting solution was stirred at room temperature for 20 minutes and 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 concentrated under reduced pressure to give 1-chloromethylcyclopentanamine HCl salt (29 g, 100%): CI-MS m / z 171 ((M + H) ⁺ ).

B8a. General method for the synthesis of 2-aminoethylsulfonate ester. Synthesis of (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride.

<Step 1>

A solution of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt (2.15 g, 4.4 mmol) in CH ₂ Cl ₂ (50 mL) was yellowish. Treated with a solution of CH ₂ N ₂ in Et ₂ O until maintained. The resulting solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed sequentially with 1N HCl solution (2 × 100 mL) and saturated NaCl solution (50 mL), then dried (MgSO ₄ ) and concentrated under reduced pressure (1S, 2R) -N- (Benzyloxycarbonyl) -O-tert-butylthreonine methyl ester (1.44 g, 100%) was obtained: TLC (25% EtOAc / hexanes) Rf 0.54.

<Step 2>

(1S, 2R) in Et ₂ O (20mL) -N- of (benzyloxycarbonyl) -O-tert- butyl-threonine methyl ester LiBH ₄ in Et ₂ O (9mL) To a solution of (1.4g, 4.4mmol) Saturated solution was added and the reaction mixture was heated at reflux for 2 h and then cooled to 20 ° C. Water (5 mL) was added to the resulting mixture, then 1N HCl solution was added until no gas was generated. The ether layer was washed with saturated NaCl solution (50 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to (1R, 2R) -N- (benzyloxycarbonyl) -1- (hydroxymethyl) -2- (tert-butoxy) propanamine (1.69 g, 99%) was obtained: TLC (25% EtOAc / hexanes) Rf 0.20.

<Step 3>

Of (1R, 2R) -N- (benzyloxycarbonyl) -1- (hydroxymethyl) -2- (tert-butoxy) propanamine (1.6 g, 5.4 mmol) in anhydrous pyridine (30 mL) at 4 ° C. Methanesulfonyl chloride (0.75 mL, 9.7 mmol) was added dropwise to the solution. The reaction was stirred for 5.5 h, then diluted with EtOAc (200 mL) and washed with 1N HCl solution (4 × 200 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to afford (1R, 2R) -N- (benzyloxycarbonyl) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propane as an oil. Amine (2.03 g, 100%) was obtained: TLC (25% EtOAc / hexanes) Rf 0.31.

<Step 4>

To a solution of (1R, 2R) -N- (benzyloxycarbonyl) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanamine (2.03 g, 5.5 mmol) in MeOH (50 mL) 4M HCl solution (dioxane; 1.5 mL, 6.0 mmol) and 10% Pd / C (0.20 g) were added. The resulting slurry was stirred for 2 h under H ₂ (1 atm), then treated with Celite (R) and concentrated under reduced pressure to give (1R, 2R) -1- (methanesulfonyloxymethyl) -2- ( tert-butoxy) propaneammonium chloride (1.6 g, 100%) was obtained.

B8b. General method for the synthesis of 2-aminoethylsulfonate ester. Synthesis of N- (2-tosyloxyethyl) -2-methylprop-2-ene-1-ammonium trifluoroacetate.

<Step 1>

To a solution of N- (tert-butoxycarbonyl) glycine tert-butyl ester (3.97 g, 17.2 mmol) in DMF (70 mL) at 0 ° C. was added sodium hexamethyldisilazide (3.78 g, 20.6 mmol) and the result The mixture was stirred for 25 minutes and then warmed 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 then diluted with EtOAc (300 mL). The EtOAc solution was washed sequentially with water (4 times 500 mL) and saturated NaCl solution (4 times 500 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to yield N- (tert-butoxycarbonyl) -N- (2-Methylprop-2-enyl) glycine tert-butyl ester (4.03 g, 82%) was obtained: TLC (10% EtOAc / hexanes) Rf 0.51.

<Step 2>

Lithium borohydride solution of N- (tert-butoxycarbonyl) -N- (2-methylprop-2-enyl) glycine tert-butyl ester (0.26 g, 0.93 mmol) in Et ₂ O (3 mL) After treatment with (0.011 g), the mixture was stirred overnight at room temperature. Water (2 mL) was added to the resulting mixture, followed by 1N HCl until gas evolution ceased. The organic phase was washed with saturated NaHCO ₃ solution (20 mL), dried (MgSO ₄ ) and then concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , gradient from 10% EtOAc / hexanes to 50% EtOAc / hexanes) to give N- (tert-butoxycarbonyl) -N- (2-hydroxyethyl) -1-amino- 2-Methylprop-2-ene (0.113 g, 57%) was obtained: TLC (10% EtOAc / hexanes) Rf 0.66.

<Step 3>

N- (tert-butoxycarbonyl) -N- (2-hydroxyethyl) -1-amino-2-methylprop-2-ene (21.1 g, 98 mmol in Et ₂ O (800 mL) at −78 ° C. Potassium tert-butoxide (1M in tert-butanol, 103 mL, 103 mmol) was slowly added to the solution. The reaction mixture was briefly warmed to −45 ° C., then cooled to −78 ° C. and treated with a solution of p-toluenesulfonyl chloride (18.7 g, 98.0 mmol) in Et ₂ O (100 mL). The resulting mixture was warmed to -45 ° C and treated with water (500 mL). The organic phase was washed with saturated NaCl solution (800 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to N- (tert-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2 -Methylprop-2-ene (36.4 g, 101%) was obtained: TLC (25% EtOAc / hexanes) Rf 0.56.

<Step 4>

Solid N- (tert-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2-methylprop-2-ene (15 g, 55.7 mmol) was cooled to 0 ° C. and TFA (200 mL )). The reaction mixture was allowed to warm to room temperature and then concentrated under reduced pressure. The residual oil was crystallized from Et ₂ O (500 mL) to give N- (2-tosyloxyethyl) -2-methylprop-2-ene-1-ammonium trifluoroacetate (16.7 g, 78%).

B9a. General method for the synthesis of 3-chloropropyl- and 4-chlorobutylamine. Synthesis of N-isobutyl-3-chloropropylamine HCl Salt.

<Step 1>

Isobutaldehyde (9.0 mL, 99.1 mmol, 1.5 equiv) and MgSO ₄ (7.5 g) were added to a solution of 3-aminopropanol (91 g, 65.4 mmol) in toluene (100 mL) to exothermic reaction. The slurry was stirred for 30 minutes and additional MgSO ₄ (7.5 g) was added followed by stirring overnight. The resulting mixture was filtered and concentrated under reduced pressure. The condensate was again concentrated under reduced pressure and the two residues were mixed to give 2-isopropyltetrahydro-1,3-oxazine (5.18 g, 61%) as a colorless oil: 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), 3.07-3.13 (m, 1H), 3.60-3.76 (m , 2H), 4.00-4.05 (m, 1H).

<Step 2>

A small amount of NaBH ₄ (2.17 g, 57.4 mmol, 1.5 equiv) over 15 minutes in a solution of 2-isopropyltetrahydro-1,3-oxazole (4.94 g, 38.2 mmol) in pure EtOH (100 mL) at 0 ° C. Each was added and the resulting mixture was stirred at room temperature overnight. The resulting solution was concentrated under reduced pressure, then treated with EtOAc (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 NaCl solution. The combined aqueous layers were back extracted with EtOAc (150 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give N-isobutyl-3-hydroxypropylamine (5.04 g, 100%) as a colorless oil: ¹ H NMR (CDCl ₃ ) δ0.84 (d, J = 6.6 Hz, 6H), 1.60-1.71 (m, 3H), 2.36 (d, J = 6.6 Hz, 2H), 2.80 (dd, J = 5.9, 5.9 Hz, 2H), 3.10-3.30 ( br s, 2H), 3.74 (dd, J = 5.5, 5.5 Hz, 2H); ¹³ C NMR (CDCl ₃ ) δ 20.5, 28.1, 30.6, 50.0, 57.8, 64.1.

<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 was stirred at room temperature for 4 hours. Stirred. The resulting slurry was concentrated under reduced pressure to give N-isobutyl-3-chloropropylamine HCl salt: ¹ H NMR (CDCl 3) δ1.12 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H), 4.24 (q, J = 7.0 Hz, 2H), 4.55 (s, 1H), 5.00 (s, 2H); ¹³ C NMR (CDCl ₃ ) δ 13.9, 27.8, 38.2, 61.5, 67.1, 67.3, 117.0, 167.1, 180.7; CI-LRMS m / z (relative bundle) 150 ((M + H) ⁺ , 100%).

B10a. General method for the synthesis of 2-chlorothiazolidinium salts. Synthesis of (4S) -2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride.

<Step 1>

(2S) -4-methyl-2- (isobutylamino) pentan-1-ol HCl salt in 2-butanone (20 mL) (Method B4c; 0.21 g, 1.0 mmol) and CS ₂ (0.30 mL, 5.0 mmol, 5.0 equivalents) was added Cs ₂ CO ₃ (0.72 g, 2.20 mmol, 2.2 equiv) and the resulting mixture was heated at reflux overnight. The resulting orange solution was concentrated under reduced pressure and the residue was triturated with EtOAc (25 mL). The residual solid was washed with EtOAc (25 mL) and the combined EtOAc phases were concentrated under reduced pressure. The residue was taken up on SiO ₂ and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc / hexanes) to (4S) -3,4-diisobutyl-1,3-thiazolidine-2 as a yellow oil. -Thione (0.11 g, 52%) was obtained.

<Step 2>

A solution of (4S) -3,4-diisobutyl-1,3-thiazolidine-2-thione (5.0 g, 21.6 mmol) in SOCl ₂ (31 mL, 0.43 mol) was heated at 70 ° C. for 2.5 h. Then cooled to room temperature and concentrated under reduced pressure to afford (4S) -2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride as semisolid: ¹ H NMR 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 (br m, 1H), 3.61-3.68 (m, 1H), 3.86-3.95 (br m, 2H), 4.50-4.57 (m, 1H), 4.97-5.06 (br m, 1H). This material was dissolved in dichloroethane (180 mL) to make a 0.12 M stock solution (assuming quantitative conversion to thiazolidinium chloride).

C. Methods for the Synthesis of Imino Heterocycles

C1a. General method for the synthesis of 2-imino-1,3-thiazolidine via the reaction of 2-chloroethylamine with isothiocyanate. Synthesis of (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine.

(1S) -1- (chloromethyl) -3-methylbutanammonium chloride (method B7a; 1.14g, 3.71mmol) suspended in CH ₂ Cl ₂ (15 mL) and 2-methyl-4-nitrophenyl isothiocyanate (0.72 g, 3.71 mmol) was added Et ₃ N (1.08 mL, 7.78 mmol) via syringe. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated NaHCO ₃ solution and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , gradient from 10% EtOAc / hexanes to 30% EtOAc / hexanes) to (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl- 1,3-thiazolidine (0.91 g, 47%) was obtained: TLC (25% EtOAc / hexanes) Rf 0.46.

C1b. General method for the synthesis of 2-imino-1,3-thiazolidine via the reaction of 2-chloroethylamine with isothiocyanate. Synthesis of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt.

N- (1-S)-(1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) amine HCl salt in CH ₂ Cl ₂ (1.1 L) at 15 ° C. (Method B7c; 95 g, 0.41 4-cyano-2-ethylphenyl isothiocyanate (method A2b; 72 g, 0.38 mol) was added to a solution of mol, 1.08 equiv), followed by diisopropylethylamine (200 mL, 1.15 mol, 3.0 equiv) The reaction was slightly exothermic. When the reaction was cooled to room temperature again, the ice bath was removed and the reaction stirred at room temperature for 4 hours. The reaction was then diluted with CH ₂ Cl ₂ (500 mL), washed with 1N NaOH solution (3 × 500 mL), then dried (MgSO ₄ ) and concentrated under reduced pressure. The remaining black oil (132 g) was dissolved in CH ₂ Cl ₂ (50 mL) and filtered through a plug of silica gel (5 g SiO ₂ / g crude product) with the aid of a 5% EtOAc / hexane solution to give an oil (120 g). (4S) -2- (4-cyano-2-ethylphenylimino) -3, as a white solid, which was dissolved in EtOAc (400 mL) and slowly treated with HCl solution (1M in Et ₂ O, 500 mL). 4-Diisobutyl-1,3-thiazolidine HCl salt (95 g, 66%) was obtained: 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 = 7.7 Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J = 7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J = 11.4,7.7 Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J = 14.3, 8.1 Hz, 1H ), 7.32 (d, J = 8.1 Hz 1H), 7.51 (dd, 1H, J = 8.1, 1.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H).

C1c. General method for the synthesis of 2-imino-1,3-thiazolidine via the reaction of 2-chloroethylamine with isothiocyanate. (4S) Synthesis of 2- (2-chloro-4-cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine.

To a slurry of 2-chloro-4-cyano-6-methylphenyl isothiocyanate (0.10 g, 0.50 mmol) and poly (4-vinylpyridine) (0.030 g) in CH ₂ Cl ₂ (1S) in DMF (2 mL) ) -1- (chloromethyl) -3-methylbutanammonium chloride (method B7a; 0.086 g, 0.50 mol, 1.0 equiv) was added and the resulting mixture was stirred at 55 ° C. for 16 h, then concentrated under reduced pressure I was. The residue was purified by column chromatography (30 g, gradient from 10% EtOAc / hexanes to 20% EtOAc / hexanes) to (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -4 -Isobutyl-1,3-thiazolidine (0.052 g, 34%) was obtained.

C1d. General method for the synthesis of 2-imino-1,3-thiazolidine via the reaction of 2-chloroethylamine with isothiocyanate. Synthesis of (4S) -2- (4-chloro-2- (trifluoromethyl) phenylimino) -3-isobutyl-1,3-thiazolidine.

N- (hydroxyethyl) -N-isobutylamine was converted to N- (chloroethyl) -N-isobutylammonium chloride in a similar manner to Method B7c. 4-chloro-2- (trifluoro) in a slurry of N- (chloroethyl) -N-isobutylammonium chloride (0.10 mmol, 0.10 M) and poly (4-vinylpyridine) (0.030 g) in DMF (1.0 mL). Rhomethyl) phenyl isothiocyanate solution (0.25M in THF, 0.40 mL, 0.10 mmol) was added and the resulting mixture was heated at 55 ° C. in a sand bath for 16 h. The resulting slurry was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C-18 column, gradient from 0.1% TFA / 20% CH ₃ CN / 79.9% water to 0.1% TFA / 99.9% CH ₃ CN) (4S) -2- (4- Chloro-2- (trifluoromethyl) phenylimino) -3-isobutyl-1,3-thiazolidine (0.020 g, 59%) was obtained.

C1e. General method for the synthesis of 2-imino-1,3-thiazolidine via the reaction of 2-chloroethylamine with isothiocyanate. Synthesis of 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane.

1-chloromethylcyclopentanamine HCl salt in anhydrous 1,2-dichloroethane (10 mL) (Method B7e; 0.25 g, 1.32 mmol) and 2,4-dimethyl-3-cyano-5-pyridyl isothiocyanate (Method A2c; 0.23 g, 1.32 mmol) was added dropwise Et ₃ N (1 mL) via syringe. The resulting mixture was stirred at 50 ° C. overnight and then treated with saturated NaHCO ₃ solution. The resulting mixture was extracted with CH ₂ Cl ₂ (3 × 25 mL). The combined organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , 40% EtOAc / hexane) to give 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4]. Nonane (0.192 g, 51%) was obtained: CI-MS m / z 287 ((M + H) ⁺ ).

C1f. General method for the synthesis of 2-imino-1,3-thiazolidine via the reaction of 2-chloroethylamine with isothiocyanate. Synthesis of 2- (3-quinolimino) -3,5-diisobutyl-1,3-thiazolidine.

3-Quinoline isothiocyanate was prepared in a similar manner to Method A2c. 3-quinoline isothiocyanate (0.1 g, 0.54 mmol) and N- (1-S)-(1- (chloromethyl) -3-methylbutyl) -N- (iso in anhydrous CH ₂ Cl ₂ (2 mL) To a solution of butyl) amine HCl salt (method B7c; 0.113 g, 0.54 mmol) was added dropwise diisopropylethylamine (0.208 g, 1.61 mmol). The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , 30% EtOAc / hexanes) to give 2- (3-quinolimino) -3,5-diisobutyl-1,3-thiazolidine (0.02 g, 0.9%) Obtained: ES-MS m / z 342 ((M + H) ⁺ ).

C2a. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isothiocyanate after conversion of ethanolamine to 2-chloroethylamine. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

SOCl ₂ (15.7 mL, 216 mmol) was added to a solution of 1-amino-1- (hydroxymethyl) cyclopentane (method B1c; 20.7 g, 180 mmol) and HCl (4M in p-dioxane, 400 mL) and the resulting The solution was heated at 100 ° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, then treated with 2-methyl-4-nitrophenyl isothiocyanate (31.4 g, 162 mmol) and 1,2-dichloroethane (400 mL) and N-methylmorpholine (49 mL, 449 mmol ). The resulting mixture was heated at 70 ° C. for 18 hours, cooled to room temperature and then concentrated under reduced pressure. The residue was treated with heated EtOAc, filtered and concentrated under reduced pressure. The residue was recrystallized (MeOH) to give 2- (2-methyl-4nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (38.3 g, 81%): TLC (25% EtOAc / Hexane) Rf 0.27.

C2b. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isothiocyanate after conversion of ethanolamine to 2-chloroethylamine. Synthesis of 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.5] decane.

Dissolve 1-amino-1- (hydroxymethyl) cyclohexane (method B1a) in p-dioxane (80 mL), then treat with SOCl ₂ in a similar manner to method C2a and then 2-methyl-4-nitrophenyl Treatment with isothiocyanate gave 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.5] decane (20%), which wasobutyl in a similar manner to Method D2a. Reaction with bromide gave 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.5] decane (0.026 g, 2%): TLC (20% EtOAc / hexanes) Rf 0.69.

C2c. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isothiocyanate after conversion of ethanolamine to 2-chloroethylamine. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutylspiro [1,3-thiazolidine-4,2'-bicyclo [2.2.1] heptane].

2- (isobutylamino) -2- (hydroxymethyl) norbornane (method B2a; 0.24 g, 1.2 mmol) was treated with SOCl ₂ in a similar manner to method C2a, followed by 2-methyl-4-nitrophenyl iso Treatment with thiocyanate gave 2- (2-methyl-4-nitrophenylimino) -3- (2-isobutylspiro [1,3-thiazolidine-4,2'-bicyclo [2.2. 1] heptane] (0.022 g, 5%) was obtained: TLC (25% EtOAc / hexanes) Rf 0.72.

C2d. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isothiocyanate after conversion of ethanolamine to 2-chloroethylamine. 3-isobutyl-4-methylene-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidin-5-one and (4S) -3-isobutyl-4-carbomethoxy Synthesis of 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine HCl salt.

Treatment of (R) -N-isobutylserine methyl ester HCl salt (Method B3a; 2.28 g, 10.8 mmol) with SOCl ₂ in a similar manner to Method C2a followed by 2-methyl-4-nitrophenyl isothiocyanate It was. The resulting material was purified by column chromatography (SiO ₂ , gradient from hexane to 10% EtOAc / hexanes) to 3-isobutyl-4-methylene-2- (2-methyl-4-nitrophenylimino) -1 , 3-thiazolidin-5-one (0.028 g, 10%) was obtained, followed by (S) -3-isobutyl-4-carbonylethoxy-2- (2-methyl-4-nitrophenyl Mino) -1,3-thiazolidine HCl salt (0.192 g, 56%) was obtained. 3-isobutyl-4-methylene-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidin-5-one: TLC (25% EtOAc / hexane) Rf 0.40. (S) -3-isobutyl-4-carbomethoxy-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine HCl salt: TLC (free base, 25% EtOAc / hexane ) Rf 0.50.

C2e. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isothiocyanate after conversion of ethanolamine to 2-chloroethylamine. 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) is reacted with SOCl _{2 in a} similar manner to method C2a, followed by 2-methyl-4-nitrophenyl isothio Reaction with cyanate gave 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (0.44 g, 17%): CI-MS m / z 374 ((M + H) ⁺ ).

C2f. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isothiocyanate after conversion of ethanolamine to 2-chloroethylamine. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4,4-dimethyl-1,3-thiazolidine.

N-isobutyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a similar manner to Method B4a. Until saturated, HCl was bubbled into a solution of N-isobutyl-1,1dimethyl-2-hydroxyethanamine (1.45 g, 10 mmol) in toluene (20 mL). SOCl ₂ (10 mmol) was added dropwise at room temperature, stirred at room temperature for 1 hour, and then stirred at 50 ° C. for 1 hour. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in CHCl ₃ (20 mL). 2-methyl-4-nitro-phenyl isothiocyanate (1.94 g, 10 mmol) was added to the resulting solution, followed by dropwise addition of a solution of Et ₃ N (10 mmol) in CHCl ₃ (10 mL) at room temperature. The resulting mixture was heated at reflux for 3 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and the resulting solution was washed sequentially with 10% aqueous NaOH solution (50 mL) and saturated NaCl solution (50 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography (9% EtOAc / petroleum ether) and the resulting solid was recrystallized (petroleum ether) to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4 , 4-dimethyl-1,3-thiazolidine (0.6 g, 63%) was obtained: mp 97 ° C. If necessary, the product was converted to HCl salt by dissolving free base (5 mmol) in Et ₂ O (50 mL) and treating this solution with 2N etheric HCl solution until no solid precipitate formed. The resulting slurry was filtered and the resulting solid was washed with Et ₂ O (25 mL) followed by EtOAc (25 mL).

C3a. General method for the synthesis of 2-imino-1,3-thiazolidine homologue via reaction with isothiocyanate after conversion of hydroxyalkylamine to chloroalkylamine. 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 reacted with SOCl _{2 in a} similar manner to Method C2a and then 2-methyl-4-nitrophenyl isothiocyanate Was reacted with (R) -4-isopropyl-2- (2-methyl-4-nitrophenylimino) -2,3,4,5-tetrahydro-1,3-thiazine (100%). .

C4a. General method for the synthesis of 2-imino-1,3-oxazolidine through the reaction of 2-chloroethylamine and isocyanate. Synthesis of 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane.

1- (chloromethyl) -1- (cyclohexylamino) cyclopentane HCl salt in 1,2-dichloroethane (10 mL) (Method B7b; 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenyl isocyanate (0.75 g, 4.2 mmol) was added N-methylmorpholine (0.92 mL, 8.4 mmol). The resulting solution was heated at 50 ° C. for 18 hours and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , gradient from hexane to 10% EtOAc / hexanes) 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) ⁺ ).

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

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) To 2-methyl-4-nitrophenyl isocyanate (0.0955 g, 0.536 mmol) was added, followed by Et ₃ N (0.080 mL, 1.15 mmol). The resulting solution was stirred overnight at 37 ° C., cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (50 mL) and washed with water (50 mL). The organic layer was extracted with 2N HCl solution. The aqueous layer was made basic with 1N NaOH solution and extracted with CH ₂ Cl ₂ (50 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -1,3- as a yellow oil. Oxazolidine (0.020 g, 14%) was obtained: CI-MS m / z 276 ((M + H) ⁺ ).

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

(1R, 2R) -1- (methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride (method B8a; 1.5 g, 5.5 mmol) was prepared in a similar manner as Method C1a 2-methyl-4- Reacted with nitrophenyl isothiocyanate to give 4 (S)-(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) -tert-butoxyethyl) -1,3-thiazolidine in isobutyl in a similar manner to method D2a Reacted with bromide to give (4S) -4- (1 (R) -tert-butoxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine (0. 26 g, 56%) was obtained: TLC (25% EtOAc / hexanes) Rf 0.67.

C6a. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isocyanide dichloride after conversion of chloroethylamine to 2-thioethylamine. Synthesis of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt.

N- (1-S)-(1- (chloromethyl) -3-methylbutyl) -N (isobutyl) amine HCl salt in a solution of sodium hydrogen sulfide (69 g, 1.2 mol, 2.2 equiv) in water (500 mL) Method B7c: 126 g, 0.55 mol, 1.0 equiv) was added. The resulting mixture was stirred at room temperature for 8 hours, after which 4-cyano-2-ethylphenyl isocyanide dichloride (method A3a; 125 g, 0.5 mol, 1.0 equiv) was added followed by addition of isopropyl alcohol (500 mL). It was. The resulting mixture was stirred at room temperature for 1 hour, then 3.6MK ₂ CO ₃ 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 concentrated under reduced pressure and the residue was treated with EtOAc (2 L). The organic layer was washed with water (2 × 500 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to give a black oil (160 g). Dissolving the oil in CH ₂ Cl ₂ (150mL) and, by passing a 5% EtOAc / hexanes on silica gel plug with the help of a solution (3g SiO ₂ / 1g crude product) containing the desired product and some residual isocyanic cyanide dichloride An oil (134 g) was obtained. This oil was dissolved in EtOAc (500 mL) and treated with HCl (IN in Et ₂ O, 500 mL). The resulting (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt was isolated 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 = 7.7 Hz , 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1H), 2.82 (q, J = 7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J = 11.4 , 7.7 Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J = 14.3, 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.51 (dd, J = 8.1, 1.8 Hz, 1 H), 7.58 (d, J = 1.8 Hz, 1 H).

C6b. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isocyanide dichloride after conversion of chloroethylamine to 2-thioethylamine. Synthesis of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt.

To a solution of sodium hydrogen sulfide (31 g, 0.55 mol, 2.2 equiv) in water (250 mL) was added 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane HCl salt (method B7d; 60 g, 0.25 mol, 1.0 equiv) Was added. The resulting mixture was stirred at room temperature for 8 hours, after which 2-methyl-4-nitrophenyl isocyanide dichloride (method A3b; 125 g, 0.25 mol, 1.0 equiv) was added followed by addition of isopropyl alcohol (300 mL). . The resulting mixture was stirred at room temperature for 1 hour, then 3.6MK ₂ CO ₃ solution (305 mL, 2.0 equiv, 0.5 mol) was added. The mixture was stirred at room temperature overnight. The upper aqueous organic layer of the result was separated and concentrated under reduced pressure, then the residue was treated with EtOAc (1 L). The resulting organic layer was washed with water (2 × 200 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The residual oil (86g), the CH ₂ Cl ₂ was dissolved in (50mL) and, 5% EtOAc / hexanes on silica gel plug with the help of a solution (3g SiO ₂ / 1g crude product) and filtration the desired product and some residual isocyanic cyanide with An oil (34 g) containing dichloride was obtained. This oil was dissolved in EtOAc (300 mL) and treated with HCl (IN in Et ₂ O, 1.5 L). The resulting solid was isolated by filtration to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane HCl salt (36.8 g) as a white powder. : 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 (br s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 7.96-8.04 (m, 1H), 8.03 (d, J = 3 Hz, 1H).

C6c. General method for the synthesis of 2-imino-1,3-thiazolidine via reaction with isocyanide dichloride after conversion of chloroethylamine to 2-thioethylamine. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

<Step 1>

Diisopropyl azodicarboxylate (21.5 g, 0.107 mol, 1.3 equivalents) and 1-cyclopentylamino-1 in a 0 ° C. solution of Ph ₃ P (27.9 g, 0.107 mol, 1.3 equivalents) in anhydrous THF (400 mL) -(Hydroxymethyl) cyclopentane (method B4d; 15.0 g, 0.082 mol) was added successively. The resulting slurry 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 concentrated to about 100 mL under reduced pressure. The residue was dissolved in EtOAc (200 mL) and the resulting solution was extracted (5 × 125 mL) with 1N HCl solution. The combined aqueous layers were washed with EtOAc (2 × 200 mL), neutralized to pH 7.0-7.5 with K ₂ CO ₃ and then extracted with EtOAc (5 × 200 mL). The organic layers were mixed, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was dried in vacuo to give 1-cyclopentylamino-1- (thioacetylmethyl) cyclopentane (19.1 g) as a yellow oil: TLC (10% EtOAc / hexane) Rf 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 content) 242 ((M + H) ⁺ , 100%).

<Step 2>

A solution of 1-cyclopentylamino-1- (thioacetylmethyl) cyclopentane (19.1 g) in 0.33M KOH solution (273 mL, 0.090 mol, 1.1 equiv) dissolved in MeOH: H ₂ O 9: 1 was added for 30 minutes. Stirred. The reaction mixture was concentrated under reduced pressure and the residue was dried in vacuo to afford crude 1-cyclopentylamino-1 (thiomethyl) cyclopentane as a yellow oil: TLC (10% EtOAc / hexane) Rf 0.18 (stripes); ¹ H NMR (CD ₃ OD) δ1.32-1.71 (m, 14H), 1.87-1.94 (m, 2H), 2.67 (s, 2H), 3.07-3.14 (m, 1H); FAB-LRMS m / z (relative content) 200 ((M + H) ⁺ , 19%). This material was used immediately in the next step without further purification.

<Step 3>

A solution of crude 1-cyclopentylamino-1- (thiomethyl) cyclopentane in anhydrous CH ₂ Cl ₂ (100 mL) at 0 ° C. was added crude 2-methyl-4-nitrophenyl isocyanide dichloride (method A3b; 19.1 g Treated with a slurry of 1-cyclopentylamino-l- (thioacetylmethyl) cyclopentane in 0.082 mol, CH ₂ Cl ₂ (200 mL), followed by Et ₃ N (30 mL, 0.215 mol, 2.6 Equivalent weight), and the reaction mixture was allowed to warm to room temperature and stirred for 2 days. N, N-dimethylethylenediamine (92 g, 0.023 mol, 0.3 equiv) was added and the reaction mixture was stirred for 1 h. Silica gel (50 g) was added and the resulting mixture was concentrated under reduced pressure. The residue was dried in vacuo and purified by flash chromatography (11 × 10 cm SiO ₂ , 5% EtOAc / hexanes) to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3- as a yellow granular solid. Thia-1-azaspiro [4.4] nonane (17.8 g, 60% total) was obtained: mp 120-121 ° C .; TLC (10% EtOAc / hexane) Rf 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 content) 360 ((M + H) ⁺ , 100%). Anal for C ₁₉ H ₂₅ N ₃ 0 ₂ S: calc.- C, 63.48; H, 7.01; N, 11.69. Found- C, 63.48; H, 6.89; N, 11.76.

C7a. General method for the synthesis of 2-imino-1,3-oxazolidine via the reaction of hydroxyethylamine with isocyanate dichloride. Synthesis of 2- (4-cyano-2-ethylphenylimino) -3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine.

A solution of N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine (method B4b; 0.12 g, 0.69 mmol) in THF (2.5 mL) was dissolved in NaH in THF (5 mL) via syringe at room temperature. (95%, 0.05 g, 1.2 mmol) was added dropwise. After the reaction mixture was stirred for 15 minutes, a solution of 4-cyano-2-ethylphenyl isocyanate dichloride (method A3a; 0.15 g, 0.63 mmol) in THF (2.5 mL) was added dropwise via syringe. The resulting mixture was stirred overnight, then treated with 5% citric acid solution (10 mL) and with EtOAc (25 mL). The organic phase was washed sequentially with 5% citric acid solution (20 mL), H ₂ O (20 mL) and saturated NaCl solution (20 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , 5% EtOAc / hexanes) to give 2- (4-cyano-2-ethylphenylimino) -3-cyclopentyl-4,4-dimethyl-1,3 as a yellow solid. Oxazolidine (0.09 g, 43%) was obtained: mp 112-114 ° C .; TLC (15% EtOAc / hexanes) Rf 0.60; ¹ H 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 = 8.1, 1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H); CI-MS m / z (relative content) 312 ((M + H) ⁺ , 100%). HRMS for C ₁₇ H ₂₃ N ₃ O ₃ : calcd. 311.1998. Found- 311.1991.

C7b. General method for the synthesis of 2-imino-1,3-oxazolidine via the reaction of hydroxyethylamine with isocyanate dichloride. Synthesis of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-oxazolidine.

4-cyano-2-ethylphenyl isocyanide dichloride (THE A3a; 0.42 g, 1.83 mmol, 1.2 equiv) and (2S) -4-methyl-2- (isobutylamino) pentane- in THF (5 mL) Et ₃ N (0.5 mL) was added to a solution of 1-ol (method B4c; 0.26 g, 1.52 mmol). 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 concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 5% EtOAc / hexanes to 10% EtOAc / hexanes) to (4S) -2- (4-cyano-2-ethylphenylimino) -3,4 as a yellow oil. -Diisobutyl-1,3-oxazolidine (0.15 g) was obtained: TLC (10% EtOAc / hexanes) Rf 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 = 7.5 Hz, 1H), 2.58 (q, J = 7.5 Hz, 2H), 3.01 (dd, J = 14.0, 6.3 Hz, 1H), 3.33 (dd, J = 13.6, 8.8 Hz, 1H), 3.73-3.83 (m, 1H), 3.94 (app t, J = 7.5 Hz, 1H), 4.37 (app t, J = 7.9 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 7.33 (dd , J = 8.1, 1.8 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H); 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%).

C8a. General method for the synthesis of 2-imino-4-oxoheterocycles via reaction of isothiocyanates with amines followed by reaction with haloic acid halides. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-4-one.

To a solution of 2-methyl-4-nitrophenyl isothiocyanate (0.190 g, 1.0 mmol) in DMF (5.3 mL) was added isobutylamine (0.4 M solution in DMF, 5.3 mL) and the reaction mixture was analyzed by TLC ( Hexane: EtOAc = 3: 1) was stirred for 4 hours, a time when the isothiocyanate was consumed. Chloroacetic acid (0.8 M solution in DMF, 4.0 mL) was added to the resulting mixture, followed by N-methylmorpholine (0.7 mL, 6.4 mmol). The reaction mixture was stirred at 80 ° C. for 18 h and then partitioned between water (10 mL) and EtOAc (25 mL). The aqueous phase was back extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with saturated NaCl solution (25 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was purified by MPLC (Biotage 40 S silica gel column, gradient from 5% EtOAc / hexanes to 33% EtOAc / hexanes) to give 2- (2-methyl-4-nitrophenylimino) -3 as a pale yellow oil. -Isobutyl-1,3-thiazolidin-4-one (0.52 g, 85%) was obtained.

C9a. General method for the synthesis of 2-imino-1,3-thiazolidine via acid catalyzed ring closure after the reaction of hydroxyethylamine with isothiocyanate. Synthesis of 2- (2,6-dichlorophenylimino) -3-cyclohexyl-4,4-dimethyl-1,3-thiazolidine.

N-cyclohexyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a similar manner to Method B4a. 2,6-dichlorophenyl isothiocyanate (1.2 g, 6.0 mmol) and N-cyclohexyl-1,1-dimethyl-2-hydroxyethanamine (1.0 g, 6.0 mmol) in CH ₂ Cl ₂ (10 mL) The solution of was stirred at room temperature for 20 hours. The resulting mixture was concentrated under reduced pressure and then treated with 33% HCl solution (15 mL). The resulting mixture was heated at reflux for 1 h, cooled to room temperature and neutralized with 45% NaOH solution. The resulting slurry was filtered and the resulting solid was washed with water (20 mL) and then recrystallized (EtOH) to give 2- (2,6-dichlorophenylimino) -3-cyclohexyl-4,4-dimethyl- 1,3-thiazolidine (0.70 g, 33%) was obtained: mp 134 ° C. If necessary, the product was converted to HCl salt by dissolving in free base (5 mmol) in Et ₂ O (50 mL) and treating this solution with 2N etheric HCl solution until no solid precipitate formed. The resulting slurry was filtered and the resulting solid was washed with Et ₂ O (25 mL) followed by EtOAc (25 mL).

C10a. General method for the reaction of 2-chlorothiazolinium salts with aniline. 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 Et ₃ N (0.5 mL, 3.6 mmol, 10 equiv) in p-dioxane (5 mL) was diluted with dichloroethane (method) B10a; 0.12 M, 0.5 mL, 0.36 mmol) was added to a solution of (4S) -2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride. The resulting mixture was stirred at 70 ° C. overnight, then cooled to room temperature and diluted with EtOAc (25 mL). The EtOAc mixture was washed sequentially with water (2 × 25 mL) and saturated NaCl solution (25 mL), dried (Na ₂ SO ₄ ) and then concentrated under reduced pressure. The residue was taken up on SiO ₂ and purified by MPLC (Biotage 40 S silica gel column; 5% EtOAc / hexanes) to 2- (2- (N-phenylcarbamoyl) phenylimino) -3,4-diiso Butyl-1,3-thiazolidine (0.090 g, 61%) was obtained.

C11a. General method for the synthesis of 2-imino-1,3-thiazolidin-5-one via the reaction of an amino acid ester with isothiocyanate. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-5-one.

A solution of N-isobutylglycine ethyl ester (0.41 g, 2.57 mmol) in water (5 mL) was treated with Et ₃ N (0.71 mL, 5.15 mmol) and then 2-methyl-4-nitrophenyl in acetone (5 mL) Treated with a solution of isothiocyanate (0.50 g, 2.57 mmol). The resulting mixture was heated at 40 ° C. for 2 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was separated between water (25 mL) and ethyl acetate (25 mL). The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to afford 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-5-one (0.16 g, 88%) Obtained: mp 152 C.

D. General method for interconversion of iminoheterocycles

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

(4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt (method C6a; 304 g, 0.8 mol), water (1 L ) And EtOAc (1.4 L) were added NaHCO ₃ (150 g, 1.78 mol, 2.2 equiv). The resulting mixture was stirred for 1 hour. The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting viscous oil was treated with EtOH and concentrated twice under reduced pressure to afford (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1, as a low temperature molten solid. 3-thiazolidine (264 g, 96%) was obtained: mp 50 ° C; [a] _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 mlz 344 ((M + H) ⁺ ).

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

1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane HCl salt dissolved in a mixture of water (300 mL) and EtOAc (500 mL) (method) NaHCO ₃ (15 g, 0.178 mol, 1.3 equiv) was added to C6b; 52.4 g, 0.132 mol). The mixture was stirred for 1 hour, and the resulting organic layer was dried (MgSO ₄ ) and then concentrated under reduced pressure. The resulting pale yellow solid was treated with EtOH (100 mL) and concentrated twice under reduced pressure to yield 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4]. Nonnan (46 g, 97%) was obtained: 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, 1 H), 6.87 (d, J = 8.5 Hz, 1 H), 8.02 (m, 2H); CI-MS m / z 360 ((M + H) ⁺ ).

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

(4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine (method C1a; 0.10 g, 0.34 mmol) in isobutyl bromide in DMF (2 mL) (0.11 mL, 1.03 mmol) and a slurry of Cs ₂ CO ₃ (0.12 g, 0.38 mmol) were heated at 90 ° C. for 18 hours, then cooled to 20 ° C., diluted with EtOAc (50 mL) and washed with water ( 200 mL twice). The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure, then the residue was purified by chromatography (SiO ₂ , gradient from 100% hexanes to 10% EtOAc / hexanes). The resulting material was dissolved in CH ₂ Cl ₂ (10 mL), treated with HCl solution (1M in Et ₂ O, 2 mL) and then concentrated under reduced pressure to give (4S) -2- (2-methyl-4-nitrophenyl Imino) -3,4-diisobutyl-1,3-thiazolidine HCl salt (0.088 g, 68%) was obtained: TLC (free base, 20% EtOAc / hexanes) Rf 0.74.

D2b. General method for ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

A solution of 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (method C2a; 33.2 g, 114 mmol) in DMF (1 L) was dissolved in NaOH (690 g, 17.3 mol). ) And cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was stirred at 20-40 ° C. for 18 h and then with water (1.5 L). Concentrated HCl solution was added to adjust the pH to 0 and the mixture was extracted with EtOAc (80 mL). The organic phase was washed with 1N HCl solution (1 L), dried (MgSO ₄ ) and then concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (500 mL) and filtered through a pad of silica gel (9 × 4 cm). Hexane was added to the resulting solution and the volatiles were slowly removed by partial vacuum until crystals formed. The solid was collected to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (10.9 g, 26%) as yellow crystals: mp 118-9 ° C .; TLC (5% EtOAc / hexanes) Rf 0.34.

D2c. General method for ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of (4R) -3-isobutyl-4-isopropyl-2- (2-methyl-4-nitrophenylimino) tetrahydro-2H-1,3-thiazine.

(R) -4-isopropyl-2- (2-methyl-4-nitrophenylimino) -2,3,4,5-tetrahydro-1,3-thiazine (method C3a) similar to method D2a Reaction with isobutyl bromide in a (4R) -3-isobutyl-4-isopropyl-2- (2-methyl-4-nitrophenylimino) tetrahydro-2H-1,3-thiazine (0.081 g , 32%). TLC (33% EtOAc / hexanes) Rf 0.76.

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

A solution of 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine (prepared in a similar manner as described in Method C1a; 0.084 g, 0.35 mmol) in CH ₂ Cl ₂ (5 mL) To propionyl chloride (0.033 g, 0.35 mmol) and Et ₃ N (0.049 mL, 0.35 mmol) were added. The mixture was stirred at room temperature for 1 hour and then diluted with CH ₂ Cl ₂ (40 mL). The resulting solution was washed sequentially with H ₂ O (10 mL) and saturated NaCl solution (10 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc / hexanes) to afford 2- (2-methyl-4-nitrophenylimino) -3-propanoyl-1,3-thiazolidine (0.036 g, 35%). Obtained: FAB-MS m / z 294 ((M + H) ⁺ ).

D2e. General method for ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of 1- (cyclohexylmethyl) -2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane in DMF (1.00 mL) (Method C2a; 0.10 g, 0.3432 mmol) and bromomethylcyclohexane ( 1.00 mL) was added NaOH (ca. 0.13 g). The resulting mixture was stirred at 45 ° C. for 2 days, at which time the mixture turned from dark red to bright orange. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residual oil was purified by chromatography (SiO ₂ ; 5% EtOAc / hexanes) to give 1- (cyclohexylmethyl) -2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [ 4.4] nonane (0.042 g, 32%) was obtained: mp 85-7 ° C.

D2f. General method for ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.

(4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine (method C1c; 0.050 g, 0.16 mmol in DMF (1.0 mL) NaH (0.0045 g, 1.1 equiv) was added to the solution, 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 concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C-18 column, gradient from 0.1% TFA / 20% CH ₃ CN / 79.9% water to 0.1% TFA / 99.9% CH ₃ CN) (4S) -2- (2- Chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt (0.030 g, 52% yield) was obtained.

D2g. General method for ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-prop-2-enyl) -4,4-dimethyl-1,3-thiazolidine HBr salt.

2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-1,3-thiazolidine was prepared in a similar manner as described in Method Cla. 2-methylprop-2-ene- in a suspension of 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-1,3-thiazolidine (1.5 mmol) in toluene (10 mL). 1-day bromide (4.5 mmol) was added and the reaction mixture was heated at reflux for 3 hours (the time at which the reaction was judged to be complete by TLC). The resulting precipitate was filtered at 50 ° C. The collected solid was washed with toluene (20 mL) and CH ₂ Cl ₂ (20 mL) to give 2- (2-methyl-4nitrophenylimino) -3- (2-methyl-prop-2-enyl) -4, 4-Dimethyl-1,3-thiazolidine HBr salt (1.14 g, 77%) was obtained: mp 229 ° C.

D2h. General method for ring-nitrogen alkylation of 2-imino heterocycles. Synthesis of 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane (method C1e; 0.192 g, 0.669 mmol in anhydrous DMF (0.5 mL) NaH (95%; 0.62 g, 6.69 mmol) was added in portions to a solution of isobutyl bromide (0.5 mL). The resulting mixture was heated at 50 ° C. for 3 hours, then treated with MeOH (about 0.5 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , gradient from 20% EtOAc / hexanes to 100% CH ₂ Cl ₂ ) to 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -1- Isobutyl-3-thia-1-azaspiro [4.4] nonane (0.04 g, 17%) was obtained: CI-MS m / z 343 ((M + H) ⁺ ).

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

The TFA (8 mL) solution was cooled to 4 ° C. and solid (4S) -4- (1 (R) -tert-butoxyethyl) -3-isobutyl-2- (2-methyl-4- via cannula Nitrophenylimino) -1,3-thiazolidine (method C5b; 0.16 g, 0.42 mmol) was added. The resulting solution was warmed to 20 ° C. and stirred at this temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between Et ₂ O (100 mL) and saturated NaHCO ₃ solution (100 mL). The ether layer was dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ ; gradient from hexane to 10% EtOAc / hexanes) to (4S) -4- (1 (R) -hydroxyethyl) -3-isobutyl-2- (2-methyl 4-nitrophenylimino) -1,3-thiazolidine (0.13 g, 90%) was obtained: TLC (25% EtOAc / hexanes) Rf 0.13.

D4a. 2-imino-1,3-thiazolidine 3-oxide and 2-imino-1,3-thiazolidine 3,3-dio via oxidation of 2-imino-1,3-thiazolidine General method for the synthesis of seeds. 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane 3-oxide and 1-cyclopentyl-2- (2-methyl-4 -Synthesis of nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane 3,3-dioxide.

1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane in CH ₂ Cl ₂ (5 mL) (Method D2b; 0.041 g, 0.11 mmol) And a solution of m-chloroperbenzoic acid (about 80%, 0.040 g, 0.19 mmol) for 30 minutes, then washed with saturated NaHCO ₃ , dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , gradient from hexane to 30% EtOAc / hexanes) to 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] Nonane 3,3-dioxide (0.030 g, 67%) was obtained and then 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [ 4.4] nonane 3-oxide (0.011 g, 26%) was obtained. 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane 3,3-dioxide: TLC (25% EtOAc / hexane) Rf 0.27. 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane 3-oxide: TLC (25% EtOAc / hexane) Rf 0.10.

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

2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine is prepared in a similar manner to Method C2a, and 1-bromo-3,3-dimethyl-2 in a similar manner to Method D2a. Alkylation with butanone gave 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-oxobutyl) -1,3-thiazolidine. Of 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-oxobutyl) -1,3-thiazolidine (0.022 g, 0.065 mmol) in MeOH (2 mL) To the solution was added NaBH ₄ (0.0096 g, 0.26 mmol) in portions. The resulting mixture was stirred at room temperature for 4 hours, then separated between EtOAc (10 mL) and H ₂ O (5 mL), and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed sequentially with H ₂ O (15 mL) and saturated NaCl solution (15 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc / hexane) to give 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-hydroxybutyl) -1,3-thia Zolidine (0.024 g, 92%) was obtained: FAB-MS m / z 338 ((M + H) ⁺ ).

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

<Step 1>

(4S) -2- (4-methoxycarbonyl-2-methylphenylimino) -3,4-diisobutyl-1,3-thia in a mixture of MeOH (1.5 mL) and H ₂ O (1.5 mL) LiOH (0.016 g, 0.39 mmol) was added to a solution of zolidine (prepared in a similar manner as described in Method D2a; 0.035 g, 0.097 mmol). The resulting mixture was stirred at room temperature for 2 days and then concentrated under reduced pressure. The pH of the residue was adjusted to 1 with 1% HCl solution and then extracted with EtOAc (4 × 10 mL). The combined organic layers were washed sequentially with H ₂ O (15 mL) and saturated NaCl solution (15 mL) and dried (Na ₂ SO ₄ ). Concentration under reduced pressure gave (4S) -2- (4-carboxy-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine (0.034 g, 100%): TLC (40 % EtOAc / hexanes) Rf 0.08. This material was used in the next step without further purification.

<Step 2>

Solution of (4S) -2- (4-carboxy-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine (0.035 g, 0.10 mmol) in CH ₂ Cl ₂ (5 mL) To carbonyl diimidazole (0.047 g, 0.29 mmol) was added. The mixture was stirred at room temperature for 2 hours and then anhydrous NH ₃ (about 30 drops) was condensed at -78 ° C into the solution. The resulting mixture was allowed to warm to room temperature overnight and then treated with H ₂ O (20 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL), washed sequentially with H ₂ O (20 mL) and saturated NaCl solution (20 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc / hexanes) to give (4S) -2- (4-carbamoyl-2-methylphenylimino) -3,4-diisobutyl-1,3- as a white solid. Thiazolidine (0.027 g, 73%) was obtained: mp 130-131 ° C.

D6b. General method for interconversion of carboxylic acid derivatives. Synthesis of 2- (2-ethyl-4- (N-methylcarbamoyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Solution of 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (method D9a; 0.58 g, 0.167 mmol) in CHCl ₃ (5 mL) To SOCl ₂ (0.06 mL, 0.83 mmol) was added. The reaction mixture was heated at reflux for 3 h and then concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (3 mL) and treated with methylamine (2.0 M in THF, 4 mL). The reaction mixture was stirred at room temperature for 2 hours and then treated with 1N NaOH solution (10 mL). The resulting mixture was extracted with CH ₂ Cl ₂ (3 × 20 mL) and the combined organic layers washed with saturated NaCl solution (20 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc / hexane) to give 2- (2-ethyl-4- (N-methylcarbamoyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [ 4.4] nonane (36 g, 56%) was obtained: TLC (30% EtOAc / hexanes) Rf 0.44.

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

4-iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate in a similar manner to Method A2b. At the same time, 1-amino-1- (hydroxymethyl) cyclopentane was converted to a chloromethyl analog and then reacted with isothiocyanate in a manner similar to Method C2a to yield 2- (4-iodo-2-propylphenyl. Mino) -3-thia-1-azaspiro [4.4] nonane was obtained. 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 DMF (4 mL) The slurry was heated at 140 ° C. overnight. The resulting mixture was cooled to room temperature, concentrated under reduced pressure and then purified by flash chromatography (10% EtOAc / hexanes) to afford 2- (4-cyano-2-propylphenylimino) -3-thia as a white solid. -1-Azaspiro [4.4] nonane (0.26 g, 65%) was obtained: TLC (30% EtOAc / hexanes) Rf 0.37.

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

<Step 1>

4-iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenyl isothiocyanate in a similar manner to Method A2b. 2- (2,3-dimethyl-4-iodophenylimino) -3-thia-1-azaspiro [4.4] nonane was prepared in a manner similar to that described in Method C2a, and then similar to that described in Method D2a. Alkylated with isobutyl bromide. Iodophenyl Compound (0.009 g, 0.021 mmol), (trimethylsilyl) acetylene (30 mL, 0.21 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (0.005 g) and CuI (0.012 g, 0.063) in Et ₃ N (2 mL) mmol) was stirred at room temperature for 18 hours. The resulting slurry was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (2% EtOAc / hexane) 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%) was obtained.

<Step 2>

2- (2,3-dimethyl-4- (2-trimethylsilyl-1-ethynyl) phenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane in MeOH (2 mL) 0.005 g, 0.0125 mmol) and NaOH (0.006 g, 0.15 mmol) were stirred overnight at room temperature. The reaction mixture was diluted with CH ₂ Cl ₂ (20 mL), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (2% EtOAc / hexane) to give 2- (2,3-dimethyl-4-ethynylphenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane (4.4). 0.0032 g, 78%) was obtained: TLC (20% EtOAc / hexanes) Rf 0.70.

D9a. General method for the synthesis of benzoic acid via hydrolysis of benzonitrile. Synthesis of 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4] nonane was prepared in a similar manner to method C2a, and thiazolidine was alkylated in a similar manner to method D2b. 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. 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 HCl (15 mL) was prepared. After heating at 占 폚 overnight, cooling to room temperature gave a white precipitate. The resulting mixture was adjusted to pH 6.5 using 1N NaOH solution and then extracted with CH ₂ Cl ₂ (4 × 40 mL). The combined organic layers were washed sequentially with water (30 mL) and saturated NaCl solution (30 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to yield 2- (4-carboxy-2-ethylphenylimino as a white solid. ) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.34 g, 100%) was obtained: mp 208-209 ° C.

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

2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (THE D9a; 0.046 g, 0.128 mmol in THF (10 mL) at −78 ° C.) Methyllithium (1.4 M in EtOAc, 0.91 mL, 1.28 mmol) was added to the solution. The reaction mixture was gradually warmed 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 HCl solution (2 mL) was added. The mixture was stirred for 0.5 h and then treated with saturated NaHCO ₃ solution (10 mL). The resulting mixture was extracted with EtOAc (4 times 20 mL) and the combined organic layers were washed with saturated NaCl solution (30 mL), then dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by preparative TLC (10% EtOAc / hexane) to give 2- (4-acetyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (4.4) as a white solid. 0.032 g, 73%) was obtained: mp 114-115 ° C.

D11a. General method for the conversion of nitrile to aldehyde. 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 in a similar manner to method C2a, and thiazolidine was alkylated in a similar manner to method D2b. 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. 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 ° C. DIBAL (1.0 M in toluene, 1.20 mL, 1.20 mmol) was added to the solution. The reaction mixture was stirred at −78 ° C. for 3 h, then EtOAc (3 mL) was added at −78 ° C., stirring continued for 0.5 h, then wet silica gel (5% water, 2 g). The reaction mixture was allowed to warm to room temperature, stirred for 3 hours and then filtered through a Celite® pad. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (30% EtOAc / hexane) to give 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1 as a white solid. Azaspiro [4.4] nonane (0.16 g, 75%) was obtained: mp 104-105 ° C.

D12a. General method for 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 LiCl (0.0076 g, 0.182 mmol) was added followed by DBU (0.025 g, 0.167 mmol) and triethyl phosphonoacetate (0.041 g, 0.182 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by flash chromatography (3% EtOAc / hexane) to give 2- (2-ethyl-4-((1E) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl- as a colorless oil. 3-thia-1-azaspiro [4.4] nonane (0.029 g, 48%) was obtained: TLC (30% EtOAc / hexanes) Rf 0.68.

D12b. General method for 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.

2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane in CH ₂ Cl ₂ (10 mL) (Method D11a; 0.041 g, 0.115 mmol) ) Was added MeNO ₂ (2 drops) and piperidine (4 drops). The reaction mixture was stirred at reflux overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (3% EtOAc / hexanes) to give 2- (2-ethyl-4-((1E) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia as a red solid. -1-Azaspiro [4.4] nonane (0.022 g, 48%) was obtained: mp 141-142 ° C.

D12c. General method for 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.

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 EtOH (10 mL) To malononitrile (0.007 g, 0.104 mmol) and piperidine (4 drops) were added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc / hexane) to give 2- (2-ethyl-4- (2,2-dicyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1 as a yellow solid. Azaspiro [4.4] nonane (0.012 g, 28%) was obtained: mp 135-136 ° C.

D12d. General method for 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 KOH (0.024 g, 0.36 mmol) in CH ₃ CN (20 mL) at reflux temperature 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (method D11a; 0.127 g, 0.36 mmol) was added. The reaction mixture was heated at reflux for 4 hours, cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with water (15 mL) and extracted with CH ₂ Cl ₂ (3 × 15 mL). The combined organic layers were washed with saturated NaCl solution and dried (Na ₂ SO ₄ ). The resulting material was purified by preparative TLC (30% EtOAc / hexanes) to give 2- (2-ethyl-4- (2-cyanovinyl) phenylimino) -cyclo as a 1: 3 cis / trans isomer mixture. Pentyl-3-thia-1-azaspiro [4.4] nonane (0.050 g) was obtained: TLC (30% EtOAc / hexanes) Rf 0.56.

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

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

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

2-Chloroethylammonium chloride (Compound 1) was reacted with 4-nitrophenyl isothiocyanate 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-ene-1- Il) -1,3-thiazolidine was obtained. Of 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine (0.20 g) in poly (phosphate) (0.4 mL) The mixture was heated at 80 ° C. for 5 hours. The reaction mixture was then dissolved in 0 ° C. water (20 mL) with the aid of sonication. The pH of the aqueous mixture was adjusted to 12 with 1N NaOH solution and then extracted with EtOAc (3 × 25 mL). The combined organic phases were dried (K ₂ CO ₃ ) and concentrated 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.

<Production of Specific Compound>

A description of the detailed preparation steps used to prepare the specific compounds described in Tables 1-4 is provided below. Many of the compounds listed in the table can be synthesized by the following various methods. Accordingly, the following specific examples are merely illustrative of the invention and should not be construed as limiting the scope of the invention in any way.

<Compound 1>

Reaction of 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine by reacting 2-chloroethylamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a Got it.

<Compound 2>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 4-nitrophenylisothiocyanate according to Method C1a to give 2- (4-nitrophenylimino) -1,3-thiazolidine, followed by Method D2a Was reacted with isobutyl bromide to yield 2- (4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine.

<Compound 3>

After 2-chloroethylammonium chloride (Compound 1) is reacted with 2-methyl-4-nitrophenyl isothiocyanate, it is reacted with isobutyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenyl Mino) -3-isobutyl-1,3-thiazolidine was obtained.

<Compound 4>

2-chloroethylammonium chloride (Compound 1) was reacted with 2,3-dichlorophenyl isothiocyanate according to Method C1a to give 2- (2,3-dichlorophenylimino) -1,3-thiazolidine Thereafter, the mixture was reacted with isobutyl bromide according to Method D2a to give 2- (2,3-dichlorophenylimino) -3-isobutyl-1,3-thiazolidine.

<Compound 5>

According to Method C1d, N-chloroethyl-N'-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2- (2-methoxy 4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine was obtained.

<Compound 6>

N-chloroethyl-N'-isobutylammonium chloride (prepared as described in Method B7c) according to Method C1d is reacted with 4-cyanophenyl isothiocyanate to give 2- (4-cyanophenylimino) 3-isobutyl-1,3-thiazolidine was obtained.

<Compound 7>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-5-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with isobutyl bromide according to Method D2a to 2- ( 2-Methyl-5-nitrophenylimino) -3-isobutyl-1,3-thiazolidine HCl salt was obtained.

<Compound 8>

According to Method C1d, N-chloroethyl-N'-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano 2-ethylphenylimino) -3-isobutyl-1,3-thiazolidine was obtained.

<Compound 9>

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

<Compound 10>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by 1-bromo-2-methyl-2-propene according to Method D2a And reacted with 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine. 2- (4-nitrophenylimino) -3- (2-methylprop-1-en-1-yl) -1, by reversing 3-allyl-1,3-thiazolidine according to method D14a, 3-thiazolidine was obtained.

<Compound 11>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to obtain thiazolidine, followed by 1-bromo-2-methyl- according to method D2a Reaction with 2-propene gave 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine.

<Compound 12>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by 1-bromo-2-methyl-2-propene according to Method D2a And reacted with 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine.

<Compound 13>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 3,4-dichlorophenyl isothiocyanate to give thiazolidine according to method C1a, followed by 1-bromo-2-methyl-2- according to method D2a Reaction with propene gave 2- (3,4-dichlorophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine.

<Compound 14>

N- (2-hydroxyethyl) -N- (2-methylbutyl) amine was reacted with SOCl ₂ according to Method B7a to give N- (2-chloroethyl) -N- (2-methylbutyl) ammonium chloride . According to method C1a, chloroethylamine is reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl)- 1,3-thiazolidine was obtained.

<Compound 15>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to obtain thiazolidine, followed by 4-bromobut-1-ene according to method D2a And reacted with 2- (2-methyl-4-nitrophenylimino) -3- (but-1-en-4-yl) -1,3-thiazolidine.

<Compound 16>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by 1-bromobut-2-yne according to Method D2a The reaction was carried out to obtain 2- (2-methyl-4-nitrophenylimino) -3- (but-2-yn-1-yl) -1,3-thiazolidine.

<Compound 17>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with 2-ethylbutyl bromide according to Method D2a -(2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1,3-thiazolidine was obtained.

<Compound 18>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with 2-methylbutyl bromide according to Method D2a -(2-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl) -1,3-thiazolidine was obtained.

Compound 19

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with 1-nonyl bromide according to Method D2a (2-methyl-4-nitrophenylimino) -3- (1-nonyl) -1,3-thiazolidine was obtained.

<Compound 20>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with 2,2-dimethylpropyl bromide according to Method D2a To give 2- (2-methyl-4-nitrophenylimino) -3- (2,2-dimethylpropyl) -1,3-thiazolidine.

Compound 21

2-butylamine was converted to N- (2-hydroxyethyl) -N- (2-butyl) amine in accordance with Method B5a. The amine was reacted with SOCl ₂ according to Method B7a to give N- (2-chloroethyl) -N- (2-butyl) ammonium chloride. According to method C1a, chloroethylamine is reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (2-butyl) -1,3- Obtained thiazolidine.

Compound 22

3-pentylamine was converted to N- (2-hydroxyethyl) -N- (3-pentyl) amine according to method B5a. The amine was reacted with SOCl ₂ according to Method B7a to give N- (2-chloroethyl) -N- (3-pentyl) ammonium chloride. Reaction of chloroethylamine with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (3-pentyl) -1,3- Obtained thiazolidine.

Compound 23

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with 1-heptyl bromide according to Method D2a (2-methyl-4-nitrophenylimino) -3- (1-heptyl) -1,3-thiazolidine was obtained.

<Compound 24>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to obtain thiazolidine, followed by 8-bromo-1-octene according to method D2a The reaction was carried out to obtain 2- (2-methyl-4-nitrophenylimino) -3- (oct-1-en-8-yl) -1,3-thiazolidine.

Compound 25

2-propyl-1-hydroxypentane was converted to 1-bromo-2-propylpentane according to Method B2b, step 2. Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by 1-bromo-2-propylpentane according to Method D2a And reacted with 2- (2-methyl-4-nitrophenylimino) -3- (2-propyl-1-pentyl) -1,3-thiazolidine.

Compound 26

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate to give thiazolidine according to method C1a, followed by 1,1-dicyclopropylbut- according to method D2a. Reaction with 1-en-4-yl bromide 2- (2-methyl-4-nitrophenylimino) -3- (1,1-dicyclopropylbut-1-en-4-yl) -1,3 Obtained thiazolidine.

<Compound 27>

According to Method C8a, 2,6-dichloro-4-nitrophenyl isothiocyanate is reacted with 2-butylamine and then with chloroacetic acid to react 2- (2,6-dichloro-4-nitrophenylimino)- 3- (2-butyl) -1,3-thiazolidin-4-one was obtained.

<Compound 28>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate to give thiazolidine according to method C1a, followed by (E / Z) -1,3 according to method D2a. Reacting with dibromopropene to give 2- (2-methyl-4-nitrophenylimino) -3- (bromoprop-1-en-3-yl) -1,3-thiazolidine E- Obtained as a / Z-mixture. 2- (2-methyl-4-nitrophenylimino) -3-((Z) -bromoprop-1-en-3-yl) -1,3-thiazoli by separating the mixture using preparative TLC Dean got it.

<Compound 29>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to obtain thiazolidine, followed by (E) -1,3-dichloro according to method D2a Reaction with propene afforded 2- (2-methyl-4-nitrophenylimino) -3-((E) -chloroprop-1-en-3-yl) -1,3-thiazolidine.

<Compound 30>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to obtain thiazolidine, followed by 3-chloro-1-propyne and according to method D2a The reaction was carried out to obtain 2- (2-methyl-4-nitrophenylimino) -3- (prop-1-yn-3-yl) -1,3-thiazolidine.

Compound 31

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate to give thiazolidine according to method C1a, followed by (E / Z) -1,3 according to method D2a. Reacting with dibromopropene to give 2- (2-methyl-4-nitrophenylimino) -3- (bromoprop-1-en-3-yl) -1,3-thiazolidine E- Obtained as a / Z-mixture. 2- (2-methyl-4-nitrophenylimino) -3-((E) -bromoprop-1-en-3-yl) -1,3-thiazoli by separating the mixture using preparative TLC Dean got it.

Compound 32

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to give thiazolidine, followed by ethyl (Z) -4-chloro- according to method D2a Reaction with 3-ethoxybut-2-enoate to react 2- (2-methyl-4-nitrophenylimino) -3- (1-ethoxycarbonyl-2-ethoxyprop-1-ene-3 -Yl) -1,3-thiazolidine was obtained.

Compound 33

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to obtain thiazolidine, followed by methyl 4-bromobutanoate according to method D2a The reaction was carried out to obtain 2- (2-methyl-4-nitrophenylimino) -3- (1-methoxycarbonyl-3-propyl) -1,3-thiazolidine.

Compound 34

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with methyl chloroacetate according to Method D2a 2-methyl-4-nitrophenylimino) -3- (1-methoxycarbonylmethyl) -1,3-thiazolidine was obtained.

Compound 35

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with α-chloroacetophenone according to Method D2a -(2-methyl-4-nitrophenylimino) -3- (1-oxo-1-phenyl-2-ethyl) -1,3-thiazolidine was obtained. The ketone was reduced according to method D5a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-hydroxy-1-phenyl-2-ethyl) -1,3-thiazolidine.

Compound 36

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by 1-chloro-3,3-dimethyl according to Method D2a Reaction with 2-butanone gave 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine .

<Method 37>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by 1-chloro-2-butanone according to Method D2a The reaction was carried out to obtain 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-1-butyl) -1,3-thiazolidine.

<Method 38>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by 1-chloro-2-butanone according to Method D2a The reaction was carried out to obtain 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-1-butyl) -1,3-thiazolidine. The ketone was reduced according to Method D5a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-hydroxy-1-butyl) -1,3-thiazolidine.

<Method 39>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by 1-chloro-3,3-dimethyl according to Method D2a Reaction with 2-butanone gave 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine . The ketone was reduced according to method D5a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-hydroxy-3,3-dimethyl-1-butyl) -1,3-thiazolidine. Got it.

<Compound 40>

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to obtain thiazolidine, followed by 5-bromo-2-pentanone according to method D2a And reacted to give 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-5-pentanyl) -1,3-thiazolidine.

Compound 41

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate to give thiazolidine according to method C1a, followed by 1,1,3-trichloro- according to method D2a. Reacted with 1-propene to yield 2- (2-methyl-4-nitrophenylimino) -3- (1,1-dichloroprop-1-en-3-yl) -1,3-thiazolidine Got it.

Compound 42

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by reaction with propionyl chloride according to Method D2d to 2- ( 2-methyl-4-nitrophenylimino) -3- (1-oxo-1-propyl) -1,3-thiazolidine was obtained.

Compound 43

Reaction of 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain thiazolidine, followed by (E) -1-chloro-5 according to Method D2a Reaction with methoxy-2-pentene to give 2- (2-methyl-4-nitrophenylimino) -3-((E) -5-methoxypent-2-en-1-yl) -1,3 Obtained thiazolidine.

<Compound 44>

2-hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to obtain 4-aza-1-oxaspiro [4.4] nonane. Oxazolidine was reduced according to Method B4b, step 2 to afford N-cyclopentyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-cyclopentyl-N- (2-chloroethyl) amine. The amine is reacted with 2-methyl-4-nitrophenyl isothiocyanate according to method C1d to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclopentyl) -1,3-thiazolidine Got.

<Compound 45>

2-hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to obtain 4-aza-1-oxaspiro [4.4] nonane. Oxazolidine was reduced according to Method B4b, step 2 to afford N-cyclopentyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-cyclopentyl-N- (2-chloroethyl) amine. The amine is reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to method C1d to give 2- (2-methoxy-4-nitrophenylimino) -3- (cyclopentyl) -1,3-thia Obtained zolidine.

Compound 46

2-hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to obtain 4-aza-1-oxaspiro [4.4] nonane. Oxazolidine was reduced according to Method B4b, step 2 to afford N-cyclopentyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-cyclopentyl-N- (2-chloroethyl) amine. The amine was reacted with 2,3-dichlorophenyl isothiocyanate according to Method C1d to give 2- (2,3-dichlorophenylimino) -3-cyclopentyl-1,3-thiazolidine.

Compound 47

Cyclohex-2-en-1-one was reduced according to Method B2b, Step 1C to give cyclohex-2-en-1-ol. The alcohol was converted to 3-bromo-1-cyclohexene according to method B2b, step 2. The halide was converted to N- (cyclohex-2-en-1-yl) -N- (2-hydroxyethyl) amine according to method B2b, step 3. The alcohol was reacted with SOCl ₂ according to Method B7a to give N- (cyclohex-2-en-1-yl) -N- (2-chloroethyl) ammonium chloride. Reaction of chloroethylamine with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclohex-2-ene-1- Il) -1,3-thiazolidine was obtained.

Compound 48

2-hydroxyethylamine and cyclohexanone were reacted according to Method B4a, Step 1 to obtain 4-aza-1-oxaspiro [4.5] decane. Oxazolidine was reduced according to Method B4a, Step 2 to afford N-cyclohexyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-cyclohexyl-N- (2-chloroethyl) amine. The amine is reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to process C1d to give 2- (2-methyl-4-nitrophenylimino) -3-cyclohexyl-1,3-thiazolidine. Got it.

Compound 49

N- (2-hydroxyethyl) aniline was reacted with SOCl ₂ according to Method B7a to give N- (2-chloroethyl) anilinium chloride. According to Method C1a, chloroethylamine is reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-phenyl-1,3-thiazolidine. Got it.

<Compound 50>

2-hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to afford N-cycloheptyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cycloheptyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-cycloheptyl-1,3-thiazolidine.

Compound 51

2-hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclooctyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-cyclooctyl-1,3-thiazolidine.

Compound 52

2-hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclooctyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2- (2-methoxy-4-nitrophenylimino) -3-cyclooctyl-1,3-thiazolidine .

Compound 53

2-hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclooctyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3-cyclooctyl-1,3-thiazolidine.

Compound 54

2-hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine.

<Compound 55>

2-hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine is reacted with 2-methyl-4-nitrophenyl isothiocyanate to yield 2- (2-methyl-4-nitrophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine. Got it.

Compound 56

2-hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine.

<Compound 57>

2-hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine.

Compound 58

2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,2-dichlorophenyl isothiocyanate to give 2- (2,2-dichlorophenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Compound 59

2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

<Compound 60>

2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Compound 61

2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2- (2,3-dimethylphenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Compound 62

2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2- (3-chloro-2-methylphenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Compound 63

2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

<Compound 64>

2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Compound 65

2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine is reacted with 2-methyl-4-nitrophenyl isothiocyanate to yield 2- (2-methyl-4-nitrophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine. Got it.

Compound 66

2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Compound 67

2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2- (2,3-dimethylphenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Compound 68

2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2- (3-chloro-2-methylphenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Compound 69

2-hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3- (cyclohexylmethyl) -1,3-thiazolidine.

Compound 70

2-hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine is reacted with 2-methyl-4-nitrophenyl isothiocyanate to yield 2- (2-methyl-4-nitrophenylimino) -3- (cyclohexylmethyl) -1,3-thiazolidine. Got it.

<Compound 71>

2-hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine is reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2- (2-methoxy-4-nitrophenylimino) -3- (cyclohexylmethyl) -1,3-thiazoli Dean got it.

Compound 72

1-cyclohexyl-1-ethylamine was converted to N- (2-hydroxyethyl) -N- (1-cyclohexyl-1-ethyl) amine according to Method B5a. The alcohol was reacted with SOCl ₂ according to Method B7a to afford N- (2-chloroethyl) -N- (1-cyclohexyl-1-ethyl) ammonium chloride. Reaction of chloroethylamine with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-1-ethyl) -1,3-thiazolidine was obtained.

Compound 73

2-hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-benzyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2- (3-chloro-2-methylphenylimino) -3-benzyl-1,3-thiazolidine.

<Compound 74>

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

<Compound 75>

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

<Compound 76>

2-hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-benzyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidine.

<Compound 77>

2-hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-benzyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3-benzyl-1,3-thiazolidine.

Compound 78

2-hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N- (4-chlorobenzyl) -N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N- (4-chlorobenzyl) -N- (2-chloroethyl) ammonium chloride. Chloroethylamine is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3- (4-chlorobenzyl) -1,3-thia Obtained zolidine.

Compound 79

2-hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N- (4-chlorobenzyl) -N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to give N- (4-chlorobenzyl) -N- (2-chloroethyl) ammonium chloride. Reaction of chloroethylamine with 2-chloro-4-cyanophenyl isothiocyanate to give 2- (2-chloro-4-cyanophenylimino) -3- (4-chlorobenzyl) -1,3-thia Obtained zolidine.

Compound 80

2-hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine is reacted with 2-methyl-4-nitrophenyl isothiocyanate to yield 2- (2-methyl-4-nitrophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine. Got it.

Compound 81

2-hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine is reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2- (2-methoxy-4-nitrophenylimino) -3- (cycloheptylmethyl) -1,3-thiazoli Dean got it.

Compound 82

2-hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine.

Compound 83

2-hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7c to afford N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 4-cyanophenyl isothiocyanate to give 2- (4-cyanophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine.

Compound 84

Methyl cyclododecanecarboxylate was reduced according to Method B2b, step 1 to give cyclododecylmethanol. The alcohol was converted to cyclododecylmethylbromide according to method B2b, step 2. The halide was reacted with 2-hydroxyethylamine according to Method B2b, Step 3 to give N- (2-hydroxyethyl) -N- (cyclododecylmethyl) amine. The alcohol was reacted with SOCl ₂ according to Method B7a to give N- (2-chloroethyl) -N- (cyclododecylmethyl) ammonium chloride. Reaction of chloroethylamine with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a gives 2- (2-methyl-4-nitrophenylimino) -3- (cyclododecylmethyl) -1,3 Obtained thiazolidine.

Compound 85

2- (2-methyl-4-nitrophenylimino) -1,3-thia by reacting 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a After obtaining zolidine, it is reacted with 3- (chloromethyl) -6,6-dimethylbicyclo [3.1.1] hept-2-ene according to Method D2a to give 2- (4-nitrophenylimino) -3- ((6,6-dimethylbicyclo [3.1.1] hept-2-en-3-yl) methyl) -1,3-thiazolidine was obtained.

<Compound 86>

2- (2-methyl-4-nitrophenylimino) -1,3-thia by reacting 2-chloroethylammonium chloride (Compound 1) with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a After obtaining zolidine, it 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.

<Compound 87>

3-aminoquinoline was converted to 3-quinoline isothiocyanate according to Method A2c. (1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, step 1-2. The alcohol was converted to N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. According to Method C1f, 3-quinoline isothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride to give 2- (3-quinolyl Mino) -3,5-diisobutyl-1,3-thiazolidine was obtained.

Compound 88

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, step 1-2. The alcohol was converted to N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. According to Method C1f, 4-nitrophenyl isothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride to give 2- (4-nitrophenyl Imino) -3,5-diisobutyl-1,3-thiazolidine was obtained.

Compound 89

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, step 1-2. The alcohol was converted to N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. According to Method C1f, 4-cyanophenyl isothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride to give 2- (4-cyano Nophenylimino) -3,5-diisobutyl-1,3-thiazolidine was obtained.

Compound 90

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt by reacting thiazolidine with isobutyl bromide according to method D2a Got.

Compound 91

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1R) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4R) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. (4R) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt by reacting thiazolidine with isobutyl bromide according to method D2a Got.

<Compound 92>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1R) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 2-methyl-5-nitrophenyl isothiocyanate is reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4R) -2- (2-methyl-5- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. (4R) -2- (2-methyl-5-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt by reacting thiazolidine with isobutyl bromide according to method D2a Got.

<Compound 93>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-5-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-5- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. (4S) -2- (2-methyl-5-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt by reacting thiazolidine with isobutyl bromide according to method D2a Got.

<Compound 94>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1R) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4R) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. (4R) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3-methyl-1,3-thiazolidine HCl salt by reacting thiazolidine with methyl iodide according to method D2a Got.

Compound 95

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3-methyl-1,3-thiazolidine HCl salt by reacting thiazolidine with methyl iodide according to method D2a Got.

<Compound 96>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1R) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 2-methyl-5-nitrophenyl isothiocyanate is reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4R) -2- (2-methyl-5- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. (4R) -2- (2-methyl-5-nitrophenylimino) -4-isobutyl-3-methyl-1,3-thiazolidine HCl salt by reacting thiazolidine with methyl iodide according to method D2a Got.

Compound 97

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with 1-bromo-2-ethylbutane according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (2-ethyl -1-butyl) -1,3-thiazolidine HCl salt was obtained.

<Compound 98>

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

<Compound 99>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2-Ethyl-4-cyanophenyl isothiocia according to Method C1a Nate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3- Obtained thiazolidine. Thiazolidine is reacted with isobutyl bromide according to Method D2f to give (4S) -2- (2-ethyl-4-cyanophenylimino) -4-isobutyl-3- (2-oxo-3,3- Dimethyl-1-butyl) -1,3-thiazolidine was obtained.

<Compound 100>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with cyclopropylmethyl bromide according to method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (cyclopropylmethyl) -1,3 Obtained thiazolidine.

<Compound 101>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with cyclobutylmethyl bromide according to method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (cyclobutylmethyl) -1,3 Obtained thiazolidine.

<Compound 102>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with 2-chloro-3,3-dimethyl-2-butanone according to Method D2a to (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3 -(2-oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine was obtained. Reducing the ketone according to method D5a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (3,3-dimethyl-2-hydroxy-1-butyl) -1,3-thiazolidine was obtained.

<Compound 103>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 2,6-dimethyl-4-nitroaniline was converted to 2,6-dimethyl-4-nitrophenyl isothiocyanate according to method A2b. According to Method C1a, 2,6-dimethyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl- 4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2,6-dimethyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt was obtained.

<Compound 104>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 2,3-dichlorophenyl isothiocyanate was 1S) -1- (chloromethyl) -3-methylbutanammonium chloride to react with (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine Got. Thiazolidine is reacted with 3-bromopentane according to Method D2a to (4S) -2- (2,3-dichlorophenylimino) -4-isobutyl-3- (3-pentyl) -1,3- Obtained thiazolidine.

<Compound 105>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with 5-iodoheptane according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (5-heptyl) -1, 3-thiazolidine was obtained.

<Compound 106>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 2,3-dichlorophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to (4S) -2- (2-methyl-4-nitrophenyl Imino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2,3-dichlorophenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Compound 107

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1c, 2- (trifluoromethyl) -4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2 -(Trifluoromethyl) -4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine trifluoroacetate salt was obtained.

<Compound 108>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1c, 2- (trifluoromethyl) -4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2 -(Trifluoromethyl) -4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2f to give (4S) -2- (2- (trifluoromethyl) -4-nitrophenylimino) -3,4-diisobutyl-1,3- Thiazolidine trifluoroacetate salt was obtained.

Compound 109

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

<Compound 110>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1c, 2-chloro-4-cyano-6-methylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2- Chloro-4-cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2f to give (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-thia Zolidine trifluoroacetate salt was obtained.

<Compound 111>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 4- (methoxycarbonyl) -2-methylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (4- (Methoxycarbonyl) -2-methylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4- (methoxycarbonyl) -2-methylphenylimino) -3,4-diisobutyl-1,3-thia Obtained zolidine.

Compound 112

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. 3,5-dimethyl-4-nitroaniline was converted to 3,5-dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, step 3. According to Method C1a, 3,5-dimethyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (3,5- Dimethyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. 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 Got.

Compound 113

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 4- (methoxycarbonyl) -2-methylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (4- (Methoxycarbonyl) -2-methylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4- (methoxycarbonyl) -2-methylphenylimino) -3,4-diisobutyl-1,3-thia Obtained zolidine. Thiazolidine was saponified according to Method D6a, Step 1 to obtain (4S) -2- (4-carboxy-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine. The acid was coupled with ammonia as described in Process D6a, Step 2 to (4S) -2- (4-carbamoyl-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazoli Dean got it.

Compound 114

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 4-fluoro-2-methylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (4-fluoro-2 -Methylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-fluoro-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine .

Compound 115

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

<Compound 116>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 4-bromo-2-methylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (4-bromo-2 -Methylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-bromo-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine .

Compound 117

(1S) -1- (hydroxymethyl) -3-methylbutylamine is reacted with SOCl ₂ according to Method C2a, followed by reaction with 4-cyano-2-ethylphenyl isothiocyanate (4S) -2 -(4-cyano-2-ethylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine. Got it.

Compound 118

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was 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. 2-Methyl-4-nitrophenyl isothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride according to Method C1b (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained.

Compound 119

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was 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-amino-3-methylpyridine was converted to 3-methyl-4-pyridylisocyanate according to method A2b. According to Method C1b, 3-methyl-4-pyridyl isothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained.

<Compound 120>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to method A2b. According to Method C2a, 4-nitro-1-naphthyl isothiocyanate is reacted with (1S) -1- (hydroxymethyl) -3-methylbutylamine to give (4S) -2- (4-nitro-1- Naphthylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine was reacted with isobutyl bromide according to method D2a to give (4S) -2- (4-nitro-1-naphthylimino) -3,4-diisobutyl-1,3-thiazolidine .

<Compound 121>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was 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. According to Method C1f, 4-nitrophenyl isothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride to give (4S) -2- ( 4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained.

Compound 122

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was 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. According to Method C1f, 4-cyanophenyl isothiocyanate is reacted with N- (1S)-(chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride (4S) -2- (4 -Cyanophenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained.

<Compound 123>

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was 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-amino-3-methylpyridine was converted to 3-methyl-4-pyridylisocyanate according to method A2b. According to Method C1b, 3-methyl-4-pyridylisothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained. Thiazolidine was oxidized according to Method D4a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine 1-oxide. .

Compound 124

(1S, 2S) -1- (hydroxymethyl) -2-methylbutylamine was converted to (1S, 2S) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S, 2S) -1- (chloromethyl) -2-methylbutanammonium chloride to give (4S) -2- (2-methyl- 4-nitrophenylimino) -4-((2S) -2-butyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-((2S) -2-butyl) -3-isobutyl- 1,3-thiazolidine HCl salt was obtained.

Compound 125

N- (tert-butoxycarbamoyl)-(1S, 2R) -1 from N- (tert-butoxycarbamoyl)-(L) -allo-isoleucine as described in Method B1a, step 2 -(Hydroxymethyl) -2-methylbutylamine was prepared. Carbamate was converted to (1S, 2R) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7b. According to Method C1e, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S, 2R) -1- (chloromethyl) -2-methylbutanammonium chloride to give (4S) -2- (2-methyl- 4-nitrophenylimino) -4-((2R) -2-butyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-((2R) -2-butyl) -3-isobutyl- 1,3-thiazolidine HCl salt was obtained.

Compound 126

N- (tert-butoxycarbamoyl)-(1S) -1-cyclohexyl-2- from N- (tert-butoxycarbamoyl)-(L) -cyclohexylglycine according to Method B1a, step 2 Hydroxyethylbutylamine was prepared. Carbamate is reacted with SOCl ₂ according to Method B1b and the resulting material is reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-cyclohexyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-cyclohexyl-3-isobutyl-1,3-thiazolidine HCl salt was obtained.

Compound 127

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) -isoleucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. According to method C1a, 4-methoxycarbonyl-2-methylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride to give (4S) -2- (4-methoxy Carbonyl-2-methylphenylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-methoxycarbonyl-2-methylphenylimino) -4- (2-butyl) -3-isobutyl-1, 3-thiazolidine was obtained.

<Compound 128>

(1S) -1-isopropyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-isopropylethylammonium chloride according to Method B7a. Reaction of (4S) -2- (2-methyl-4-nitrophenyl by reacting 2-methyl-4-nitrophenyl isothiocyanate with (1S) -2-chloro-1-isopropylethylammonium chloride according to method C1a Imino) -4-isopropyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-isobutyl-1,3-thiazolidine HCl salt was obtained.

Compound 129

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) -isoleucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 5-aminoindan-1-one was converted to 1-oxo-5-indanyl isothiocyanate according to method A2a. Isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride according to Method C1a to (4S) -2- (1-oxo-5-indanylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (1-oxo-5-indanylimino) -4- (2-butyl) -3-isobutyl-1,3- Obtained thiazolidine.

<Compound 130>

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

Compound 131

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) -isoleucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-3- (trifluoromethyl) aniline was converted to 4-cyano-3- (trifluoromethyl) phenyl isothiocyanate according to Method A2a, step 3. Isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride according to Method C1a to (4S) -2- (4-cyano-3- (trifluoromethyl) phenyl Imino) -4- (2-butyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-cyano-3- (trifluoromethyl) phenylimino) -4- (2-butyl) -3-iso Butyl-1,3-thiazolidine was obtained.

Compound 132

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) -isoleucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to method A2b. According to Method C1a 4-nitro-1-naphthyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride to give (4S) -2- (4-nitro-1- Naphthylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. 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. Got it.

Compound 133

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) -isoleucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. According to method C1a, 4-cyano-2-ethylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride to give (4S) -2- (4-cyano- 2-ethylphenylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-cyano-2-ethylphenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine Got.

Compound 134

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) -isoleucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 4-cyano-2-methylaniline was synthesized as described in Method A1a. Aniline was converted to 4-cyano-2-methylphenyl isothiocyanate as described in Method A2a, Step 3. According to Method C1a, 4-cyano-2-methylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride to (4S) -2- (4-cyano-2 -Methylphenylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-cyano-2-methylphenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine. Got it.

Compound 135

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) -isoleucine methyl ester as described in Method B1b. 2-hydroxyethylamine was 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. Aniline was converted to 4-cyano-2,5-dimethylphenyl isothiocyanate as described in method A2a, step 3. According to Method C1a, 4-cyano-2,5-dimethylphenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride to give (4S) -2- (4-sia No-2,5-dimethylphenylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-cyano-2,5-dimethylphenylimino) -4-butyl-3-isobutyl-1,3-thia Obtained zolidine.

Compound 136

(1S) -1- (hydroxymethyl) -2-methylbutylamine was prepared from (L) -isoleucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanammonium chloride as described in Method B7a. 2,5-methylaniline was converted to 2,5-dimethyl-4-nitrophenyl isothiocyanate according to method A2a. According to Method C1a, 2,5-dimethyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutanammonium chloride to give (4S) -2- (2,5- Dimethyl-4-nitrophenylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. 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-thiazoli Dean got it.

Compound 137

According to Method C2a, (1R) -1-isopropyl-2-hydroxyethylamine is reacted with SOCl ₂ , followed by 2-methyl-4-nitrophenyl isothiocyanate to react with (4R) -2- (2 -Methyl-4-nitrophenylimino) -4-isopropyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-isobutyl-1,3-thiazolidine Got.

<Compound 138>

According to Method C2a, (1S) -1-isopropyl-2-hydroxyethylamine is reacted with SOCl ₂ and then with 2-methyl-4-nitrophenyl isothiocyanate (4S) -2- (2 -Methyl-4-nitrophenylimino) -4-isopropyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with cyclopentyl bromide according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-cyclopentyl-1,3-thiazolidine Got.

Compound 139

(1S) -1-benzyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-benzylethylammonium chloride according to Method B7b. According to Method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -2-chloro-1-benzylethylammonium chloride to give (4S) -2- (2-methyl-4-nitrophenyl Mino) -4-benzyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-benzyl-3-isobutyl-1,3-thiazolidine HCl A salt was obtained.

<Compound 140>

(1S) -1-phenyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-phenylethylammonium chloride according to Method B7b. According to Method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -2-chloro-1-benzylethylammonium chloride to give (4S) -2- (2-methyl-4-nitrophenyl Mino) -4-phenyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-phenyl-3-isobutyl-1,3-thiazolidine HCl A salt was obtained.

Compound 141

2-piperiddenmethanol was prepared from methyl pipecolinate as described in Method Blb. 2-hydroxyethylamine was converted to 2-chloromethylpiperidinium chloride according to Method B7a. Reaction of 2-methyl-4-nitrophenyl isothiocyanate with 2-chloromethylpiperidinium chloride according to method C1a gives 9- (2-methyl-4-nitrophenylimino) -1-aza-8-thia Bicyclo [4.3.0] nonane was obtained.

Compound 142

2-Pyrrolidinemethanol was prepared from proline methyl ester as described in Method Blb. 2-hydroxyethylamine was converted to 2-chloromethylpyrrolidinium chloride according to Method B7a. 3- (2-methyl-4-nitrophenylimino) -2,5,6,7 by reacting 2-methyl-4-nitrophenyl isothiocyanate with 2-chloromethylpyrrolidinium chloride according to method C1a , 7a-pentahydro-2-thiapyrrolidin was obtained.

Compound 143

(1S) -1- (4-hydroxyphenylmethyl) -2-hydroxyethylamine was prepared from (L) -tyrosine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (4S) -2-isopropyl-4- (4-hydroxyphenylmethyl) -1,3-oxazolidine according to Method B4c, step 1. Oxazolidine was reduced to N-((1S) -1- (4-hydroxyphenylmethyl) -2-hydroxyethyl) -N-isobutylamine according to Method B4c, step 2. The resulting 2-hydroxyethylamine was treated with SOCl ₂ according to Method B7c to give N-((1S) -1- (4-hydroxyphenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride . Reaction of 2-ethyl-4-cyanophenyl isothiocyanate with N-((1S) -1- (4-hydroxyphenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride according to method C1b To give (4S) -2- (2-ethyl-4-cyanophenylimino) -4- (4-hydroxyphenylmethyl) -3-isobutyl-1,3-thiazolidine HCl salt.

Compound 144

(1S) -1- (4-chlorophenylmethyl) -2-hydroxyethylamine was prepared from (L) -4-chlorophenylalanine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (4S) -2-isopropyl-4- (4-chlorophenylmethyl) -1,3-oxazolidine according to Method B4c, step 1. Oxazolidine was reduced to N-((1S) -1- (4-chlorophenylmethyl) -2-hydroxyethyl) -N-isobutylamine according to Method B4c, step 2. The resulting 2-hydroxyethylamine was treated with SOCl ₂ according to Method B7c to give N-((1S) -1- (4-chlorophenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride. 2-ethyl-4-cyanophenyl isothiocyanate is reacted with N-((1S) -1- (4-chlorophenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride according to method C1b. (4S) -2- (2-ethyl-4-cyanophenylimino) -4- (4-chlorophenylmethyl) -3-isobutyl-1,3-thiazolidine HCl salt was obtained.

Compound 145

(1S) -1- (benzylthiomethyl) -2-hydroxyethylamine was prepared from (L) -S-benzylcysteine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (4S) -2-isopropyl-4- (benzylthiomethyl) -1,3-oxazolidine according to Method B4c, step 1. Oxazolidine was reduced to N-((1S) -1- (benzylthiomethyl) -2-hydroxyethyl) -N-isobutylamine according to Method B4c, step 2. The resulting 2-hydroxyethylamine was treated with SOCl ₂ according to Method B7c to give N-((1S) -1- (benzylthiomethyl) -2-chloroethyl) -N-isobutylammonium chloride. 2-ethyl-4-cyanophenyl isothiocyanate is reacted with N-((1S) -1- (benzylthiomethyl) -2-chloroethyl) -N-isobutylammonium chloride according to Method C1b (4S ) -2- (2-ethyl-4-cyanophenylimino) -4- (benzylthiomethyl) -3-isobutyl-1,3-thiazolidine HCl salt was obtained.

<Compound 146>

(R) -N-isobutylserine methyl ester HCl salt was prepared from (D) -serine methyl ester as described in method B3a. The ester is reacted with SOCl ₂ according to process C2a and then with 2-methyl-4-nitrophenyl isothiocyanate to give (4S) -2- (2-methyl-4-nitrophenylimino) -4- ( Methoxycarbonyl) -3-isobutyl-1,3-thiazolidine HCl salt was obtained.

Compound 147

(S) -N-isobutylserine methyl ester HCl salt was prepared from (L) -serine methyl ester as described in method B3a. The ester is reacted with SOCl ₂ according to method C2a and then with 2-methyl 4-nitrophenyl isothiocyanate to give (4R) -2- (2-methyl-4-nitrophenylimino) -4- (meth). Toxylcarbonyl) -3-isobutyl-1,3-thiazolidine HCl salt was obtained.

<Compound 148>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. Reaction of (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2-methyl-4-nitrophenyl isothiocyanate following method C5b, followed by isobutyl Reacted with bromide to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazoli Got Dean.

Compound 149

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. According to Method C5b (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride is reacted with 2-methyl-4-nitrophenyl isothiocyanate and then cyclopentyl Reacted with bromide to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazoli Got Dean.

<Compound 150>

(1R, 2S) -1-methanesulfonyloxymethyl from (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. After reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2-methyl-4-nitrophenyl isothiocyanate according to method C5b, cyclopentyl Reacted with bromide to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazoli Dean got it.

Compound 151

(1R, 2S) -1-methanesulfonyloxymethyl from (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. After reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2-methyl-4-nitrophenylisothiocyanate according to method C5b, isobutyl Reacted with bromide to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1S) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazoli Got Dean.

Compound 152

(1R, 2S) -1-methanesulfonyloxymethyl from (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. According to Method C5b, (1R, 2S) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride is reacted with 4-cyano-2-methylphenyl isothiocyanate, followed by cyclopentyl Reacted with bromide to give (4R) -2- (4-cyano-2-methylphenylimino) -4-((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazoli Dean got it.

Compound 153

(1R, 2S) -1-methanesulfonyloxymethyl from (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to method A2b. Reaction of (1R, 2S) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 4-nitronaphthyl isothiocyanate followed by isobutyl bromide according to method C5b To give (4R) -2- (4-nitro-1-naphthylimino) -4-((1S) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine .

Compound 154

(1R, 2S) -1-methanesulfonyloxymethyl from (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to method A2b. Reaction of (1R, 2S) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to method C5b To give (4R) -2- (4-nitro-1-naphthylimino) -4-((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine .

Compound 155

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 1-amino-5,6,7,8-tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride according to method C5b was prepared with 4-nitro-5,6,7,8-tetrahydronaphth-1- After reacting with one isothiocyanate, it was reacted with cyclopentyl bromide to give (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4- ( (1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained.

<Compound 156>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 1-amino-5,6,7,8-tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride according to method C5b was prepared with 4-nitro-5,6,7,8-tetrahydronaphth-1- After reacting with one isothiocyanate, it is reacted with isobutyl bromide to give (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4- ( (1R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained.

<Compound 157>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2-isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to method A2a. According to Method C5b, (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride is reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by iso Reaction with butyl bromide to give (4R) -2- (2-isopropyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-isobutyl-1,3- Obtained thiazolidine.

<Compound 158>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2-isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to method A2a. According to method C5b, (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride is reacted with 2-isopropyl-4-nitrophenyl isothiocyanate and then cyclo Reaction with pentyl bromide to (4R) -2- (2-isopropyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3- Obtained thiazolidine.

Compound 159

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2,3-dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method A2b. After reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method C5b, Reacted with cyclopentyl bromide to give (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1, 3-thiazolidine was obtained.

<Compound 160>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2,3-dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method A2b. After reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method C5b, Reacted with isobutyl bromide to give (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-isobutyl-1, 3-thiazolidine was obtained.

Compound 161

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2,3-dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method A2b. After reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method C5b, Reaction with 2-ethyl-1-butyl bromide to give (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3- (2-ethyl-1-butyl) -1,3-thiazolidine was obtained.

<Compound 162>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 1-amino-4-cyano-5,6,7,8-tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to method A2b. (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride according to method C5b was prepared with 4-cyano-5,6,7,8-tetrahydronaphthyl isothio. After reacting with cyanate, it is reacted with cyclopentyl bromide to give (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1- tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained.

<Compound 163>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 1-amino-4-cyano-5,6,7,8-tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to method A2b. (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride according to method C5b was prepared with 4-cyano-5,6,7,8-tetrahydronaphthyl isothio. After reacting with cyanate, it is reacted with isobutyl bromide to give (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1- tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained

<Compound 164>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. Reaction of (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2-methyl-4-nitrophenyl isothiocyanate following method C5b, followed by isobutyl Reacted with bromide to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxy) -3-isobutyl-1,3-thiazolidine Got. Determination of tert-butyl ether according to method D3a to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-isobutyl- 1,3-thiazolidine was obtained.

<Compound 165>

(1R, 2S) -1-methanesulfonyloxymethyl from (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to method A2b. According to Method C5b, (1R, 2S) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride is reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide To give (4R) -2- (4-nitro-1-naphthylimino) -4-((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine . (4R) -2- (4-nitro-1-naphthylimino) -4-((1S) -1-hydroxyethyl) -3-cyclopentyl- by deprotecting tert-butyl ether according to method D3a 1,3-thiazolidine was obtained.

<Compound 166>

(1R, 2S) -1-methanesulfonyloxymethyl from (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. After reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2-methyl-4-nitrophenylisothiocyanate according to method C5b, cyclopentyl Reacted with bromide to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazoli Dean got it. The tert-butyl ether was deprotected according to method D3a to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1S) -1-hydroxyethyl) -3-cyclopentyl- 1,3-thiazolidine was obtained.

<Compound 167>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. According to Method C5b (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride is reacted with 2-methyl-4-nitrophenyl isothiocyanate and then cyclopentyl Reacted with bromide to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazoli Dean got it. Deprotection of tert-butyl ether according to method D3a to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-cyclopentyl- 1,3-thiazolidine was obtained.

<Compound 168>

(1R, 2S) -1-methanesulfonyloxymethyl from (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. After reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2-methyl-4-nitrophenyl isothiocyanate according to method C5b, cyclopentyl Reacted with bromide to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazoli Dean got it. The tert-butyl ether was deprotected according to method D3a to give (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1S) -1-hydroxyethyl) -3-cyclopentyl- 1,3-thiazolidine was obtained.

<Compound 169>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2-tert-butyl-4-cyanoaniline was converted to 2-tert-butyl-4-cyanophenyl isothiocyanate according to Method A2b. After reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2-tert-butyl-4-cyanophenyl isothiocyanate according to method C5b And (4R) -2- (2-tert-butyl-4-cyanophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-cyclopentyl- by reacting with cyclopentyl bromide 1,3-thiazolidine was obtained. (4R) -2- (2-tert-butyl-4-cyanophenylimino) -4-((1R) -1-hydroxyethyl) -3- by deprotecting the tert-butyl ether according to method D3a Cyclopentyl-1,3-thiazolidine was obtained.

<Compound 170>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2-tert-butyl-4-cyanoaniline was converted to 2-tert-butyl-4-cyanophenyl isothiocyanate according to method bA2a. After reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2-tert-butyl-4-cyanophenyl isothiocyanate according to method C5b And (4R) -2- (2-tert-butyl-4-cyanophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-isobutyl- by reacting with isobutyl bromide 1,3-thiazolidine was obtained. (4R) -2- (2-tert-butyl-4-cyanophenylimino) -4-((1R) -1-hydroxyethyl) -3- by deprotecting the tert-butyl ether according to method D3a Isobutyl-1,3-thiazolidine was obtained.

Compound 171

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to method A2b. Reaction of (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to method C5b To give (4R) -2- (4-nitro-1-naphthylimino) -4-((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine . The tert-butyl ether was deprotected according to method D3a to give (4R) -2- (4-nitro-1-naphthylimino) -4-((1R) -1-hydroxyethyl) -3-cyclopentyl- 1,3-thiazolidine was obtained.

Compound 172

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 1-amino-5,6,7,8-tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride according to method C5b was prepared with 4-nitro-5,6,7,8-tetrahydronaphth-1- After reacting with one isothiocyanate, it was reacted with cyclopentyl bromide to give (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4- ( (1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. Deprotection of tert-butyl ether according to method D3a to give (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4-((1R)- 1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained.

<Compound 173>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 1-amino-5,6,7,8-tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate according to Method A2a. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride according to method C5b was prepared with 4-nitro-5,6,7,8-tetrahydronaphth-1- After reacting with one isothiocyanate, it is reacted with isobutyl bromide to give (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4- ( (1R) -1-tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Deprotection of tert-butyl ether according to method D3a to give (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4-((1R)- 1-hydroxyethyl) -3-isobutyl-1,3-thiazolidine was obtained.

Compound 174

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2-isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to method A2a. According to Method C5b, (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride is reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by iso Reaction with butyl bromide to give (4R) -2- (2-isopropyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-isobutyl-1,3- Obtained thiazolidine. (4R) -2- (2-isopropyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-isobutyl by deprotecting tert-butyl ether according to method D3a -1,3-thiazolidine was obtained.

Compound 175

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2-isopropylaniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to method A2a. According to method C5b, (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride is reacted with 2-isopropyl-4-nitrophenyl isothiocyanate and then cyclo Reaction with pentyl bromide to (4R) -2- (2-isopropyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3- Obtained thiazolidine. (4R) -2- (2-isopropyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-cyclopentyl by deprotecting tert-butyl ether according to method D3a -1,3-thiazolidine was obtained.

<Compound 176>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2,3-dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method A2b. After reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method C5b, Reaction with 2-ethyl-1-butyl bromide to give (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3- (2-ethyl-1-butyl) -1,3-thiazolidine was obtained. The tert-butyl ether was deprotected according to method D3a to give (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3- ( 2-ethyl-1-butyl) -1,3-thiazolidine was obtained.

Compound 177

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2,3-dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method A2b. After reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method C5b, Reacted with isobutyl bromide to give (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-isobutyl-1, 3-thiazolidine was obtained. (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-iso by deprotecting the tert-butyl ether according to method D3a Butyl-1,3-thiazolidine was obtained.

Compound 178

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 2,3-dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method A2b. After reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method C5b, Reacted with cyclopentyl bromide to give (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1, 3-thiazolidine was obtained. (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-cyclo by deprotecting tert-butyl ether according to method D3a Pentyl-1,3-thiazolidine was obtained.

Compound 179

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 1-amino-4-cyano-5,6,7,8-tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to method A2b. (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride according to method C5b was prepared with 4-cyano-5,6,7,8-tetrahydronaphthyl isothio. After reacting with cyanate, it is reacted with cyclopentyl bromide to give (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1- tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1-hydride by deprotection of tert-butyl ether according to method D3a Oxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained.

<Compound 180>

(1R, 2R) -1-methanesulfonyloxymethyl from (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-tert-butylthreonine dicyclohexylamine salt as described in Method B8a ) -2- (tert-butoxy) propaneammonium chloride was prepared. 1-amino-4-cyano-5,6,7,8-tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to method A2b. (1R, 2R) -1-methanesulfonyloxymethyl) -2- (tert-butoxy) propaneammonium chloride according to method C5b was prepared with 4-cyano-5,6,7,8-tetrahydronaphthyl isothio. After reacting with cyanate, it is reacted with isobutyl bromide to give (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1- tert-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1-hydride by deprotection of tert-butyl ether according to method D3a Oxyethyl) -3-isobutyl-1,3-thiazolidine was obtained.

Compound 181

Reaction of 2-amino-1,3-propanediol with excess SOCl ₂ according to method C2a followed by 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenyl Imino) -4- (chloromethyl) -1,3-thiazolidine was obtained. Thiazolidine was reacted with N-methylamine according to Method D13a to obtain 2- (2-methyl-4-nitrophenylimino) -4- (N-methylaminomethyl) -1,3-thiazolidine. , 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (N-isobutyl-N-methylaminomethyl) -1,3- by reacting with isobutyl bromide according to method D2a Obtained thiazolidine.

Compound 182

According to Method C2a, 2-amino-1,3-propanediol is reacted with excess SOCl ₂ , followed by 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenyl Imino) -4- (chloromethyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with dimethylamine according to Method D13a to give 2- (2-methyl-4-nitrophenylimino) -4- (N-isobutyl-N-methylaminomethyl) -1,3-thiazolidine Was obtained, followed by reaction with isobutyl bromide according to method D2a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (N, N-dimethylaminomethyl) -1,3- Obtained thiazolidine.

<Compound 183>

According to method C2a, (L) -histidinol is reacted with SOCl ₂ and then with 2-methyl-4-nitrophenyl isothiocyanate to react with (4S) -2- (2-methyl-4-nitrophenylimino ) -4- (1- (isobutylimidazoli) methyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (1- (isobutylimidazolyl) Methyl) -1,3-thiazolidine was obtained.

Compound 184

According to method C2a, (L) -histidinol is reacted with SOCl ₂ and then with 2-methyl-4-nitrophenyl isothiocyanate to react with (4S) -2- (2-methyl-4-nitrophenylimino ) -4- (1- (isobutylimidazoli) methyl) -1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (3- (isobutylimidazolyl) Methyl) -1,3-thiazolidine was obtained.

Compound 185

2-hydroxypropylamine was converted to 2-chloropropylammonium chloride according to Method B7a. Reaction of 2-methyl-4-nitrophenyl isothiocyanate with 2-chloropropylammonium chloride according to method C1a to give 2- (2-methyl-4-nitrophenylimino) -5-methyl-1,3-thia Obtained zolidine. Thiazolidine is reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2 -En-1-yl) -5-methyl-1,3-thiazolidine HBr salt was obtained.

Compound 186

2-phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to obtain N-isobutyl-2-phenyl-2-hydroxyethylamine. The ethanolamine is reacted with SOCl ₂ according to Method C2f and then with 2-chloro-4- (trifluoromethyl) phenyl isothiocyanate to react 2- (2-chloro-4- (trifluoromethyl) phenyl Imino) -3-isobutyl-5-phenyl-1,3-thiazolidine HCl salt was obtained.

<Compound 187>

2-phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to obtain N-isobutyl-2-phenyl-2-hydroxyethylamine. Reaction of ethanolamine with SOCl ₂ according to method C2f followed by reaction with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3-isobutyl-5-phenyl-1 , 3-thiazolidine was obtained.

<Compound 188>

3-phenyl-2-hydroxypropylamine was reacted with isobutyraldehyde according to Method B4c, step 1 to give 2-isopropyl-5-benzyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-3-phenyl-2-hydroxypropylamine. Propanolamine is reacted with SOCl ₂ according to Method C2f and then with 2,3-dichlorophenyl isothiocyanate to react with 2- (2,3-dichlorophenylimino) -3-isobutyl-5-benzyl-1 , 3-thiazolidine HCl salt was obtained.

<Compound 189>

2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl-2-methyl-2-hydroxypropylamine. Propanolamine is reacted with SOCl ₂ according to Method C2f, followed by reaction with 2,6-dichlorophenyl isothiocyanate to 2- (2,6-dichlorophenylimino) -3-cyclohexyl-5,5-dimethyl -1,3-thiazolidine was obtained.

Compound 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 was obtained. After reacting N-((1R) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine with SOCl ₂ according to Method C2f, 2,3-dichloro Reaction with phenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3-((1R) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazoli Dean HCl salt was obtained.

<Compound 191>

(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 was obtained. After reacting N-((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine with SOCl ₂ according to Method C2f, 2,4-dichloro Reaction with phenyl isothiocyanate to give 2- (2,4-dichlorophenylimino) -3-((1S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazoli Dean HCl salt was obtained.

<Compound 192>

(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 was obtained. After reacting N-((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine with SOCl ₂ according to Method C2f, 2,3-dichloro Reaction with phenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3-((1S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazoli Dean HCl salt was obtained.

<Compound 193>

2-methyl-2-hydroxypropylamine is reacted with SOCl ₂ according to Method C2f, followed by reaction with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -5, 5-Dimethyl-1,3-thiazolidine was obtained. According to Method B5b, 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1,3-thiazolidine is reacted with ethylene oxide to give 2- (2,3-dichlorophenylimino)- 5,5-dimethyl-1,3-thiazolidine HCl salt was obtained.

<Compound 194>

According to Method C1a, 2-methyl-2-hydroxypropylamine is reacted with SOCl ₂ and then with 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylimino ) -5,5-dimethyl-1,3-thiazolidine was obtained.

<Compound 195>

According to Method C1a, 2-methyl-2-hydroxypropylamine is reacted with SOCl ₂ and then with 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylimino ) -5,5-dimethyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2 -En-1-yl) -5,5-dimethyl-1,3-thiazolidine HBr salt was obtained.

<Compound 196>

According to Method C1a, 2-methyl-2-hydroxypropylamine is reacted with SOCl ₂ and then with 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylimino ) -5,5-dimethyl-1,3-thiazolidine was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2g to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5,5-dimethyl-1,3-thiazolidine.

<Compound 197>

2-methyl-2-hydroxypropylamine is reacted with SOCl ₂ according to Method C1a, followed by reaction with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -5, 5-Dimethyl-1,3-thiazolidine was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2g to give 2- (2,3-dichlorophenylimino) -3-isobutyl-5,5-dimethyl-1,3-thiazolidine.

<Compound 198>

2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl-2-methyl-2-hydroxypropylamine. Propanolamine is reacted with SOCl ₂ according to Method C2f, followed by 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylimino) -3-cyclohexyl-5 , 5-dimethyl-1,3-thiazolidine was obtained.

<Compound 199>

2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to give N-cyclohexyl-2-methyl-2-hydroxypropylamine. Propanolamine is reacted with SOCl ₂ according to Method C2f and then with 2,3-dichlorophenyl isothiocyanate to react 2- (2,3-dichlorophenylimino) -3-cyclohexyl-5,5-dimethyl -1,3-thiazolidine was obtained.

<Compound 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 was obtained. According to Method C2f, N-((1R) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with SOCl ₂ , followed by 2-methyl-4 Reacted with nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-((1R) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1, 3-thiazolidine HCl salt was obtained.

<Compound 201>

(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 was obtained. According to Method C2f, N-((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with SOCl ₂ , followed by 2-methyl-4 Reacted with nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-((1S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1, 3-thiazolidine HCl salt was obtained.

<Compound 202>

Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to afford N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. According to method C2f, N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with SOCl ₂ , followed by 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylimino) -3-isopropyl-5,5-dimethyl-1,3-thiazolidine was obtained.

Compound 203

Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to afford N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. According to method C2f, N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with SOCl ₂ and then with 2,3-dichlorophenyl isothiocyanate to react 2- (2 , 3-dichlorophenylimino) -3-isopropyl-5,5-dimethyl-1,3-thiazolidine was obtained.

Compound 204

Isobutylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to afford N-isobutyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. According to method C2f, N-isobutyl-N- (2,2-dimethyl-2-hydroxyethyl) amine is reacted with SOCl ₂ and then with 2,4-dichlorophenyl isothiocyanate to react 2- (2 , 4-Dichlorophenylimino) -3-isobutyl-5,5-dimethyl-1,3-thiazolidine HCl salt was obtained.

Compound 205

1,1-dimethyl-2-hydroxyamine was converted to 1,1-dimethyl-2-chloroethylammonium chloride according to Method B7a. 2- (2-methyl-4-nitrophenylimino) -4,4 by reacting 2-methyl-4-nitrophenyl isothiocyanate with 1,1-dimethyl-2-chloroethylammonium chloride according to method C1a -Dimethyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to give 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-3- (2 -Methylprop-2-en-1-yl) -1,3-thiazolidine HBr salt was obtained.

Compound 206

Methyl aminoisobutyric acid was converted to methyl aminoisobutyrate HCl salt according to Method B1c, step 1. The ester was reduced to 3-hydroxy-2-methyl-2-propylamine according to Method B1c, Step 2. Treatment of 2-hydroxyethylamine with SOCl ₂ according to Method B7b, followed by treatment with 2-methyl-3-nitrophenyl isothiocyanate according to Method C1a to 2- (2-methyl-4-nitrophenylimino ) -4,4-dimethyl-1,3-thiazolidine was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-3-isobutyl-1,3-thiazolidine.

<Compound 207>

1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 1- (cyclohexylamino) -1-hydroxymethylcyclopentane was synthesized as described in method B4a. Treatment of 2-hydroxyethylamine with SOCl ₂ according to Method C2a followed by 2-methyl-4-nitrophenyl isothiocyanate to give 3-cyclohexyl-2- (2-methyl-4-nitrophenyl Mino) -1-thia-3-azaspiro [4.4] nonane was obtained.

Compound 208

2-ethylaniline was converted to 2-ethylacetanilide according to Method A2a, step 1. Acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, step 2. Acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. Aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. Reaction of 2-chloroethylamine with 2-ethyl-4-nitrophenyl isothiocyanate according to method C1a gives 2- (2-ethyl-4-nitrophenylimino) -1-thia-3-azaspiro [4.4 ] Nonan was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2- (2-ethyl-4-nitrophenylimino) -1-thia-3-azaspiro [4.4] nonane.

Compound 209

2-n-propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. Aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to method A2b. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. Reaction of 2-chloroethylamine with 4-iodo-2-n-propylphenyl isothiocyanate according to method C1a gives 2- (4-iodo-2-n-propylphenylimino) -1-thia- 3-azaspiro [4.4] nonane was obtained. Thiazolidine is reacted with cyclopentyl bromide according to method D2b to give 3-cyclopentyl-2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro [4.4] nonane. Got it. Phenyl iodide was reacted with CuCN according to Method D7a to give 3-cyclopentyl-2- (4-cyano-2-n-propylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

<Compound 210>

2-isopropylaniline was converted to 4-iodo-2-isopropylaniline according to Method A5a. Aniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to method A2b. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. 2-chloroethylamine is reacted with 4-iodo-2-isopropylphenyl isothiocyanate according to method C1a to give 2- (4-iodo-2-isopropylphenylimino) -1-thia-3- Azaspiro [4.4] Nonan was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2- (4-iodo-2-isopropylphenylimino) -1-thia-3-azaspiro [4.4] nonane . Phenyl iodide was reacted with CuCN according to Method D7a to give 3-cyclopentyl-2- (4-cyano-2-isopropylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

<Compound 211>

2-tert-butylaniline was converted to 4-iodo-2-tert-butylaniline according to Method A5a. Aniline was converted to 4-iodo-2-tert-butylphenyl isothiocyanate according to method A2b. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. 2-chloroethylamine is reacted with 4-iodo-2-tert-butylphenyl isothiocyanate according to method C1a to give 2- (4-iodo-2-tert-butylphenylimino) -1-thia- 3-azaspiro [4.4] nonane was obtained. Thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2- (4-iodo-2-tert-butylphenylimino) -1-thia-3-azaspiro [4.4] nonane. Got it. Phenyl iodide was reacted with CuCN according to Method D7a to give 3-cyclopentyl-2- (4-cyano-2-tert-butylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

<Compound 212>

1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The amino alcohol is reacted with 2-methylcyclopentanone according to method B4a, step 1 to give 13-aza-1-methyl-6-oxodisspiro [4.2.4.1] tridecane, followed by method B4a, step 2 Reduction with NaBH ₄ gave 1- (2-methylcyclopentyl) amino-1- (hydroxymethyl) cyclopentane. According to method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ , followed by 2-methyl-4-nitrophenyl isothiocyanate to react with 3- (2-methylcyclopentyl) -2- (2-methyl- 4-nitrophenylimino) -1-thia-3-azaspiro [4.4] nonane was obtained.

Compound 213

1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. The reaction of 2-chloroethylamine with 2-methyl-4-nitrophenyl isothiocyanate according to process C1e gives 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4 ] Nonan was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Compound 214

2-ethylaniline was converted to 2-ethylacetanilide according to Method A2a, step 1. Acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, step 2. Acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. Aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. Reaction of 2-chloroethylamine with 2-ethyl-4-nitrophenyl isothiocyanate according to method C1a gives 2- (2-ethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4 ] Nonan was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-ethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Compound 215

2-n-propylaniline was converted to 2-n-propylacetanilide according to Method A2a, step 1. Acetanilide was converted to 2-n-propyl-4-nitroacetanilide according to Method A2a, step 2. Acetanilide was deprotected according to Method A2a, Step 3 to give 2-n-propyl-4-nitroaniline. Aniline was converted to 2-n-propyl-4-nitrophenyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. Reaction of 2-chloroethylamine with 2-n-propyl-4-nitrophenyl isothiocyanate according to process C1a to give 2- (2-n-propyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-n-propyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane .

<Compound 216>

2-isopropylaniline was converted to 2-isopropylacetanilide according to Method A2a, Step 1. Acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to Method A2a, step 2. Acetanilide was deprotected according to Method A2a, Step 3 to give 2-isopropyl-4-nitroaniline. Aniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. Reaction of 2-chloroethylamine with 2-isopropyl-4-nitrophenyl isothiocyanate according to method C1a gives 2- (2-isopropyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] Nonan was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-isopropyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Compound 217

2,3-dimethyl-4-nitroaniline was synthesized as described in method A4a. Aniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate as described in Method A2d. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7e to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. According to Method C1c, 2-chloroethylamine is reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate to give 2- (2,3-dimethyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-isopropyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Compound 218

3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. The reaction of 2-chloroethylamine with 3-methyl-4-nitrophenyl isothiocyanate according to process C1a gives 2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4 ] Nonan was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Compound 219

1-amino-5,6,7,8-tetrahydronaphthalin was converted to 1-acetamino-5,6,7,8-tetrahydronaphthalin according to Method A2a, step 1. Acetanilide was converted to 1-acetamino-4-nitro-5,6,7,8-tetrahydronaphthalin according to Method A2a, step 2. Acetanilide was deprotected according to method A2a, step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthalin. Aniline was converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. According to Method C1a, 2-chloroethylamine is reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate to give 2- (4-nitro-5,6,7,8 -Tetrahydro-1-naphthylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (4-nitro-5,6,7,8-tetrahydro-1-naphthylimino) -3-thia-1 -Azaspiro [4.4] Nonan obtained.

<Compound 220>

1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7e to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. 2-Chloroethylamine was reacted with 4-cyanophenyl isothiocyanate according to Method C1a to give 2- (4-cyanophenylimino) -3-thia-1-azaspiro [4.4] nonane. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (4-cyanophenylimino) -3-thia-1-azaspiro [4.4] nonane.

Compound 221

4-cyano-2-methylaniline was synthesized as described in Method A1a. Aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. Reaction of 2-chloroethylamine with 4-cyano-2-methylphenyl isothiocyanate according to process C1a gives 2- (4-cyano-2-methylphenylimino) -1-thia-3-azaspiro [4.4 ] Nonan was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-iodo-2-methylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

Compound 222

1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. According to Method C1a, 2-chloroethylamine is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-methylphenylimino) -1-thia-3-azaspiro [ 4.4] gave a nonan. Thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-cyano-2-methylphenylimino) -1-thia-3-azaspiro [4.4] nonane.

Compound 223

1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. 1-amino-4-cyanonaphthalene was converted to 4-cyano-1-naphthyl isothiocyanate according to Method A2a, step 3. According to Method C1a, 2-chloroethylamine is reacted with 4-cyano-1-naphthyl isothiocyanate to give 2- (4-cyano-1-naphthylimino) -1-thia-3-azaspiro [4.4] Nonan was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-cyano-1-naphthylimino) -1-thia-3-azaspiro [4.4] nonane.

<Compound 224>

2,3-dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to method A5a. Aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7e to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. Reaction of 2-chloroethylamine with 2,3-dimethyl-4-iodophenyl isothiocyanate according to method C1e to give 2- (2,3-dimethyl-4-iodophenylimino) -1-thia- 3-azaspiro [4.4] nonane was obtained. 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. Got it. Phenyl iodide was reacted with CuCN according to Method D7a to give 3-isobutyl-2- (2,3-dimethyl-4-cyanophenylimino) -1-thia-3-azaspiro [4.4] nonane.

<Compound 225>

2,3-dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to method A5a. Aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. According to Method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ and then with 2,3-dimethyl-4-iodophenyl isothiocyanate to react 2- (2,3-dimethyl-4-iodophenyl Imino) -1-thia-3-azaspiro [4.4] nonane was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give 3-isobutyl-2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro [4.4] nonane. Got it. 3-isobutyl-2- (2,3-dimethyl-4- (2-trimethylsilylethynyl) phenylimino) -1-thia-3 by reacting phenyl iodide with trimethylsilylacetylene according to method D8a, step 1 -Azaspiro [4.4] Nonan obtained. Deprotecting the silylacetylene according to method D8a, step 2 to give 3-isobutyl-2- (2,3-dimethyl-4-ethynylphenylimino) -1-thia-3-azaspiro [4.4] nonane .

Compound 226

2,3-dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to method A5a. Aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to method A2a, step 3. 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7e to give the 1-amino-1- (chloromethyl) cyclopentane HCl salt. Reaction of 2-chloroethylamine with 2,3-dimethyl-4-iodophenyl isothiocyanate according to method C1e to give 2- (2,3-dimethyl-4-iodophenylimino) -1-thia- 3-azaspiro [4.4] nonane was obtained. 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. Got it.

Compound 227

2,3-dimethylaniline was converted to 2,3-dimethyl-6-nitroaniline according to method A4a. Aniline was converted to 2,3-dimethyl-6-nitrophenyl isothiocyanate according to method A2d. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate to give 2- (2,3-dimethyl-6-nitrophenylimino) -3- Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2b to give 2- (2,3-dimethyl-6-nitrophenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane .

Compound 228

2-cyano-5-nitrothiophene was reduced to 2-amino-5-cyanothiophene according to Method A1a. Aminothiophene was converted to 5-cyano-1-thiophene isothiocyanate according to Method A2b. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 5-cyano-1-thiophene isothiocyanate according to Method C1e to give 2- (5-cyanothienylimino) -3-thia-1-aza Spiro [4.4] nonane was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 2- (5-cyanothienylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 229>

6-amino-3-cyano-2,3-dimethylpyridine was converted to 3-cyano-2,3-dimethyl-6-pyridyl isothiocyanate according to Method A2c. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, the 1-chloromethylcyclopentanamine HCl salt is reacted with 3-cyano-2,3-dimethyl-6-pyridyl isothiocyanate to give 2- (3-cyano-2,3-dimethyl- 6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with isobutyl bromide according to Method D2h to give 2- (5-bromothienylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 230>

1- (hydroxymethyl) cyclopentanamine was prepared according to Method B1c. According to Method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ , followed by 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylimino) -3- Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine is reacted with 1-bromo-2-ethylbutane according to method D2a to give 2- (2-methyl-4-nitrophenylimino) -1- (2-ethyl-1-butyl) -3-thia -1-azaspiro [4.4] nonane was obtained.

Compound 231

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine is reacted with 3-bromopentane according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1- (3-pentyl) -3-thia-1-azaspiro [4.4 ] Nonan was obtained.

<Compound 232>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. Thiazolidine is reacted with isopropyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (2-propyl) -3-thia-1-azaspiro [4.4] nonane. Got it.

Compound 233

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. Thiazolidine is reacted with 3-bromo-2-methylpropene according to method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (2-methylprop-1-ene-3 -Yl) -3-thia-1-azaspiro [4.4] nonane was obtained.

Compound 234

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. Reaction of thiazolidine with allyl bromide according to method D2e results in 2- (2-methyl-4-nitrophenylimino) -1- (prop-1-en-3-yl) -3-thia-1-aza Spiro [4.4] nonane was obtained.

Compound 235

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. 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 Got.

Compound 236

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. 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 Got.

Compound 237

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. Thiazolidine is reacted with 2- (bromomethyl) tetrahydro-2H-pyran according to Method D2e to 2- (2-methyl-4-nitrophenylimino) -1- (tetrahydro-2H-pyran-2 -Ylmethyl) -3-thia-1-azaspiro [4.4] nonane was obtained.

Compound 238

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. Thiazolidine is reacted with 2- (2-bromoethyl) -1,3-dioxane according to method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (2- (1, 3-dioxan-2-yl) ethyl) -3-thia-1-azaspiro [4.4] nonane was obtained.

<Compound 239>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-methyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylphenylimino) -3-thia-1. -Azaspiro [4.4] Nonan obtained. Thiazolidine was reacted with cyclobutyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1-cyclobutyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 240>

1- (hydroxymethyl) cyclopentanamine was prepared according to Method B1c. Treatment of 2-hydroxyethylamine with SOCl ₂ according to Method C2a followed by 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylphenylimino) -3 -Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Compound 241

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. According to Method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ and then with 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylphenylimino) -3 -Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane . Oxidation of thiazolidine with m-CPBA according to Method D4a to 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane 3-oxide Got.

Compound 242

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. According to Method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ and then with 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylphenylimino) -3 -Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane . Thiazolidine was oxidized with m-CPBA according to Method D4a to 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane 3,3- Dioxide was obtained.

<Compound 243>

2-ethylaniline was protected as 2-ethylacetanilide according to Method A2a, Step 1. Acetamide was converted to 2-ethyl-4-nitroaniline and then deprotected according to method A2a, step 2. Aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to method A2a, step 3. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2-ethyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2-ethyl-4-nitrophenylphenylimino) -3-thia-1. -Azaspiro [4.4] Nonan obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-ethyl-4-nitrophenylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Compound 244

3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, step 3. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 3-methyl-4-nitrophenyl isothiocyanate to give 2- (3-methyl-4-nitrophenylimino) -3-thia-1- Azaspiro [4.4] Nonan was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (3-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Compound 245

2,3-dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, step 1. Acetamide was converted to 2,3-dimethyl-4-nitroaniline and then deprotected according to method A2a, step 2. Aniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method A2a, step 3. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to method C1e to give 2- (2,3-dimethyl-4-nitrophenylimino) -3- Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2,3-dimethyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. .

Compound 246

2,3-dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, step 1. Acetamide was converted to 2,3-dimethyl-6-nitroaniline and then deprotected according to method A2a, step 2. Aniline was converted to 2, -dimethyl-6-nitrophenyl isothiocyanate according to method A2a, step 3. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate to give 2- (2,3-dimethyl-6-nitrophenylimino) -3- Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2,3-dimethyl-6-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane .

Compound 247

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. Reaction of 1-chloromethylcyclopentanamine HCl salt with 4-iodophenyl isothiocyanate according to process C1e gives 2- (4-iodophenylphenylimino) -3-thia-1-azaspiro [4.4] Got nonan. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodophenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide was reacted with CuCN according to Method D2h to give 2- (4-cyanophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 248>

4-Cyano-2-methylaniline was prepared according to Method A1a. Aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to method A2b. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-methylphenyl isothiocyanate to give 2- (4-cyanophenylphenylimino) -3-thia-1-azaspiro [4.4] Nonan was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 249>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 250>

4-iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to method A2b. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was sequentially reacted with SOCl ₂ and 4-iodo-2-n-propylphenyl isothiocyanate according to Method C2a to give 2- (4-iodo-2-n-propylphenylimino). -3-thia-1-azaspiro [4.4] nonane was obtained. 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. Got it. Phenyl iodide was reacted with CuCN according to Method D7a to give 2- (4-cyano-2-n-propylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Compound 251

4-iodo-2-isopropylaniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to method A2b. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. According to method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ , followed by 4-iodo-2-isopropylphenyl isothiocyanate to react 2- (4-iodo-2-isopropylphenylimino ) -3-thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2-isopropylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane . Phenyl iodide was reacted with CuCN according to Method D7a to give 2- (4-cyano-2-isopropylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Compound 252

4-iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenyl isothiocyanate according to method A2b. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. According to Method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ and then with 4-iodo-2,3-dimethylphenyl isothiocyanate to react 2- (4-iodo-2,3-dimethylphenyl Imino) -3-thia-1-azaspiro [4.4] nonane was obtained. 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. Got it. Phenyl iodide was reacted with CuCN according to Method D7a to give 2- (4-cyano-2,3-dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Compound 253

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 254>

4-Cyano-2-methylaniline was prepared according to Method A1a. Aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to method A2b. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-methylphenyl isothiocyanate to give 2- (4-cyanophenylphenylimino) -3-thia-1-azaspiro [4.4] Nonan was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 255>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was 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.

<Compound 256>

Methyl 4-amino-3-methylbenzoate was converted to 4-methoxycarbonyl-2-methylphenyl isothiocyanate according to method A2b. 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. According to method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ , followed by 4-methoxycarbonyl-2-methylphenyl isothiocyanate to react 2- (4-methoxycarbonyl-2-methylphenylimino ) -3-thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2h to give 2- (4-methoxycarbonyl-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane .

Compound 257

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. By reacting benzoic acid with methylamine according to method D6b, 2- (4- (N-methylcarbamoyl) -2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane Got.

Compound 258

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. By reacting benzoic acid with dimethylamine according to method D6b, 2- (4- (N, N-dimethylcarbamoyl) -2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4 ] Nonan was obtained.

<Compound 259>

2,3-dichloroaniline was converted to 2,3-dichloroformanilide according to Method A3a, step 1. Formanilide was converted to 2,3-dichlorophenyl isocyanide dichloride according to Method A3a, step 2. 1-hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B1c. 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to Method B4d, step 1. Oxazolidin was reductively ring-opened according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. Substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (acetylthiomethyl) cyclopentane according to Method C6c, step 1. Thioacetate was hydrolyzed according to Method C6c, step 2 to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. According to method C6c, 2-thioethylamine is reacted with 2,3-dichlorophenyl isocyanide dichloride to give 2- (2,3-dichlorophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] Nonan was obtained.

Compound 260

2- (trifluoromethyl) aniline was converted to 2- (trifluoromethyl) formanilide according to Method A3a, step 1. Formanilide was converted to 2- (trifluoromethyl) phenyl isocyanide dichloride according to Method A3a, step 2. 1-hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B1c. 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to Method B4d, step 1. Oxazolidin was reductively ring-opened according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. Substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, step 1. Thioacetate was hydrolyzed according to Method C6c, step 2 to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. 2-thioethylamine is reacted with 2- (trifluoromethyl) phenyl isocyanide dichloride according to method C6c to 2- (2- (trifluoromethyl) phenylimino) -1-cyclopentyl-3- Thia-1-azaspiro [4.4] nonane was obtained.

<Compound 261>

4- (trifluoromethyl) aniline was converted to 4- (trifluoromethyl) formanilide according to Method A3a, step 1. Formanilide was converted to 4- (trifluoromethyl) phenyl isocyanide dichloride according to Method A3a, step 2. 1-hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B1c. 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to Method B4d, step 1. Oxazolidin was reductively ring-opened according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. Substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, step 1. Thioacetate was 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 to 2- (4- (trifluoromethyl) phenylimino) -1-cyclopentyl-3- Thia-1-azaspiro [4.4] nonane was obtained.

Compound 262

2-chloro-3-methylaniline was converted to 2-chloro-3-methylformanilide according to Method A3a, step 1. Formanilide was converted to 2-chloro-3-methylphenyl isocyanide dichloride according to Method A3a, step 2. 1-hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B1c. 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to Method B4d, step 1. Oxazolidin was reductively ring-opened according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. Substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, step 1. Thioacetate was hydrolyzed according to Method C6c, step 2 to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. According to method C6c, 2-thioethylamine is reacted with 2-chloro-3-methylphenyl isocyanide dichloride to give 2- (2-chloro-3-methylphenylimino) -1-cyclopentyl-3-thia-1- Azaspiro [4.4] Nonan was obtained.

Compound 263

3- (trifluoromethyl) aniline was converted to 3- (trifluoromethyl) formanilide according to Method A3a, step 1. Formanilide was converted to 3- (trifluoromethyl) phenyl isocyanide dichloride according to Method A3a, step 2. 1-hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B1c. 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to Method B4d, step 1. Oxazolidin was reductively ring-opened according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. Substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, step 1. Thioacetate was 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 2- (3- (trifluoromethyl) phenylimino) -1-cyclopentyl-3- Thia-1-azaspiro [4.4] nonane was obtained.

Compound 264

3-chloro-2-methylaniline was converted to 3-chloro-2-methylformanilide according to Method A3a, step 1. Formanilide was converted to 3-chloro-2-methylphenyl isocyanide dichloride according to Method A3a, step 2. 1-hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B1c. 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to Method B4d, step 1. Oxazolidin was reductively ring-opened according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. Substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, step 1. Thioacetate was hydrolyzed according to Method C6c, step 2 to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. According to method C6c, 2-thioethylamine is reacted with 3-chloro-2-methylphenyl isocyanide dichloride to give 2- (3-chloro-2-methylphenylimino) -1-cyclopentyl-3-thia-1- Azaspiro [4.4] Nonan was obtained.

Compound 265

2,3-dichloro-4-methylaniline was converted to 2,3-dichloro-4-methylformanilide according to Method A3a, step 1. Formanilide was converted to 2,3-dichloro-4-methylphenyl isocyanide dichloride according to Method A3a, step 2. 1-hydroxymethylcyclopentanamine HCl salt was synthesized according to Method B1c. 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro [4.2.4.1] tridecane according to Method B4d, step 1. Oxazolidin was reductively ring-opened according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. Substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, step 1. Thioacetate was hydrolyzed according to Method C6c, step 2 to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. According to Method C6c, 2-thioethylamine is reacted with 2,3-dichloro-4-methylphenyl isocyanide dichloride to give 2- (2,3-dichloro-4-methylphenylimino) -1-cyclopentyl-3- Thia-1-azaspiro [4.4] nonane was obtained.

<Compound 266>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. According to Method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ , followed by 4-bromo-2-methylphenyl isothiocyanate to react 2- (4-bromo-2-methylphenylimino) -3- Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-bromo-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 267>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced in accordance with Method D11a to afford 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Compound 268

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced in accordance with Method D11a to afford 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with triethyl phosphonoacetate according to method D12a to give 2- (2-ethyl-4-((1E) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia- 1-azaspiro [4.4] nonane was obtained.

<Compound 269>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced in accordance with Method D11a to afford 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with nitromethane according to method D12b to give 2- (2-ethyl-4-((1E) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4 ] Nonan was obtained.

Compound 270

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced in accordance with Method D11a to afford 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with triethyl phosphonoacetate according to method D12a to give 2- (2-ethyl-4-((1E) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia- 1-azaspiro [4.4] nonane was obtained. Saponification of the esters according to method D6a gave 2- (2-ethyl-4-((1E) -2-carboxyvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane Got.

<Compound 271>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced in accordance with Method D11a to afford 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with malononitrile according to method D12c to give 2- (2-ethyl-4- (2,2-dicyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4 ] Nonan was obtained.

Compound 272

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced in accordance with Method D11a to afford 2- (4-formyl-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 give 2- (2-ethyl-4-((1E) -2-acetylvinyl) phenylimino) -1-cyclopentyl-3 -Thia-1-azaspiro [4.4] nonane was obtained.

<Compound 273>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. According to Method C1e, 1-chloromethylcyclopentanamine HCl salt is reacted with 4-cyano-2-ethylphenyl isothiocyanate to give 2- (4-cyano-2-ethylphenylimino) -3-thia- 1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was reduced in accordance with Method D11a to afford 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde is reacted with acetonitrile according to method D12d to give 2- (2-ethyl-4-((1E) -2-cyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [ 4.4] gave a nonan.

Compound 274

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. According to Method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ , followed by 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylimino) -3- Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cyclohexyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1-cyclohexyl-3-thia-1-azaspiro [4.4] nonane.

<Compound 275>

1-hydroxymethylcyclopentanamine was prepared according to Method B1c. According to Method C2a, 2-hydroxyethylamine is reacted with SOCl ₂ , followed by 2-methyl-4-nitrophenyl isothiocyanate to react 2- (2-methyl-4-nitrophenylimino) -3- Thia-1-azaspiro [4.4] nonane was obtained. Thiazolidine was reacted with cycloheptyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1-cycloheptyl-3-thia-1-azaspiro [4.4] nonane.

Compound 276

The 1-aminocyclohexane-1-carboxylic acid was protected as benzyloxycarbonylamine according to Method B1a, Step 1. 1- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid was reduced to 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) cyclohexane according to Method B1a, step 2. Carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1- (hydroxymethyl) cyclohexane. Treatment of 2-hydroxyethylamine with SOCl ₂ according to method C2a followed by 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- Thia-1-azaspiro [4.5] decane was obtained. Thiazolidine was alkylated with isobutyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-isobutyl-3-thia-1-azaspiro [4.5] decane.

<Compound 277>

2-Methyl-4-nitroaniline was converted to 2-methyl-4-nitroformanilide according to Method A3a, Step 1. Formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a, step 2. 3-aminotetrahydro-2H-pyran-3-carboxylic acid was converted to methyl ester according to Method Blb, Step 1. Methyl 3-aminotetrahydro-2H-pyran-3-carboxylate was reduced to 3-amino-3- (hydroxymethyl) tetrahydro-2H-pyran according to Method Blb, Step 2. 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-1-aza-3,7-dioxaspiro [4.5] decane. Oxazolidine was reduced with 3-isobutylamino-3- (hydroxymethyl) tetrahydro-2H-pyran. Substituted 2-hydroxyethylamine was converted to 3-isobutylamino-3- (acetylthiomethyl) tetrahydro-2H-pyran according to Method C6c, step 1. The thioacetate was saponified according to Method C6c, Step 2 to obtain 3-isobutylamino-3- (thiomethyl) tetrahydro-2H-pyran. 2-thioethylamine is reacted with 2-methyl-4-nitrophenyl isocyanide dichloride to give 2- (2-methyl-4-nitrophenylimino-1-isobutyl-1-aza-7-oxa-3 -Tiaspiro [4.5] decane was obtained.

Compound 278

2-Methyl-4-nitroaniline was converted to 2-methyl-4-nitroformanilide according to Method A3a, Step 1. Formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a, step 2. 4-Aminotetrahydro-2H-pyran-4-carboxylic acid was converted to methyl ester according to Method Blb, Step 1. Methyl 4-aminotetrahydro-2H-pyran-4-carboxylate was reduced to 4-amino-4- (hydroxymethyl) tetrahydro-2H-pyran according to Method Blb, Step 2. 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-1-aza-3,8-dioxaspiro [4.5] decane. Oxazolidine was reduced with 4-isobutylamino-4- (hydroxymethyl) tetrahydro-2H-pyran. Substituted 2-hydroxyethylamine was converted to 4-isobutylamino-4- (acetylthiomethyl) tetrahydro-2H-pyran according to Method C6c, step 1. The thioacetate was saponified according to Method C6c, Step 2 to obtain 4-isobutylamino-4- (thiomethyl) tetrahydro-2H-pyran. 2-thioethylamine is reacted with 2-methyl-4-nitrophenyl isocyanide dichloride to give 2- (2-methyl-4-nitrophenylimino-1-isobutyl-1-aza-8-oxa-3 -Tiaspiro [4.5] decane was obtained.

<Compound 279>

The 2-amino-2-norbornane-1-carboxylic acid as isomer mixture was converted to N-benzyloxycarbonyl analogs according to Method B la, Step 1. 1- (benzyloxycarbonylamino) -2-norbornane-1-carboxylic acid was prepared according to Method B1a, Step 2, and 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) -2-nor Reduced to Bornan. Carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1- (hydroxymethyl) -2-norbornane. 2-hydroxyethylamine was alkylated with isobutyl bromide according to Method B2a to give N-isobutyl-1-amino-1- (hydroxymethyl) -2-norbornane. The alkylated 2-hydroxyethylamine was treated with SOCl ₂ according to Method B7a to give the N-isobutyl-2-chloroethylamine HCl salt. Treatment of chloroethylamine with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a gives 2- (2-methyl-4-nitrophenylimino) -3-isobutylspiro [1,3-thiazoli Dean-4,3'-bicyclo [3.2.1] octane was obtained.

Compound 280

N- (tert-butoxycarbonyl)-(L) -valine was converted to (S) -3- (tert-butoxycarbonylamino) -1-diazo-4-methylpentane- according to Method B6a, Step 1. Switched to 2-on. The diazo compound was converted to methyl (R) -3- (tert-butoxycarbonylamino) -4-methylpentanoate according to Method B6a, step 2. The ester was reduced according to Method B6a, step 3 to afford (R) -3- (tert-butoxycarbonylamino) -4-methylpentan-1-ol. Carbamate was deprotected and converted to (R) -3-amino-1-chloro-4-methylpentane according to Method B7e. Treatment of 3-chloropropylamine with 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a gives (4R) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-1 , 3-thiazine was obtained. (4R) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1,3-thiazine HCl salt by alkylating thiazine with isobutyl bromide according to method D2a Got.

<Compound 281>

3-aminopropanol was reacted with butyraldehyde according to Method B9a, Step 1 to give 2-isopropyltetrahydro-1,3-oxazine. Oxazine was reduced according to Method B9a, Step 2 to afford N-isobutyl-3-hydroxypropylamine. 3-hydroxypropylamine was reacted with SOCl ₂ according to Method B9a, Step 3 to obtain an N-isobutyl-3-chloropropylamine HCl salt. The reaction of 3-chloropropylamine with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a gives 2- (2-methyl-4-nitrophenylimino) -3-isobutyltetrahydro-1,3 -Got thiazine.

Compound 282

4-aminobutanol was reacted with butyraldehyde according to Method B9a, Step 1 to give 2-isopropyltetrahydro-1,3-oxazepine. 1,3-Oxazepine was reduced according to Method B9a, Step 2 to obtain N-isobutyl-3-hydroxybutylamine. 3-hydroxybutylamine was reacted with SOCl ₂ according to Method B9a, Step 3 to obtain an N-isobutyl-3-chlorobutylamine HCl salt. 3-chlorobutylamine is reacted with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyltetrahydro-1,3 -Tiazepine was obtained.

<Compound 283>

According to Method C8a, 3-methyl-4-nitrophenyl isothiocyanate is reacted with isobutylamine and then with chloroacetic acid to react 2- (3-methyl-4-nitrophenylimino) -3-isobutyl- 1,3-thiazolidin-4-one was obtained.

<Compound 284>

According to method C8a, 3-methyl-4-nitrophenyl isothiocyanate is reacted with benzylamine and then with chloroacetic acid to react 2- (3-methyl-4-nitrophenylimino) -3- (phenylmethyl) -1,3-thiazolidin-4-one was obtained.

<Compound 285>

The reaction of 3-methyl-4-nitrophenyl isothiocyanate with 2-methyl-1-butylamine according to method C8a followed by chloroacetic acid to give 2- (3-methyl-4-nitrophenylimino)- 3- (2-methylbutyl) -1,3-thiazolidin-4-one was obtained.

<Compound 286>

Reaction of 3-methyl-4-nitrophenyl isothiocyanate with 1-amino-1-cyclohexylethane according to method C8a, followed by reaction with chloroacetic acid to give 2- (3-methyl-4-nitrophenylimino) 3- (1-cyclohexylethyl) -1,3-thiazolidin-4-one was obtained.

<Compound 287>

Reaction of 2-methyl-4-nitrophenyl isothiocyanate with isobutylamine according to method C8a, followed by reaction with chloroacetic acid to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl- 1,3-thiazolidin-4-one was obtained.

<Compound 288>

Reaction of 2-methyl-4-nitrophenyl isothiocyanate with 2-methyl-1-butylamine according to method C8a, followed by chloroacetic acid to give 2- (2-methyl-4-nitrophenylimino)- 3- (2-methylbutyl) -1,3-thiazolidin-4-one was obtained.

<Compound 289>

According to method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with benzylamine and then with chloroacetic acid to react 2- (2-methyl-4-nitrophenylimino) -3- (phenylmethyl) -1,3-thiazolidin-4-one was obtained.

Compound 290

According to Method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with isobutylamine and then with α-chloropropionic acid to react 2- (2-methyl-4-nitrophenylimino) -3-iso. Butyl-5-methyl-1,3-thiazolidin-4-one was obtained.

<Compound 291>

Reaction of 2-methyl-4-nitrophenyl isothiocyanate with 1-amino-1-cyclohexylethane according to method C8a, followed by reaction with chloroacetic acid to give 2- (2-methyl-4-nitrophenylimino) 3- (1-cyclohexylethyl) -1,3-thiazolidin-4-one was obtained.

<Compound 292>

Reaction of 2-methyl-4-nitrophenyl isothiocyanate with (1S) -1-amino-1-cyclohexylethane according to method C8a, followed by reaction with chloroacetic acid to give 2- (2-methyl-4-nitro Phenylimino) -3-((1S) -1-cyclohexylethyl) -1,3-thiazolidin-4-one was obtained.

<Compound 293>

According to method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1R) -1-amino-1-cyclohexylethane and then with chloroacetic acid to react 2- (2-methyl-4-nitro Phenylimino) -3-((1R) -1-cyclohexylethyl) -1,3-thiazolidin-4-one was obtained.

<Compound 294>

2-methyl-4-nitrophenyl isothiocyanate is reacted with isobutylamine according to method C8a, followed by reaction with α-chloro-α-phenylacetic acid to give 2- (2-methyl-4-nitrophenylimino). 3-isobutyl-5-phenyl-1,3-thiazolidin-4-one was obtained.

<Compound 295>

According to Method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1R) -1-amino-1-cyclohexylethane and then with α-chloropropionic acid to react with 2- (2-methyl-4 -Nitrophenylimino) -3-((1R) -1-cyclohexylethyl) -5-methyl-1,3-thiazolidin-4-one was obtained.

<Compound 296>

According to Method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1R) -1-amino-1-cyclohexylethane and then with α-chloro-α-phenylacetic acid to give 2- (2 -Methyl-4-nitrophenylimino) -3-((1R) -1-cyclohexylethyl) -5-phenyl-1,3-thiazolidin-4-one was obtained.

<Compound 297>

According to Method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1-amino-1-cyclohexylethane and then with α-chloropropionic acid to react with 2- (2-methyl-4 -Nitrophenylimino) -3-((1S) -1-cyclohexylethyl) -5-methyl-1,3-thiazolidin-4-one was obtained.

<Compound 298>

According to Method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1-amino-1-cyclohexylethane and then with α-chloro-α-phenylacetic acid to give 2- (2 -Methyl-4-nitrophenylimino) -3-((1S) -1-cyclohexylethyl) -5-phenyl-1,3-thiazolidin-4-one was obtained.

<Compound 299>

2-methyl-4-nitrophenyl isothiocyanate is reacted with 2-ethyl-1-butylamine according to Method C8a, followed by reaction with α-chloropropionic acid to 2- (2-methyl-4-nitrophenylimino ) -3- (2-ethyl-1-butyl) -5-methyl-1,3-thiazolidin-4-one was obtained.

<Compound 300>

2-methyl-4-nitrophenyl isothiocyanate is reacted with isobutylamine according to method C8a, followed by 2-chloro-4-methylpentanoic acid to react 2- (2-methyl-4-nitrophenylimino ) -3-isobutyl-5-isobutyl-1,3-thiazolidin-4-one was obtained.

<Compound 301>

According to Method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with 2-ethyl-1-butylamine and then with 2-chloro-4-methylpentanoic acid to react 2- (2-methyl-4 -Nitrophenylimino) -3-isobutyl-5- (2-ethyl-1-butyl) -1,3-thiazolidin-4-one was obtained.

Compound 302

2-methyl-4-nitrophenyl isothiocyanate is reacted with 2-methylbutylamine according to method C8a, followed by 2-chloro-4-methylpentanoic acid to react 2- (2-methyl-4-nitrophenyl Imino) -3- (2-butyl) -5-isobutyl-1,3-thiazolidin-4-one was obtained.

Compound 303

According to method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with 2-methylbutylamine, and then 2-chloro-3-methylbutanoic acid is used to react 2- (2-methyl-4-nitrophenyl. Mino) -3- (2-butyl) -5-isopropyl-1,3-thiazolidin-4-one was obtained.

<Compound 304>

2-methyl-4-nitrophenyl isothiocyanate is reacted with isobutylamine according to method C8a, followed by 2-chloro-3-methylbutanoic acid to react 2- (2-methyl-4-nitrophenylimino). 3-isobutyl-5-isopropyl-1,3-thiazolidin-4-one was obtained.

Compound 305

Reaction of 2-methyl-4-nitrophenyl isothiocyanate with (2S) -2-methyl-1-butylamine according to method C8a followed by chloroacetic acid to react 2- (2-methyl-4-nitrophenyl Imino) -3-((2S) -2-methyl-1-butyl) -1,3-thiazolidin-4-one was obtained.

Compound 306

According to Method C8a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with 2-ethyl-1-butylamine, followed by 2-chloro-3-methylbutanoic acid to react 2- (2-methyl-4- Nitrophenylimino) -3- (2-ethyl-1-butyl) -5-isopropyl-1,3-thiazolidin-4-one was obtained.

Compound 307

(R) -N-isobutylserine methyl ester HCl salt was prepared from (D) -serine methyl ester as described in method B3a. The alcohol is reacted with SOCl ₂ according to Method B7b and then reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-iso. Butyl-4-methylene-1,3-thiazolidin-5-one was obtained.

Compound 308

According to method C8a, 2,4,6-trichlorophenyl isothiocyanate is reacted with 2-butylamine and then with chloroacetic acid to react 2- (2,4,6-trichlorophenylimino) -3- (2-butyl) -1,3-thiazolidin-4-one was obtained.

Compound 309

According to method C8a, 3,4-dichlorophenyl isothiocyanate is reacted with 2-methylbutylamine and then with chloroacetic acid to react 2- (3,4-dichlorophenylimino) -3- (2-butyl) -1,3-thiazolidin-4-one was obtained.

<Compound 310>

Reaction of N-isobutylglycine ethyl ester with 2-methyl-4-nitrophenyl isothiocyanate according to method C11a gives 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3 -Thiazolidin-5-one was obtained.

<Compound 311>

The reaction of 2-methyl-4-nitrophenyl isothiocyanate with 2-ethyl-1-butylamine according to method C8a followed by chloroacetic acid to give 2- (2-methyl-4-nitrophenylimino)- 3- (2-ethyl-1-butyl) -1,3-thiazolidin-4-one was obtained.

<Compound 312>

N-isobutylleucine ethyl ester is reacted with 2-methyl-4-nitrophenyl isothiocyanate according to method C11a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3,4 -Diisobutyl-1,3-thiazolidin-5-one was obtained.

<Compound 313>

N-isobutylproline ethyl ester is reacted with 2-methyl-4-nitrophenyl isothiocyanate according to method C11a to 4- (2-methyl-4-nitrophenylimino) -1-oxophydro-2- Obtained thiapyrrolidin.

Compound 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 was obtained. The ester was reduced according to Method B8b, step 2 to afford N- (tert-butoxycarbonyl) -N- (2-hydroxyethyl) -1-amino-2-methylprop-2-ene. N- (tert-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2-methylprop-2 by treating alcohol with p-toluenesulfonyl chloride according to Method B8b, step 3 -Got yen. Carbamate was deprotected according to Method B8b, step 4 to obtain N- (2-tosyloxyethyl) -2-methylprop-2-ene-1-ammonium trifluoroacetate. Tosylate is reacted with 2-methyl-4-nitrophenyl isocyanate according to method C5a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -1, 3-oxazolidine was obtained.

Compound 315

(L) -valine methyl ester was reduced to (1S) -1- (hydroxymethyl) -2-methylpropylamine according to Method Blb, Step 2. 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give (4S) -2,4-diisopropyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to give (1S) -1- (hydroxymethyl) -N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7b to give (1S) -1- (chloromethyl) -N-isobutyl-2-methylpropylamine. Chloroethylamine is reacted with 2-methyl-4-nitrophenyl isocyanate according to method C4a to (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1 , 3-oxazolidine was obtained.

Compound 316

(L) -Leucine methyl ester was reduced to (1S) -1- (hydroxymethyl) -3-methylbutylamine according to Method Blb, Step 2. 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to give (1S) -1- (hydroxymethyl) -N-isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7b to give (1S) -1- (chloromethyl) -N-isobutyl-3-methylbutylamine. According to Method C4a, chloroethylamine is reacted with 2-methyl-4-nitrophenyl isocyanate to give (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3 Obtained oxazolidine.

Compound 317

(L) -Leucine methyl ester was reduced to (1S) -1- (hydroxymethyl) -3-methylbutylamine according to Method Blb, Step 2. 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to give (1S) -1- (hydroxymethyl) -N-isobutyl-3-methylbutylamine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, step 1. Formanilide was reacted with SOCl ₂ and SO ₂ Cl ₂ according to Method A3a, Step 2 to give 4-cyano-2-ethylphenyl isocyanide dichloride. Substituted 2-hydroxyethylamine was reacted with 4-cyano-2-ethylphenyl isocyanide dichloride according to Method C7b to give (4S) -2- (4-cyano-2-ethylphenylimino)-. 3,4-Diisobutyl-1,3-oxazolidine was obtained.

Compound 318

2-amino-2-methyl-1-propanol was reacted with cyclopentanone according to Method B4b, Step 1 to obtain 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane. Oxazolidine was reduced according to Method B4b, step 2 to afford N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine. 2-Methyl-4-nitroaniline was converted to 2-methyl-4-nitroformanilide according to Method A3a, Step 1. Formanilide was reacted with SOCl ₂ and SO ₂ Cl ₂ according to Method A3a, Step 2 to give 2-methyl-4-nitrophenyl isocyanide dichloride. Substituted 2-hydroxyethylamine is reacted with 2-methyl-4-nitrophenyl isocyanide dichloride according to Method C7a to 2- (2-methyl-4-nitrophenylimino) -3-cyclopentyl-4 , 4-dimethyl-1,3-oxazolidine was obtained.

Compound 319

2-amino-2-methyl-1-propanol was reacted with cyclopentanone according to Method B4b, Step 1 to obtain 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane. Oxazolidine was reduced according to Method B4b, step 2 to afford N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, step 1. Formanilide was reacted with SOCl ₂ and SO ₂ Cl ₂ according to Method A3a, Step 2 to give 4-cyano-2-ethylphenyl isocyanide dichloride. The substituted 2-hydroxyethylamine is reacted with 4-cyano-2-ethylphenyl isocyanide dichloride according to method C7a to give 2- (4-cyano-2-ethylphenylimino) -3-cyclopentyl -4,4-dimethyl-1,3-oxazolidine was obtained.

<Compound 320>

1-aminocyclopentanecarboxylic acid was converted to methyl ester according to Method B1c, step 1. The ester was reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. Hydroxyethylamine was reacted with cyclopentanone according to Method B4d, Step 1 to give 6-aza-12-oxadispiro [4.1.4.2] tridecane. Oxazolidine was reduced according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7b to give 1- (cyclopentylamino) -1- (chloromethyl) cyclopentane. 2-chloroethylamine is reacted with 2-methyl-4-nitrophenyl isocyanate according to method C4a to 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] Nonan was obtained.

Compound 321

1-aminocyclopentanecarboxylic acid was converted to methyl ester according to Method B1c, step 1. The ester was reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. 2-hydroxyethylamine was reacted with cyclobutanone according to Method B4a, Step 1 to give 5-aza-12-oxadispiro [3.1.4.2] dodecane. Oxazolidine was reduced according to Method B4a, Step 2 to give 1- (cyclobutylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7b to give 1- (cyclobutylamino) -1- (chloromethyl) cyclopentane. 2-chloroethylamine is reacted with 2-methyl-4-nitrophenyl isocyanate according to method C4a to 1-cyclobutyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] Nonan was obtained.

Compound 322

1-aminocyclopentanecarboxylic acid was converted to methyl ester according to Method B1c, step 1. The ester was reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. Hydroxyethylamine was reacted with cyclohexanone according to Method B4a, Step 1 to give 6-aza-13-oxadispiro [4.1.5.2] tedecane. Oxazolidine was reduced according to Method B4a, Step 2 to give 1- (cyclohexylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7b to give 1- (cyclohexylamino) -1- (chloromethyl) cyclopentane. 2-chloroethylamine is reacted with 2-methyl-4-nitrophenyl isocyanate according to method C4a to 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] Nonan was obtained.

Compound 323

1-aminocyclopentanecarboxylic acid was converted to methyl ester according to Method B1c, step 1. The ester was reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. Hydroxyethylamine was reacted with cyclopentanone according to Method B4d, Step 1 to give 6-aza-12-oxadispiro [4.1.4.2] tridecane. Oxazolidine was reduced according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, step 1. Formanilide was reacted with SOCl ₂ and SO ₂ Cl ₂ according to Method A3a, Step 2 to give 4-cyano-2-ethylphenyl isocyanide dichloride. Substituted 2-hydroxyethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride according to Method C7a to 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3 -Oxa-1-azaspiro [4.4] nonane was obtained.

Compound 324

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, step 1-2. The alcohol was converted to N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. According to Method C1f, 4-nitrophenyl isothiocyanate is reacted with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride to give 2- (4-nitrophenyl Thio) -1,5-diisobutylimidazoline was obtained.

Compound 325

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with 5-iodoheptane according to Method D2a to give (4S) -2- (N- (4-heptyl) -N- (2-methyl-5-nitrophenyl) amino) -4-isobutyl -1,3-thiazoline was obtained.

Compound 326

(1R) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (D) -leucine methyl ester according to Method Blb. 2-hydroxyethylamine was converted to (1R) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 2-methyl-5-nitrophenyl isothiocyanate is reacted with (1R) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4R) -2- (2-methyl-5- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4R) -2- (N-isobutyl-N- (2-methyl-5-nitrophenyl) amino) -4-isobutyl-1,3- Thiazoline HCl salt was obtained.

Compound 327

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to method C1a, 2-methyl-4-nitrophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4- Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with neopentyl bromide according to method D2a to give (4S) -2- (N- (2,2-dimethylpropyl) -2-methyl-4-nitrophenylamino) -4-isobutyl-1, 3-thiazoline was obtained.

Compound 328

(1S) -1- (hydroxymethyl) -3-methylbutylamine was prepared from (L) -leucine methyl ester as described in Method B1b. 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. According to Method C1a, 2,3-dichlorophenyl isothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutanammonium chloride to (4S) -2- (2,3-dichlorophenylimino ) -4-isobutyl-1,3-thiazolidine was obtained. Thiazolidine is reacted with 3-bromopentane according to Method D2a to (4S) -2- (N- (3-pentyl) -2-methyl-4-nitrophenylamino) -4-isobutyl-1,3 -Tiazoline was obtained.

table

The compounds described in Tables 1 to 4 below were synthesized according to the methods described above.

(a) Hewlett Packard 1100 HPLC equipped with Finnigan LCQ MS detector and 2 × 300 mm Phenomenex 3 μM C-18 column; Flow rate 1.0 mL / min; Buffer A: 0.02% TFA / 2% CH ₃ CN / water, buffer B: 0.018% TFA / 98% CH ₃ CN / water; Hold 100% Buffer A for 1 minute, gradient for 3 minutes from 100% Buffer A to 100% Buffer B, hold for 100% Buffer B for 1 minute, gradient for 100 minutes from 100% Buffer B to 100% Buffer A, 100% Buffer A hold for 1.5 minutes.

(b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detectors (254 and 220 nm) and 4 × 100 mm Dynamax 3 μM C-18 column; Flow rate 1.5 mL / min; Buffer A: 0.5% TFA / water, buffer B: 0.5% TFA / CH ₃ CN; Gradient for 10 minutes from 100% Buffer A to 100% Buffer B, hold 100% Buffer B for 5 minutes.

(c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and 4 × 125 mm nucleosyl 3 μM C-18 column; Flow rate 2.0 mL / min; Buffer A: 0.01 mol% H ₃ PO ₄ / water, buffer B: 0.01 mol% H ₃ PO ₄ / CH ₃ CN; 10% buffer B 1 minute, gradient from 10% buffer B to 90% buffer B for 8 minutes, gradient from 90% buffer B to 10% buffer B for 4 minutes.

(d) Renin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dynamax 8 μM C-18 column; Flow rate 18 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 30% Buffer B to 100% Buffer B for 25 minutes, hold 100% Buffer B for 30 minutes.

(e) Lanin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dynamax 8 μM C-18 column; Flow rate 18 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 50% Buffer B to 60% Buffer B for 25 minutes, from 60% to 100% for 32 minutes.

(f) Renin Dynamax HPLC equipped with UV-DII dual wavelength detectors (254 and 220 nm) and 21 × 2500 mm Microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 30% Buffer B to 100% Buffer B for 25 minutes, hold 100% Buffer B for 30 minutes.

(g) Lenin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 50% Buffer B to 100% Buffer B for 25 minutes, 100% Buffer B maintained for 7 minutes.

(h) Renin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 10% Buffer B to 100% Buffer B for 30 minutes, 100% Buffer B maintained for 7 minutes.

(i) Lanin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 4.6 × 100 mm microsorb 5 μM C-8 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 10% Buffer B to 100% Buffer B for 5 minutes, hold 100% Buffer B for 1.5 minutes.

(j) Lenin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 20% Buffer B to 100% Buffer B for 30 minutes, 100% Buffer B maintained for 7 minutes.

(a) Hewlett Packard 1100 HPLC equipped with a Finigan LCQ MS detector and a 2 × 300 mm Phenomenex 3 μM C-18 column; Flow rate 1.0 mL / min; Buffer A: 0.02% TFA / 2% CH ₃ CN / water, buffer B: 0.018% TFA / 98% CH ₃ CN / water; Hold 100% Buffer A for 1 minute, gradient for 3 minutes from 100% Buffer A to 100% Buffer B, hold for 100% Buffer B for 1 minute, gradient for 100 minutes from 100% Buffer B to 100% Buffer A, 100% Buffer A hold for 1.5 minutes.

(b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detectors (254 and 220 nm) and a 4 × 100 mm Dynamax 3 μM C-18 column; Flow rate 1.5 mL / min; Buffer A: 0.5% TFA / water, buffer B: 0.5% TFA / CH ₃ CN; Gradient for 10 minutes from 100% Buffer A to 100% Buffer B, hold 100% Buffer B for 5 minutes.

(c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and 4 × 125 mm nucleosyl 3 μM C-18 column; Flow rate 2.0 mL / min; Buffer A: 0.01 mol% H ₃ PO ₄ / water, buffer B: 0.01 mol% H ₃ PO ₄ / CH ₃ CN; 10% buffer B 1 minute, gradient from 10% buffer B to 90% buffer B for 8 minutes, gradient from 90% buffer B to 10% buffer B for 4 minutes.

(d) Renin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dynamax 8 μMC-18 column; Flow rate 18 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 30% Buffer B to 100% Buffer B for 25 minutes, hold 100% Buffer B for 30 minutes.

(e) Lanin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dynamax 8 μM C-18 column; Flow rate 18 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 50% Buffer B to 60% Buffer B for 25 minutes, from 60% to 100% for 32 minutes.

(f) Renin Dynamax HPLC equipped with UV-DII dual wavelength detectors (254 and 220 nm) and 21 × 2500 mm Microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 30% Buffer B to 100% Buffer B for 25 minutes, hold 100% Buffer B for 30 minutes.

(g) Lenin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 50% Buffer B to 100% Buffer B for 25 minutes, 100% Buffer B maintained for 7 minutes.

(h) Renin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 10% Buffer B to 100% Buffer B for 30 minutes, 100% Buffer B held for 7 minutes.

(i) Lanin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 4.6 × 100 mm microsorb 5 μM C-8 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 10% Buffer B to 100% Buffer B for 5 minutes, hold 100% Buffer B for 1.5 minutes.

(j) Lenin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 20% Buffer B to 100% Buffer B for 30 minutes, 100% Buffer B maintained for 7 minutes.

(a) Hewlett Packard 1100 HPLC equipped with a Finigan LCQ MS detector and a 2 × 300 mm Phenomenex 3 μM C-18 column; Flow rate 1.0 mL / min; Buffer A: 0.02% TFA / 2% CH ₃ CN / water, buffer B: 0.018% TFA / 98% CH ₃ CN / water; Hold 100% Buffer A for 1 minute, gradient for 3 minutes from 100% Buffer A to 100% Buffer B, hold for 100% Buffer B for 1 minute, gradient for 100 minutes from 100% Buffer B to 100% Buffer A, 100% Buffer A hold for 1.5 minutes.

(b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detectors (254 and 220 nm) and a 4 × 100 mm Dynamax 3 μM C-18 column; Flow rate 1.5 mL / min; Buffer A: 0.5% TFA / water, buffer B: 0.5% TFA / CH ₃ CN; Gradient for 10 minutes from 100% Buffer A to 100% Buffer B, hold 100% Buffer B for 5 minutes.

(c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and 4 × 125 mm nucleosyl 3 μM C-18 column; Flow rate 2.0 mL / min; Buffer A: 0.01 mol% H ₃ PO ₄ / water, buffer B: 0.01 mol% H ₃ PO ₄ / CH ₃ CN; 10% buffer B 1 minute, gradient from 10% buffer B to 90% buffer B for 8 minutes, gradient from 90% buffer B to 10% buffer B for 4 minutes.

(d) Renin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dynamax 8 μM C-18 column; Flow rate 18 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 30% Buffer B to 100% Buffer B for 25 minutes, hold 100% Buffer B for 30 minutes.

(e) Lanin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dynamax 8 μM C-18 column; Flow rate 18 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 50% Buffer B to 60% Buffer B for 25 minutes, from 60% to 100% for 32 minutes.

(f) Renin Dynamax HPLC equipped with UV-DII dual wavelength detectors (254 and 220 nm) and 21 × 2500 mm Microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 30% Buffer B to 100% Buffer B for 25 minutes, hold 100% Buffer B for 30 minutes.

(g) Lenin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 50% Buffer B to 100% Buffer B for 25 minutes, 100% Buffer B maintained for 7 minutes.

(h) Renin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 10% Buffer B to 100% Buffer B for 30 minutes, 100% Buffer B maintained for 7 minutes.

(i) Lanin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 4.6 × 100 mm microsorb 5 μM C-8 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 10% Buffer B to 100% Buffer B for 5 minutes, hold 100% Buffer B for 1.5 minutes.

(j) Lenin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 20% Buffer B to 100% Buffer B for 30 minutes, 100% Buffer B maintained for 7 minutes.

(a) Hewlett Packard 1100 HPLC equipped with a Finigan LCQ MS detector and a 2 × 300 mm Phenomenex 3 μM C-18 column; Flow rate 1.0 mL / min; Buffer A: 0.02% TFA / 2% CH ₃ CN / water, buffer B: 0.018% TFA / 98% CH ₃ CN / water; Hold 100% Buffer A for 1 minute, gradient for 3 minutes from 100% Buffer A to 100% Buffer B, hold for 100% Buffer B for 1 minute, gradient for 100 minutes from 100% Buffer B to 100% Buffer A, 100% Buffer A hold for 1.5 minutes.

(b) Ranin Dynamax HPLC equipped with UV-DII dual wavelength detectors (254 and 220 nm) and 4 × 100 mm Dynamax 3 μMC-18 columns; Flow rate 1.5 mL / min; Buffer A: 0.5% TFA / water, buffer B: 0.5% TFA / CH ₃ CN; Gradient for 10 minutes from 100% Buffer A to 100% Buffer B, hold 100% Buffer B for 5 minutes.

(c) Hewlett Packard 1090 HPLC equipped with UV detector (210 nM) and 4 × 125 mm nucleosyl 3 μM C-18 column; Flow rate 2.0 mL / min; Buffer A: 0.01 mol% H ₃ PO ₄ / water, buffer B: 0.01 mol% H ₃ PO ₄ / CH ₃ CN; 10% buffer B 1 minute, gradient from 10% buffer B to 90% buffer B for 8 minutes, gradient from 90% buffer B to 10% buffer B for 4 minutes.

(d) Renin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dynamax 8 μM C-18 column; Flow rate 18 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 30% Buffer B to 100% Buffer B for 25 minutes, hold 100% Buffer B for 30 minutes.

(e) Lanin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dynamax 8 μM C-18 column; Flow rate 18 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 50% Buffer B to 60% Buffer B for 25 minutes, from 60% to 100% for 32 minutes.

(f) Renin Dynamax HPLC equipped with UV-DII dual wavelength detectors (254 and 220 nm) and 21 × 2500 mm Microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 30% Buffer B to 100% Buffer B for 25 minutes, hold 100% Buffer B for 30 minutes.

(g) Lenin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 50% Buffer B to 100% Buffer B for 25 minutes, 100% Buffer B maintained for 7 minutes.

(h) Renin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 10% Buffer B to 100% Buffer B for 30 minutes, 100% Buffer B maintained for 7 minutes.

(i) Lanin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 4.6 × 100 mm microsorb 5 μM C-8 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 10% Buffer B to 100% Buffer B for 5 minutes, hold 100% Buffer B for 1.5 minutes.

(j) Lenin Dynamax HPLC equipped with UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm microsorb 5 μM C-18 column; Flow rate 20 mL / min; Buffer A: 0.1% TFA / 99.9% water, Buffer B: 0.1% TFA / 99.9% CH ₃ CN; Gradient from 20% Buffer B to 100% Buffer B for 30 minutes, 100% Buffer B maintained for 7 minutes.

Biological analysis

The activity that a given compound binds to the progesterone receptor can usually be analyzed according to the procedures described below. This procedure was used to measure the progesterone binding activity of the compounds of the present invention.

Progesterone Receptor Binding Assay

Binding to a siliconized glass test tube cooled in an ice bath containing various concentrations of the compound to be analyzed, the cytoplasm of T47D cells (100 μl of solution to bind at least 4000 cpm) and ³ H-progesterone (50 μl, 10 nM, NET-381) 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. This mixture was incubated at 4 ° C. for 16 hours and treated with charcoal (250 μl 0.5% mixture of dextran-coated 0.05% charcoal washed twice with binding buffer). The resulting mixture was incubated at 4 ° C. for 10 minutes. The tube was centrifuged at 20 ° C. (20 min at 2800 × g). The supernatant was transferred to a scintillation vial containing scintillation liquid (4 mL). The remaining ³ H-progesterone was measured with a Packard 1900 TR Beta Counter. Each assay included the following controls: 1) total binding group (compound free), 2) nonspecific binding group (400 nM progesterone), and 3) positive control group (2 nM progesterone or known inhibitor).

Compounds of the invention inhibited the binding of ³ H-progesterone to the progesterone receptor by 30% or more at a concentration of 200 nM. The active ranges of the compounds of the present invention for progesterone receptor binding assays at 200 nM compound concentrations are listed in Table 5.

The examples can be repeated with similar success rates by substituting the reactants described generally or specifically and / or by manipulating the conditions of the invention used in the examples.

Other embodiments of the invention will be apparent to those skilled in the art upon consideration of the specification or practice of the invention described herein. The foregoing specification and examples are merely illustrative of the invention, and the true scope and spirit of the invention will be defined by the following claims.

Claims (9)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I> Where R is aryl having 6 to 14 carbon atoms; Or heteroaryl having 3 to 10 carbon atoms 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 having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms containing 1 to 3 rings; Heterocycloalkyl containing 4 to 7 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms containing 1 to 3 rings; Or alkynyl having 3 to 10 carbon atoms, R ² , R ³ and R ⁴ are independently H; Alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms; Aryl having 6 to 13 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; CO ₂ R ⁵ (R ⁵ is alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or halocycloalkyl having 3 to 6 carbon atoms); halogen; And ═O (which represents two groups of R ² , R ³ and R ⁴ ), X is O or S (O) _y (y is 0, 1 or 2), n is 2, 3, 4 or 5, p is the sum of the R ² , R ³ and R ⁴ substituents but not hydrogen, T is alkyl having 1 to 4 carbon atoms; Alkoxy having 1 to 4 carbon atoms; Aryl having 6 to 10 carbon atoms; CO ₂ H; CO ₂ R ⁵ ; Alkenyl having 2 to 4 carbon atoms; Alkynyl having 2 to 4 carbon atoms; C (O) C ₆ H ₅ ; C (O) N (R ⁶ ) (R ⁷ ) (R ⁶ is H or alkyl of 1 to 5 carbon atoms, R ⁷ is H or alkyl of 1 to 5 carbon atoms); S (O) _{y '} R ⁸ (y' is 1 or 2, R ⁸ is alkyl of 1 to 5 carbon atoms); SO ₂ F; CHO; OH; NO ₂ ; CN; halogen; OCF ₃ ; N-oxides; OC (R ⁹ ) ₂ -O (oxygen is bonded to an adjacent position on R and R ⁹ is H, halogen or alkyl of 1 to 4 carbon atoms); C (O) NHC (O) (carbon is bonded to an adjacent position on R); And C (O) C ₆ H ₄ (a carbonyl carbon and a ring carbon in the ortho position on carbonyl is bonded to an adjacent position on R), t is 1 to 5, Provided that the substituent residue T is alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, aryl having 6 to 10 carbon atoms, CO ₂ R ⁵ , alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, 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 , T Is optionally alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, CO ₂ R ⁵ , CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ), CHO, OH, NO ₂ , CN, halogen, May include a second substituent selected from the group consisting of S (O) _y R ⁸ or ═O, wherein the number of second substituents is 1 or 2, except for halogen, which may be used up to the perhalo level, G is halogen; OH; OR ⁵ ; = 0 (indicates two substituents G); Alkyl having 1 to 4 carbon atoms; Alkenyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 7 carbon atoms; Heterocycloalkyl having 3 to 5 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Cycloalkenyl having 5 to 7 carbon atoms; Heterocycloalkenyl having 4 to 6 carbon atoms containing 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 ); Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; NO ₂ ; CN; S (O) _y R ⁸ ; SO ₃ R ⁸ ; And it is a substituent selected from the group consisting of SO ₂ N (R ⁶ ) (R ⁷ ), g is 0 to 4, except for halogen, which may be used up to the perhalo level, Provided that substituent G is alkyl having 1 to 4 carbons, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heterocycloalkyl having 3 to 5 carbon atoms, cycloalkenyl having 5 to 7 carbon atoms or 4 to 6 carbon atoms If is heterocycloalkenyl, G may comprise a second substituent, which is a halogen, optionally used up to the perhalo level; If substituent G is aryl or heteroaryl, G may optionally comprise a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, said second substituent being 3 or less for an alkyl moiety For halogen up to the perhalo level, Q is alkyl having 1 to 4 carbon atoms; Haloalkyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 8 carbon atoms; Alkoxy having 1 to 8 carbon atoms; Alkenyl having 2 to 5 carbon atoms; Cycloalkenyl having 5 to 8 carbon atoms; Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; CO ₂ R ⁵ ; = 0 (indicates two substituents Q); OH; halogen; N (R ⁶ ) (R ⁷ ), S (O) _y R ⁸ ; SO ₃ R ⁸ ; And it is a substituent selected from the group consisting of SO ₂ N (R ⁶ ) (R ⁷ ), q is 0 to 4, Provided that when substituent Q is aryl or heteroaryl, Q may optionally include a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, wherein the second substituent is 3 or less for an alkyl moiety And up to the perhalo level for halogen, Also, a) two of (Q) _q R ¹ , (Q) _q R ² , (Q) _q R ³ and (Q) _q R ⁴ are bonded to N, O and S together with the atom (s) to which they are attached Can form a 3-8 membered non-aromatic ring of spiro or bispy containing 0-2 heteroatoms selected from the group consisting of: b) when n is 2 or 3, at least one of R ² , R ³ and R ⁴ is not H, c) when n is 2 and X is O, when t is 1, T is selected from the list of substituents of T except for alkyl, and the 4-position of the 1,3-oxazolidine ring must comprise substituents, d) when n is 3 and X is O, when t is at least 1, at least one T is selected from the list of substituents of T except for alkyl and alkoxy, e) when n is 2 or 3 and X is O or S, the sum of the non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is 5 or more, f) 5-position of R when n is 2, X is O, and the 4-position of the 1,3-oxazolidine ring comprises a carbonyl group and R comprises a halogen in 2- and 4-positions Contains H, g) when n is 2 and X is O, the 4-position of the ring may comprise carbonyl only if the 5-position of the 1,3-oxazolidine ring contains one or more non-Han substituents; , h) when n is 2, X is S (O) _y , the 4-position of the 1,3-thiazolidine ring contains a carbonyl group, R ¹ is substituted with a methyl group, and G is a phenyl group, the phenyl group A second substituent, i) when n is 4, X is S and G is CO ₂ R ^5, then R ⁵ contains at least two carbons; A compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I> Where R is phenyl or pyridyl, R ¹ is alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms containing 1 to 3 rings; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms containing 1 to 3 rings; Or alkynyl having 3 to 10 carbon atoms, R ² , R ³ and R ⁴ are independently H; Alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms; And ═O (which represents two groups of R ² , R ³ and R ⁴ ), X is O or S (O) _y (y is 0, 1 or 2), n is 2 or 3, p is the sum of the R ² , R ³ and R ⁴ substituents but not hydrogen, T is alkyl having 1 to 4 carbon atoms; Alkoxy having 1 to 4 carbon atoms; Alkenyl having 2 to 4 carbon atoms; Alkynyl having 2 to 4 carbon atoms; NO ₂ ; CN; And a substituent selected from the group consisting of halogen, t is 1 to 5, Provided that when the substituent residue T is alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms or alkynyl having 2 to 4 carbon atoms, T is optionally alkyl having 1 to 4 carbon atoms and 1 to 4 carbon atoms. Alkoxy of 4, CO ₂ R ⁵ (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 of 3 to 6 carbon atoms), CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ) (R ⁶ is H or alkyl of 1 to 5 carbon atoms, R ⁷ is H or alkyl of 1 to 5 carbon atoms), CHO, OH, NO ₂ , CN, And a second substituent selected from the group consisting of halogen, S (O) _y R ⁸ (R ⁸ is alkyl having 1 to 5 carbon atoms) and ═O (which represents two second substituents). 2 The number of substituents is 1 or 2, except for halogen, which may be used up to the perhalo level, G is halogen; OR ⁵ ; Alkyl having 1 to 4 carbon atoms; Alkenyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 7 carbon atoms; Cycloalkenyl having 5 to 7 carbon atoms; Aryl having 6 to 10 carbon atoms; And a substituent selected from the group consisting of CN, g is 0 to 4, except for halogen, which may be used up to the perhalo level, Provided that substituent G is alkyl having 1 to 4 carbon atoms, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or cycloalkenyl having 5 to 7 carbon atoms, G is a halogen optionally used to the perhalo level. May contain 2 substituents; If substituent G is aryl, G may optionally comprise a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, said second substituent being 3 or less for an alkyl moiety and for halogen Up to the perhalo level, Q is alkyl having 1 to 4 carbon atoms; Haloalkyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 8 carbon atoms; Alkoxy having 1 to 8 carbon atoms; Alkenyl having 2 to 5 carbon atoms; Cycloalkenyl having 5 to 8 carbon atoms; CO ₂ R ⁵ ; = 0 (indicates two substituents Q); OH; halogen; N (R ⁶ ) (R ⁷ ) and S (O) _y R ⁸ is a substituent selected from the group consisting of q is 0 to 4, only, a) two of (Q) _q R ¹ , (Q) _q R ² , (Q) _q R ³ and (Q) _q R ⁴ are bonded to N, O and S together with the atom (s) to which they are attached Can form a 3-8 membered non-aromatic ring of spiro or bispy containing 0-2 heteroatoms selected from the group consisting of: b) when n is 2 or 3, at least one of R ² , R ³ and R ⁴ is not H, c) when n is 2 and X is O, when t is 1, T is selected from the list of substituents of T except for alkyl, and the 4-position of the 1,3-oxazolidine ring must comprise substituents, d) when n is 3 and X is O, when t is at least 1, at least one T is selected from the list of substituents of T except for alkyl and alkoxy, e) when n is 2 or 3 and X is O or S, the sum of the non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is 5 or more, f) 5-position of R when n is 2, X is O, and the 4-position of the 1,3-oxazolidine ring comprises a carbonyl group and R comprises a halogen in 2- and 4-positions Contains H, g) when n is 2 and X is O, the 4-position of the ring may comprise carbonyl only if the 5-position of the 1,3-oxazolidine ring contains at least one non-H substituent; , h) when n is 2, X is S (O) _y , the 4-position of the 1,3-thiazolidine ring contains a carbonyl group, R ¹ is substituted with a methyl group, and G is a phenyl group, the phenyl group A second substituent. A compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I> Where R is phenyl or pyridyl, R ¹ is alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms containing 1 to 3 rings; Alkenyl having 2 to 10 carbon atoms; Or cycloalkenyl having 5 to 12 carbon atoms containing 1 to 3 rings, R ² , R ³ and R ⁴ are independently H; Alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms; Alkenyl having 2 to 10 carbon atoms; And it is selected from the group consisting of cycloalkenyl of 5 to 12 carbon atoms, X is O or S (O) _y (y is 0, 1 or 2), n is 2 or 3, p is the sum of the R ² , R ³ and R ⁴ substituents but not hydrogen, T is alkyl having 1 to 4 carbon atoms; Alkenyl having 2 to 4 carbon atoms; NO ₂ ; CN; And a substituent selected from the group consisting of halogen, t is 1 to 5, Provided that when the substituent residue T is alkyl having 1 to 4 carbon atoms or alkenyl having 2 to 4 carbon atoms, T is optionally alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, and CO ₂ R ⁵ (R ⁵ has 1 to 4 carbon atoms). Alkyl of 4, haloalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or halocycloalkyl of 3 to 6 carbon atoms, CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ) (R ⁶ is H or alkyl of 1 to 5 carbon atoms, R ⁷ is H or alkyl of 1 to 5 carbon atoms, CHO, OH, NO ₂ , CN, halogen, S (O) _y R ⁸ (R ⁸ is 1 carbon atom) To alkyl) and = 0, wherein the number of second substituents is 1 or 2, except for halogen, which may be used up to the perhalo level, G is halogen; Alkyl having 1 to 4 carbon atoms; Alkenyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 7 carbon atoms; Cycloalkenyl having 5 to 7 carbon atoms; And a substituent selected from the group consisting of 6 to 10 carbon atoms, g is 0 to 4, except for halogen, which may be used up to the perhalo level, Provided that substituent G is alkyl having 1 to 4 carbon atoms, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or cycloalkenyl having 5 to 7 carbon atoms, G is a halogen optionally used to the perhalo level. May contain 2 substituents; If substituent G is aryl, G may optionally comprise a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, said second substituent being 3 or less for an alkyl moiety and for halogen Up to the perhalo level, Q is alkyl having 1 to 4 carbon atoms; Haloalkyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 8 carbon atoms; Alkoxy having 1 to 8 carbon atoms; Alkenyl having 2 to 5 carbon atoms; Cycloalkenyl having 5 to 8 carbon atoms; And a substituent selected from the group consisting of halogen, q is 0 to 4, only, a) two of (Q) _q R ¹ , (Q) _q R ² , (Q) _q R ³ and (Q) _q R ⁴ are bonded to N, O and S together with the atom (s) to which they are attached Can form a 3-8 membered non-aromatic ring of spiro or bispy containing 0-2 heteroatoms selected from the group consisting of: b) when n is 2 or 3, at least one of R ² , R ³ and R ⁴ is not H, c) when n is 2 and X is O, when t is 1, T is selected from the list of substituents of T except for alkyl, and the 4-position of the 1,3-oxazolidine ring must comprise substituents, d) when n is 3 and X is O, when t is at least 1, at least one T is selected from the list of substituents of T except for alkyl, e) When n is 2 or 3 and X is O or S, the sum of the non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is 5 or more. The method of claim 1, (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-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-methylphenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane, 2- (4-cyano-2,3-dimethylphenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane, 2- (4-cyano-2-methylphenylimino) -1- (1-ethyl-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 2- (4-cyano-2,3-dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The method of claim 1, 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-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 A compound selected from the group consisting of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-methyl-1,3-thiazolidin-4-one. The method of claim 1, 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4,4-dimethyl-1,3-oxazolidine, 1-cyclopentyl-2- (4-cyano-2-ethylphenylimino) -3-oxa-1-azaspiro [4.4] nonane, 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane, and 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 and a pharmaceutically acceptable carrier. A1) Promotes bone formation for the treatment or prevention of osteopenia or osteoporosis in bone weakness diseases, A2) Promotes fracture healing, B1) Activity as a therapeutic agent for female congestive diseases, B2) Prevention of endometrial implantation, B3) Induction of labor, B4) Treatment of progesterone deficiency, B5) Promoting awareness and maintenance of pregnancy, B6) Preeclampsia, alleviation of preterm and early delivery, B7) Promoting sperm production, inducing acrosome reactions, oocyte maturation or oocyte in vitro Treatment of infertility, including fertilization, C1) Treatment of menstrual irregularities, C2) Treatment of dysfunctional uterine bleeding, C3) Treatment of androgen hyperplasia of the ovary, C4) Treatment of aldosterone hyperplasia of the ovary, C5) Premenstrual syndrome and premenstrual tension C7) alleviation of premenstrual behavioral disorders, C7) treatment of menopausal disorders, including menopausal changes, emotional changes, sleep disorders and vaginal dryness, C8) enhancement of female sexual acceptance and male sexual acceptance, C9) postmenopausal Incontinence Treatment, C10) improvement of sensory and motor function, C11) improvement of short-term memory, C12) alleviation of postpartum depression, C13) treatment of genital atrophy, C14) prevention of postoperative adhesion production, C15) regulation of uterine immune function, C16) prevention of myocardial incomplete fractures, D1) hormone replacement therapy, E1) treatment of cancer including breast cancer, uterine cancer, ovarian cancer and endometrial cancer, E2) treatment of endometriosis, E3) treatment of uterine fibrosis, F1) hirsutism An effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the treatment of F2) inhibition of hair growth, G1) activity as a male contraceptive, G2) activity as an abortion, and H1) promotion of myelin repair A method of treating said symptom in a mammal by administering to said animal. <Formula II> Where R is aryl having 6 to 14 carbon atoms; Or heteroaryl having 3 to 10 carbon atoms 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 having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms containing 1 to 3 rings; Heterocycloalkyl containing 4 to 7 carbon atoms and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 rings and containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms containing 1 to 3 rings; Or alkynyl having 3 to 10 carbon atoms, R ² , R ³ and R ⁴ are independently H; Alkyl having 1 to 10 carbon atoms; Cycloalkyl having 3 to 12 carbon atoms; Alkenyl having 2 to 10 carbon atoms; Cycloalkenyl having 5 to 12 carbon atoms; Aryl having 6 to 13 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; CO ₂ R ⁵ (R ⁵ is alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or halocycloalkyl having 3 to 6 carbon atoms); halogen; And ═O (which represents two groups of R ² , R ³ and R ⁴ ), X is O or S (O) _y (y is 0, 1 or 2), n is 2, 3, 4 or 5, p is the sum of the R ² , R ³ and R ⁴ substituents but not hydrogen, s is 0, 1 or 2 as the number of double bonds in the ring, T is alkyl having 1 to 4 carbon atoms; Alkoxy having 1 to 4 carbon atoms; Aryl having 6 to 10 carbon atoms; CO ₂ H; CO ₂ R ⁵ ; Alkenyl having 2 to 4 carbon atoms; Alkynyl having 2 to 4 carbon atoms; C (O) C ₆ H ₅ ; C (O) N (R ⁶ ) (R ⁷ ) (R ⁶ is H or alkyl of 1 to 5 carbon atoms, R ⁷ is H or alkyl of 1 to 5 carbon atoms); S (O) _{y '} R ⁸ (y' is 1 or 2, R ⁸ is alkyl of 1 to 5 carbon atoms); SO ₂ F; CHO; OH; NO ₂ ; CN; halogen; OCF ₃ ; N-oxides; OC (R ⁹ ) ₂ -O (oxygen is bonded to an adjacent position on R and R ⁹ is H, halogen or alkyl of 1 to 4 carbon atoms); C (O) NHC (O) (carbon is bonded to an adjacent position on R); And C (O) C ₆ H ₄ (carbonyl carbon and ring carbon in the ortho position on carbonyl are bonded to adjacent positions on R), t is 1 to 5, Provided that the substituent residue T is alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, aryl having 6 to 10 carbon atoms, CO ₂ R ⁵ , alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, 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 , T Is optionally alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, CO ₂ R ⁵ , CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ), CHO, OH, NO ₂ , CN, halogen, May include a second substituent selected from the group consisting of S (O) _y R ⁸ or ═O, wherein the number of second substituents is 1 or 2, except for halogen, which may be used up to the perhalo level, G is halogen; OH; OR ⁵ ; = 0 (indicates two substituents G); Alkyl having 1 to 4 carbon atoms; Alkenyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 7 carbon atoms; Heterocycloalkyl having 3 to 5 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; Cycloalkenyl having 5 to 7 carbon atoms; Heterocycloalkenyl having 4 to 6 carbon atoms containing 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 ); Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; NO ₂ ; CN; S (O) _y R ⁸ ; SO ₃ R ⁸ ; And it is a substituent selected from the group consisting of SO ₂ N (R ⁶ ) (R ⁷ ), g is 0 to 4, except for halogen, which may be used up to the perhalo level, Provided that substituent G is alkyl having 1 to 4 carbons, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heterocycloalkyl having 3 to 5 carbon atoms, cycloalkenyl having 5 to 7 carbon atoms or 4 to 6 carbon atoms If is heterocycloalkenyl, G may optionally include a second substituent which is a halogen used up to the perhalo level; If substituent G is aryl or heteroaryl, G may optionally comprise a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, said second substituent being 3 or less for an alkyl moiety For halogen up to the perhalo level, Q is alkyl having 1 to 4 carbon atoms; Haloalkyl having 1 to 4 carbon atoms; Cycloalkyl having 3 to 8 carbon atoms; Alkoxy having 1 to 8 carbon atoms; Alkenyl having 2 to 5 carbon atoms; Cycloalkenyl having 5 to 8 carbon atoms; Aryl having 6 to 10 carbon atoms; Heteroaryl having 3 to 9 carbon atoms containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; CO ₂ R ⁵ ; = 0 (indicates two substituents Q); OH; halogen; N (R ⁶ ) (R ⁷ ), S (O) _y R ⁸ ; SO ₃ R ⁸ ; And it is a substituent selected from the group consisting of SO ₂ N (R ⁶ ) (R ⁷ ), q is 0 to 4, Provided that when substituent Q is aryl or heteroaryl, Q may optionally include a second substituent independently selected from the group consisting of alkyl and halogen having 1 to 4 carbon atoms, wherein the second substituent is 3 or less for an alkyl moiety And up to the perhalo level for halogen, In addition, two of (Q) _q R ¹ , (Q) _q R ² , (Q) _q R ³ and (Q) _q R ⁴ are bonded to N, O and S together with the atom (s) to which they are attached It is possible to form a 3-8 membered non-aromatic ring of spiro or bispyro containing 0 to 2 heteroatoms selected from the group consisting of: The method of claim 8, wherein the mammal is a human.