JP2002534517A - Substituted 2-arylimino heterocycles for use as progesterone receptor binders and compositions containing them - Google Patents

Abstract

  (57) [Summary] The present invention relates to 2-arylimino-1,3-thiazolidines, 2-arylimino-2,3,4,5-tetrahydro-1,3-thiazines, 2-arylimino-1,3-thiazolidine-4. 2-arylimino heterocycles, including -ones, 2-arylimino-1,3-thiazolidine-5-ones and 2-arylimino-1,3-oxazolidines, and their regulation of progesterone receptor-mediated processes And pharmaceutical compositions suitable for use in such treatments.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to heterocyclic drugs, and more particularly to 2-arylimino heterocycles, pharmaceutical compositions containing them, and progesterone receptors.
(sterone receptor) -mediated process.

BACKGROUND Agents that bind to progesterone receptors are available in a wide variety of indications, including those indicated in the paragraphs described below: A1) Cortico in bone weakness Steroid-induced osteoporosis [Picardo et al., Drug Safety 15, 347 (1996)], postmenopausal osteoporosis including osteoporosis or Paget's disease or improving bone formation for the purpose of preventing and / or treating osteoporosis [Manzi et al. Soc. Gynecol
. Invest 1, 302 (1994); Scheven et al., Biochem.
. Biophys. Res. Commun. , 186, 54 (1992); Ve.
Rhaar et al., Bone, 15, 307 (1994);
Cium and Phosphorus in Health Diseases
es ", Anderson and Garner (edited), CRC Press,
207 (1996); Scheven et al., Biochem. Biophys. R
es. Commun. 186, 54 (1992)] A2) As an agent for improving fracture healing, B1) Female contraactive agent (contragestive)
[Cadepond et al., Annu. Rev .. Med. , 48
129 (1997); Heikinheimo Clin. Pharmaco
Kinet. 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) fetal mortus [(Heikinheimo Clin.
Pharmacokinet. 33, 7 (1997); Cadepond et al.,
Annu. Rev .. Med. , 48, 129 (1997)], induction of labor [Heikinheimo Clin. Pharmacokinet.
33, 7 (1997); Karalis et al., Ann. N. Y. Acad. Sc
i. , 771, 551 (1995)], B4) Treatment of luteal deficiency [Pretzsh et al., Zentralbl. Gynae
kol. 119 (Suppl. 2), 25 (1997); Bezer et al., "
Molecular and Cellular Aspects of Pe
riimplation Processes ", Dey (edit), Sp
Ringer-Verlag, 27 (1995)], B5) Improved recognition and maintenance of pregnancy [Bezer et al., "Molecular"
and Cellular Aspects of Periimplanta
Tion Processes ", Dey (editing), Springer-Ver
lag, p. 27 (1995)], B6) Preeclampsia, pregnancy ejaculation and prevention of preterm delivery [Yallampalli et al., WO 97/34, 922)], B7) Promotion of spermatogenesis, acrosome reaction Fertility treatments, including the induction of oocytes, oocyte maturation or in vitro fertilization of oocytes [Baldi et al. Steroid
Biochem. Mol. Biol. , 53, 199 (1995); Bald.
i, et al., Trends Endocrinol. Metab. , 6, 198 (19
95); Blackwell et al., Colloq. INSERM, 236, 165
(1995); Blackwell et al., Cell. Signaling 5,
531 (1993); Cork et al., Zygote, 2, 289 (1994); M.
eizel, Biol. Reprod. , 56, 569 (1997)], C1) Treatment of dysmenorrhea [Coll Capdevila et al., Eur. J. Co
ntracept. Reprod. Health Care, 2, 229 (19
97); Adashi et al., Keio J .; Med. , 44, 124 (1995)
C2) Treatment of dysfunctional uterine bleeding [Col. Capdevila et al., Eur. J
. Contracept. Reprod. Health Care, 2,229
(1997); Adashi et al., Keio J. et al. Med. , 44, 124 (19
95)], C3) Treatment of ovarian female pseudohyperyangiosis [Schaison et al., Androg. E
xcess Disorder. Women, 715 (1997)], C4) Treatment of ovarian hyperaldosterone [Adashi et al., Keio J. et al. Me
d. , 44, 124 (1995)], C5) Reduction of premenstrual syndrome and premenstrual tension [Mortola, Curr. Op
in. Endocrinol. Diabetes, 2, 483 (1995); A
Dashi et al., Keio J. et al. Med. , 44, 124 (1995)], C6) Treatment of premenstrual behavior disorder [Constant et al., Hormone Res.
, 40, 141 (1993)], C7) Crimeracteric disorder
ance), ie, hot flashes [Sarrel
, Int. J. Fertil. Women's Med. , 42, 78 (199
7); Backstrom et al., Ciba Found. Symp. , 121, 1
71 (1995)], mood changes [Backstrom et al., Ciba Found.
. Symp. 121, 171 (1995)], sleep disorders [Sarrel, In.
t. J. Fertil. Women's Med. , 42, 78 (1997)]
And vaginal dryness [Sarrel, Int. J. Fertil. Woman's M
ed. , 42, 78 (1997)] [Adashi et al., Keio J. et al. Med. C8) Female sexual acceptability [Diet et al., Eur. J. Contracept
. Reprod. Health Care, 2 (4), 253 (1997); M
cCarthy et al., Trends Endocrinol. Metab. , 7,
327-333 (1996); Mani et al., Horm. Behav. , 31,2
44 (1997)] and male sexual activity acceptance [Johnson et al., Ess.
entitled Reproduction, 2nd edition, Blackwell Sc
identific Pub. C9) Treatment of postmenopausal urinary incontinence [Makinen et al., Maturitas, 22].
233 (1995); Batra et al. Urology, 138, 1301
(1987)], C10) Improvement of sensory and motor function [Backstrom et al., Ciba Fou
nd. Symp. , 121, 171 (1995)], C11) Improvement of short-term memory [Backstrom et al., Ciba Found. Sy
mp. 121, 171 (1995)], C12) Reduction of postpartum depression [Dalton, Practitioner, 22]
9, 507 (1985)], C13) Treatment of genital atrophy [Sarrel, Int. J. Fertil. Wom
en's Med. , 42, 78 (1997)], C14) Prevention of postoperative adhesion formation [Ustun, Gynecol. Obstet.
Invest. 46, 202 (1998)], C15) Regulation of uterine immune function [Hansen et al., J. Mol. Reprod. Ferti
l. , 49 (Suppl.), 69 (1995)], C16) Prevention of myocardial infarction [Sarrel, Int. J. Fertil. Wome
n's Med. , 42, 78 (1997)], D1) Hormone replacement therapy [Casper et al., J. Am. Soc. Gynecol. In
Vest, 3, 225 (1996)], E1) Breast cancer [Cadepod et al., Annu. Rev .. Med. , 48, 129 (
1997); Pike et al., Endocr. -Relat. Cancer, 4, 1
25 (1997)], uterine cancer [Heikinheimo Clin. Pharm
acokinet. , 33, 7 (1997)], ovarian cancer [Pike et al., Endo.
cr. -Relat. Cancer, 4, 125 (1997); Hughes,
WO 98 / 10,771] and endometrial carcinoma [Satyaswalloop, C
ontrib. Oncol. , 50, 258 (1995); Pike et al., End.
ocr. -Relat. Cancer, 4, 125 (1997)] E2) Treatment of endometriosis [Cadepod et al., Annu. Rev .. Med. , 4
8, 129 (1997); Heikinheimo Clin. Pharmac
okinet. , 33, 7 (1997); Edmonds, Br. J. Obst
et. Gynaecol. , 103 (Suppl. 14), 10 (1996);
Adashi et al., Keio J. et al. Med. , 44, 124 (1995)], E3) Treatment of uterine fibroids [Cadepod et al., Annu. Rev .. Med. ,
48, 129 (1997); Adashi et al., Keio J. et al. Med. , 44,
124 (1995)], F1) Treatment of hirsutism [Orentreich et al., US Pat. No. 4,684,635;
Azziz et al. Clin. Endocrinol. Metab. , 80, 3
406 (1995)], F2) Inhibition of hair growth [Houssay et al., Acta Physiol. Lati
noam. , 28, 11 (1978)], G1) As male contraceptives [Hargreave et al., Int. Congr. , Sy
mp. Semin. Ser. , 12, 99 (1997); Meriggiola.
Et al. Androl. , 18, 240 (1997)], G2) As an abortion drug [Michna et al., Pharm. Ztg. , 141, 11 (
1996)], and H1) facilitation of mylin repair [Baulieu et al.
Cell. Mol. Neurobiol. , 16, 143 (1996); Bau.
lieu et al., Multi. Scler. 3, 105 (1997); Schumak
er et al., Dev. Neurosci. , 18, 6 (1996); Koenig et al., Science, 268, 1500 (1995)].

At present, progesterone or progestin, alone or in combination with estrogens, has been clinically indicated for: contraception [Merck Manu
al; Merck & Co .; (1992)], Treatment of gastrointestinal bleeding due to arteriovenous birth defects [Merck Manual; Merck & Co. (1992)],
Treatment of recurrent metatarsal pressure fractures complicated by undermenstruation or amenorrhea [Merck
Manual; Merck & Co. (1992)], treatment of premenstrual syndrome [PMS, premenstrual tension; Merck Manual; Merck & Co .; (
1992)], hormone replacement therapy after menopause [M
erck Manual; Merck & Co. (1992)], Treatment of Hot Flash During Menopause and Subsequent Insomnia and Fatigue [Merck M.
anual; Merck & Co. (1992)], treatment of dysfunctional uterine bleeding when pregnancy is not desired [Merck Manual; Merck & Co. (1
992)], and suppression of endometriosis [Merck Manual; Merck
& Co. (1992)], suppression of breast cancer [Merck Manual; Mer]
ck & Co. (1992)], Endometrial cancer suppression [Merck Manua]
l; Merck & Co. (1992)], or suppression of luteal insufficiency [Mer
ck Manual; Merck & Co. (1992)]. Prevention of osteoporosis, treatment of vulva and / or vaginal atrophy, treatment to reduce severe vasomotor syndrome associated with menopause, treatment of secondary amenorrhea, abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology Treatment, prevention of pregnancy, or adjuvant and temporary treatment of inoperable, recurrent and metastatic endometrial or renal cell carcinoma [Merck Ma
natural; Merck & Co. (1998)], for example, medroxyprogesterone, progestin and the like are shown alone or in combination with estrogen.

SUMMARY [0004] The present invention is directed to non-steroidal 2-arylimino- and 2-heteroaryls that exhibit affinity for progesterone receptors and thus can regulate progesterone receptor-mediated processes by acting as progestins and / or antiprogestins An imino heterocyclic compound is provided.

The present invention relates to a compound of formula (I)

[0006]

Embedded image

Wherein R is selected from the group consisting of aryl having 6 to 14 carbon atoms or N, O and S
A heteroaryl having 1-3 carbon atoms containing 1-3 heteroatoms represented by
Provided that R is not benzofuran or benzothiophene;¹Is an alkyl having 1 to 10 carbon atoms, and a 3 to 12 carbon atoms containing 1 to 3 rings.
1-3 heteroatoms selected from the group consisting of chloroalkyl, N, O and S
And a heterocycloalkyl having 4 to 7 carbon atoms containing 1 to 3 rings, and having 2 to 2 carbon atoms.
10 alkenyl, cycloalkenyl having 5 to 12 carbon atoms containing 1-3 rings,
Or alkynyl having 3-10 carbon atoms;^Two, R^ThreeAnd R^FourIs independently H, alkyl having 1 to 10 carbons, and carbon having 1 to 10 carbons.
3-12 cycloalkyl, carbon number 2-10 alkenyl, carbon number 5-12
The group consisting of cycloalkenyl, aryl having 6-13 carbon atoms, N, O and S
A heteroaryl having 1-3 carbon atoms containing 1-3 heteroatoms selected from
O_TwoR^Five(Where R^FiveIs an alkyl having 1 to 4 carbon atoms and a halo having 1 to 4 carbon atoms.
Alkyl, cycloalkyl having 3-6 carbon atoms, or halocyclo having 3-6 carbon atoms
Alkyl), halogen, and the group R^Two, R^ThreeAnd R^FourCorresponds to two of
X is O or S (O)_y(Where y is 0, 1 or 2), n is 2, 3, 4 or 5 and p is a non-H substituent R^Two, R^ThreeAnd R^FourT is an alkyl having 1 to 4 carbons, an alkoxy having 1 to 4 carbons, and a 6-carbon
10 aryls, CO_TwoH, CO_TwoR^FiveAn alkenyl having 2-4 carbon atoms and a carbon number of
2-4 alkynyl, C (O) C₆H_Five, C (O) N (R⁶) (R⁷) (Where R ⁶ Is H or alkyl having 1-5 carbon atoms and R⁷Is H or 1-carbon
5) is S (O)_y'R⁸(Where y 'is 1 or 2 and
R⁸Is an alkyl having 1 to 5 carbons), SO_TwoF, CHO, OH, NO_Two,
CN, halogen, OCF_Three, N-oxide, OC (R⁹)_Two-O (where acid
Are bonded to adjacent positions on R and R⁹Is H, halogen or carbon number
Is alkyl of 1-4), C (O) NHC (O) (where carbon is adjacent to R
And C (O) C₆H_Four(Where the carbonyl charcoal
And the ring carbons ortho to this carbonyl are linked to adjacent positions on R.
Wherein t is 1-5, provided that the substituted moiety T is alkyl having 1-4 carbon atoms, and t is 1-5.
1-4 alkoxy, aryl having 6-10 carbon atoms, CO_TwoR^FiveHaving 2-4 carbon atoms
Alkynyl having 2-4 carbon atoms, C (O) C₆H_Five, C (O) N (R ⁶ ) (R⁷), S (O)_y'R⁸, OC (R⁹)_Two-O or C (O) C₆H_FourAt the time
Is optionally alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons,
O_TwoR^Five, CO_TwoH, C (O) N (R⁶) (R⁷), CHO, OH, NO_Two, CN, Ha
Rogen, S (O)_yR⁸Or a second substituent selected from the group consisting of = O
May have the second substituent number up to the level of perhalo
G is halogen, OH, OR^Five= O corresponding to two substituents G, carbon number 1-
4 alkyl, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms
, N, O and S, the number of heteroatoms selected from the group consisting of 1-3 and the number of carbon atoms is
3-5 heterocycloalkyl, cycloalkenyl having 5-7 carbon atoms, N, O and
A heteroatom selected from the group consisting of
Telocycloalkenyl, CO_TwoR^Five, C (O) N (R⁶) (R⁷), Having 6-1 carbon atoms
The number of heteroatoms selected from the group consisting of 0 aryl, N, O and S is 1-
Heteroaryl having 3 to 9 carbon atoms, NO_Two, CN, S (O)_yR⁸, SO_ThreeR⁸
, And SO_TwoN (R⁶) (R⁷G is 0-4 except for halogens available up to the level of perhalo, with the proviso that g is 0-4,
Substituent G is alkyl having 1-4 carbons, alkenyl having 1-4 carbons,
Is 3-7 cycloalkyl, 3-5 carbon atoms heterocycloalkyl, carbon atoms
5-7 cycloalkenyl or heterocycloalkenyl having 4-6 carbon atoms
In some cases, G may optionally reduce the second substituent, halogen, to the level of perhalo.
And when the substituent G is aryl or heteroaryl,
G is optionally selected from the group consisting of alkyl having 1 to 4 carbon atoms and halogen.
May have a second substituent selected, and the number of the second substituent may be
Not more than 3 in the case of a rutile moiety and the level of perhalo in the case of a halogen
Q is alkyl having 1 to 4 carbons, haloalkyl having 1 to 4 carbons, and 3 carbons.
-8 cycloalkyl, 1-8 carbon alkoxy, 2-5 carbon alk
Nyl, cycloalkenyl having 5-8 carbons, aryl having 6-10 carbons, N,
3-9 carbon atoms containing 1-3 heteroatoms selected from the group consisting of O and S
A heteroaryl, CO_TwoR^Five= O, OH, halogen corresponding to two substituents Q
, N (R⁶) (R⁷), S (O)_yR⁸, SO_ThreeR⁸, And SO_TwoN (R⁶) (R⁷)
Q is 0-4, provided that when the substituent Q is aryl or heteroaryl,
Q is optionally independent of the group consisting of alkyl and halogen having 1-4 carbon atoms
May have a second substituent selected, and the number of the second substituent may be
Not more than 3 in the case of a rutile moiety and the level of perhalo in the case of a halogen
And a) (Q)_qR¹, (Q)_qR^Two, (Q)_qR^ThreeAnd (Q)_qR^FourTwo of are connected
And together with one or more of the atoms to which they are attached
A 3-8 membered member containing 0-2 heteroatoms selected from the group consisting of N, O and S
May form a spiro or non-spiro non-aromatic ring; b) when n = 2 or 3, R^Two, R^ThreeAnd R^FourAt least one of is other than H
C) when n = 2, X = O and t = 1, T is a substituent other than alkyl,
Selected from the list of T and the 1,3-oxazolidine ring has a substituent at the 4-position
D) at least one when n = 3 and X = O and t is equal to or greater than 1
Is selected from the above list of substituents T excluding alkyl and alkoxy.
E) R when n = 2 or 3 and X = O or S¹, R^Two, R^ThreeAnd R^FourIn
The total number of non-hydrogen atoms is at least 5;
R has H at the 5-position when R has a halogen at the 2- and 4-positions thereof; g) When n = 2 and X = O, the 1,3-oxazolidine ring has a carbonyl at the 4-position
Only when the ring has at least one non-H substituent at the 5-position, h) n = 2 and X = S (O)_yThe 1,3-thiazolidine ring has a carbonyl group at the 4-position
Holding, R¹Is a substituted methyl group and G is a phenyl group,
The phenyl group has a second substituent, i) n = 4, X = S and G is CO_TwoR^FiveR^FiveContains at least two carbons,
And a pharmaceutically acceptable salt thereof.

[0008] The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier in addition to the compound of formula (I) as disclosed above.

[0009] Compounds of the present invention, like certain related compounds of the prior art, modulate progesterone receptor-mediated processes by exhibiting affinity for progesterone receptors and consequently having the ability to act as progestins and / or antiprogestins. We believe it is useful for the purposes listed in the background section as a result of having the ability to do so.

[0010] The claimed method of treatment may employ certain compounds of the prior art that were not previously recognized as being useful for this purpose, and thus a set of compounds used in the claimed method of treatment. It should be noted that the definition of compound (Formula II) is broader than the set of compounds defined in Formula I. Thus, the present invention further relates to a method of treating a mammal for the purpose of achieving an effect, wherein such effect comprises: A1) treating or preventing osteopenia or osteoporosis in a bone weakening disease. A2) Improvement of fracture healing, B1) Activity as a female contrastive agent, B2) Prevention of endometrial implantation, B3) Induction of labor, B4) Treatment of luteal deficiency, B5 B) improving pregnancy awareness and maintenance; B6) preventing preeclampsia, eclampsia and preterm delivery in pregnancy; B7) facilitating spermatogenesis, inducing an acrosome response, oocyte maturation or in vitro fertilization of oocytes. C1) Treatment of dysmenorrhea, C2) Treatment of dysfunctional uterine bleeding, C3) Treatment of ovarian female pseudohyperyangminium, C4) Ovarian aldos Treatment of hypertelonism, C5) reduction of premenstrual syndrome and premenstrual tension, C6) reduction of premenstrual behavior disorders, C7) of Crimecteric disorders including menopause transition, mood changes, sleep disorders and vaginal dryness Treatment, C8) Improve female and male sexual acceptance, C9) Treat postmenopausal urinary incontinence, C10) Improve sensory and motor function, C11) Improve short-term memory, C12) Reduce postpartum depression C13) Treatment of genital atrophy, C14) Prevention of postoperative adhesion formation, C15) Modulation of uterine immune function, C16) Prevention of myocardial infarction, D1) Hormone replacement therapy, E1) Breast cancer, uterine cancer, ovarian cancer and uterus E2) treatment of endometriosis, E3) treatment of uterine fibroids, F1) treatment of hirsutism, F2) suppression of hair growth, G1) male evacuation G2) activity as an abortion drug, and H1) facilitating myelin repair, wherein the method comprises treating the mammal with the formula (II)

[0011]

Embedded image

Wherein R is an aryl having 6-14 carbon atoms or selected from the group consisting of N, O and S
A heteroaryl having 1-3 carbon atoms containing 1-3 heteroatoms represented by
Provided that R is not benzofuran or benzothiophene;¹Is an alkyl having 1 to 10 carbon atoms, and a 3 to 12 carbon atoms containing 1 to 3 rings.
1-3 heteroatoms selected from the group consisting of chloroalkyl, N, O and S
And a heterocycloalkyl having 1-3 carbon atoms having 1-3 rings and 6-carbon atoms.
1 to 3 heteroatoms selected from the group consisting of N, O and S
Having 3 to 9 carbon atoms, having 1 to 3 carbon atoms and 1 to 3 rings, having 2 to 10 carbon atoms
Alkenyl, cycloalkenyl having 1-3 carbon atoms containing 1-3 rings, or
Alkynyl having 3-10 carbon atoms, R^Two, R^ThreeAnd R^FourIs independently H, alkyl having 1 to 10 carbons, and carbon having 1 to 10 carbons.
3-12 cycloalkyl, carbon number 2-10 alkenyl, carbon number 5-12
The group consisting of cycloalkenyl, aryl having 6-13 carbon atoms, N, O and S
A heteroaryl having 1-3 carbon atoms containing 1-3 heteroatoms selected from
O_TwoR^Five(Where R^FiveIs an alkyl having 1 to 4 carbon atoms and a halo having 1 to 4 carbon atoms.
Alkyl, cycloalkyl having 3-6 carbon atoms, or halocyclo having 3-6 carbon atoms
Alkyl), halogen, and the group R^Two, R^ThreeAnd R^FourCorresponds to two of
X is O or S (O)_y(Where y is 0, 1 or 2), n is 2, 3, 4 or 5 and p is a non-H substituent R^Two, R^ThreeAnd R^FourS represents the number of double bonds in the ring, and is 0, 1 or 2. T is alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, carbon number Is 6-
10 aryls, CO_TwoH, CO_TwoR^FiveAn alkenyl having 2-4 carbon atoms and a carbon number of
2-4 alkynyl, C (O) C₆H_Five, C (O) N (R⁶) (R⁷) (Where R ⁶ Is H or alkyl having 1-5 carbon atoms and R⁷Is H or 1-carbon
5) is S (O)_y'R⁸(Where y 'is 1 or 2 and
R⁸Is an alkyl having 1 to 5 carbons), SO_TwoF, CHO, OH, NO_Two,
CN, halogen, OCF_Three, N-oxide, OC (R⁹)_Two-O (where acid
Are bonded to adjacent positions on R and R⁹Is H, halogen or carbon number
Is alkyl of 1-4), C (O) NHC (O) (where carbon is adjacent to R
And C (O) C₆H_Four(Where the carbonyl charcoal
And the ring carbons ortho to this carbonyl are linked to adjacent positions on R.
Wherein t is 1-5, provided that the substituted moiety T is alkyl having 1-4 carbon atoms, and t is 1-5.
1-4 alkoxy, aryl having 6-10 carbon atoms, CO_TwoR^FiveHaving 2-4 carbon atoms
Alkynyl having 2-4 carbon atoms, C (O) C₆H_Five, C (O) N (R ⁶ ) (R⁷), S (O)_y'R⁸, OC (R⁹)_Two-O or C (O) C₆H_FourAt the time
Is optionally alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons,
O_TwoR^Five, CO_TwoH, C (O) N (R⁶) (R⁷), CHO, OH, NO_Two, CN, Ha
Rogen, S (O)_yR⁸Or a second substituent selected from the group consisting of = O
May have the second substituent number up to the level of perhalo
G is halogen, OH, OR^Five= O corresponding to two substituents G, carbon number 1-
4 alkyl, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms
, N, O and S, the number of heteroatoms selected from the group consisting of 1-3 and the number of carbon atoms is
3-5 heterocycloalkyl, cycloalkenyl having 5-7 carbon atoms, N, O and
A heteroatom selected from the group consisting of
Telocycloalkenyl, CO_TwoR^Five, C (O) N (R⁶) (R⁷), Having 6-1 carbon atoms
The number of heteroatoms selected from the group consisting of 0 aryl, N, O and S is 1-
Heteroaryl having 3 to 9 carbon atoms, NO_Two, CN, S (O)_yR⁸, SO_ThreeR⁸
, And SO_TwoN (R⁶) (R⁷G is 0-4 except for halogens available up to the level of perhalo, with the proviso that g is 0-4,
Substituent G is alkyl having 1-4 carbons, alkenyl having 1-4 carbons,
Is 3-7 cycloalkyl, 3-5 carbon atoms heterocycloalkyl, carbon atoms
5-7 cycloalkenyl or heterocycloalkenyl having 4-6 carbon atoms
In some cases, G may optionally reduce the second substituent, halogen, to the level of perhalo.
And when the substituent G is aryl or heteroaryl,
G is optionally selected from the group consisting of alkyl having 1 to 4 carbon atoms and halogen.
May have a second substituent selected, and the number of the second substituent may be
Not more than 3 in the case of a rutile moiety and the level of perhalo in the case of a halogen
Q is alkyl having 1 to 4 carbons, haloalkyl having 1 to 4 carbons, and 3 carbons.
-8 cycloalkyl, 1-8 carbon alkoxy, 2-5 carbon alk
Nyl, cycloalkenyl having 5-8 carbons, aryl having 6-10 carbons, N,
3-9 carbon atoms containing 1-3 heteroatoms selected from the group consisting of O and S
A heteroaryl, CO_TwoR^Five= O, OH, halogen corresponding to two substituents Q
, N (R⁶) (R⁷), S (O)_yR⁸, SO_ThreeR⁸, And SO_TwoN (R⁶) (R⁷)
Q is 0-4, provided that when the substituent Q is aryl or heteroaryl,
Q is optionally independent of the group consisting of alkyl and halogen having 1-4 carbon atoms
May have a second substituent selected, and the number of the second substituent may be
Not more than 3 in the case of a rutile moiety and the level of perhalo in the case of a halogen
And (Q)_qR¹, (Q)_qR^Two, (Q)_qR^ThreeAnd (Q)_qR^FourTwo of are connected
And together with one or more of the atoms to which they are attached
3-8 membered spins containing 0-2 heteroatoms selected from the group consisting of
Or a non-spiro non-aromatic ring may be formed, with the proviso that the compound represented by the formula or a pharmaceutically acceptable salt thereof is administered in an effective amount.
Comprising.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of formula (I) have been broadly defined in the above summary.
In the compound represented by the formula (I), the following groups apply to suitable groups.

R is preferably phenyl or pyridyl.

R ¹ is preferably alkyl having 1 to 10 carbons, cycloalkyl having 1 to 3 carbons and 3 to 12 carbons, alkenyl having 2 to 10 carbons, and 1 to 3 carbons. It is cycloalkenyl having 5 to 12 carbon atoms including 3 or alkynyl having 3 to 10 carbon atoms. R ¹ is more preferably alkyl having 1 to 10 carbons, cycloalkyl having 1 to 3 carbons, 3 to 12 carbons, alkenyl having 2 to 10 carbons, or 1-3 ring. And is cycloalkenyl having 5 to 12 carbon atoms.

R ² , R ³ and R ⁴ are preferably H, alkyl having 1 to 10 carbons, cycloalkyl having 3 to 12 carbons, alkenyl having 2 to 10 carbons, and carbon having 1 to 10 carbons. 5-1
A second cycloalkenyl, or = O, (This carbonyl corresponds to two of the radicals R ^2, R ³ and R ^4), R ^2, R ³ and R ⁴ is more preferably, H, Alkyl having 1-10 carbon atoms, cycloalkyl having 3-12 carbon atoms, 2-1 carbon number
It is alkenyl of 0 or cycloalkenyl having 5 to 12 carbon atoms.

X is preferably O or S (O) _y (where y is 0, 1 or 2)
It is.

The subscript n represents the number of carbons present in the ring, preferably 2 or 3.

The subscript p represents the sum of the non-H substituents R ² , R ³ and R ⁴ and is preferably 1 or 2.

T is preferably an alkyl having 1 to 4 carbons, an alkoxy having 1 to 4 carbons,
It is a group selected from the group consisting of alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, NO ₂ , CN and halogen. T is more preferably alkyl having 1 to 4 carbons, alkenyl having 2 to 4 carbons, NO ₂ , CN or halogen.

The subscript t represents the number of substituents T and is 1-5, more preferably 1-3.

The substituted moiety T is an alkyl having 1 to 4 carbon atoms, an alkoxy having 1 to 4 carbon atoms,
When T is alkenyl having 2-4 or alkynyl having 2-4 carbons,
Alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, CO_TwoR^Five, CO _Two H, C (O) N (R⁶) (R⁷), CHO, OH, NO_Two, CN, halogen, S (
O)_yR⁸, And = 0 with a second substituent preferably selected from the group consisting of
The number of said second substituent may be used up to the level of perhalo
1 or 2 except for halogen.

The term “second substituent” as used in this application means a substituent on a substituent,
It does not mean "secondary" as used in defining the degree of substitution at the carbon.

When using the terms “haloalkyl” and “halocycloalkyl” in this application,
These are used for the purpose of referring to groups which may contain any number of halogen atoms up to the perhalo level.

G is preferably halogen, OR ⁵ , alkyl having 1 to 4 carbons, 1 carbon
Alkenyl of -4, cycloalkyl of 3-7 carbons, cycloalkenyl of 5-7 carbons, aryl of 6-10 carbons and CN.
G is more preferably 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 carbon number. Is an aryl of 6-10.

The subscript g represents the number of substituents G and is 0-4, more preferably 0-2, except for halogens which can be used up to the level of perhalo.

Q is preferably alkyl having 1-4 carbon atoms, haloalkyl having 1-4 carbon atoms, cycloalkyl having 3-8 carbon atoms, alkoxy having 1-8 carbon atoms, and carbon atom having 1-8 carbon atoms. 2
-5 alkenyl, 5-8 carbon cycloalkenyl, CO ₂ R ⁵ , ＯO, OH
, Halogen, N (R ⁶ ) (R ⁷ ) and S (O) _y R ⁸ . Q
Is more preferably an alkyl having 1 to 4 carbon atoms, a haloalkyl having 1 to 4 carbon atoms, a cycloalkyl having 3 to 8 carbon atoms, an alkoxy having 1 to 8 carbon atoms, and having 2 carbon atoms.
Alkenyl of -5, cycloalkenyl of 5 to 8 carbon atoms or halogen.

The present invention also includes a pharmaceutically acceptable salt of the compound represented by the above formula I. Suitable pharmaceutically acceptable salts are well-known to those skilled in the art and include inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluoromethane Sulfonic acid, sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid,
Includes base salts such as maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as alkali cations (eg, Li ⁺ , Na ⁺ or K ⁺ ), alkaline earth cations (eg, Mg ⁺² , Ca ⁺² or Ba ⁺² ), salts of ammonium bases as well as salts of organic bases, including aliphatic and aromatic substituted ammonium and quaternary ammonium cations such as triethylamine, N, N-
Diethylamine, N, N-dicyclohexylamine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo “4.3.0” None-5-ene (D
BN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DB
Includes the acid salts of the cations resulting from the protonation or peralkylation of U).

Many of the compounds of formula I have an asymmetric carbon and can therefore exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention provides compounds of formula I
Any of the racemic and optically active forms of the compounds described in and having progesterone receptor binding activity.

The most preferred 2-imino-1,3-thiazolidines and 2-imino- of the present invention
Ring-extended analogs of 1,3-thiazolidine are: (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- (prope -2-ene-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 most preferred thiazolidine-4-ones of the present invention are: 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine-4-one, 2- (3-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine-4-one, 2- (2-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidine- 4-one, 2- (3-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidine-4-one, 2- (2-methyl-4-nitrophenylimino) -3- (2 -Methyl-1-butyl) -1,3-thiazolidine-4-one, 2- (3-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl) -1,3-thiazolidine- 4-one, - (2-methyl-4-nitrophenyl imino) -3- (1-cyclohexyl -
1-ethyl) -1,3-thiazolidine-4-one, 2- (3-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-
1-ethyl) -1,3-thiazolidine-4-one, 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1,3-thiazolidine-4-one 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-methylene-1,3-thiazolidine-4-one; and 2- (2-methyl-4-nitrophenylimino) -3- Isobutyl-5-methyl-1,3-thiazolidine-4-one.

The most preferred oxazolidines of the present invention are: 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 agent of the present invention can be used alone or simultaneously with other therapeutic agents. For example, when the agent is used for A1 or A2, it is used as a calcium source, vitamin D
Alternatively, it may be used in combination with analogs of vitamin D and / or estrogen replacement therapy.
), Treatment with a source of fluoride, treatment with calcitonin or a calcitonin analog or treatment with a bisphosphonate such as alendronate. When the agent is used for B1 to B7, it may be used in conjunction with a therapeutic such as an estrogen replacement therapeutic. When the agent is used for C1 to C16, E1 to E3 or F1 or F2, it may be used concomitantly with a therapeutic agent such as an estrogen replacement therapeutic and / or a gonadotropin releasing hormone antagonist. When the agent is used for G1 or G2, it may be used concomitantly with a therapeutic agent such as an androgen.

The methods of the present invention contemplate methods for use in treating progesterone receptor mediated conditions in both humans and other mammals.

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

The preparation of a composition intended for oral use may be carried out by any suitable method known in the art of making pharmaceutical compositions. The composition may contain one or more active agents selected from the group consisting of diluents, sweeteners, flavoring agents, coloring agents, and preservatives to produce a palatable preparation.

In the case of tablets, this contains the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for use in the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granules and disintegrants such as corn starch or alginic acid, and binders such as stearin Acid magnesia, stearic acid or talc and the like. The tablets can be uncoated or the tablets can be coated by known techniques in order to extend the action over a longer period by delaying the disintegration and absorption taking place in the gastrointestinal tract. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. It is also possible to prepare such compounds in solid, rapid release form.

Examples of orally used preparations are also hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules. It can be a gelatin capsule, in which case the active ingredient is mixed with a water or oil vehicle such as peanut oil, liquid paraffin or olive oil.

It is also possible to use aqueous suspensions which contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, while dispersing or wetting agents are naturally occurring phosphatides, such as Derived from lecithin or the like, or a condensation product of an alkylene oxide and a fatty acid, such as stearate of polyoxyethylene, or a condensation product of an ethylene oxide and a long-chain fatty alcohol, such as heptadecaethyleneoxycetanol, or a fatty acid and hexitol. Condensation products of ethylene oxide with partial esters, such as monooleate of polyoxyethylene sorbitol, or derived from fatty acids and anhydrous hexitol Condensation products of partial esters with ethylene oxide, may be such as monooleate polyethylene sorbitan. Such aqueous suspensions may also contain one or more preservatives, for example, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as ethyl or n-propyl p-hydroxybenzoate, For example, sucrose or saccharin can be contained.

In dispersible powders and granules suitable for use in the formation of an aqueous suspension by the addition of water, the active ingredient is mixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Provide in the state of. Examples of suitable dispersing or wetting agents and suspending agents have been mentioned above. It is also possible for additional excipients to be present, such as, for example, sweetening, flavoring and coloring agents.

The compounds can also be in the form of non-aqueous liquid preparations, such as oily suspensions, which are prepared by converting the active ingredient into vegetable oils, for example, arachis.
s) It can be carried out by suspending in oil, olive oil, sesame oil or peanut oil or in mineral oil such as liquid paraffin. Such oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. The composition can be preserved by the addition of an antioxidant such as ascorbic acid.

[0042] The pharmaceutical compositions of the present invention can also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum acacia or tragacanth, naturally occurring phosphatides such as soybean, lecithin, and esters or partial esters derived from fatty acids and anhydrous hexitol, such as monooleate of sorbitan, and It may be a condensation product of the partial ester and ethylene oxide, such as monooleate of polyoxyethylene sorbitan. Such emulsions may also contain sweetening and flavoring agents.

It is also possible to formulate syrups and elixirs with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
Such preparations may also contain a demulcent, a preservative, flavoring and coloring agents.

The compounds may also be administered in the form of rectal suppositories or vaginal administration of the drug. Attempt to mix this drug with a suitable non-irritating excipient that is solid at the appropriate normal temperature but liquid at rectal or vaginal temperatures, thus melting and releasing the drug in the rectum or vagina , The preparation of the composition can be carried out. Such materials include cocoa butter and polyethylene glycol.

The compounds of the present invention can also be administered transdermally using methods known to those skilled in the art (eg, Chien, Transdermal Co.).
controlled Systemic Medicines "; Marce
l Dekker, Inc. 1987; Lipp et al., WO 94/04157.
, March 3, 1994). For example, a solution or suspension formed by placing a compound of Formula I in a suitable volatile solvent, which may optionally contain a penetration enhancer, is added to a solution known to those skilled in the art. It may be combined with physical additives, such as matrix materials and germicides. After sterilization, the resulting mixture may be formulated into dosage forms according to known procedures. In addition, solutions or suspensions of the compounds of formula I may be formulated into a lotion or salve after treatment with an emulsifier and water.

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

[0047] Penetration-enhancing materials suitable for use in transdermal delivery systems are known to those skilled in the art and include, for example, mono- or polyhydroxy alcohols, such as ethanol, propylene glycol or benzyl alcohol, saturated or Unsaturated or unsaturated C ₈ -C ₁₈ fatty alcohols, such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C ₈ -C ₁₈ fatty acids, such as stearic acid, and saturated or unsaturated fatty esters having up to 24 carbon atoms, such as acetic acid; Methyl caproic, lauric, myristic, stearic or palmitic acid,
Ethyl, propyl, isopropyl, n-butyl, s-butyl, i-butyl, t-
Butyl or monoglycerin esters, or saturated or unsaturated dicarboxylic acid diesters having a total carbon number of 24 or less, such as diisopropyl adipate;
Examples include diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, urea and their derivatives, and ethers such as dimethyl isosorbide and monoethyl ether of diethylene glycol. Or monohydroxy or polyhydroxy alcohols in a suitable penetration enhancing formulations saturated or unsaturated C ₈ -C ₁₈ fatty alcohols, saturated or unsaturated C ₈ -C ₁₈ fatty acids, saturated or unsaturated fatty number of 24 or less carbon atoms Mixture of one or more materials selected from esters, saturated or unsaturated dicarboxylic acid diesters having a total carbon number of 24 or less, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers Can also be contained.

[0048] Binding materials suitable for use in transdermal delivery systems are known to those skilled in the art,
It includes polyacrylates, silicones, polyurethanes, block polymers,
Includes styrene-butadiene copolymer, natural rubber and synthetic rubber. It is also possible to use cellulose ethers, derivatized polyethylenes and silicates as matrix components. Additional additives, such as viscous resins or oils, can be added to increase the viscosity of such matrices.

With respect to all of the usage regimes disclosed herein for compounds of formula I,
Preferably the daily oral dosage regimen is 0.01 to 200 mg / kg of total body weight
To When administered by injection, including intravenous, intramuscular, subcutaneous and parenteral injections and the use of infusion techniques, the daily dosage is preferably 0.03 kg / kg of total body weight.
Make from 1 to 200 mg. In the case of rectal administration, the daily dose is preferably 0.01 to 200 mg / kg of total body weight. In the case of vaginal administration, the daily dosage is preferably from 0.01 to 200 / kg of total body weight.
mg. In the case of topical administration, the daily dosage is preferably 0.1 to 200 mg, ranging from 1 to 4 times daily. The transdermal concentration will preferably need to be such that a daily dosage of from 0.01 to 200 mg / kg is maintained. For administration by inhalation, the daily dose is preferably between 0.01 and 10 mg / kg of total body weight.

Those of skill in the art will understand that the particular dosage regimen depends on a variety of factors, all of which are routinely considered when administering a medicament. However, the particular dosage level of a given patient will also depend on a variety of factors, including but not limited to the activity of the particular compound used, the age of the patient, the weight of the patient, the general It will also be appreciated that this includes the physical health, gender of the patient, the patient's diet, the time of administration, the route of administration, excretion rates, drug combinations, and the severity of the condition being treated. Furthermore, those skilled in the art will be able to use conventional therapeutic tests to determine the optimal course of treatment, i.e., if the mode of treatment and the number of days are fixed, the compound of Formula I or a pharmaceutically acceptable compound thereof. Those skilled in the art will also understand that the number of daily doses of the salt can be ascertained.

The disclosures of all applications, patents and publications cited above and below are hereby incorporated by reference in their entirety.

The compounds of formula I can be prepared using known chemical reactions and procedures, not only by the following production methods but also by known methods (or reverse methods) by other methods and procedures known to those skilled in the art. Starting materials which can be prepared from known compounds). Nevertheless, the following general methods of preparation are provided to assist the practitioner in synthesizing the compounds of the present invention, and more specific individual examples are provided in the experimental section. This example is merely illustrative and is not intended to limit the invention in any way and should not be construed as such.

(List of Abbreviations and Acronyms) The following terms, as used herein, have the meanings indicated. AcOH acetic acid anh anhydrous BOC t-butoxycarbonyl conc concentration 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 ™ MgSiO ₃ .xH ₂ O m-CPBA 3-chloroperoxybenzoic acid MeOH Methanol pet. eter Petroleum ether (boiling range 30-60 ° C.) THF tetrahydrofuran TFA trifluoroacetic acid (general production method) arylamines, arylisocyanates, arylisothiocyanates, asymmetric arylthioureas, arylisocyanate dichlorides and 2-arylimino The synthesis of -1,3-heterocycles can be carried out using known methods [Katritzky et al., Comprehensive Heterocycll.
ic Chemistry; Perma Press: Oxford, U
K (1984), March, Advanced Organic Chemi.
string, 3rd edition; John Wiley: New York (1985)].
For example, aryl isocyanates (2) are available in reactions with phosgene or phosgene equivalents, such as carbonyldiimidazole, diphosgene or triphosgene, and arylisothiocyanates (3) are arylamines and thiophosgene or thiophosgene equivalents. For example, it is available in reactions such as thiocarbonyldiimidazole (Scheme I). Also, many types of aryl isocyanates and aryl isothiocyanates are commercially available. The aryl isothiocyanate is then reacted with a primary amine to give thiourea 4 [Hahn et al., Han'guk Nonwa Hakhoechi 19
97, 40, 139; Durr, U.S. Pat. No. 4,079,144; Ender.
s U.S. Pat. No. 4,148,799].

[0054]

Embedded image

As shown in Scheme II, a thiourea is reacted with an α-haloketone such as α-bromoketone (5) and then dehydrated to give a thiazoline (6) [Hahn et al., Han'guk. Nonghwa Hakhoechi 1
997, 40, 139; Durr U.S. Pat. No. 4,079,144; Ende
rs U.S. Pat. No. 4,148,799].

[0056]

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Similarly, thioureas can be converted to α-halo acid halides [Giri et al., Asian J. Am. Ch
em. 1992, 4, 785; Lakhan et al., Agric. Biol. Che
m. 1982, 46, 557], α-haloacids [Dogan et al., Spectros
c. Lett. 1983, 16, 499; Seeda et al., Indian J. Mol. H
eterocycl. Chem. 1993, 3, 81], and α-haloesters [Seda et al., Indian J. Am. Heterocycl. Chem. 19
93, 3, 81] to give 4-thiazolidinone (10).

[0058]

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Further, the arylisothiocyanate (3) is converted to an allylamine [Tsoi et al., Zh
. Org. Khim. 1983, 19, 2605] and propargylamine [
Azerbaev et al., Khim. Geterotsikl. Soedin. 19
72,471] to give the corresponding thiourea, which is treated with acid to give the pentasubstituted thiazolidine (Scheme IV).

[0060]

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Also, reacting an aryl isothiocyanate with hydroxylamine (17) can yield an N-hydroxyalkylthiourea (18) (Scheme V). Next, treatment of the thiourea with an acid results in a 2-imino-1,3-heterocycle (19) [Jen et al., J. Am. Med. Chem. 1975, 18, 90; Tyukh
Teneva et al., Khim. Geterotsikl. Soedin. 1985
Olszenko-Piontkawa et al., Org. Pre
p. Proced. Int. 11971, 3, 27]. Reaction of hydroxyalkyl thioureas (18) with SOCl ₂ gives chloroalkyl analogs (20), which are treated with base to effect cyclization to give heterocycles (19) [Cherb
uliez et al., Helv. Chim. Acta 1967, 50, 331; Fe
lix et al., U.S. Patent No. 4,806,653].

[0062]

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Alternatively, as shown in Scheme VI, an N-hydroxyalkylthiourea (
Treatment of 18) with HgO or an alkylating agent such as methyl iodide followed by a base gives the corresponding oxygen-containing heterocycle [Jen et al. Med. Ch
em. 1975, 18, 90; Ignatova et al., Khim. Geterot
sikl. Soedin. 1974, 354].

[0064]

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It has been reported that the reaction of a chloroalkylisothiocyanate with an arylamine results in the formation of the corresponding sulfur 2-phenylimino-1,3-heterocycle [Sagn
et al., U.S. Pat. No. 3,651,053; U.S. Pat.
No. 6].

[0066]

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The arylamine is converted to a source of formylation, such as formic acetic anhydride (formic acid).
react with tic anhydride to form formanilide (25),
It can then be converted to the aryl isocyanide dichloride by oxidation [Ferchland et al., DE 3,134,134;
hle et al., Angew. Chem. 1967, 79, 663]. The reaction of aryl isocyanide dichloride (26) with hydroxylamine (27) produces an oxygen-containing 2-phenylimino-1,3-heterocycle (30) [Wol
U.S. Pat. No. 3,787,575 to Iweber; U.S. Pat.
199] and reacting it with hydroxylamide (28) to give thiazolidinone (31). In addition, aryl isocyanide dichloride reacts with aminomercaptan (29) to give sulfur-containing 2-phenylimino-1,2
It has also been shown that a 3-heterocycle (32) occurs [Thibault FR 1,510,015].

[0068]

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When hydroxylamine is treated with CS _{2 in} the presence of a base, 1,3
-Thiaza-2-thione results (Scheme IX). Thion (34) is replaced with SOCl ₂
Reacts with to produce moisture-unstable imidate (35),
It has been reported that treatment of this with an arylamine produces a sulfur-containing 2-imino-1,3-heterocycle [Hanefeld et al., Arch. Pharm. 19
85, 318, 60; ibid, 1988, 321, 199].

[0070]

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Both oxygen-containing 2-imino-1,3-heterocycles and sulfur-containing 2-imino-1,3-heterocycles can undergo further work-up. Thus, for example, as shown in Scheme X, treatment of an N3-unsubstituted 2-phenylimino-1,3-heterocycle with an electrophile, typically in the presence of a base, results in an N3-substituted product. [Ambertsumova et al., Chem. Heterocycl. Comp
d. 1997, 33, 475; Mizrak et al., Khim. Geterots
ikl. Soedin. 1990, 563; Olszenko-Piontko
wa et al., Org. Prep. Proced. Int. 11971, 3, 27].

[0072]

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In addition, as shown in Scheme XI, the sulfur-containing 2-imino-1,3-
Oxidation of the heterocycle can yield sulfoxides or sulfones [Chi
Zhevskayaet et al., Khim. Geterotsikl. Soedin
. 1971, 96; Panday et al. Indian Chem. Soc. 1
972, 49, 171].

[0074]

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Detailed Experimental Procedures Detailed examples for preparing the compounds of the present invention are shown in the detailed synthetic procedures below.
In the compound tables shown below, the synthesis of each compound is shown with back reference to their typical preparation steps.

EXAMPLES All reactions were performed under positive pressure of dry argon or dry nitrogen using flame-dried or oven-dried glassware, unless otherwise specified. And stirred. In the case of a sensitive liquid or solution, it was transferred by syringe or cannula and passed through a rubber septum into the reactor. Commercial grade reagents and solvents were used without further purification.

Unless otherwise stated, the term “concentrated under reduced pressure” refers to using a Buchi rotary evaporator at about 15 mm Hg. Valve-to-valve (bulb-
To-bulb) concentration is performed using an Aldrich Kugelrohr apparatus, where the temperature refers to the oven temperature. Degrees Celsius without compensation for all temperatures (
° C). All parts and percentages are by volume unless otherwise indicated.

Thin layer chromatography (TLC) using a plate [Whatman ™] whose glass substrate was pre-coated (250 μm) with silica gel 60A F-254
). Visualization of the plate was performed using one or more of the following techniques: (a) UV illumination, (b) iodine vapor exposure, (c) heating the plate after immersion in a 10% solution of phosphomolybdic acid in ethanol. (D) heating after immersing the plate in a cerium sulfate solution and / or (e) heating after immersing the plate in an acidic ethanolic solution of 2,4-dinitrophenylhydrazine. 230-400 mesh EM
Column chromatography (flash chromatography) was performed using Science ™ silica gel. A plate into which SiO ₂ was previously cast and formed [Harrison Research Chromatotron's Al
ltech ™]] was used to perform rotary chromatography.

The melting point (mp) is measured using a Thomas-Hoover melting point apparatus or a Mettler FP66 automatic melting point apparatus and no correction is made. Mattson
Fourier transform infrared spectra were obtained using a 4020 Galaxy Series spectrophotometer.

The Me_FourSi (δ 0.00) or residual protonated solvent (CHCl_Three δ 7.
26; MeOH δ 3.30; DMSO δ 2.49) as a standard.
General Electric GN-Omega 300 (3
00 MHz) Proton (¹H) Nuclear magnetic resonance (NMR) spectrum
Was measured. Solvent (CDCl_Three δ 77.0; MeOD-d_ThreeΔ 49.
0; DMSO-d₆ General El using δ 39.5) as a standard
carbon with an electric GN-Omega 300 (75 MHz) spectrometer. ¹³ C) An NMR spectrum was measured.

The low-resolution mass spectrum (MS) and the high-resolution mass spectrum (HRM)
S) by electron impact (EI), chemical ionization (CI) or fast atom bombardment (FAB)
Obtained as a mass spectrum. Electron Impact Mass Spectroscopy (EI-MS) was applied to the sample introduction Vacuum Desorption Chemical I
Hewlett Packard with onizion Probe
d Obtained using a 5989A mass spectrometer. The ion source was kept at 250 ° C. Electron impact ionization was performed with an electron energy of 70 eV and a capture current of 300 μA. Liquid-cesium secondary ion mass spectra (FAB-MS), the latest version of fast atom collisions, were obtained using a Kratos Concept 1-H spectrometer. Hewlett Packard MS-Engine (
5989A), and using methane or ammonia as a reagent gas (1 × 10 ⁻⁴ torr to 2.5 × 10 ⁻⁴ torr) to obtain a chemical ionization mass spectrum (CI-
MS). Direct insertion / desorption chemical ionization (DCI) probe (Vaccume)
tricks, Inc. ) Was raised to 0-1.5 amps in 10 seconds and held at 10 amps until no trace of the sample was seen (~ 1-2 minutes). Spectral scans were taken from 50-800 amu at 2 seconds per scan. Quaternary (quat
nnary pump, tunable wavelength detector, C-18 column, and Finnigan LCQ with electrospray ionization
Hewlett Packard equipped with ion trap mass spectrometer
HPLC-Electrospray mass spectra (1100 HPLC)
HPLC ES-MS). The spectrum was scanned from 120-800 amu using an ion time variable depending on the number of ions entering the source. HP-1 methyl silicon column (0.33 mM coating; 25 mx
0.2mm) and Hewlett Packard 5971 Mass Sel
Gas chroma-ion selective mass spectra (GC-MS) were obtained using a Hewlett Packard 5890 gas chromatograph equipped with an active Detector (ionization energy 70 eV).

Elemental analysis was performed using Robertson Microlit Labs (Madiso).
nNJ). The NMR spectrum, LRMS, elemental analysis and HRMS of this compound were consistent with the assigned structure.

Examples of the preparation of the compounds of the present invention are shown in the synthetic procedures detailed below. The compound tables below list the synthesis of each compound reverting to typical manufacturing steps. A. Synthesis of imine precursor A1a. General method for synthesizing aniline from nitrobenzene. 4-cyano-2
-Synthesis of methylaniline.

[0084]

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The description [J. Med. Chem. (1991), 34, 3295], and the synthesis of 4-cyano-2-methylaniline was performed. 3-methyl-
4-Nitrobenzonitrile (2.0 g, 12.34 mmol) in acetic acid (20 L)
The solution contained SnCl ₂ (9.6 g, 49.38 mmol) was added to concentrated HCl (
(20 mL) was added dropwise. After stirring the mixture for 3 hours, it was carefully added to a 0 ° C. saturated NH ₄ OH solution (120 mL). The resulting mixture was extracted with EtOAc (4x30mL). The combined organic layers were washed successively with H ₂ O (30 mL) and saturated NaCl solution (30 mL) and dried (
Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc / hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92%): TLC (30% EtOAc in hexane) ) _Rf 0.23. This material was used without further purification. A2a. General synthesis method of isothiocyanate. Synthesis of 4-nitro-2-n-propylisothiocyanate.

[0086]

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Step 1 2-n-propylaniline (8.91 g, 66 mmol) and Et ₃ N (14 m
Acetic anhydride (106 mmol) in CH ₂ Cl ₂ (60 mL).
10.9 mL, 99 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight before being treated with a 1N HCl solution (40 mL). This acidic mixture is
Extracted with H ₂ Cl ₂ (2 × 30 mL). The organic layers are combined and successively H ₂ O (4
0 mL), 1N NaOH solution _{(40mL), H 2 O (} 40mL), and washed with saturated NaCl solution (40 mL), dried (Na ₂ SO _4), and concentrated under reduced pressure. The resulting powder is purified by crystallization (EtOAc) to give 2-n-
Propyl acetanilide was obtained as white needles (7.85 g, 67%). TL
C (30% EtOAc / hex) _Rf 0.37.

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Step 2 2-n-propylacetanilide (1.15 g, 6.50 mmol) was added to TFA
(20 mL) at -5 ° C with NaNO_Two(0.55g
, 6.50 mmol). The mixture was stirred at -5 ° C for 3 hours, _Two Treated with O (30 mL). The resulting aqueous solution was washed with EtOAc (3 × 20
mL). The organic layers were combined and 1N NaOH solution (30 mL), H_Two
Wash with O (30 mL) and saturated NaCl solution (40 mL) and dry (Na_Two
SO_Four) And concentrated under reduced pressure. The residue is concentrated HCl solution (30 mL)
And heated to 100 ° C. overnight. Cool the resulting mixture to 0 ° C. in an ice bath
After recirculation, the pH was carefully adjusted to 10 using a 50% NaOH solution. this
The basic mixture was extracted with EtOAc (4x30mL). Combine the organic layers together
Then H_TwoWash with O (30 mL) and saturated NaCl solution (40 mL) and dry
Dry (Na_TwoSO_Four) And concentrated under reduced pressure. Flash chroma the residue
Purification by chromatography (5% EtOAc / hex) gave 2-n-propyl-
4-Nitroacetanilide was obtained as a yellow solid (0.56 g, 48%): TL
C (2% EtOAc / hex) R_f0.47.

[0090]

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Step 3 2-propyl-4-nitroacetanilide (0.56 g, 0.31 mmol)
In toluene (30 mL) was added to thiophosgene (0.2
(4 mL, 0.31 mmol) was added dropwise. 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 / hex) to give 2-propyl-4-nitrophenylisothiocyanate as a yellow oil (0.65 g, 95%): T
LC (20% EtOAc / hex) _Rf 0.82. A2b. General synthesis method of isothiocyanate. Synthesis of 4-cyano-2-ethylphenylisothiocyanate.

[0092]

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4-Amino-3-ethylbenzonitrile (75 g, 0.51 mol) was dissolved in toluene
(1 L) was added to thiophosgene (43 mL, 0.56 mol, 1.1 equivalent).
Volume) was added slowly with a syringe. A viscous slurry formed within 5 minutes. This
Heating the reaction mixture to reflux temperature reduced the viscosity. The reaction mixture is brought to reflux temperature.
After heating for 5 hours each time, it was cooled to room temperature. Concentrate the resulting mixture under reduced pressure
After that, the residue is_TwoCl_Two(600 mL) and concentrate under reduced pressure
In this way, 4-cyano-2-ethylphenylisothiocyanate was converted to a light tan crystal.
Obtained as neutral solid (98 g, 100%):¹1 H NMR (DMSO-d₆) Δ1.
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 synthesis method of isothiocyanate. 2,4-dimethyl-3-cia
Synthesis of no-5-pyridyl isothiocyanate.

[0094]

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A mixture of CaCO ₃ (0.41 g, 4.11 mmol) in a 1: 2 mixture of water: CH ₂ Cl ₂ (9 mL in total) was stirred at room temperature with vigorous stirring. 6-amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0
. (68 mmol) in CH ₂ Cl ₂ (1 mL) was added. After cooling the reaction mixture to 0 ° C., thiophosgene (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 obtained that the 2,4-dimethyl-3-cyano-6-pyridyl isothiocyanate, purified by chromatography _{(SiO 2, 10% EtOAc /} hex) (0.12g, 91%): CI- MS m / z 190 ((M + H) +).
A2d. General synthesis method of isothiocyanate. Synthesis of 2,3-dimethyl-4-nitrophenylisothiocyanate.

[0096]

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After adding thiophosgene (0.3 mL, 1.3 eq) to a solution of 2,3-dimethyl-4-nitroaniline (0.5 g, 1.0 eq) in toluene (50 mL), The reaction mixture was heated to reflux overnight. After concentrating the resulting mixture under reduced pressure, the residue was purified by column chromatography (25% CH ₂ C).
The l ₂ / hex) to give the the 2,3-dimethyl-4-nitrophenyl isothiocyanate as a light yellow solid ^{(0.30g, 48%): 1} H NMR
(CDCl ₃ ) δ 2.39 (s, 3H), 2.41 (s, 3H), 7.20 (d
, J = 8.4 Hz, 1H); CI-MS m / z 200 ((M + H) ^<+> ). A2e. General synthesis method of isothiocyanate. Synthesis of 2,3-dimethyl-6-nitrophenyl isothiocyanate.

[0098]

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After adding thiophosgene (2.5 mL, 1.8 eq) to a solution of 2,3-dimethyl-6-nitroaniline (3.0 g, 1.0 eq) in toluene (150 mL), The reaction mixture was heated to reflux overnight. After concentrating the resulting mixture under reduced pressure, the residue was purified by column chromatography (10% CH ₂
Purification by Cl ₂ / hex) 2,3- dimethyl-6-nitrophenyl isothiocyanate as a light yellow solid ^{(3.63g, 95%): 1} H NM
R (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 synthesis method of arylisonitrile dichloride. 4-cyano-
Synthesis of 2-ethylphenyl isocyanide dichloride.

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Step 1 Acetic anhydride (235 mL, 2.5 mol, 2.6 eq) was added to formic acid (118 mL, 3.
(1 mol, 3.2 equiv.), The resulting solution was heated to 60 ° C. for 2 hours. After cooling the reaction to room temperature, a solution of 4-amino-3-ethylbenzonitrile (140 g, 0.96 mol) in anhydrous THF (700 mL) was added so that the reaction temperature did not exceed 45 ° C. Added at a rate (about 20 minutes). After cooling the resulting solution to room temperature, it was concentrated under reduced pressure to EtOH (600 m
L) and concentrated again under reduced pressure to give 4-cyano-2-ethylformanilide as a light tan solid (167 g, 100%): ¹ H NM.
R (CDCl ₃ ) δ 1.13 (t, J = 7.3 Hz, 3H), 2.48 (q, J
= 7.3 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 8.35 (d
, J = 8.5 Hz, 1H), 8.37 (s, 1H), 9.89 (br s, 1H)
).

[0102]

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Step 2 4-cyano-2-ethylformanilide (167 g, 0.96 mol, 1.0 equiv) was placed in SOCl ₂ (525 mL, 6.05 mol, 6.3 equiv) in an ice bath.
Sulfuryl chloride (112 mL, 1.4 mol, 1.4 equiv) was added via syringe to the solution that had been cooled to <RTIgt; Then, after removing the cooling bath, the reaction was cooled to 50 ° C.
Heated overnight. The resulting mixture was concentrated under reduced pressure and CH ₂ Cl ₂ (600
mL) and concentrated again under reduced pressure. The residue is treated with Et ₂ O (800 m
L) and filtered through a pad of Magnosil ™ to give 4
-Cyano-2-ethylphenylisocyanide dichloride was obtained as an oil (
210 g, 96%): ¹ H NMR (CDCl ₃ ) δ 1.13 (t, J = 7.3 H)
z, 3H), 2.49 (q, 2H, J = 7.3 Hz), 7.15 (d, J = 8.
2Hz, 1H), 8.35-8.40 (m, 2H). A3b. General synthesis method of arylisonitrile dichloride. 2-methyl-
Synthesis of 4-nitrophenyl isocyanide dichloride.

[0104]

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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 brought to 60 ° C. in 2.2.
Heat for 5 hours. After cooling to room temperature, 2-methyl-4-nitroaniline (152
g (1.64 mol, 1.0 eq) in anhydrous THF (1.2 L) was added at an addition rate such that the reaction temperature did not exceed 45 ° C (about 30 minutes). After cooling the resulting solution to room temperature, it was concentrated under reduced pressure to half its volume and the reaction product was filtered off to give 2-methyl-4-nitroformanilide a light tan color. Obtained as a solid (295 g, 100%): ¹ H NM
R (CDCl ₃ ) δ 2.31 (s, 3H), 8.03 (m, 2H), 8.24 (
d, J = 8.8 Hz, 1H), 8.39 (brs, 1H), 9.94 (br)
s, 1H).

[0106]

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Step 2 To 2-methyl-4-nitroformanilide (167 g, 0.96 mol) was added SOC
After addition of l ₂ (525 mL, 6.05 mol, 6.3 equiv), the resulting solution was cooled to 0 ° C. Sulfuryl chloride (112 mL, 1.4 mol, 1.4 eq) was added via syringe, the cooling bath was removed and the reaction was heated to 60 ° C. for 4 hours before cooling to room temperature overnight. After concentrating the reaction mixture to half volume under reduced pressure, the resulting slurry was filtered. This solid is treated with 50% Et ₂ O
/ Hex solution to give 2-methyl-4-nitrophenylisocyanide dichloride as a yellow solid (323 g, 85%): ¹ H NMR (CD
Cl 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 synthesizing nitroaniline from aniline. Synthesis of 2,3-dimethyl-6-nitroaniline and 2,3-dimethyl-4-nitroaniline.

[0108]

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Step 1 2,3-Dimethylaniline (1.1 mL, 1.00 eq.) And Et ₃ N (1.5
Acetyl chloride (0.73 mL, 1.25 eq) was added over 30 minutes to a solution of CH ₂ Cl ₂ (15 mL) at 0 ° C. The reaction mixture was stirred at room temperature overnight, then 2N HCl solution (10 mL) and CH ₂ Cl ₂ (25 mL).
mL). The resulting mixture was extracted with EtOAc (3x25mL). The organics were combined and 2N HCl solution (2 × 25 mL), water (2 × 25 mL)
mL), saturated NaHCO ₃ solution (2 × 25 mL) and saturated NaCl solution (2 × 25 mL).
25 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure.
2,3-Dimethylacetanilide was obtained as a white solid (1.25 g, 93%).
: ¹ H NMR (CDCl ₃ ) δ 2.05 (s, 3H), 2.15 (s, 3H),
2.25 (s, 3H), 6.95 (d, J = 7.5 Hz, 1H), 7.02 (a
ppt, J = 7.5 Hz, 1H), 7.35 (d, J = 6.9 Hz, 1H).

[0110]

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Step 2 2,3-Dimethylacetanilide (14.0 g, 1.0 equiv) was added to concentrated H ₂ SO ₄ (
35 mL) at 0 ° C. in HNO ₃ (5.1 mL, 1.0 mL).
25 eq.) Over 30 minutes. The resulting mixture was stirred at room temperature for 15 minutes and then treated with ice water (500 mL) to give a yellow precipitate. The solid was taken out and washed with water to obtain 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, 1.5 H), 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, 0.5 H), 7.63 (d, J = 8.7 Hz, 0.5 H), 7
. 76 (d, J = 8.1 Hz, 1H). This mixture was used in the next step without further purification.

[0112]

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Step 3 To a solution containing the nitroacetanilide mixture (16.0 g, 1.0 equiv) was added a 60% H ₂ SO ₄ solution (150 mL). The solution was heated to reflux for 1 hour, then cooled to room temperature and treated with 2N NaOH solution in ice water (100 mL). The resulting mixture was extracted with EtOAc (3x50mL). The combined organic layers were washed with a saturated NaHCO ₃ solution (2 × 50 mL) and a saturated NaCl solution (2 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (10% CH ₂ Cl ₂ / hex) to give 2,3-dimethyl-6-nitroaniline (5.5 g, 43%) followed by 2,3-dimethyl-4. -Nitroaniline (1.5 g, 12%) was obtained. Two, three
-Dimethyl-6-nitroaniline (5.5 g, 43%): ¹ H NMR (CDC
l ₃ ) δ 2.05 (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 H)
z, 1H): ¹ H NMR (DNSO-d ₆ ) δ 2.10 (s, 3H), 2.30
(S, 3H), 6.50 (d, J = 8.7 Hz, 1H), 7.15 (brs,
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 (DNSO-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 synthesis of iodoaniline. Synthesis of 4-iodo-2-n-propylaniline.

[0114]

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NaH was added to a solution of 2-n-propylaniline in MeOH (25 mL).
A solution of CO ₃ (5.0 g, 59.9 mmol) in H ₂ O (25 mL) was added. After adding iodine (8.4 g, 33.3 mmol) in portions over 70 minutes while maintaining the temperature at 10 ° C., the mixture was stirred at 10 ° C. for 30 minutes. The resulting mixture was diluted with H ₂ O (30 mL) and then diluted with EtOAc (4 × 40).
mL). Combine the organic layers and sequentially add a 5% Na ₂ S ₂ O ₃ solution (30
mL) and saturated NaHCO ₃ solution (30 mL) and dried (Na ₂ SO ₄ )
After allowing to concentrate, it was concentrated under reduced pressure to obtain 4-iodo-2-n-propylaniline (9.4 g, 98%): TLC (20% EtOAc / hex) R _f 0.43
. This material was used in the next step without further purification. B. Method for Producing 2-Imino Heterocycle Precursor B1a. General method for synthesizing ethanolamine by reduction of amino acid derivatives. 1
Synthesis of -amino-1- (hydroxymethyl) cyclohexane.

[0116]

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Step 1 To a solution of 1-aminocyclohexane-1-carboxylic acid (10.0 g, 70.0 mmol) in a 1 M NaOH solution (100 mL) was added benzyl chloroformate (12.0 ml, 84.0 mmol). ) Was added. The reaction mixture was stirred for 2 hours while maintaining the pH at 9 by adding 1M NaOH solution as needed. After washing the resulting solution with Et ₂ O ( ₂ × 100 mL), the pH of the aqueous layer was adjusted to 0 with concentrated HCl solution and the solution was 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 / hex) R _f 0.
07.

[0118]

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Step 2 1- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid (
4.16 g, 15.0 mmol) and N-methylmorpholine (1.81 mL, 16
. Isobutyl chloroformate (2.14 mL, 16.5 mmol) at 4 ° C. was slowly added to a solution of 5 mmol) in DME (15 mL).
The reaction mixture was stirred for 5 minutes, then filtered and placed in a pre-cooled (4 ° C.) flask. Sodium borohydride (0.85 g, 22.5 mmol) was added in water (7 mL) followed immediately by water (500 mL). The reaction was then warmed to 20 ° C. and stirred for 30 minutes. The reaction mixture was extracted with CH ₂ Cl ₂ and then concentrated under reduced pressure to obtain 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) cyclohexane (4.0 g, 100%).
): TLC (25% EtOAc / hex) _Rf 0.11.

[0120]

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Step 3 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) cyclohexane (4.0 g, 15 mmol) and 10% Pd / C (0.40 g) in MeO
The slurry formed in H (75 ml) was stirred under H ₂ (1 atm) for 1 hour and then treated with Celite ™. The resulting mixture was filtered and concentrated under reduced pressure to give 1-amino-1- (hydroxymethyl) cyclohexane. B1b. General method for synthesizing ethanolamine by reduction of amino acid derivatives. (
Synthesis of 1S) -1- (hydroxymethyl) -3-methylbutylamine.

[0122]

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Step 1 (L) -Leucine (315 g, 2.4 mol) was added to MeOH (3.2 L) at -15 ° C.
) In the suspension containing SOCl ₂ (315 mL, 4.32 mol, 1.8 eq)
Was added dropwise at a rate such that the temperature of the reaction did not exceed 5 ° C. After the addition was completed, the reaction mixture was warmed to room temperature and stirred overnight. After concentration of the resulting mixture under reduced pressure, Et ₂ O (3 L) was slowly added to the residue, resulting in a precipitate. After the mixture was cooled in an ice bath, it was worked up by adding additional MeOH (3 L) relatively quickly. The crystals were collected after 1 hour at 0 ° C. and dried to give the HCl salt of the methyl ester of (L) -leucine as a crystalline white solid (394 g, 86%): mp 147-149 ° C .; ¹ H NMR. (CD ₃ O
D) 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).

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Step 2 (L) -HCl salt of methyl ester of leucine (254 g, 1.4 mol), N
aHCO ₃ (118 g, 1.4 mol, 1.0 equivalent) and water (1.8 L) were added to Et.
OH (1.8 L) was added to the mixture at 5 ° C. with NaBH ₄ (159
g, 4.2 mol, 3.0 equiv) were added in portions (about 70 minutes) at an addition rate such that the reaction temperature did not exceed 15 ° C. After the addition of NaBH ₄ is completed, remove the ice bath and heated overnight reaction at reflux temperature. The resulting mixture was cooled in an ice bath to room temperature. The resulting slurry was filtered to remove the solid from EtOH (750 mL
). The combined filtrates were concentrated under reduced pressure to about 950 mL. The residue was diluted with EtOAc (2.5 L) and then 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 was obtained as a pale yellow oil (112 g, 65%): ¹ H NMR (CDCl ₃ ) δ 0.88-0.93.
(M, 6H), 1.17 (t, J = 7.7 Hz, 2H), 1.68-1.80 (
m, 2H), 1.82 (brs, 2H), 2.86-2.91 (m, 1H),
3.22 (dd, J = 10.7, 8.1 Hz, 1H), 3.56 (dd, J = 1
0.3, 3.6 Hz, 1H). B1c. General method for synthesizing ethanolamine by reduction of amino acid derivatives. 1
-Synthesis of hydroxymethylcyclopentanamine.

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Step 1 A suspension of 1-aminocyclopentanecarboxylic acid (675 g, 5.23 mol, 1.0 equiv.) In MeOH (6.5 L) was treated with an ice / MeOH bath at −15. While maintaining the temperature at 0 ° C, SOCl ₂ (687 mL, 9.4 mol, 1.8 equivalents) was added dropwise thereto at a rate such that the reaction temperature did not exceed 7 ° C. After the addition was complete, the cooling was removed and the reaction was stirred at room temperature overnight, then concentrated under reduced pressure. After the residue was treated with CH ₂ Cl ₂ (1L), by concentrating under reduced pressure to give the HCl salt of 1-amino-cyclopentanecarboxylic acid methyl as a white solid (938
g, 100%): ¹ H NMR (CD ₃ OD) d1.87-1.94 (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.

[0128]

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Step 2 HCl salt of methyl 1-aminocyclopentanecarboxylate (310 g, 1.73
Mol) in a solution of EtOH (12.5 L) and water (2.5 L) was treated with NaHCO ₃ (145 g, 1.73 mol, 1.0 equiv).
The resulting mixture was then cooled to 5 ° C. in an ice bath before NaBH ₄ (196
g, 5.2 mol, 3.0 equivalents) were added in portions (about 75 minutes) at an addition rate such that the reaction temperature did not exceed 15 ° C. After the addition of NaBH ₄ was complete, the ice bath removed and the reaction was heated to reflux temperature overnight, cooled to room temperature in an ice bath, and filtered.
After washing the resulting solid with EtOH (750 mL), the combined filtrates were concentrated under reduced pressure. Next, the resulting slurry was washed with EtOAc (2.5 L).
Processed. The organic layer was washed with 1N NaOH solution (2 × 750 mL) and the aqueous layer was back-extracted with EtOAc (2 × 500 mL). Dry the organic layers together (
MgSO ₄ ) and concentrated under reduced pressure to give 1-hydroxymethylcyclopentanamine as a low melting wax (169 g, 85%): ¹ HN.
MR (CDCl ₃ ) δ 1.38-1.44 (m, 2H), 1.58-1.69 (
m, 4H), 1.70-1.84 (m, 2H), 2.11 (brs, 3H),
3.36 (s, 2H), CI-MS m / z 116 ((M + H) ^<+> ). B2a. General method for N-alkyl substitution of ethanolamine by substitution reaction.
Synthesis of 2- (isobutylamino) -2- (hydroxymethyl) norbornane.

[0130]

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In a manner analogous to that of Method B1a, 2-aminonorbornane-2-carboxylic acid was converted to 2-amino-2- (hydroxymethyl) norbornane as a mixture of diastereomers. 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 to 90 ° C. for 92 hours and then cooled to room temperature. , EtOAc (100m
L) and saturated NaHCO ₃ solution (100 mL). Organic layer is saturated Na
After washing with a Cl solution (50 mL), drying (MgSO ₄ ) and concentrating under reduced pressure, 2- (isobutylamino) -2- (hydroxymethyl) norbornane was obtained as a diastereomer mixture (0 .24 g, 55%): GC-MS m
/ Z 197 (M ⁺ ). B2b. General method for N-alkyl substitution of ethanolamine by substitution reaction.
Synthesis of N-hydroxyethyl-N-cyclohex-1-enylmethylamine.

[0132]

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Step 1 Methyl cyclohex-1-enecarboxylate (4.56 g, 32 mmol) was added to T
The solution formed by placing in HF (100 mL) was stirred at -78 ° C.
DIBAL (1 M in THF, 130 mmol, 130 mL) was added dropwise thereto. This
Was stirred at −78 ° C. for 4 hours and then saturated NaHCO 3_ThreeWith the solution (40 mL)
Processed. The aqueous layer was extracted with EtOAc (4 × 20 mL) and the combined organic layers were washed with H 2. _Two O (40 mL) and saturated NaCl solution (40 mL), dry (Na_TwoS
O_Four) And concentrated under reduced pressure. Residual cyclohex-1-enyl methano
Was used directly in the next step without further purification: TLC (30% EtOAc /
hex) R_f0.44.

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Step 2 Cyclohex-1-enylmethanol (3.58 g, 32 mmol) was added to CH ₂
To a solution of the resulting solution in 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 is pentane (
60 mL) and filtered. The filtrate was concentrated under reduced pressure, and purified by column chromatography (5% EtOAc / hex) to give 1-bromomethyl-
1-Cyclohexene was obtained as an oil (3.25 g, 57% over two steps).
: TLC (30% EtOAc / hex) _Rf 0.91.

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Step 3 A solution of 1-bromomethyl-1-cyclohexene (3.25 g) and 2-aminoethanol (6 mL) in trichloroethylene (40 mL) is heated to reflux for 3 days and cooled to room temperature After that, 1N NaOH solution (30 mL
). After the aqueous layer was extracted with CH ₂ Cl ₂ (4 × ₂₀ mL), the combined organic layers were washed with H ₂ O (30 mL) and saturated NaCl solution (30 mL), dried (Na ₂ SO ₄ ), and dried under reduced pressure. Concentrated under. The residue was purified by vacuum distillation to give N-hydroxyethyl-N-cyclohex-1-enylmethylamine as a colorless oil (1.78 g, 62%): bp 92-94 ° C (6 mmHg).
). B3a. General method for N-alkyl substitution of ethanolamine by reductive alkyl substitution. Synthesis of the HCl salt of the methyl ester of (R) -N-isobutylserine.

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(D) Isobutyraldehyde (1.5 mL, 16.3 g) in a suspension of the HCl salt of the methyl ester of serine (2.13 g, 13.7 mmol) in 1,2-dichloroethane. (4 mmol) and sodium triacetoxyborohydride (4.3 g, 20.5 mmol). The reaction mixture was stirred at room temperature for 24 hours, then 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 then 1M HCl solution in ether (25 mL)
Processed. The resulting mixture was concentrated under reduced pressure to give the HCl salt of the methyl ester of (R) -N-isobutylserine (2.27 g, 79%): N
MR (DMSO-d ₆ ) δ 0.94 (dd, J = 6.7, 3.0 Hz, 6H),
1.97-2.11 (m, 1H), 2.76-2.91 (m, 1H), 3.76
(S, 3H), 3.86 (dd, J = 12.1, 4.1 Hz, 1H), 3.99
(Dd, J = 12.4, 3.2 Hz, 1H), 4.13-4.21 (m, 1H)
. B4a. General method for N-alkyl substitution of ethanolamine by 2-alkyl-1,3-oxazolidine formation followed by reduction. 1- (cyclohexylamino)-
Synthesis of 1- (hydroxymethyl) cyclopentane.

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Step 1 1-Amino-1- (hydroxymethyl) cyclopentane (Method B1c; 1.4
4 g, 12.54 mol) in CH ₂ Cl ₂ (10 mL) at 4 ° C. was added to TFA (0.097 mL, 1.25 mmol), cyclohexanone (
After addition of 1.30 mL, 12.54 mmol) and sodium sulfate (2 g), the reaction was warmed to 20 ° C. The reaction was stirred for 72 hours, then washed successively with water (10 mL) and saturated NaHCO ₃ solution (20 mL) and dried (MgSO 4).
O ₄ ), and then concentrated under reduced pressure to give 14-aza-7-oxadispiro [
4.2.5.1] tetradecane was obtained (2.38 g, 97%): GC-MS m
/ Z 195 (M ⁺ ).

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Step 2 LiAlH ₄ (0.93 g, 24.4 mmol) and AlCl ₃ (3.24 g, 2
(4.4 mmol) in THF at 4 ° C.
A solution of 7-oxadisspiro [4.2.5.1] tetradecane (2.38 g, 12.2 mmol) in THF (15 mL) was added dropwise. The resulting mixture was warmed to 20 ° C, stirred for 45 minutes, and then cooled to 4 ° C. water(
The reaction was quenched by the slow addition of (5 mL) (quenc
After h), 1N NaOH solution (85 mL) was added to dissolve the resulting solid. The resulting solution was extracted with Et ₂ O (200mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to obtain 1- (
Cyclohexylamino) -1- (hydroxymethyl) cyclopentane was obtained (1)
. 89 g, 79%): GC-MS m / z 197 (M ^<+> ). B4b. General method for N-alkyl substitution of ethanolamine by 2-alkyl-1,3-oxazolidine formation followed by reduction. N-cyclopentyl- (1,1-
Synthesis of dimethyl-2-hydroxyethyl) amine.

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Step 1 2-Amino-2-methyl-1-propanol (15.0 g, 0.168 mol)
And cyclopentanone (14.9 mL, 0.168 mol, 1.0 equiv.) And p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol, 0.05 equiv.) In toluene (300 mL). The resulting mixture was stirred at reflux overnight.
The reaction mixture was then cooled to room temperature, diluted with EtOAc (500 mL), washed with saturated NaHCO ₃ solution (250 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. , 4-aza-3,3-dimethyl-1-oxaspiro [
4.4] Nonane was obtained as a pale yellow oil (15.5 g, 60%): ¹ H NM.
R (CDCl ₃ ) δ 1.12 (s, 6H), 1.65 (m, 5H), 1.80 (
m, 2H), 1.97 (m, 2H), 3.45 (s, 2H).

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Step 2 Next, 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane (1
A solution of 5.5 g (0.10 mol) in EtOH (85 mL) was added at 0 ° C. with NaBH ₄ (5.47 g, 0.145 mol, 1.45 eq) at a reaction temperature of 10 ° C. The addition was made at a rate not to exceed (about 1 hour). The reaction mixture was then warmed to room temperature and stirred for 18 hours. The resulting mixture is washed with water (100 m
After treatment under L), concentration under reduced pressure gave a paste. MeOH (100m
After addition of L), the mixture was again concentrated under reduced pressure. The residue is taken as EtOA
c (300 mL) and water (150 mL). Dry the organic layer (Na ₂ S
O ₄ ) and concentrated under reduced pressure to obtain N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine as a pale yellow oil (13.0).
g, 83%): ¹ H NMR (CDCl ₃ ) δ 1.07 (s, 6H), 1.24 (
m, 3H), 1.50 (m, 2H), 1.65 (m, 2H), 1.87 (m, 2H)
H), 3.0 (m, 1H), 3.22 (s, 2H); CI-MS m / z 15
8 ((M + H) ⁺ ). B4c. General method for N-alkyl substitution of ethanolamine by 2-alkyl-1,3-oxazolidine formation followed by reduction. Synthesis of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol.

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Step 1 (1S) -1- (hydroxymethyl) -3-methylbutylamine (Method B1b
152 g, 1.3 mol) and isobutyraldehyde (118 mL, 1.3 mol,
(1.0 eq.) In toluene (1.5 L) was heated at reflux until the theoretical amount of water was collected in a Dean-Stark trap (23.4 mL). The reaction mixture was concentrated to about 700 mL by distillation. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure to a constant weight to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine as a pale yellow oil. (223 g, 100%): ¹ H NMR (CDCl ₃ ) δ
0.88-0.99 (m, 12H), 1.18-1.35 (m, 1H), 1.4
2-1.56 (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).

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Step 2 (4S) -2-Isopropyl-4-isobutyl-1,3-oxazolidine (2
23 g, 1.3 mol) in EtOH (1.1 L) and -13 in an ice / MeOH bath.
° C. NaBH ₄ in which had been cooled solution (70.3 g, 1.82 mol) the reaction temperature was added in portions at a rate of addition that does not exceed 10 ° C. (about 2 hours). The reaction mixture was warmed to room temperature and stirred overnight, then filtered through a coarse sintered glass funnel. The resulting solid was washed with EtOH. After combining the filtrates and concentrating under reduced pressure, 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 give (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as a viscous pale yellow oil (192 g, 85%): ¹ H NMR (CDCl ₃ ) δ 0.90-0.9.
6 (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-alkyl substitution of ethanolamine by 2-alkyl-1,3-oxazolidine formation followed by reduction. 1- (cyclopentylamino)-
Synthesis of 1- (hydroxymethyl) cyclopentane.

[0152]

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Step 1 1-Hydroxymethylcyclopentanamine (Method B1c; 263 g, 2.3
Mol) and cyclopentanone (220 mL, 1.3 mol, 1.1 equiv.) In toluene (2.7 L) yields a solution of the theoretical amount of water at reflux temperature (41.4 mL). The mixture was heated while azeotropically removing water. The reaction mixture was concentrated to 700 mL by simple distillation, cooled to room temperature, and concentrated under reduced pressure to a constant weight to give 6-aza-12-oxadisspiro [4.1.4.
2] Tridecane was obtained as a pale yellow oil (414 g, 100%): ¹ H NM.
_{R (CDCl 3) δ1.55-1.89 (m} , 17H), 3.60 (s, 2H)
.

[0154]

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Step 2 6-aza-12-oxadisspiro [4.1.4.2] tridecane (124 g,
0.69 mol) in EtOH (NaBH a solution prepared by dissolving 600 mL) thereto while maintaining the -13 ° C. in an ice / MeOH bath ₄ (38 g, 1.0 mol, 1.45 temperature 10 ° C. eq) (Approximately 30 minutes)
. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was added to water (500 m
L) and concentrated under reduced pressure. Remaining paste in EtOAc (1 L)
And water (600 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to obtain 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane as a white powder (107 g, 85%). : ¹ H N
MR (CDCl ₃ ) δ1.23-1.28 (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 synthesizing ethanolamine by reacting amine with epoxide. Synthesis of N- (hydroxyethyl) -N- (2-butyl) amine.

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A solution of s-butylamine (60 mL, 0.60 mmol) in MeOH (40 mL) was added to a solution of ethylene oxide (40 mL) at room temperature using a cannula.
(10 mL, 0.20 mmol) was added dropwise. 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 as a colorless oil (16.4 g).
, 70%): Boiling point 109-112 ° C (6 mmHg). B5b. General method for synthesizing ethanolamine by reacting amine with epoxide. Synthesis of N- (3-phenyl-2-hydroxypropyl) -N-isobutylamine.

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A mixture of 2,3-epoxypropylbenzene (10 g, 74.5 mmol) and isobutylamine (5.4 g, 74.5 mmol) was 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):
Boiling point 115-117 ° C (1 mmHg). B6a. General method for synthesizing propanolamine by Arndt Eisert homologation of amino acids followed by reduction. Synthesis of (R) -3- (t-butylamino) -4-methylpentanol.

[0160]

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Step 1 N- (t-butoxycarbonyl)-(L) -valine (4.32 g, 19.9 mmol) and N-methylmorpholine (2.3 mL, 20.9 mmol) were added to DME (
30 mL) at −10 ° C. at isobutyl chloroformate (10 mL).
2.27 mL, 21.0 mmol). The resulting mixture was stirred at room temperature for 15 minutes, then filtered and the solid was washed with cold DME. The filtrate was -10
After cooling to ° C., the solution was treated with CH ₂ N ₂ in Et ₂ O until the yellow color persisted, and the resulting mixture was warmed to 20 ° C.
After stirring for minutes, the mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ , gradient from hexane to 30% EtOAc / hex) to give (S) -3- (t-butoxycarbonylamino) -1-diazo-4-
Methylpentan-2-one was obtained (1.82 g, 38%): TLC (10% Et
OAc / hex) _Rf 0.11.

[0162]

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Step 2 By placing (S) -3- (t-butoxycarbonylamino) -1-diazo-4-methylpentan-2-one (1.83 g, 7.6 mmol) in MeOH (100 mL). After heating the resulting solution to reflux temperature, a solution of silver benzoate in Et ₃ N and filtered (0.50 g of silver benzoate in 5 mL of Et ₃ N, 0.5 mL ) Was added. After the first gas evolution ceased (about 0.5 minutes), additional silver solution (0.5 mL) was added. This process was repeated until no gas was generated even when the silver salt was added. The resulting mixture was cooled to 20 ° C., treated with Celite ™, and then filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in Et ₂ O (100 mL) and then successively 1N HC
1 solution (100 mL), saturated NaHCO ₃ solution (100 mL) and saturated NaC
1 (50 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to obtain methyl (R) -3- (t-butoxycarbonylamino) -4-methylpentanoate ( 1.63 g, 87%): TLC (10% EtOAc / hex)
_Rf 0.29.

[0164]

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Step 3 Methyl (R) -3- (t-butoxycarbonylamino) -4-methylpentanoate (1.62 g, 6.6 mmol) with lithium borohydride in a manner analogous to step 2 of method B8a. This gave (R) -3- (t-butoxycarbonylamino) -4-methylpentanol (93%). B7a. General method for the synthesis of chloroethylamine. Synthesis of (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride.

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(1S) -1- (Hydroxymethyl) -3-methylbutylamine (Method B1b
5.40 g, 46.1 mmol) in CH_TwoCl_Two(200mL)
The resulting solution was saturated with HCl gas while cooling on an ice bath. SOCl _Two (4.0 mL, 55.3 mmol) was added and the reaction was brought to reflux for 2.5
After heating for an hour, it was cooled to room temperature and concentrated under reduced pressure. Et the residue_TwoO and
By grinding together, (1S) -1- (chloromethyl) -3-methylbutamate
Ammonium chloride was obtained (5.67 g, 71%): EI-MS m / z
 136 ((M + H)⁺). B7b. General method for the synthesis of chloroethylamine. 1- (chloromethyl) -1-
Synthesis of the HCl salt of (cyclohexylamino) cyclopentane.

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1- (Cyclohexylamino) -1- (hydroxymethyl) cyclopentane (Method B4a; 1.9 g, 4.9 g) in 4 M HCl solution (p-dioxane, 40 mL).
6 mmol) and SOCl ₂ (0.84 mL, 11.5 mmol).
Heated to 0 ° C. for 18 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to give crude 1- (chloromethyl) -1- (cyclohexylamino) cyclopentane HCl salt (2.84 g) which was further purified. Used in the next step without purification. B7c. General method for the synthesis of chloroethylamine. Synthesis of the HCl salt of N- (1S)-(1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) amine.

[0170]

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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 to a solution of SOCl ₂ (167 mL). ) Was added over 15 minutes. After the SOCl ₂ addition was completed, the reaction was heated to 90 ° C. overnight. Next, the reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The dark oil residue was dissolved in CH ₂ Cl ₂ ( ₂ L) and concentrated under reduced pressure. After dissolving the red-brown residue in Et ₂ O (1 L), hexane (750 mL) was added dropwise over 8 hours. The resulting slurry was stirred overnight, filtered and washed with a 40% EtOAc / hex solution,
The HCl salt of N- (1S)-(1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) amine was obtained as a dark brown solid (276 g): ¹ H NMR (C
_{DCl 3) δ0.93-1.00 (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 (d
d, J = 13.2, 3.6 Hz, 1H). B7d. General method for the synthesis of chloroethylamine. 1- (chloromethyl) -1-
Synthesis of the HCl salt of (cyclopentylamino) cyclopentane.

[0172]

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1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane (
SOCl ₂ (84 mL) was added over 15 minutes to a solution of Method B1c; 140 g, 0.76 mol, 1.0 equiv) in toluene (1.4 L).
After the end of the SOCl ₂ addition, the reaction mixture already warmed to 40 ° C.
Heated to ° C overnight. After cooling the resulting solution to room temperature, HCl (p
-4N in dioxane, 100 mL), and the reaction was heated to 60 C for 3 hours before stirring at room temperature overnight. The resulting mixture is concentrated under reduced pressure to half its original volume, at which point a precipitate begins to form. The resulting slurry was stirred for 4 hours and diluted with Et ₂ O. The resulting precipitate was filtered and washed with Et ₂ O ( ₂ × 50 mL) to give 1- (chloromethyl)
-HCl salt of 1- (cyclopentylamino) cyclopentane was converted to off-white (o
ff-white) (125 g, 70%): ¹ H NMR (C
_{DCl 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, 1H). B7e. General method for the synthesis of chloroethylamine. Synthesis of the HCl salt of 1-chloromethylcyclopentanamine.

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HCl salt of 1-hydroxymethylcyclopentanamine (Method B1c; 20 g
, 0.17 mol) in anhydrous p-dioxane (65 mL) was added HCl (4 M in p-dioxane, 65 mL, 0.26 mol). After stirring the resulting solution at room temperature for 20 minutes, SOCl ₂ (22.7 g, 0
. 19 mol) was added dropwise. The reaction mixture was heated to 80 ° C. for 2 days, cooled to room temperature, and then concentrated under reduced pressure to obtain H of 1-chloromethylcyclopentanamine.
The Cl salt was obtained (29 g, 100%): CI-MS m / z 171 ((M + H)
+). B8a. General method for synthesizing 2-aminoethylsulfonate ester. (1R,
Synthesis of 2R) -1- (methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride.

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Step 1 The dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine (2.15 g, 4.4 mmol) was converted to C
The resulting solution in H ₂ Cl ₂ (50 mL) was treated with a solution of CH ₂ N ₂ in Et ₂ O until the yellow color persisted. The resulting solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), then 1N HCl solution (2 × 100 mL) and saturated NaCl solution (50 mL)
After successively washing with, drying (MgSO ₄ ) and concentrating under reduced pressure, (
The methyl ester of 1S, 2R) -N- (benzyloxycarbonyl) -Ot-butylthreonine was obtained (1.44 g, 100%): TLC (25% EtOAc
/ Hex) _Rf 0.54.

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Step 2 Methyl ester of (1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine (1.4 g, 4.4 mmol) produced by placing in Et ₂ O (20 mL). A saturated solution of LiBH ₄ in Et ₂ O (9 m
L) was added and the reaction mixture was heated to reflux for 2 hours and then cooled to 20 ° C. After water (5 mL) was added to the resulting mixture, a 1N HCl solution was added until no more gas evolved. The ether layer was washed with a saturated NaCl solution (5
0 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to obtain (
1R, 2R) -N- (benzyloxycarbonyl) -1- (hydroxymethyl)
-2- (t-Butoxy) propanamine was obtained (1.69 g, 99%): TLC
(25% EtOAc / hex) _Rf 0.20.

[0180]

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Step 3 (1R, 2R) -N- (benzyloxycarbonyl) -1- (hydroxymethyl) -2- (t-butoxy) propanamine (1.6 g, 5.4 mmol) was added to anhydrous pyridine (30 mL). ) Was added dropwise at 4 ° C. to the solution resulting from the addition of methanesulfonyl chloride (0.75 mL, 9.7 mmol). This reaction was taken as 5.
After stirring for 5 h, diluted with EtOAc (200 mL) and diluted with 1N HCl solution (4
x 200 mL). After the combined organic layers were dried (MgSO ₄ ),
By concentrating under reduced pressure, (1R, 2R) -N- (benzyloxycarbonyl)
-1- (Methanesulfonyloxymethyl) -2- (t-butoxy) propanamine was obtained as an oil (2.03 g, 100%): TLC (25% EtOAc /
hex) _Rf 0.31.

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Step 4 (1R, 2R) -N- (benzyloxycarbonyl) -1- (methanesulfonyloxymethyl) -2- (t-butoxy) propanamine (2.03 g, 5.5
Mmol) in MeOH (50 mL).
1 solution (dioxane; 1.5 mL, 6.0 mmol) and 10% Pd / C (0
. 20 g) was added. The resulting slurry was stirred under H ₂ (1 atm) for 2 h, then treated with Celite ™, filtered and concentrated under reduced pressure to give (1R, 2R) -1- (methane Sulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride was obtained (1.6 g, 100%). B8b. General method for synthesizing 2-aminoethylsulfonate ester. N- (2-tosyloxyethyl) -2-methylprop-2-ene-1-trifluorotrifluoroacetate
Synthesis of ammonium.

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Step 1 t-butyl ester of N- (t-butoxycarbonyl) glycine (3.97 g)
, 17.2 mmol) in DMF (70 mL).
At 0 C sodium hexamethyldisilazide (3.78 g, 20.6 mmol) was added and the resulting mixture was stirred for 25 minutes before warming 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 is washed sequentially with water (4 × 500 mL) and saturated NaC
1 solution (4 × 50 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to give N- (t-butoxycarbonyl) -N- (2-methylprop-2-
The t-butyl ester of (enyl) glycine was obtained (4.03 g, 82%): TLC
(10% EtOAc / hex) _Rf 0.51.

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Step 2 The t-butyl ester of N- (t-butoxycarbonyl) -N- (2-methylprop-2-enyl) glycine (0.26 g, 0.93 mmol) was added to Et ₂ O (3
mL), and the resulting solution was charged into lithium borohydride (0.011 mL).
g) and stirred overnight at room temperature. Water (2 m) was added to the resulting mixture.
After addition of L), 1N HCl was added dropwise until gas evolution ceased. The organic phase was washed with a saturated NaHCO ₃ solution (20 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue is chromatographed (SiO ₂ , 10% EtOAc /
Hex to 50% EtOAc / hex gradient) to give N- (t
-Butoxycarbonyl) -N- (2-hydroxyethyl) -1-amino-2-methylprop-2-ene was obtained (0.113 g, 57%): TLC (10% EtO).
Ac / hex) R _f 0.66.

[0188]

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Step 3 N- (t-butoxycarbonyl) -N- (2-hydroxyethyl) -1-amino-2-methylprop-2-ene (21.1 g, 98 mmol) was added to Et ₂ O (8
(00 mL) at −78 ° C. was slowly added potassium t-butoxide (1M in t-butanol, 103 mL, 103 mmol).
After warming short time the reaction mixture to -45 ° C., cooled to -78 ° C., p-toluenesulfonyl chloride (18.7 g, 98.0 mmol) is in solution (100 mL) contained in Et ₂ O Processed. Next, the resulting mixture was warmed to -45 ° C and treated with water (500 mL). The organic phase is saturated NaCl solution (800 mL)
, Dried (MgSO ₄ ) and concentrated under reduced pressure to give N- (t-
Butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2-methylprop-2-ene was obtained (36.4 g, 101%): TLC (25% EtO).
Ac / hex) R _f 0.56.

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Step 4 Solid N- (t-butoxycarbonyl) -N- (2-tosyloxyethyl)
-1-Amino-2-methylprop-2-ene (15 g, 55.7 mmol) was added to 0
Cooled to ° C. and dissolved in TFA (200 mL). The reaction mixture was warmed to room temperature and concentrated under reduced pressure. The remaining oil was crystallized from Et ₂ O (500 mL) to give N- (2-tosyloxyethyl) -trifluoroacetate.
2-Methylprop-2-en-1-ammonium was obtained (16.7 g, 78%).
. B9a. General synthesis of 3-chloropropyl- and 4-chlorobutylamine. Synthesis of HCl salt of N-isobutyl-3-chloropropylamine.

[0192]

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Step 1 3-Aminopropanol (91 g, 65.4 mmol) was added to toluene (100 m
L) into the resulting solution, isobutyraldehyde (9.0 mL, 99 mL).
. An exotherm occurred upon addition of 1 mmol, 1.5 eq) and MgSO ₄ (7.5 g). After stirring the slurry for 30 minutes, an additional amount (7.5 g) of MgSO ₄
Was added and the slurry was stirred overnight. After filtering the resulting mixture,
Concentrated under reduced pressure. After concentrating the concentrate again under reduced pressure, the two residues were combined to give 2-isopropyltetrahydro-1,3-oxazine as a colorless oil (5.18 g, 61%): ¹ H NMR (CDCl ₃ ) δ 0.8
4-0.88 (m, 6H), 1.24 to 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)
.

[0194]

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Step 2 2-Isopropyltetrahydro-1,3-oxazole (4.94 g, 38.
2 mmol) in anhydrous EtOH (100 mL).
After addition of NaBH ₄ (2.17 g, 57.4 mmol, 1.5 eq) in small portions over 15 min at ℃ C, the resulting mixture was stirred at room temperature overnight. After concentrating the resulting mixture under reduced pressure, EtOAc (150 mL) and water (10 mL) were added.
0 mL) (Note: gas evolved) and stirred at room temperature for 30 minutes. The resulting organic layer was washed with a saturated NaCl solution. The combined aqueous layers were combined with EtOAc (1
(50 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give N-isobutyl-3-hydroxypropylamine as a colorless oil (5.04 g, 100%): ¹ H NMR (CDCl ₃ ) δ0.
84 (d, J = 6.6 Hz, 6H), 1.60-1.71 (m, 3H), 2.3
6 (d, J = 6.6 Hz, 2H), 2.80 (dd, J = 5.9, 5.9 Hz,
2H), 3.10-3.30 (brs, 2H), 3.74 (dd, J = 5.5)
5.5 Hz, 2H), ¹³ C NMR (CDCl ₃ ) δ 20.5, 28.1, ₃
0.6, 50.0, 57.8, 64.1.

[0196]

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Step 3 A solution of N-isobutyl-3-hydroxypropylamine (1.01 g, 7.70 mmol) in toluene (100 mL) was charged with SOCl ₂ (
(1.37 g, 11.6 mmol, 1.5 equiv) was added and the resulting mixture was stirred at room temperature for 4 hours. The resulting slurry was concentrated under reduced pressure to give the HCl salt of N-isobutyl-3-chloropropylamine: ¹ H.
NMR (CDCl ₃ ) δ 1.12 (s, 9H), 1.28 (t, J = 7.0H)
z, 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, ₃
8.2, 61.5, 67.1, 67.3, 117.0, 167.1, 180.7
CI-LRMS m / z [rel abundance]
150 ((M + H) ⁺ , 100%). B10a. General synthesis method for 2-chlorothiazolidinium salts. (4S) -2-
Synthesis of chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride.

[0198]

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Step 1 H of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol
Cl salt (Method B4c; 0.21 g, 1.0 mmol) and CS ₂ (0.30 mL,
5.0 mmol, 5.0 eq) of 2-butanone (Cs ₂ CO ₃ to the mixture which caused by putting in 20 mL) (0.72 g, 2.20 mmol, 2.2 after equiv), The resulting mixture was heated to reflux overnight. After concentrating the resulting orange solution under reduced pressure, the residue was taken up in EtOAc (25 m
L) and ground. After washing the remaining solid with EtOAc (25 mL), the combined EtOAc phases were concentrated under reduced pressure. The residue was absorbed on SiO ₂ and MPLC (Biotage 40 S silica gel column; 5% EtOAc
/ Hex) to give (4S) -3,4-diisobutyl-1,3-thiazolidine-2-thione as a yellow oil (0.11 g, 52%).

[0200]

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Step 2 (4S) -3,4-Diisobutyl-1,3-thiazolidine-2-thione (5.
(G, 21.6 mmol) in SOCl ₂ (31 mL, 0.43 mol) was heated to 70 ° C. for 2.5 hours, then cooled to room temperature and concentrated under reduced pressure. Gave (4S) -2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride as a semi-solid: 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 give a 0.12 M stock solution (assuming quantitative conversion to thiazolidinium chloride). C. Method for synthesizing imino heterocycle C1a. General method for synthesizing 2-imino-1,3-thiazolidine by reacting 2-chloroethylamine with isothiocyanate. (4S) -2- (2-methyl-4
Synthesis of -nitrophenylimino) -4-isobutyl-1,3-thiazolidine.

[0202]

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(1S) -1- (chloromethyl) -3-methylbutane ammonium chloride (Method B7a; 1.14 g, 3.71 mmol) and 2-methyl-4-nitrophenylisothiocyanate (0.72 g, 3 .71 mmol) in CH ₂ Cl ₂ (15
Et ₃ N (1.08 mL, 7.78 mmol) was added via syringe to the mixture suspended in (mL). The resulting solution was stirred at room temperature for 18 hours.
The reaction mixture was washed with a saturated NaHCO ₃ solution and then concentrated under reduced pressure. The residue is chromatographed (SiO ₂ , 10% EtOAc / hex to 30%
Purification by gradient to EtOAc / hex) provided (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine (0.91 g, 47%). ): TLC (25% EtOAc / hex) R _f 0.46
. C1b. General method for synthesizing 2-imino-1,3-thiazolidine by reacting 2-chloroethylamine with isothiocyanate. (4S) -2- (4-cyano-2
-Ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine
Synthesis of Cl salt.

[0204]

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HCl salt of N- (1S)-(1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) amine (Method B7c; 95 g, 0.41 mol, 1.08 equivalents)
In CH ₂ Cl ₂ (1.1 L) at 15 ° C. was added 4-cyano-2-ethylphenylisothiocyanate (Method A2b; 72 g, 0.38 mol) followed by diisopropylethylamine (200 mL, 1.15 mol, 3.
(0 equiv.) Caused some exotherm. Upon cooling the reaction to room temperature, the ice bath was removed and the reaction was stirred at room temperature for 4 hours. The reaction was then diluted with CH ₂ Cl ₂ (500 mL) and 1N NaOH solution (3 × 500 m
L), dried (MgSO ₄ ) and concentrated under reduced pressure. The residual dark oil (132 g) was dissolved in CH ₂ Cl ₂ (50 mL) and then 5% EtOAc
Filtration through a silica gel column (5 g of SiO _{2 /} g of crude product) with the aid of a solution of hexane / hexane to give an oil (120 g) which was then taken up in EtOAc
Dissolved in (400 mL) and HCl solution (Et ₂ O in 1M, 500 mL) by slowly treated with, (4S) -2- (4-cyano-2-ethylphenyl imino) -3,4-diisobutyl -1 The HCl salt of 3,3-thiazolidine was obtained as a white solid (95 g, 66%): ¹ H NMR (CDCl ₃ ) δ 0.96 (d, J = 5.
9 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 1.12 (m, 6H
), 1.23 (t, J = 7.7 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, 1H), 7.58 (d, J = 1.8 Hz, 1H).
C1c. General method for synthesizing 2-imino-1,3-thiazolidine by reacting 2-chloroethylamine with isothiocyanate. (4S) -2- (2-chloro-4
Synthesis of -cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine.

[0206]

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2-Chloro-4-cyano-6-methylphenylisothiocyanate (0.10
g, 0.50 mmol) and poly (4-vinylpyridine) (0.030 g) in CH _Two Cl_Two(1S) -1- (chloromethyl)-
3-methylbutane ammonium chloride (Method B7a; 0.086 g, 0.5
(0 mol, 1.0 equiv.) In DMF (2 mL).
The resulting mixture was stirred at 55 ° C. for 16 hours and then concentrated under reduced pressure.
Was. The residue was purified by column chromatography (30 g, 10% EtOAc / he
(gradient from x to 20% EtOAc / hex) to give (4S) -2
-(2-chloro-4-cyano-6-methylphenylimino) -4-isobutyl-
1,3-Thiazolidine was obtained (0.052 g, 34%). C1d. 2-Imi by the reaction of 2-chloroethylamine and isothiocyanate
A general method for synthesizing no-1,3-thiazolidine. (4S) -2- (4-chloro-2
-(Trifluoromethyl) phenylimino) -3-isobutyl-1,3-thiazo
Synthesis of lysine.

[0208]

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In a manner analogous to Method B7c, N- (hydroxyethyl) -N-isobutylamine was converted to N- (chloroethyl) -N-isobutylammonium chloride. N- (chloroethyl) -N-isobutylammonium chloride (0.10
Mmol, 0.10 M) and poly (4-vinylpyridine) (0.030 g) in DM
F (1.0 mL) into a slurry of 4-chloro-2- (trifluoromethyl) phenylisothiocyanate (0.25M in THF, 0.25M).
(40 mL, 0.10 mmol) was added and the resulting mixture was heated in a sand bath to 55 ° C. for 16 hours. After filtering the resulting slurry, the filtrate was concentrated under reduced pressure. The residue was preparative reverse phase HPLC (C-18 column, 0.1% from _{0.1% TFA / 20% CH 3} CN / 79.9% water TFA / 99
. Purification by reaching gradient) to 9% CH ₃ CN, was obtained (4S) -2- (4-chloro-2- (trifluoromethyl) phenylimino) -3-isobutyl-1,3-thiazolidine ( 0.020 g, 59%). C1e. General method for synthesizing 2-imino-1,3-thiazolidine by reacting 2-chloroethylamine with isothiocyanate. Synthesis of 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane.

[0210]

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HCl salt of 1-chloromethylcyclopentanamine (Method B7e; 0.25 g
1.32 mmol) and 2,4-dimethyl-3-cyano-5-pyridylisothiocyanate (Method A2c; 0.23 g, 1.32 mmol) in anhydrous 1,2-dichloroethane (10 mL). Et ₃ N (with a syringe)
1 mL) was added dropwise. After heating the resulting mixture to 50 ° C. overnight,
Cooled to room temperature and treated with saturated NaHCO ₃ solution. The resulting mixture was extracted with CH ₂ Cl ₂ (3x25mL). Dry the combined organic layers (Na ₂ S
After O ₄ ), the mixture was concentrated under reduced pressure. Purification of the residue by chromatography _{(SiO 2, 40% EtOAc /} hex), 2- (2,4- dimethyl-3
-Cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane was obtained (0.192 g, 51%). CI-MS m / z 287 ((M + H) +
). C1f. General method for synthesizing 2-imino-1,3-thiazolidine by reacting 2-chloroethylamine with isothiocyanate. 2- (3-quinolyl imino) -3
Of 5,5-diisobutyl-1,3-thiazolidine.

[0212]

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The 3-quinoline isothiocyanate was prepared in a manner similar to Method A2c. 3
-Quinoline isothiocyanate (0.1 g, 0.54 mmol) and N- (1S)
-(1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) amine H
Cl salt (Method B7c; 0.113 g, 0.54 mmol) was added to anhydrous CH ₂ Cl ₂ (2
mL) in a solution of diisopropylethylamine (0.20 mL).
8 g, 1.61 mmol) were added dropwise. The resulting mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The residue is chromatographed (SiO ₂
, 30% EtOAc / hex) to give 2- (3-quinolyl imino).
-3,5-diisobutyl-1,3-thiazolidine was obtained (0.02 g, 0.9%
). ES-MS m / z 342 ((M + H) +). C2a. A general method for synthesizing 2-imino-1,3-thiazolidine by converting ethanolamine to 2-chloroethylamine and reacting with isothiocyanate. 2- (2-methyl-4-nitrophenylimino) -3-thia-1-
Synthesis of azaspiro [4.4] nonane.

[0214]

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20. 1-Amino-1- (hydroxymethyl) cyclopentane (Method B1c;
After adding SOCl ₂ (15.7 mL, 216 mmol) to a solution formed from 7 g, 180 mmol) and HCl (4 M in p-dioxane, 400 mL), the resulting solution was heated to 100 ° C. for 18 hours. . The reaction mixture was concentrated under reduced pressure to give 2-methyl-4-nitrophenyl isothiocyanate (31.4 g, 1
62 mmol) and 1,2-dichloroethane (400 mL) followed by N 2
-Treated with methyl morpholine (49 mL, 449 mmol). The resulting mixture was heated to 70 ° C. for 18 hours, cooled to room temperature, and then concentrated under reduced pressure. The residue was treated with hot EtOAc, filtered and concentrated under reduced pressure. The residue was recrystallized (MeOH) to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (38.3 g, 8
1%). TLC (25% EtOAc / hex) _Rf 0.27. C2b. A general method for synthesizing 2-imino-1,3-thiazolidine by converting ethanolamine to 2-chloroethylamine and reacting with isothiocyanate. 1-isobutyl-2- (2-methyl-4-nitrophenylimino)
Synthesis of -3-thia-1-azaspiro [4.5] decane.

[0216]

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In a manner similar to Method C2a, 1-amino-1- (hydroxymethyl) cyclo
After dissolving the xane (method B1a) in p-dioxane (80 mL), the SOCl _Two Followed by treatment with 2-methyl-4-nitrophenyl isothiocyanate
With 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro
[4.5] After obtaining decane (20%), this is brominated in a manner analogous to method D2a.
By reacting with isobutyl, 1-isobutyl-2- (2-methyl-4-nitto
Rophenylimino) -3-thia-1-azaspiro [4.5] decane was obtained (0.
026 g, 2%). TLC (20% EtOAc / hex) R_f0.69. C2c. After converting ethanolamine to 2-chloroethylamine,
Synthesize 2-imino-1,3-thiazolidine by reacting with ocyanate
General method. 2- (2-methyl-4-nitrophenylimino) -3-isobutyl
Spiro [1,3-thiazolidine-4,2'-bicyclo [2.2.1] heptane]
Synthesis of

[0218]

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In a manner analogous to Method C2a, 2- (isobutylamino) -2- (hydroxymethyl) norbornane (Method B2a; 0.24 g, 1.2 mmol) was added to SOCl ₂
Followed by treatment with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (2-isobutylspiro [1,3-thiazolidine-4,2. '-Bicyclo [2.2.1] heptane] was obtained as an oil (0.022 g, 5%): TLC (25% EtOAc / hex).
_Rf 0.72. C2d. A general method for synthesizing 2-imino-1,3-thiazolidine by converting ethanolamine to 2-chloroethylamine and reacting with isothiocyanate. 3-isobutyl-4-methylene-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine-5-one and (4S) -3-isobutyl-4-carbomethoxy-2- (2- Methyl-4-nitrophenylimino)-
Synthesis of the HCl salt of 1,3-thiazolidine.

[0220]

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In a manner analogous to Method C2a, the HCl salt of the methyl ester of (R) -N-isobutylserine (Method B3a; 2.28 g, 10.8 mmol) was added to SOCl ₂ followed by 2-methyl-4-nitro Treated with phenylisothiocyanate. The resulting material was subjected to column chromatography (SiO ₂ , hexane to 10% EtOA).
c / hex) to give 3-isobutyl-4-methylene-2.
-(2-Methyl-4-nitrophenylimino) -1,3-thiazolidine-5-one (0.028 g, 10%) followed by (S) -3-isobutyl-4-carbomethoxy-2- (2 -Methyl-4-nitrophenylimino) -1,3-thiazolidine HCl salt (0.192 g, 56%) was obtained. 3-isobutyl-4-methylene-
2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine-5
ON: TLC (25% EtOAc / hex) _Rf 0.40. (S) -3-isobutyl-4-carbomethoxy-2- (2-methyl-4-nitrophenylimino)-
HCl salt of 1,3-thiazolidine: TLC (free base, 25% EtOAc / he
x) R _f 0.50. C2e. A general method for synthesizing 2-imino-1,3-thiazolidine by converting ethanolamine to 2-chloroethylamine and reacting with isothiocyanate. Synthesis of 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

[0222]

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In a manner analogous to Method C2a, 1- (cyclohexylamino) -1- (hydroxymethyl) cyclopentane (Method B4a; 1.89 g, 9.59 mmol) was converted to S
By reacting with OCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate, 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4 Nonane was obtained (0.44 g, 17%
). CI-MS m / z 374 ((M + H) ^<+> ). C2f. A general method for synthesizing 2-imino-1,3-thiazolidine by converting ethanolamine to 2-chloroethylamine and reacting with isothiocyanate. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4,4-dimethyl-1,3-thiazolidine.

[0224]

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N-Isobutyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner similar to Method B4a. HCl was bubbled into a solution of N-isobutyl-1,1-dimethyl-2-hydroxyethanamine (1.45 g, 10 mmol) in toluene (20 mL) until saturated. SOCl ₂ (10 mmol) was added dropwise to this solution at room temperature, and the mixture was stirred at room temperature for 1 hour and at 50 ° C. for 1 hour. After concentrating the resulting mixture under reduced pressure, the residue is
HCl ₃ (20 mL). The resulting solution has 2-methyl-
4-nitrophenyl isothiocyanate (1.94 g, 10 mmol) was added, Et ₃ N (10 mmol) was added dropwise at room temperature a solution contained in CHCl ₃ (10 mL). 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 successively added with 10% aqueous NaOH (50 mL) and saturated Na
After washing with a Cl solution (50 mL), drying (MgSO ₄ ), and concentration 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 was obtained (0.6 g, 63%): mp 97 ° C. Where appropriate, the product free base (5 mmol) is dissolved in Et ₂ O (50 mL) and the product is treated with a 2N HCl solution in ether until the solid no longer precipitates, whereby the HCl salt is obtained. Was changed to After filtering the resulting slurry, the resulting solid was washed with Et ₂ O (25 mL) followed by EtOAc (2 mL).
5 mL). C3a. A general method for synthesizing 2-imino-1,3-thiazolidine homologs by converting a hydroxyalkylamine into a chloroalkylamine and then reacting with an isothiocyanate. (R) -4-isopropyl-2- (2-methyl-4-
Synthesis of (nitrophenylimino) -2,3,4,5-tetrahydro-1,3-thiazine.

[0226]

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In a manner analogous to Method C2a, (R) -3- (t-butoxycarbonylamino)
-4-Methylpentanol (Method B6a) was added to SOCl ₂ followed by 2-methyl-4.
By reacting with -nitrophenyl isothiocyanate, (R) -4-isopropyl-2- (2-methyl-4-nitrophenylimino) -2,3,4,5-tetrahydro-1,3-thiazine is obtained. (100%). C4a. A general method for synthesizing 2-imino-1,3-oxazolidine by reacting 2-chloroethylamine with isocyanate. 1-cyclohexyl-2
-(2-Methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [
4.4] Synthesis of nonane.

[0228]

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HC of 1- (chloromethyl) -1- (cyclohexylamino) cyclopentane
1-salt (Method B7b; 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenylisocyanate (0.75 g, 4.2 mmol) in 1,2-dichloromethane (10 mL). N-methylmorpholine (0.9
(2 mL, 8.4 mmol). Bring the resulting mixture to 50 ° C for 1
After heating for 8 hours, the mixture was cooled to 20 ° C. and concentrated under reduced pressure. Chromatography of the residue (SiO ₂ , gradient from hexane to 10% EtOAc / hex)
To give 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane (0.021).
g, 1.4%): CI-MS m / z 358 ((M + H) ^<+> ). C5a. A general method for synthesizing a 2-imino heterocycle by reacting an aminoethylsulfonate ester with an isocyanate or an isothiocyanate. 2-
Synthesis of (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -1,3-oxazolidine.

[0230]

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N- (2-Tosyloxyethyl) -2-methylprop-2-trifluorotrifluoroacetate
A solution of ene-1-ammonium (method B8b, step 4; 0.21 g, 0.548 mmol) in p-dioxane (5 mL) was added to 2-methyl-ammonium.
4-nitrophenyl isocyanate (0.0955g, 0.536 mmol) followed by Et ₃ N (0.080mL, 1.15 mmol) was added. The resulting mixture was stirred at 37 ° C. overnight, cooled to room temperature, and concentrated under reduced pressure.
The residue was dissolved in CH ₂ Cl ₂ (50mL) and washed with water (50 mL).
The organic layer was extracted with a 2N HCl solution. The aqueous layer was made basic with a 1N NaOH solution and then extracted with CH ₂ Cl ₂ (50 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -1, 3-Oxazolidine was obtained as a yellow oil (0.020 g, 14%): CI-MS m / z 276 ((
M + H) ⁺ ). C5b. A general method for synthesizing a 2-imino heterocycle by reacting an aminoethylsulfonate ester with an isocyanate or an isothiocyanate. (4
Synthesis of S) -4- (1 (R) -t-butoxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine.

[0232]

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(1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (t-butoxy) propanammonium chloride (Method B8a; 1.5 g, 5.5 mmol) analogous to the manner described in Method C1a (4S)-(1 (R) -t-butoxyethyl) -2- (2-methyl-4-nitrophenylimino) -1 by reacting with 2-methyl-4-nitrophenylisothiocyanate in the manner described above. , 3-Thiazolidine was obtained (1.2 g, 67%). This (4S) -2- (2-methyl-4-nitrophenylimino) -4- (1 (R) -tert-butoxyethyl) -1,3-thiazolidine was converted to isobutyl bromide in a manner analogous to method D2a. By reacting (4S
) -4- (1 (R) -t-butoxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine (0.26 g,
56%): TLC (25% EtOAc / hex) _Rf 0.67. C6a. A general method for synthesizing 2-imino-1,3-thiazolidine by converting chloroethylamine to 2-thioethylamine and then reacting it with isocyanide dichloride. (4S) -2- (4-cyano-2-ethylphenylimino)
Synthesis of the HCl salt of -3,4-diisobutyl-1,3-thiazolidine.

[0234]

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Sodium hydrogen sulfide (69 g, 1.2 mol, 2.2 eq) was added to water (500 mL)
N- (1S)-(1- (chloromethyl) -3-
HCl salt of methylbutyl) -N- (isobutyl) amine (Method B7c; 126 g)
, 0.55 mol, 1.0 equivalent). After stirring the resulting mixture at room temperature for 8 hours, 4-cyano-2-ethylphenylisocyanide dichloride (Method A3a; 125 g, 0.5 mol, 1.0 equiv) was added followed by isopropyl alcohol (500 mL). Was added. After the resulting mixture was stirred for 1 hour at room temperature, 3.6M solution of K ₂ CO ₃ (305 mL, 2.0 eq, 1.1 mol)
Was added and the mixture was stirred at room temperature overnight. After concentrating the resulting organic layer under reduced pressure, the residue was treated with EtOAc (2 L). The organic layer was washed with water (2x
(500 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to give a dark oil (160 g). The oil was dissolved in CH ₂ Cl ₂ (150 mL) and passed through a silica gel column (3 g SiO _{2 /} g crude) with the aid of a 5% EtOAc / hex solution to give the desired product. An oil was obtained containing some residual isocyanide dichloride (134 g). This oil is treated with EtOA
It was dissolved in c (500 mL), and treated with HCl (Et ₂ O in 1N, 500 mL). The resulting HCl salt of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine was filtered off (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, 3
H), 2.10-2.20 (m, 1H), 2.82 (q, J = 7.7 Hz, 2H
), 3.06-3.14 (m, 2H), 3.55 (dd, J = 11.4, 7.7)
Hz, 1H), 4.18-4.25 (m, 1H), 5.02 (dd, J = 14.
3, 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.51 (
dd, J = 8.1, 1.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H)
). C6b. A general method for synthesizing 2-imino-1,3-thiazolidine by converting chloroethylamine to 2-thioethylamine and then reacting it with isocyanide dichloride. Synthesis of the HCl salt of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

[0236]

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Sodium hydrogen sulfide (31 g, 0.55 mol, 2.2 equiv) was added to water (250 mL).
) Is added to the HCl salt of 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane (Method B7d; 60 g, 0.25 mol, 1
. 0 eq.). After stirring the reaction mixture at room temperature for 8 hours, 2-methyl-
4-nitrophenyl isocyanide dichloride (Method A3b; 125 g, 0.2
(5 mol, 1.0 eq) followed by isopropyl alcohol (300 mL). The reaction mixture was stirred at room temperature for 1 hour and then a 3.6 M K ₂ CO ₃ solution (30
(5 mL, 2.0 eq, 0.5 mol). The reaction was stirred overnight at room temperature. After separation of the resulting upper aqueous organic layer and concentration under reduced pressure, the residue was treated with EtOAc (1 L). The resulting organic layer is washed with water (2 × 200 m
L), dried (MgSO ₄ ) and concentrated under reduced pressure. The remaining oil (86 g) was dissolved in CH ₂ Cl ₂ (50 mL) and then 5% EtOAc / he.
x silica gel plug (3 g SiO _{2 /} g crude product) with the aid of x solution
To give an oil containing the desired product and some residual isocyanide dichloride (34 g). This oil was dissolved in EtOAc (300 mL) and treated with HCl (1 N in Et ₂ O, 1.5 L). The resulting solid is removed by filtration to give 1-cyclopentyl-2- (2-methyl-4.
-Nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane HC
The salt was obtained as a white powder (36.8 g): ¹ H NMR (CD ₃ OD) δ 1.4.
0-1.55 (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. A general method for synthesizing 2-imino-1,3-thiazolidine by converting hydroxyethylamine to 2-thioethylamine and then reacting with isocyanide dichloride. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

[0238]

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Step 1 Ph ₃ P (27.9 g, 0.107 mol, 1.3 eq) was added to anhydrous THF (400
solution) at 0 ° C. in a solution of diisopropyl azodicarboxylate (21.5 g, 0.107 mol, 1.3 eq) and 1-cyclopentylamino-1- (hydroxymethyl) cyclopentane (Method B4d; 15.0 g)
, 0.082 mol). After stirring the resulting slurry for 30 minutes, thiolactic acid (7.6 mL)
, 0.107 mol, 1.3 eq.). The resulting yellow solution was 15
After stirring for minutes, the mixture was concentrated under reduced pressure to about 100 mL. Et the residue
After dissolving in OAc (200 mL), the resulting solution was diluted with 1N HC
Extracted with 1 solution (5 × 125 mL). Combine the aqueous layers with EtOAc (2 × 20
0 mL), neutralized with K ₂ CO _{3 so} that the pH becomes 7.0-7.5,
Extracted with EtOAc (5 × 200 mL). Dry the combined organic layers (Na ₂ S
After O ₄ ), the mixture was concentrated under reduced pressure. By drying the residue under vacuum,
1-Cyclopentylamino-1- (thioacetylmethyl) cyclopentane was obtained as a yellow oil (19.1 _g ): TLC (10% EtOAc / hexane) R _f
0.16; ¹ H NMR (CDCl ₃ ) δ 1.20-1.87 (m, 16H), 2
. 34 (s, 3H), 2.92-3.02 (m, 1H), 3.15 (s, 2H)
¹³ C NMR (CDCl ₃ ) δ 23.9, 25.2, 29.3, 36.4, 4
0.1, 55.8, 73.0, 169.8; CI-LRMS m / z (rel abundance) 242 ((M + H) ^<+> , 100%).

[0240]

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Step 2 0.33 M KOH solution in 9: 1 MeOH: H ₂ O (273 mL, 0.09
(0 mol, 1.1 equivalents) in 1-cyclopentylamino-1- (thioacetylmethyl) cyclopentane (19.1 g) was stirred for 30 minutes. After concentrating the reaction mixture under reduced pressure, the residue was dried under vacuum to give crude 1-cyclopentylamino-1- (thiomethyl) cyclopentane as a yellow oil: TLC (10% EtOAc / Hexane) R _f 0.18 (stripes); ¹ H NMR (CD ₃ OD) δ 1.32-1.71 (m, 14H), 1.87
-1.94 (m, 2H), 2.67 (s, 2H), 3.07-3.14 (m, 1
H); FAB-LRMS m / z (rel abundance) 200 ((M + H) ⁺ ,
19%). This material was used directly in the next step without further purification.

[0242]

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Step 3 Crude 1-cyclopentylamino-1- (thiomethyl) cyclopentane was converted to anhydrous CH _Two Cl_Two(100 mL) at 0 ° C. with crude 2-methyl-4.
-Nitrophenyl isocyanide dichloride (Method A3b; 19.1 g, 0.0
82 mol, 1-cyclopentylamino-1- (thioacetylmethyl) cyclopen
1.0 equivalent) based on tan_TwoCl_Two(200 mL)
Etched slurry followed by Et_ThreeWith N (30 mL, 0.215 mol, 2.6 equiv)
After working up, the reaction mixture was warmed to room temperature and stirred for 2 days. N, N-dimethyl
After addition of ethylenediamine (92 g, 0.023 mol, 0.3 eq.)
The reaction mixture was stirred for 1 hour. After adding silica gel (50 g), as a result
The resulting mixture was concentrated under reduced pressure. After drying the residue under vacuum overnight,
Rush chromatography (11x10cm SiO_Two, 5% EtOAc / h
ex) to give 1-cyclopentyl-2- (2-methyl-4-nitro)
Phenylimino) -3-thia-1-azaspiro [4.4] nonane as a yellow granular solid
(17.8 g, 60% overall): mp 120-121 ° C .; TLC (1
0% EtOAc / hexane) R_f0.45;¹H NMR (CDCl_Three) Δ1.4
7-1.91 (m, 14H), 2.22 (s, 3H), 2.46-2.55 (m
, 2H), 3.03 (s, 2H); 3.66 (quintet, J = 8.8 Hz, 1H)
, 6.89 (d, J = 8.5 Hz, 1H), 7.95-8.03 (m, 2H); ¹³ C NMR (CDCl_Three) 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 (
Real abundance) 360 ((M + H)⁺, 100%). Analysis, C₁₉H_{twenty five}N_ThreeO_Two
Calculated for S: C, 63.48; H, 7.01; N, 11.69. measured value:
C, 63.48; H, 6.89; N, 11.76. C7a. Hydroxyethylamine is reacted with aryl isocyanate dichloride
General method of synthesizing 2-imino-1,3-oxazolidine by reacting. 2
-(4-cyano-2-ethylphenylimino) -3-cyclopentyl-4,4-
Synthesis of dimethyl-1,3-oxazolidine.

[0244]

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N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine (
Method B4b; 0.12 g, 0.69 mmol) in THF (2.5 mL) was added to a solution of NaH (95%, 0.05 g, 1 g) using a syringe.
. (2 mmol) was added dropwise to a slurry of THF (5 mL) at room temperature. After stirring the reaction mixture for 15 minutes, a solution of 4-cyano-2-ethylphenylisocyanate dichloride (Method A3a; 0.15 g, 0.63 mmol) in THF (2.5 mL) was syringed. Was dropped. After stirring the resulting mixture overnight, a 5% citric acid solution (10 m
L) followed by EtOAc (25 mL). The organic phase was sequentially extracted 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 is purified by chromatography (SiO ₂ , 5% EtOAc / hex) to give 2
-(4-cyano-2-ethylphenylimino) -3-cyclopentyl-4,4-
Dimethyl-1,3-oxazolidine was obtained as a yellow solid (0.09 g, 43%
): 112-114 ° C; TLC (15% EtOAc / hexane) R _f 0.6
0; ¹ H NMR (CDCl ₃ ) δ 1.16 (t, J = 7.5 Hz, 3H);
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 (rel abundance) 312 ((M + H) ^<+> , 100%).
Calculated for _{HRMS C 17 H 23 N 3 O} 3: 311.1998. Measurement value: 311
. 1991. C7b. General method of synthesizing 2-imino-1,3-oxazolidine by reacting hydroxyethylamine with aryl isocyanate dichloride. (
Synthesis of 4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-oxazolidine.

[0246]

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4-Cyano-2-ethylphenyl isocyanide dichloride (Method A3a;
. 42 g, 1.83 mmol, 1.2 equiv) and (2S) -4-methyl-2- (isobutylamino) pentan-1-ol (Method B4c; 0.26 g, 1.52 mmol) in THF (5 mL). Et ₃ N (0.5
mL) was added. After stirring the resulting mixture at room temperature for 1 hour,
-Treated with (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 / hex to 10% EtOAc / hex) to give (4S) -2- (4-cyano-2-ethylphenylimino) -3.
, 4-Diisobutyl-1,3-oxazolidine was obtained as a yellow oil (0.1
5g): TLC (10% EtOAc / hex) R _f 0.35; ¹ H NMR (CD
_{Cl 3) δ0.81-1.00 (m, 12H} ), 1.14 (t, J = 4.8Hz
, 3H), 1.25-1.43 (m, 2H), 1.53-1.70 (m, 2H)
, 2.57 (sevenfold line, 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 (d
d, J = 13.6, 8.8 Hz, 1H), 3.73-3.83 (m, 1H), 3
. 94 (appt, J = 7.5 Hz, 1H), 4.37 (appt, 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. A general method for synthesizing a 2-imino-4-oxo heterocycle by reacting isothiocyanate with an amine and then reacting with a halo acid halide. 2- (
Synthesis of 2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine-4-one.

[0248]

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[0249] 2-Methyl-4-nitrophenylisothiocyanate (0.190 g, 1.0
Mmol) in DMF (5.3 mL), and the reaction mixture was stirred for 4 hours after addition of isobutylamine (0.4 M in DMF, 5.3 mL), at which point TLC analysis (Hexane: EtOAc 3: 1)
Indicated that the isothiocyanate had been consumed. The resulting mixture was added to chloroacetic acid (0.8 M in DMF, 4.0 mL) followed by N-methylmorpholine (
0.7 mL, 6.4 mmol). The reaction mixture was stirred at 80 ° C. for 18 hours before partitioning between water (10 mL) and EtOAc (25 mL). The aqueous phase is E
Back-extract with tOAc (2 × 10 mL). The combined organic layers were washed with a saturated NaCl solution (25 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue is purified by MPLC (Biotage 40 S silica gel column, gradient from 5% EtOAc / hex to 33% EtOAc / hex) to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-
1,3-Thiazolidin-4-one was obtained as a pale yellow oil (0.52 g, 85
%). C9a. A general method for synthesizing 2-imino-1,3-thiazolidine by reacting hydroxyethylamine with isothiocyanate and then performing ring closure using an acid as a catalyst. Synthesis of 2- (2,6-dichlorophenylimino) -3-cyclohexyl-4,4-dimethyl-1,3-thiazolidine.

[0250]

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N-cyclohexyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to method B4a. 2,6-dichlorophenylisothiocyanate (1.2 g, 6.0 mmol) and N-cyclohexyl-1,1-dimethyl-2
- hydroxy ethanamine (1.0 g, 6.0 mmol) CH ₂ Cl ₂ (10m
L) and the resulting solution was stirred at room temperature for 20 hours. The resulting mixture was concentrated under reduced pressure and then treated with a 33% HCl solution (15 mL). The resulting mixture was heated to reflux for 1 hour and, after cooling to room temperature, 45%
Was neutralized with NaOH solution. The resulting slurry is filtered, the resulting solid is washed with water (20 mL) and then recrystallized (EtOH) to give 2- (2,6-dichlorophenylimino) -3-cyclohexyl. -4,4-Dimethyl-1,3-thiazolidine was obtained (0.70 g, 33%): mp 134 ° C.
Optionally, dissolve the product free base (5 mmol) in Et ₂ O (50 mL) and treat the solution with a 2N HCl solution in ether until no more solids precipitate, Was changed to the HCl salt. After filtration of the resulting slurry, it was washed with EtOAc (25 mL) followed resulting solid in Et ₂ O (25mL). C10a. General method of reacting 2-chlorothiazolinium salts with aniline.
Synthesis of 2- (2- (N-phenylcarbamoyl) phenylimino) -3,4-diisobutyl-1,3-thiazolidine.

[0252]

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(4S) -2-Chloro-3,4-diisobutyl-4,5-dihydro-1,3-
A solution of thiazolinium chloride in dichloroethane (Method B10a;
0.12 M, 0.5 mL, 0.36 mmol), 2-(N-phenylcarbamoyl) aniline (0.097 g, 0.36 mmol, 1.0 eq) and Et ₃ N (
A solution of 0.5 mL, 3.6 mmol, 10 equiv) in p-dioxane (5 mL) was added. The resulting mixture was heated to 70 ° C. overnight, then cooled to room temperature and diluted with EtOAc (25 mL). This EtOAc
The mixture was washed sequentially with water (2 × 25 mL) and saturated NaCl solution (25 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue is SiO ₂
MPLC (Biotage 40 S silica gel column; 5% Et
OAc / hex) to give 2- (2- (N-phenylcarbamoyl)
Phenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained (0.
090 g, 61%). C11a. A general method for synthesizing 2-imino-1,3-thiazolidine-5-one by reacting an amino acid ester with isothiocyanate. 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine-5
-Synthesis of on.

[0254]

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A solution of the ethyl ester of N-diisobutylglycine (0.41 g, 2.57 mmol) in water (5 mL) was added to Et ₃ N (0.71 mL, 5
. (15 mmol) followed by a solution of 2-methyl-4-nitrophenylisothiocyanate (0.50 g, 2.57 mmol) in acetone (5 mL). The resulting mixture was heated to 40 ° C. for 2 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was combined with water (25 mL) and ethyl acetate (25 mL).
A) divided between. The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-
1,3-Thiazolidin-5-one was obtained (0.16 g, 88%): mp 152 ° C.
. D. General Method for Interconversion of Imino Heterocycles D1a. General method for neutralizing imino heterocyclic salts. (4S) -2- (4-cyano-2
Synthesis of -ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

[0256]

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(4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diiso
HCl salt of butyl-1,3-thiazolidine (Method C6a; 304 g, 0.8 mol
), Water (1 L) and EtOAc (1.4 L) in a mixture of NaHCO_Three(150g,
(1.78 mol, 2.2 eq). The resulting mixture was stirred for 1 hour.
Stirred. Dry the organic layer (MgSO_Four) And concentrated under reduced pressure. The result and
The viscous oil obtained was treated twice with EtOH and concentrated under reduced pressure twice.
To give (4S) -2- (4-cyano-2-ethylphenylimino) -3
, 4-Diisobutyl-1,3-thiazolidine was obtained as a low melting solid (264
g, 96%): melting point 50 ° C .; [a]_D= + 2.4, (c1.0, CH_ThreeOH);¹
H NMR (CDCl_Three) 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, 1H); CI-MS m / z 344 ((M + H) ⁺ ). D1b. General method for neutralizing imino heterocyclic salts. 1-cyclopentyl-2- (2-
Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] no
Synthesis of Nan.

[0258]

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1-Cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-
HCl salt of thia-1-azaspiro [4.4] nonane (Method C6b; 52.4 g,
0.132 mol) in water (300 mL) and EtOAc (500 mL) which in NaHCO ₃ (15 g were dissolved in a mixture of 0.178 mole, 1.3 eq) was added. The mixture was stirred for 1 hour and the resulting organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting light yellow solid was added to EtOH (10
0 mL), followed by concentration under reduced pressure twice to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. Obtained (46 g, 97%): mp 111-112 DEG C .; ¹
1 H NMR (CDCl ₃ ) δ 1.49-1.53 (m, 2H), 1.63-1.
80 (m, 8H), 1.81-1.91 (m, 4H), 2.21 (s, 3H),
3.02 (s, 2H), 3.60-3.70 (m, 1H), 6.87 (d, J =
8.5 Hz, 1H), 8.02 (m, 2H); CI-MS m / z 360 ((
M + H) ⁺ ). D2a. General ring nitrogen alkyl substitution method for 2-imino heterocycles. (4S) -2-
(2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-
Synthesis of the HCl salt of thiazolidine.

[0260]

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(4S) -2- (2-Methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine (Method C1a; 0.10 g, 0.34 mmol) and isobutyl bromide (0. 11 mL, 1.03 mmol) and Cs ₂ CO ₃ (0.12 g, 0
. 38 mmol) in DMF (2 mL).
After heating to 18 ° C. for 18 hours, it was cooled to 20 ° C., diluted with EtOAc (50 mL), and washed with water (2 × 200 mL). After drying the organic phase (MgSO ₄ ) and concentrating under reduced pressure, the residue is chromatographed (SiO ₂ , 100% hex).
To 10% EtOAc / hex). The resulting material was dissolved in CH ₂ Cl ₂ (10 mL), treated with HCl solution (1 M in Et ₂ O, 2 mL) and concentrated under reduced pressure to give (4S) -2- (2- The HCl salt of methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained (0.088 g, 68%): TLC (free base, 20% EtOAc / he).
x) R _f 0.74. D2b. General ring nitrogen alkyl substitution method for 2-imino heterocycles. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

[0262]

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2- (2-Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (Method C2a; 33.2 g, 114 mmol) was added to DMF (1 m
L) was treated with NaOH (690 g, 17.3 mol) and cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was treated at 20-40 ° C. for 18 hours. After stirring, the mixture was cooled to 4 ° C. and water (1.5 L
). After adjusting the pH to 0 by adding concentrated HCl solution, the mixture is
Extracted with tOAc (80 mL). The organic phase was washed with 1N HCl solution (1 L), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue is CH ₂ Cl ₂ (
(500 mL) and filtered through a pad of silica gel (9 × 4 cm). After hexane was added to the resulting solution, volatiles were slowly removed by applying a degree of vacuum until crystals formed. By collecting solids,
1-Cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained as yellow crystals (10.9 g, 26
%): Melting point 118-9 [deg.] C; TLC (5% EtOAc / hex) _Rf 0.34. D2c. General ring nitrogen alkyl substitution method for 2-imino heterocycles. (4R) -3-
Synthesis of isobutyl-4-isopropyl-2- (2-methyl-4-nitrophenylimino) tetrahydro-2H-1,3-thiazine.

[0264]

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In a manner analogous to Method D2a, (R) -4-isopropyl-2- (2-methyl-
4-nitrophenylimino) -2,3,4,5-tetrahydro-1,3-thiazine (method C3a) is reacted with isobutyl bromide to give (4R) -3-isobutyl-4-isopropyl-2- ( (2-Methyl-4-nitrophenylimino) tetrahydro-2H-1,3-thiazine was obtained (0.081 g, 32%). TLC (3
3% EtOAc / hex) _Rf 0.76. D2d. General ring nitrogen alkyl substitution method for 2-imino heterocycles. 2- (2-methyl-4-nitrophenylimino) -3-propanoyl-1,3-thiazolidine.

[0266]

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2- (2-Methyl-4-nitrophenylimino) -1,3-thiazolidine (prepared in a manner analogous to that described in Method C1a; 0.084 g, 0.35 mmol) was treated with CH ₂ Cl ₂ (5 mL) was added which caused by putting the propionyl chloride (0.033 g, 0.35 mmol) and Et ₃ N (0.049mL, 0.3
5 mmol) was added. The mixture was stirred at room temperature for 1 hour and then CH ₂ Cl ₂ (4
0 mL). The resulting solution was sequentially washed with H ₂ O (10 mL)
After washing with a saturated NaCl solution (10 mL) and drying (Na ₂ SO ₄ ),
Concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc / hex) to give 2- (2-methyl-4-nitrophenylimino) -3-propanoyl-1,3-thiazolidine (0.036 g) , 35%): FAB-MS
m / z 294 ((M + H) ^<+> ). D2e. General ring nitrogen alkyl substitution method for 2-imino heterocycles. 1- (cyclohexylmethyl) -2- (2-methyl-4-nitrophenylimino) -3-thia-
Synthesis of 1-azaspiro [4.4] nonane.

[0268]

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2- (2-Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (Method C2a; 0.10 g, 0.3432 mmol) and bromomethylcyclohexane (1. (00 mL) in DMF (1.00 mL) was added to NaOH (約 0.13 g). The resulting mixture was stirred at 45 ° C. for 2 days, during which time it turned from deep red to light orange. Then, the reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The remaining oil was chromatographed; Purification by _{(SiO 2 5% EtOAc / hex} ), 1- ( cyclohexylmethyl) -2- (2-methyl-4-nitrophenyl imino) -3-thia-1 Azaspiro [4.4] nonane was obtained (0.042
g, 32%): melting point 85-7 ° C. D2f. General ring nitrogen alkyl substitution method for 2-imino heterocycles. (4S) -2-
Synthesis of trifluoroacetate of (2-chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

[0270]

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(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) was added to a solution of NaH (0.
0045 g, 1.1 eq.) And the resulting mixture was added at room temperature for 5 hours.
Stirred for minutes. Next, isobutyl bromide (0.053 mL, 3 eq) was added, and the resulting mixture was stirred at 98 ° C. for 4 hours. After the reaction mixture was filtered, it was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (C-18 column, 0.1% TFA / 20% CH ₃ CN / 79.9% water to 0.1% TFA / 9
(4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3 by purifying with 9.9% CH ₃ CN.
-The trifluoroacetic acid salt of thiazolidine was obtained (0.030 g, 52% yield). D2g. General ring nitrogen alkyl substitution method for 2-imino heterocycles. 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-prop-2-enyl)-
Synthesis of the HBr salt of 4,4-dimethyl-1,3-thiazolidine.

[0272]

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2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-1,3
-Thiazolidine was prepared in a manner similar to that described in Method C1a. 2- (
A suspension of 2-methyl-4-nitrophenylimino) -4,4-dimethyl-1,3-thiazolidine (1.5 mmol) in toluene (10 mL) was added to 2-methylpropane bromide. After the addition of 2-en-1-yl (4.5 mmol), the reaction mixture was heated to reflux for 3 hours, at which point TLC determined the reaction was complete. The resulting precipitate was filtered at 50 ° C. The collected solid by washing with toluene (20 mL) and _{CH 2 Cl 2 (20mL),} 2- (2- methyl-4-nitrophenyl imino) -3- (2-methyl - prop-2-enyl) The HBr salt of -4,4-dimethyl-1,3-thiazolidine was obtained (1.14 g, 77%): mp 229 ° C. D2h. General ring nitrogen alkyl substitution method for 2-imino heterocycles. 2- (2,4-
Dimethyl-3-cyano-6-pyridylimino) -1-isobutyl-3-thia-1
-Synthesis of azaspiro [4.4] nonane.

[0274]

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2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1
-Azspiro [4.4] nonane (Method Cle; 0.192 g, 0.669 mmol) and isobutyl bromide (0.5 mL) in anhydrous DMF (0.5 mL) were added to a solution of NaH (95%). %; 0.62 g, 6.69 mmol) were added in portions. After heating the resulting mixture to 50 ° C. for 3 hours, MeOH was added.
(About 0.5 mL) and concentrated under reduced pressure. The residue was purified by chromatography; Purification by (SiO ₂ gradient ranging from 20% EtOAc / hex to _{100% CH 2 Cl 2),} 2- (2,4- dimethyl-3-cyano-6- Pirijiruimino) - 1-isobutyl-3-thia-1-azaspiro [4.4] nonane was obtained (0
. 04g, 17%): CI-MS m / z 343 ((M + H) +). D3a. General deprotection method for t-butoxycarbamoyl protected alcohol. (4
Synthesis of S) -4- (1 (R) -hydroxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine.

[0276]

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After cooling the solution of TFA (8 mL) to 4 ° C., it was passed through a cannula to form a solid (4 mL).
S) -4- (1 (R) -tert-Butoxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine (Method C5b;
(16 g, 0.42 mmol). The resulting solution was warmed to 20 ° C. and stirred at this temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was partitioned between Et ₂ O (100mL) and saturated NaHCO ₃ solution (100 mL). After the ether layer was dried (MgSO ₄ ), it was concentrated under reduced pressure.
The residue is chromatographed (SiO ₂ ; hexane to 10% EtOAc /
hex) to give (4S) -4- (1 (R) -hydroxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino)-.
1,3-Thiazolidine was obtained (0.13 g, 90%): TLC (25% EtOAc)
c / hex) _Rf 0.13. D4a. A general method for synthesizing 2-imino-1,3-thiazolidine 3-oxide and 2-imino-1,3-thiazolidine 3,3-dioxide by oxidation of 2-imino-1,3-thiazolidine. 1-cyclopentyl-2- (2-methyl-4
-Nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane 3-
Synthesis of 3,3-dioxide of oxide and 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane

[0278]

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1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-
Thia-1-azaspiro [4.4] nonane (Method D2b; 0.041 g, 0.11
Mmol) and m- chloroperbenzoic acid (approximately 80%, 0.040 g, 0.19 mmol) and stirring CH ₂ Cl ₂ (solution that caused by putting in 5 mL) 30 min, saturated NaHCO ₃ After washing and drying (MgSO ₄ ), it was concentrated under reduced pressure. The residue was chromatographed (SiO ₂ ; hexane to 30% EtOAc)
/ Hex) to give 3,3-dioxide of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. (0.030 g, 67%) followed by 3-oxide of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (0.011 g). , 26%). 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-
3,3-dioxide of azaspiro [4.4] nonane: TLC (25% EtOA
c / hex) R _f 0.27. 3-oxide of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane: TLC (25% EtOAc / hex) _Rf 0.10. D5a. General method for the reduction of heterocycles containing ketones or aldehydes. 2-
Synthesis of (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-hydroxybutyl) -1,3-thiazolidine.

[0280]

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After preparing 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine in a manner similar to that described in Method C2a, it was prepared in a manner similar to that described in Method D2a. To give 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-oxobutyl) by alkyl substitution with 1-bromo-3,3-dimethyl-2-butanone. -1,3-Thiazolidine was obtained. 2- (2-Methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-oxobutyl) -1,3-thiazolidine (0.022 g, 0.065 mmol) is placed in MeOH (2 mL). The resulting solution was added to NaBH ₄ (0
. 0096 g, 0.26 mmol) were added in portions. After the mixture formed as a result was stirred for 4 hours at room temperature, then partitioned between EtOAc (10 mL) and H ₂ O (5mL), and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed sequentially with H ₂ O (15 mL), saturated NaCl solution (15 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue is purified by preparative TLC
(20% EtOAc / hexane) to give 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-hydroxybutyl) -1.
, 3-Thiazolidine was obtained (0.024 g, 92%): 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.

[0282]

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Step 1 (4S) -2- (4-methoxycarbonyl-2-methylphenylimino) -3
, 4-Diisobutyl-1,3-thiazolidine (prepared in a manner similar to that described in Method D2a; 0.035 g, 0.097 mmol) in MeOH (1.5 mL)
) And H ₂ O (1.5 mL) in a mixture of LiOH (
(0.016 g, 0.39 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), saturated NaCl solution (15 mL) and then dried (Na ₂ SO ₄ ). By performing the concentration under reduced pressure, (4S) -2- (4
-Carboxy-2-methylphenylimino) -3,4-diisobutyl-1,3-
Thiazolidine was obtained (0.034 g, 100%): TLC (40% EtOAc /
hex) _Rf 0.08. This material was used in the next step without further purification.

[0284]

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Step 2 (4S) -2- (4-Carboxy-2-methylphenylimino) -3,4-di
Isobutyl-1,3-thiazolidine (0.035 g, 0.10 mmol) was added to CH _Two Cl_TwoCarbonyldiimidazole (5 mL).
0.047 g, 0.29 mmol). The mixture is stirred at room temperature for 2 hours.
After that, NH3 was added to this solution at -78C._Three(About 30 drops) was condensed. The result and
The resulting mixture was allowed to warm to room temperature overnight before_TwoTreated with O (20 mL)
. The aqueous layer is CH_TwoCl_Two(3 × 20 mL) and sequentially extracted with H_TwoO (20 mL
) And washed with saturated NaCl solution (20 mL), dried (Na_TwoSO_Four) After
And concentrated under reduced pressure. The residue was purified by flash chromatography (40% Et
OAC / hexane) to give (4S) -2- (4-carbamoyl-2).
-Methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine
Obtained as a color solid (0.027 g, 73%): mp 130-131 <0> C. D6b. General method for interconversion of carboxylic acid derivatives. 2- (2-ethyl-4- (
N-methylcarbamoyl) phenylimino) -1-cyclopentyl-3-thia-
Synthesis of 1-azaspiro [4.4] nonane

[0286]

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2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-
3-Thia-1-azaspiro [4.4] nonane (Method D9a; 0.58 g, 0.1
(67 mmol) in CHCl ₃ (5 mL).
l ₂ (0.06 mL, 0.82 mmol) was added. The reaction mixture was heated at reflux for 3 hours 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 a 1N NaOH solution (10 mL). After extracting the resulting mixture with CH ₂ Cl ₂ (3 × 20 mL),
The combined organic layers were washed with a 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 was obtained (36 g, 56%): TLC (30% EtOAc / hex)
_Rf 0.44. D7a. General method for synthesizing cyanoarylimines from iodoarylimines. Synthesis of 2- (4-cyano-2-propylphenylimino) -3-thia-1-azaspiro [4.4] nonane

[0288]

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In a manner similar to Method A2b, 4-iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphenylisothiocyanate. At the same time
-Amino-1- (hydroxymethyl) cyclopentane is converted to a chloromethyl analog and then reacted with the isothiocyanate in a manner analogous to Method C2a to give 2- (4-iodo-2-propylphenylimino). ) -3-Thia-1-azaspiro [4.4] nonane was obtained. 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) The slurry resulting from placing in DMF (4 mL) was heated to 140 ° C. overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure before flash chromatography (1.
(0% EtOAc / hex) to give 2- (4-cyano-2-propylphenylimino) -3-thia-1-azaspiro [4.4] nonane as a white solid (0.26 g, 65%): TLC (30% EtOAc / hex) R _f 0.
37. D8a. General synthesis method of phenylacetylene. 2- (2,3-dimethyl-4
-Ethynylphenylimino) -1-isobutyl-3-thia-1-azaspiro [4
. 4] Synthesis of nonane

[0290]

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Step 1 In a manner similar to Method A2b, 4-iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenylisothiocyanate. Method C2a
2- (2,3-Dimethyl-4-iodophenylimino) -3-thia-1-azaspiro [4.4] nonane was prepared in a manner similar to that described in Method D2a and described in Method D2a. Alkyl substitution with isobutyl bromide in a similar manner. The iodophenyl compound (0.009 g, 0.021 mmol)
And (trimethylsilyl) acetylene (30 mL, 0.21 mmol) and Pd (P
A mixture of Ph ₃ ) ₂ Cl ₂ (0.005 g) and CuI (0.012 g, 0.063 mmol) in Et ₃ N (2 mL) was stirred at room temperature for 18 hours. After filtering the resulting slurry, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (2% EtOAc / hex) to give
2- (2,3-Dimethyl-4- (2-trimethylsilyl-1-ethynyl) phenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane was obtained (0.005 g, 59). %).

[0292]

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Step 2 2- (2,3-Dimethyl-4- (2-trimethylsilyl-1-ethynyl) phenylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane (
A mixture of 0.005 g, 0.0125 mmol) and NaOH (0.006 g, 0.15 mmol) in MeOH (2 mL) was stirred at room temperature overnight. 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 / hex)
) To give 2- (2,3-dimethyl-4-ethynylphenylimino)
-1-isobutyl-3-thia-1-azaspiro [4.4] nonane was obtained (0.0
03.2 g, 78%): TLC (20% EtOAc / hex) _Rf 0.70. D9a. General method for synthesizing benzoic acid by hydrolysis of benzonitrile. 2- (
Synthesis of 4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane

[0294]

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2- (4-cyano-2-ethylphenylimino) in a manner analogous to method C2a
-3-Thia-1-azaspiro [4.4] nonane was prepared and the thiazolidi
By subjecting the compound to an alkyl substitution in a manner analogous to method D2b.
Cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-a
Zaspiro [4.4] nonane was obtained. 2- (4-cyano-2-ethylphenylimi)
No) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.
32 g, 9.42 mmol) in concentrated HCl (15 mL).
The solution was heated to 100 ° C. overnight and then cooled to room temperature, resulting in a white precipitate. Conclusion
The pH of the resulting mixture was adjusted to 6.5 with 1N NaOH solution and then CH _Two Cl_Two(4 × 40 mL). Combine the organic layers and sequentially add water (30 mL
) And washed with saturated NaCl solution (30 mL), dried (Na_TwoSO_Four) After
And concentrated under reduced pressure to give 2- (4-carboxy-2-ethylphenylimino).
) -1-Cyclopentyl-3-thia-1-azaspiro [4.4] nonane as white solid
Obtained as a body (0.34 g, 100%): mp 208-209 <0> C. D10a. General method for converting carboxylic acids to ketones. 2- (4-acetyl
-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro
B. Synthesis of [4.4] nonane

[0296]

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2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-
3-Thia-1-azaspiro [4.4] nonane (Method D9a; 0.046 g, 0.
128 mmol) in THF (10 mL).
℃ with methyl lithium (Et ₂ O in 1.4M, 0.91 mL, 1.28 mmol)
Was added. During this time, the reaction mixture gradually warmed to room temperature and was stirred overnight. Trimethylsilyl chloride (0.5 mL) was added and the mixture was stirred at room temperature for 2 hours.
After stirring for 1 hour, a 1N HCl solution (2 mL) was added. 0.5% of this mixture
After stirring for an hour, it was treated with a saturated NaHCO ₃ solution (10 mL). The resulting mixture was extracted with EtOAc (4 × 20 mL) and the combined organic layers were washed with saturated NaCl solution (30 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by preparative TLC (10% EtOAc / hex) to give 2- (4-acetyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4]. Nonane was obtained as a white solid (0.0
32 g, 73%): mp 114-115 [deg.] C. D11a. General method for converting nitriles to aldehydes. Synthesis of 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane

[0298]

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2- (4-cyano-2-ethylphenylimino) in a manner analogous to method C2a
3-Thia-1-azaspiro [4.4] nonane is prepared and the thiazolidine is subjected to alkyl substitution in a manner analogous to method D2b to give 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 -78C with DIBAL (1.0 M in toluene, 1.20 mL, 1.2 mL).
0 mmol) was added. The reaction mixture was stirred at −78 ° C. for 3 h, and at −78 ° C., EtOAc (3 mL) was added and stirring was continued for 0.5 h before adding moistened silica gel (5% water, 2 g). Was. The reaction mixture was warmed to room temperature and stirred for 3 hours before being filtered through a pad of Celite ™. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (30% EtOAc / hex) to give 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-. Thia-1-azaspiro [4.4] nonane was obtained as a white solid (0
. 16g, 75%): mp 104-105 ° C. D12a. General method of chain homologation of aldehydes or ketones. 2- (2-ethyl-4-((1E) -2-ethoxycarbonylvinyl) phenylimino) -1-
Synthesis of cyclopentyl-3-thia-1-azaspiro [4.4] nonane

[0300]

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2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3
-Thia-1-azaspiro [4.4] nonane (Method D11a; 0.053 g;
149 mmol) in CH ₃ CN.
0076 g, 0.182 mmol) followed by DBU (0.025 g, 0.167
Mmol) and triethyl phosphonoacetate (0.041 g, 0.182 mmol) were added. 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 / hex) to give 2- (2-ethyl-4-((1E) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-. Thia-1-azaspiro [4.
4] Nonane was obtained as a colorless oil (0.029 g, 48%): TLC (30%
EtOAc / hex) _Rf 0.68. D12b. General method of chain homologation of aldehydes or ketones. Synthesis of 2- (2-ethyl-4-((1E) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane

[0302]

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[0303] 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3
-Thia-1-azaspiro [4.4] nonane (Method D11a; 0.041 g;
115 mmol) in CH ₂ Cl ₂ (10 mL).
eNO ₂ (2 drops) and piperidine (4 drops) was added. The reaction mixture was heated to reflux overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (3% EtOAc / hex) to give 2- (
2-Ethyl-4-((1E) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained as a red solid (0.022 g, 48%). : Melting point 141-142 ° C. D12c. General method of chain homologation of aldehydes or ketones. 2- (2-ethyl-4- (2,2-dicyanovinyl) phenylimino) -1-cyclopentyl-
Synthesis of 3-thia-1-azaspiro [4.4] nonane

[0304]

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2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3
-Thia-1-azaspiro [4.4] nonane (Method D11a; 0.037 g;
Malononitrile (0.007 g, 0.104 mmol) and piperidine (4 drops) were added to a solution of 104 mmol) in EtOH (10 mL). 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 / hex) to give 2- (2
-Ethyl-4- (2,2-dicyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained as a yellow solid (0.
012g, 28%): mp 135-136 ° C. D12d. General method of chain homologation of aldehydes or ketones. Synthesis of 2- (2-ethyl-4- (2-cyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane

[0306]

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A solution of KOH (0.024 g, 0.36 mmol) in CH ₃ CN (20 ml) was added at reflux to 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl. -3-Thia-1-azaspiro [4.4] nonane (
(Method D11a; 0.127 g, 0.36 mmol). The reaction mixture was heated at reflux for 4 hours, cooled to room temperature, and concentrated under reduced pressure. After the residue was diluted with water (15 mL), and extracted with CH ₂ Cl ₂ (3x15mL). The combined organic layers were washed with a saturated NaCl solution and then dried (Na ₂ SO ₄ ). The resulting material was purified by preparative TLC (30% EtOAc / hex) to give 2- (2-ethyl-4- (2-cyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1. -Azaspiro [4.4] nonane was obtained as a 1: 3 cis / trans isomer mixture (0.050 g): TLC (30% EtOAc
/ Hex) _Rf 0.56. D13a. General alkyl substitution method for chloromethyl side chains. 2- (2-methyl-
Synthesis of 4-nitrophenylimino) -4- (N-methylaminomethyl) -1,3-thiazolidine.

[0308]

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A solution of methylamine in methanol (2.0 M, 5 mL) was added to 2- (2
-Methyl-4-nitrophenylimino) -4- (chloromethyl) -1,3-thiazolidine (prepared in a manner 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. After concentrating the mixture under reduced pressure, the resulting residue is purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ) to give 2
-(2-Methyl-4-nitrophenylimino) -4- (N-methylaminomethyl) -1,3-thiazolidine was obtained as a solid (0.014 g, 35%). D14a. Rearrangement of carbon-carbon double bond using acid catalyst. Synthesis of 2- (4-nitrophenylimino) -3- (2-methylprop-1-en-1-yl) -1,3-thiazolidine.

[0310]

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The 2- (4-nitrophenyl) -1,3-thiazolidine was obtained by reacting 2-chloroethylammonium chloride (Heading 1) with 4-nitrophenylisothiocyanate according to Method C1a. This thiazolidine was converted to 1- according to Method D2a.
Reaction with bromo-2-methyl-2-propene provided 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine. 2- (4-nitrophenylimino) -3- (2-methylprop-
2-en-1-yl) -1,3-thiazolidine (0.20 g) was converted to poly (phosphoric acid) (
(0.4 mL) was heated to 80 ° C. for 5 hours. The reaction mixture was then dissolved in water at 0 ° C. (20 mL) with the aid of sonication. The pH of the aqueous mixture was adjusted to 12 with a 1N NaOH solution, followed by EtOAc (3 ×
25 mL). The combined organic layers 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 was obtained.

(Production of Specific Compounds) Detailed production steps used for producing the specific compounds listed in Tables 1-4 are described below. Many of the compounds listed in this table can be synthesized according to various methods. Accordingly, the following specific examples are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. Heading 1

[0313]

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The HCl salt of 2-chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine. Was. Heading 2

[0315]

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Reaction of 2-chloroethylammonium chloride (heading 1) with 4-nitrophenylisothiocyanate according to method C1a to give 2- (4-nitrophenylimino) -1,3-thiazolidine, Is reacted with isobutyl bromide according to method D2a to give 2- (4-nitrophenylimino) -3.
-Isobutyl-1,3-thiazolidine was obtained. Heading 3

[0317]

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The 2- (2-methyl-4-nitrophenyl) is obtained by reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenyl isothiocyanate and isobutyl bromide according to Method D2a. Imino) -3
-Isobutyl-1,3-thiazolidine was obtained. Heading 4

[0319]

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The 2- (2,3) is obtained by reacting 2-chloroethylammonium chloride (heading 1) with 2,3-dichlorophenylisothiocyanate according to method C1a.
-Dichlorophenylimino) -1,3-thiazolidine is reacted with isobutyl bromide according to method D2a to give 2- (2,3-dichlorophenylimino) -3-isobutyl-1,3-thiazolidine. Obtained. Heading 5

[0321]

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N-chloroethyl-N′-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 2-methoxy-4-nitrophenylisothiocyanate according to Method C1d to give 2- (2-methoxy-4- (Nitrophenylimino) -3-isobutyl-1,3-thiazolidine was obtained. Heading 6

[0323]

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N-chloroethyl-N′-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 4-cyanophenylisothiocyanate according to Method C1d to give 2- (4-cyanophenylimino) -3-isobutyl -1
, 3-thiazolidine. Heading 7

[0325]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-5-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this is reacted with isobutyl bromide according to method D2a. 2- (2-methyl-5-nitrophenylimino) -3-isobutyl-1,
The HCl salt of 3-thiazolidine was obtained. Heading 8

[0327]

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The N-chloroethyl-N′-isobutylammonium chloride (prepared as described in Method B7c) is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1d to give 2- (4-cyano-2- Ethylphenylimino) -3-isobutyl-1,3-thiazolidine was obtained. Heading 9

[0329]

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The reaction of N-chloroethyl-N′-isobutylammonium chloride (prepared as described in Method B7c) with 4-chloro-2- (trifluoromethyl) phenylisothiocyanate according to Method C1d yields 2- (4- Chloro-2- (
Trifluoromethyl) phenylimino) -3-isobutyl-1,3-thiazolidine was obtained. Heading 10

[0331]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 4-nitrophenylisothiocyanate according to Method C1a to form a thiazolidine, this was converted to 1-bromo-2-methyl-2- according to Method D2a. By reacting with propene, 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine was obtained. This 3-allyl-1,
The 3-thiazolidine is subjected to a rearrangement according to method D14a to give 2- (4-nitrophenylimino) -3- (2-methylprop-1-en-1-yl) -1,3.
-Thiazolidine was obtained. Heading 11

[0333]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine, this was converted to 1-bromo-2- according to Method D2a. Methyl-2
-By reacting with propene, 2- (2-methyl-4-nitrophenylimino)
-3- (2-Methylprop-2-en-1-yl) -1,3-thiazolidine was obtained. Heading 12

[0335]

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After reacting 2-chloroethylammonium chloride (heading 1) with 4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was converted to 1-bromo-2-methyl-2- according to method D2a. By reacting with propene, 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine was obtained. Heading 13

[0337]

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After reacting 2-chloroethylammonium chloride (heading 1) with 3,4-dichlorophenylisothiocyanate according to Method C1a to form a thiazolidine, this was converted to 1-bromo-2-methyl-2 according to Method D2a. -By reacting with propene, 2- (3,4-dichlorophenylimino) -3- (2-
Methylprop-2-en-1-yl) -1,3-thiazolidine was obtained. Heading 14

[0339]

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The reaction of N- (2-hydroxyethyl) -N- (2-methylbutyl) amine with SOCl ₂ according to Method B7a yields N- (2-chloroethyl) -N- (2
-Methylbutyl) ammonium chloride was obtained. This chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl) -1, 3-Thiazolidine was obtained. Heading 15

[0341]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was converted to 4-bromobut-1-ene according to method D2a. By reacting with ene, 2- (2-methyl-4-nitrophenylimino) -3- (but-1-en-4-yl) -1,3-thiazolidine was obtained. Heading 16

[0343]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine, this was converted to 1-bromobut-2-ene according to Method D2a. By reacting with in, 2- (2-methyl-4-nitrophenylimino) -3- (but-2-yn-1-yl) -1,3-thiazolidine was obtained. Heading 17

[0345]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was reacted with 2-ethylbutyl bromide according to method D2a. By reacting, 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1,3-thiazolidine was obtained. Heading 18

[0347]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was reacted with 2-methylbutyl bromide according to method D2a. By reacting, 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl) -1,3-thiazolidine was obtained. Heading 19

[0349]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was reacted with 1-nonyl bromide according to method D2a. By reacting, 2- (2-methyl-4-nitrophenylimino) -3- (1-nonyl)-
1,3-Thiazolidine was obtained. Heading 20

[0351]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was converted to 2,2-bromide according to method D2a. By reacting with dimethylpropyl, 2- (2-methyl-4-nitrophenylimino) -3- (
(2,2-Dimethylpropyl) -1,3-thiazolidine was obtained. Heading 21

[0353]

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According to Method B5a, 2-butylamine was converted to N- (2-hydroxyethyl) -N-
(2-butyl) amine. This amine is converted to SOCl according to Method B7a. _Two With N- (2-chloroethyl) -N- (2-butyl) ammonium
Um chloride was obtained. This chloroethylamine was treated with 2-methionine according to Method C1a.
2-nitrophenylisothiocyanate to give 2- (2-methyl
4-nitrophenylimino) -3- (2-butyl) -1,3-thiazolidine
I got Heading 22

[0355]

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According to Method B5a, 3-pentylamine was converted to N- (2-hydroxyethyl) -N
-(3-pentyl) amine. The amine is converted to SO 2 according to Method B7a.
By reacting with Cl ₂ , N- (2-chloroethyl) -N- (3-pentyl) ammonium chloride was obtained. This chloroethylamine was converted to 2 according to Method C1a.
-Methyl-4-nitrophenylisothiocyanate to give 2- (2
-Methyl-4-nitrophenylimino) -3- (3-pentyl) -1,3-thiazolidine was obtained. Heading 23

[0357]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was reacted with 1-heptyl bromide according to method D2a. By reacting, 2- (2-methyl-4-nitrophenylimino) -3- (1-heptyl) -1,3-thiazolidine was obtained. Heading 24

[0359]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to form a thiazolidine, this was reacted with 8-bromo-1- according to Method D2a. By reacting with octene, 2- (2-methyl-4-nitrophenylimino) -3- (oct-1-en-8-yl) -1,3-thiazolidine was obtained. Heading 25

[0361]

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The 2-propyl-1-hydroxypentane was converted to 1-bromo-2-propylpentane according to Method B2b, Step 2. The reaction of 2-chloroethiammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give the thiazolidine, which is then carried out according to method D2
Reaction with 1-bromo-2-propylpentane according to a) gives 2- (2-methyl-4-nitrophenylimino) -3- (2-propyl-1-pentyl) -1.
, 3-thiazolidine. Heading 26

[0363]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine, this was converted to 1,1-bromide according to Method D2a. Reaction with dicyclopropylbut-1-en-4-yl gives 2- (2-methyl-4-nitrophenylimino) -3- (1,1-dicyclopropylbut-1-en-4. -Yl) -1,3-thiazolidine. Heading 27

[0365]

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The reaction of 2,6-dichloro-4-nitrophenylisothiocyanate with 2-butylamine followed by chloroacetic acid according to Method C8a gives 2- (2,6-dichloro-4-nitrophenylimino) -3- (2-Butyl) -1,3-thiazolidine-4-one was obtained. Heading 28

[0367]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was converted to (E / Z)-according to method D2a. By reacting with 1,3-dibromopropene, 2- (2-methyl-4-nitrophenylimino)
-3- (Bromoprop-1-en-3-yl) -1,3-thiazolidine is converted to E / z
Obtained as a mixture. By separating the mixture using preparative TLC, 2- (2
-Methyl-4-nitrophenylimino) -3-((Z) -bromoprop-1-en-3-yl) -1,3-thiazolidine was obtained. Heading 29

[0369]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was converted to (E) -1,1 according to method D2a. By reacting with 3-dichloropropene, 2- (2-methyl-4-nitrophenylimino) -3 is obtained.
-((E) -Chloroprop-1-en-3-yl) -1,3-thiazolidine was obtained. Heading 30

[0371]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to give a thiazolidine, this was converted to 3-chloro-1- according to method D2a. By reacting with propyne, 2- (2-methyl-4-nitrophenylimino) -3- (prop-1-yn-3-yl) -1,3-thiazolidine was obtained. Heading 31

[0373]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was converted to (E / Z)-according to method D2a. By reacting with 1,3-dibromopropene, 2- (2-methyl-4-nitrophenylimino)
-3- (bromoprop-1-en-3-yl) -1,3-thiazolidine by E / Z
Obtained as a mixture. By separating the mixture using preparative TLC, 2- (2
-Methyl-4-nitrophenylimino) -3-((E) -bromoprop-1-en-3-yl) -1,3-thiazolidine was obtained. Heading 32

[0375]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to form a thiazolidine, this was converted to (Z) -4- according to Method D2a. Reaction with ethyl chloro-3-ethoxybut-2-enoate gives 2- (2-methyl-4-nitrophenylimino) -3- (1-ethoxycarbonyl-2-ethoxyprope-1.
-En-3-yl) -1,3-thiazolidine was obtained. Heading 33

[0377]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine, this was reacted with methyl 4-bromobutanoate according to Method D2a. By reacting, 2- (2-methyl-4-nitrophenylimino) -3- (1-
Methoxycarbonyl-3-propyl) -1,3-thiazolidine was obtained. Heading 34

[0379]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this is reacted with methyl chloroacetate according to method D2a. Thereby, 2- (2-methyl-4-nitrophenylimino) -3- (1-methoxycarbonylmethyl) -1,3-thiazolidine was obtained. Heading 35

[0381]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was reacted with α-chloroacetophenone according to method D2a. To give 2- (2-methyl-4-nitrophenylimino) -3- (1-
(Oxo-1-phenyl-2-ethyl) -1,3-thiazolidine was obtained. The ketone is reduced according to method D5a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-hydroxy-1-phenyl-2-ethyl) -1,3.
-Thiazolidine was obtained. Heading 36

[0383]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was converted to 1-chloro-3, By reacting with 3-dimethyl-2-butanone, 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine is obtained. Obtained. Method 37

[0385]

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After reacting 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, this was converted to 1-chloro-2- according to method D2a. By reacting with butanone, 2- (2-methyl-4-nitrophenylimino) -3- (2-
(Oxo-1-butyl) -1,3-thiazolidine was obtained. Method 38

[0387]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to form a thiazolidine, this was reacted with 1-chloro-2- according to Method D2a. By reacting with butanone, 2- (2-methyl-4-nitrophenylimino) -3- (2-
(Oxo-1-butyl) -1,3-thiazolidine was obtained. Method D5a for this ketone
To give 2- (2-methyl-4-nitrophenylimino)
-3- (2-Hydroxy-1-butyl) -1,3-thiazolidine was obtained. Method 39

[0389]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine, this was converted to 1-chloro-3, By reacting with 3-dimethyl-2-butanone, 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine is obtained. Obtained. The ketone is reduced according to Method D5a to give 2- (2
-Methyl-4-nitrophenylimino) -3- (2-hydroxy-3,3-dimethyl-1-butyl) -1,3-thiazolidine was obtained. Heading 40

[0391]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to form a thiazolidine, this was converted to 5-bromo-2- according to Method D2a. By reacting with pentanone, 2- (2-methyl-4-nitrophenylimino) -3- (2
-Oxo-5-pentanyl) -1,3-thiazolidine was obtained. Heading 41

[0393]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give a thiazolidine, this was converted to 1,1,3- according to Method D2a. Trichloro-1
-By reacting with propene, 2- (2-methyl-4-nitrophenylimino)
-3- (1,1-Dichloroprop-1-en-3-yl) -1,3-thiazolidine was obtained. Heading 42

[0395]

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Reaction of 2-chloroethylammonium chloride (heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to method C1a to form a thiazolidine, which is then reacted with propionyl chloride according to method D2d. With 2- (2-methyl-4-nitrophenylimino) -3- (1-oxo-
1-propyl) -1,3-thiazolidine was obtained. Heading 43

[0397]

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After reacting 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to form a thiazolidine, this was converted to (E) -1- according to Method D2a. By reacting with chloro-5-methoxy-2-pentene, 2- (2-methyl-4-nitrophenylimino) -3-((E) -5-methoxypent-2-en-1-yl) -1,
3-Thiazolidine was obtained. Heading 44

[0399]

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The reaction of 2-hydroxyethylamine with cyclopentanone according to step 1 of method B4b gave 4-aza-1-oxaspiro [4.4] nonane. This oxazolidine was reduced according to Step 2 of Method B4b to give N-cyclopentyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-cyclopentyl-N-
This gave (2-chloroethyl) amine. This amine was converted to 2 according to Method C1d.
-Methyl-4-nitrophenylisothiocyanate to give 2- (2
-Methyl-4-nitrophenylimino) -3- (cyclopentyl) -1,3-thiazolidine was obtained. Heading 45

[0401]

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The reaction of 2-hydroxyethylamine and cyclopentanone according to step 1 of method B4b gave 4-aza-1-oxaspiro [4.4] nonane. This oxazolidine was reduced according to Step 2 of Method B4b to give N-cyclopentyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-cyclopentyl-N-
This gave (2-chloroethyl) amine. This amine was converted to 2 according to Method C1d.
-Methoxy-4-nitrophenylisothiocyanate to give 2- (
2-methoxy-4-nitrophenylimino) -3- (cyclopentyl) -1,3
-Thiazolidine was obtained. Heading 46

[0403]

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Reaction of 2-hydroxyethylamine with cyclopentanone according to Step 1 of Method B4b provided 4-aza-1-oxaspiro [4.4] nonane. This oxazolidine was reduced according to Step 2 of Method B4b to give N-cyclopentyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-cyclopentyl-N-
This gave (2-chloroethyl) amine. This amine was converted to 2 according to Method C1d.
, 3-Dichlorophenylisothiocyanate to give 2- (2,3-
Dichlorophenylimino) -3-cyclopentyl-1,3-thiazolidine was obtained. Heading 47

[0405]

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The cyclohex-2-en-1-one was reduced according to step 1 of method B2b to give cyclohex-2-en-1-ol. This alcohol was converted to 3-bromo-1-cyclohexene according to step 2 of method B2b. This halide is converted to N- (cyclohex-2-ene-1
-Yl) -N- (2-hydroxyethyl) amine. This alcohol is reacted with SOCl ₂ according to Method B7a to give N- (cyclohex-2-yl).
En-1-yl) -N- (2-chloroethyl) ammonium chloride was formed. This chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclohex-2-en-1-yl)-. 1,3-Thiazolidine was obtained. Heading 48

[0407]

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Reaction of 2-hydroxyethylamine with cyclohexanone according to Step 1 of Method B4a provided 4-aza-1-oxaspiro [4.5] decane. This oxazolidine was reduced according to Step 2 of Method B4a to give N-cyclohexyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-cyclohexyl-N-
This gave (2-chloroethyl) amine. This amine was converted to 2 according to Method C1d.
-Methoxy-4-nitrophenylisothiocyanate to give 2- (
2-methyl-4-nitrophenylimino) -3-cyclohexyl-1,3-thiazolidine was obtained. Heading 49

[0409]

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N- (2-Hydroxyethyl) aniline was reacted with SOCl ₂ according to Method B7a to give N-2-chloroethyl) anilium chloride. This chloroethylamine was reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-phenyl-1,3-thiazolidine. Heading 50

[0411]

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The N-cycloheptyl-N- (2-hydroxyethyl) amine was generated by reacting 2-hydroxyethylamine with cycloheptyl bromide according to Method B2a. This alcohol is reacted with SOCl ₂ according to Method B7c to give N 2
-Cycloheptyl-N- (2-chloroethyl) ammonium chloride was produced. This chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3.
-Cycloheptyl-1,3-thiazolidine was obtained. Heading 51

[0413]

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The N-cyclooctyl-N- (2-hydroxyethyl) amine was generated by reacting 2-hydroxyethylamine with cyclooctyl bromide according to Method B2a. This alcohol is reacted with SOCl ₂ according to Method B7c to give N 2
-Cyclooctyl-N- (2-chloroethyl) ammonium chloride was formed. This chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3.
-Cyclooctyl-1,3-thiazolidine was obtained. Heading 52

[0415]

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The N-cyclooctyl-N- (2-hydroxyethyl) amine was generated by reacting 2-hydroxyethylamine with cyclooctyl bromide according to Method B2a. This alcohol is reacted with SOCl ₂ according to Method B7c to give N 2
-Cyclooctyl-N- (2-chloroethyl) ammonium chloride was formed. This chloroethylamine is reacted with 2-methoxy-4-nitrophenylisothiocyanate to give 2- (2-methoxy-4-nitrophenylimino)
-3-Cyclooctyl-1,3-thiazolidine was obtained. Heading 53

[0417]

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The N-cyclooctyl-N- (2-hydroxyethyl) amine was generated by reacting 2-hydroxyethylamine with cyclooctyl bromide according to Method B2a. This alcohol is reacted with SOCl ₂ according to Method B7c to give N 2
-Cyclooctyl-N- (2-chloroethyl) ammonium chloride was formed. The chloroethylamine was reacted with 2,3-dichlorophenylisothiocyanate to obtain 2- (2,3-dichlorophenylimino) -3-cyclooctyl-1,3-thiazolidine. Heading 54

[0419]

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Reacting 2-hydroxyethylamine with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to yield N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2,3-dichlorophenylisothiocyanate to obtain 2- (2,3-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine. Heading 55

[0421]

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Reacting 2-hydroxyethylamine with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to yield N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2-methyl-4-nitrophenylisothiocyanate to obtain 2- (2-methyl-4-nitrophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine. Heading 56

[0423]

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The reaction of 2-hydroxyethylamine with cyclopropylmethyl bromide according to method B2a gives N-cyclopropylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to yield N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenylisothiocyanate to obtain 2- (2,4-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine. Heading 57

[0425]

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Reacting 2-hydroxyethylamine with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to yield N-cyclopropylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 3,4-dichlorophenylisothiocyanate to obtain 2- (3,4-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine. Heading 58

[0427]

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Reacting 2-hydroxyethylamine with cyclobutylmethyl bromide according to Method B2a yielded N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine is reacted with 2,2-dichlorophenylisothiocyanate to give 2- (2,2-dichlorophenylimino) -3.
-(Cyclobutylmethyl) -1,3-thiazolidine was obtained. Heading 59

[0429]

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The reaction of 2-hydroxyethylamine with cyclobutylmethyl bromide according to Method B2a yielded N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine is reacted with 2,4-dichlorophenylisothiocyanate to give 2- (2,4-dichlorophenylimino) -3.
-(Cyclobutylmethyl) -1,3-thiazolidine was obtained. Heading 60

[0431]

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Reacting 2-hydroxyethylamine with cyclobutylmethyl bromide according to Method B2a yielded N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine is reacted with 3,4-dichlorophenylisothiocyanate to give 2- (3,4-dichlorophenylimino) -3.
-(Cyclobutylmethyl) -1,3-thiazolidine was obtained. Heading 61

[0433]

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Reacting 2-hydroxyethylamine with cyclobutylmethyl bromide according to Method B2a yielded N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine is reacted with 2,3-dimethylphenylisothiocyanate to give 2- (2,3-dimethylphenylimino) -3.
-(Cyclobutylmethyl) -1,3-thiazolidine was obtained. Heading 62

[0435]

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Reacting 2-hydroxyethylamine with cyclobutylmethyl bromide according to Method B2a yielded N-cyclobutylmethyl-N- (2-hydroxyethyl) amine. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclobutylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 3-chloro-2-methylphenylisothiocyanate to obtain 2- (3-chloro-2-methylphenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine. Heading 63

[0437]

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Reacting 2-hydroxyethylamine with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2,3-dichlorophenylisothiocyanate to obtain 2- (2,3-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine. Heading 64

[0439]

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Reacting 2-hydroxyethylamine with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 3,4-dichlorophenylisothiocyanate to obtain 2- (3,4-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine. Heading 65

[0441]

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Reacting 2-hydroxyethylamine with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2-methyl-4-nitrophenylisothiocyanate to obtain 2- (2-methyl-4-nitrophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine. Heading 66

[0443]

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Reacting 2-hydroxyethylamine with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenylisothiocyanate to obtain 2- (2,4-dichlorophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine. Heading 67

[0445]

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Reacting 2-hydroxyethylamine with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3-dimethylphenylisothiocyanate to obtain 2- (2,3-dimethylphenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine. Heading 68

[0447]

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Reacting 2-hydroxyethylamine with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclopentylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 3-chloro-2-methylphenylisothiocyanate to obtain 2- (3-chloro-2-methylphenylimino) -3- (cyclopentylmethyl) -1,3-thiazolidine. Heading 69

[0449]

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Reacting 2-hydroxyethylamine with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2,3-dichlorophenylisothiocyanate to obtain 2- (2,3-dichlorophenylimino) -3- (cyclohexylmethyl) -1,3-thiazolidine. Heading 70

[0451]

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Reacting 2-hydroxyethylamine with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2-methyl-4-nitrophenylisothiocyanate to obtain 2- (2-methyl-4-nitrophenylimino) -3- (cyclohexylmethyl) -1,3-thiazolidine. Heading 71

[0453]

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Reacting 2-hydroxyethylamine with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N-cyclohexylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2-methoxy-4-nitrophenylisothiocyanate to obtain 2- (2-methoxy-4-nitrophenylimino) -3- (cyclohexylmethyl) -1,3-thiazolidine. Heading 72

[0455]

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The 1-cyclohexyl-1-ethylamine was converted to N- (2-hydroxyethyl) -N- (1-cyclohexyl-1-ethyl) amine according to Method B5a. This alcohol is reacted with SOCl ₂ according to Method B7a to give N- (2
-Chloroethyl) -N- (1-cyclohexyl-1-ethyl) ammonium chloride was formed. This chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-1-ethyl) -1.
, 3-thiazolidine. Heading 73

[0457]

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Reacting 2-hydroxyethylamine with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-benzyl-
N- (2-chloroethyl) ammonium chloride was formed. This chloroethylamine is reacted with 3-chloro-2-methylphenylisothiocyanate to give 2- (3-chloro-2-methylphenylimino) -3-benzyl-1,3.
-Thiazolidine was obtained. Heading 74

[0459]

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Reacting 2-hydroxyethylamine with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-benzyl-
N- (2-chloroethyl) ammonium chloride was formed. This chloroethylamine was reacted with 3,4-dichlorophenylisothiocyanate to obtain 2- (3,4-dichlorophenylimino) -3-benzyl-1,3-thiazolidine. Heading 75

[0461]

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Reaction of 2-hydroxyethylamine with benzyl bromide according to Method B2a yielded N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-benzyl-
N- (2-chloroethyl) ammonium chloride was formed. This chloroethylamine was reacted with 2,4-dichlorophenylisothiocyanate to obtain 2- (2,4-dichlorophenylimino) -3-benzyl-1,3-thiazolidine. Heading 76

[0463]

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The reaction of 2-hydroxyethylamine with benzyl bromide according to Method B2a gave N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-benzyl-
N- (2-chloroethyl) ammonium chloride was formed. This chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-benzyl-1,3.
-Thiazolidine was obtained. Heading 77

[0465]

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Reacting 2-hydroxyethylamine with benzyl bromide according to Method B2a to give N-benzyl-N- (2-hydroxyethyl) amine. The alcohol is reacted with SOCl ₂ according to Method B7c to give N-benzyl-
N- (2-chloroethyl) ammonium chloride was formed. This chloroethylamine was reacted with 2,3-dichlorophenylisothiocyanate to obtain 2- (2,3-dichlorophenylimino) -3-benzyl-1,3-thiazolidine. Heading 78

[0467]

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The reaction of 2-hydroxyethylamine with 4-chlorobenzyl bromide according to method B2a gives N- (4-chlorobenzyl) -N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N- (4-chlorobenzyl) -N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 4-cyano-2-ethylphenylisothiocyanate to obtain 2- (4-cyano-2-ethylphenylimino) -3- (4-chlorobenzyl) -1,3-thiazolidine. . Heading 79

[0469]

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Reacting 2-hydroxyethylamine with 4-chlorobenzyl bromide according to Method B2a to give N- (4-chlorobenzyl) -N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to give N- (4-chlorobenzyl) -N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2-chloro-4-cyanophenylisothiocyanate to obtain 2- (2-chloro-4-cyanophenylimino) -3- (4-chlorobenzyl) -1,3-thiazolidine. . Heading 80

[0471]

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Reacting 2-hydroxyethylamine with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to yield N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2-methyl-4-nitrophenylisothiocyanate to obtain 2- (2-methyl-4-nitrophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine. Heading 81

[0473]

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Reacting 2-hydroxyethylamine with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to yield N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2-methoxy-4-nitrophenylisothiocyanate to obtain 2- (2-methoxy-4-nitrophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine. Headline 82

[0475]

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Reacting 2-hydroxyethylamine with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to yield N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 2,3-dichlorophenylisothiocyanate to obtain 2- (2,3-dichlorophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine. Heading 83

[0477]

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Reacting 2-hydroxyethylamine with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N- (2-hydroxyethyl)
The amine was generated. This alcohol was reacted with SOCl ₂ according to Method B7c to yield N-cycloheptylmethyl-N- (2-chloroethyl) ammonium chloride. This chloroethylamine was reacted with 4-cyanophenylisothiocyanate to obtain 2- (4-cyanophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine. Heading 84

[0479]

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Cyclododecyl methanol was obtained by reducing methyl cyclododecanecarboxylate according to step 1 of method B2b. This alcohol was converted to cyclododecylmethyl bromide according to step 2 of method B2b. The halide was reacted with 2-hydroxyethylamine according to Step 3 of Method B2b to give N- (2-hydroxyethyl) -N- (cyclododecylmethyl) amine. This alcohol is reacted with SOCl ₂ according to Method B7a to give N-
(2-Chloroethyl) -N- (cyclododecylmethyl) ammonium chloride was produced. This chloroethylamine was converted to 2-methyl-4- according to Method C1a.
By reacting with nitrophenyl isothiocyanate, 2- (2-methyl-4-
Nitrophenylimino) -3- (cyclododecylmethyl) -1,3-thiazolidine was obtained. Heading 85

[0481]

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Reaction of 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a yields 2- (
After the formation of 2-methyl-4-nitrophenylimino) -1,3-thiazolidine, it is converted to 3- (chloromethyl) -6,6-dimethylbicyclo [3.1.1] hept-2 according to method D2a. -(4-nitrophenylimino) -3-((6,6-dimethylbicyclo [3.1.1] hept-2-en-3-yl) methyl) -1,3 -Thiazolidine was obtained. Heading 86

[0483]

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Reaction of 2-chloroethylammonium chloride (Heading 1) with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a yields 2- (
After the formation of 2-methyl-4-nitrophenylimino) -1,3-thiazolidine, this is reacted with 5- (bromomethyl) bicyclo [2.1.1] hept-2-ene according to method D2a. 2- (4-nitrophenylimino) -3- (
(Bicyclo [2.1.1] hept-2-en-5-yl) methyl) -1,3-thiazolidine was obtained. Heading 87

[0485]

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The 3-aminoquinoline was changed to 3-quinoline isothiocyanate according to Method A2c. (1S) -1- (Hydroxymethyl) -3-methylbutylamine was generated from the methyl ester of (L) -leucine as described in Method B1b. This 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Step B-2 of Method B4c. This alcohol was converted to N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. The 3-quinoline isothiocyanate was converted to N- (1
By reacting with (S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride, 2- (3-quinolylimino) -3,5-diisobutyl-1,3-thiazolidine was obtained. Heading 88

[0487]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in step 1-2 of method B4c (
2S) -4-methyl-2- (isobutylamino) pentanol. This alcohol was converted to N- (1S) -1- (chloromethyl) as described in Method B7c.
-3-methylbutyl) -N- (isobutyl) ammonium chloride. 4-Nitrophenyl isothiocyanate is converted to N- (1S) according to Method C1f.
By reacting with 1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride, 2- (4-nitrophenylimino) -3,5-
Diisobutyl-1,3-thiazolidine was obtained. Heading 89

[0489]

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From the methyl ester of (L) -leucine as described in Method B1b, (1
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in step 1-2 of method B4c (
2S) -4-methyl-2- (isobutylamino) pentanol. This alcohol was converted to N- (1S) -1- (chloromethyl) as described in Method B7c.
-3-methylbutyl) -N- (isobutyl) ammonium chloride. 4-Cyanophenylisothiocyanate is converted to N- (1S) according to Method C1f.
By reacting with 1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride, 2- (4-cyanophenylimino) -3,5-
Diisobutyl-1,3-thiazolidine was obtained. Heading 90

[0490]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4S) -2- (2-methyl-
4-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained.
This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4)
S) -2- (2-Methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt was obtained. Heading 91

[0493]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4R) -2- (2-methyl-
4-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained.
This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4)
R) -2- (2-Methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt was obtained. Heading 92

[0495]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride. By reacting 2-methyl-5-nitrophenylisothiocyanate with (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4R) -2- (2-methyl-
5-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained.
This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4)
R) -2- (2-Methyl-5-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt was obtained. Heading 93

[0497]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride. By reacting 2-methyl-5-nitrophenylisothiocyanate with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4S) -2- (2-methyl-
5-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained.
This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4)
S) -2- (2-Methyl-5-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine HCl salt was obtained. Heading 94

[0499]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4R) -2- (2-methyl-
4-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained.
This thiazolidine is reacted with methyl iodide according to Method D2a to give (4R
) The HCl salt of 2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3-methyl-1,3-thiazolidine was obtained. Heading 95

[0501]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4S) -2- (2-methyl-
4-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained.
This thiazolidine is reacted with methyl iodide according to Method D2a to give (4S
) The HCl salt of 2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3-methyl-1,3-thiazolidine was obtained. Heading 96

[0503]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride. By reacting 2-methyl-5-nitrophenyl isothiocyanate with (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4R) -2- (2-methyl
5-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained.
This thiazolidine is reacted with methyl iodide according to Method D2a to give (4R
) The HCl salt of 2- (2-methyl-5-nitrophenylimino) -4-isobutyl-3-methyl-1,3-thiazolidine was obtained. Heading 97

[0505]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4S) -2- (2-methyl-
4-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained.
This 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). ) The HCl salt of -1,3-thiazolidine was obtained. Heading 98

[0507]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Methyl-4-nitrophenylisothiocyanate is prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. . This thiazolidine is reacted with 1-chloro-3,3-dimethyl-2-butanone according to method D2a to give (4S)-
2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (2-
(Oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine was obtained. Heading 99

[0509]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Ethyl-4-cyanophenylisothiocyanate is prepared according to method C1a (1S
) -1- (chloromethyl) -3-methylbutaneammonium chloride to give (4S) -2- (2-ethyl-4-cyanophenylimino) -4-isobutyl-1,3-thiazolidine. . The thiazolidine was reacted with isobutyl bromide according to Method D2f to give (4S) -2- (2-ethyl-4-cyanophenylimino) -3,4-diisobutyl-1,3-thiazolidine. Heading 100

[0511]

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The (1) -methyl ester of (L) -leucine was converted to (1) as described in Method B1b.
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Methyl-4-nitrophenylisothiocyanate is prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. . This thiazolidine is reacted with cyclopropylmethyl bromide according to method D2a to give (4S) -2- (2-methyl-
4-nitrophenylimino) -4-isobutyl-3- (cyclopropylmethyl)
-1,3-Thiazolidine was obtained. Heading 101

[0513]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Methyl-4-nitrophenylisothiocyanate is prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. . This thiazolidine is reacted with cyclobutylmethyl bromide according to Method D2a to give (4S) -2- (2-methyl-4
-Nitrophenylimino) -4-isobutyl-3- (cyclobutylmethyl) -1
, 3-thiazolidine. Heading 102

[0515]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Methyl-4-nitrophenylisothiocyanate is prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. . This thiazolidine is reacted with 2-chloro-3,3-dimethyl-2-butanone according to method D2a to give (4S)-
2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (2-
(Oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine was obtained. The ketone is reduced 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. Heading 103

[0517]

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(1S) -1- (Hydroxymethyl) -3-as described in Method B7a
Methylbutylamine was changed to (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride. 2,6-Dimethyl-4-nitroaniline was converted to 2,6-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. By reacting 2,6-dimethyl-4-nitrophenylisothiocyanate with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a, (4S) -2- (2-methyl-4 -Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (2
, 6-Dimethyl-4-nitrophenylimino) -3,4-diisobutyl-1,3
-The HCl salt of thiazolidine was obtained. Heading 104

[0519]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
, 3-Dichlorophenylisothiocyanate was converted to (1S) -1 according to Method C1a.
By reacting with (chloromethyl) -3-methylbutane ammonium chloride, (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. This thiazolidine was converted to 3- according to Method D2a.
By reacting with bromopentane, (4S) -2- (2,3-dichlorophenylimino) -4-isobutyl-3- (3-pentyl) -1,3-thiazolidine was obtained. Heading 105

[0521]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Methyl-4-nitrophenylisothiocyanate is prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. . This 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. I got Heading 106

[0523]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
, 3-Dichlorophenylisothiocyanate was converted to (1S) -1 according to Method C1a.
By reacting with (chloromethyl) -3-methylbutane ammonium chloride, (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. This thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (2,3-dichlorophenylimino) -3,4-diisobutyl-1,3-thiazolidine. Heading 107

[0525]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-(Trifluoromethyl) -4-nitrophenylisothiocyanate was prepared according to method C1.
(4S) -2- (2- (trifluoromethyl) -4 by reacting with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to c.
-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine trifluoroacetate was obtained. Heading 108

[0527]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-(Trifluoromethyl) -4-nitrophenylisothiocyanate was prepared according to method C1.
(4S) -2- (2- (trifluoromethyl) -4 by reacting with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to c.
-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2f to give (4S
) -2- (2- (Trifluoromethyl) -4-nitrophenylimino) -3,4
Trifluoromethyl acetate of diisobutyl-1,3-thiazolidine was obtained. Heading 109

[0529]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 4
-Cyano-2- (trifluoromethyl) phenylisothiocyanate was prepared according to method C1.
(4S) -2- (4-cyano-2- (trifluoromethyl) phenylimino) -4-isobutyl- by reacting with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to c. 1,3-Thiazolidine was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2f to give (4S
) -2- (4-Cyano-2- (trifluoromethyl) phenylimino) -3,4
Trifluoromethyl acetate of diisobutyl-1,3-thiazolidine was obtained. Heading 110

[0531]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Chloro-4-cyano-6-methylphenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1c to give (4S) -2- (2-chloro- 4-Cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2f to give (4S) -2-
The trifluoromethyl acetate of (2-chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained. Heading 111

[0533]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 4
-(Methoxycarbonyl) -2-methylphenylisothiocyanate was prepared according to method C1.
(4S) -2- (4- (methoxycarbonyl) -2 by reacting with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to c.
-Methylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S
) -2- (4- (Methoxycarbonyl) -2-methylphenylimino) -3,4
-Diisobutyl-1,3-thiazolidine was obtained. Heading 112

[0535]

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The (1) -methyl ester of (L) -leucine was converted to (1) as described in Method B1b.
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 3
The 5,5-dimethyl-4-nitroaniline was converted to 3,5-dimethyl-4-nitrophenylisothiocyanate according to step 3 of method A2a. 3,5-Dimethyl-4-nitrophenylisothiocyanate was converted to (1S) -1 according to Method C1a.
By reacting with-(chloromethyl) -3-methylbutane ammonium chloride, (4S) -2- (3,5-dimethyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine was obtained. The thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (3,5-dimethyl-4-
(Nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained. Heading 113

[0537]

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The (1) -methyl ester of (L) -leucine was converted to (1
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 4
-(Methoxycarbonyl) -2-methylphenylisothiocyanate was prepared according to method C1.
(4S) -2- (4- (methoxycarbonyl) -2 by reacting with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to a.
-Methylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S
) -2- (4- (Methoxycarbonyl) -2-methylphenylimino) -3,4
-Diisobutyl-1,3-thiazolidine was obtained. Saponification of this thiazolidine by Method D
6a to give (4S) -2- (4-carboxy-2-
Methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained.
This acid is coupled with ammonia as described in Step 2 of Method D6a to give (4S) -2- (4-carbamoyl-2-methylphenylimino) -3,4-
Diisobutyl-1,3-thiazolidine was obtained. Heading 114

[0539]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 4
-Fluoro-2-methylphenylisothiocyanate was prepared according to Method C1a (1
(4S) -2- (4-Fluoro-2-methylphenylimino) -4 by reacting with (S) -1- (chloromethyl) -3-methylbutane ammonium chloride.
-Isobutyl-1,3-thiazolidine was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-fluoro-2-
Methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained. Heading 115

[0541]

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The (1) -methyl ester of (L) -leucine was converted to (1) as described in Method B1b.
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 4
-Chloro-2-methylphenylisothiocyanate is prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (4-chloro-2-methylphenylimino) -4-isobutyl-1,3-thiazolidine. . This thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-chloro-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine. Heading 116

[0543]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 4
-Bromo-2-methylphenylisothiocyanate was prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (4-bromo-2-methylphenylimino) -4-isobutyl-1,3-thiazolidine. . This thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-bromo-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine. Heading 117

[0545]

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(4S) -2- (4) by reacting (1S) -1- (hydroxymethyl) -3-methylbutylamine with SOCl ₂ followed by 4-cyano-2-ethylphenylisothiocyanate according to method C2a. -Cyano-2-ethylphenylimino) -4-isobutyl-1,3-thiazolidine was obtained. This thiazolidine was used in Method D
Reaction with isobutyl bromide according to 2a gives (4S) -2- (4-cyano-
(2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained. Heading 118

[0547]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was converted to (2S) -4- as described in Method B4c.
Methyl-2- (isobutylamino) pentan-1-ol. The resulting 2-hydroxyethylamine was converted to N- (1S)-according to Method B7c.
1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride. By reacting 2-methyl-4-nitrophenylisothiocyanate 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. Heading 119

[0549]

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The (1) -methyl ester of (L) -leucine was converted to (1
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was converted to (2S) -4- as described in Method B4c.
Methyl-2- (isobutylamino) pentan-1-ol. The resulting 2-hydroxyethylamine was converted to N- (1S)-according to Method B7c.
1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride. 4-Amino-3-methylpyridine was converted to 3-methyl-4-pyridyl isocyanate according to Method A2b. By reacting 3-methyl-4-pyridylisothiocyanate 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. Heading 120

[0551]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. The 4-nitro-1-naphthylisothiocyanate is reacted with (1S) -1- (hydroxymethyl) -3-methylbutylamine according to Method C2a to give (4S) -2- (4-nitro-1-naphthylimino).
-4-Isobutyl-1,3-thiazolidine was obtained. This thiazolidine was prepared according to method D2.
(4S) -2- (4-nitro-1)
-Naphthylimino) -3,4-diisobutyl-1,3-thiazolidine was obtained. Heading 121

[0553]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was converted to (2S) -4- as described in Method B4c.
Methyl-2- (isobutylamino) pentan-1-ol. The resulting 2-hydroxyethylamine was converted to N- (1S)-according to Method B7c.
1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride. 4-nitrophenyl isothiocyanate was prepared according to method C1f.
According to the following procedure, to react with (4S) -2- (4-nitrophenylimino) -3,4-diisobutyl by reacting with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride. -1,3-Thiazolidine was obtained.
Heading 122

[0555]

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The methyl ester of (L) -leucine was converted to (1) as described in Method B1b.
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was converted to (2S) -4- as described in Method B4c.
Methyl-2- (isobutylamino) pentan-1-ol. The resulting 2-hydroxyethylamine was converted to N- (1S)-according to Method B7c.
1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride. 4-Cyanophenylisothiocyanate was prepared according to method C1f.
According to the following procedure to react with N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride to give (4S) -2- (4-cyanophenylimino) -3,4-diisobutyl. -1,3-Thiazolidine was obtained.
Heading 123

[0557]

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The (1) from the methyl ester of (L) -leucine as described in Method B1b
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was converted to (2S) -4- as described in Method B4c.
Methyl-2- (isobutylamino) pentan-1-ol. The resulting 2-hydroxyethylamine was converted to N- (1S)-according to Method B7c.
1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride. 4-Amino-3-methylpyridine was converted to 3-methyl-4-pyridyl isocyanate according to Method A2b. By reacting 3-methyl-4-pyridylisothiocyanate 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. The thiazolidine was oxidized according to Method D4a to obtain 1-oxide of (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine. Heading 124

[0559]

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(1S, 2S) -1- (Hydroxymethyl) as described in Method B7a
-2-Methylbutylamine was changed to (1S, 2S) -1- (chloromethyl) -2-methylbutane ammonium chloride. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1S, 2S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to Method C1a, (4S)-
2- (2-methyl-4-nitrophenylimino) -4 ((2S) -2-butyl)
-1,3-Thiazolidine was obtained. This 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, The HCl salt of 3-thiazolidine was obtained. Heading 125

[0561]

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N- (t-butoxycarbamoyl) as described in Step 2 of Method B1a
-(1S, 2R) -1- (hydroxymethyl) -2-methylbutylamine is converted to N-
Prepared from (t-butoxycarbamoyl)-(L) -allo-isoleucine. This carbamate was converted to (1S, 2R) -1- (chloromethyl) -2-methylbutane ammonium chloride as described in Method B7b. 2-Methyl-4-nitrophenylisothiocyanate was prepared according to method C1e (1S, 2R
) -1- (chloromethyl) -2-methylbutane ammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4 ((
2R) -2-Butyl) -1,3-thiazolidine was obtained. This 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, The HCl salt of 3-thiazolidine was obtained. Heading 126

[0563]

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According to step B of method B1a, N- (t-butoxycarbamoyl)-(1S)-
1-Cyclohexyl-2-hydroxyethylbutylamine was prepared from N- (t-butoxycarbamoyl)-(L) -cyclohexylglycine. The carbamate is reacted with SOCl ₂ according to Method B1b and the resulting material is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give (4S) -2- (2-methyl-4- Nitrophenylimino)-
4-Cyclohexyl-1,3-thiazolidine was obtained. This thiazolidine was used in Method D
Reaction with isobutyl bromide according to 2a gives (4S) -2- (2-methyl-
4-nitrophenylimino) -4-cyclohexyl-3-isobutyl-1,3-
The HCl salt of thiazolidine was obtained. Heading 127

[0565]

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The (1S) -1- (hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. 4-methoxycarbonyl-2-methylphenylisothiocyanate was prepared according to method C1.
(4S) -2- (4-methoxycarbonyl-2-methylphenylimino) -4 (2-butyl)-by reacting with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to a. 1,3-Thiazolidine was obtained. This 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. Heading 128

[0567]

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The (1S) -1-isopropyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-isopropylethylammonium chloride as described in Method B7a. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1S) -2-chloro-1-isopropylethylammonium chloride according to Method C1a, (4S) -2- (2-methyl-4-nitrophenylimino) -4-Isopropyl-1,3-thiazolidine was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4S) -2-
The HCl salt of (2-methyl-4-nitrophenylimino) -4-isopropyl-3-isobutyl-1,3-thiazolidine was obtained. Heading 129

[0569]

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(1S) -1- (Hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. The 5-aminoindan-1-one was converted to 1-oxo-5-indanyl isothiocyanate according to Method A2a. This isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to Method C1a to give (4S) -2- (1-oxo-5-indanilimino).
-4- (2-Butyl) -1,3-thiazolidine was obtained. This thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S) -2- (1-oxo-5-indanilimino) -4- (2-butyl) -3-isobutyl-1,3-thiazolidine. . Heading 130

[0571]

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(1S) -1- (Hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. 4-Chloro-3- (trifluoromethyl) aniline was converted to 4-chloro-3- (trifluoromethyl) phenylisothiocyanate according to Step 3 of Method A2a. By reacting 4-chloro-3- (trifluoromethyl) phenylisothiocyanate with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to Method C1a, (4S) -2- (4-chloro -3- (
(Trifluoromethyl) phenylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. The 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. Heading 131

[0573]

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(1S) -1- (Hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. 4-Cyano-3- (trifluoromethyl) aniline was converted to 4-cyano-3- (trifluoromethyl) phenylisothiocyanate according to Step 3 of Method A2a. This isothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to Method C1a to obtain (4
S) -2- (4-Cyano-3- (trifluoromethyl) phenylimino) -4-
(2-Butyl) -1,3-thiazolidine was obtained. This thiazolidine was prepared according to method D2a.
(4S) -2- (4-cyano-3-
(Trifluoromethyl) phenylimino) -4- (2-butyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 132

[0575]

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(1S) -1- (Hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. 4-nitro-1-naphthylisothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to Method C1a to give (4S) -2- (4-nitro-1
-Naphthylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. This 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. Heading 133

[0577]

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(1S) -1- (Hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. 4-Cyano-2-ethylphenylisothiocyanate is prepared according to method C1a (
By reacting with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride, (4S) -2- (4-cyano-2-ethylphenylimino) -4 is obtained.
-(2-Butyl) -1,3-thiazolidine was obtained. This thiazolidine was prepared according to method D2.
(4S) -2- (4-cyano-2) by reacting with isobutyl bromide according to a.
-Ethylphenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine was obtained. Heading 134

[0579]

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(1S) -1- (Hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. 4-Cyano-2-methylaniline was synthesized as described in Method A1a. This aniline was converted to 4-cyano-2-methylphenylisothiocyanate as described in Step 3 of Method A2a. The 4-cyano-2-methylphenylisothiocyanate is reacted with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to Method C1a to give (4S) -2- (4-cyano-2-methyl (Phenylimino) -4- (2-butyl) -1,3-thiazolidine was obtained. This thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-cyano-2-methylphenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine. Heading 135

[0581]

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(1S) -1- (Hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. 2,5-Dimethyl-4-nitrobenzonitrile was converted to 4-cyano-2,5-methylaniline according to Method A1a. This aniline is used in Step 3 of Method A2a.
Was converted to 4-cyano-2,5-dimethylphenylisothiocyanate as described above. By reacting 4-cyano-2,5-dimethylphenylisothiocyanate with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to Method C1a, (4S) -2- (4-cyano-2 , 5-Dimethylphenylimino) -4- (2-butyl) -1,3-thiazolidine.
This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4)
S) -2- (4-Cyano-2,5-dimethylphenylimino) -4-butyl-3
-Isobutyl-1,3-thiazolidine was obtained. Heading 136

[0583]

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The (1S) -1- (hydroxymethyl) -2-methylbutylamine was generated from the methyl ester of (L) -isoleucine as described in Method B1b.
This 2-hydroxyethylamine was converted to (1S)-as described in Method B7a.
It was changed to 1- (chloromethyl) -2-methylbutane ammonium chloride. 2,5-Dimethylaniline was converted to 2,5-dimethyl-4-nitrophenylisothiocyanate according to Method A2a. By reacting 2,5-dimethyl-4-nitrophenylisothiocyanate with (1S) -1- (chloromethyl) -2-methylbutane ammonium chloride according to Method C1a, (4S) -2
-(2,5-dimethyl-4-nitrophenylimino) -4- (2-butyl) -1
, 3-thiazolidine. This thiazolidine was reacted with isobutyl bromide according to method D2a to give (4S) -2- (2,5-dimethyl-4-nitrophenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine. . Heading 137

[0585]

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According to method C2a, (1R) -1-isopropyl-2-hydroxyethylamine is reacted with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate to give (4R) -2- (2-methyl- 4-nitrophenylimino)-
4-Isopropyl-1,3-thiazolidine was obtained. This thiazolidine was prepared according to method D2.
(4R) -2- (2-methyl-4)
-Nitrophenylimino) -4-isopropyl-3-isobutyl-1,3-thiazolidine was obtained. Heading 138

[0587]

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The (1S) -1-isopropyl-2-hydroxyethylamine is reacted according to method C2a with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate to give (4S) -2- (2-methyl- 4-nitrophenylimino)-
4-Isopropyl-1,3-thiazolidine was obtained. This thiazolidine was prepared according to method D2.
a) reacting with cyclopentyl bromide according to (a) to obtain (4S) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-cyclopentyl-1,
3-Thiazolidine was obtained. Heading 139

[0589]

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(1S) -1-benzyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-benzylethylammonium chloride according to Method B7b. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1S) -2-chloro-1-benzylethylammonium chloride according to Method C1a, (4S) -2- (2-methyl-4-nitrophenylimino) -4-Benzyl-1,3-thiazolidine was obtained. The 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
Salt was obtained. Heading 140

[0591]

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(1S) -1-Phenyl-2-hydroxyethylamine was converted to (1S) -2-chloro-1-phenylethylammonium chloride according to Method B7b. By reacting 2-methyl-4-nitrophenylisothiocyanate with (1S) -2-chloro-1-benzylethylammonium chloride according to Method C1a, (4S) -2- (2-methyl-4-nitrophenylimino) -4-phenyl-1,3-thiazolidine was obtained. The 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.
Salt was obtained. Heading 141

[0593]

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2-Piperidenemethanol was generated from methyl pipecolinate as described in Method B1b. This 2-hydroxyethylamine was converted to 2-chloromethylpiperidinium chloride according to Method B7a. 2-Methyl-4-nitrophenylisothiocyanate is reacted with 2-chloromethylpiperidinium chloride according to Method C1a to give 9- (2-methyl-4-nitrophenylimino) -1-aza-8-thiabicyclo [4. .3.0] nonane was obtained. Heading 142

[0595]

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2-Pyrrolidine methanol was generated from the methyl ester of proline as described in Method B1b. This 2-hydroxyethylamine was converted to 2-chloromethylpyrrolidinium chloride according to Method B7a. 2-methyl-4
3- (2-methyl-4-nitrophenylimino) -2,5,6,7,7a-pentahydro-2- by reacting -nitrophenylisothiocyanate with 2-chloromethylpyrrolidinium chloride according to method C1a. Thiapyrrolidine was obtained. Heading 143

[0597]

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From the methyl ester of (L) -tyrosine as described in Method B1b, (1
S) -1- (4-Hydroxyphenylmethyl) -2-hydroxyethylamine was produced. This 2-hydroxyethylamine is prepared according to Step 1 of Method B4c (
4S) -2-Isopropyl-4- (4-hydroxyphenylmethyl) -1,3-
Oxazolidine. Reduction of this oxazolidine by step 2 of method B4c
To give N-((1S) -1- (4-hydroxyphenylmethyl) -2-hydroxyethyl) -N-isobutylamine. Treatment of the resulting 2-hydroxyethylamine with SOCl ₂ according to Method B7c yields N-((1S) -1- (4-hydroxyphenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride. Was. 2-Ethyl-4-cyanophenylisothiocyanate was converted to N-((1S) according to Method C1b.
By reacting with (1- (4-hydroxyphenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride, (4S) -2- (2-ethyl-4
The HCl salt of -cyanophenylimino) -4- (4-hydroxyphenylmethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 144

[0599]

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(1S) -1- (4-Chlorophenylmethyl) -2-hydroxyethylamine was generated from the methyl ester of (L) -4-chlorophenylalanine as described in Method B1b. This 2-hydroxyethylamine was converted to (4S) -2-isopropyl-4- (4-chlorophenylmethyl) according to Step 1 of Method B4c.
It was changed to -1,3-oxazolidine. Reduction of this oxazolidine by method B4
Subjected according to step 2 of c to give N-((1S) -1- (4-chlorophenylmethyl) -2-hydroxyethyl) -N-isobutylamine. The resulting 2-hydroxyethylamine was converted to SOCl ₂ according to Method B7c.
To give N-((1S) -1- (4-chlorophenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride. 2-Ethyl-4-cyanophenylisothiocyanate was converted to N-((1S
) -1- (4-Chlorophenylmethyl) -2-chloroethyl) -N-isobutylammonium chloride to give (4S) -2- (2-ethyl-4-
The HCl salt of (cyanophenylimino) -4- (4-chlorophenylmethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 145

[0601]

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(1S) -1- (benzylthiomethyl) -2-hydroxyethylamine was generated from the methyl ester of (L) -S-benzylcysteine as described in Method B1b. This 2-hydroxyethylamine was converted to (4S) -2-isopropyl-4- (benzylthiomethyl) -1,3-oxazolidine according to Step 1 of Method B4c. The oxazolidine was reduced according to Method B4c, Step 2, to give N-((1S) -1- (benzylthiomethyl) -2-hydroxyethyl) -N-isobutylamine. The resulting 2-hydroxyethylamine is treated with SOCl ₂ according to Method B7c to give N- (
(1S) -1- (benzylthiomethyl) -2-chloroethyl) -N-isobutylammonium chloride was produced. By reacting 2-ethyl-4-cyanophenylisothiocyanate with N-((1S) -1- (benzylthiomethyl) -2-chloroethyl) -N-isobutylammonium chloride according to Method C1b, (4S) -2- The HCl salt of (2-ethyl-4-cyanophenylimino) -4- (benzylthiomethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 146

[0603]

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From the methyl ester of (D) -serine as described in Method B3a, (R)
The HCl salt of the methyl ester of -N-isobutylserine was formed. The ester is reacted with (4S) -2- (2-methyl-4-nitrophenylimino) -4- (methoxycarbonyl) according to method C2a by reacting with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate. The HCl salt of -3-isobutyl-1,3-thiazolidine was obtained. Heading 147

[0605]

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From the (L) -serine methyl ester to the (S) as described in Method B3a
The HCl salt of the methyl ester of -N-isobutylserine was formed. This ester is reacted with (4R) -2- (2-methyl-4-nitrophenylimino) -4- (methoxycarbonyl) according to method C2a by reacting with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate. The HCl salt of -3-isobutyl-1,3-thiazolidine was obtained. Heading 148

[0607]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. By reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2-methyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b ( 4R) -2- (2-Methyl-4-nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 149

[0609]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -Ot-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride is reacted according to Method C5b with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide ( 4R) -2- (2-methyl-4
-Nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-
Cyclopentyl-1,3-thiazolidine was obtained. Heading 150

[0611]

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The (1R, 2S) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. By reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to method C5b ( 4R) -2- (2-methyl-4
-Nitrophenylimino) -4-((1S) -1-t-butoxyethyl) -3-
Cyclopentyl-1,3-thiazolidine was obtained. Heading 151

[0613]

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The (1R, 2S) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. (1R, 2S) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride is reacted according to Method C5b with 2-methyl-4-nitrophenylisothiocyanate followed by isobutyl bromide ( 4R) -2- (2-Methyl-4-nitrophenylimino) -4-((1S) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 152

[0615]

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The (1R, 2S) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. By reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 4-cyano-2-methylphenylisothiocyanate followed by cyclopentyl bromide according to Method C5b ( 4R) -2- (4-cyano-2
-Methylphenylimino) -4-((1S) -1-t-butoxyethyl) -3-
Cyclopentyl-1,3-thiazolidine was obtained. Heading 153

[0617]

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The (1R, 2S) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (4R) -2 by reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 4-nitronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b.
-(4-Nitro-1-naphthylimino) -4-((1S) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 154

[0619]

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The (1R, 2S) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (4R) by reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b.
-2- (4-Nitro-1-naphthylimino) -4-((1S) -1-t-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. Heading 155

[0621]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 1-amino-5,6,7,8-
Tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate according to Method A2a. (1R, 2R)
-1-Methanesulfonyloxymethyl) -2- (t-butoxy) propaneammonium chloride is prepared according to Method C5b with 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate followed by cyclopentyl bromide. By reacting, (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4-((1R) -1-t-butoxyethyl) -3-cyclopentyl- 1,3-Thiazolidine was obtained. Heading 156

[0623]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -Ot-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 1-amino-5,6,7,8-
Tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate according to Method A2a. (1R, 2R)
-1-Methanesulfonyloxymethyl) -2- (t-butoxy) propaneammonium chloride is reacted with 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate followed by isobutyl bromide according to Method C5b. By reacting, (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphthy-1
-Ilimino) -4-((1R) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 157

[0625]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a. (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t
-Butoxy) propaneammonium chloride is reacted according to method C5b with 2-isopropyl-4-nitrophenylisothiocyanate followed by isobutyl bromide to give (4R) -2- (2-isopropyl-4-nitrophenylimino)
-4-((1R) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 158

[0627]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -Ot-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a. (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t
-Butoxy) propane ammonium chloride is reacted with (4R) -2- (2-isopropyl-4-nitrophenylimino) -4 according to method C5b by reaction with 2-isopropyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide. -((1R) -1-t-butoxyethyl) -3-cyclopentyl-1,
3-Thiazolidine was obtained. Heading 159

[0629]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. Reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b. Gave (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. Heading 160

[0631]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, give (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. Reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b. With (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-isobutyl-
1,3-Thiazolidine was obtained. Heading 161

[0633]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride was prepared according to Method C5b, followed by 2,3-dimethyl-4-nitrophenylisothiocyanate,
By reacting with ethyl-1-butyl, (4R) -2- (2,3-dimethyl-4
-Nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-
(2-Ethyl-1-butyl) -1,3-thiazolidine was obtained. Heading 162

[0635]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 1-amino-4-cyano-5,
6,7,8-Tetrahydronaphthalene is converted to 4-cyano-5,6 according to Method A2b.
, 7,8-tetrahydronaphthyl isothiocyanate. (1R, 2
R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride is reacted with 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate followed by cyclopentyl bromide according to method C5b. Thus, (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1-t-butoxyethyl) -3-cyclopentyl-1
, 3-thiazolidine. Heading 163

[0637]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 1-amino-4-cyano-5,
6,7,8-Tetrahydronaphthalene is converted to 4-cyano-5,6 according to Method A2b.
, 7,8-tetrahydronaphthyl isothiocyanate. (1R, 2
R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride is reacted with 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate followed by isobutyl bromide according to method C5b. Thus, (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine I got Heading 164

[0639]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. By reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2-methyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b ( 4R) -2- (2-Methyl-4-nitrophenylimino) -4-((1R) -1-t-butoxy) -3-isobutyl-1,3-thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (2-methyl-4-nitrophenylimino).
-4-((1R) -1-Hydroxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 165

[0641]

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From the dicyclohexylamine salt of (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a to give (1R, 2S) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (4R) by reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b.
-2- (4-Nitro-1-naphthylimino) -4-((1S) -1-t-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (4-nitro-1-naphthylimino) -4-((1S) -1-hydroxyethyl) -3-cyclopentyl-1, 3-Thiazolidine was obtained. Heading 166

[0643]

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From the dicyclohexylamine salt of (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a to give (1R, 2S) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. By reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to method C5b ( 4R) -2- (2-methyl-4
-Nitrophenylimino) -4-((1S) -1-t-butoxyethyl) -3-
Cyclopentyl-1,3-thiazolidine was obtained. Deprotection according to method D3a gives t-
By removing butyl ether, (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1S) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. . Heading 167

[0645]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride is reacted according to Method C5b with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide ( 4R) -2- (2-methyl-4
-Nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-
Cyclopentyl-1,3-thiazolidine was obtained. Deprotection according to method D3a gives t-
By removing butyl ether, (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. . Heading 168

[0647]

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From the dicyclohexylamine salt of (L)-(1S, 2S) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2S) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. By reacting (1R, 2S) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2-methyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to method C5b ( 4R) -2- (2-methyl-4
-Nitrophenylimino) -4-((1S) -1-t-butoxyethyl) -3-
Cyclopentyl-1,3-thiazolidine was obtained. Deprotection according to method D3a gives t-
By removing butyl ether, (4R) -2- (2-methyl-4-nitrophenylimino) -4-((1S) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. . Heading 169

[0649]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2-t-butyl-4-cyanoaniline was converted to 2-t-butyl-4-cyanophenylisothiocyanate according to Method A2b. (1R, 2R) -1-methanesulfonyloxymethyl)-
2- (t-Butoxy) propane ammonium chloride was converted to 2 according to Method C5b.
By reacting -t-butyl-4-cyanophenylisothiocyanate followed by cyclopentyl bromide, (4R) -2- (2-t-butyl-4-cyanophenylimino) -4-((1R) -1 -T-butoxyethyl) -3-cyclopentyl-
1,3-Thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a yields (4R) -2- (2-t-butyl-4-cyanophenylimino) -4-((1R) -1-hydroxyethyl) -3-. Cyclopentyl-1,3-
Thiazolidine was obtained. Heading 170

[0651]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2-t-butyl-4-cyanoaniline was converted to 2-t-butyl-4-cyanophenylisothiocyanate according to Method A2a. (1R, 2R) -1-methanesulfonyloxymethyl)-
2- (t-Butoxy) propane ammonium chloride was converted to 2 according to Method C5b.
By reacting -tert-butyl-4-cyanophenylisothiocyanate followed by isobutyl bromide, (4R) -2- (2-tert-butyl-4-cyanophenylimino) -4-((1R) -1 -T-butoxyethyl) -3-isobutyl-1,3-
Thiazolidine was obtained. Removal of the t-butyl ether by deprotection according to method D3a gives (4R) -2- (2-t-butyl-4-cyanophenylimino) -4-.
((1R) -1-hydroxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 171

[0653]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride was converted to 4-nitro-1- according to Method C5b.
By reacting with naphthyl isothiocyanate followed by cyclopentyl bromide (
4R) -2- (4-nitro-1-naphthylimino) -4-((1R) -1-t-
(Butoxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. Method D
Removal of t-butyl ether by deprotection according to 3a gives (4R) -2- (4
-Nitro-1-naphthylimino) -4-((1R) -1-hydroxyethyl)-
3-Cyclopentyl-1,3-thiazolidine was obtained. Heading 172

[0655]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 1-amino-5,6,7,8-
Tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate according to Method A2a. (1R, 2R)
-1-Methanesulfonyloxymethyl) -2- (t-butoxy) propaneammonium chloride is prepared according to Method C5b with 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate followed by cyclopentyl bromide. By reacting, (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4-((1R) -1-t-butoxyethyl) -3-cyclopentyl- 1,3-Thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4-((1R) -1 -Hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. Heading 173

[0657]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -Ot-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 1-amino-5,6,7,8-
Tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate according to Method A2a. (1R, 2R)
-1-Methanesulfonyloxymethyl) -2- (t-butoxy) propaneammonium chloride is reacted with 4-nitro-5,6,7,8-tetrahydronaphth-1-ylisothiocyanate followed by isobutyl bromide according to Method C5b. By reacting, (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphthy-1
-Ilimino) -4-((1R) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4-((1R) -1 -Hydroxyethyl) -3-
Isobutyl-1,3-thiazolidine was obtained. Heading 174

[0659]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a. (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t
-Butoxy) propaneammonium chloride is reacted according to method C5b with 2-isopropyl-4-nitrophenylisothiocyanate followed by isobutyl bromide to give (4R) -2- (2-isopropyl-4-nitrophenylimino)
-4-((1R) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (2-isopropyl-4-nitrophenylimino) -4- (
(1R) -1-Hydroxyethyl) -3-isobutyl-1,3-thiazolidine was obtained. Heading 175

[0661]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2-Isopropylaniline was converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Method A2a. (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t
-Butoxy) propane ammonium chloride is reacted with (4R) -2- (2-isopropyl-4-nitrophenylimino) -4 according to method C5b by reaction with 2-isopropyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide. -((1R) -1-t-butoxyethyl) -3-cyclopentyl-1,
3-Thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (2-isopropyl-4-nitrophenylimino).
-4-((1R) -1-Hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine was obtained. Heading 176

[0663]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -Ot-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. (1R, 2R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride was prepared according to Method C5b, followed by 2,3-dimethyl-4-nitrophenylisothiocyanate,
By reacting with ethyl-1-butyl, (4R) -2- (2,3-dimethyl-4
-Nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-
(2-Ethyl-1-butyl) -1,3-thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl).
-3- (2-Ethyl-1-butyl) -1,3-thiazolidine was obtained. Heading 177

[0665]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. Reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by isobutyl bromide according to Method C5b. With (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-isobutyl-
1,3-Thiazolidine was obtained. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-. Isobutyl-1,3-thiazolidine was obtained. Heading 178

[0667]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 2,3-Dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenylisothiocyanate according to Method A2b. Reacting (1R, 2R) -1-methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride with 2,3-dimethyl-4-nitrophenylisothiocyanate followed by cyclopentyl bromide according to Method C5b. Gave (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-t-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4-((1R) -1-hydroxyethyl) -3-. Cyclopentyl-1,3-thiazolidine was obtained. Heading 179

[0669]

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From the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -Ot-butylthreonine as described in Method B8a, (1R, 2R) -1-methanesulfonyl Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 1-amino-4-cyano-5,
6,7,8-Tetrahydronaphthalene is converted to 4-cyano-5,6 according to Method A2b.
, 7,8-tetrahydronaphthyl isothiocyanate. (1R, 2
R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride is reacted with 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate followed by cyclopentyl bromide according to method C5b. Thus, (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1-t-butoxyethyl) -3-cyclopentyl-1
, 3-thiazolidine. Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1-hydroxyethyl ) -3-Cyclopentyl-1,3-thiazolidine was obtained. Heading 180

[0671]

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The (1R, 2R) -1-methanesulfonyl from the dicyclohexylamine salt of (L)-(1S, 2R) -N- (benzyloxycarbonyl) -O-t-butylthreonine as described in Method B8a Oxymethyl) -2- (t-butoxy)
Propane ammonium chloride was formed. 1-amino-4-cyano-5,
6,7,8-Tetrahydronaphthalene is converted to 4-cyano-5,6 according to Method A2b.
, 7,8-tetrahydronaphthyl isothiocyanate. (1R, 2
R) -1-Methanesulfonyloxymethyl) -2- (t-butoxy) propane ammonium chloride is reacted with 4-cyano-5,6,7,8-tetrahydronaphthylisothiocyanate followed by isobutyl bromide according to method C5b. Thus, (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1-t-butoxyethyl) -3-isobutyl-1,3-thiazolidine I got Removal of t-butyl ether by deprotection according to method D3a gives (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4-((1R) -1-hydroxyethyl ) -3-Isobutyl-1,3-
Thiazolidine was obtained. Heading 181

[0673]

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According to method C2a, 2-amino-1,3-propanediol was added to excess SOC
Subsequent to l ₂ followed by reaction with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -4- (chloromethyl).
-1,3-Thiazolidine was obtained. This thiazolidine was converted to N- according to Method D13a.
After reacting with methylamine to produce 2- (2-methyl-4-nitrophenylimino) -4- (N-methylaminomethyl) -1,3-thiazolidine,
This was reacted with isobutyl bromide according to method D2a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (N-isobutyl-N-
Methylaminomethyl) -1,3-thiazolidine was obtained. Heading 182

[0675]

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According to method C2a, 2-amino-1,3-propanediol was added to excess SOC
Subsequent to l ₂ followed by reaction with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -4- (chloromethyl).
-1,3-Thiazolidine was obtained. The thiazolidine is reacted with dimethylamine according to Method D13a to give 2- (2-methyl-4-nitrophenylimino)
After producing -4- (N-isobutyl-N-methylaminomethyl) -1,3-thiazolidine, this is reacted with isobutyl bromide according to method D2a to give 2
-(2-methyl-4-nitrophenylimino) -3-isobutyl-4- (N, N
-Dimethylaminomethyl) -1,3-thiazolidine was obtained. Heading 183

[0677]

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According to method C2a, (L) -histidinol is reacted with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate to give (4S) -2- (
There was obtained 2-methyl-4-nitrophenylimino) -4- (1- (isobutylimidazolyl) methyl) -1,3-thiazolidine. This 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. Heading 184

[0679]

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(4S) -2- (by reacting (L) -histidinol with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate according to method C2a
There was obtained 2-methyl-4-nitrophenylimino) -4- (1- (isobutylimidazolyl) methyl) -1,3-thiazolidine. This 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. Heading 185

[0681]

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The 2-hydroxypropylamine was converted to 2-chloropropylammonium chloride according to Method B7a. Reacting 2-methyl-4-nitrophenylisothiocyanate with 2-chloropropylammonium chloride according to Method C1a gives 2- (2-methyl-4-nitrophenylimino) -5-methyl-
1,3-Thiazolidine was obtained. The thiazolidine was converted to 2-bromide according to Method D2g.
Reaction with methylprop-2-en-1-yl gives 2- (2-methyl-4-yl).
Nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -5
An HBr salt of -methyl-1,3-thiazolidine was obtained. Heading 186

[0683]

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Reacting 2-phenyl-2-hydroxyethylamine with isobutyraldehyde according to Step 1 of Method B4c to give 2-isopropyl-5-phenyl-1,
3-Oxazolidine was obtained. This oxazolidine was reduced according to step 2 of method B4c to give N-isobutyl-2-phenyl-2-hydroxyethylamine. Following SOCl ₂ 2-chloro-4- (trifluoromethyl) possible is reacted with phenyl isothiocyanate in 2 according to this ethanolamine method C2f (2-chloro-4- (trifluoromethyl) phenylimino) -
The HCl salt of 3-isobutyl-5-phenyl-1,3-thiazolidine was obtained. Heading 187

[0685]

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The 2-phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to step 1 of method B4c to give 2-isopropyl-5-phenyl-1,3-oxazolidine according to step 2 of method B4c. This oxazolidine was reduced according to step 2 of method B4c to give N-isobutyl-2-phenyl-2-hydroxyethylamine. This ethanolamine was used in Method C2f
To give 2- (2,3-dichloro-phenylimino) -3-isobutyl- by reacting with SOCl ₂ followed by 2,3-dichlorophenylisothiocyanate according to
5-Phenyl-1,3-thiazolidine was obtained. Heading 188

[0687]

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The reaction of 3-phenyl-2-hydroxypropylamine with isobutyraldehyde according to step 1 of method B4c gives 2-isopropyl-5-benzyl-1
, 3-Oxazolidine. Reduction of this oxazolidine by step 2 of method B4c
To give N-isobutyl-3-phenyl-2-hydroxypropylamine. This propanolamine is reacted with SOCl ₂ followed by 2,3-dichlorophenylisothiocyanate according to Method C2f to give 2- (
2,3-dichlorophenylimino) -3-isobutyl-5-benzyl-1,3-
The HCl salt of thiazolidine was obtained. Heading 189

[0689]

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Reacting 2-methyl-2-hydroxypropylamine with cyclohexanecarboxaldehyde according to Step 1 of Method B4c to give 2-cyclohexyl-5
5-Dimethyl-1,3-oxazolidine was obtained. The oxazolidine is reduced according to step 2 of method B4c to give N-cyclohexyl-2-methyl-
2-Hydroxypropylamine was obtained. This propanolamine is reacted according to method C2f with SOCl ₂ followed by 2,6-dichlorophenylisothiocyanate to give 2- (2,6-dichlorophenylimino) -3-cyclohexyl-
5,5-Dimethyl-1,3-thiazolidine was obtained. Heading 190

[0691]

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According to Method B5b, (1R) -1-cyclohexyl-1-ethylamine was converted to 1,
By reacting with 2-epoxy-2-methylpropane, N-((1R) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine was obtained. This N-((1R) -1-cyclohexyl-1-ethyl) -N
-(2,2-Dimethyl-2-hydroxyethyl) amine was converted to S according to Method C2f.
OCl ₂ followed by that reacted with 2,3-dichlorophenyl isothiocyanate 2- (2,3-dichlorophenyl imino) -3 - ((1R) -1-cyclohexyl-1-ethyl) -5,5-dimethyl - The HCl salt of 1,3-thiazolidine was obtained. Heading 191

[0693]

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According to Method B5b, (1S) -1-cyclohexyl-1-ethylamine was converted to 1,
By reacting with 2-epoxy-2-methylpropane, N-((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine was obtained. This N-((1S) -1-cyclohexyl-1-ethyl) -N
-(2,2-Dimethyl-2-hydroxyethyl) amine was converted to S according to Method C2f.
By reacting with OCl ₂ followed by 2,4-dichlorophenylisothiocyanate, 2- (2,4-dichlorophenylimino) -3-((1S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl- The HCl salt of 1,3-thiazolidine was obtained. Heading 192

[0696]

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According to Method B5b, (1S) -1-cyclohexyl-1-ethylamine was converted to 1,
By reacting with 2-epoxy-2-methylpropane, N-((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine was obtained. This N-((1S) -1-cyclohexyl-1-ethyl) -N
-(2,2-Dimethyl-2-hydroxyethyl) amine was converted to S according to Method C2f.
By reacting with OCl ₂ followed by 2,3-dichlorophenylisothiocyanate, 2- (2,3-dichlorophenylimino) -3-((1S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl- The HCl salt of 1,3-thiazolidine was obtained. Heading 193

[0697]

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The 2-methyl-2-hydroxypropylamine was converted to SOCl ₂ according to Method C2f.
Followed by reaction with 2,3-dichlorophenylisothiocyanate to give 2-
(2,3-Dichlorophenylimino) -5,5-dimethyl-1,3-thiazolidine was obtained. 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1,
The HCl salt of 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1,3-thiazolidine was obtained by reacting 3-thiazolidine with ethylene oxide according to Method B5b. Heading 194

[0699]

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The 2-methyl-2-hydroxypropylamine is converted to SOCl ₂ according to method C1a.
Followed by reaction with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -5,5-dimethyl-1,3.
-Thiazolidine was obtained. Heading 195

[0701]

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The 2-methyl-2-hydroxypropylamine is converted to SOCl ₂ according to method C1a.
Followed by reaction with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -5,5-dimethyl-1,3.
-Thiazolidine was obtained. The 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-
The HBr salt of dimethyl-1,3-thiazolidine was obtained. Heading 196

[0703]

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The 2-methyl-2-hydroxypropylamine is converted to SOCl ₂ according to method C1a.
Followed by reaction with 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -5,5-dimethyl-1,3.
-Thiazolidine was obtained. The thiazolidine was reacted with isobutyl bromide according to Method D2g to obtain 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5,5-dimethyl-1,3-thiazolidine. Heading 197

[0705]

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The 2-methyl-2-hydroxypropylamine is converted to SOCl ₂ according to method C1a.
Followed by reaction with 2,3-dichlorophenylisothiocyanate to give 2-
(2,3-Dichlorophenylimino) -5,5-dimethyl-1,3-thiazolidine was obtained. The thiazolidine was reacted with isobutyl bromide according to Method D2g to obtain 2- (2,3-dichlorophenylimino) -3-isobutyl-5,5-dimethyl-1,3-thiazolidine. Heading 198

[0707]

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The reaction of 2-methyl-2-hydroxypropylamine with cyclohexanecarboxaldehyde according to step 1 of method B4c gives 2-cyclohexyl-5
5-Dimethyl-1,3-oxazolidine was obtained. The oxazolidine is reduced according to step 2 of method B4c to give N-cyclohexyl-2-methyl-
2-Hydroxypropylamine was obtained. This propanolamine is reacted with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate according to method C2f to give 2- (2-methyl-4-nitrophenylimino) -3-cyclohexyl-5,5-dimethyl -1,3-Thiazolidine was obtained. Heading 199

[0709]

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The reaction of 2-methyl-2-hydroxypropylamine with cyclohexanecarboxaldehyde according to step 1 of method B4c gives 2-cyclohexyl-5
5-Dimethyl-1,3-oxazolidine was obtained. The oxazolidine is reduced according to step 2 of method B4c to give N-cyclohexyl-2-methyl-
2-Hydroxypropylamine was obtained. This propanolamine is reacted with SOCl ₂ followed by 2,3-dichlorophenylisothiocyanate according to Method C2f to give 2- (2,3-dichlorophenylimino) -3-cyclohexyl-
5,5-Dimethyl-1,3-thiazolidine was obtained. Heading 200

[0711]

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According to Method B5b, (1R) -1-cyclohexyl-1-ethylamine was converted to 1,
By reacting with 2-epoxy-2-methylpropane, N-((1R) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine was obtained. N-((1R) -1-cyclohexyl-1-ethyl) -N- (
2,2-Dimethyl-2-hydroxyethyl) amine was converted to SOC according to method C2f.
Following reaction with l ₂ followed by 2-methyl-4-nitrophenylisothiocyanate, 2- (2-methyl-4-nitrophenylimino) -3-((1R) -1-
H of cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazolidine
A Cl salt was obtained. Heading 201

[0713]

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According to Method B5b, (1S) -1-cyclohexyl-1-ethylamine was converted to 1,
By reacting with 2-epoxy-2-methylpropane, N-((1S) -1-cyclohexyl-1-ethyl) -N- (2,2-dimethyl-2-hydroxyethyl) amine was obtained. N-((1S) -1-cyclohexyl-1-ethyl) -N- (
2,2-Dimethyl-2-hydroxyethyl) amine was converted to SOC according to method C2f.
Subsequent to the reaction with l ₂ followed by 2-methyl-4-nitrophenylisothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3-((1S) -1-
H of cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazolidine
A Cl salt was obtained. Heading 202

[0715]

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[0715] N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine was obtained by reacting isopropylamine with 1,2-epoxy-2-methylpropane according to Method B5b. N-isopropyl-N- (2,2-dimethyl-2
- hydroxyethyl) amine by reacting with subsequently 2-methyl-4-nitrophenyl isothiocyanate in SOCl ₂ according to Method C2f 2- (2-methyl-4-nitrophenyl imino) -3-isopropyl-5,5 -Dimethyl-1,
3-Thiazolidine was obtained. Heading 203

[0717]

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The isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. N-isopropyl-N- (2,2-dimethyl-2
-Hydroxyethyl) amine was prepared according to method C2f following SOCl ₂ followed by 2,3-
By reacting with dichlorophenylisothiocyanate, 2- (2,3-dichlorophenylimino) -3-isopropyl-5,5-dimethyl-1,3-thiazolidine was obtained. Heading 204

[0719]

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[0720] N-isobutyl-N- (2,2-dimethyl-2-hydroxyethyl) amine was obtained by reacting isobutylamine with 1,2-epoxy-2-methylpropane according to Method B5b. 2- (2,4-Dichlorophenylimino) is obtained by reacting N-isobutyl-N- (2,2-dimethyl-2-hydroxyethyl) amine with SOCl ₂ followed by 2,4-dichlorophenylisothiocyanate according to method C2f. H of -3-isobutyl-5,5-dimethyl-1,3-thiazolidine
A Cl salt was obtained. Heading 205

[0721]

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The 1,1-dimethyl-2-hydroxyethylamine is converted to 1,1 according to Method B7a.
-Dimethyl-2-chloroethylammonium chloride. 2-Methyl-4-nitrophenylisothiocyanate is reacted with 1,1-dimethyl-2-chloroethylammonium chloride according to Method C1a to give 2- (2-
Methyl-4-nitrophenylimino) -4,4-dimethyl-1,3-thiazolidine was obtained. This thiazolidine was converted to 2-methylprop-2-bromobromide according to Method D2g.
By reacting with en-1-yl, 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-3- (2-methylprop-2-en-1-yl) -1
, 3-thiazolidine HBr salt was obtained. Heading 206

[0723]

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The methylaminoisobutyric acid was converted to the HCl salt of methylaminoisobutyrate according to step 1 of method B1c. The ester was reduced according to Step 2 of Method B1c to give 3-hydroxy-2-methyl-2-propylamine.
This 2-hydroxyethylamine is treated with SOCl ₂ according to Method B7b and then with ₂ -methyl-3-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -4. , 4-Dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-3-isobutyl-1,3-thiazolidine. Heading 207

[0725]

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[0727] 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 1- (Cyclohexylamino) -1-hydroxymethylcyclopentane was synthesized as described in Method B4a. This 2-hydroxyethylamine is treated with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 3-cyclohexyl-2- (2
-Methyl-4-nitrophenylimino) -1-thia-3-azaspiro [4.4]
I got Nonan. Heading 208

[0727]

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The 2-ethylaniline was converted to 2-ethylacetanilide according to Step 1 of Method A2a. This acetanilide was converted to 2-ethyl- according to Step 2 of Method A2a.
Changed to 4-nitroacetanilide. Deprotection of this acetanilide by Method A
Subjected according to step 3 of 2a to give 2-ethyl-4-nitroaniline. This aniline was converted to 2-ethyl-4-nitrophenylisothiocyanate according to Step 3 of Method A2a. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. This 2-hydroxyethylamine is reacted with SOCl ₂ according to Method B7a to give 1-amino-1
The HCl salt of-(chloromethyl) cyclopentane was obtained. This 2-chloroethylamine is reacted with 2-ethyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-ethyl-4-nitrophenylimino) -1-thia-3-azaspiro [4.4]. I got Nonan. This 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. Heading 209

[0729]

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[0739] 2-n-Propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. This aniline was converted to 4-iodo-2- according to Method A2b.
Changed to n-propylphenyl isothiocyanate. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c.
The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine is reacted with 4-iodo-2-n-propylphenylisothiocyanate according to Method C1a to give 2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro [ 4.4] Nonane was obtained.
This 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 was obtained. The phenyl iodide is reacted with CuCN according to Method D7a to give 3-cyclopentyl-2- (4-cyano-2-n-propylphenylimino) -1-thia-3-azaspiro [4.4.
] Nonan was obtained. Heading 210

[0731]

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[0732] 2-Isopropylaniline was converted to 4-iodo-2-isopropylaniline according to Method A5a. This aniline was converted to 4-iodo-2- according to Method A2b.
Changed to isopropylphenylisothiocyanate. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c.
The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine is reacted with 4-iodo-2-isopropylphenylisothiocyanate according to Method C1a to give 2- (4-iodo-2-isopropylphenylimino) -1-thia-3-azaspiro [4.4]. I got Nonan.
This thiazolidine is reacted with cyclopentyl bromide according to method D2b to give 3-cyclopentyl-2- (4-iodo-2-isopropylphenylimino)-.
1-Thia-3-azaspiro [4.4] nonane was obtained. The phenyl iodide is reacted with CuCN according to Method D7a to give 3-cyclopentyl-2- (4-cyano-2-isopropylphenylimino) -1-thia-3-azaspiro [4.4.
] Nonan was obtained. Heading 211

[0733]

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[0734] 2-t-Butylaniline was converted to 4-iodo-2-t-butylaniline according to Method A5a. This aniline was converted to 4-iodo-2-t- according to Method A2b.
Changed to butylphenyl isothiocyanate. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. This 2
- it is reacted with SOCl ₂ according to the method B7a the hydroxyethylamine 1-amino-1- (chloromethyl) to give the HCl salt of cyclopentane. This 2-
2- (4-Iodo-2-t-butylphenylimino) -1-thia-3-azaspiro [4.4 is obtained by reacting chloroethylamine with 4-iodo-2-t-butylphenylisothiocyanate according to method C1a. ] Nonan was obtained. This thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2- (4-iodo-2-t-butylphenylimino) -1-thia-3.
-Azaspiro [4.4] nonane was obtained. The phenyl iodide is reacted with CuCN according to Method D7a to give 3-cyclopentyl-2- (4-cyano-2-t
-Butylphenylimino) -1-thia-3-azaspiro [4.4] nonane was obtained. Heading 212

[0735]

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[0736] 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. This amino alcohol was prepared according to Step 1 of Method B4a, 2
-Methylcyclopentanone to give 13-aza-1-methyl-6-oxodispiro [4.2.4.1] tridecane, which was then added to NaBH ₄
In accordance with step 2 of method B4a to give 1- (2-methylcyclopentyl) amino-1- (hydroxymethyl) cyclopentane. The 2-hydroxyethylamine is reacted with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 3- (2-methylcyclopentyl) -2- (2-methyl-4-nitrophenylimino. ) -1-
Thia-3-azaspiro [4.4] nonane was obtained. Heading 213

[0737]

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[0738] 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. This 2-chloroethylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4]. I got Nonan. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-.
Thia-1-azaspiro [4.4] nonane was obtained. Heading 214

[0739]

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The 2-ethylaniline was converted to 2-ethylacetanilide according to Step 1 of Method A2a. This acetanilide was converted to 2-ethyl- according to Step 2 of Method A2a.
Changed to 4-nitroacetanilide. Deprotection of this acetanilide by Method A
Subjected according to step 3 of 2a to give 2-ethyl-4-nitroaniline. This aniline was converted to 2-ethyl-4-nitrophenylisothiocyanate according to Step 3 of Method A2a. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. This 2-hydroxyethylamine is reacted with SOCl ₂ according to Method B7a to give 1-amino-1
The HCl salt of-(chloromethyl) cyclopentane was obtained. The 2-chloroethylamine is reacted with 2-ethyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-ethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4]. I got Nonan. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-ethyl-4
-Nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. Heading 215

[0741]

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The 2-n-propylaniline was converted to 2-n-propylacetanilide according to Step 1 of Method A2a. This acetanilide was converted to 2-n-propyl-4-nitroacetanilide according to Step 2 of Method A2a. The acetanilide is deprotected according to step 3 of method A2a to give 2-n-propyl-
4-Nitroaniline was obtained. The aniline is converted to 2-n according to Step 3 of Method A2a.
-Propyl-4-nitrophenylisothiocyanate. Method B1c
1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in (1). The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. This 2-chloroethylamine is converted to 2-n-propyl- according to Method C1a.
By reacting with 4-nitrophenylisothiocyanate, 2- (2-n-propyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine is 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 was obtained. Heading 216

[0734]

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The 2-isopropylaniline was converted to 2-isopropylacetanilide according to Step 1 of Method A2a. This acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to method A2a, step 2. The acetanilide is deprotected according to step 3 of method A2a to give 2-isopropyl-
4-Nitroaniline was obtained. This aniline was converted to 2-isopropyl-4-nitrophenylisothiocyanate according to Step 3 of Method A2a. Method B1c
1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in (1). The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine was converted to 2-isopropyl- according to method C1a.
Reaction with 4-nitrophenylisothiocyanate gave 2- (2-isopropyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-isopropyl-4-nitrophenylimino).
3-Thia-1-azaspiro [4.4] nonane was obtained. Heading 217

[0745]

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[0746] 2,3-Dimethyl-4-nitroaniline was synthesized as described in Method A4a. The aniline was converted to 2,3-dimethyl-4 as described in Method A2d.
-Nitrophenyl isothiocyanate. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7e to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. This 2
-Chloroethylamine is reacted with 2,3-dimethyl-4-nitrophenylisothiocyanate according to method C1c to give 2- (2,3-dimethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4. 4] Nonane was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-isopropyl-4-nitrophenylimino) -3-thia-1.
-Azaspiro [4.4] nonane was obtained. Heading 218

[0747]

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According to method A2a, step 3, 3-methyl-4-nitroaniline is converted to 3-methyl-
Changed to 4-nitrophenyl isothiocyanate. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine is reacted with 3-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4]. I got Nonan. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2.
-(3-Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4
. 4] Nonane was obtained. Heading 219

[0749]

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The 1-amino-5,6,7,8-tetrahydronaphthalene was converted to 1-acetamino-5,6,7,8-tetrahydronaphthalene according to step 1 of method A2a. This acetanilide is prepared according to Step 2 of Method A2a by 1-acetamino-4
-Nitro-5,6,7,8-tetrahydronaphthalene. The acetanilide is deprotected according to Step 3 of Method A2a to give 1-amino-
4-Nitro-5,6,7,8-tetrahydronaphthalene was obtained. This aniline is converted to 4-nitro-5,6,7,8-tetrahydro-1- according to step 3 of method A2a.
It was changed to naphthyl isothiocyanate. 1 as described in method B1c.
-Amino-1- (hydroxymethyl) cyclopentane was synthesized. The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine is reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthylisothiocyanate according to Method C1a to give 2- (4-nitro-5.
6,7,8-Tetrahydro-1-naphthylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. The 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] Nonane was obtained. Heading 220

[0751]

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1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7e to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. This 2-chloroethylamine was reacted with 4-cyanophenylisothiocyanate according to Method C1a to give 2- (4-cyanophenylimino) -3-thia-1-azaspiro [4.4] nonane. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2.
-(4-Cyanophenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. Heading 221

[0753]

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[0756] 4-Cyano-2-methylaniline was synthesized as described in Method A1a. This aniline was converted to 4-cyano-2-methylphenylisothiocyanate according to step 3 of method A2a. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. This 2-hydroxyethylamine is reacted with SOCl ₂ according to Method B7a to give 1-amino-1
The HCl salt of-(chloromethyl) cyclopentane was obtained. The 2-chloroethylamine is reacted with 4-cyano-2-methylphenylisothiocyanate according to Method C1a to give 2- (4-cyano-2-methylphenylimino) -1-thia-3-azaspiro [4.4]. I got Nonan. This thiazolidine is reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-iodo-2).
-Methylphenylimino) -1-thia-3-azaspiro [4.4] nonane was obtained. Heading 222

[0755]

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[0756] 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to Method C1a to give 2- (4-cyano-2-methylphenylimino) -3-thia-1-azaspiro [4.4]. I got Nonan. This thiazolidine is reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-cyano-2-methylphenylimino) -1-.
Thia-3-azaspiro [4.4] nonane was obtained. Heading 223

[0757]

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[0758] 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7a to give the HCl salt of 1-amino-1- (chloromethyl) cyclopentane. 1-Amino-4-cyanonaphthalene is converted to Step 3 of Method A2a.
To 4-cyano-1-naphthyl isothiocyanate according to 2-
Chloroethylamine was reacted with 4-cyano-1-naphthylisothiocyanate according to Method C1a to give 2- (4-cyano-1-naphthylimino) -1-thia-3-azaspiro [4.4] nonane. This thiazolidine is reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-cyano-
1-Naphthylimino) -1-thia-3-azaspiro [4.4] nonane was obtained. Heading 224

[0759]

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The 2,3-dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline as described in Method A5a. This aniline was converted to 2,3-dimethyl-4-iodophenylisothiocyanate according to Step 3 of Method A2a.
1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. This 2-hydroxyethylamine was converted to S according to Method B7e.
The HCl salt of 1-amino-1- (chloromethyl) cyclopentane was obtained by reaction with OCl ₂ . The 2-chloroethylamine was converted to 2,3- according to Method Cle.
By reacting with dimethyl-4-iodophenylisothiocyanate, 2- (2
, 3-Dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [4
. 4] Nonane was obtained. This thiazolidine was reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2- (2,3-dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [4.4] nonane. . The phenyl iodide is reacted with CuCN according to Method D7a to give 3-isobutyl-2-
(2,3-Dimethyl-4-cyanophenylimino) -1-thia-3-azaspiro [4.4] nonane was obtained. Heading 225

[0761]

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[0978] 2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3- according to Step 3 of Method A2a.
Changed to dimethyl-4-iodophenylisothiocyanate. 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine the followed according to the method C2a in SOCl ₂ by reacting 2,3-dimethyl-4-iodophenyl isothiocyanate 2- (2,3-dimethyl-4-iodophenyl) -1- thia -3-Azaspiro [4.4] nonane was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give 3-isobutyl-2- (2,3-dimethyl-4-.
Iodophenylimino) -1-thia-3-azaspiro [4.4] nonane was obtained.
The phenyl iodide is reacted with trimethylsilylacetylene according to Step 1 of Method D8a to give 3-isobutyl-2- (2,3-dimethyl-4- (2-trimethylsilylethynyl) phenylimino) -1-thia-3-azaspiro. [4.4
] Nonan was obtained. The silylacetylene is deprotected according to Step D2 of Method D8a to give 3-isobutyl-2- (2,3-dimethyl-4-ethynylphenylimino) -1-thia-3-azaspiro [4.4] nonane I got Heading 226

[0763]

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[0764] 2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline as described in Method A5a. This aniline was converted to 2,3-dimethyl-4-iodophenylisothiocyanate according to Step 3 of Method A2a.
1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. This 2-hydroxyethylamine was converted to S according to Method B7e.
The HCl salt of 1-amino-1- (chloromethyl) cyclopentane was obtained by reaction with OCl ₂ . The 2-chloroethylamine was converted to 2,3- according to Method Cle.
By reacting with dimethyl-4-iodophenylisothiocyanate, 2- (2
, 3-Dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [4
. 4] Nonane was obtained. This thiazolidine was reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2- (2,3-dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [4.4] nonane. . Heading 227

[0765]

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[0766] 2,3-Dimethylaniline was converted to 2,3-dimethyl-6-nitroaniline as described in Method A4a. This aniline was converted to 2, according to Method A2d.
Changed to 3-dimethyl-6-nitrophenyl isothiocyanate. Method B1
1-Hydroxymethylcyclopentanamine was prepared according to c. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. HCl of 1-chloromethylcyclopentanamine
The salt is reacted with 2,3-dimethyl-6-nitrophenylisothiocyanate according to method C1e to give 2- (2,3-dimethyl-6-nitrophenylimino)
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine is 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 was obtained. Heading 228

[0767]

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Reduction of 2-cyano-5-nitrothiophene according to Method A1a gave 2-amine-5-cyanothiophene. This aminothiophene was converted to 5-cyano-1-thiophene isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 5-cyano-1-thiopheneisothiocyanate according to method C1e to give 2- (5-cyanothienylimino) -3-thia-1-.
Azaspiro [4.4] nonane was obtained. This thiazolidine was reacted with isobutyl bromide according to Method D2a to give 2- (5-cyanothienylimino) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane. Heading 229

[0769]

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According to method A2c, 6-amino-3-cyano-2,3-dimethylpyridine was converted to 3
-Cyano-2,3-dimethyl-6-pyridylisothiocyanate.
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 3-cyano-2,3-dimethyl-6-pyridylisothiocyanate according to method C1e to give 2- (3-cyano-2,3-dimethyl-
6-Pyridylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine is reacted with isobutyl bromide according to Method D2h to give 2- (
3-cyano-2,3-dimethyl-6-pyridylimino) -1-isobutyl-3-
Thia-1-azaspiro [4.4] nonane was obtained. Heading 230

[0771]

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[0772] 1- (Hydroxymethyl) cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is sequentially converted to SOCl ₂ according to Method C2a.
Then, by reacting with 2-methyl-4-nitrophenylisothiocyanate, 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [
4.4] Nonane was obtained. This thiazolidine was converted to 1-bromo-2 according to Method D2a.
-(2-methyl-4-nitrophenylimino) -1- (2-ethyl-1-butyl) -3-thia-1-azaspiro [4.4] by reacting with -ethylbutane.
I got Nonan. Heading 231

[0773]

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[0774] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with 3-bromopentane according to 2b, 2- (4-cyano-2-ethylphenylimino) -1- (3-pentyl) -3-thia-1-azaspiro [4
. 4] Nonane was obtained. Heading 232

[0775]

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[0776] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with isopropyl bromide according to 2e, 2- (2-methyl-4-nitrophenylimino) -1- (2-propyl) -3-thia-1-azaspiro [4.
4] Nonane was obtained. Heading 233

[0777]

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[0778] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with 3-bromo-2-methylpropene according to 2e, 2- (2-methyl-4-nitrophenylimino) -1- (2-methylprop-1-en-3-
Il) -3-thia-1-azaspiro [4.4] nonane was obtained. Heading 234

[0779]

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[0780] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with allyl bromide according to 2e, 2- (2-methyl-4-nitrophenylimino) -1- (prop-1-en-3-yl) -3-thia-1-azaspiro [4.4] I got Nonan. Heading 235

[0781]

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[0782] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
2e to give 2- (2-methyl-
4-nitrophenylimino) -1- (cyclopropylmethyl) -3-thia-1-
Azaspiro [4.4] nonane was obtained. Heading 236

[0783]

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[0784] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
Reaction with cyclohexylmethyl bromide according to 2e gives 2- (2-methyl-
4-nitrophenylimino) -1- (cyclohexylmethyl) -3-thia-1-
Azaspiro [4.4] nonane was obtained. Heading 237

[0785]

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[0786] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
Reaction with 2- (bromomethyl) tetrahydro-2H-pyran according to 2e gives 2- (2-methyl-4-nitrophenylimino) -1- (tetrahydro-2
H-pyran-2-ylmethyl) -3-thia-1-azaspiro [4.4] nonane was obtained. Heading 238

[0787]

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[0788] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with 2- (2-bromoethyl) -1,3-dioxane according to 2e, 2- (2-methyl-4-nitrophenylimino) -1- (2- (1,3-dioxan-2-yl) Ethyl) -3-thia-1-azaspiro [4.4] nonane was obtained. Heading 239

[0789]

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[0790] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to method C1e to give 2- (2-methyl-4-nitrophenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclobutyl bromide according to 2e, 2- (2-methyl-4-nitrophenylimino) -1-cyclobutyl-3-thia-1-azaspiro [4.4] is obtained.
I got Nonan. Heading 240

[0791]

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[0792] 1- (Hydroxymethyl) cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is reacted with SOCl ₂ followed by 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (
2-Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4
] Nonan was obtained. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Heading 241

[0793]

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[0793] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
The 2-hydroxyethylamine is treated according to method C2a with SOCl ₂ followed by 2-
By reacting with methyl-4-nitrophenylisothiocyanate, 2- (2-
Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. This thiazolidine is oxidized with m-CPBA according to Method D4a to give 3- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane 3- Oxide was obtained. Heading 242

[0795]

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[0796] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
The 2-hydroxyethylamine is treated according to method C2a with SOCl ₂ followed by 2-
By reacting with methyl-4-nitrophenylisothiocyanate, 2- (2-
Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. This thiazolidine is oxidized with m-CPBA according to Method D4a to give 3- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane 3,3 3-Dioxide was obtained. Heading 243

[0797]

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The 2-ethylaniline was protected as 2-ethylacetanilide according to Step 1 of Method A2a. This acetamide was converted to 2-ethyl-4-nitroaniline, which was deprotected according to step 2 of method A2a. This aniline was converted to 2-ethyl-4-nitrophenylisothiocyanate according to Step 3 of Method A2a. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine was converted to 2-ethyl-4- according to Method Cle.
By reacting with nitrophenyl isothiocyanate, 2- (2-ethyl-4-
Nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained.
This thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2-ethyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Heading 244

[0799]

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The 3-methyl-4-nitroaniline was converted to 3-methyl-nitroaniline according to Step 3 of Method A2a.
Changed to 4-nitrophenyl isothiocyanate. According to method B1c, 1-
Hydroxymethylcyclopentanamine was prepared. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine was prepared according to method C1e.
Was reacted with 3-methyl-4-nitrophenylisothiocyanate to obtain 2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. This thiazolidine is reacted with cyclopentyl bromide according to Method D2b to give 2- (3-methyl-4-nitrophenylimino) -1
-Cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 245

[0801]

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The 2,3-dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, Step 1. This acetamide is converted to 2,3-dimethyl-
After conversion to 4-nitroaniline, it was deprotected according to step 2 of method A2a. The aniline is converted to 2,3-dimethyl- according to Step 3 of Method A2a.
Changed to 4-nitrophenyl isothiocyanate. According to method B1c, 1-
Hydroxymethylcyclopentanamine was prepared. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine was prepared according to method C1e.
To give 2- (2,3-dimethyl-4-nitrophenylimino) -3-thia-1.
-Azaspiro [4.4] nonane was obtained. This 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. . Heading 246

[0803]

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The 2,3-dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, Step 1. This acetamide is converted to 2,3-dimethyl-
After conversion to 6-nitroaniline, it was deprotected according to step 2 of method A2a. The aniline is converted to 2,3-dimethyl- according to Step 3 of Method A2a.
Changed to 6-nitrophenyl isothiocyanate. According to method B1c, 1-
Hydroxymethylcyclopentanamine was prepared. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine was prepared according to method C1e.
To give 2- (2,3-dimethyl-6-nitrophenylimino) -3-thia-1.
-Azaspiro [4.4] nonane was obtained. This 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. . Heading 247

[0805]

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[0806] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. Reaction of the HCl salt of 1-chloromethylcyclopentanamine with 4-iodophenylisothiocyanate according to Method C1e affords 2- (4-iodophenylimino) -3-thia-1-azaspiro [4.4] nonane. Was. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodophenylimino) -1-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. Heading 248

[0807]

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[0808] 4-Cyano-2-methylaniline was prepared according to Method A1a. This aniline was converted to 4-cyano-2-methylphenylisothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-methylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-methylphenylimino) -3-thia-1-azaspiro. [4.4] Nonane was obtained. This 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. Heading 249

[0809]

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[0810] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. Heading 250

[0811]

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[0812] 4-Iodo-2-n-propylaniline is converted to 4-iodo-2 according to Method A2b.
-N-propylphenylisothiocyanate. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is converted to SOCl ₂ and 4-iodo-2-n sequentially according to Method C2a.
-Propylphenylisothiocyanate to give 2- (4-iodo-
2-n-Propylphenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2-n-propylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. . The phenyl iodide is reacted with CuCN according to Method D7a to give 2- (4-cyano-2-
(n-Propylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 251

[0813]

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[0814] 4-Iodo-2-isopropylaniline is converted to 4-iodo-2 according to Method A2b.
-Isopropylphenylisothiocyanate. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. This 2-hydroxyethylamine is reacted sequentially with SOCl ₂ and 4-iodo-2-isopropylphenylisothiocyanate according to Method C2a to give 2- (4-iodo-
2-isopropylphenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2-isopropylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The phenyl iodide is reacted with CuCN according to Method D7a to give 2- (4-cyano-2-
(Isopropylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 252

[0815]

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[0816] 4-Iodo-2,3-dimethylaniline is converted to 4-iodo-2 according to Method A2b.
, 3-dimethylphenylisothiocyanate. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. This 2-hydroxyethylamine was sequentially treated with SOCl ₂ and 4-iodo-2,3 according to Method C2a.
-Dimethylphenylisothiocyanate to give 2- (4-iodo-
(2,3-Dimethylphenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-iodo-2,3-dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. . The phenyl iodide is reacted with CuCN according to Method D7a to give 2- (4-cyano-2,
3-Dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 253

[0817]

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[0838] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Heading 254

[0819]

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[0820] 4-Cyano-2-methylaniline was prepared according to Method A1a. This aniline was converted to 4-cyano-2-methylphenylisothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-methylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-methylphenylimino) -3-thia-1-azaspiro. [4.4] Nonane was obtained. This 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. Headline 255

[0821]

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[0827] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. This benzoic acid was prepared according to method D1.
Oa was converted to 2- (4-acetyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Heading 256

[0823]

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[0827] Methyl 4-amino-3-methylbenzoate was converted to 4-methoxycarbonyl-2-methylphenylisothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine is reacted sequentially with SOCl ₂ and 4-methoxycarbonyl-2-methylphenylisothiocyanate according to Method C2a to give 2- (
4-Methoxycarbonyl-2-methylphenylimino) -3-thia-1-azaspiro [4.4] nonane was obtained. This 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. Heading 257

[0825]

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[0827] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. This benzoic acid was prepared according to method D6.
By reacting with methylamine according to b, 2- (4- (N-methylcarbamoyl) -2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 258

[0827]

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[0827] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. This benzoic acid was prepared according to method D6.
b) to give 2- (4- (N, N-dimethylcarbamoyl) -2-ethylphenylimino) -1-cyclopentyl-3-thia-
1-Azaspiro [4.4] nonane was obtained. Heading 259

[0829]

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The 2,3-dichloroaniline was converted to 2,3-dichloroanilide according to Step 1 of Method A3a. This formanilide was converted to 2,3-dichlorophenylisocyanide dichloride according to step 2 of method A3a. Method B1c
Was synthesized according to the following procedure. This 2-hydroxyethylamine was prepared according to Step 1 of Method B4d using 13-aza-6-
Oxazispiro [4.2.4.1] tridecane. This oxazolidine was subjected to reductive ring opening according to Step 2 of Method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. This substitution 2
-Hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (acetylthiomethyl) cyclopentane according to Step 1 of Method C6c. This thioacetate was hydrolyzed according to Method C6c, Step 2, to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. This 2-thioethylamine is reacted with 2,3-dichlorophenylisocyanide dichloride according to method C6c to give 2- (2,3-dichlorophenylimino) -1-.
Cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 260

[0831]

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The 2- (trifluoromethyl) aniline was converted to 2- (trifluoromethyl) formanilide according to Step 1 of Method A3a. Use this formanilide in Method A
Converted to 2- (trifluoromethyl) phenyl isocyanide dichloride according to step 2 of 3a. The HCl salt of 1-hydroxymethylcyclopentanamine was synthesized according to Method B1c. This 2-hydroxyethylamine was converted to 13-aza-6-oxadisspiro [4.2.4.1] tridecane according to Step 1 of Method B4d. This oxazolidine was subjected to reductive ring opening according to Step 2 of Method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. This substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Step 1 of Method C6c. This thioacetate was hydrolyzed according to Method C6c, Step 2, to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. The 2-thioethylamine is reacted with 2- (trifluoromethyl) phenyl isocyanide dichloride according to method C6c to give 2-thioethylamine.
(2- (Trifluoromethyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 261

[0832]

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The 4- (trifluoromethyl) aniline was converted to 4- (trifluoromethyl) formanilide according to Method A3a, Step 1. Use this formanilide in Method A
It was converted to 4- (trifluoromethyl) phenyl isocyanide dichloride according to step 2 of 3a. The HCl salt of 1-hydroxymethylcyclopentanamine was synthesized according to Method B1c. This 2-hydroxyethylamine was converted to 13-aza-6-oxadisspiro [4.2.4.1] tridecane according to Step 1 of Method B4d. This oxazolidine was subjected to reductive ring opening according to Step 2 of Method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. This substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Step 1 of Method C6c. This thioacetate was hydrolyzed according to Method C6c, Step 2, to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. This 2-thioethylamine is reacted with 4- (trifluoromethyl) phenyl isocyanide dichloride according to method C6c to give 2-thioethylamine.
(4- (Trifluoromethyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 262

[0835]

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The 2-chloro-3-methylaniline was converted to 2-chloro-3-methylaniline according to Step 1 of Method A3a.
Changed to 3-methylformanilide. This formanilide was converted to 2-chloro-3-methylphenylisocyanide dichloride according to Step 2 of Method A3a. HC of 1-hydroxymethylcyclopentanamine according to Method B1c
1 salt was synthesized. This 2-hydroxyethylamine was converted to 13-aza-6-oxadisspiro [4.2.4.1] tridecane according to Step 1 of Method B4d. This oxazolidine was subjected to reductive ring opening according to Step 2 of Method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was treated with 1 according to Step 1 of Method C6c.
-(Cyclopentylamino) -1- (thioacetylmethyl) cyclopentane. This thioacetate was hydrolyzed according to Method C6c, Step 2, to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. The 2-thioethylamine is reacted with 2-chloro-3-methylphenyl isocyanide dichloride according to Method C6c to give 2- (2-chloro-3
-Methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [
4.4] Nonane was obtained. Heading 263

[0837]

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The 3- (trifluoromethyl) aniline was converted to 3- (trifluoromethyl) formanilide according to Method A3a, Step 1. Use this formanilide in Method A
It was converted to 3- (trifluoromethyl) phenyl isocyanide dichloride according to step 2 of 3a. The HCl salt of 1-hydroxymethylcyclopentanamine was synthesized according to Method B1c. This 2-hydroxyethylamine was converted to 13-aza-6-oxadisspiro [4.2.4.1] tridecane according to Step 1 of Method B4d. This oxazolidine was subjected to reductive ring opening according to Step 2 of Method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. This substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Step 1 of Method C6c. This thioacetate was hydrolyzed according to Method C6c, Step 2, to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. This 2-thioethylamine is reacted with 3- (trifluoromethyl) phenyl isocyanide dichloride according to method C6c to give 2-thioethylamine.
(3- (Trifluoromethyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 264

[0839]

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The 3-chloro-2-methylaniline was converted to 3-chloro-methyl according to Step 1 of Method A3a.
Changed to 2-methylformanilide. This formanilide was converted to 3-chloro-2-methylphenylisocyanide dichloride according to Step 2 of Method A3a. HC of 1-hydroxymethylcyclopentanamine according to Method B1c
1 salt was synthesized. This 2-hydroxyethylamine was converted to 13-aza-6-oxadisspiro [4.2.4.1] tridecane according to Step 1 of Method B4d. This oxazolidine was subjected to reductive ring opening according to Step 2 of Method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was treated with 1 according to Step 1 of Method C6c.
-(Cyclopentylamino) -1- (thioacetylmethyl) cyclopentane. This thioacetate was hydrolyzed according to Method C6c, Step 2, to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. This 2-thioethylamine is reacted with 3-chloro-2-methylphenyl isocyanide dichloride according to Method C6c to give 2- (3-chloro-2
-Methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [
4.4] Nonane was obtained. Heading 265

[0841]

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The 2,3-dichloro-4-methylaniline was converted to 2,3 according to Step 1 of Method A3a.
-Dichloro-4-methylformanilide. This formanilide was converted to 2,3-dichloro-4-methylphenylisocyanide dichloride according to step 2 of method A3a. The HCl salt of 1-hydroxymethylcyclopentanamine was synthesized according to Method B1c. This 2-hydroxyethylamine is converted to method B
Converted to 13-aza-6-oxadisspiro [4.2.4.1] tridecane according to step 1 of 4d. This oxazolidine was subjected to reductive ring opening according to Step 2 of Method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. This substituted 2-hydroxyethylamine was prepared according to method C6c.
1- (cyclopentylamino) -1- (thioacetylmethyl) according to step 1 of
Changed to cyclopentane. This thioacetate was hydrolyzed according to Method C6c, Step 2, to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane. The 2-thioethylamine was converted to 2 according to Method C6c.
Is reacted with 2,3-dichloro-4-methylphenylisocyanide dichloride to give 2- (2,3-dichloro-4-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. Obtained. Heading 266

[0843]

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[0838] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine is reacted sequentially with SOCl ₂ and 4-bromo-2-methylphenylisothiocyanate according to Method C2a to give 2-
(4-Bromo-2-methylphenylimino) -3-thia-1-azaspiro [4.
4] Nonane was obtained. This 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. Heading 267

[0845]

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[0838] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile is reduced according to method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3.
-Thia-1-azaspiro [4.4] nonane was obtained. Heading 268

[0847]

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[0848] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile is reduced according to method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3.
-Thia-1-azaspiro [4.4] nonane was obtained. This aldehyde is prepared according to method D12.
a) reacting with triethyl phosphonoacetate according to a.
((1E) -2-Ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 269

[0849]

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[0850] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile is reduced according to method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3.
-Thia-1-azaspiro [4.4] nonane was obtained. This aldehyde is prepared according to method D12.
2- (2-Ethyl-4-((1E)
-2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1-
Azaspiro [4.4] nonane was obtained. Heading 270

[0851]

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[0851] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile is reduced according to method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3.
-Thia-1-azaspiro [4.4] nonane was obtained. This aldehyde is prepared according to method D12.
a) reacting with triethyl phosphonoacetate according to a.
((1E) -2-Ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. This ester was saponified according to Method D6a to give 2- (2-ethyl-4-((1E)-).
2-carboxyvinyl) phenylimino) -1-cyclopentyl-3-thia-1
-Azaspiro [4.4] nonane was obtained. Heading 271

[0853]

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[0851] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile is reduced according to method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3.
-Thia-1-azaspiro [4.4] nonane was obtained. This aldehyde is prepared according to method D12.
c to react with malononitrile to give 2- (2-ethyl-4- (2,2
-Dicyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 272

[0855]

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[0981] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile is reduced according to method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3.
-Thia-1-azaspiro [4.4] nonane was obtained. This aldehyde is prepared according to method D12.
reacting with diethyl (2-oxopropyl) phosphonate according to a.
(2-ethyl-4-((1E) -2-acetylvinyl) phenylimino) -1-
Cyclopentyl-3-thia-1-azaspiro [4.4] nonane was obtained. Heading 273

[0857]

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[0858] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine was converted to the HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt of 1-chloromethylcyclopentanamine is reacted with 4-cyano-2-ethylphenylisothiocyanate according to method C1e to give 2- (4-cyano-2-ethylphenylimino)-.
3-Thia-1-azaspiro [4.4] nonane was obtained. This thiazolidine was used in Method D
By reacting with cyclopentyl bromide according to 2b, 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.
4] Nonane was obtained. The nitrile is reduced according to method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3.
-Thia-1-azaspiro [4.4] nonane was obtained. This aldehyde is prepared according to method D12.
d) to react with acetonitrile to give 2- (2-ethyl-4-((1E
) -2-Cyanovinyl) phenylimino) -1-cyclopentyl-3-thia-1
-Azaspiro [4.4] nonane was obtained. Heading 274

[0859]

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[0838] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine is reacted sequentially with SOCl ₂ and 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2-
(2-Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.
4] Nonane was obtained. This 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. Heading 275

[0861]

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[0861] 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c.
This 2-hydroxyethylamine is reacted sequentially with SOCl ₂ and 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2-
(2-Methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.
4] Nonane was obtained. This 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. . Heading 276

[0863]

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[0838] 1-Aminocyclohexane-1-carboxylic acid was protected as benzyloxycarbonylamine according to Step 1 of Method B1a. 1- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid is reduced according to step 2 of method B1a to give 1- (benzyloxycarbonylamino) -1- (
(Hydroxymethyl) cyclohexane was formed. The carbamate was deprotected according to Method B1a, Step 3, to give 1-amino-1- (hydroxymethyl) cyclohexane. This 2-hydroxyethylamine is treated sequentially with SOCl ₂ and 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-.
Thia-1-azaspiro [4.5] decane was obtained. This thiazolidine is subjected to alkyl substitution with isobutyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenylimino) -1-isobutyl-3-thia-1-azaspiro [4.5] decane. Was. Heading 277

[0865]

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The 2-methyl-4-nitroaniline was converted to 2-methyl-nitroaniline according to Step 1 of Method A3a.
Changed to 4-nitroformanilide. This formanilide was converted to 2-methyl-4-nitrophenylisocyanide dichloride according to Step 2 of Method A3a. 3-Aminotetrahydro-2H-pyran- according to Step 1 of Method B1b
The 3-carboxylic acid was changed to its methyl ester. Methyl 3-aminotetrahydro-2H-pyran-3-carboxylate was reduced according to Method B1b, Step 2, to give 3-amino-3- (hydroxymethyl) tetrahydro-2H-pyran. This 2-hydroxyethylamine is reacted with isobutyraldehyde according to Step 1 of Method B4c to give 2-isopropyl-1-aza-3.
, 7-Dioxaspiro [4.5] decane. This oxazolidine was reduced to give 3-isobutylamino-3- (hydroxymethyl) tetrahydro-2H-pyran. This substituted 2-hydroxyethylamine was converted to 3-isobutylamino-3- (acetylthiomethyl) according to Step 1 of Method C6c.
Changed to tetrahydro-2H-pyran. Saponification of this thioacetate by Method C
Followed according to step 2 of 6c to give 3-isobutylamino-3- (thiomethyl) tetrahydro-2H-pyran. This 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-thiaspiro [4.5] decane was obtained. Heading 278

[0867]

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The 2-methyl-4-nitroaniline was converted to the 2-methyl-nitroaniline according to Step 1 of Method A3a.
Changed to 4-nitroformanilide. This formanilide was converted to 2-methyl-4-nitrophenylisocyanide dichloride according to Step 2 of Method A3a. 4-Aminotetrahydro-2H-pyran- according to Step 1 of Method B1b
The 4-carboxylic acid was changed to its methyl ester. Methyl 4-aminotetrahydro-2H-pyran-4-carboxylate was reduced according to Method B1b, Step 2, to give 4-amino-4- (hydroxymethyl) tetrahydro-2H-pyran. This 2-hydroxyethylamine is reacted with isobutyraldehyde according to Step 1 of Method B4c to give 2-isopropyl-1-aza-3.
, 8-Dioxaspiro [4.5] decane. This oxazolidine was reduced to give 4-isobutylamino-4- (hydroxymethyl) tetrahydro-2H-pyran. This substituted 2-hydroxyethylamine was converted to 4-isobutylamino-4- (acetylthiomethyl) according to Step 1 of Method C6c.
Changed to tetrahydro-2H-pyran. Saponification of this thioacetate by Method C
Followed according to step 2 of 6c to give 4-isobutylamino-4- (thiomethyl) tetrahydro-2H-pyran. This 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-thiaspiro [4.5] decane was obtained. Heading 279

[0869]

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Method B using 2-amino-2-norbornane-1-carboxylic acid as a mixture of isomers
Converted to the N-benzyloxycarbonyl analog according to step 1 of 1a. 1-
(Benzyloxycarbonylamino) -2-norbornane-1-carboxylic acid is reduced according to Step 2 of Method B1a to give 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) -2-norbornane. Was. The carbamate was deprotected according to step 3 of method B1a to give 1-amino-1- (hydroxymethyl) -2-norbornane. This 2-hydroxyethylamine was alkyl-substituted with isobutyl bromide according to Method B2a to give N-isobutyl-1-amino-1- (hydroxymethyl) -2-norbornane. This alkyl-substituted 2-hydroxyethylamine was prepared according to method B7a.
To give the HCl salt that is N- isobutyl-2-chloroethylamine treatment with SOCl ₂ according to. This chloroethylamine was converted to 2-methyl- according to Method 1Ca.
Treatment with 4-nitrophenylisothiocyanate gives 2- (2-methyl-4
-Nitrophenylimino) -3-isobutylspiro [1,3-thiazolidine-4
, 3'-Bicyclo [3.2.1] octane] was obtained. Heading 280

[0871]

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[0887] N- (t-Butoxycarbonyl)-(L) -valine was converted to (S) -3- (t-butoxycarbonylamino) -1-diazo-4-methylpentan-2-one according to Method B6a, Step 1. Was changed to. This diazo compound was converted to methyl (R) -3- (t-butoxycarbonylamino) -4-methylpentanoate according to Step 2 of Method B6a. The ester was reduced according to step 3 of method B6a to give (R) -3- (t-butoxycarbonylamino) -4-methylpentan-1-ol. The carbamate was converted to (R) -3-amino-1-chloro-4-methylpentane by deprotection according to method B7e.
The 3-chloropropylamine is treated with 2-methyl-4-nitrophenylisothiocyanate according to Method C2a to give (4R) -2- (2-methyl-4-
(Nitrophenylimino) -4-isopropyl-1,3-thiazine was obtained. The thiazine is subjected to alkyl substitution with isobutyl bromide according to Method D2a to give HCl of (4R) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1,3-thiazine. Salt was obtained. Heading 281

[0873]

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[0887] The 3-aminopropanol was reacted with butyraldehyde according to Step 1 of Method B9a to give 2-isopropyltetrahydro-1,3-oxazine. This oxazine was reduced according to Step 2 of Method B9a to give N-isobutyl-3-hydroxypropylamine. To give the HCl salt that is N- isobutyl-3-chloro-propylamine is reacted with SOCl ₂ according to step 3 of the method B9a this 3-hydroxypropyl amine. This 3-chloropropylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyltetrahydro-1,3-thiazine. Obtained. Heading 282

[0875]

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The 4-aminobutanol was reacted with butyraldehyde according to Step 1 of Method B9a to give 2-isopropyltetrahydro-1,3-oxazepine. The 1,3-oxepine is reduced according to step 2 of method B9a to give N
-Isobutyl-3-hydroxybutylamine was obtained. To give the HCl salt that is N- isobutyl-3-chloro-butyl-amine is reacted with SOCl ₂ according to step 3 of the 3-hydroxybutyl amine method B9a. The 3-chlorobutylamine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyltetrahydro-1,3-thiazepine. Was. Heading 283

[0877]

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[0887] The 2- (3-methyl-4-methyl-4-nitrophenylisothiocyanate is reacted with isobutylamine followed by chloroacetic acid according to Method C8a to give 2- (3-methyl-4-
(Nitrophenylimino) -3-isobutyl-1,3-thiazolidine-4-one was obtained. Heading 284

[0877]

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The reaction of 3-methyl-4-nitrophenylisothiocyanate with benzylamine followed by chloroacetic acid according to Method C8a gives 2- (3-methyl-4-nitrophenylimino) -3- (phenylmethyl)- 1,3-thiazolidine-4-
Got on. Heading 285

[0881]

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[0891] 3-Methyl-4-nitrophenylisothiocyanate was treated with 2 according to Method C8a.
-Methyl-1-butylamine followed by reaction with chloroacetic acid to give 2- (3-
Methyl-4-nitrophenylimino) -3- (2-methylbutyl) -1,3-thiazolidine-4-one was obtained. Heading 286

[0883]

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[0884] 3-Methyl-4-nitrophenylisothiocyanate was treated with 1 according to Method C8a.
-Amino-1-cyclohexylethane followed by chloroacetic acid to give 2
-(3-Methyl-4-nitrophenylimino) -3- (1-cyclohexylethyl) -1,3-thiazolidine-4-one was obtained. Heading 287

[0885]

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The 2- (2-methyl-4-methyl-4-nitrophenylisothiocyanate was reacted with isobutylamine followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-
(Nitrophenylimino) -3-isobutyl-1,3-thiazolidine-4-one was obtained. Heading 288

[0887]

Embedded image

[0888] 2-Methyl-4-nitrophenylisothiocyanate was treated with 2 according to Method C8a.
-Methyl-1-butylamine followed by reaction with chloroacetic acid to give 2- (2-
Methyl-4-nitrophenylimino) -3- (2-methylbutyl) -1,3-thiazolidine-4-one was obtained. Heading 289

[0889]

Embedded image

The reaction of 2-methyl-4-nitrophenylisothiocyanate with benzylamine followed by chloroacetic acid according to Method C8a affords 2- (2-methyl-4-nitrophenylimino) -3- (phenylmethyl)- 1,3-thiazolidine-4-
Got on. Heading 290

[0891]

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[0993] The 2- (2-methyl-2-nitrophenylisothiocyanate is reacted with isobutylamine followed by α-chloropropionic acid according to Method C8a to give 2- (2-
Methyl-4-nitrophenylimino) -3-isobutyl-5-methyl-1,3-
Thiazolidin-4-one was obtained. Heading 291

[0893]

Embedded image

[0981] 2-Methyl-4-nitrophenylisothiocyanate was treated with 1 according to Method C8a.
-Amino-1-cyclohexylethane followed by chloroacetic acid to give 2
-(2-Methyl-4-nitrophenylimino) -3- (1-cyclohexylethyl) -1,3-thiazolidine-4-one was obtained. Heading 292

[0895]

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According to method C8a, 2-methyl-4-nitrophenylisothiocyanate was converted to (
By reacting with 1S) -1-amino-1-cyclohexylethane followed by chloroacetic acid, 2- (2-methyl-4-nitrophenylimino) -3-((1S) -1
-Cyclohexylethyl) -1,3-thiazolidine-4-one. Heading 293

[0897]

Embedded image

According to method C8a, 2-methyl-4-nitrophenylisothiocyanate was converted to (
By reacting with 1R) -1-amino-1-cyclohexylethane followed by chloroacetic acid, 2- (2-methyl-4-nitrophenylimino) -3-((1R) -1
-Cyclohexylethyl) -1,3-thiazolidine-4-one. Heading 294

[0899]

Embedded image

The 2-methyl-4-nitrophenyl isothiocyanate is reacted with isobutylamine followed by α-chloro-α-phenylacetic acid according to Method C8a to give 2-
(2-methyl-4-nitrophenylimino) -3-isobutyl-5-phenyl-
1,3-Thiazolidin-4-one was obtained. Heading 295

[0901]

Embedded image

The 2-methyl-4-nitrophenylisothiocyanate was prepared according to Method C8a by (
By reacting 1R) -1-amino-1-cyclohexylethane followed by α-chloropropionic acid, 2- (2-methyl-4-nitrophenylimino) -3- (
(1R) -1-cyclohexylethyl) -5-methyl-1,3-thiazolidine-
The 4-one was obtained. Heading 296

[0903]

Embedded image

The 2-methyl-4-nitrophenylisothiocyanate was prepared according to Method C8a (
1R) -1-amino-1-cyclohexylethane followed by α-chloro-α-phenylacetic acid to give 2- (2-methyl-4-nitrophenylimino)-
3-((1R) -1-cyclohexylethyl) -5-phenyl-1,3-thiazolidine-4-one was obtained. Heading 297

[0905]

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The 2-methyl-4-nitrophenylisothiocyanate was prepared according to Method C8a by (
By reacting 1S) -1-amino-1-cyclohexylethane followed by α-chloropropionic acid, 2- (2-methyl-4-nitrophenylimino) -3- (
(1S) -1-cyclohexylethyl) -5-methyl-1,3-thiazolidine-
The 4-one was obtained. Heading 298

[0907]

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The 2-methyl-4-nitrophenylisothiocyanate was prepared according to Method C8a (
1S) -1-Amino-1-cyclohexylethane followed by α-chloro-α-phenylacetic acid to give 2- (2-methyl-4-nitrophenylimino)-
3-((1S) -1-cyclohexylethyl) -5-phenyl-1,3-thiazolidine-4-one was obtained. Heading 299

[0909]

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[0910] 2-Methyl-4-nitrophenylisothiocyanate was treated with 2 according to Method C8a.
-Ethyl-1-butylamine is reacted with α-chloropropionic acid to give 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -5-methyl-1. , 3-Thiazolidine-4-one. Heading 300

[0911]

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The 2- (2-methyl-4-nitrophenylimino)-is obtained by reacting 2-methyl-4-nitrophenylisothiocyanate with isobutylamine followed by 2-chloro-4-methylpentanoic acid according to method C8a. 3-isobutyl-5-isobutyl-1,3-thiazolidine-4-one was obtained. Heading 301

[0913]

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[0914] 2-Methyl-4-nitrophenylisothiocyanate was treated with 2 according to Method C8a.
-Ethyl-1-butylamine followed by 2-chloro-4-methylpentanoic acid to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5- (2-ethyl-1- (Butyl) -1,3-thiazolidine-4-one.
Heading 302

[0915]

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[0916] 2-Methyl-4-nitrophenylisothiocyanate was treated with 2 according to Method C8a.
-Methylbutylamine followed by reaction with 2-chloro-4-methylpentanoic acid to give 2- (2-methyl-4-nitrophenylimino) -3- (2-butyl)-
5-Isobutyl-1,3-thiazolidine-4-one was obtained. Heading 303

[0917]

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[0918] 2-Methyl-4-nitrophenylisothiocyanate was treated with 2 according to Method C8a
-Methylbutylamine followed by 2-chloro-3-methylbutanoic acid to give 2- (2-methyl-4-nitrophenylimino) -3- (2-butyl) -5.
-Isopropyl-1,3-thiazolidine-4-one was obtained. Heading 304

[0919]

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[0920] 2-Methyl-4-nitrophenylisothiocyanate is reacted with isobutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to give 2
-(2-Methyl-4-nitrophenylimino) -3-isobutyl-5-isopropyl-1,3-thiazolidine-4-one was obtained. Heading 305

[0921]

Embedded image

[0922] 2-Methyl-4-nitrophenylisothiocyanate was prepared according to Method C8a by (
By reacting with 2S) -2-methyl-1-butylamine followed by chloroacetic acid, 2- (2-methyl-4-nitrophenylimino) -3-((2S) -2-methyl-1-butyl)- 1,3-Thiazolidin-4-one was obtained. Heading 306

[0923]

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[0924] 2-Methyl-4-nitrophenylisothiocyanate was treated with 2 according to Method C8a.
-Ethyl-1-butylamine is reacted with 2-chloro-3-methylbutanoic acid to give 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -5-. Isopropyl-1,3-thiazolidine-4-one was obtained.
Heading 307

[0925]

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[0926] From the methyl ester of (D) -serine as described in Method B3a, (R)
The HCl salt of the methyl ester of -N-isobutylserine was prepared. The alcohol is reacted with SOCl ₂ according to Method B7b and then with 2-methyl-4-nitrophenylisothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4. -Methylene-1,3-
Thiazolidine-5-one was obtained. Heading 308

[0927]

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[0928] 2,4,6-Trichlorophenylisothiocyanate was treated with 2 according to Method C8a.
-Butylamine was reacted with chloroacetic acid to give 2- (2,4,6-trichlorophenylimino) -3- (2-butyl) -1,3-thiazolidine-4-one. Heading 309

[0929]

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The reaction of 3,4-dichlorophenylisothiocyanate with 2-methylbutylamine followed by chloroacetic acid according to Method C8a gives 2- (3,4-dichlorophenylimino) -3- (2-butyl) -1,3 -Thiazolidine-4-one was obtained. Heading 310

[0931]

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[0932] The ethyl ester of N-isobutylglycine is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C11a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3. -Thiazolidine-5-
Got on. Heading 311

[0933]

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[0932] 2-Methyl-4-nitrophenylisothiocyanate was treated with 2 according to Method C8a.
-Ethyl-1-butylamine followed by reaction with chloroacetic acid to give 2- (2-
Methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1,
3-Thiazolidin-4-one was obtained. Heading 312

[0935]

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The (4S) -2- (by reacting the ethyl ester of N-isobutylleucine with 2-methyl-4-nitrophenylisothiocyanate according to Method C11a
2-Methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine-5-one was obtained. Heading 313

[0937]

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[0938] The ethyl ester of N-isobutylproline is reacted with 2-methyl-4-nitrophenylisothiocyanate according to Method C11a to give 4- (2-methyl-4-nitrophenylimino) -1-oxoperhydro-2. -Thiapyrrolidine was obtained. Heading 314

[0939]

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[0939] The t-form of N- (t-butoxycarbonyl) glycine according to step 1 of method B8b
The butyl ester is reacted with 3-bromo-2-methylpropene to give N- (t
-Butoxycarbonyl) -N- (2-methylprop-2-enyl) glycine t
-Butyl ester was obtained. The ester was reduced according to Method B8b, Step 2, to give N- (t-butoxycarbonyl) -N- (2-hydroxyethyl) -1-amino-2-methylprop-2-ene. Method B of this alcohol
8b by treatment with p-toluenesulfonyl chloride according to step 3
(T-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-
2-Methylprop-2-ene was obtained. The carbamate was deprotected according to step 4 of method B8b to give N- (2-tosyloxyethyl) -2-methylprop-2-en-1-ammonium trifluoroacetate. This tosylate is reacted with 2-methyl-4-nitrophenylisocyanate according to Method C5a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -1,3-. Oxazolidine was obtained. Heading 315

[0941]

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The (L) -valine methyl ester was reduced according to Step 1 of Method B1b to give (1S) -1- (hydroxymethyl) -2-methylpropylamine. The 2-hydroxyethylamine is reacted with isobutyraldehyde according to step 1 of method B4c to give (4S) -2,4-diisopropyl-1,3-
Oxazolidine was obtained. The oxazolidine is reduced according to step 2 of method B4c to give (1S) -1- (hydroxymethyl) -N-isobutyl-2
-Methylpropylamine was obtained. This substituted 2-hydroxyethylamine was prepared using Method B
Reacting with SOCl ₂ according to 7b to give (1S) -1- (chloromethyl)-
N-isobutyl-2-methylpropylamine was obtained. This chloroethylamine is reacted with 2-methyl-4-nitrophenylisocyanate according to method C4a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1,3. -Oxazolidine was obtained. Heading 316

[0943]

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The (L) -leucine methyl ester was reduced according to Step 2 of Method B1b to give (1S) -1- (hydroxymethyl) -3-methylbutylamine. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Step 1 of Method B4c to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine. This oxazolidine was reduced according to step 2 of method B4c to give (1S) -1- (hydroxymethyl) -N-isobutyl-3-methylbutylamine. This substituted 2-hydroxyethylamine was reacted with SOCl ₂ according to Method B7b to give (1S) -1- (chloromethyl) -N-isobutyl-3-methylbutylamine. This chloroethylamine is reacted with 2-methyl-4-nitrophenylisocyanate according to method C4a to give (4S) -2- (2-methyl-4-nitrophenylimino) -3.
, 4-Diisobutyl-1,3-oxazolidine were obtained. Heading 317

[0945]

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The (L) -leucine methyl ester was reduced according to Step 2 of Method B1b to give (1S) -1- (hydroxymethyl) -3-methylbutylamine. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Step 1 of Method B4c to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine. This oxazolidine was reduced according to step 2 of method B4c to give (1S) -1- (hydroxymethyl) -N-isobutyl-3-methylbutylamine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Step 1 of Method A3a. This formanilide is converted to SOCl ₂ and S
By reacting with O ₂ Cl ₂ , 4-cyano-2-ethylphenyl isocyanide dichloride was obtained. The substituted 2-hydroxyethylamine was converted to 4 according to Method C7b.
-Cyano-2-ethylphenylisocyanide dichloride to react (
4S) -2- (4-Cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-oxazolidine was obtained. Heading 318

[0947]

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[0948] Reaction of 2-amino-2-methyl-1-propanol with cyclopentanone according to Step 1 of Method B4b gives 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane. Was. This oxazolidine is reduced by step 2 of method B4b.
To give N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine. 2-Methyl-4-nitroaniline was converted to 2-methyl-4-nitroformanilide according to Step 1 of Method A3a. This formanilido is reacted with SOCl ₂ and SO ₂ Cl ₂ according to step 2 of the method A3a give 2-methyl-4-nitrophenyl isocyanide two mistakes chloride.
The substituted 2-hydroxyethylamine is reacted with 2-methyl-4-nitrophenyl isocyanide dichloride according to Method C7a to give 2- (2-methyl-
4-nitrophenylimino) -3-cyclopentyl-4,4-dimethyl-1,3
-Oxazolidine was obtained. Heading 319

[0949]

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[0950] Reaction of 2-amino-2-methyl-1-propanol with cyclopentanone according to step 1 of method B4b gives 4-aza-3,3-dimethyl-1-oxaspiro [4.4] nonane. Was. This oxazolidine is reduced by step 2 of method B4b.
To give N-cyclopentyl- (1,1-dimethyl-2-hydroxyethyl) amine. 4-Amino-3-ethylbenzonitrile was converted to method A
Conversion to 4-cyano-2-ethylformanilide according to step 1 of 3a. To give 4-cyano-2-ethylphenyl isocyanide two mistakes chloride is reacted with SOCl ₂ and SO ₂ Cl ₂ according to step 2 of the formanilide method A3a. The substituted 2-hydroxyethylamine was converted to 4-cyano- according to Method C7a.
By reacting with 2-ethylphenylisocyanide dichloride, 2- (4-cyano-2-ethylphenylimino) -3-cyclopentyl-4,4-dimethyl-
1,3-Oxazolidine was obtained. Heading 320

[0951]

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[0981] 1-Aminocyclopentanecarboxylic acid was converted to its methyl ester according to step 1 of method B1c. The ester was reduced according to Method B1c, Step 2, to give 1-hydroxymethylcyclopentanamine. This hydroxyethylamine was reacted with cyclopentanone according to Step 1 of Method B4d to give 6-aza-12-oxadisspiro [4.1.4.2] tridecane. This oxazolidine was reduced according to step 2 of method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. This substituted 2-hydroxyethylamine is converted to SOCl ₂ according to Method B7b.
And 1- (cyclopentylamino) -1- (chloromethyl) cyclopentane was obtained. This 2-chloroethylamine is reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4 .4] Nonane was obtained. Heading 321

[0953]

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[0954] 1-Aminocyclopentanecarboxylic acid was converted to its methyl ester according to Step 1 of Method B1c. The ester was reduced according to Method B1c, Step 2, to give 1-hydroxymethylcyclopentanamine. This 2-hydroxyethylamine was reacted with cyclobutanone according to Step 1 of Method B4a to give 5-aza-12-oxadisspiro [3.1.4.2] dodecane. This oxazolidine was reduced according to step 2 of method B4a 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. The 2-chloroethylamine was converted to 2-methyl- according to Method C4a.
By reacting with 4-nitrophenyl isocyanate, 1-cyclobutyl-2-
(2-Methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4
. 4] Nonane was obtained. Heading 322

[0955]

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[0956] 1-Aminocyclopentanecarboxylic acid is prepared according to Method B1c, Step 1,
It was changed to tilester. This ester is reduced according to step 2 of method B1c.
To give 1-hydroxymethylcyclopentanamine. This
Of hydroxyethylamine with cyclohexanone according to Step 1 of Method B4a
6-aza-13-oxadisspiro [4.1.5.2] tetradeca
I got it. Subjecting the oxazolidine to a reduction according to step 2 of method B4a
1- (cyclohexylamino) -1- (hydroxymethyl) cyclopenta
I got it. This substituted 2-hydroxyethylamine is converted to SOCl according to Method B7b. _Two With 1- (cyclohexylamino) -1- (chloromethyl) cy
Clopentane was obtained. This 2-chloroethylamine was prepared according to Method C4a.
1-cyclohexyl by reacting with tyl-4-nitrophenyl isocyanate
2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azas
Pyro [4.4] nonane was obtained. Heading 323

[0957]

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[0958] 1-Aminocyclopentanecarboxylic acid was converted to its methyl ester according to step 1 of method B1c. The ester was reduced according to Method B1c, Step 2, to give 1-hydroxymethylcyclopentanamine. This hydroxyethylamine was reacted with cyclopentanone according to Step 1 of Method B4d to give 6-aza-12-oxadisspiro [4.1.4.2] tridecane. This oxazolidine was reduced according to step 2 of method B4d to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Step 1 of Method A3a. This formanilide is reacted with SOCl ₂ and SO ₂ Cl ₂ according to step 2 of method A3a to give 4-
Cyano-2-ethylphenyl isocyanide dichloride was obtained. The substituted 2-hydroxyethylamine is reacted with 2-methyl-4-nitrophenylisocyanide dichloride according to Method C7a to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro. [4.4] Nonane was obtained. Heading 324

[0959]

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The (1) from the methyl ester of (L) -leucine was as described in Method B1b.
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in step 1-2 of method B4c (
2S) -4-methyl-2- (isobutylamino) pentanol. This alcohol was converted to N- (1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. The 4-nitrophenyl isothiocyanate was converted to N- (
1S) -1- (chloromethyl) -3-methylbutyl) -N- (isobutyl) ammonium chloride to give 2- (4-nitrophenylthio) -1,
5-Diisobutylimidazoline was obtained. Heading 325

[0961]

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The (1) -methyl ester of (L) -leucine was converted to (1) as described in Method B1b.
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Methyl-4-nitrophenylisothiocyanate is prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. . This 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. Heading 326

[0963]

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[0965] According to Method B1b, the methyl ester of (L) -leucine was converted to (1R) -1- (
(Hydroxymethyl) -3-methylbutylamine. This 2-hydroxyethylamine was converted to (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride as described in Method B7a. 2-methyl-5
By reacting -nitrophenylisothiocyanate with (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride according to method C1a (
4R) -2- (2-methyl-5-nitrophenylimino) -4-isobutyl-1
, 3-thiazolidine. This thiazolidine is reacted with isobutyl bromide according to Method D2a to give (4R) -2- (N-isobutyl-N- (2-methyl-
HCl of 5-nitrophenyl) amino) -4-isobutyl-1,3-thiazoline
Salt was obtained. Heading 327

[0965]

Embedded image

The (1) -methyl ester of (L) -leucine was converted to (1) as described in Method B1b.
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
-Methyl-4-nitrophenylisothiocyanate is prepared according to method C1a (1S
) -1- (Chloromethyl) -3-methylbutanammonium chloride to give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. . This 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. Heading 328

[0967]

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The (1) -methyl ester of (L) -leucine was converted to (1) as described in Method B1b.
S) -1- (Hydroxymethyl) -3-methylbutylamine was produced. This 2-hydroxyethylamine was prepared as described in Method B7a for (1S) -1-
(Chloromethyl) -3-methylbutane ammonium chloride. 2
, 3-Dichlorophenylisothiocyanate was converted to (1S) -1 according to Method C1a.
-(Chloromethyl) -3-methylbutane ammonium chloride to give (4S) -2- (2,3-dichlorophenylimino) -4-isobutyl-1
, 3-thiazolidine. This thiazolidine is reacted with 3-bromopentane according to method D2a to give (4S) -2- (N- (3-pentyl) -2-methyl-4-nitrophenylamino) -4-isobutyl-1,3-thiazoline. I got

[0969]

[Table 1]

[0970]

[Table 2]

[0971]

[Table 3]

[0972]

[Table 4]

[0973]

[Table 5]

[0974]

[Table 6]

[0975]

[Table 7]

[0976]

[Table 8]

[0977]

[Table 9]

[0978]

[Table 10]

[0979]

[Table 11]

[0980]

[Table 12]

[0981]

[Table 13]

[0982]

[Table 14]

[0983]

[Table 15]

[0984]

[Table 16]

[0985]

[Table 17]

[0986]

[Table 18]

[0987]

[Table 19]

[0988]

[Table 20]

[0989]

[Table 21]

[0990]

[Table 22]

[0991]

[Table 23]

[0992]

[Table 24]

[0993]

[Table 25]

[0994]

[Table 26]

[0995]

[Table 27]

[0996]

[Table 28]

[0997]

[Table 29]

[0998]

[Table 30]

[0999]

[Table 31]

[1000]

[Table 32]

[1001]

[Table 33]

[1002]

[Table 34]

(A) Finnigan LCQ MS detector and 2 × 300 mm Phenom
Hewlett Pack with enex 3 uM C-18 column
ard 1100 HPLC; flow rate 1.0 mL / min; buffer A: 0.02% TF
A / 2% CH ₃ CN / water, Buffer B: 0.018% TFA / 98% CH 3 CN / water; 100% Buffer A at 1 min hold, over 3 minutes 100% 100% Buffer A Gradient to buffer B, hold at 100% buffer B for 1 minute, gradient from 100% buffer B to 100% buffer A over 0.5 minutes, hold at 100% buffer A for 1.5 minutes. (B) UV-DII dual wavelength detector (254 and 220nm) and 4x100mm D
Ranin Dyna with ynmax 3 uM C-18 column
max HPLC; flow rate 1.5 mL / min; buffer A: 0.5% TFA / water; buffer B: 0.5% TFA / CH ₃ CN; 100% buffer A to 100 over 10 minutes.
Gradient to% buffer B, hold at 100% buffer B for 5 minutes. (C) UV detector (210 nm) and 4 × 125 mm Nucleosil 3
Hewlett Packard 109 with uM C-18 column
0 HPLC; flow rate 2.0 mL / min; buffer A: 0.01 mol% H ₃ PO ₄ / water;
Buffer B: 0.01 mol% H ₃ PO ₄ / CH ₃ CN; 10% buffer B for 1 minute, 8
Gradient from 10% buffer B to 90% buffer B over 4 min. Gradient from 90% buffer B to 10% buffer B over 4 min. (D) UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dy
Lanin Dynam with namax 8 uM C-18 column
ax HPLC; flow rate 18 mL / min; buffer A: 0.1% TFA / 99.9% water; buffer B: 0.1% TFA / 99.9% CH ₃ CN; 30% buffer over 25 minutes Gradient from B to 100% buffer B, hold at 100% buffer B for 30 minutes. (E) UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dy
Lanin Dynam with namax 8 uM C-18 column
ax HPLC; flow rate 18 mL / min; buffer A: 0.1% TFA / 99.9% water; buffer B: 0.1% TFA / 99.9% CH ₃ CN; 50% buffer over 25 minutes Gradient from B to 60% buffer B, gradient from 60% to 100% over 32 minutes. (F) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, 30% with 100% buffer B Hold for a minute. (G) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 50% buffer B to 100% buffer B over 25 minutes, 7% with 100% buffer B Hold for a minute. (H) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 30 minutes, 7% with 100% buffer B Hold for a minute. (I) UV-DII dual wavelength detector (254 and 220 nm) and 4.6 × 100 mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; 1 over 5 minutes
Gradient from 0% buffer B to 100% buffer B, hold at 100% buffer B for 1.5 minutes. (J) UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 20% buffer B to 100% buffer B over 30 minutes, 7% with 100% buffer B Hold for a minute. Table 2. 2-imino-1,3-thiazolidine-4-ones and 2-imino-1
, 3-Thiazolidine-5-ones

[1004]

[Table 35]

[1005]

[Table 36]

[1006]

[Table 37]

[1007]

[Table 38]

(A) Finnigan LCQ MS detector and 2 × 300 mm Phenom
Hewlett Pack with enex 3 uM C-18 column
ard 1100 HPLC; flow rate 1.0 mL / min; buffer A: 0.02% TF
A / 2% CH ₃ CN / water, Buffer B: 0.018% TFA / 98% CH 3 CN / water; 100% Buffer A at 1 min hold, over 3 minutes 100% 100% Buffer A Gradient to buffer B, hold at 100% buffer B for 1 minute, gradient from 100% buffer B to 100% buffer A over 0.5 minutes, hold at 100% buffer A for 1.5 minutes. (B) UV-DII dual wavelength detector (254 and 220nm) and 4x100mm D
Ranin Dyna with ynmax 3 uM C-18 column
max HPLC; flow rate 1.5 mL / min; buffer A: 0.5% TFA / water; buffer B: 0.5% TFA / CH ₃ CN; 100% buffer A to 100 over 10 minutes.
Gradient to% buffer B, hold at 100% buffer B for 5 minutes. (C) UV detector (210 nm) and 4 × 125 mm Nucleosil 3
Hewlett Packard 109 with uM C-18 column
0 HPLC; flow rate 2.0 mL / min; buffer A: 0.01 mol% H ₃ PO ₄ / water;
Buffer B: 0.01 mol% H ₃ PO ₄ / CH ₃ CN; 10% buffer B for 1 minute, 8
Gradient from 10% buffer B to 90% buffer B over 4 min. Gradient from 90% buffer B to 10% buffer B over 4 min. (D) UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dy
Lanin Dynam with namax 8 uM C-18 column
ax HPLC; flow rate 18 mL / min; buffer A: 0.1% TFA / 99.9% water; buffer B: 0.1% TFA / 99.9% CH ₃ CN; 30% buffer over 25 minutes Gradient from B to 100% buffer B, hold at 100% buffer B for 30 minutes. (E) UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dy
Lanin Dynam with namax 8 uM C-18 column
ax HPLC; flow rate 18 mL / min; buffer A: 0.1% TFA / 99.9% water; buffer B: 0.1% TFA / 99.9% CH ₃ CN; 50% buffer over 25 minutes Gradient from B to 60% buffer B, gradient from 60% to 100% over 32 minutes. (F) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, 30% with 100% buffer B Hold for a minute. (G) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 50% buffer B to 100% buffer B over 25 minutes, 7% with 100% buffer B Hold for a minute. (H) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 30 minutes, 7% with 100% buffer B Hold for a minute. (I) UV-DII dual wavelength detector (254 and 220 nm) and 4.6 × 100 mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; 1 over 5 minutes
Gradient from 0% buffer B to 100% buffer B, hold at 100% buffer B for 1.5 minutes. (J) UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 20% buffer B to 100% buffer B over 30 minutes, 7% with 100% buffer B Hold for a minute.

[1009]

[Table 39]

[1010]

[Table 40]

(A) Finnigan LCQ MS detector and 2 × 300 mm Phenom
Hewlett Pack with enex 3 uM C-18 column
ard 1100 HPLC; flow rate 1.0 mL / min; buffer A: 0.02% TF
A / 2% CH ₃ CN / water, Buffer B: 0.018% TFA / 98% CH 3 CN / water; 100% Buffer A at 1 min hold, over 3 minutes 100% 100% Buffer A Gradient to buffer B, hold at 100% buffer B for 1 minute, gradient from 100% buffer B to 100% buffer A over 0.5 minutes, hold at 100% buffer A for 1.5 minutes. (B) UV-DII dual wavelength detector (254 and 220nm) and 4x100mm D
Ranin Dyna with ynmax 3 uM C-18 column
max HPLC; flow rate 1.5 mL / min; buffer A: 0.5% TFA / water; buffer B: 0.5% TFA / CH ₃ CN; 100% buffer A to 100 over 10 minutes.
Gradient to% buffer B, hold at 100% buffer B for 5 minutes. (C) UV detector (210 nm) and 4 × 125 mm Nucleosil 3
Hewlett Packard 109 with uM C-18 column
0 HPLC; flow rate 2.0 mL / min; buffer A: 0.01 mol% H ₃ PO ₄ / water;
Buffer B: 0.01 mol% H ₃ PO ₄ / CH ₃ CN; 10% buffer B for 1 minute, 8
Gradient from 10% buffer B to 90% buffer B over 4 min. Gradient from 90% buffer B to 10% buffer B over 4 min. (D) UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dy
Lanin Dynam with namax 8 uM C-18 column
ax HPLC; flow rate 18 mL / min; buffer A: 0.1% TFA / 99.9% water; buffer B: 0.1% TFA / 99.9% CH ₃ CN; 30% buffer over 25 minutes Gradient from B to 100% buffer B, hold at 100% buffer B for 30 minutes. (E) UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dy
Lanin Dynam with namax 8 uM C-18 column
ax HPLC; flow rate 18 mL / min; buffer A: 0.1% TFA / 99.9% water; buffer B: 0.1% TFA / 99.9% CH ₃ CN; 50% buffer over 25 minutes Gradient from B to 60% buffer B, gradient from 60% to 100% over 32 minutes. (F) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, 30% with 100% buffer B Hold for a minute. (G) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 50% buffer B to 100% buffer B over 25 minutes, 7% with 100% buffer B Hold for a minute. (H) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 30 minutes, 7% with 100% buffer B Hold for a minute. (I) UV-DII dual wavelength detector (254 and 220 nm) and 4.6 × 100 mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; 1 over 5 minutes
Gradient from 0% buffer B to 100% buffer B, hold at 100% buffer B for 1.5 minutes. (J) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 20% buffer B to 100% buffer B over 30 minutes, 7% with 100% buffer B Hold for a minute.

[1012]

[Table 41]

(A) Finnigan LCQ MS detector and 2 × 300 mm Phenom
Hewlett Pack with enex 3 uM C-18 column
ard 1100 HPLC; flow rate 1.0 mL / min; buffer A: 0.02% TF
A / 2% CH ₃ CN / water, Buffer B: 0.018% TFA / 98% CH 3 CN / water; 100% Buffer A at 1 min hold, over 3 minutes 100% 100% Buffer A Gradient to buffer B, hold at 100% buffer B for 1 minute, gradient from 100% buffer B to 100% buffer A over 0.5 minutes, hold at 100% buffer A for 1.5 minutes. (B) UV-DII dual wavelength detector (254 and 220nm) and 4x100mm D
Ranin Dyna with ynmax 3 uM C-18 column
max HPLC; flow rate 1.5 mL / min; buffer A: 0.5% TFA / water; buffer B: 0.5% TFA / CH ₃ CN; 100% buffer A to 100 over 10 minutes.
Gradient to% buffer B, hold at 100% buffer B for 5 minutes. (C) UV detector (210 nm) and 4 × 125 mm Nucleosil 3
Hewlett Packard 109 with uM C-18 column
0 HPLC; flow rate 2.0 mL / min; buffer A: 0.01 mol% H ₃ PO ₄ / water;
Buffer B: 0.01 mol% H ₃ PO ₄ / CH ₃ CN; 10% buffer B for 1 minute, 8
Gradient from 10% buffer B to 90% buffer B over 4 min. Gradient from 90% buffer B to 10% buffer B over 4 min. (D) UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dy
Lanin Dynam with namax 8 uM C-18 column
ax HPLC; flow rate 18 mL / min; buffer A: 0.1% TFA / 99.9% water; buffer B: 0.1% TFA / 99.9% CH ₃ CN; 30% buffer over 25 minutes Gradient from B to 100% buffer B, hold at 100% buffer B for 30 minutes. (E) UV-DII dual wavelength detector (254 and 220 nm) and 2500 mm Dy
Lanin Dynam with namax 8 uM C-18 column
ax HPLC; flow rate 18 mL / min; buffer A: 0.1% TFA / 99.9% water; buffer B: 0.1% TFA / 99.9% CH ₃ CN; 50% buffer over 25 minutes Gradient from B to 60% buffer B, gradient from 60% to 100% over 32 minutes. (F) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 30% buffer B to 100% buffer B over 25 minutes, 30% with 100% buffer B Hold for a minute. (G) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 50% buffer B to 100% buffer B over 25 minutes, 7% with 100% buffer B Hold for a minute. (H) UV-DII dual wavelength detector (254 and 220nm) and 21x2500mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 10% buffer B to 100% buffer B over 30 minutes, 7% with 100% buffer B Hold for a minute. (I) UV-DII dual wavelength detector (254 and 220 nm) and 4.6 × 100 mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; 1 over 5 minutes
Gradient from 0% buffer B to 100% buffer B, hold at 100% buffer B for 1.5 minutes. (J) UV-DII dual wavelength detector (254 and 220 nm) and 21 × 2500 mm
Ranin equipped with a Microsorb 5 uM C-18 column
Dynamax HPLC; flow rate 20 mL / min; buffer A: 0.1% TFA / 9
9.9% water, buffer B: 0.1% TFA / 99.9% CH ₃ CN; gradient from 20% buffer B to 100% buffer B over 30 minutes, 7% with 100% buffer B Hold for a minute. Biological Protocols The activity of a given compound to bind to a progesterone receptor can be routinely assessed according to the procedures disclosed below. Using this procedure, the activity of the compounds of the invention for binding to progesterone was determined. Progesterone Receptor Binding Assay Silicon-coated glass tubes were cooled on an ice-water bath while adding to the binding buffer (100 mL; 50 mM Tris, pH 7.4, containing various concentrations of the compound to be evaluated). 10 mM molybdic acid, 2 mM EDTA, 150 m
M NaCl, 5% glycerol, 1% DMSO), T47D cytosol (
100 μL of solution that will give a binding of at least 4000 cpm) and ³
H-progesterone (50 μL, 10 nM, NET-381) was added. After incubating the mixture for 16 hours at 4 ° C., 250 μL of a 0.5% mixture of charcoal (0.05% dextran-coated charcoal was washed twice with binding buffer)
). The resulting mixture was incubated at 4 ° C for 10 minutes. The tubes were centrifuged at 4 ° C. (2800 × g for 20 minutes). The supernatant was transferred to a scintillation bottle containing scintillation fluid (4 mL).
Residual ³ H-progesterone was measured on a Packard 1900TR beta counter. Each assay included the following control groups: 1) total binding group (no compound), 2) non-specific binding group (with 400 nM progesterone), and 3) positive control group (2 nM progesterone or known inhibitor). Accompany).

It was confirmed that when the compound of the present invention was used at a compound concentration of 200 nM, the binding of ³ H-progesterone to the progesterone receptor was suppressed to a degree equal to or greater than 30%. The range of activity of the compounds of the present invention in the progesterone receptor binding assay at a compound concentration of 200 nM is listed in Table 5.

[1015]

[Table 42]

[1016]

[Table 43]

[1017]

[Table 44]

[1018]

[Table 45]

[1019]

[Table 46]

[1020] The foregoing example is repeated by substituting the reactants and / or operating conditions of the present invention as generally or specifically described for the reactants and / or operating conditions used in the examples set forth above. Similar effects can be obtained.

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/428 A61K 31/428 4C086 31/429 31/429 31/437 31/437 31/54 31/54 A61P 5/00 A61P 5/00 5/24 5/24 9/10 9/10 13/00 13/00 15/00 15/00 15/04 15/04 15/08 15/08 15/10 15/10 15/16 15/16 17/00 17/00 19/00 19/00 19/10 19/10 25/00 25/00 25/24 25/24 25/28 25/28 35/00 35/00 41 / 00 41/00 C07D 233/42 C07D 233/42 263/28 263/28 277/42 277/42 277/60 277/60 279/06 279/06 417/06 417/06 417/12 417/12 513 / 04 325 513/04 325 345 345 513/10 513/10 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, I, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR , CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, K Z, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Brennan, Kyasarin Earl 06460 Mil Ford, Connecticut, United States 06, Maine Treat 70 (72) Inventor Britelli, David Earl 06405 Blanford Stony Creek Road, Connecticut, United States 240 (72) ) Inventor Barock, William H. 06612 Easton Herman Lane 60, Connecticut, United States of America 60 (72) Inventor Chien, Jinxiang 06514 Ham Den Bee-4 Highview Terrace 15, 06514 Hamster, United States of America Connecticut, United States of America 15 (72) Inventor Kolibi, William El, United States 06524 Bethany Frances Drive 9, Connecticut 9 (72) Inventor Darry, Robert 06513 East Haven Arica, 86, Connecticut, USA 86 (72) Inventor Jillson, Jeffrey S.A. 06405 Braunford Gouldrain, Connecticut, United States 58 (72) Inventor Clunder, Harold Sea E. 66611 Tranval Academy Road, Connecticut, United States of America 27 (72) Inventor Raslop, William E., United States 06479 Plantsville, Connecticut, United States Green Valley Drive 138 (72) Inventor Liu, Paying 06443 Madeison Devonshire Lane, Connecticut, United States of America 228 (72) Inventor Mace, Carroll Anne 08551 Lingose Mountain Road 145, New York, USA 155 (72) Inventor Redman, Anico・ M 06418 Derby East Street, Connecticut, USA 66 (72) Inventor Scott, William J. 06437 Gil Ford Saddle Hill Drive 210, (72) Ambient Urbanes, Claus Germany Day-42329 Buppertal-Berdercyutlase 11 (72) Inventor Wolanin, Donald Jey 06477 Orange Long Meadow Road, Connecticut, United States 320 F-term (reference) 4C033 AC04 4C036 AA08 AB03 AB09 4C056 BB11 4C063 AA01 BB09 CC62 CC92 DD12 DD62 EE01 4C072 AA01 AA04 BB02 CC01 CC11 CC16 EE13 FF03 FF07 FF15 GG08 HH02 4C086 AA01 AA02 AA03 BC38 BC69 BC82 GA04 GA08 GA09 Z10A02 Z14 Z14 ZB26 ZC03 ZC10 ZC11

Claims (9)

[Claims] (1) Formula (1)[Wherein, R is selected from the group consisting of aryl having 6 to 14 carbon atoms or N, O and S]
A heteroaryl having 1-3 carbon atoms containing 1-3 heteroatoms represented by
Provided that R is not benzofuran or benzothiophene;¹Is an alkyl having 1 to 10 carbon atoms, and a 3 to 12 carbon atoms containing 1 to 3 rings.
1-3 heteroatoms selected from the group consisting of chloroalkyl, N, O and S
And a heterocycloalkyl having 4 to 7 carbon atoms containing 1 to 3 rings, and having 2 to 2 carbon atoms.
10 alkenyl, cycloalkenyl having 5 to 12 carbon atoms containing 1-3 rings,
Or alkynyl having 3-10 carbon atoms;^Two, R^ThreeAnd R^FourIs independently H, alkyl having 1 to 10 carbons, and carbon having 1 to 10 carbons.
3-12 cycloalkyl, carbon number 2-10 alkenyl, carbon number 5-12
The group consisting of cycloalkenyl, aryl having 6-13 carbon atoms, N, O and S
A heteroaryl having 1-3 carbon atoms containing 1-3 heteroatoms selected from
O_TwoR^Five(Where R^FiveIs an alkyl having 1 to 4 carbon atoms and a halo having 1 to 4 carbon atoms.
Alkyl, cycloalkyl having 3-6 carbon atoms, or halocyclo having 3-6 carbon atoms
Alkyl), halogen, and the group R^Two, R^ThreeAnd R^FourCorresponds to two of
X is O or S (O)_y(Where y is 0, 1 or 2), n is 2, 3, 4 or 5 and p is a non-H substituent R^Two, R^ThreeAnd R^FourT is an alkyl having 1 to 4 carbons, an alkoxy having 1 to 4 carbons, and a 6-carbon
10 aryls, CO_TwoH, CO_TwoR^FiveAn alkenyl having 2-4 carbon atoms and a carbon number of
2-4 alkynyl, C (O) C₆H_Five, C (O) N (R⁶) (R⁷) (Where R ⁶ Is H or alkyl having 1-5 carbon atoms and R⁷Is H or 1-carbon
5) is S (O)_y'R⁸(Where y 'is 1 or 2 and
R⁸Is an alkyl having 1 to 5 carbons), SO_TwoF, CHO, OH, NO_Two,
CN, halogen, OCF_Three, N-oxide, OC (R⁹)_Two-O (where acid
Are bonded to adjacent positions on R and R⁹Is H, halogen or carbon number
Is alkyl of 1-4), C (O) NHC (O) (where carbon is adjacent to R
And C (O) C₆H_Four(Where the carbonyl charcoal
And the ring carbons ortho to this carbonyl are linked to adjacent positions on R.
Wherein t is 1-5, provided that the substituted moiety T is alkyl having 1-4 carbon atoms, and t is 1-5.
1-4 alkoxy, aryl having 6-10 carbon atoms, CO_TwoR^FiveHaving 2-4 carbon atoms
Alkynyl having 2-4 carbon atoms, C (O) C₆H_Five, C (O) N (R ⁶ ) (R⁷), S (O)_y'R⁸, OC (R⁹)_Two-O or C (O) C₆H_FourAt the time
Is optionally alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons,
O_TwoR^Five, CO_TwoH, C (O) N (R⁶) (R⁷), CHO, OH, NO_Two, CN, Ha
Rogen, S (O)_yR⁸Or a second substituent selected from the group consisting of = O
May have the second substituent number up to the level of perhalo
G is halogen, OH, OR^Five= O corresponding to two substituents G, carbon number 1-
4 alkyl, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms
, N, O and S, the number of heteroatoms selected from the group consisting of 1-3 and the number of carbon atoms is
3-5 heterocycloalkyl, cycloalkenyl having 5-7 carbon atoms, N, O and
A heteroatom selected from the group consisting of
Telocycloalkenyl, CO_TwoR^Five, C (O) N (R⁶) (R⁷), Having 6-1 carbon atoms
The number of heteroatoms selected from the group consisting of 0 aryl, N, O and S is 1-
Heteroaryl having 3 to 9 carbon atoms, NO_Two, CN, S (O)_yR⁸, SO_ThreeR⁸
, And SO_TwoN (R⁶) (R⁷G is 0-4 except for halogens available up to the level of perhalo, with the proviso that g is 0-4,
Substituent G is alkyl having 1-4 carbons, alkenyl having 1-4 carbons,
Is 3-7 cycloalkyl, 3-5 carbon atoms heterocycloalkyl, carbon atoms
5-7 cycloalkenyl or heterocycloalkenyl having 4-6 carbon atoms
In some cases, G may optionally reduce the second substituent, halogen, to the level of perhalo.
And when the substituent G is aryl or heteroaryl,
G is optionally selected from the group consisting of alkyl having 1 to 4 carbon atoms and halogen.
May have a second substituent selected, and the number of the second substituent may be
Not more than 3 in the case of a rutile moiety and the level of perhalo in the case of a halogen
Q is alkyl having 1 to 4 carbons, haloalkyl having 1 to 4 carbons, and 3 carbons.
-8 cycloalkyl, 1-8 carbon alkoxy, 2-5 carbon alk
Nyl, cycloalkenyl having 5-8 carbons, aryl having 6-10 carbons, N,
3-9 carbon atoms containing 1-3 heteroatoms selected from the group consisting of O and S
A heteroaryl, CO_TwoR^Five= O, OH, halogen corresponding to two substituents Q
, N (R⁶) (R⁷), S (O)_yR⁸, SO_ThreeR⁸, And SO_TwoN (R⁶) (R⁷)
Q is 0-4, provided that when the substituent Q is aryl or heteroaryl,
Q is optionally independent of the group consisting of alkyl and halogen having 1-4 carbon atoms
May have a second substituent selected, and the number of the second substituent may be
Not more than 3 in the case of a rutile moiety and the level of perhalo in the case of a halogen
And a) (Q)_qR¹, (Q)_qR^Two, (Q)_qR^ThreeAnd (Q)_qR^FourTwo of are connected
And together with one or more of the atoms to which they are attached
A 3-8 membered member containing 0-2 heteroatoms selected from the group consisting of N, O and S
May form a spiro or non-spiro non-aromatic ring; b) when n = 2 or 3, R^Two, R^ThreeAnd R^FourAt least one of is other than H
C) when n = 2, X = O and t = 1, T is a substituent other than alkyl,
Selected from the list of T and the 1,3-oxazolidine ring has a substituent at the 4-position
D) at least one when n = 3 and X = O and t is equal to or greater than 1
Is selected from the above list of substituents T excluding alkyl and alkoxy.
E) R when n = 2 or 3 and X = O or S¹, R^Two, R^ThreeAnd R^FourIn
The total number of non-hydrogen atoms is at least 5;
R has H at the 5-position when R has a halogen at the 2- and 4-positions thereof; g) When n = 2 and X = O, the 1,3-oxazolidine ring has a carbonyl at the 4-position
Only when the ring has at least one non-H substituent at the 5-position, h) n = 2 and X = S (O)_yThe 1,3-thiazolidine ring has a carbonyl group at the 4-position
Holding, R¹Is a substituted methyl group and G is a phenyl group,
The phenyl group has a second substituent, i) n = 4, X = S and G is CO_TwoR^FiveR^FiveContains at least two carbons,
And a pharmaceutically acceptable salt thereof. 2. The formula: [Wherein, R is phenyl or pyridyl, R ¹ is alkyl having 1 to 10 carbons, cycloalkyl having 1 to 3 carbons, 3 to 12 carbons, and 2 to 10 carbons. Alkenyl, having 5 to 5 carbon atoms containing 1 to 3 rings
12 cycloalkenyl or alkynyl having 3 to 10 carbon atoms, wherein R ² , R ³ and R ⁴ are independently H, alkyl having 1 to 10 carbons, cycloalkyl having 3 to 12 carbons. Alkyl, alkenyl having 2 to 10 carbon atoms, 5 to 12 carbon atoms
X is O or S (O) _y, wherein y is 0, 1 or ² , wherein cycloalkenyl of the formula O corresponds to two of the groups R ² , R ³ and R ^4. Or 2), n is 2 or 3, p is the sum of non-H substituents R ² , R ³ and R ⁴ , T is alkyl having 1-4 carbons, carbon Alkoxy having 1 to 4 carbon atoms and 2 carbon atoms
4 is a substituent selected from the group consisting of alkenyl, alkynyl having 2-4 carbon atoms, NO ₂ , CN and halogen; t is 1-5, provided that the substituted moiety T has 1 carbon atom; In the case of alkyl of -4, alkoxy of 1-4 carbon, alkenyl of 2-4 carbon or alkynyl of 2-4 carbon, T may be alkyl of 1-4 carbon, 1 carbon -4 alkoxy, CO ₂ R ⁵ (where R ⁵ is alkyl having 1 to 4 carbon atoms, 1 carbon atom)
-4 haloalkyl, cycloalkyl having 3-6 carbon atoms, or 3-6 carbon atoms
Is a halocycloalkyl of), CO ₂ H, C (O) N (R ⁶ ) (R ⁷ ) wherein R ⁶ is H or alkyl having 1 to 5 carbon atoms and R ⁷ is H or the number of carbon atoms is alkyl of 1-5), CHO, OH, NO _2, CN, ^{_{halogen, S (O) y R 8}} ( wherein, R ⁸ is alkyl of 1-5 carbon atoms), and Halogen which may have a second substituent selected from the group consisting of = O corresponding to two of the second substituents, wherein the number of the second substituent is available up to the level of perhalo And G is halogen, OR ⁵ , alkyl having 1 to 4 carbons, alkenyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, carbon A cycloalkenyl having a number of 5-7,
G is a substituent selected from the group consisting of aryl and CN having 6 to 10 carbon atoms, and g is 0-4 except for halogens usable up to the level of perhalo, provided that the substituent G is G is optionally the second substituent when it is an alkyl of 1-4, alkenyl of 1-4 carbon, cycloalkyl of 3-7 carbon or cycloalkenyl of 5-7 carbon. The halogen may have up to the level of perhalo and when the substituent G is aryl, G may optionally have 1-4 carbon atoms.
May have a second substituent independently selected from the group consisting of alkyl and halogen, wherein the number of said second substituent is 3 or less in the case of an alkyl moiety and Is the level of perhalo, Q is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, 3 carbons
-8 cycloalkyl, cycloalkenyl alkoxy having a carbon number of 1-8, an alkenyl having a carbon number of 2-5, carbon atoms 5-8, CO ₂ R ^5, ₂ one corresponding to substituent Q = O, A substituent selected from the group consisting of OH, halogen, N (R ⁶ ) (R ⁷ ) and S (O) _y R ⁸ , wherein q is 0-4, provided that a) (Q) _q ^{Two of} R ¹ , (Q) _q R ² , (Q) _q R ³ and (Q) _q R ⁴ may be linked and together with one or more atoms to which they are attached And may form a 3-8 membered spiro or non-spiro non-aromatic ring containing 0-2 heteroatoms selected from the group consisting of N, O and S, b) n = 2 or when the 3 least one of R ^2, R ³ and R ⁴ is other than H, c) n = 2 when at X = O of t = 1 at T is selected from the above list of substituents T excluding alkyl and the 1,3-oxazolidine ring must have a substituent at the 4-position, d) n = 3 and X = O and t When is equal to or greater than 1, at least one T is selected from the above list of substituents T except alkyl and alkoxy; e) when n = 2 or 3 and X = O or S The total number of non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is at least 5, f) n = 2, X ＝ O, the 1,3-oxazolidine ring has a carbonyl group at the 4-position and R is R has H at the 5-position when it has a halogen at the 2-position and 4-position, and g) when n = 2 and X = O, the 1,3-oxazolidine ring may have a carbonyl at the 4-position. Has at least one non-H substituent at the 5-position Is only, and h) n = 2 at X = S (O) _y 1,3 thiazolidine ring has a 4-position to the carbonyl group, a methyl group R ¹ is substituted and G is a phenyl group Wherein the phenyl group has a second substituent, with the proviso that the phenyl group has a second substituent.] And a pharmaceutically acceptable salt thereof. 3. The formula: [Wherein, R is phenyl or pyridyl, R ¹ is alkyl having 1 to 10 carbons, cycloalkyl having 1 to 3 carbons, 3 to 12 carbons, and 2 to 10 carbons. R ² , R ³ and R ⁴ are each independently H, alkyl having 1 to 10 carbons, and alkenyl or cycloalkenyl having 1 to 3 carbons and 5 to 12 carbons containing 1 to 3 rings. 3-12 cycloalkyl, 2-10 carbon atoms alkenyl and 5 carbon atoms
A substituent selected from the group consisting of 12 cycloalkenyls, X is O or S (O) _y, where y is 0, 1 or 2; Wherein p is the sum of non-H substituents R ² , R ³ and R ⁴ ; T is alkyl having 1-4 carbons, alkenyl having 2-4 carbons, NO ₂ , CN
And t is 1-5, with the proviso that when the substituted moiety T is alkyl of 1-4 carbons or alkenyl of 2-4 carbons, T may optionally have 1-4 alkyl, alkoxy having 1-4 carbon atoms, CO ₂ R ⁵ (where R ⁵ is alkyl having 1-4 carbon atoms, haloalkyl having 1-4 carbon atoms, 3-carbon atoms) 6 cycloalkyl or halocycloalkyl having 3-6 carbon atoms), CO ₂ H, C (O) N (R ⁶ )
(R ⁷⁾ (wherein, R ⁶ is alkyl and and R ⁷ H or carbon atoms 1-5 is H or a carbon number of alkyl 1-5), CHO, OH, NO 2, CN, Optionally having a second substituent selected from the group consisting of halogen, S (O) _y R ⁸ (where R ⁸ is alkyl having 1 to 5 carbon atoms), and ＝ O. 2 above
G is halogen, alkyl of 1-4 carbons, G is 1-4 of carbon, provided that the number of substituents is 1 or 2 except for halogens available up to the level of perhalo. G is a substituent selected from the group consisting of alkenyl, cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-7 carbon atoms and aryl having 6-10 carbon atoms; Except for usable halogen, it is 0-4, provided that substituent G is alkyl having 1-4 carbon atoms, alkenyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms or carbon atom having 3-7 carbon atoms. When 5-7 cycloalkenyl, G may optionally have a second substituent halogen up to the level of perhalo and when substituent G is aryl, G may optionally have 1-4 carbon atoms.
May have a second substituent independently selected from the group consisting of alkyl and halogen, wherein the number of said second substituent is 3 or less in the case of an alkyl moiety and Is the level of perhalo, Q is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, 3 carbons
-8 is a substituent selected from the group consisting of cycloalkyl having 1 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 halogen; 0-4, with the proviso that a) two of (Q) _q R ¹ , (Q) _q R ² , (Q) _q R ³ and (Q) _q R ⁴ may be linked and Is a 3-8 membered spiro or non-spiro non-aromatic containing 0-2 heteroatoms selected from the group consisting of N, O and S together with one or more atoms to which is attached B) when n = 2 or 3, at least one of R ² , R ³ and R ⁴ is other than H; c) n = 2, X = O and t = 1 When T is selected from the above list of substituents T excluding alkyl and 1,3-oxazo The gin ring must have a substituent at the 4-position, d) at least one T excluding alkyl when n = 3 and X = O and t is equal to or greater than 1 E) that when n = 2 or 3 and X = O or S, the total number of non-hydrogen atoms in R ¹ , R ² , R ³ and R ⁴ is at least 5; And a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, wherein (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- (prope -2-ene-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, a compound selected from the group consisting of: 5. The compound according to claim 1, wherein 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine-4-one, 2- (3-methyl- 4-nitrophenylimino) -3-isobutyl-1,3-thiazolidine-4-one, 2- (2-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidine-4-one, 2 -(3-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidine-4-one, 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-1- Butyl) -1,3-thiazolidine-4-one, 2- (3-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl) -1,3-thiazolidine-4-one, 2 -(2-methyl-4-nito Phenylimino) -3- (1-cyclohexyl -
1-ethyl) -1,3-thiazolidine-4-one, 2- (3-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-
1-ethyl) -1,3-thiazolidine-4-one, 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1,3-thiazolidine-4-one 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-methylene-1,3-thiazolidine-4-one and 2- (2-methyl-4-nitrophenylimino) -3- A compound selected from the group consisting of: isobutyl-5-methyl-1,3-thiazolidine-4-one. 6. The compound according to claim 1, wherein 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 compound selected from the group consisting of: . 7. A pharmaceutical composition comprising the compound according to claim 1, 2, 3, 4, 5 or 6, and a pharmaceutically acceptable carrier. 8. A compound in a mammal or a pharmaceutically acceptable salt thereof.
A1) Treat or prevent osteopenia or osteoporosis in bone weakening diseases
A2) Improve fracture healing, B1) Use as a female contragative agent, B2) Prevent endometrial implantation, B3) Induce labor, B4) Treat luteal deficiency, B5) B6) Preeclampsia, prevention of eclampsia and preterm delivery in pregnancy, B7) Enhancement of spermatogenesis, induction of acrosome reaction, oocyte maturation or oocyte
Infertility treatment, including in vitro fertilization of the vesicles, C1) treatment of dysmenorrhea, C2) treatment of dysfunctional uterine bleeding, C3) treatment of ovarian female pseudohyperyangiosis, C4) treatment of ovarian hyperaldosterone, C5 C) reduction of premenstrual syndrome and premenstrual tension, C6) reduction of premenstrual behavior disorders, C7) Crimerak, including transitional periods of menopause, mood changes, sleep disorders and vaginal dryness
Treatment of teric disorders, C8) Improvement of female and male sexual acceptance, C9) Treatment of postmenopausal urinary incontinence, C10) Improvement of perception and motor function, C11) Improvement of short-term memory, C12) Postpartum depression C13) Treatment of genital atrophy, C14) Prevention of postoperative adhesion formation, C15) Regulation of uterine immune function, C16) Prevention of myocardial infarction, D1) Hormone replacement, E1) Breast cancer, uterine cancer, ovarian cancer And E2) treatment of endometriosis, E3) treatment of uterine fibroids, F1) treatment of hirsutism, F2) suppression of hair growth, G1) male contraceptive G2) activity as an abortive agent, and H1) facilitating myelin repair.
The compound has the general formula:[Wherein, R is selected from the group consisting of aryl having 6 to 14 carbon atoms or N, O and S]
A heteroaryl having 1-3 carbon atoms containing 1-3 heteroatoms represented by
Provided that R is not benzofuran or benzothiophene;¹Is an alkyl having 1 to 10 carbon atoms, and a 3 to 12 carbon atoms containing 1 to 3 rings.
1-3 heteroatoms selected from the group consisting of chloroalkyl, N, O and S
And a heterocycloalkyl having 1-3 carbon atoms having 1-3 rings and 6-carbon atoms.
1 to 3 heteroatoms selected from the group consisting of N, O and S
Having 3 to 9 carbon atoms, having 1 to 3 carbon atoms and 1 to 3 rings, having 2 to 10 carbon atoms
Alkenyl, cycloalkenyl having 1-3 carbon atoms containing 1-3 rings, or
Alkynyl having 3-10 carbon atoms, R^Two, R^ThreeAnd R^FourIs independently H, alkyl having 1 to 10 carbons, and carbon having 1 to 10 carbons.
3-12 cycloalkyl, carbon number 2-10 alkenyl, carbon number 5-12
The group consisting of cycloalkenyl, aryl having 6-13 carbon atoms, N, O and S
A heteroaryl having 1-3 carbon atoms containing 1-3 heteroatoms selected from
O_TwoR^Five(Where R^FiveIs an alkyl having 1 to 4 carbon atoms and a halo having 1 to 4 carbon atoms.
Alkyl, cycloalkyl having 3-6 carbon atoms, or halocyclo having 3-6 carbon atoms
Alkyl), halogen, and the group R^Two, R^ThreeAnd R^FourCorresponds to two of
X is O or S (O)_y(Where y is 0, 1 or 2), n is 2, 3, 4 or 5 and p is a non-H substituent R^Two, R^ThreeAnd R^FourS represents the number of double bonds in the ring, and is 0, 1 or 2. T is alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, carbon number Is 6-
10 aryls, CO_TwoH, CO_TwoR^FiveAn alkenyl having 2-4 carbon atoms and a carbon number of
2-4 alkynyl, C (O) C₆H_Five, C (O) N (R⁶) (R⁷) (Where R ⁶ Is H or alkyl having 1-5 carbon atoms and R⁷Is H or 1-carbon
5) is S (O)_y'R⁸(Where y 'is 1 or 2 and
R⁸Is an alkyl having 1 to 5 carbons), SO_TwoF, CHO, OH, NO_Two,
CN, halogen, OCF_Three, N-oxide, OC (R⁹)_Two-O (where acid
Are bonded to adjacent positions on R and R⁹Is H, halogen or carbon number
Is alkyl of 1-4), C (O) NHC (O) (where carbon is adjacent to R
And C (O) C₆H_Four(Where the carbonyl charcoal
And the ring carbons ortho to this carbonyl are linked to adjacent positions on R.
Wherein t is 1-5, provided that the substituted moiety T is alkyl having 1-4 carbon atoms, and t is 1-5.
1-4 alkoxy, aryl having 6-10 carbon atoms, CO_TwoR^FiveHaving 2-4 carbon atoms
Alkynyl having 2-4 carbon atoms, C (O) C₆H_Five, C (O) N (R ⁶ ) (R⁷), S (O)_y'R⁸, OC (R⁹)_Two-O or C (O) C₆H_FourAt the time
Is optionally alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons,
O_TwoR^Five, CO_TwoH, C (O) N (R⁶) (R⁷), CHO, OH, NO_Two, CN, Ha
Rogen, S (O)_yR⁸Or a second substituent selected from the group consisting of = O
May have the second substituent number up to the level of perhalo
G is halogen, OH, OR^Five= O corresponding to two substituents G, carbon number 1-
4 alkyl, alkenyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms
, N, O and S, the number of heteroatoms selected from the group consisting of 1-3 and the number of carbon atoms is
3-5 heterocycloalkyl, cycloalkenyl having 5-7 carbon atoms, N, O and
A heteroatom selected from the group consisting of
Telocycloalkenyl, CO_TwoR^Five, C (O) N (R⁶) (R⁷), Having 6-1 carbon atoms
The number of heteroatoms selected from the group consisting of 0 aryl, N, O and S is 1-
Heteroaryl having 3 to 9 carbon atoms, NO_Two, CN, S (O)_yR⁸, SO_ThreeR⁸
, And SO_TwoN (R⁶) (R⁷G is 0-4 except for halogens available up to the level of perhalo, with the proviso that g is 0-4,
Substituent G is alkyl having 1-4 carbons, alkenyl having 1-4 carbons,
Is 3-7 cycloalkyl, 3-5 carbon atoms heterocycloalkyl, carbon atoms
5-7 cycloalkenyl or heterocycloalkenyl having 4-6 carbon atoms
In some cases, G may optionally reduce the second substituent, halogen, to the level of perhalo.
And when the substituent G is aryl or heteroaryl,
G is optionally selected from the group consisting of alkyl having 1 to 4 carbon atoms and halogen.
May have a second substituent selected, and the number of the second substituent may be
Not more than 3 in the case of a rutile moiety and the level of perhalo in the case of a halogen
Q is alkyl having 1 to 4 carbons, haloalkyl having 1 to 4 carbons, and 3 carbons.
-8 cycloalkyl, 1-8 carbon alkoxy, 2-5 carbon alk
Nyl, cycloalkenyl having 5-8 carbons, aryl having 6-10 carbons, N,
3-9 carbon atoms containing 1-3 heteroatoms selected from the group consisting of O and S
A heteroaryl, CO_TwoR^Five= O, OH, halogen corresponding to two substituents Q
, N (R⁶) (R⁷), S (O)_yR⁸, SO_ThreeR⁸, And SO_TwoN (R⁶) (R⁷)
Q is 0-4, provided that when the substituent Q is aryl or heteroaryl,
Q is optionally independent of the group consisting of alkyl and halogen having 1-4 carbon atoms
May have a second substituent selected, and the number of the second substituent may be
Not more than 3 in the case of a rutile moiety and the level of perhalo in the case of a halogen
And (Q)_qR¹, (Q)_qR^Two, (Q)_qR^ThreeAnd (Q)_qR^FourTwo of are connected
And together with one or more of the atoms to which they are attached
3-8 membered spins containing 0-2 heteroatoms selected from the group consisting of
Or a non-spiro non-aromatic ring may be formed. 9. The method of claim 8, wherein said mammal is a human.