MXPA01006675A - Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents - Google Patents

Abstract

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

Description

2-Substituted arylimino heterocycles and compositions containing them, for use as CAMPO progesterone receptor binding agents: * This invention relates to heterocyclic pharmaceutical compositions, and more particularly to heterocyclic 2-arylimino pharmaceutical compositions containing them, its use to modulate mid-progesterone processes. BACKGROUND An agent that binds to the progesterone receptor can be used for a wide variety of indications, including those shown in the instructional paragraphs below: A1) to enhance bone formation in diseases where there is bone weakening, for prevention and / or treatment of osteopenia or osteoporosis (Manzi, et al., J. Soc. Gynecol.Invest., i, 302 (1994); Scheven, et al., Biochem. Biophys. Rest. Commun., 186, 54 ( 1992); Verhaar, et al., Bone 15, 307 (1994); Ontjes, in "Calcium and Phosphorus in Health diseases, "Anderson and Garner (Eds.), CRC Press, 207, (1996); Scheven et al., Biochem. Biophys. Res. Commun, 186, 54 (1992) including corticosteroid-induced osteoporosis (Picardo, et al., Drug Safetv 15, 347 (1996), postmenopausal osteoporosis, or Paget's disease; A2) as an agent to improve the healing of a fracture; B1) as a female contraceptive agent, (Cadepond et al., Annu.

Med., 48 ^ 129 (1997); Heikinheimo Clin. Pharmacokinet., 33, 7; Li and colab., Adv. Contracept., 11., 285 (1995); Spitz and colab., Adv. Contracept. 8, 1 (1992); Spitz and colab., Annu. Rev. Pharmacol. Toxicol., 36, 47 (1996); B2) for the prevention of endometrial implantation (Cadepond et al., Annu. Rev. Med., 48, 129 (1997); B3) for induction of delivery (Heikinheimo Clin. Pharmacokinefr, 33, 7 (1997), Karalis et al., Ann., NY Acad. Sci., 771, 551 (1995)), including the case of fetus mortus (Heikinheimo, Clin. Pharmacokinet, 33, 7 (1997); Cadepond y colab., Annu. Rev. Med., 48, 129 (1997)); B4) for the treatment of luteal deficiency (Pretzsh et al.,) Zentralbl. Gynaekol., 119 (Suppl 2), 25 (1997); Bezer et al., In "Molecular and Cellular Aspects of Periimplantation Processes", Dey (Ed.). Springer- Verlag, p. 27 (1995); B5) to increase the recognition and maintenance of pregnancy (Bezer et al., In "Molecular and Cellular Aspects of Periimplantation Processes", Dey (ed.), Springer-Verlag, P. 27 (1995)); B6) to counteract preeclampsia, eclampsia of pregnancy and early delivery (Yallampalli et al., WO 97 / 34,922): B7) for the treatment of infertility, including the promotion of spermatogenesis, the induction of the acryl reaction. soma, oracleito maturation, and in vitro fertilization of oolicitos (Baldi et al., J. Steroid Bichem Mol. Biol., 53, 199 (1995); Baldi and colab., Trends Endocrinol. Metab., 6, 198 (1995); Blackweil and colab., Colloq. INSERM, 236, 165 (nineteen ninety five); Blackmore et al., Cell, Signaling, 5, 531 (1993); Cork and colab., Zygote, 2, 289 (1994); Meizel, Biol. Reprod., 56, 569 (1997)); C1) for the treatment of dysmenorrhea (Coll Capdevila et al., Eur. J.

Contracept. Reprod. Health Care 2, 229 (1997); Adashi et al., Keio J. Med., 44, 124 (1995)); C2) for the treatment of dysfunctional uterine bleeding (Coll Capdevila et al., Eur. J. Contracept, Reprod. Health Care, 2, 229 (1997), Adashi et al., Keio J, Med., 44, 124 ( nineteen ninety five)); ' C3) for the treatment of hyperandroginism of the ovary (Schaison et al., Androg.Excess Disord Women, 715 (1997)); C4) for the treatment of hyperaldosteronism of the ovary (Adashi et al., Keio J. Med., 44, 124 (1995); C5) for the treatment of premenstrual syndrome and / or premenstrual tension (Mortola, Curr. Opin. Endocrinol Diabetes, 2, 483 (1995)); Adashi and colab. Keio J. Med., 44, 124 (1995)); C6) for the treatment of perimenstrual behavior disorders (Constant et al., Hormone Res., 40 I41 (1993); C7) for the treatment of climeractic disorder, eg, transition of menopause (Adashi et al., Keio J. Med., 44, 124 (1995)) including heats (Sarrel, Int. J. Fertile, Women's Med., 42 ^ 78, Báckstrom et al., Ciba Found. Symp., 121, 171 (1995), changes in moods Báckstróm y colab., Ciba Found. Symp.121, 171 (1995)), sleep disturbance (Sarrel, Int, J. Fertile, Women's Med., 42, 78 (1997)) and vaginal dryness (Sarrel, Int. J. Fertil., Women's Med., 42, 78 (1997)); C8) to increase female sexual receptivity (Dei et al., Eur. J.

Contracept. Reprod. Health Care, 2, (4), 253 (1997); McCarthy and co-workers, Endocrinol Trends Metab. 7, 327-333 (1996); Maní y colab., Horm. Behav., 31, 244 (1997) and male sexual receptivity (Johnson et al., In Éssential Reproduction, 2nd ed., Blackweil Scientific Pub., London p. 177 (1984)); C9) for the treatment of menopausal urinary incontinence (Marinen et al., Maturitas, 22, 233 (1995), Batra et al., J Urology 138, 1301 (1987), C10) to improve motor and sensory functions ( Báckstrom et al., Ciba Found, Symp. 121, 171 (1995)); C11) to improve short-term memory (Báckstróm y colab., Ciba Found.

Symp.121 171 (1995)): C12) for the treatment of postpartum depression (Dalton, Practitioner, 229, 507 (1985)); C13) for the treatment of genital atrophy (Sarrel, Int., J. Fertile., Women's Med., 42, 78 (1997)); C14) for the prevention of post-operative adherence formation (Ustun, Gynecol. Obstet. Invest., 46, 202 (1998)); C15) for the regulation of uterine immune function (Hansen et al., J. Reprod. Fertil., 49_ (Suppl)., 69 (1995); C16) for the prevention of myocardial infarction (Sarrel, Int. J. Fertile, Women's Med., 42, 78 (1997); D1) for hormone replacement therapy (Casper et al., J. Soc. Gynecol. Invest., 3, 225 (1996)); E1) for the treatment of cancer, including breast cancer (Cadepond et al., Annu., Rev. Med., 48, 129 (1997), Pike et al., Endocr.-Relat. Cancer, 4, 125 (1997)), uterine cancer (Heikinheimo Clin Pharmacokinet, 33, 7 (1997), ovarian cancer (Pike et al., Endocr-Relat. Cancer, 4, 125 (1997), Hughes, WO 98 / 10,771), and endometrial cancer (Satyaswaroop, Contrib. Oncol., 5C 258 (1995). ); Pike and colab., Endocr.-Relat. Cancer, 4, 125 (1997)); E2) for the treatment of endometriosis (Cadepond et al., Annu < Rev.

Med., 48, 129 (1997); Heikinheimo, Clin, Pharmacokinet., 33, 7, (1997); Edmonds, Br. J. Obstet. Gynaecol., 103, (suppl 14), 10 (1996); Adashi et al., Keio J. Med., 44 24 (1995)); E3) for the treatment of uterine fibrosis (Cadepond et al., Annu. Rev., Med., 48, 129 (1997); Adashi et al., Keio J. Med., 44, 124 (1995); F1) for the treatment of hirsutism (Orentreich and colab, USA 4684635; Azziz et al., J. Clin, Endocrinol., Metab., 80, 3406 (1995); F2) for the inhibition of hair growth (Houssay et al., Acta Physiol. Latinoam., 28, 11 (1978); G1) as a male contraceptive (Harbreave et al., Int. Congr., Symp.

Semin. Ser., 12, 99 (1997); Meriggiola et al., J. Androl, 18, 240 (1997); G2) as an abortifacient (Michna et al., Pharm. Ztg., Í41, 11 (1996)); and H1) for the promotion of bone marrow repair (Bauliey et al., Cell, Mol Neurobiol., 16, 143 (1996)); Bauliey y colab., Mult. Scler., 3, 105 (1997); Schumaker and colab., Dev. Neurosci. 18.6 (1996); Koening and colab., Science, 268, 1500 (1995)). In common form, progesterone or pregestins alone or in combination with estrogens are indicated clinically: for contraception (Merck Manual, Merck &Co. (1992); for the treatment of gastrointestinal bleeding due to arteriovenous malformations (Merck Manual Merck &Co., (1992); for the treatment of recurrent metatarsal stress fractures complicated by oligomenorrhea or amenorrhea (Merck Manual; Merck &Co. (1992); for the treatment of premenstrual syndrome (PMS); Premenstrual tension, Merck Manual, Merck &Co. (1992), for postmenopausal hormone replacement therapy (Merck Manual, Merck &Co. (1992)), for the treatment of heats and subsequent insomnia and fatigue during of menopause (Merck Manual, Merck &Co. (1992)), for the treatment of dysfunctional uterine bleeding when pregnancy is not desired (Merck Manual, Merck &Co. (1992), and for the suppression of endometriosis ( Merck Manual; Merck & Co. (1992)), breast cancer (Merck Manual, Merck &Co. (1992)), endometrial cancer (Merck Manual, Merck &Co. (1992)), or luteal insufficiency (Merck Manual; Merck & Co. (1992)). For example, medroxyprogesterone, a progestin, alone or in combination with estrogen is indicated for the prevention of osteoporosis, treatment of vaginal and / or vulvar atrophy, treatment of moderate to severe vasomotor symptoms associated with menopause, treatment of secondary amenorrhea. , treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, prevention of pregnancy, or as complementary therapy and palliative treatment of metastatic and recurrent, inoperable renal or endometrial carcinoma (Merck Manual, Merck &Co. (1998) ). COMPENDIUM OF THE INVENTION. This invention provides heterocyclic 2-arylimino- and 2-heteroarylimino non-steroid compounds, which have affinity for the progesterone receptor, and therefore can act as progestins and / or antiprogestins, thereby modulating the processes mediated by the receptor. progesterone. This invention relates to compounds having the formula (I) Where ' R is aryl of 6-14 carbons; or heteroaryl of 3-10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O and S, with the proviso that R is other than benzofuran or benzothiophene; R1 is alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons and containing 1-3 rings; 4-7 carbon heterocycloalkyl and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons and containing 1-3 rings; or alkynyl of 3-10 carbons; R2, R3, and R4 are independently selected from the group consisting of H; alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons; aryl of 6 - 13 carbons; 3-9 carbon heteroaryl and containing 1-3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; where R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons or halocycloalkyl of 3-6 carbons; halogen y = O, representing two of the groups R2, R3, and R4; X is O or S (O) y; where y is O, 1, or 2; n is 2, 3, 4, or 5; p is the sum of non-substituents H R2, R3, and R4; T is a substituent selected from the group consisting of alkyl of 1-4 carbons; 1-4 carbon alkoxy; aryl of 6 - 10 carbons; CO2H; CO2R5; 2-4 carbon alkenyl; 2-4 carbon alkynyl; C (O) C6H5; C (O) N (R6) (R7); where R6 is H or alkyl of 1-5 carbon; and R7 is H or alkyl of 1-5 carbon; S (O) and R8; where y 'is 1 or 2; and R8 is alkyl of 1-5 carbon; SO2F; CHO; OH; NO2; CN; halogen; OCF3; Oxide-N; O-C (R) 2-O, the oxygens being connected to the adjacent positions in R; and wherein R9 is H, halogen, or alkyl of 1-4 carbons; C (O) NHC (O), the carbons being connected to the adjacent positions in R; and C (O) CsH4, the carbonyl carbon and the ortho carbon ring being connected to the adjacent positions in R; t is 1 - 5; provided that when the substituent fraction T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, aryl of 6-10 carbons, CO2R5, alkenyl of 2-4 carbons, alkynyl of 2-4 carbons, C (O) C6H5 , C (O) N (R6) (R7), S (O) and R8, OC (R9) 2-0, or C (O) C6H4l when T optionally can support secondary substituents selected from the group consisting of alkyl of 1-4 carbons; 1-4 carbon alkoxy; CO2R5; CO2H; C (O) N (R6) (R7); CHO; OH; NO2; CN; halogen; S (O) and R8; or = O, the amount of said secondary substituents being 1 or 2 with the exception of halogen, which can be used above the level of the perhalo; G is a substituent selected from the group consisting of halogen; OH; OR R5 '= O, represented by two substituents G; alkyl of 1-4 carbons; alkenyl of 1-4 carbons; 3-7 carbon cycloalkyl; heterocycloalkyl of 3 - 5 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; 5-7 carbon cycloalkenyl; heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; C (O) N (R6) (R7); aryl of 6 - 10 carbons; heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N, O and S; NO2; CN; S (SO) and R8; SO3R8: and SO2N (R6) (R7); g is 0-4 with the exception of halogen, which can be used up to the level of the perhalo; provided that when the substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbon, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, when g optionally can support secondary substituents of halogen up to the level of the perhalo; and when the substituent G is aryl or heteroaryl, then G optionally can support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties, and up to the level of the perhalo for halogen; Q is a substituent selected from the group consisting of alkyl of 1-4 carbons; haloalkyl of 1-4 carbons; cycloalkyl of 3-8 carbons; alkoxy of 1-8 carbon; 2-5 carbon alkenyl; cycloalkenyl of 5-8 carbons; aryl of 6 - 10 carbons; heteroaryl of 3-9 carbons and containing from 1 to 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; = O, representing two Q substituents; OH; halogen; N (R6) (R7); S (O) and R8; SO3 R8; and SO2 N (R6) (R7); q is 0-4, provided that when the substituent Q is aryl or heteroaryl, then Q optionally can support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3. , for alkyl fractions and up to the perhalo level for halogen; and with the further proviso that: a) two of (Q) qR1, (Q) qR2, (Q) qR3, and (Q) qR4 can be collected and taken together with the atom (s) to which they are attached form a non-aromatic spiro or non-spiro ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N, O, and S; b) when n = 2 or 3, at least one R2, R3 and R4 is other than H; c) when n = 2, and X = O, if T = 1, when T is selected from the list of substituents T above except alkyl, and the -4 position of the 1,3-oxazolidine ring must support a substituent; d) when n = 3 and X = O, is equal to or greater than 1, then at least one T is selected from the list of substituents T cited above, except alkyl and alkoxy; e) when n = 2 or 3 and X = O or S, then the sum of the non-hydrogen atoms in R1, R2, R3, and R4, are at least 5; f) when n = 2, X = O, position 4- of ring 1, 3 oxazolidine can support a carbonyl group, and R supports halogen in its 2- and 4- positions, then position 5 of R supports H; g) when n = 2 and X = O, the 4- position of the 1,3-oxazolidine ring can support a carbonyl if the fifth position of said ring supports at least one non-H substituent; h) when n = 2; X = S (O) y, the 4- position of the 1,3-thiazolidine ring supports a carbonyl group, R 1 is a substituted methyl group, and G is a phenyl group, then said phenyl group supports a secondary substituent; ¡) When n = 4, X = S, and G is CO 2R5, then R5 contains at least 2 carbons; and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions which They include a compound of the formula (I) as disclosed above, plus a pharmaceutically acceptable carrier. As a result of its affinity for the progesterone receptor and its resulting ability to act as progestins and / or antiprogestins, and thus modulate the progesterone receptor-mediated processes, the compounds of this invention, as well as certain related compounds of the prior art , it is believed that they are useful for the purposes listed in the background section. It should be noted that the definition of a set of compounds for use in the claimed method of treatment (formula II) is broader than the set of compounds defined by formula (I), because the treatment method can employ certain compounds of the prior art that have not previously been recognized as useful for these purposes. Accordingly, the invention further relates to a method for treating a mammal that achieves an effect, where the effect is: A1) to increase bone formation in diseases where bone debit is present for the treatment or pre-ionization of the osteopenia or osteoporosis; A2) improvement in fracture healing; B1) activity as a female contraceptive agent; B2) prevention of endometrial implantation; B3) induction of delivery B4) treatment of luteal deficiency; B5) better recognition and maintenance of pregnancy; B6) counteract preeclampsia, eclampsia of pregnancy and early delivery; B7) treatment of infertility, including the promotion of spermatogenesis, induction of the acrosome reaction, oocyte maturation or in vitro fertilization of oocytes; C1) treatment of adismenorrhea; C2) treatment of dysfunctional uterine bleeding; C3) treatment of ovarian hyperandroginism; C4) treatment of ovarian hyperaldosteronism; C5) relief of premenstrual syndrome and premenstrual tension; C6) relief of perimenstrual behavior disorders; C7) treatment of climacteric disturbance including menopausal transition, changes in mood, sleep disturbance and vaginal dryness; C8) increase in female sexual receptivity and male sexual receptivity; C9) treatment of menopausal urinary incontinence; C10) improvement of motor and sensory functions; C1 1) improvement of short-term memory; C12) relief of 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 therapy; E1) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer and endometrial cancer; E2) treatment of endometriosis; E3) treatment of uterine fibrosis; F1) treatment of hirsutism; , F2) inhibition of hair growth; G1) activity as masculine anticoncepetivo; G2) activity as an abortifacient; and H1) promotion of marrow repair; which comprises administering to said mammal an effective amount of a compound of the formula (II) where R is aryl of 6-14 carbons; or heteroaryl of 3-10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene; R1 is alkyl of 1-10 carbons; 3-12 carbon cycloalkyl and containing 1-3 rings; 4-7 carbon heterocycloalkyl and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S; 6-10 carbon aryl; 3-9 carbon heteroaryl and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O and S; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons and containing 1-3 rings; or alkynyl of 3-10 carbons; R2, R3, and R4 are independently selected from the group consisting of H; alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons; aryl of 6 - 13 carbons; heteroaryl of 3-9 carbons and containing from 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; where R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons or halocycloalkyl of 3-6 carbons; halogen; y = O, representing two of the groups R2, R3, and R4; X is O or S (O) y; where y is 0, 1, or 2; n is 2, 3, 4, or 5; p is the sum of non-substituents H, R2, R3, and R4; s represents the number of double bonds in the ring and is 0, 1, or 2; T is a substituent selected from the group consisting of alkyl of 1-4 carbons; 1-4 carbon alkoxy; aryl of 6 - 10 carbons; CO2H; CO2R5; 2-4 carbon alkenyl; 2-4 carbon alkynyl; C (O) C6H5; C (0) N (R6) (R7); where R6 is H or alkyl of 1-5 carbon; and R7 is H or alkyl of 1-5 carbon; S (O) R8; where y 'is 1 or 2; and R8 is alkyl of 1-5 carbon; SO2F; CHO; OH; NO2; CN; halogen; OCF3; Oxide-N; O-C (R9) 2-O, the oxygens being connected to the adjacent positions in R; and wherein R9 is H, halogen, or alkyl of 1-4 carbons; C (O) NHC (O), the carbons being connected to the adjacent positions in R; and C (O) C6H4, the carbonyl carbon and the ortho carbon ring being connected to the adjacent positions in R; t is 1 - 5; provided that when the substituent fraction T is alkyl of 1-4 carbons; alkoxy of 1-4 carbons, aryl of 6-10 carbons, CO2R5, alkenyl of 2-4 carbons, alkynyl of 2-4 carbons, C (O) C6H5, C (O) N (R6) (R7), S ( O) and R8, OC (R9) 2-O, or C (O) C6H4, when T optionally can support secondary substituents selected from the group consisting of alkyl of 1-4 carbons; 1-4 carbon alkoxy; CO2R5; CO2H; C (O) N (R6) (R7); CHO; OH; NO2; CN; halogen; S (O) and R8; or = O, the amount of said secondary substituents being 1 or 2 with the exception of halogen, which can be used up to the level of the perhalo; G is a substituent selected from the group consisting of halogen; OH; OR5; = O, representing two substituents G; alkyl of 1-4 carbons; alkenyl of 1-4 carbons; 3-7 carbon cycloalkyl; heterocycloalkyl of 3 - 5 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; 5-7 carbon cycloalkenyl; heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; C (O) N (R6) (R7); aryl of 6 - 10 carbons; heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N, O and S; NO2; CN; S (SO) and R8; SO3 R8: and SO2 N (R6) (R7); g is 0-4 with the exception of halogen, which can be used up to the level of the perhalo; provided that when the substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbon, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then G optionally can support secondary halogen substituents up to the level of the perhalo; and when the substituent G is aryl or heteroaryl, then G optionally can support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties, and up to the level of the perhalo for halogen; Q is a substituent selected from the group consisting of alkyl of 1-4 carbons; haloalkyl of 1-4 carbons; cycloalkyl of 3-8 carbons; alkoxy of 1-8 carbon; 2-5 carbon alkenyl; cycloalkenyl of 5-8 carbons; aryl of 6 - 10 carbons; heteroaryl of 3-9 carbons and containing from 1 to 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; = O, representing two Q substituents; OH; halogen; N (R6) (R7); S (O) and R8; SO3 R8; and SO2 N (R6) (R7); q is 0-4, provided that when the substitute Q is aryl or heteroaryl, then Q optionally can support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3. for alkyl fractions and up to the perhalo level for halogen; and with the further proviso that two of (Q) qR1, (Q) qR2, (Q) qR3, and (Q) qR4 can be joined together and taken together with the atom (s) to which they are attached they form a ring non-aromatic spiro or non-spiro of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N, O, and S; and the pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of the formula (I) have been broadly defined in the above summary. In the compounds of the formula (I), the following group preferences apply: R is preferably phenyl or pyridyl. R1 is preferably alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons and containing 1-3 rings, alkenyl of 2-10 carbons, cycloalkenyl of 5-12 carbons and containing of 1-3 rings, or alkynyl of 3-10. carbons. R1 is more preferably alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons and containing 1-3 rings, alkenyl of 2-10 carbons or cycloalkenyl of 5-12 carbons and containing 1-3 rings. R2, R3 and R4 are preferably H, alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons, alkenyl of 2-10 carbons, cycloalkenyl of 5-12 carbons, or = O, in which the carbonyl represents two of the Groups R2, R3 and R4 , R2, R3 and R4 are preferably H, alkyl of 1-10 carbons, cycloalkyl of 3-12 carbons, alkenyl of 2-10 carbons or cycloalkenyl of 5-12 carbons. X is preferably O or S (O) y, where y is 0, 1, or 2. The subscript n, representing the number of carbons in the ring, is preferably 2 or 3. The subscript p, representing the sum of substituents not -H, R2, R3 and R4, is preferably 1 or 2. T is a substituent preferably selected from the group consisting of alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkenyl of 2-4 carbons, alkynyl of 2 -4 carbons, NO2, CN, and halogen. T is more preferably alkyl of 1-4 carbons, alkenyl of 2-4 carbons, NO2, CN, or halogen. The subscript t, representing the number of substituents T is 1-5, more preferably 1-3.

When the substituent fraction T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkenyl of 2-4 carbons, or alkynyl of 2-4 carbons, then T optionally can support secondary substituents preferably selected from the group consisting of alkyl of 1-4 carbons, alkoxy of 1-4 carbons, CO2R5, CO2H, C (0) N (R6) (R7), CHO, OH, NO2, CN, halogen, S (O) and R8 y = O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which can be used up to the level of the perhalo. As used in this application, the term "secondary substituent" means a substituent on a substituent, not "secondary" as used to define the degree of substitution to a carbon. As used in this application, the terms "haloalkyl" and "halocycloalkyl" are used to refer to groups which may contain halogen atoms in any number up to the level of per-halo. G is preferably selected from the group consisting of halogen, O R5, alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, cycloalkenyl of 5-7 carbons, aryl of 6-10 carbons and CN . G is more preferably halogen, alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, cycloalkenyl of 5-7 carbons, or aryl of 6-10 carbons. The subscript g, representing the number of substituents G, is 0-4, more preferably 0-2, with the exception of halogen, which can be used up to the level of the perhalo. Q is preferably selected from the group consisting of alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-8 carbons, alkoxy of 1-8 carbon, alkenyl of 2-5 carbons, cycloalkenyl of 5-8 carbons , CO2R5, = O, OH, halogen, N (R6) (R7), and S (O) and R8; Q is more preferably alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-8 carbons, alkoxy of 1-8 carbon, alkenyl of 2-5 carbons, cycloalkenyl of 5-8 carbons, or halogen. The present invention also includes pharmaceutically acceptable salts of the compounds of the formula I. The pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of organic and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid , phosphoric acid, methanesulfonic acid, trifuromethanesulfonic acid, sulfonic acid, acetic acid, trifuroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid; succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (eg Li + Na + or K +), alkaline toric cations (eg Mg + 2, Ca + 2 or Ba + 2) , the ammonium cations, as well as the acid salts of organic bases, including quaternary ammonium cations, substituted aromatic and aliphatic ammonium, such as those arising from the protonation or peralkylation of triethylamine,? /, / V-diethylamine,? /, / V-dicyclohexylamine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] pctane (DABCO), 1,5-diazabicyclo [4.3.0] no-5 -eno (DBN) and 1,8-diazabicyclo [5.4.0) undec-7-ene (DBU). A number of compounds of Formula I possess asymmetric carbons and can therefore exist in optically active and racemic forms. The methods of separation of the enantiomeric and diastereomeric mixtures are well known to the person skilled in the art. The present invention encompasses any of the optically active and racemic forms of the compounds described in Formula I possessing progesterone receptor binding activity.

The most preferred 2-amino-1,3-thiazolidines and the expanded homologues of 2-amino-1,3-thiazolidines of the invention are the following: (4s) -2- (2-methyl-4-) nitrophenolyl) -3-isobutyl-4-isopropyl-1,3-thiazole; (4 s) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazole dina; (4 s) -2- (2-methyl-4-nitrophenolimino) -3-isobutyl-4- (trifluoromethyl) -1,3-thiazolidine; (4 s) -2- (2-methyl-4-nitrophenlimin) -3-cyclopentyl-4-isobutyl! -1,3-thiazolidine; (4 s) -2- (2-methyl-4-n-phenylphenyl-1-yl) -3-isobutyl-4-ylpropyl-1,3-tiazolidine; (4 s) -2- (2-methyl-4-nitrophenylmethyl) -3-cyclopentyl-4-isopropyl-1,3-thiazolidine; (4R) -2- (2-methyl-4-nitrophenlimino) -3-isobutyl-4-isopropyl tetrahydro-2 / - / - 1, 3-thiazole dina; (4 s) -2- (4-Nitro-1-naphthylamino) -3-cyclopentyl-4 - ((1f?) -1-hydroxyethyl) -1,13-thiazole; 2- (4-cyano-2-methylphenylimino) -1-cyclopentyl-3-thia-1 -azaspiro [4.4] nonane; 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-tia-1-azaspiro [4.4] nonane; 2- (4-cyanolphenylimino) -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-azaspyrro [4,4] nonane; 2- (4-cyano-2-methylphenylamino) -1- (1-ethyl-1-propyl) -3-thia-1-azaspiro [4, 4] nonane; 2- (4-cyano-1-naphthylmethyl) -1-isobutyl-3-thia-1-azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino) -1 - (prop-2-en-1-yl) -3-thia-1 -azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino) -1-isopropyl-3-thia-1-azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino) -1 -isobutyl-3-thia-1 -azaspiro [4.4] nonane; 2- (2-methyl-4-n -trofenylamino) -1-cyclopentyl-3-thia-1-azaspyrro [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-nitrophenolimino) -1-cyclopentyl-3-tia-1-azaspiro [4.4] nonane; and 2- (4-cyano-2,3-dimethyl-4-nitrophenimlimino) -1-cyclopentyl-3-yl-1-azaspyrro [4,4] nonane; The most preferred thiazolidin-4-ones of the invention are the following: 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-4-one; -4-nitrophenylimino) -3-isobutyl-1, 3-thiazolidin-4-one; -4-nitrophenylimino) -3-benzyl-1,3-thiazolidin-4-one; -4-nitrophenlimino) -3-benzyl-1, 3-thiazolidin-4-one; -4-nitrophenylimino) -3- (2-methyl-1-butyl) -1, 3-azoiidin-4-one; -4-nitrophenylimino) -3- (2-methyl-1-butyl) -1,3-thiazolidin-4-one; -4-nitrophenylimino) -3- (1-cyclohexyl-1-ethyl) -1,3-azolidin-4-one; -4-nitrophenyl-amino) -3- (1-cyclohexyl-1-etyl) -1,3-thiazolidin-4-one; -4-nitrophenolinylamino) -3- (2-ethyl-1-butyl) -1,3-azolidin-4-one; -4-nitrophenyl-amino) -3-isobutyl-5-methylene-1, 3-tiazolid-4-one; and -4-nitrophenyliminyl) -3-isobutyl-5-methyl-1,3-thiazolidin-4-one; The most preferred oxazolidines of the invention are the following: 2- (2-methyl-4-nitrophenimyl) -3-isobutyl-4,4-dimethyl-1-loxazolidine; 1-Cyclopentyl-2- (4-cyano-2-ethylphenylimino) -3-oxa-1-azaspiro [4) 4] nonane; 1-Cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4]; nonane and 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1 -azaspiro [4.4] nonane; The therapeutic agents of the invention can be used alone or concurrently with other therapies. For example, when employed as in A1 or A2, the agent may be used in combination with a source of calcium, vitamin D or vitamin D analogues, and / or anti-resorptive therapies such as estrogen replacement therapy, treatment with a source of fluoride, treatment with calcitonin or with a calcitonin analog or treatment with a bisphosphonate such as alendronate. When employed as in B1 to B7, the agent can be used with therapies such as estrogen replacement therapy. When employed as in C1 to C16, E1 to E3, or F1 or F2, the agent can be used concurrently with therapies such as estrogen replacement therapy and / or gonadotropin-releasing hormone agonist. When employed as in G1 or G2, the agent can be used concurrently with therapies such as androgen. The method of the invention is projected to be employed for the treatment of mediated progesterone receptor conditions in both humans and other mammals. The compounds can be administered orally, dermatological, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in unit dose formulations. The term "administered by injection" includes intravenous, intra-articular, intramuscular, subcutaneous and parenteral injections, as well as the use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more pharmaceutically non-toxic carriers and, if desired, other active ingredients. The compositions intended for oral use can be prepared according to any suitable method known in the art for the manufacture of the pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preservatives to provide flavorful preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of the tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulating and disintegrating agents, for example grain starch, or alginic acid; and binding agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time retardant material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds can also be prepared in solid form, or rapid release. Formulations for oral use may be presented as hard gelatin capsules, where the active ingredient is mixed with an inert diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or in an oil medium, for example, peanut oil, liquid paraffin or olive oil. Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of the aqueous suspensions can also be used. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia gum; Dispersing or wetting agents can be naturally occurring phosphating, for example, lecithin or the condensation products of alkylene oxide with fatty acids, for example polyoxyethylene stearate or the condensation products of ethylene oxide with aliphatic alcohols of long chain, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxythylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents may also be present. The compounds may also be present in the form of non-aqueous liquid formulations, for example, oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, oil sesame or peanut oil (peanut) or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of antioxidants such as ascorbic acid. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a veget oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be gums which are of natural origin, for example acacia gum or tragacanth gum, phosphates of natural origin, for example, soya bean, leticin and esters or partial esters derived from fatty acids and hexitol anhydrides , for example sorbitan monooleate, and condensation products of the aforementioned partial ethers with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. The syrups and the elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain an emollient, a preservative and flavoring and coloring agents. The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is a solid at ordinary temperatures, but liquid at rectal or vaginal temperature and will therefore fluidify in the rectum and vagina to release the drug. Such materials include cocoa butter and polyethylene glycols. The compounds of the invention can also be administered transdermally using methods known to those skilled in the art (see for example: Chien, "Transdermal Controlled Systemic Medications," Marcel Dekker, Inc., 1987. Lipp et al. WO 94/041573mar94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent that optionally contains agents that increase penetration can be combined with additional additives known to those skilled in the art, such as matrix and bactericidal materials. After sterilization, the resulting mixture can be formulated following the known procedures in the dosage forms.

In addition, in the treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I can be formulated in a lotion or ointment. Suitable solvents for processing the transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons, such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from the lower alcohols, the lower ketones, the lower carboxylic acid esters, the polar ethers, the lower hydrocarbons, the halogenated hydrocarbons. Suitable penetration enhancement materials for transdermal application systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated C6-C2 fatty alcohols or not. saturated such as lauryl alcohol or cetyl-alchol, saturated or unsaturated C8-Ci8 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec -butylbutylbutyl, tert-butyl or esters of monoglycerin of acetic acid, caprónico acid, lauric acid, myristic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as adipate of diisoporyl, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancement materials include phosphatidyl derivatives such as licitine or cephalin, terpenes, amides, ketones, ureas and their derivatives, and tate ethers such as dimethyl isosorbid and diethylene glycol monoethyl. Suitable penetration enhancement formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, unsaturated and unsaturated C8-C8 fatty alcohols, saturated or unsaturated C8-C8 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, derivatives of phosphatidyl, terpenes, amides, ketones, ureas and their derivatives and ethers. Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene copolymers, and synthetic and natural gums. Cellulose ethers, derivatized polyethylenes and silicates can also be used as matrix components. Additional additives, such as viscous resins or oils can be added to increase the viscosity of the matrix. For all regimens the use disclosed herein for the compounds of Formula I, the daily oral dosing regimen will preferably be from 0.01 to 200 mg / Kg of the total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection and the use of infusion techniques will preferably be from 0.01 to 200 mg / kg of the total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg / Kg of the total body weight. The daily vaginal dosing regimen will preferably be 0.01 to 200 mg / Kg of the total body weight. The daily topical dosing regimen will preferably be from 0.1 to 200 mg administered between one and four times daily. The transdermal concentration will preferably be that required to maintain a daily dose from 0.01 to 200 mg / kg. The dosage regimen of inhalation * will preferably be 0.01 to 10 mg / kg of total body weight. It will be appreciated by those skilled in the art that the particular method of administration depends on a variety of factors, all of which are considered routine when administering therapeutics.

It will also be understood, however, that the specific dose level for any given patient will depend on a variety of factors, including, but not limited to, the activity of the specific compound employed, the age of the patient, the body weight of the patient. patient, the general health of the patient, the patient's gender, the patient's diet, time of administration, route of administration, percentage of excretion, combinations of the drug and the importance of the condition undergoing therapy. It will also be appreciated by the person skilled in the art that the optimum course of treatment, eg, the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given by a defined number of days, can be determined by those skilled in the art using conventional treatment tests. Full disclosures of all applications, patents and publications cited above and below are incorporated herein by reference. The compounds of Formula I can be prepared by means of the use of chemical reactions and known procedures, of the known compounds (or of the starting materials, which in turn, which are produced of the known compounds) by means of methods preparations shown below as well as by other reactions and methods known to those skilled in the art. However, the following general preparative methods are presented to assist practitioners in synthesizing the compounds of the invention with more detailed particular examples presented in the experimental section. The examples are for illustrative purposes only and are not intended, and should not be construed as limiting the invention in any way. LIST OF ABBREVIATIONS AND ACRONY As used herein, the following terms have the meanings indicated. AcOH anhydrous anhydrous acid BOC tert-butoxycarbonyl conc concentrate dec decomposition DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene DIBAL diisobutylaluminum hydride DME 1, 2-dimethoxyethane DMF? /,? / - dimethylformamide DMSO dimethisulfoxide EtOAc acetate ethyl EtOH ethanol (100%) Et2O diethyl ether Et3N triethylamine KmnO4 potassium permanganate Magnosil® MgSiO3 xH2O m-CPBA 3-chloroperoxybenzoic acid meOH methanol pet.tether petroleum ether (boiling range 30-60 ° C) THF tetrahydrofuran TFA acid trifluoroacetic 'GENERAL PREPARATIVE METHODS Aryl amines, aryl isocyanates, aryl isothiocyanates, aryl nostrus thioureas, aryl isocyanate dichlorides and 2-arylmethane-1, 3-heterocycles can be synthesized using the known methodology ( Katritzky, and colab.

Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984). March. Advanced Organic Chemistry, 3rd Ed.,; John Wiley: New York (1985)). For example, aryl socianates (2) are available from the reaction of phosgene or an equivalent of phosgene, such as diimidazole carbonyl, diphosgene or triphosgene, and aryl sothiocyanates (3) is available from the reaction of an aryl amine with thiophosgene or an equivalent of thiosphosgene such as thiocarbonyl diimidazole (Scheme I). Also many aryl isocyanates and aryl sothiocyanates are commercially available. The reaction of an aryl isothiocyanate with a primary amine then supplies thiourea 4 (Hahn et al., Han'guk Nonghwa Hakhoechi 1997, 40, 139; Dürr US Pat. 4,079,144; Enders Patent US 4,148,799).

Scheme I 0 CI "Cl 'R1 As shown in Scheme II, the thioureas react with α-halochetones, eg a-bromo-ketone 5, to supply, after dehydration, the thiazole (6) (Hahn and colab Han'guk Nonghwa Hakhoechi 1997, 40, 139; Dürr Patent US 4,079,144; Enders Patent US 4,148,799) Scheme II Similarly, the thioureas react with halides of α-halo acids (Giri et al., Asían J. Chem. 1992, 4, 785; Lakhan et al., Agrie. Biol. Chem. 1982, 46, 557), α-halo acids (Dogan et al., Spectrosc. Lett, 1983, 16, 499, Seada et al., Indian J. Heterocycl, Chem.1993, 3, 81), and a-haloesters (Seada et al., Indian J. Heterocycl, Chem. 1993, 3 81) to provide 4-thiazolidinones (10).

Scheme lll The aryl (3) isothiocyanates also react with allylamines (Tsoi et al., Zh. Org. Khim, 1083, 19, 2605) and propargylamines (Azerbaev et al., Khim Geterotsikl Soedin, 1972, 471) to form the corresponding thioureas, which in the acid treatment it supplies 5-substituted thiazolidines (Scheme IV). Scheme IV ArSCN H + H + The aryl sothiocyanates can also be reacted with hydroxylamines (17) to form? / -hydroxyalkyl thourea 18 (Scheme V). The treatment of thiourea with acid then leads to 2-amino-1,3-heterocycle 19 (Jen et al., J. Med. Chem. 1975, 18, 90; Tyukhteneva et al., Khim. Geterotsikl, Soedin, 1985, 12 1629; Olszenko-Piontkowa et al., Org. Prep. Procedure, Int. 11971, 3, 27). The reaction of hydroxyalkyl thiourea 18 with SOCI2 supplies the chloralkyl analogue 20, which in the base treatment will cycle to supply heterocycle 19 (Cherbuliez et al., Helv. Chim Acta 1967, 50, 331; Felix et al. USA 4,806,653). Scheme V Ar ArSC Alternatively, as shown in Scheme VI, the treatment * of N-hydroxyalkyl thiourea 18 with HgO or an alkylating agent, such as methyl iodide followed by a base provides the corresponding corresponding oxygen-containing heterocycle (Jen et al., J. Med. Chem, 1975, 18, 90, Ignatova and co-workers Khim Geterotsikl, Soedin, 1974, 354). Scheme VI Ar Chloroalkyl isothiocyanate has been reported to react with the arylamines to provide the corresponding 2-phenylimino-1,3-heterocycle sulfide (Sagner et al., US Patent 3,651,053; Ibid US Patent 3,737,536). . Scheme Vil 24 The arylamines react with a formylating source, such as formic acetic anhydride to form formanilide 25, which can then be converted by oxidation to the aryl isocyanide dichloride (Ferchland et al., DE 3,134,134, for a review, see: Kuehle et al. Chem 1967, 79, 663). The aryl hydrogen dichlorides (26) react with hydroxylamines (27) to give oxygen-containing 2-phenylimino-1,3-heterocycle (Wollweber, US Patent 3,787,575; US Patent 3,686,199) and with hydroxylamide 28 to give thiazolidinone 31. Further, it has been shown that aryl cyanide dichloride reacts with aminomercaptans (29) to give 2-phenylimino-1,3-heterocycle containing sulfur 32 (Thibault French Patent 1, 510,015). Scheme VIII The treatment of hydroxylamines with CS2 in the presence of a base will generate 1,3-thiaza-2-thione (Scheme IX). It has been reported that thione reacts with SOCI2 to give hydroscopically labile imidate 35, which, in treatment with an aryl amine, supplies the sulfur-containing 2-methyl-1, 3-heterocycle (Hanefeld et al., Arch. Pharm 1985, 318.60, Ibid 1988, 321, 199). Scheme IX HO HN'R1 CS2 > and x h baascee 33 34 35 36 Both the 2-imino-1, 3-heterocycles containing sulfur and containing oxygen can then be processed. Thus, for example, as shown in Scheme X, the treatment of N3-unsubstituted 2-phenylimin-1, 3heterocycles with electrophiles, usually in the presence of a base, supplies the N3-substituted product (Abartsumova and collaborated Chem, Heterocycl, Compd. 1997, 33, 475, Mizrakh et al., Khim Geterotsikl, Soedin, 1990, 563, Olszenko-Piontkowa et al., Org, Prep. Procedure, Int. 11971, 3, 27) Scheme X In addition, as shown in Scheme XI, 2-amino-1, 3-heterocycles x containing sulfur can be oxidized to sulfoxide or sulfone (Chizhevskayaet et al., Khim. Geterotsikl. Soedin., 1971, 96; Pandey et al. J. Indian Chem. Soc, 1972, 49, 171). Scheme XI DETAILED EXPERIMENTAL PROCEDURES Detailed examples of the preparations of the compounds of the invention are provided in the following detailed synthetic procedures. In the tables of the compounds that follow, the synthesis of each compound is referenced later in these exemplary preparatory steps. EXAMPLES All reactions were carried out in oven-dried or flame-dried glassware under positive pressure of dry argon or dry nitrogen, and was agitated in magnetic form unless indicated otherwise. Sensitive liquids and solutions were transferred via a syringe or cannula and introduced into the reaction vessels by means of a rubber septum. Commercial grade reagents and solvents were used without further purification. Unless otherwise specified, the term "concentration under reduced pressure" refers to the use of the Buchi rotary evaporator at approximately 15 mmHg. The bulb-to-bulb concentrations were conducted using an Aldrich Kugeirohr apparatus, and in these cases the temperatures refer to the furnace temperatures. All temperatures are reported uncorrected in Celcius degrees (° C). Unless stated otherwise, all parts and percentages are by volume.

Thin layer chromatography (TLC) was carried out on plates of 250 μm 60 A F-254 silica gel bonded in Whatman® pre-coated glass. The visualization of the plates was carried out by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersing the plate in a cerium sulfate solution followed by heating, (e) melting the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. The chromatography column (flash chromatography) was carried out using 230-400 mesh EM Science ® silica gel. Rotary chromatography was carried out using pre-molded SiO2 plates (Altech®) from Harrison Research Chromatotron. The melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettier FP66 automated melting point apparatus and are not corrected. The infrared spectra of transformation Fourier were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Nuclear magnetic resonance (1H) proton spectra (NMR) were measured with a spectrometer (300 MHz General Electric GN-Omega 300 with either Me Si (d0.00) or residual protonated solvent (CHCI3 d 7.26, MeOH d 3.30, DMSO d 2.49) as standard The carbon NMR (13C) spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCI3, d 77.0, MeOD-d3, d 49.0, DMSO-d6 d 39.5) as standard The low resolution mass spectra (MS) and the high resolution mass spectra (HRMS) were obtained as electron impact (El), chemical ionization (Cl), or as mass spectra (FAS) of fast atomic bombardment The electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989 A mass spectrometer equipped with a Vacumetrics Chemical Deactivation Ionization Tester for the sample introduction. ° C. The electron impact ionization was carried out or with electron energy of 70eV and a trap current of 300 μA. The mass spectra of secondary cesium-liquid ion (FAB¬ MS), an updated version of the rapid atomic bombardment, were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989 A) with methane or ammonia as a gas reagent (1 x 10-torr at 2.5 x 104 torr). The direct insertion de-sorption chemical ionization test (DCI) (Vaccumetrics, Inc.) was buffered 0-1.5 amps in 10 sec. And maintained at 10 amps until all the traces of the sample disappeared (-1-2 min). The spectra were scanned from 50-800 amu (atomic mass unit) to 2 seconds per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-packard 1100 PHLC equipped with a quaternary pump, a wavelength detector, a C-18 column, and a mass trap spectrometer of LCQ Finnigan ion with electrospray ionization. The spectra were x scanned from 120-800 amu using a variable ion time, according to the number of ¡ions at the source. Gas chromatography - selective ion mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with HP-1 methyl silicone column (0.33 mM coating, 25 mx 0.2 mm) and a Detector Selective Mass Hewlett Packard 5971 energy ionization 70 eV. The elemental analyzes were conducted by Robertson spectra Microlit Labs., Madison NJ, NMR spectra, LRMS for elemental analyzes, and HRMS for the compounds were consistent with the assigned structures. Examples of the preparations of the compounds of the invention are provided in the following detailed synthetic procedures. In the tables of the compounds that follow, reference is made to the synthesis of each compound of these preparatory steps of the examples. A. Synthesis of Imine A1a precursors. General method of synthesis of anilines of nitrobenzenes. Synthesis of 4-cyano-2-methylaniline. 4-Cyano-2-methylanilyl was synthesized as described above (J. Med. Chem. (1991), 34, 3295): To a solution of 3-methyl-4-nitrobenzontromile (2.0 g, 12.34 mmol ) in acetic acid (20 L) was added dropwise a solution of SnCl 2 (9.6 g, 49.38 mmol) in conc. HCl (20mL). After stirring for 3 h, the mixture was carefully added to a saturated NH 4 OH solution (120 mL) at 0 ° C. The resulting mixture was extracted with EtOAc (4x30 mL). The combined organic layers were subsequently washed with H 2 O (30 mL) and a saturated NaCl solution (30 mL), dried (Na 2 SO 4) and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc / hex) to give 4-cyano-2-methlaniline as a bench solid (1.48 g 92%): TLC (30% EtOAc in hexane) R ^ O.23 . This material was used with subsequent purification.

A2a. General method for the synthesis of isothiocyanates. The synthesis of isothiocyanate 4-nitro-2-p-propyl Step 1 To a solution of 2-p-propylaniline (8.91 g, 66 mmol) and Et3N (14 mL, 106 mmol) in CH2Cl2 (60 mL) was added acetic anhydride (10.9 mL, 99 mmol) dropwise. The resulting mixture was allowed to stir at room temperature, overnight, then treated with 1 N HCl solution (40 mL). The acidic mixture was extracted with CH2Cl2 (2x 30 mL). The combined organic layers were washed sequentially with H2O (40 mL), a 1 N NaOH solution (40 mL), H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4) and concentrated under pressure. reduced. The resulting powders were purified by crystallization (EtOAc) to give 2-7-propylacetanilide as white needles (7.85 g 67%). TLC (30% EtOAc / hex) R / 0.37.

Step 2 NaNO2 (0.55 g, 6.50 mmol) was added to a solution of 2-n-propylacetanilide (1.15 g, 6.50 mmol) in TFA (2 (f mL) at -5 ° C. The mixture was allowed to stir to - 5o C for 3 h, then treated with H2O (30 mL) The resulting aqueous solution was extracted with EtOAc (3x20 mL) The combined organic layers were washed with a solution of 1 N NaOH (30 mL), H2O (30 mL). mL) and saturated NaCl solution (40 mL), dried (Na2SO4) and concentrated under reduced pressure, the residue was dissolved in a concent of HCl solution (30 mL) and heated at 100 ° C overnight. The resulting mixture was cooled to 0 ° C with an ice bath, then the pH 10 was carefully adjusted with 50% NaOH solution. The basic mixture was extracted with EtOAc (4 x 30 mL). The combined organic layers were subsequently washed with H2O (30 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc / hex) to give 2-n-propyl-4-nitroacetanilide as a yellow solid (0.56 g, 48%): TLC (20% EtOAc / hex) R, 0.47.

Step 3 To a solution of 2-propyl-4-nitroacetanilide (0.56 g, 0.31 mmol) in toluene (30 mL) was added thiophosgene (0.24 mL, 0.31 mmol) dropwise. The mixture was heated to reflux temperature 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-nitrophenyl isothiocyanate as a yellow oil (0.65 g, 95%: TLC (20% EtOAc / hex) R, 0.82. A2b General method for the synthesis of sothiocyanates The synthesis of isothiocyanate of 4-cyano-2-ethylphenyl.

To a solution of 4-amino-3-ethylbenzonitrile (75 g, 0.51 mol) in toluene was added (1 L) thiofosgen, (43 mL, 0.56 mol, 1.1 equiv.) Slowly by means of a syringe. Within 5 min a viscous slurry was formed. The reaction mixture was heated to reflux temperature and the viscosity decreased. The reaction mixture was heated at reflux temperature for 5 hrs, then allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure and then the residue was treated with CH2Cl2 (600 mL) and concentrated under reduced pressure to give 4-cyano-2-ethylphenyl isothiocyanate as a mild tan solid crystalline solid (98 g, 100%). : 1 H NMR (DMSO-dβ) d 1.18 (t, J = 7.4 Hz, 3 H), 2.69 (q = 7.4 Hz, 2 H), 7.55 (d, = 7.0 Hz, 1 H), 7.75 (d, J = 7.0 Hz, 2H), 7.84 (s, 1 H); MS (CI-MS) m / z 189 ((M + H) +). A2c. General method for the synthesis of isothiocyanates. The isothiocyanate synthesis of 2,4-dimethyl-3-cyano-5-pyridyl.

A suspension of 6-amino-3-cyano-2,4-dimethylpyridine (0.1 g, 0.68 mmol) in CH 2 Cl 2 (1 mL) was added to a vigorously stirred mixture of CaCO 3 (0.41 g 4.11 mmol) in a 1: 2 water: CH2Cl2 mixture (total 9 mL) at room temperature. The reaction mixture was cooled to 0 ° C and thiophosgene (0.09 g, 0.78 mmol) was added drop by drop. The resulting mixture was allowed to warm to room temperature and was stirred overnight. The resulting aqueous layer was subsequently extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), dried (MgSO), and concentrated under reduced pressure. The residue was purified by chromatography (S¡02, 10% EtOAc / hex) to give 2,4-dimethyl-3-cyano-6-pyridyl isothiocyanate. (0.12 g, 91%): CI-MS m / z 190 ((M + H) +). x A2a. General method for the synthesis of sothiocyanates. The synthesis of 2,3-dimethyl-6-nitrophenyl sothiocyanate.

To a solution of 2,3-dimethyl-4-nitroaniline (0.5 g, 1.0 equiv.) In toluene (50 mL) was added thiophosgene, (0.3 mL, 1.3 equiv.) And the reaction mixture was heated to room temperature. reflux throughout the night. The resisting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (25% CH2CI2 / hex) to give 2,3-dimethyl-4-nitrophenol isothiocyanate as a mild yellow solid (0.30 g, 48% ): 1 H NMR (CDCl 3) d 2.39 (s, 3 H), 2.41 (s, 3 H), 7.20 (d J = 8.4 Hz, 1 H); CI-MS m / z 200 ((M + H) +) A2e. General method for the synthesis of sothiocyanates. The synthesis of isothiocyanate 2,3-dimethyl-6-nitrophenyl.

To a solution of 2,3-dimethyl-6-nitrotylan (3.0 g, 1.0 equiv.) In toluene (150 mL) x thiophosgene was added (2.5 mL, 1.8 equiv.) And the The reaction mixture was heated to reflux temperature overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (10% CH2Cl2 / hex) to give 2,3-dimethyl-6-nitrophenyl sothiocyanate as a mild yellow solid (3.63 g, 95%). : 1 H NMR (CDCl 3) d 2.39 (s, 3 H), 2.40 (s, 3 H), 7.17 (d J = 8.4 Hz, 1 H), 7.83 (dJ = 8.7 Hz, 1 H) A3a. General method of synthesis of aryl isonitrile dichlorides. Synthesis of 4-cyano-2-ethylphenyl isocyanide dichloride Step 1 Acetic anhydride (2.35 mL, 2.5 mol, 2.6 equiv.) Was added to formic acid (118 mL, 3.1 mol, 3.2 equiv.) And the resulting solution was heated at 60 ° C for 2 hours. After the reaction was cooled to room temperature, a solution of 4-amino-3-ethylbenzonitrile (140g, 0.96 mol) in anh. THF (700 mL) in a proportion such that the reaction temperature did not exceed 45 ° C (about 20 min.), When the resulting solution was cooled to room temperature, concentrated under reduced pressure, treated with EtOH (600 mL) and concentrated again under reduced pressure to give 4-cyano-2-ethylformanilide as a mild tan solid (167 g, 100%): 1H NMR (CDCl 3) d 1.13 (t, J = 7.3 Hz, 3H) 2.48 ( q, J = 7.3 Hz, 2H) 7.65 (d, J = 8.5 Hz, 1 H) 8.35 (dJ = 8.5 Hz, 1 H), 8.37 (s, 1 H) 9.89 (br s, 1 H).

Step 2 To a solution of 4-cyano-2-ethylformanilide (167 g, 96 mol, 1.0 equiv.) In SOCI2 (525 mL, 6.05 mol, 6.3 equiv.) Which had been cooled to 0 ° C with a bath On ice, sulfuryl chloride (112 mL, 1.4 mol, 1.4 equiv.) was added via syringe. Then the ice bath was removed and the reaction was heated at 50 ° C overnight. The resulting mixture was concentrated with reduced pressure , treated with CH2Cl2 (600 mL) and concentrated again with reduced pressure. The residue was dissolved in Et2O (800 mL) and filtered through a Magnosil® pad to give isocyanide dichloride 4- cyano-2-ethylfer.il as an oil (210 g, 96%): 1 H NMR (CDCl 3 ) d 1.13 (t, J = 7.3 Hz, 3H), 2.49 (q, 2H J = 7.3 Hz) 7.15 (d, J = 8.2 Hz, 1 H) 8.35-8.40 (m, 2H). A.3b. General method of synthesis of aryl isonitrile dichlorides. The synthesis of isocyanide dichloride 2-methyl-4-nitrophenyl.

Step 1 Acetic anhydride (400 mL, 4.26 mol, 2.6 equiv.) Was added to formic acid (200 mL, 5.25 mol, 3.2 equiv.) And the resulting solution was heated at 60 ° C for 2.25 hours. After cooling to room temperature, a solution of 2-methyl-4-nitroaniline (152 g, 1.64 mol, 1.0 equiv.) In anh. THF (1.2 L) in a proportion that the reaction temperature did not exceed 45 ° C (about 30 min.), When the resulting solution was cooled to room temperature, it was concentrated at half volume with reduced pressure and the product of the reaction was removed by filtration yielding 2-methyl-4-nitroformanilide as a mild tan solid (295 g, 100%): 1 H NMR (CDCl 3) d 2.31 (s, 3 H), 8.03 (m 2 H), 8.24 (d, J = 8.8 Hz, 1 H) 8.39 (br s, 1 H), 9.94 (br s, 1 H).

Step 2 SOCI2 (525 mL, 6.05 mol, 6.3 equiv.) Was added to 2-methyl-4-nitroformanolide (167 g, 0.96 mol) and the resulting solution was cooled to 0 ° C. Sulfuryl chloride (12 mL, 1.4 mol, 1.4 equiv.) Was added via syringe; the cooling bath was removed and the reaction was heated at 60 ° C for 4 hours, then allowed to cool to room temperature overnight. The mixture x of the reaction was concentrated to half the volume under reduced pressure and the resulting slurry was filtered. The solids were washed with 50% Et2O / hex to produce iso-n-2-methyl-4-nitrophenyl dichloride as a yellow solid (323 g, 85%) 1 H NMR (CDCl 3) d 2.19 (s, 3 H), 7.20 ( d, J = 8.5 Hz, 1 H) 8.15 (d, J = 8.5 Hz, 1 H), 8. 2 (s, 1 H). A4a. General method for the synthesis of nitroanilines of anilines. The synthesis of 2,3-dimethyl-6-nitroaniline and 2,3-dimethyl-4-nitroanilin.

Step 1 To a solution of 2,3-dimethylaniline (1.1 mL equiv.) And Et3N (1.5 mL 1.30 equiv.) In CH2Cl2 (15 mL) at 0 ° C was added acetyl chloride (0.73 mL, 1.25 equiv.) For 30 minutes. min. The reaction mixture was allowed to stir overnight at room temperature, then treated with 2N HCl solution (10 mL) and CH2Cl2 (25 mL). The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organics were washed with a solution of 2N HCl (2 x 25 mL), water (2 x 25 mL), a saturated solution of NaHCO3 (2 x 25 mL) and a saturated solution of NaCl (2x 25 mL), dried Na2SO4) and concentrated under reduced pressure to give 2,3-dimethylacetanilide as a white solid (1.25 g, 93%). %): 1 H NMR (CDCl 3) d 2.05 (s, 3 H), 2.15 (s, 3 H), 2.25 (s, 3 H), 6.95 (d, J = 7.5 Hz, 1 H), 7.02 (app t, .J = 7.5 Hz, 1 H), 7.35 (d, J = 6.9 Hz, 1 H).

To a solution of 2,3-dimethylacetanilide (14.0 g 1.0 equiv.) In conc. H2ST4 (35 mL) at 0 ° C was added HN03 (5.1 mL, 1.25 equiv.) For 30 minutes. The resulting mixture was allowed to stir at room temperature for 15 minutes, then treated with ice water (500 mL) to form a yellow precipitate. The solids were removed and washed with water to allow 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) d 2.15 (s, 1.5 H), 2.22 (s, 1.5 H), 2.37 (s, 1.5 H), 2.38 (s, 1.5 H), 2.41 (s, 1.5 H), 5.93 (br s 1 H), 7.15 (d, .J = 8.7 Hz, 0.5 H), 7.63 (d, J = 8.7 Hz, 0.5H), 7.76 (d, J = 8.1 Hz, 1 H). This mixture was used in the next step without further purification.

Step 3 To a solution of the mixture of nitroacetanilides (16.0 g, 1.0 equiv.) Was added 60% of a solution of H2SO (150 mL). The solution was heated at reflux temperature for 1 hour, then cooled to room temperature and treated with a 2N NaOH solution in ice water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (2 x 50 mL) and saturated NaCl solution (2 x 50 mL), dried (Na2SO) and concentrated under reduced pressure. The residue was purified by column chromatography (10% CH2CI4 / hex) to provide 2,3-dimethyl-6-nitroaniline (5.5 g, 43%), followed by 2,3-di-nitl-4-nitroaniline (1.5 g). 12%), 2,3-dimethyl-6-nitroanilin (5.5 g, 43%): 1 H NMR (CDCl 3) d 2.05 (s, 3 H), 2.20 (s, 3 H), 6.15 (br s 2H), 6.45 (d, .J = 8.7 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 1 H); 1H NMR (DMSO-d6) d 2.10 (s, 3H), 2.30 (s, 3H), 6.50 (d, .J = 8.7 Hz, 1 H), 7, 15 (br, s, 2H), 7.75 (d, J = 9.0 Hz, 1 H), 2,3-dimethyl-4-nitroaniline: 1 H NMR (CDCl 3) d 2.10 (s, 3H), 2.45 (s, 3H), 4.05 (br s 2H), 6.45 (d, J = 9.0 Hz, 1 H), 7.65 (d, J = 8.7 Hz, 1 H): 1 H NMR (DMSO-de) d 2.00 (s, 3H), 2.35 (s) , 3H), 6.12 (br s, 2H), 6.53 (d, .J = 9.0 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 1 H); A5a General method for the synthesis of iodoanilines. The synthesis of 4- iodo-2-n-propilanilina.

AS a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHCO3 (5.0 g 59.5 mmol) in H2O (25 mL). Iodine (8.4 g 33.3 mmol) was added as a portion for 70 minutes while maintaining the temperature at 10 ° C, then the mixture was allowed to stir at 10 ° C for 30 minutes. The resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (4 x 40 mL). The combined organic layers were sequentially washed with a 5% solution of Na2 S2O3 (30 mL) and a saturated solution of NaHCO3 (30 mL), dried (NA2SO) and concentrated under reduced pressure to give 4-2-2-. n-propylaniline (9.4 g 98%): TLC (20% EtOAc / hex) R ^ 0.43. This material was used in the next step without further purification. B Methods to Form Precursors to 2-aminoheterocycles. B1a. Generate method! for the synthesis of ethanolamines via the reduction of amino acid derivatives. Synthesis of 1-amino- (hydroxymethyl) cydohexane.

Step 1 To a solution of 1-aminocyclohexane-1-carboxylic acid (10.0 g, 70.0 mmol) in a solution of 1 M NaOH (100 mL) was added benzyl chloroformate (12.0 mL, 84.0 mmol). The reaction mixture was stirred for 2 hrs while maintaining pH 9 by adding a 1M NaOH solution as necessary. The resulting solution was washed with Et2O (2 x 100 mL), then the aqueous layer was adjusted to pH 0 with a concent. HCl solution and the solution was extracted with EtOAc (3 x 150 mL). The combined organic layers were dried with (MgSO4) and concentrated under reduced pressure to yield 1- (benzyloxycarbonylamino-cyclohexane-1-carboxylic acid (17.3 g, 89%): TLC (25% EtOAc / hex) R, 0.07.

Step 2 To a solution of l- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid (4.16 g, 15.0 mol) and N-methylmorpholine (1.81 mL, 16.5 mol) in DME (15 mL) at 4 ° C chloroformate was added very slowly. Isobutyl (2.14 mL, 16.5 mol) and the reaction mixture was stirred for 5 min, then filtered into a pre-cooled flask (4 ° C). Sodium borohydride (0.85 g, 22.5 mol) in water 7 (mL) was added followed immediately by water (500 mL). The reaction was heated to 20 ° C and stirred for 30 minutes. The reaction mixture was extracted with CH 2 Cl 2 and concentrated under reduced pressure to yield 1- (benzyloxycarbonylannino) -1- (hydroxymethyl) cyclohexane (4.0 g, 100%): TLC (25% EtOAc / hex) R, 0.11 Step 3 A slurry of 1- (benzyloxycarbonylamino) -1 (hydroxymethyl) cyclohexane (4.0 g, 15 mmol) and 10% Pd / C (0.40 g) in MeOH (75 mL) was stirred with H2 (1 atm.) For 1 hour. h, then treated with Celite®. The resulting mixture was filtered and concentrated under reduced pressure to give 1-amino-1- (hydroxymethyl) cyclohexane. B1 b. General method for the synthesis of ethanolamines via the reduction of amino acid derivatives. Synthesis of (1S) -1- (hydroxymethyl) -3-methylbutylamine.

Step 1 To a suspension of leucine- (L), (315 g, 2.4 mol) in MeOH (3.2 L) at -15 ° C was added SOCI (315 mL, 4.32 mol, 1.8 equiv.) Dropwise in such proportion than the temp. of the reaction did not exceed 5 ° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and was stirred overnight. The resulting mixture was concentrated under reduced pressure and Et 2 O (3 L) was added very slowly to the residue to produce a precipitate. The mixture was cooled with an ice bath, treated with additional MeOH (3 L) relatively quickly. After 1 hr at 0 ° C, the crystals were collected and dried to give methyl leucine ester HCl salt - (L) as a crystalline solid (394 g, 86%): mp 147-149 ° C; 1H-NMR (CD3OD) d 0.78-0.98 (m, 6h), 1.58-1.72 (m, 3H), 3.76 (s, 3H), 3.92 (t, .J = 7.3 Hz, 1 H).

Step 2 To a mixture of methyl ester leucine-HCl salt (L) (254 g, 1.4 mol), NaHCO3, (118 g, 1.4 mol, 1.0 equiv.) And water (1.8 L) in EtOH (1.8 L) in 5 ° C NaBH 4, (159 g, 4.2 mol, 3.0 equiv.) Was added in portions to such a ratio that the reaction temperature did not exceed 15 ° C (approximately 70 min). After it was finished with the addition of NaBH4, the ice bath was removed and the reaction was heated to reflux temperature overnight. The resulting mixture was cooled to room temperature with the aid of an ice bath. The resulting slurry was filtered and the solids were washed with EtOH (750 mL). The combined filtrates were concentrated to approximately 950 ml under reduced pressure. The residue was diluted with EtOAc (2.5 L) and extracted with a 1 N NaOH solution (2 x 1 L). The aqueous layer was subsequently extracted with EtOAc (2 x 750 mL). The combined organic x was dried (MgSO4) and concentrated under reduced pressure to yield (1 S) -1- (hydroxymethyl) -3-methylbutylamine as a yellow oil (112 g, 65%): 1 H NMR (CDCl 3) d 0.88-0.93 (m, 6H), 1.17 (t, .J = 7.7 Hz, 2H), 1.68-1.80 (m, 2H), 1.82 (br s 2H), 2.86-2.91 (m, 1 H), 3.22 ( dd J = 10.7, 8.1 Hz, 1 H), 3.56, (dd, J = 10.3, 3.6 Hz, 1 H). B1c General method for the synthesis of ethanolamines via the reduction of amino acid derivatives. The synthesis of 1-hydroxymethylcyclopentanamine.

Step 1 To a suspension of 1-aminocyclopentanecarboxylic acid, (675 g, 5.23 mol, 1.0 equiv.) In MeOH (6.5 L) maintained at -15 ° C with an ice bath / MeOH was added SOCI2 (687 mL, 9.4 mol. , 1.8 equiv.), Drop by drop in such proportion that the reaction temperature did not exceed 7 ° C. After the addition was complete, the cold was removed, the reaction was allowed to stir at room temperature throughout. overnight, then concentrated with reduced pressure. The residue was treated with CH2Cl2 (1 L) and concentrated under reduced pressure to provide 1-aminocicpentanecarboxylate HCl salt as a white solid (938 g, 100%): 1 H NMR (CD3OD) d 1.87-1.94 (m, 8H) 3.83 (s, 3H); NMR (DMSO-d6) d 1.67-1.71 x (m, 2H), 1.83-1.98 (m, 4H), 2.06-2.14 (m, 2H), 3.73 (s, 3H), 8.81 (br s 3H). This material was used in the next step without further purification.

Step 2 To a solution of methyl 1-aminocyclopentanecarboxylate HCl salt (31 J D g, 1.72 mol) in EtOH solution (12.5 L) and water (2.5 L) was treated with NaHCO3 (145 g, 1.73 mol, 1.0 equiv. ). The resulting mixture was cooled to 5 ° C with an ice bath and NaBH 4 (196 g, 5.2 mol, 3.0 equiv.) Was added in portions to such a ratio that the reaction temperature did not exceed 15 ° C (approximately 75 min. .). After the addition of NaBH 3 was complete, the ice bath was removed and the reaction was heated at reflux temperature overnight, cooled to room temperature with the aid of an ice bath and filtered. The resulting solids were washed with EtOH (750 mL) and the combined filtrates were concentrated under reduced pressure. The resulting slurry was then treated with EtOAc (2.5 L). The organic layer was washed with a solution of 1 N NaOH (2 x 750 mL) and the aqueous layer was subsequently extracted with EtOAc (2 x 500 mL). The combined organic layers were dried (MgSO) and concentrated under reduced pressure to give 1-hydroxymethylcyclopentanamine as a melting wax. (169 g, 85%): 1 H NMR (CDCl 3) d 1.38-1.44 (m, 2 H), 1.58-1.69 (m, 4 H), 1.70-1.84 (m, 2 H), 2.11 (br s, 3 H), 3.36 (s, 2H). CI-MS m / z 116 ((M + H) +). B2a. General method for N-alkylation of ethanolamines via substitution reactions. Synthesis of 2- (isobutylamino) -2- (hydroxymethyl) norbornane.

H 2-Aminonorbornane-2-carboxylic acid was converted to 2-amino-2- (hydromethyl!) Norbornane as a diastereomeric mixture in a manner analogous to Method B1a. A solution of amino alcohol (0.31 g, 2.16 mmol) and sbutylbutyl bromide (0.23 mL, 2.16 mL) in DMF (3 mL) was heated at 90 ° C for 92 hrs, then cooled to room temperature and partitioned. between EtOAc (100 mL) and saturated NaHCO3 solution (100 mL). The organic layer was washed with a saturated solution of NaCl (50 mL), dried (MgSO), and concentrated under reduced pressure to give 2- (but -butyllamino) -2-hydroxyethyl) norbornane as a diastereomeric mixture (0.24 g, 55%): GC-MS m / z 197 (M +). B2b. General method for N-alkylation of ethanolamines via substitution reactions. Synthesis of N-hydroxyethyl-N-cyclohex-1-enylmethylamine.

To a solution of methyl cyclohex-1-enecarboxylate (4.56 g, 32 mmol) in THF (100 mL) at -78 ° C was added DIBAL (1 m in THF, 130 mmol, 130 mL) dropwise. The mixture was allowed to stir at -78 ° C for 4 hrs then treated with saturated solution in NaHCO3 (40mL). The aqueous layer was extracted with EtOAc (4 x 20 mL) and the combined organic layers were washed in H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO) and concentrated under reduced pressure. The residual cyclohex-1-enylmethanol was used directly for the next step without purification; TCL (30% EtOAc / hex) R ^ 0.44.

Step 2 To a solution of cyclohex-1-enylmethanol (3.58 g, 32 mmol) in CH 2 Cl 2 (40 mL) at 0 ° C was added PPh 3 (36 mmol, 9.39 g) and CBr (39 mmol, 12.96 g). The mixture was allowed to stir at temp. atmosphere throughout the night and concentrate with reduced pressure. The residue was diluted with pentane (60 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (5% EtOAc / hex) to give 1-bromomethyl-1-cyclohexene as an oil (3.25 g, 57% over two steps): TLC (30% EtOAc / hex) R, 0.91 Step 3 A solution of 1-bromomethyl-1-cyclohexene (3.25 g) and 2-aminoethanol (6 mL) in trichlorethylene (40 mL) was heated at reflux temperature for 3 d, cooled to temp. environment, and diluted with a solution of 1 N NaOH (30 mL). The aqueous layer was extracted with CH2Cl2 (4 x 20 mL) and the combined organic layers were washed with H2O (30 mL) and a saturated solution in NaCI (30 mL), hedged in (Na2SO) and concentrated under reduced pressure. The residue was purified by vacuum distillation to give N-hydroxyethyl-N-cyclohex-1-enylmethylamine as a colorless oil (1.78 g, 62%): bp 92-94 ° C (6 mmHg). B3 - General method for N-alkylation of ethanolamines via reductive alkylation. Synthesis of methyl ester HCl salt of (R) -N-isobutylserine.

To a suspension of methyl ester serine HCl-salt (D) (2.13 g, 13.7 mmol) in 1,2-dichloroethane was added, butyraldehyde (1.5 mL, 16.4 mmol) and sodium triacetoxyborohydride (4.3 g, 20.5 mmol). The reaction mixture was stirred at room temperature for 24 hrs, then partitioned between Et 2 O (100 x mL), and a saturated solution of NaHCO 3 (100 mL). The organic layer was washed with a saturated solution of NaHCO3 (3 x 100 mL), dried with (MgSO), and treated with a solution of 1M HC1 in ether (25 mL). The resulting mixture was concentrated under reduced pressure to yield methyl ester (R) -N-isobutylserine HCl salt (2.27 g, 79%): NMR (DMSO-dG) d 0.94 (dd, J = 6.7, 3.0 Hz, 6H); 1.97-2.11 (m, 1 H); 2.76-2.91 (m, 1 H); 3.76 (s, 3H): 3.86 (dd, J = 12.1, 4.1 Hz, 1 H), 3.99 (dd, J = 12.4, 3.2 Hz, 1 H), 4. 13-4.21 (m, 1 H) B4a. General method for the N-alkylation of ethanolamines via the formation of 2-alkyl-1,3-oxazolidine followed by reduction. Synthesis of 1- (cyclohexylamino) -1- (hydroxymethyl) cyclopentane.

Step 1 To a solution of 1-amino-1- (hydroxymethyl) cyclopentane (Ble method, 1.44 g, 12.54 mmol) in CH 2 Cl 2 (10 mL) at 4 ° C was added TFA (0.097 mL, 1.25 mmol), cyclohexanone (1.30 mL, 12.54 mmol) and sodium sulfate (2 g) and the reaction was heated to 20 ° C. The reaction was stirred for 72 hrs and subsequently washed with water (10 mL) and a saturated solution of NaHCO3 ( 20 mL), dried over (MgSO) and concentrated under reduced pressure to give 14-aza-7-oxadispiro [4.2.5.1] tetradecane (2.38 g, 97%): GC-MS m / z 195 (M +).

Step 2 To a solution of LialH4 (0.93 g 24.4 mmol) and AICI3 (3.24 g, 24.4 mmol) in THF at 4 ° C was added dropwise a solution of 14-aza-7- oxadispiro [4.2. 5.1] tetradecane (2.38 g, 12.2 mmol.) In THF (15 mL). The resulting mixture was heated to 20 ° C and stirred for 45 min. It was then cooled to 4 ° C. Water (5 mL) was added slowly to quench the reaction and a solution of 1 N NaOH (85 mL) was added to dissolve the resulting solids. The resulting solution was extracted with Et2O (200 mL). The organic layer was dried (Na2SO) and concentrated under reduced pressure to yield 1- (cyclohexylamino) -1 - (hydroxymethyl) cyclopentane 1.89 g (79%): GC-MS m / z 197 (M +) B4b. General method for the N-alkylation of ethanolamines via the formation of 2-alkyl-1,3-oxazolidine followed by reduction. Synthesis of N-cyclopentyl (1,1-dimethyl-2-hydroxyethyl) amine.

Step 1 A mixture of 2-amino-2-methyl-1-propanol (15.0 g, 0.168 mol), cyclopentanone (14.9 mL, 0.168 mol, 1.0 equiv.) And p-toluensolfonic acid monohydrate (1.6 g 8.4 mmol, 0.05 equiv.) In toluene (300 mL) was stirred at reflux temperature overnight. The reaction mixture was then cooled to room temperature, diluted with EtOAc (500 mL), and then washed with a saturated NaHCO3 (250 mL), dried (Na2SO4), and concentrated under reduced pressure to produce aza-3,3-dimethyl-1-oxaspiro [4.4] nonane as a pale yellow oil (15.5 g, 60%): 1 H NMR (CDCl 3) d 1.12 (s, 6 H), 1.65 (m, 5 H), 1.80 (m, 2H), 1.97 (m, 2H), 3145 (s, 2H).

Step 2 To a solution of 4-aza-3,3-dimethyl-1-oxaspyrro [4,4] nonane (15.5 g 0.10 mol) in EtOH (85 mL) at 0 ° C was then added NaBH 4 (5.47 g). 0.145 mol, 1.45 equlv.) at a rate in which the reaction temperature did not exceed 10 ° C (approximately 1 h.). The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The resulting mixture was treated with water (100 mL) and concentrated to a paste under reduced pressure. MeOH (100 L) was added and the mixture was reconcentrated under reduced pressure. The residue was treated with EtOAc (300 mL) and water (150 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to produce N-cyclopentyl- (1, 1-dimethyl-2-hydroxyethyl) amine as a pale yellow oil (13.0 g, 83%): 1 H NMR (CDCl 3) d 1.07 (s, 6 H), 1.24 (m, 3 H), 1.50 (m, 2 H ), 1.65 (m, 2H), 1.87 (m, 2H), 3.0 (m, 1 H), 3.22 (s, 2H) CI-MS m / z 158 ((M + H) +). B4c. General method for the N-alkylation of ethanolamines via the formation of 2-alkyl 1,3-oxazolidine followed by reduction. Synthesis of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol.

Step 1 A solution of (1 S) -1- (hydroxymethyl) -3-methylbutylamine was heated (Method B1 b; 152 g, 1.3 mol.) And isobutyraldehyde (118 mL, 1.3 mol, 1.0 equiv.) In toluene (1.5 L) at temp. of reflux, until the theoretical amount of water had been collected in a Dean-Stark trap (23.4 mL). The reaction mixture was concentrated by distillation in about 700 mL. The resulting mixture was cooled to temp. environment and was concentrated under reduced pressure to a constant weight to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine as a pale yellow oil (223 g, 100%): 1 H NMR (CDCl 3) d 0.88-0.99 (m, 12 H), 1.18 -1.35 (m, 1 H), 1.42-1.56 (M, 1 H), 1.61- 1.79 (m, 4H), 3.08 (t, J = 7.4 Hz, 1 H), 3.20-3.34 (m, 1 H), 3.85 (t, J = 7.4 Hz, 1 H), 4.18 (dd, J = 7.3, 3.4 Hz, 1 H).

Step 2 < To a solution of (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine (223g, 1.3 mol) in EtOH (1.1 L) cooled to -13 ° C with ice bath / MeOH was added NaBH4 (Tt) ), 3g, 1.82 mol.) In portions at such a rate that the reaction temperature did not exceed 10 ° C (approximately 2 h). The reaction mixture was allowed to warm to room temperature stirred overnight, then it was filtered by means of a rough sintered glass funnel. The resulting solids were washed with EtOH. The combined filtrate was concentrated under reduced pressure and the residue was treated with EtOAc (2 L) and water (1 L). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield (2S) -4-methyl-2- (isobutylamino) pentan-l-ol as a pale yellow viscous oil (192 g, 85%): 1H NMR (CDCl 3) d 0.90-0.96 (m, 12H), 1.18-1.24 (m, 1 H), 1.32-1.39 (m, 1 H), 1.58-1.72 (m, 2H), 2.33 (dd, J = 11, 1, 7.0 Hz, 1 H), 2.49 (dd, J = 11, 1, 7.0 Hz, 1 H), 2.63-2.67 (m, 1 H), 3.19 (dd, J = 10.3, 6.2 Hz, 1 H), 3.60 (dd, J = 10.3, 6.2 Hz, 1 H). B4d. General method for the N-alkylation of ethanolamines via the formation of 2-a! Quil-1,3-oxazolidine followed by reduction. Synthesis of 1-. { cyclopentylamino) -1- (hydroxymethyl) cyclopentane.

Step 1 A solution of 1-hydroxymethylcyclinepentanamine (Ble method: 263 * g, 2.3 mol) and cyclopentanone (220 mL, 1.3 mol, 1.1 equiv.) In toluene (2.7 L) was heated at reflux temperature with azeotropic water removal until that the theoretical amount of water had been collected (41, 4 mL). The reaction mixture was concentrated to 700 mL by simple distillation, then cooled to room temperature and concentrated under constant pressure under reduced pressure to give 6-aza-12-oxadispiro [4.1.4.2] tridecane (414 g, 100% ) as a pale yellow oil: 1 H NMR (CDCl 3) d 1.55-1.89 (m, 17H), 3.60 (s, 2H).

Step 2 To a solution of 6-aza-12-oxadispiro [4.1.4.2] tridecane (124 g, 0.69 mol) dissolved in EtOH (600 mL) maintained at -13 ° C with an ice bath / MeOH was added NaBH ( 38 g, 1.0 mol, 1.45 equiv.) In portions at a temp. environment that did not exceed 10 ° C (approximately 30 min.). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water (500 mL) and concentrated under reduced pressure. The residual slurry was separated between EtOAc (1 L) and water (600 mL). The organic layer was dried (Na2SO) and concentrated under reduced pressure to produce l- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane as a white powder (107 g, 85%): 1 H NMR (CDC) d 1.23-1.28 (m, 2H), 1.46-1.57 (m, 8H), 1.58-1.69 (m, 4H) «1.82-1.86 (m, 2H), 2.94-3.06 (m, 1 H), 3.30 (s, 2H). B5a. General method for the synthesis of ethanolamines via the reaction of amines with epoxides. Synthesis of N- (hydroxyethyl) -N- (2-butyl) amine.

.OH N 'H To a solution of sec-butylamine (60 mL, 0.60 mmol) in MeOH (40 mL) at room temperature was added ethylene oxide (10 mL, 0.20 mmol) dropwise via a cannula. The mixture was stirred for 4 h at room temperature, then concentrated under reduced pressure. The residue was purified by vacuum distillation to give? / - (hydroxyethyl) -N- (2-butyl) amine as a colorless oil (16.4 g 70 %): bp 109-112 ° C (6 mmHg). B5b. General method for the synthesis of ethanolamines via reaction of amines with epoxides. Synthesis of? / - (3-phenyl-2-hydroxypropyl) _? / - isobutylamine. 2-3-Epoxypropyl benzene (10 g, 74.5 mmol) and isobutylamine (6.4 g, 74.5 mmol) were mixed and then treated with water (2 mL). The mixture was stirred overnight at 110 ° C, then distilled to yield N- (3-phenyl-2-hydroxypropyl) -N-isobutyiamine (6.5 g): bp 115-117 ° C (1 mmHg). B6a. General method for the synthesis of propanolamines via Arndt Eisert homologation of amino acids followed by reduction. Synthesis of (f?) - 3- (I-butylamino) -4-methylpentanol Step 1 To a solution of? / - (te -butoxycarbonyl) - (L) -valin (4.32 g, 19.9 mmol) and N-methylmorpholine (2.3 mL, 20.9 mol) in DME (30 mL) at -10 ° C added isobutyl chloroformate (2.27 mL, 21.0 mmol). The resulting mixture was stirred at room temperature for 15 min. Then it was filtered, and the solids were washed with cold DME. The filtrate was cooled to -10 ° C, then treated with a solution of CH2N2 in Et2O until a yellow color persisted, the resulting mixture was heated to 20 ° C and stirred at that temperature for 45 minutes, then the mixture was concentrated under reduced pressure. The residue was purified by chromatography (S¡02, gradient of hexane at 30% EtOAc / hex) to yield (S) -3- (tert-butoxycarbonylamino) -1-diazo-4-methylpentan-2-one (1.82 g, 38% ): TLC (10% EtOAc / hex) R, 0.11.

Step 2 A solution of (S) -3- (tert-butoxycarbonylamino) -1-diazo-4-methylopentan-2-one (1.83 g, 7.6 mmol) in MeOH (100 mL) was heated to reflux temperature and added a filtered solution of silver Benzoate in Et3N (0.50 g silver benzoate in 5 mL Et3N, 0.5 mL). After the initial gas evolution stopped (ca. 0.5 minutes) an additional silver solution (0.5 mL) was added. This process was repeated until the addition of silver salt caused that no more gas was developed. This resulting mixture was cooled to 20 ° C, treated with Celite ® and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in Et2O (100 mL) and subsequently washed with a solution of 1 N HCl (100 mL), a saturated solution of NaHCO3 (100 mL), and a saturated solution of NaCl (50 mL), dried in (MgSO4), and concentrated under reduced pressure to give methyl (ft) -3- (te / t) -butoxycarbonylamino) -4-meth1lpentanoate (1.63 g, 87%): TLC (10% EtOAc / hex) R, 0.29.

Step 3 Methyl (R) -3- (terr) -butoxycarbonylamino) -4-methylpentanoate (1.62 g, 6.6 mmol) was treated with lithium borohydride in a manner analogous to Method B8a, Step 2 to deliver (R) -3- (terf) -butoxycarbonylamino) -4-methylpentanol (93%). B7a. General method for the synthesis of chloroethylamines. Synthesis of (1S) -1- (chloromethyl) -3-methylbutanammonium chloride.

A solution of (1S) -1- (hydroxymethyl) -3-methylbutylamine (Method B1b; 5.40 g, 46.1 mmol) in CH2Cl2 (200 mL) was cooled on ice bath saturated with HCl gas. SOCI2 (4.0 mL, 55.3 mmol) was added, the reaction was heated at reflux temperature for 2.5 h, then cooled to temp. environment and concentrated under reduced pressure. The residue was triturated with Et2O to yield (1S) - (chloromethyl) -3-methylbutanemonium chloride (5.67 g, 71%): EI-MS m / z 136 ((M + H) +).

B7b. General method for the synthesis of chloro-methylamines. Synthesis of the salt of HCl 1- (cyoromethyl) -1- (cyclohexylamino) cyclopentane.

A solution of 4 M HCl (p-dioxane, 40 mL) containing 1- (cyclohexylamino) -1- (hydroxymethyl) cyclopentane (Method B4a, 1.9 g 9.6 mmol) and SOCI2 (0.84 mL, 11.5 mmol) was heated to 70 ° C. C for 18 hs. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to yield crude HCl 1- (chloromethyl) -1- (cyclohexylamino) cyclopentane salt (2.84 g), which was used in the next step without further purification. B7c. General method for the synthesis of chloroethylamines. Synthesis of the HCl salt .- (1-S) - (1- (chloromethyl) -3-methylbutyl) -V- (isobutyl) amine.

To a solution of (2S) -4-methyl-2- (isobutylamino) pentan-1-ol (Method B4c; 256 g, 1. 5 mol) and toluene (2.5 L) was added SOCL2 (167 mL) for 15 min. After the addition of SOCI2 was complete, the reaction was heated to 90 ° C overnight. The reaction solution was cooled to temp. environment and concentrated under reduced pressure. The dark oil residue was dissolved in CH2Cl2 (2L) and concentrated under reduced pressure. The reddish-brown residue was dissolved in Et 2 O (1 L), and hexane (750 mL) was added drop by drop over a period of 8 h. The resulting slurry was stirred overnight, filtered and washed with 40% EtOAc / hex solution to give HCl salt of? / - (1-S) - (1- (chloromethyl) -3-methylbutyl) -? / - (isobutyl) amine as a dark brown solid (276 g): H NMR (CDCl 3) d 0.93-1.00 (m, 6H), 1.10-1.12 (m, 6H), 1.85 (m, 4H) , 2.24-2.34 (m, 2H), 2.80-2.88 (m, 1 H), 2.90-3.02 (m, 1 H), 3.50-3.57 (m, 1 H), 3.96 (dd, J = 12.9, 5.6 Hz , 1 H), 4.10 (dd, J = 13.2, 3.6 Hz, 1 H). B7d. General method for the synthesis of chloroethylamines. Synthesis of the HCl salt 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane.

To a solution of 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane (Ble method; 140 g. 0.76 mol, 1.0 equiv.) In toluene (1.4 L), SOCI2 (84 mL) was added during a period of 15 min. After the addition of SOCI2 was completed, the reaction, which had already been heated to 40 ° C, was heated to a temperature of 60 ° C, overnight. The resulting solution was cooled to room temperature, and treated with HCl (4N in p-dioxane, 100 mL) and the reaction was heated at 60 ° C for 3 h, then stirred at room temperature overnight. The resulting mixture was concentrated at half the original volume with reduced pressure, at which time a precipitate began to form. The resulting slurry was diluted with Et 2 O and allowed to stir for 4 h. The resulting precipitate was filtered and washed with Et 2 O (2 x 50 mL) to yield HCl 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane salt as an off-white powder (125 g, 70%): 1 H NMR (CDCl 3) d 1.53-1.66 (m, 4H), 1.76-1.94 (m, 2H), 1.95-2.22 (m, 10 H), 2.28-2.34 (m, 2H), 3.40 (s, 2H), 3.63-3.73 (m , 1 HOUR). B7e. General method for the synthesis of chloroethylamines. The synthesis of the salt of HCl 1-chloromethylcyclopentanamine To a solution of HCl salt of 1-hydroxymethylcyclopentanamine (Ble method: 20 g, 0.17 mol) in anh. p-dioxane 65 (mL), HCl (4M in p-dioxane, 65 mL, 0. 26 mol). The resulting solution was stirred for 20 minutes at room temperature, then dropwise added SOCI2 (22.7g, 0.19 mol). The reaction mixture was heated at 80 ° C for 2 d, cooled to temp. atmosphere, and concentrated under reduced pressure to give a 1-chloromethylcyclopentanamine HCl salt (29 g, 100%): CI-MS m / z 171 ((M + H) +). B8a. General method for the synthesis of the esters of 2-aminoethylsulphonate. Synthesis of (1f? 2R) -1-methanesulfonyloxymethyl) -2- (ferf-butoxy) propanoammonium chloride.

Step 1 A salt solution of (L) - (1 S, 2S) -N- (benzyloxycarbonyl) -O-tep.- butyltreonine dicyclohexylamine (2.15 g, 4.4 mmol) in CH2Cl2 (50 mL) was treated with a solution of CH2N2, in Et2O until a yellow color persisted. The resulting solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed sequentially with a 1N HCl solution (2 x 100 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4) and concentrated under reduced pressure to yield methyl ester (1S, 2R). -? / - (benzyloxycarbonyl) -O-teAt-butyltreonine (1.44 g 100%): TLC (25% EtOAc / hex) Rf 0.54.

Step 2 To a solution of methyl ester (1S, 2R) -? / - (benzyloxycarbonyl) -O-tert-butyltreonine (1.4 g, 4.4 mmol) in Et2O (20 mL) was added a saturated solution of LiBH in Et2O (9 mL) and the reaction mixture was warmed to temp. reflux for 2 h, then cooled to 20 ° C. Water was added to the resulting mixture (5 mL), then a solution of 1 N HCl was added until no more gas was developed. The ether layer was washed with a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure to yield (1R, 2R) -? / - (benzyloxycarbonyl) -1- (hydroxymethyl) -2- (te f-butoxy) propanamine (1.69 g 99%): TLC 25% EtOAc / hex) R, 0.20 Step 3 To a solution of (1 R, 2R) -. V- (benzyloxycarbonyl) -1- (hydroxymethyl) -2- (te / t-butoxy) propanamine (1.6 g, 5.4 mmol) in anh of pyridine (30 mL) at 4 ° C was added methanesulfonyl chloride (0.75 mL, 9.7 mmol) drop by drop. The reaction was stirred for 5.5 h, then diluted with EtOAc (200 mL) and washed with a 1 N HCl solution (4 x 200 mL). The combined organic layers were dried in (MgSO4) and concentrated under reduced pressure to yield (1 R, 2R) -? / - (benzyloxycarbonyl) -l- (methanesulfonyloxymethyl) -2- (tert-butoxy) propanamine as an oil (2.03 g, 100%: TLC 25% EtOAc / hex) R, 0.31.

Step 4 To a solution of (1R, 2R) -? / - (benzyloxycarbonyl) -1- (methanesulfonyloxymetim) -2- (terf- or butoxy) propanamine (2.03 g, 5.5 mmol) in MeOH (50 mL) was added a solution of 4M HCl (dioxane, 1.5 mL, 6.0 mmol) and 10% Pd / C (0.20 g.). The resulting slurry was stirred under H 2 (1 atm.) For 2 h, then treated with Celite®, filtered and concentrated under reduced pressure to yield (1R, 2R) -N- (methanesulfonyloxymethyl) -2- ( / t-butoxy) propanamonium (1.6 g, 100%). 15 B8b. General method for the synthesis of 2-aminoethylsulfonate esters. ? / - (2-tosyloxyethyl) -2-methylprop-2-en-1-ammonium trifluoroacetate.

Step 1 To a solution of te / t-butyl? / - (tert-butoxycarbonyl) glycine (3.97 g, 17.2 mmol) in DMF (70 mL) at 0 ° C was added sodium hexamethyldisilazide ( 3.78 g, 20.6 mmol) and the resulting mixture was stirred for 25 min., Then allowed to warm to temp. ambient. The resulting solution was treated with 3-bromo-2-methylpropene (2.60 mL, 25.7 mmol) was stirred at temp. environment for 10 rrfin., and diluted with EtOAc (300 mL). The EtOAc solution was washed sequentially with water (4 x 500 mL) and a saturated NaCl solution (4 x 500 mL), dried (MgSO4) and concentrated under reduced pressure to produce te / t-butyl ester of / V- (tep, -butoxycarbonyl) -? Y- (2-methylprop-2-en!) Glycine (4.03 g, 82%): TLC (10% EtOAc / hex) Rf 0.51.

Step 2 A solution of tert-butyl ester of? / - (te / t-butoxycarbonyl) -N- (2-methylprop-2-enyl) glycine (0.26 g, 0.93 mmol) in Et2O (3 mL) was treated with lithium borohydride (0.011g), then stirred at temp. atmosphere throughout the night. Water was added to the resulting mixture (2 mL), then 1 N HCl was added dropwise until the evolution of gas stopped. The organic phase was washed with saturated NaHCO3 solution (20 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 10% EtOAc / 50% EtOAc / hex) to give? / - (te / t-butoxycarbonyl) - / / (2-hydroxyet 1) -1-amino-2-methylprop-2-ene (0.113 g, 57%): TLC (10% EtOAc / hex) R, 0.66.

Step 3 To a solution of / V- (te / -butoxycarbonyl) -? / - (2-hydroxyethyl) -1-amino-2-methylprop-2-ene (21.1 g, 98 mmol) in Et2O ( 800 mL) at -78 ° C was slowly added potassium tert-butoxide (1 m in te / t-butanol, 103 mL, 103 mmol.). The mixture was allowed to warm briefly to -45 ° C, then cooled to -78 ° C, and treated with a solution of p-toluenesulfonyl chloride (18.7 g, 98.0 mmol) in Et2O (100 mL). The resulting mixture was then heated to -45 ° C and treated with water (500 mL). The organic phase was washed with a saturated solution of NaCl (800 mL), dried in (MgSO), and concentrated under reduced pressure to give / V- (te-t-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2-methy1prop-2-ene (36.4 g, 101%) : TLC (25% EtOAc / hex) Rf 0.56.

TsO HN- \\ f X- CF3C02H Step 4 The solid? / - (tert-butoxycarbonyl) -N- (2-tosyloxyethyl) -1-amino-2-methy1pfop-2-ene (15 g, 55.7 mmol) was cooled to 0 ° C and was dissolved in TFA (200 mL). The reaction mixture was allowed to warm to room temperature, and then concentrated under reduced pressure. The residual oil was crystallized using Et2O (500 mL) to provide N- (2-tosyloxyethyl) -2-methylprop-2-ene-1-ammonium trifluoroacetate (16.7 9, 78%). B9a. General method for the synthesis of 3-chloropropyl- and 4-chlorobutylamines. Synthesis of the HCl salt? / - isobutyl-3-chloropropylamine.

Step 1 To a solution of 3-aminopropanol (91 g, 65.4 mmol) in toluene (100 mL) was added isobutraldehyde (9.0 mL, 99.1 mmol, 1.5 equiv.) And MgSO (7.5 g) to generate an exotherm. The slurry was stirred for 30 min. And an additional portion of MgSO (7.5 g) was added and the slurry was stirred overnight. The resulting mixture was filtered and concentrated under reduced pressure. The condensate was concentrated again under reduced pressure and 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) d 0.84-0.88 (m, 6H), 1.24-1.29 (m, 1 H), 1.51-1.66 (m, 3H), 2.77- 2.87 (m, 1 H), 3.07-3.13 (m, 1 H), 3.60-3.76 .m, 2H) , 4.00-4.05 (m, 1 H).

HO HN X Step 2 To a solution of 2-isopropyltetrahydro-1,3-oxazole (4.94 g, 38.2 mmol) in abs. (absence). EtOH (100 mL) at 0 ° C was added NaBH 4 (2.17 g, 57.4 mmol, 1.5 equiv.) In small portions for 15 min. And the resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure, then treated with EtOAc (150 mL) and water (100 mL) (CAUTION: evolution of gas), and stirred at temp. environment for 30 minutes. The resulting organic layer was washed with a saturated NaCl solution. The combined aqueous layers were subsequently extracted with EtOAc (150mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give? / -isobutyl-3-hydroxypropylamine as a colorless oil (5.04 g 100%): 1H NMR (CDCl3) d 0.84 (d, J = 6.6 Hz, 6H), 1.60-1.71 (m, 3H), 2.36 (d, J = 6.6 Hz, 2H), 2.80 (dd, J = 5.9, 5.9 Hz, 2H), 3.10-3.30 (br s, 2H), 3.74 (dd, J = 5.5, 5.5 Hz, 2H): 13 C NMR (CDCl 3) d 20.5, 28.1, 30.6, 50.0, 57.8, 64.1, Cl HN HCl XA a solution of? / - sobuyl-3-hydroxypropylamine (1.01 g 7.70 mmol) in toluene (100 mL) was added SOCI2 (1.37 g, 11.6 mmol, 1.5 equiv.) And the resulting mixture was stirred at temp. environment for 4 hours The resulting slurry was concentrated under reduced pressure to provide HCl / V-isobutyl-3-chloropropylamine salt: 1 H NMR (CDCl 3) d 1.12 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H), 4.24 (q, J = 7.0 Hz, 2H), 4. 55 (s, 1 H), 5.00 (s, 2H); 13 C NMR (CDCl 3) d 13.9, 27.8, 38.2, 61.5, 67.1, 67.3, 117.0, 167.1, 180.7; CI-LRMS m / z (re abundance) 150 ((M + H) +, 100%). B10a. General method for the synthesis of 2-chorioothiazolidinium salts. Synthesis of (4S) -2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium chloride Step 1 To a mixture of HCl (2S) -4-methyl-2- (isobutylamine) pentane-1-ol salt (Method B4c, 0.21 g, 1.0 mmol) and CS2 (0.30 mL, 5.0 mmol, 5.0 equiv.) in 2-butanone (20 mL) was added to Cs2CO3 (0.72 g, 2.20 mmol, 2.2 equiv.) and the resulting mixture was heated at reflux temperature overnight. The resulting orange solution was concentrated under reduced pressure and the residue was triturated with EtOAc (25 mL). The remaining solids were washed with EtOAc (25 mL), and the combined phases were concentrated under reduced pressure. The residue was taken up in SiO2 and purified by MPLC (Biotage 40 S on a silica gel column, 5% EtOAc / hex) to give (4S,) - 3,4-diisobutyl-1,3-tiazolid Na-2-tona as an oil A solution of (4SJ-3,4-diisobutyl-1,3-thiazolidin-2-thone (5.0 g, 21.6 mmol) in SO2 (31 mL, 0.43 mol) and warmed to 70 ° C for 2.5 h, then cooled to room temperature and concentrated under reduced pressure to obtain (4SJ-2-chloro-3,4-diisobutyl) chloride. -4,5-dihydro-1,3-thiazoliumium as a semi-solid: 1H NMR d 0.99-1.10 (m, 12H), 1.59-1.67 (m, 1 H), 1.72-1.84 (m, 1 H), 2.00-2.10 (m, 1H), 2.17-2.29 (br m, 1 H), 3.61-3.68 (m, 1 H), 3.86-3.95 (br m, 2H), 4.50-4.57 (m, 1 H), 4.97-5-06 (br m, 1 H). This material was dissolved in dichloroethane (180 mL) to make a 0.12 M stock solution (assuming a quantitative conversion to thiazolidinium chloride). C. Methods for the synthesis of Iminoheterocyclics C1a. General method for the synthesis of 2-imino-1,3-thiazolidines via the reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine.

To a mixture of ('' / S /) - 1- (chloromethyl) -3-methylbutanammonium chloride (Method B7a, 1.14 g, 3.71 mmol) and 2-methyl-4-nitrophenyl isothiocyanate (0.72 g, 3.71 mmol) suspended in CH2Cl2 (15 mL) was added Et3N via syringe (1.08 mL, 7.78 mmol). The resulting solution was stirred for 18 hours at room temperature.

The reaction mixture was washed with a saturated solution of NaHCO and concentrated under reduced pressure. The residue was purified by chromatography (gradient of S¡O2, from 10% EtOAc / hex) to 30% EtOAc / hex, to obfener (4SJ-2- (2-methyl-4-nitrophenylimino) -4-isobut! l-1, 3-thiozolidine (0.91 g, 47%): TLC (25% EtOAc / hex) R / 0.46, C1 b.General method for the synthesis of 2-imino-1,3-thiazolidine via the reaction of 2-cyoroethylamines with isothiocyanates: Synthesis of an HCl salt (4SJ-2- (4-cyano-2-ethyl-phenylimino) -3,4-diisobutyl-1,3-thiazolidine.

To a solution of an HCl salt of A / - (1-S >) - (1- (chloromethyl) -3-methylbutyl) -? / - (isobutyl) amine (Method B7c; 95 g, 0.41 mol , 1.08 equiv.) In CH2 Cl2 (1.1 L) at 15 ° C was added to 4-cyano-2-ethylphenyl isothiocyanate (Method A2b, 72 g, 0.38 mmol) followed by diisopropylethylamine, (200 mL, 1.15 mol, 3.0 equiv.) generating a slight exotherm. When the reaction was subsequently cooled to room temperature, the ice bath was stirred and the reaction was stirred at room temperature for 4 h. The reaction was then diluted with CH2Cl2 (500 mL), dried (MgSO4) and concentrated under reduced pressure. The residual dark oil (132 g) was dissolved in CH2Cl2 (50 mL) and filtered through a pad of silica gel (5 g SiO2 / g of crude product) with the aid of a 5% solution of EtOAc / hexane to obtain an oil (120 g), which was dissolved in EtOAc (400 mL) and treated very slowly with a solution of HCl (1M in Et2O, 500 mL) to give a HCl salt of (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-di. sobutyl-1,3-thiazolidine as a white solid (95 g, 66%): 1 H NMR (CDCl 3) d 0.96 (d, J = 5.9 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.12 (nV6H), 1.23 (t, J = 7.7 Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1 H), 2.82 (q, J = 7.7 Hz, 2H), 3.06-3.14 (m, 2H), 3.55 (dd, J = 11.4, 7.7 Hz, 1 H), 4.18-4.25 (m, 1 H), 5.02 (dd, J = 14.3, 8.1 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.51 (dd, 1 H, J = 8.1, 1.8 Hz, 1 H) 7.58 (d, J = 1.8 Hz, 1 H). C1c. General method for the synthesis of 2-imino-1,3-thiazolidines via the reaction of 2-chloroethylamines with sothiocyanates. Synthesis of (4S) -2- (2-chloro-4-cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine.

To a solution of isothiocyanate 2-chloro-4-cyano-6-methylphenyl (0.10 g, 0.50 mmol) and of poly (4-vinylpyridine) (0.030 g) in CH2Cl2 was added a solution of (1 S) chloride. ) -1- (Chloromethyl) -3-methylbutanemonium (Method B7a; 0. 086 g, 0.50 mol, 1.0 equiv.) In DMF (2 mL) and the resulting mixture was stirred at 55 ° C for 16 h, then concentrated under reduced pressure. The residue was purified by column chromatography (30 g gradient, 10% EtOAc / 20% EtOAc / hex) to obtain (4S) -2- (2-chloro-4-cyano-6-methylphenyl). mino) -4-isobutyl-1,3-thiazolidine (0.052 g, 34%).

C1d. General method for the synthesis of 2-amino-1,3-thiazolidine via the reaction of 2-chloroethylamines with isothiocyanates. Synthesis of (4S) -2- (4-chloro-2- (trifluoromethyl) phenylmethyl) -3-isobutyl-1,3-thiazolidine. ' The? / - (Hydroxyethyl -? / - isobutylamine was converted to? / - (chloroethyl) - / V isobutylammonium chloride in a manner analogous to Method B7c to a solution of? / - (chloroethyl) -? / -isobutylammonium (0.10 mmol, 0.1 OM) and poly (4-vinylpyridine) (0.030 g) in DMF (1.0 mL) was added a solution of 4-chloro-2- (trifluoromethyl) phenyl isothiocyanate ( 0.25 M in THF, 0.40 mL, 0.10 mmol) and the resulting mixture was heated at 55 ° C for 16 h in a sand bath The resulting slurry was filtered and the filtrate was concentrated under reduced pressure The residue was purified by HPLC preparatory reversal phase (C-18 column, gradient from 0.1% TFA 20% CH3CN / 79.9% water to 0.1% TFA / 99.9% CH3CN) to provide (4S) -2-chloro-2-trifluoromethyl) phenyl-amino) - 3-isobutyl-1,3-thiazolidine (0.020 g, 59%). C1e. General method for the synthesis of 2-imino-1,3-thiazolidines via the reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4] nonane.

To a solution of HCl salt of 1-chloromethylcyclopentanamine (Method B7e, 0.25 g, 1.32 mmol) and 2,4-dimethyl-3-cyano-5-pyridyl isothiocyanate (Method A2c, 0.23 g 1.32 mmol) in anh. 1,2-dichloroethane (10 mL) was added Et3N (1 mL) dropwise via syringe. The resulting mixture was heated at 50 ° C overnight, then cooled to room temperature, and treated with saturated NaHCO 3 solution. The resulting mixture was extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were dried with (Na2SO) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 40% EtOAc / hex) to give 2- (2,4-dimethyl-3-cyano-6-pyridylimino) -3-thia-1-azaspiro [4.4 -mononane (0.192 g 51%): CI-MS m / z 287 ((M + H) +). C1f. General method for the synthesis of 2-imino-1,3-thiazolidines via the reaction of 2-chloroethylamines with isothiocyanates. Synthesis of 2- (3-quinollimin) -3,5-diisobutyl-1,3-thiazolidine. 3-quinoline isothiocyanate was prepared in a manner analogous to Method A2c. To a solution of 3-quinoline isothiocyanate (0.1 g, 0.54 mmol) and N- (1 S) - (1-chloromethyl) -3-methylbutyl) -N- (isobutyl) amine HCl salt (Method B7c) 0.1 13 g, 0.54 mmol) in anh CH2Cl2 (2 mL) was added diisopropylethylamine (0.208 g 1.61 mmol) drop by drop.The resulting mixture was allowed to stir at room temperature overnight, then concentrated under reduced pressure The residue was purified by chromatography (SiO2, 30% EtOAc / hex) to give 2- (3-quinolylimino) -3,5-diisobutyl, 3-thiazolidine (0.02 g, 0.9%): ES-MS m / z 342 ((M + H) +) C2a General method for the synthesis of 2-amino-1,3-thiazolidines via the conversion of ethanolamines to 2-chloroethylamines followed by the reaction with isothiocyanates. 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

To a solution of 1-amino-1- (hydroxymethyl) cyclopentane (Method B1c, 20.7 g, 180 mmol) and HCl (4M in p-dioxane, 400 mL) was added SOCI2 (15.7 mL, 216 mmol) and the resulting solution it was heated at 100 ° C for 18 h. The reaction mixture was concentrated under reduced pressure, then treated with 2-methyl-4-nitrophenyl isothiocyanate (31.4 g, 162 mmol) and 1,2-dichloroethane (400 mL), followed by N-methylmorpholine (49 mL). 449 mmol). The resulting mixture was heated at 70 ° C for 18 h, cooled to temp. environment and concentrated with reduced pressure. The residue was treated with hot EtOAc, filtered and concentrated under reduced pressure. The residue was recrystallized from (MeOH) to yield 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane (38.3 g, 81%): TLC (25% EtOAb / hex) Rf0.27. C2b. General method for the synthesis of 2-imino-1,3-thiazolidines Via the conversion of ethanolamines to 2-chloroethylamines followed by the reaction with isothiocyanates. Synthesis of 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.5] decane. 1-Amino-1- (hydroxymethyl) cyclohexane (Method B1a) was dissolved in p-dioxane (80 mL) then treated with SOCI2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a for give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.5] decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to produce 1 -sobutyl- 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.5] decane (0.026 g, 2%): TLC (20% EtOAc / hex) R, 0.69. C2c. General method for the synthesis of 2-imino-1,3-thiazolidines via the conversion of ethanolamines to 2-chloroethylamines followed by the reaction with isothiocyanates. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutylspiro [1,3-thiazolidine-4,2'-bicyclo [2.2.1] heptane].

The 2- (isobutylamino) -2- (hydroxymethyl) norbomann (Method B2a, 0.24 g, 1.2 mmmol) was treated with SOCI2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to produce 2- (2-methyl-4-nitrophenylimino) -3- (2-isobutylspiro [1,3-thiazolidine-4,2'-bicyclo [2.2.1] heptane] as an oil (0.022 g, 5% ): TLC (25% EtOAc / hex) R, 0.72 C2d General method for the synthesis of 2-imino-1,3-thiazolidines via the conversion of ethanolamines to 2-chloroethylamines followed by the reaction with the sothiocyanates. Synthesis of 3-isobutyl-4-methylene-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidin-5-one and HCl salt of (4S) -3-isobutyl-4 Carbomethoxy-2- (2-methyl-4-nitrophenylimino) -1,3-thiazole dina.

A methyl ester (R) -? / - isobutyleerine HCl salt (Method B3a, 2.28 g, 10.8 mmol) was treated with SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a . The resulting material was purified by column chromatography (SiO2, gradient of 10% hexane EtOAc / hex to give 3-isobutyl-4-methylene-2- (2-methyl-4-nitrophenylimino) -1, 3- thiazolidin-5-one (0.028 g, 10% followed by HCl salt of (SJ-S-isobutyl-carbomethoxy ^^ -methyl-nitrophenyliminof-I .S-thiazolidine (0.192 g, 56%). 4-methylene-2- (2-methyl-4-nitrophenolinylamino) -1, 3-thiazoiidine-5-one; TLC (25% EtOAc / hex) Rf 0.40 HCl (S) -3-isobutyl salt -4-carbomethoxy-2- (2-methyl-4-nitrophenimimino) -1,3-thiazolidine TLC (free base, 25% EtOAc / hex) R, 0.50, C2e.General method for the synthesis of 2- Methyl-1, 3-yl .zolidines via conversion of ethanolamines to 2-chloroethylamine followed by reaction with sothiocyanates Synthesis of 1-cyclohexyl-2- (2-methyl-4) - nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. 1- (Cyclohexylamine) -1- (hydroxymethyl) cyclopentane (Method B4a, 1.89 g, 9.59 m ol) was reacted with SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to produce 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-tia-1-azaspyrro [4,4] nonane (0.44 g, 17%): CI-MS m / z 374 ((M + H) +). C2f General method for the synthesis of 2-imino-1,3-thiazolidines via the conversion of ethanolamines to 2-chloroethylamines followed by the reaction with the isothiocyanates. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4,4-d-methyl-1,3-thiazolidine The α / - isobutyl-1,1-dimethyl-2-hydroxyethanamine was prepared analogously to Method B4a. HCl was boiled in a solution of? / - isobutyl-1,1-dimethyl-2-hydroxyethamine (1.45 g, 10 mmol) in toluene (20 mL) until saturation. SOCI2 (10 mmol) was added to the solution dropwise at temp. atmosphere, stirred at temp. environment for 1 hr and at 50 ° C for 1 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in CHCl3 (20 mL). To the resulting solution was added 2-methyl-4-nitro-phenyl isothiocyanate (1.94 g, 10 mmol), then a solution of Et3N (10 mmol) n CHCl3 (10 mL) was added dropwise at temp. ambient. The resulting mixture was heated to temp. reflux for 3 h, then it was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), and the resulting solution was washed subsequently with an aq NaOH solution. 10% (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO) and concentrated under reduced pressure. The residue was purified by chromatography ((% ETOAc / pet ether) and the resulting solids recrystallized (pet ether) to give 2- (2-methyl-4-nitrophenolimino) -3 -sobutyl. -4,4-dimethyl-1,3-thiazolidine (0.6 g, 63%): mp 97 ° O When appropriate, the product was converted to HCl salt by dissolving the free base (5 mmol) in Et2O (50 mL) and treating this solution with a 2N ethereal HCL solution until that no more solids were precipitated. The resulting slurry was filtered and the resulting solids were washed with Et2O (25 mL), followed by EtOAc (25 mL). C3a. General method for the synthesis of the homologs of 2-amino-1, 3-thiazolidine via the conversion of the hydroxyalkylamines to chloroalkylamines followed by the reaction with the isothiocyanates.

Synthesis of (R) -4-isopropyl-2- (2-methyl-4-nitrophenimlimino) -2,3,4,5-tetrahydro-1,3-thiazine.

Reaction (R) -3-tert-butoxycarbonylamino) -4-methy1pentanol (Method B6a) was reacted with SOCI2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to deliver (R) -4 -sopropyl-2- (2-methyl-4-nitrophenlimin) -2,4,5,5-tetrahydro-1,3-thiazine (100%). C4a. General method for the synthesis of 2-imino-1,3-oxazolidines via the reaction of 2-chloroethylamines with isocyanates. Synthesis of 1- cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspyrro [4,43-nonane.

To a solution of HCl salt of 1- (chloromethyl) -1- (cyclohexylamino) cyclopentane (Method B7b; 1.06 g, 4.2 mmol) and isocyanate 2-methyl-4-nitrophenyl (0.75 g, 4.2 mmol) in 1,2-dichloroethane (10 mL) was added / V-methylmorpholine (0.92 mL, 8.4 mmol). The resulting mixture was heated at 50 ° C for 18 h, then cooled to 20 ° C and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 10% hexane EtOAc / hex) to yield 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspyrro [4.4] nonane (0.021 g, 1.4%): CI-MS m / z 358 ((M + H) +). C5a. General method for the synthesis of 2-iminoheterocyclines via the reaction of aminoethylsulfonate esters with isocyanates or Sothiocyanates Synthesis of 2- (2-methyl-4-nitrophenolimino) -3- (2-methylprop-2-enyl) -1,3-oxazolidine.

To a solution of N- (2-tosyloxyethyl) -2-methylprop-2-en-1-ammonium trifluoroacetate (Method B8b, Step 4, 0.21 g, 0.548 mmol) in p-dioxane isocyanate (5 mL) was added 2-methyl-4-nitrophenol (0.0955 g, 0.536 mmol), followed by Et3N (0.080 mL, 1.15 mmol). The resulting mixture was stirred at 37 ° C overnight, cooled to temp. environment and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL), and washed with water (50 mL). The organic layer was extracted with a 2N HCl solution. The aqueous layer was made basic with a solution of 1 N NaOH, and extracted with CH2Cl2 (50 mL). The organic phase was dried (Na2SO4) and concentrated under reduced pressure to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methylprop-2-enyl) -1,3-oxazolidine as an oil. yellow (0.020 g, 14%) CI-MS m / z 276 ((M + H) +). C5b. General method for the synthesis of 2-iminoheterocyclines via the reaction of aminoethyl sulfonate ethers with isocyanates or isothiocyanates. Synthesis of (4S) -4-1 (R) -ferf-butoxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine Reacted (1R, 2R) -1- (Methanesulfonyloxymethyl) -2- (te / t-butoxy) propanamonium chloride (Method B8a, 1.5 g, 5.5 mmol) with 2-methyl-4-nitrophenyl isothiocyanate in an analogous manner to that described in Method C1a to provide 4 (SH1 (^) - tert-butoxyethyl) -2- (2-methyl-4-nitrophenimlimino) -1, 3-tiazolidine (1.2 g, 67% ). (4S) -2- (2-methyl-4-nitrophenolimin) -4- (1 ((R) -teAt-butoxyethyl) -1,3-thiazolidine was reacted with isobutyl bromide in an analogous manner to Method D2a to produce (4S) -4- (1 (R) -te-butoxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine (0.26 g) , 56%): TLC (25% EtOAc / hex) Rf 0.67 C6a General Method for the synthesis of 2-amino-1,3-thiazolidines via the conversion of chloroethylamines to 2-thioethylamines followed by the reaction with Isocyanide dichlorides Synthesis of HCl salt (4S) -2- (4-Cyano-2-ethylphenylimino) -3,4-dibutybutyl-1,3-thiazolidine.

To a solution of sodium hydrogen sulfide (69 g, 1.2 mmol. 2.2 equiv.) In water (500 mL) was added HCl salt of / V- (1-S) - (1- (chloromethyl) -3- methylbutyl -? / - (isobutyl) amine (Method B7c; 126 g, 0.55 mol, 1.0 equiv.) The resulting mixture was stirred at room temp for 8 hours, then 4-cyano-2-ethylphenyl isocyanide dichloride was added. (Method A3a, 125 g, 0.5 mol, 1.0 equiv.) Followed by isopropyl alcohol (500 mL) The resulting mixture was stirred at room temperature for 1 h, then a 3.6 M K2CO3 solution (305 mL, 2.0 equiv. 1.1 mol) was added and the mixture was stirred at room temperature overnight The resulting organic layer was concentrated under reduced pressure and the residue was treated with EtOAc (2L) The organic layer was washed with water (2M). x 500 mL), dried (MgSO4) and concentrated under reduced pressure to give a dark oil.The oil was dissolved in CH2Cl2 (150 mL) and passed through a plug of silica gel (crude product 3 g SiO2. / 1 g) with the aid of a 5% EtOAc / hex solution to deliver an oil containing the desired product and some residual isocyanide dichloride (134 g). The oil was dissolved in EtOAc (500 mL) and treated with HCl (1N in Et 2 O, 500 mL). The resulting salt of HCl (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazole dina was removed by filtration (147 g, 70%): 1 H NMR (CDCl 3) d 0.96 (d, J = 5.9 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.12 (m, 6 H), 1. 23 (t, J = 7.7 Hz, 3H), 1.46-1.76 (m, 3H), 2.10-2.20 (m, 1 H), 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 (d, J = 14.3, 8.1 Hz, 1 H), 7.32 (d, J = 8.1 Hz , 1.8 Hz, 1 H), 7.51 (dd, J = 8.1, 1? 8 Hz, 1 H), 7.58 (d, J = 1.8 Hz, 1 H). C6b. General method for the synthesis of 2-amino-1,3-thiazolidines via the conversion of chloroethylamines to 2-thioethylamines followed by the reaction with isocyanide dichlorides. Synthesis of HCl salt of 1- cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-tia-1-azaspiro [4.4] nonane.

To a solution of sodium hydrogen sulfide (31 g, 0.55 mol, 2.2 equiv.) In water (250 mL) was added HCl salt of 1- (chloromethyl) -1- (cyclopentylamino) cyclopentane (Method B7d; 60 g , 0.25 mol, 1.0 equiv.). The reaction mixture was stirred at temp. environment for 8h then 2-methyl-4-nitrophenyl isocyanide dichloride (Method A3b, 125 g, 0.25 mmol, 1.0 equiv.) was added followed by isopropyl alcohol (300 mL). The reaction mixture was stirred at temp. environment for 1 hr, then a 3.6 M K2CO3 solution (305 mL, 2.0 equiv., 0.5 mol) was added. The reaction was stirred at temp. atmosphere throughout the night. The resulting upper aqueous organic layer was separated and concentrated under reduced pressure and the residue was treated with EtOAc (1 L), The resulting organic layer was washed with water (2 x 200 mL), dried (MgSO) and concentrated under reduced pressure. . The residual oil (86 g) was dissolved in CH2Cl2 (50 mL) and filtered through a plug of silica gel (crude product, 3 g, SiO2 / 1 g) with the aid of a 5% EtOAc / hex solution. to supply an oil (34 g) containing the desired product and some residual dichloride. The oil was dissolved in EtOAc (300 mL) with HCl (1 N in Et 2 O, 1.5 L). The resulting solids were filtered off to give 1-cyclopentyl-2- (2-methyl-4-nitropheninyl) -3-thia-1-azaspiro [4,4] nonane HCl salt as a powder white (36.8 g): 1 H NMR (CD3OD) d 1.40-1.55 (m, 2H), 1.55-1.68 (m, 2H), 1.68-1.80 (m, 8H), 1. 80-2.00 (m, 4H), 2.16 (s, 3H), 3.16 (s, 2H), 3.60-3.70 (m, 1 H), 6.70 (br s, 1 H), 6. 93 (d, J = 8.4 Hz, 1H), 7.96-8.04 (m, 1H), 8.03 (d, J = 3 Hz, 1H) C6c. General method for the synthesis of 2-amino-1,3-thiazolidines via the conversion of hydroxyethylamines to 2-thioethylamines followed by the reaction of isocyanide dichlorides. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenlimine) -3-thia-1-azaspiro [4,4] nonane.

Step 1 To a solution at 0 ° C of Ph3P (27.9 g, 0.107 mol, 1, 3 equiv.) In anh. THF (400 mL), diisopropyl azodicarboxylate (21.5 g, 0.107 mol, 1.3 equiv.) And 1-cyclopentylamino-1- (hydroxymethyl) cyclopentane (Method B4d, 15.0 g, 0.082 mmol.) Were added successively. . The resulting slurry was stirred for 30 min. , then treated with thiolacetic acid (7.6 mL, 0.107 mol, 1.3 equiv.). The resulting yellow solution was stirred for 15 min. and concentrated with reduced pressure to about 100 mL. The residue was dissolved in EtOAc (200 mL) and the resulting solution was extracted with a solution of 1 N HCl (5 x 125 mL). The combined aqueous layers were washed with EtOAc (2 x 200 mL), neutralized with K2CO3 to pH 7.0-7.5, then extracted with EtOAc (5 x 200 mL). The organic layers were combined, dried (Na2SO) and concentrated under reduced pressure. The residue was dried in vacuo to give cyclopentylamino-1- (thioacetylmethyl) cyclopentane as a yellow oil (19.1 g): TLC (10% EtOAc / hexanes) R, 0.16; 1 H NMR (CDCl 3) d 1.20-1.87 (m, 16 H), 2.34 (s, 3 H), 2.92-3.02 (m, 1 H), 3.15 (s, 2 H); 13 C NMR (CDCl 3) d 23.9, 25.2, 29.3, 36.4, 40.1, 55.8, 73.0, 169.8; CI-LRMS m / z (re abundance), 242 ((M + H) +, 100%).

Step 2 A solution of 1-cyclopentylamino-1- (thioacetylmethyl) cyclopentane (19.1 g) was stirred in a 0.33 M KOH solution in 9: 1 MeOH: H 2 O (273 mL, 0.090 mmol, 1.1 equiv.) Was stirred for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dried in vacuo to give crude 1-cyclopentylamino-l- (thiomethyl) cyclopentane as a yellow oil: TLC (10% EtOAc / hexanes) R, 0.18 (tape); 1 H NMR (CD3OD) d 1.32-1.71 (m, 14 H), 1.87-1.94 (m, 2H), 2.67 (s, 2H), < 3.07-3.14 (m, 1 H); FAB-LRMS m / z (re abundance) 200 ((M + H) +, 19% This material was used immediately in the next step without further purification.

Step 3 A solution of anh. CH2Cl2 of 1-cyclopentylamino-1- (thomethyl) cyclopentane (100 mL) at 0 ° C was treated with a slurry of 2-methyl-4-nitrophenyl isocyanide dichloride (Method A3b, 19.1 g, 0.082 mmol 1.0 equiv based on 1-cyclopentyllamine-1- (thioacetylmethyl) cyclopentane) in CH2Cl2 (200 mL) followed by Et 3 N (30 mL 0.215 mmol, 2.6 equiv,), and the reaction mixture was allowed to warm to temp. environment and it will shake for 2 d. N, N-dimethylethylenediamine (92 g 0.023 mol., 0.3 equiv.) Was added and the reaction mixture was stirred for 1 h. Silica gel (50 g) was added and the resulting mixture was concentrated under reduced pressure. The residue was dried overnight in vacuo and purified by flash chromatography (11 x 10 cm SiO2, 5% EtOAc / hex) to give 1-cyclopentyl-2- (2-methyl-4-nitrophenyl) ) -3-thia-1-azaspiro [4.4] nonane as a yellow granular solid (17.8 g, 60% complete): mp 120-121 ° C; TLC (10% EtOAc / hexanes) R, 0.45; H NMR (CDCI3) d 1.47-1.91 (m, 14H), 2.22 (s, 3H), 2.46-2.55 (m, 2H), 3.03 (s, 2H), 3.66 (pent, J = 8.8 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 7.95-8.03 (m, 2H); 13 C NMR (CDCI3) d 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 (abundance) 360 ((M + H) +, 100%). Anal. Caled. For C19H25N3O2S: C, 63.48; H, 7.01; N, 11.69. Desc .: C, 63.48; H, 6.89; N, 11.76 C7a. General method for the synthesis of 2-imino-1,3-oxazolidines via the reaction of hydroxyethylamines with aryl isocyanate dichlorides. Synthesis of 2- (4-cyano-2-eylphenyl-1-yl) -3-cyclopentyl-4,4-dimethyl-1, 3-oxazolidine.

A solution of? / - cyclopeptyl - (- 1,1-dimethyl-2-hydroxyethyl) amine (Method B4b; 0.12 g, 0.69 mmol) in THF (2.5 mL) was added dropwise via syringe to a slurry. NaH (95%, 0.05 g, 1.2 mmol) in THF (5 mL) temp. ambient. The reaction mixture was stirred 15 min. Then a solution of 4-cyano-2-ethylphenyl isocyanate dichloride (Method A3a, 0.15 g, 0.63 mmol) in THF (2.5 mL) was added dropwise via syringe. The resulting mixture was stirred overnight, then treated with a 5% citric acid solution (10 mL), followed by EtOAc (25 mL). The organic phase was subsequently washed with 5% citric acid solution (20 mL), H 2 O (20 mL) and a saturated NaCl solution (20 mL), dried (Na 2 SO 4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 5% EtOAc / hex) to give 2- (4-cyano-2-ethylphenylimin) -3-cyclopentyl-4,4-dimethyl-1,3-oxazolidine. as a yellow solid (0.09 g, 43%): mp 112-114 ° C; TLC (15% EtOAc / hex) R, 0.60; 1 H NMR (CDCl 3) d 1.16 (t, J = 7.5 Hz, 3H), 1.32 (s, 6H), 1.49-1.61 (m, 2H), < 1.71-1.81 (m, 2H), 1.82-1.92 (m, 2H), 2.38-2.50 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.52-3.58 (m, 1 H), 3.97 (s, 2H), 7.04 (d, J = 8.3 Hz, 1 H), 7.35 (dd, J = 8.1, 1.8 Hz, * 1 H), 7.40 (d, J = 1.8 Hz, 1 H); CI-MS m / z (re abundance) 312 ((M + H) +, 100%). HRMS Cacld for C17H23N3O3; 31 1.1998. desc .: 311.1991 C7b. General method for the synthesis of 2-methyl-1,3-oxazolidines via the reaction of hydrioxyethylamines with aryl isocyanate dichloride. Synthesis of (4S) -2- (4-cyano-2-ethylphenyl) -3,4-diisobutyl-1, 3-oxazolidine.

To a solution of 4-cyano-2-ethylphenyl hydrochloride dichloride (Method A3a, 0.42 g 1.83 mmol, 1.2 equiv.) And (2S) -4-methyl-2- (isobutylamino) pentan-1-ol (Method B4c; 0.26 g, 1.52 mmol) in THF (5 mL) was added Et3N (0.5 mL). The resulting mixture was stirred at temp. environment for 1 h, then treated with 2- (dimethylamino) ethylamine (0.5 mL). This mixture was stirred at temp. environment for 1 hour, then concentrated with reduced pressure. The residue was purified by column chromatography (gradient 5% EtOAc / hex 10% EtOAc / hex) to give (4S-2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1, 3- oxazolidine as a yellow oil (0.15 g): TLC 10% EtOAc / hex R, 0.35, 1 H NMR (CDCl 3) d 0.81-1.00 (m, 12 H), 1.14 (t, J = 4.8 Hz, 3H) , 1.25-1.43 (m, 2H), 1. 53-1.70 (m, 2H), 2.57 (sept, J = 7.5 Hz, 1 H), 2.58 (q, J = 7.5 Hz, 2H), 3.01 (dd, J = 14.0, 6.3 Hz, 1 H), 3.33 (dd, J = 13.6, 8.8 Hz, 1 H), 3.73-3.83 (M, 1 H), 3.94 (app t, J = 7.5 Hz, 1 H), 4.37 (app.t, J = 7.9 Hz , 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 8.1, 1.8 Hz, 1 H), 7.38 (d, J = 1.8 Hz, 1 H); 13 C NMR (CDCI3) d 13.8, 19.9, 20.3, 21.8, 23.6, 24.7, 24.9, 26.7, 40.6, 50.1, 55.3, 70.1, 104, 1, 120.2, 123.4, 129, 9, 131.8, 138.4, 151.4 152.9; HPLC ES-MS m / z 328, ((M + H) +, 100%). C8a. General method for the synthesis of 2-amino-4-oxoheterocycle synthesis via reaction of an isothiocyanate with an amine, followed by the reaction with a halide halide. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-4-one.

To a solution of 2-methyl-4-nitrophenyl isothiocyanate (0.190 g 1.0 mmol) in FDMF (5.3 mL) was added isobutylamine (0.4 M solution in DMF, 5.3 mL) and the reaction mixture was allowed to stir during 4 hours at which time the TLC analysis (hexane, EtOAc 3: 1) indicated the consumption of the isothiocyanate. To the resulting mixture was added chloroacetic acid (0.8 m solution in DMF 4.0 mL), followed by N-methylmorpholine (0.7 mL, 6.4 mmol). The reaction mixture was stirred at 80 ° C for 18 h, then partitioned between water (10 mL) and EtOAc (25 mL). The aqueous phase was subsequently extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with a saturated NaCl solution (25 mL), dried (Na2SO) and concentrated under reduced pressure. The resulting residue was purified by MPLC (Biotage 40 S silica gel column, gradient of 5% EtOAc.hex at 33% EtOAc / hex to give 2- (2-methyl-4-nitrophenyl-m-no) -3- Sobutyl-1, 3-thiazolidin-4-one as a pale yellow oil (0.52 g 85%) C9a General method for the synthesis of 2-imino-1,3-thiazolidines by reaction of hydroxyethylamines with isothiocyanates followed by acid catalyzed ring closure Synthesis of 2- (2,6-dichlorophenylimino) -3-cyclohexy-4,4-dimethyl-1,3-thiazolidine.

? / - Cyclohexyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method N4a. A solution of 2,6-dichlorophenyl isothiocyanate (1.2 g, 6.0 mmol) and N-cyclohexyl-1,1-dimethyl-2-hydroxyethanamine (1.0 g, 6.0 mmol) in CH 2 Cl 2 (10 mL) was stirred for 20 h at room temperature. ambient. The resulting mixture was concentrated under reduced pressure, then treated with 33% HCl solution (15 mL). The resulting mixture was heated at reflux temperature for 1 hr, cooled to room temperature and neutralized with 45% NaOH solution. The resulting slurry was filtered and the resulting solids were washed with water (20 mL), then recrystallized (EtOH) to yield 2- (2,6-dichlorophenylimino) -3-cyclohexyl-4,4-dimethyl-1, 3-thiazolidine (0.70 g 33%): mp 134 ° C. When appropriate, the product was converted to HCl salt by dissolving the free base (5 mmol, in Et2O (50 mL) and treating this solution with ethereal HCl solution until that did not precipitate more solid.

The resulting slurry was filtered and the resulting solids were washed with Et2O (25 mL) followed by EtOAc (25 mL). C10a. General method for the reaction of 2-ciotothiazolinium salts with anilines. Synthesis of 2- (2- (N-phenylcarbamoyl) phenylimino) -3,4-diisobutyl-1,3-thiazolidine.

A solution of 2 - (? / - phenylcarbamoyl) aniline (0.097 g, 0.36 mmol, 1.0 equiv.) And Et3N (0.5 mL, 3.6 mmol, 10 equiv.) In p-dioxane (5 mL) was added to a chloride solution of (4S) -2-chloro-3,4-diisobutyl-4,5-dihydro-1,3-thiazolinium in dichloroethane (Method B10a: 0.12 M, 0.5 mL, 0.36 mmol). The resulting mixture was heated at 70 ° C overnight, then cooled to room temperature and diluted with EtOAc (25 mL). The EtOAc mixture was washed sequentially with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was absorbed in SiO2, and purified by MPLC (Biotage 40 S Silica Gel column: 5% EtOAc / hex) to give 2- (2 - (/ V-Fepilcarbamoyl) phenylimino) -3,4-d¡¡sobuty-1,3-thiazolidine (0.090 g , 61%). C11a. General method for the synthesis of 2-imino-1,3-thiazolidin-5-ones via the reaction of the ethers of the amino acids with isothiocyanates. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazolidin-5-one.

A solution of ethyl ester of? / - isobutylglycine (0.41 g, 2.57 mmol) in water (5 mL) was treated with Et3N (0.71 mL, 5.15 mmol), followed by a solution of 2-methyl-4-nitrophenyl isocyanate. (0.50 g, 2.57 mmol) in acetone (5 mL). The resulting mixture was heated at 40 ° C for 2 h, then cooled to temp. environment and concentrated with reduced pressure. The residue was separated between water (25 mL and ethyl acetate (25 mL) .The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl- 1, 3-thiazolidin-5-one (0.16 g, 88%): mp 152 ° C. D1a General methods for the interconversion of immunoheterocycles D1a General method for the neutralization of iminoheterocycle salts Synthesis of (4S) -2- (4-Cyano-2-eti-Phenylimino) -3,4-diisobutyl-1,3-thiazolidine.

To a mixture of HCl (4S) -2- (4-cyano-2-ethylphenylamino) -3,4-diisobutyl-1,3-thiazolidine salt (Method C6a; 304 g, 0.8 mol), water (1 L) and EtOAc (1.4 L) was added NaHCO3 (150 g 1.78 mol, 2.2 equiv.). The resulting mixture was stirred for 1 h. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting viscous oil was treated with EtOH and concentrated under reduced pressure twice to deliver (4S) -2- (4-cyano-2-ethylphenyl) -3,4-diisobutyl-1, 3- tzolzolidine as a slow melting solid (264 g, 96%): mp 50 ° C; [α] D = +2.4 (c 1.0, CH 3 OH); 1 H NMR (CDCl 3) d 0. 92-0.99 (m, 12 H), 1.13 (t, J = 7.4 Hz, 3 H), 1.47-1.52 (m, 1 H), 1.58-1.67 (m, 2 H), 2.07 -2.11 (m, 1H), 2.54 (q, J = 7.4 Hz, 2H), 2.84-2.90 (ni, 2H), 3.28 (dd, J = 10.6, 6.6 Hz, 1 H), 3.68, (dd, J = 13.6, 8.1 Hz, 1 H), 3.81-3.87 (m, 1 H), 6.85 (d, J = 7.9 Hz, 1 H), 7.36-7.42 (m, 2H); CI-MS m / z 344 ((M + H) +). D1 b. General method for the neutralization of iminoheterocycle salts. Synthesis of 1-cyclopethyl-2- (2-methyl-4-nitrophenimlimino) -3-thia-1 -azaspiro [4.4] nonane.

To a HCl salt of 1-cyclopentyl-2- (2-methylene-4-nitrophenylmethyl) -3-thia-1-azaspiro [4,4] nonane (Method C6b; 52.4 g, 0.132 mol) dissolved in a mixture of water (300 mL) and EtOAc (500 mL) was added NaHCO3 (15 g, 0.178 mol, 1.3 equiv.) The mixture was stirred for 1 hour and the resulting organic layers were dried in ( MgSO 4) concentrated under reduced pressure. The resulting mild yellow solid was treated with EtOH (100 mL), and concentrated under reduced pressure two hete, ocíelo. Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitrophenyl) m? No) -3-t? A-1-azaspiro [4,4] nonane.

To a solution of 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspyrro [4,4] nonane (Method C2a; 33.2 g, 114 mmol.) In DMF (1 L) was treated with NaOH (690 g, 17.3 mol) and cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was stirred at 20 ° C. 40 ° C, for 18 h., Then cooled to 4 ° C, and treated with water (1.5 L). A conc. HCl to adjust the pH to 0, and the mixture was extracted with EtOAc (80 mL). The organic phase was washed with a 1 N HCl solution (1L), dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (500mL) and filtered through a pad of silica gel (9x4 cm). Hexane, the resulting solution was added and the volatiles were removed very slowly by partial vacuum until the crystals formed. The solids were collected to produce 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-tia-1-azaspyrro [4,4] nonane as yellow crystals (10.9 g 26%): mp 118-9 ° C; TLC (5% EtOAc / hex) Rf 0.34. D2c. General method for the alkylation of the nitrogen ring of 2-imino heterocycle. Synthesis of (4R) -3-isobutii-4-isopropyl-2- (2-methyl-4-nitrophenylimino) tetrahydro-2-H-1,3-thiazine. times to give 1-cyclopentyl-2- (2-methyl-4-nitrophenolimino) -3-tia-1-azaspi or [4,4] nonane (46 g, 97%) : mp 1 11-1 12 ° C; 1 H NMR (CDCl 3) d 1.49-1.53 (m, 2H), 1.63-1.80 (m, 8H), 1.81-1.91 (m, 4H), '2.21 (s, 3H), 3.02 (s, 2H), 3.60 -3.70 (m, 1 H), 6.87 (d, J = 8.5 Hz, 1 H), 8.02 (m, 2H): CI-MS m / z 360 ((M + H) +). D2a. General method for the alkylation of the nitrogen ring of 2-imino heterocycle. Synthesis of the HCl salt of (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine.

A slurry of (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine (Method C1 a, 0.10 g, 0.34 mmol), sodium bromide (0.11 g) mL, 1.03 mmol) and C2CO3 (0.12 g, 0.38 mmol) in DMF (2 mL) was heated at 90 ° C for 18 h. And then cooled to 20 ° C, diluted with EtOAc (50 mL) and washed with water (2 x 200 mL). The organic phase was dried (MgSO4), concentrated under reduced pressure, and the residue was purified by chromatography (SiO2, gradient of 100% hex at 10% EtOAc / hex). The resulting material was dissolved in CH2Cl2 (10 mL), treated with a solution of HCl (1 M in Et2O, 2 mL), then concentrated under reduced pressure to give a salt of HCl (4S) -2- (2-methyl) -4-n-phenylphenyl-1-yl) -3,4-diisobutyl-1, 3-thiazolidine (0.088 g, 68%): TLC (free base, 20% EtOAc / hex) R, 0.74. D2b. General method for alkylation of the 2-imino nitrogen ring Reacted (R) -4-isopropyl-2- (2-methyl-4-nitrophenylimino) -2,3,4,5-tetrahydro-1 , 3-thiazine Method C3a) with isobutyl bromide in a manner analogous to Method D2a to produce (4R) -3-isobutyl-4-isopropyl-2- (2-methyl-4-nitrophenynylamino) tetrahydro-2H -1, 3-thiazine (0.081 g, 32%) TLC (33% EtOAc / hex) R, 0.76. D2d. General method for the alkylation of the nitrogen ring of 2-imino heterocycle. 2- (2-Methyl-4-nitrophenylimino) -3-propanoyl-1,3-thiazolidine.

To a solution of 2- (2-methyl-4-nitrophenlimine) -1,3-t-azolidine (prepared in a manner analogous to that described in Method C1a, 0.084 g, 0.35 mmol) in CH2Cl2 ( 5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and Et3N (0.049 mL, 0.35 mmol). The mixture was allowed to stir at temp. environment for 1 h, then it was diluted with CH2CI2 (40 mL). The resulting solution was washed sequentially with H2O (10 mL) and saturated with NaCl solution (10 mL), dried (Na2SO), and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc / hex) to give 2- (2-methyl-4-nitrophenynylamino) -3-propanoyl-1,3-thiazolidine (0.036 g, 35%): Fab-MS m / z 294 ((M + H) +) D2e. General method for alkylation of the nitrogen ring of 2-imino heterocycle. Synthesis of 1- (cyclohexylmethyl) -2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane.

To a solution of 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. (Method C2a, 0.10 g, 0.3432 mmol) and bromomethylcyclohexane (1.00 mL) in DMF (1.00 mL) was added with NaOH (ca 0.13 g). The resulting mixture was stirred at 45 ° C for 2 d during which it turned from deep red to bright orange. The reaction mixture was then cooled to temp. environment, filtered and concentrated under reduced pressure. The residual oil was purified by chromatography (SiO2: 5% EtOAc / hex) to give 1- (cyclohexylmethyl) -2- (2-methyl-4-nitrophenylin) -3-thia-, 1 * -azaspiro [4, 4] nonane (0.042 g, 32%) mp 85-7 ° C. D2f. General method for the alkylation of the nitrogen ring of 2-imino heterocycle. Synthesis of the (4S) -2- (2-chloro-4-cyano-6-methylphenylamino) -3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.

To a solution of (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 NaH (0.0045 g, 1.1 equiv.), and the resulting mixture was stirred at temp. environment for 5 min. Isobutyl bromide (0.053 mL, 3 equiv.) Was then added and the resulting mixture was stirred at 98 ° C for 4 h. The reaction mixture was filtered, then concentrated under reduced pressure. The residue was purified by HPLC preparative reverse phase (column C-18, gradient from 0.1% TFA / 20% CH3CN / 79.9%, water at 0.1% TFA / 99.9% CH3CN) to provide a trifluoroacetate salt (4S) -2- (2-Chloro-4-cyano-6-methylphenylimino) -3,4-diisobutyl-1,3-tiazolidine (0.030 g, 52% yield). D2g. General method for alkylation of the nitrogen ring of 2-imino heterocycle. Synthesis of the HBr salt of 2- (2-methyl-4-nitropheniimino) -3- (2-methyl-prop-2-enyl) -4,4-dimethyl-1,3-thiazolidine. 2- (2-Methyl-4-nitrophenolinylamino) -4,4-dimethyl-1,3-thiazolidine was prepared in a manner analogous to that described in Method C1a. To a suspension of 2- (2-methyl-4-nitrophenynylamino) -4,4-dimethyl-1,3-thiazolidine (1.5 mmol) in toluene (10 mL), 2-methylpropyl bromide was added. -2-in-1-yl (4.5 mmol) and the reaction mixture was warmed to temp. reflux for 3 hrs, at which time the reaction was judged to be complete by TLC. The resulting precipitate was filtered at 50 ° C. The collected solids were then washed with toluene (20 ml) and CH 2 Cl 2 (20 ml) to produce a salt of HBr 2- (2-methyl-4-nitrophenylimino) -3- (2 -met.l-prop-2-enyl) -4,4-dimethylM, 3-thiazolidine (1.14 g, 77%); mp 229 ° C. D2h. General Method for the alkylation of the nitrogen ring of 2-imino heterocycle. Synthesis of 2- (2,4-dimethyl-3-cyano-6-pyridlimino) -1-isobutyl-3-thia-1 -azaspiro [4.4] nonane To a solution of 2- (2, 4-dimethyl-3-cyano-6-pyridyl-1-yl) -3-tia-1-azaspiro [4,4] nonane (Method C1e, 0.192 g, 0.669 mmol) and bromide of isobutyl (0.5 mL) in anh. DMF (0.5 mL) was added NaH (95%, 0.62 g, 6.69 mmol) as a portion. The resulting mixture was heated at 50 ° C for 3 h, then treated with MeOH (approximately 0.5 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 20% EtOAc / hex to 100% CH2CI2) to give 2- (2,4-d-methylene-3-cyano-6-pyridylimino) -1-isobutyl -3-thia-1 -azaspiro [4.4] nonane (0.04 g, 17%): CI-MS m / z 343 ((M + H) +). D3a. General method for the deprotection of tert-butoxycarbamoyl-protected alcohols. Synthesis of (4S) -4- (1 (R) -hydroxyethyl) -3-isobutyl-2- (2-methyl-4-nitrophenimlimino) -1,3-thiazolidine.

A solution of TFA (8 ml) was cooled to 4 ° C and added to the solid (4S) -4- (1 (R) -tert-butoxyethyl) -3-isobutyl-2- (2-methyl-4-) nitrophenylimino) -1,3-thiazolidine (Method C5b; 0.16 g, 0.42 mmol) via cannula. The resulting solution was heated to 20 ° C and stirred at that temp. for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between ETO (100 mL) and saturated NaHCO3 solution (100 mL). The ether layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SIO2); gradient hexane at 10% EtOAc / hex) to yield (4S) -4- (1 (R) -hydroxyethyi-3-isobutyl-2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine ( 0.13 g, 90%): TLC (25% EtOAc / hex) R, 0.13 D4a General method for the synthesis of 2-imino-1,3-thiazolidine 3-oxides and 2-imino-1,3-thiazolidine 3 , 3-dioxides via the oxidation of 2-imino-1,3-thiazolidines Synthesis of 1-cyclopentyl-2- (2-methyl-4-nitropheninyl) -3-thia-1- azaspiro [4,4] nonane 3-oxide and 1-cyclopentyl-2- (2-methyl-4-nitrophenolimino) -3-thia-1 -azaspiro [4,4] nonane 3,3-dioxide.

A solution of 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4,4] nonane (Method D2b, 0.041 g, 0.11 mmol) and m-acid chloroperbenzoic (about 80%, 0.040 g, 0.19 mmol) in CH2Cl2 (5 mL) was stirred for 30 min., then washed with saturated NaHCO3, dried over (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (S¡02, hexane gradient to 30% EtOAc / hex) to yield 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4,4] nonane 3,3-dioxide (0.030 g, 67%) followed by 1-cyclopentyl-2- (2-methyl-4-n-prophenylimino) -3-thia-1-azaspyrro [ 4,4] nonane 3-oxide (0.011 g, 26% 1-cyclopentyl-2- (2-methyl-4-nitrophenolinylamino) -3-thia-1-azaspyrro [4,4] nonane 3,3-dioxide; TLC (25% EtOAc / hex) Rf 0.27. 1-Cyclopentyl-2- (2-methyl-4-n-phenylphenyl-1-yl) -3-thia-1-azaspyr [4,4] nonane-3-oxide; TLC (25% EtOAc / hex) R 0.10. D5a. General method for the reduction of heterocycles containing ketones or aldehydes. Synthesis of 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-hydroxybutyl) -1,3-thiazolidine. 2- (2-Methyl-4-nitrophenimlimino) -1,3-thiazolidine was prepared in an analogous manner as described in the C2a method and was alkylated with 1-bromo-3,3-dimethyl-2-butanone in a manner analogous to that described in Method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-oxobutyl) -1,3-thiazolidine. To a solution of 2- (2-methyl-4-nitrophenylimino) -3- (3,3-dimethyl-2-oxobutyl) -1,3-t-azolidine (0.022 g, 0.065 mmol) in MeOH (2 mL) was added NaBH4 (0.0096 g, 0.26 mmol) in portions. The resulting mixture was stirred at room temp for 4 h, then it was separated between EtOAc (10 mL) and H20 (5 mL) and the aqueous layer was extracted with EtOAc (3 x 10 L). The combined organic layers were sequentially washed with H2O (15 mL), a saturated NaCl solution (15 mL) was dried with (Na2SO4), concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc / hexane) to yield 2- (2-methylene-4-nitrophenlimine) -3- (3,3-dimethyl-2-hydroxybutyl) - 1,3-thiazolidine (0.024 g, 92%): FAB-MS m / z 338 ((M + H) +). D6a. General method for the interconversion of carboxylic acid derivatives. Synthesis of (4S) -2- (4-carbamoyl-2-methylphenyl) -3,4-diisobutyl-1,3-thiazolidine.

To a solution of (4S) -2- (methoxycarbonyl-2-methylphenylimin) -3,4-diisobutyl-1,3-thiazolidine (prepared in a manner analogous to that described in Method D2a; 0.035 g, 0.097 mmol) in a mixture of MeOH (1.5 mL) and H 2 O (1.5 mL) was added LIOH (0.016 g, 0.39 mmol). The resulting mixture was stirred for 2 d at room temp, then concentrated under reduced pressure. The pH was adjusted to the residue with a 1% HCl solution, then extracted with EtOAc (4 x 10 ml). The combined organic layers were sequentially washed with H 2 O (15 mL), and a saturated NaCl solution (15 mL). , and dried on (Na2SO4). Concentrations with reduced pressure gave (4S) -2- (4-carboxy-2-methylphenylamino) -3,4-diisobutyl-1,3-thiazolidine (0.034 g, 100%): TLC 40 % EtOAc / hex) Rf 0.08. This material was used in the next step without further purification.

Step 2 To a solution of (4S) -2- (4-carboxy-2-methylphenylimino) -3,4-diisobutyl-1,3-thiazolidine (0.035 g, 0.10 mmol) in CH 2 Cl 2 (5 mL) was added diimidazole. carbonyl (0.047 g, 0.29 mmol). The mixture was allowed to stir at room temp for 2 h, then anh NH3 (about 30 drops) was condensed in a solution at -78 ° C. The resulting mixture was heated to temp. atmosphere overnight, then treated with H2O (20 mL). The aqueous layer was extracted with CH2Cl2 (3 x 20 mL), washed sequentially with H2O (20 mL) and saturated with NaCl solution (20 mL), dried (Na2SO) and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc / hexane) to give (4S) -2-4-carbamoyl-2-methylphenlimino) -3,4-diisobutyl-1,3-thiazole diene as a white solid (0.027 g, 73%): mp 130 -131 ° C. D6b. General method for the interconversion of carboxylic acid derivatives. Synthesis of 2-2- (ethyl-4- (N-methylcarbamoyl) phenylimino) -1- cyclopentyl-3-thia-1 -zaspicy [4,4] nonane.

To a solution of 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D9a, 0.58 g, 0.167 mmol) in CHCl3, (5 mL) was added SOCI2 (0.06 ml, 0.83 mmol). The reaction mixture was heated at reflux temp for 3 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (3 mL) and treated with methylamine (2.0 M in THF, 4 mL). The reaction mixture was stirred at temp. environment for 2 h, then treated with a solution of 1 N NaOH (10 mL). The resulting mixture was extracted with CH2Cl2 (3 x 20 mL), and the organic layers were washed with a saturated NaCl solution (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc / hexane) to give 2- (2-ethyl-4- (N-methylcarbamoyl) phenylimin) -1-cyclopentyl-3-tia-1-azaspiro [4 , 4] nonane (36 g 56%): TLC (30% EtOAc / hex) Ref 0.44, D7a. General method for the synthesis of cyanoarilimines from iodoarilimines. The synthesis of 2- (4-cyano-2-propylphenylimino) -3-thia-1- azaspiro [4.4] nonane. 4-iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphiol isothiocyanate analogously to that described in Method A2b. Concurrently, 1-amino-1- (hydroxymethyl) cyclopentane was converted to chloromethyl analogue, then reacted with isothiocyanant in a manner analogous to Method C2a to give 2- (4-iodo-2-propylphenylimino) -3-thia. -1-azaspiro [4.4] nonane. A slurry of 2- (4-iodo-2-propylphenylimino) -3-thia-1-azaspiro [4.4] nonane (0.54 g 1.35 mmol) and CuCN (0.24 g 2.70 mmol) in DMF (4 mL) was heated. at 140 ° C throughout the night. The resulting mixture was cooled to temp. environment, concentrated under reduced pressure and purified by chromatography (10% EtOAc / hex) to give 2- (4-cyano-2-propylphenylimino) -3t-a-1-azaspiro [4.4} nonane as a white solid (0.26 g, 65%): TLC (30% EtOAc / hex) R, 0.37.

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

Step 1 4-iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenol isothiocyanate in a form analogous to Method A2b 2- (2,3-dimethyl-4) -iodiphenyl-amino) -3-tia-1-azaspiro [4.4] nonane was prepared analogously to that described in Method C2a, then it was alkylated with isobutyl bromide in a manner analogous to that described in the D2a method: A mixture of iodophenyl compound (0.009 g, 0.021 mmol), (trimethylsilyl) acetylene (30 mL, 0.21 mmol), Pd (PPh3) CI2 (0.005 g) and Cul (0.012 g, 0.063 mmol) in Et3N (2 mL) was stirred at room temp for 18 hrs The resulting slurry was filtered, and the filtrate was concentrated under reduced pressure The residue was purified by preparative TLC (2% EtOAc / hex) to give 2- (2.3 -dimethyl-4- (2-trimethylsilyl-1-ethynyl) phenlimino) -1-isobutyl-3-tia-1-azaspiro [4.4] nonane (0.005 g, 59%).

Step 2 A mixture of 2- (2,3-dimethyl-4- (2-trimethylsilyl-1-ethynyl) phenylamino) -1 -sobuty-α-thia-1-azaspiro [4.4] nonane (0.005 g, 0.0125 mmol) and NaOH (0.006 g), 0.15 mmol) in MeOH (2 mL) was stirred overnight at temp. ambient. The reaction mixture was diluted with CH2Cl2 (20 mL), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prepartial TLC (2% EtOAc / hex) to give 2- (2,3-d-methyl-4-ethynylphenylamino) -1-isobutyl-3-t-a-1- e-.spiro [4.4] nonane (0.0032 g, 78%): TLC (20% EtOAc / hex) R, 0.70 D9a. General method for the synthesis of benzoic acids via the hydrolysis of benzonitriles. Synthesis of 2- (4-carboxy-2-ethylphenylamino) -1- cyclopentyl-3-thia-1 -azaspiro [4.4] nonane. 2- (4-Cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4,4] nonane was prepared in a manner analogous to Method C2a and the thiazolidine was alkylated in a manner analogous to Method D2b to give 2- (4-cyano-2-ethelfenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. A solution of 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (0.32 g, 9.42 mmol) in conc. HCl (15 mL) was heated at 100 ° C overnight, then cooled to temp. environment to give a white precipitate. The resulting mixture was adjusted to pH 6.5 with a solution of 1 N NaOH, then extracted with CH 2 Cl 2 (4 x 40 mL). The combined organic layers were sequentially washed with water (30 mL) and saturated with NaCI solution (30 mL), dried (Na2SO) and concentrated under reduced pressure, to give 2- (4-carboxy-2-ethylphenimlimino) - 1-cyclopentyl-3-thia-1-azaspyrro [4,4] nonane as a white solid (0.34 g 100%): mp 208-209? C. D10a. General method for the conversion of carboxylic acids into ketones. Synthesis of 2- (4-acetyl-2-eti-phenyl-imino) -12-cyclopentyl-3-t-a-1-azaspyrro [4.4-mononane.

To a solution of 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-tia-1-azaspiro [4.4] nonane (Method D9a, 0.046 g, 0.128 mmol) in THF (10 mL ) at -78 ° C methyllithium (1.4 M in Et2O, 0.91 mL, 1.28 mmol) was added. The reaction mixture was allowed to run while gradually warming to temp. environment, then agitated throughout the night. The detrimethylsilyl chloride (0.5 mL) was added and the mixture was stirred at temp. environment for 2 h, then a solution of 1 N HCl (2 mL) was added. The mixture was stirred for 0.5 h, then treated with a saturated solution of NaHCO3 (10L). The resulting mixture was extracted with EtOAc (4 x 20 mL), and then the combined organic layers were washed with a saturated NaCl solution (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative TLC (10% EtOAc / hex) to give 2- (4-acetyl-2-ethylphenylamino) -1-cyclopentyl-3-thia-1-azaspiro [4, 4] nonane as a white solid (0.0032 g, 73%): mp 1 14-1 15 ° C. D11a. General method for the conversion of nitriles into aldehydes. Synthesis of 2- (2-ethyl-4-formylphenylimino) -1- cyclopentyl-3-thia-1-azaspiro [4,4] nonane. 2- (4-Cyano-2-ethylphenylamino) -3-thia-1-azaspyrro [4,4] nonane was prepared in a manner analogous to Method C2a and the thiazolidine was alkylated in the analogous manner to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspyrro [4,4] nonane. To a solution of 2- (4-cyano-2-ethylphenylamino) -1-cyclopentyl-3-thia-1-azaspyrro [4,4] nonane, a (0.21 g, 0.60 mmol) in anh. toluene (20 mL) at -78 ° C, DIBAL (1.0 M in toluene, 1.20 mL, 1.20 mmol) was added. The mixture was stirred at -78 ° C for 3 h, then EtOAc (3 mL) was added at -78 ° C, stirring continuously for 0.5 h, and wet silica gel (5% water, 2%) was added. g). The reaction mixture was heated to temp. environment, stirred for 3 h, then 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 as a white solid (0.16 g, 75%); mp 104 -105 ° C. D12a. General methods for the approval of the chain of aldehydes or ketones. Synthesis of 2- (2-ethyl-4 - ((1 £) -2-eioxycarbonylvinyl) phenylimin) -1-cyclopentyl-3-thia-1 -zaspiro [4.4] nonane.

To a solution of 2- (2-ethyl-4-formylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D11a; 0.053 g, 0.149 mmol) in CH3CN was added LiCl (0.0076 g, 0.182 mmol) followed by DBU (0.025 g, 0.167 mmol) and triethyl phosphonoacetate (0.041 g, 0.182 mmol). The reaction mixture was stirred at room temperature for 18 h, then it was concentrated under reduced pressure. The residue was purified by flash chromatography (3% EtOAc / hex) to obtain 2- (2-ethyl-4 - ((1 £) -2-ethoxycarbonylvinyl) phenylimin) -1-cyclopentyl-3-thia -1-azaspiro [4.4] nonane as a colorless oil (0.029 g, 48%): TLC (30% EtOAc / hex) R / 0.68. D12b. General methods for the approval of the chain of aldehydes or ketones. Synthesis of 2- (2-ethyl-4 - ((1 £) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1 -zaspiro [4.4] nonane.

To a solution of 2- (2-ethyl-4-formylphenimlimino) -1-c-clopentyl-3-tia-1-azaspiro [4.4] nonane (Method D11a, 0.041 g, 0.115 mmol) in CH 2 Cl 2 He added MeNO2 (2 drops) and piperidine (4 drops). The reaction mixture was heated at reflux temperature 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 - ((1 £) -2-nitrovinyl) phenylimino) -1-cyclopentyl-3-thia-1 -azaspiro [4.4] nonane as a red solid (0.022 g, 48%): mp 141-142 ° C. D12c. General methods for the approval of aldehyde chains or ketones. Synthesis of 2- (2-ethyl-4- (2,2-dicyanovinyl) phenylimino) -1-cyclopentyl! O-3-thia-1-azaspiro [4.4] nonane.

To a solution of 2- (2-ethyl-4-formylphenyl) mn) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D11a, 0.037 g, 0.104 mmol) in EtOH (10 mL ) was added malononitrile (0.007 g, 0.104 mmol) and piperidine (4 drops). The reaction mixture was stirred for 2 h. at room temperature, then concentrated under reduced pressure. The residue was purified with the TLC preparation (20% EtOAc / hex) to give 2- (2-ethyl-4- (2,2-dicyanovinyl) phenolimin) -1- Cyclopentyl-3-thia-1-azaspiro [4.4] nonane as a yellow solid (0.012 g, 28%): mp 135-136 ° C: D12d. General method for the approval of the chains of aldehydes or ketones. Synthesis of 2- (2-ethyl-4- (cyanovinyl) phenylimino) -1- cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

To a solution of KOH (0.024 g, 0.36 mmol) in CH3CN (20 mL) was added at temp. reflux 2- (2-ethyl-4-formylphenyl) mn) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane (Method D11a, 0.127 g, 0.36 mmol). The reaction mixture was heated to temp. reflux for 4 h, cooled to temp. environment, and concentrated under reduced pressure. The residue was diluted in water (15 mL) and extracted with CH2Cl2 (3x15 mL). The combined organic layers were washed with a saturated NaCl solution and dried (Na2SO4). The resulting material was purified with the TLC preparation (30% EtOAc / hex) to give 2- (2-ethyl-4- (2- cyanovinyl) phenolimino) -1-cilcopentyl-3-t. Α-1-azaspiro [4.4] nonane as a mixture of 1: 3 cis / trans isomers (0.050 g): TLC (30% EtOAc / hex) Rf 0.56. D13a. General method for the alkylation of chloromethyl side chains. Synthesis of 2- (2-methyl-4-nitrophenynylamino) -4 - (/ V-methylaminomethyl) -1,3-thiazolidine.

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

D14a. Rearrangement of the catalyzed acid of carbon-carbon double bonds. Synthesis of 2- (4-nitrophenylimino) -3- (2-methylprop-1-en-1-yl) -1, 3-thiazolidine.

The 2-chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method C1a to give 2- (4-nitrophenyl) -1,3-thiazolidine. The thiazolidine was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2- (4-nitrophenylimino) -3- (2-methyl-2-en-1-yl) -1, 3-thiazolidine.

A mixture of 2- (4-nitrophenolimino) -3- (2-methy1prop-2-en-1-ylo) -1,3-thiazolidine (0.20 g) in polyacid phosphoric) (0.4 mL) was heated at 80 ° C for 5 h. The reaction mixture was then dissolved in water (20 mL) at 0 ° C with the aid of sonication. The aqueous mixture was adjusted to pH 12 with a solution of 1 N NaOH, then extracted with EtOAc (3 x 25 mL). The combined organic phases were dried in (K CO3) and concentrated with reduced pressure. The residue (0.21 g) was purified by preparative HPLC to give 2- (4-nitrophenylimin) -3- (2-methylprop-1-en-1-ylo) -1,3-thiazolidine. PREPARATION OF SPECIFIC COMPOUNDS Below are detailed descriptions of the preparatory steps used to prepare the specific compounds listed in Tables 1-4.

Many of the compounds listed in the Tables can be synthesized following a variety of methods. The specific examples that follow are provided for illustration only and should not be interpreted, in any way, as to limit the scope of the invention.

Entry 1 The HCl 2-Chloroethylamine salt was reacted with the 2-methyl-4-nitrophenyl-isothiocyanate according to Method C1 to obtain 2- (2-methyl-4-nitrophenolimino) -1,3-thiazolidine.

Entry 2 X > = N- W // -NO, i-Bu The 2-chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl sothiocyanate, according to Method C1a to give 2- (4-nitrophenylimino) -1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a, to obtain 2- (4-nitrophenylmethyl) -3-isobutyl-1,3-thiazolidine.

Entry 3 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate, which was reacted with isobutyl bromide according to Method D2a to give 2- (2-methyl-4-n) trofenlimino) -3-butyl-1, 3-thiazolidine.

Entry 4 2-Chloroethylammonium chloride (Entry 1) was reacted with isothiocyanate, 3-dichlorophenyl according to Method C1a, to give 2- (2,3-dichlorophenylimin) -1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2- (2,3-dichlorophenolumin) -3-butyl-1,3-thiazolidin.

Entry 5 The? / - Chloroetyl-? / '-isobutylammonium chloride (prepared as described in Method B7c) was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to Method C1d, to obtain 2- (2 -methoxy-4-nitrophenlimin) -3-isobutyl-1,3-thiazolidine.

Entry 6 The? / - Chloroethyl-? / '- isobutylammonium chloride (prepared as described in Method B7c) was reacted with 4-cyanophenyl isothiocyanate according to Method C1d, to obey 2- (4-cyano-phenyl-amino) -3-isobutyl-1,3-tiazole.

Entry 7 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-5-nitrophenyl sothiocyanate, according to Method C1a, to give thiazolidine, which was reacted with isobutyl bromide according to Method D2a, to give a salt of HCl, 2- (2-methyl-5-nitrophenylmethyl) -3-butyl-1,3-thiazole.

Entry 8 Chloride of? / - Chloroethyl-? / - - sobutyl ammonium (prepared as described in Method B7c) was reacted with 4-cyano-2-ethenoxy-thiocyanate according to Method C1d, to obtain 2- ( 4-cyano-2-ethylene-1-yl) -3-isobutyl-1,3-thiazolidine.

Entry 9 Chloroethane / V'-sulphonyl chloride (prepared as described in Method B7c) was reacted with 4-chloro-2- (trifluoromethyl) phenylisothiocyanate according to Method C1d, to give 2- (4-chloro-2- (trifluoromethyl) phenylimino-3-isobutyl-1,3-thiazolidine.

Entry 10 2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method C1a to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene according to the Method D2a to give 2- (4-nitrophenylimino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine. 3-Allyl-1,3-thiazolidine was rearranged according to Method D14a to give 2- (4-nitrophenylimino) -3- (2-methylprop-1-en-1-ylo) -1,3-t Azolidine.

Entry 11 The 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene from According to Method D2a, to give 2- (2-methyl-4-nitrophenolinylamino) -3- (2-methylprop-2-en-1-yl) -1,3-thiazolidine.

Entry 12 The 2-chloroethylammonium chloride (Input 1) was reacted with 4-nitrophenyl sothiocyanate according to Method C1a to give the thiazolidine, which was reacted with 1-bromo-2-methyl-2-propene according to Method D2a to give 2- (4-nitrophenylmethyl) -3- (2-methylprop-2-en-1-ylo) -1,3-thiazolidine.

Eted 13 The 2-Chloroethylammonium chloride (Entry 1) was reacted with 3,4-dichlorophenyl isothiocyanate according to Method C1a to obtain the thiazolinoline, which was reacted with 1-bromo-2-methyl-2-propene according to with Method D2a for the preparation of 2- (3,4-dichlorophenylimin) -3- (2-methy1prop-2-en-1-yl) -1,3-thiazolidine.

Entry 14 ? / - (2-Hydroxyethyl) -? / - (2-methylbutyl) amine, was reacted with SOCI2 according to Method B7a to give N- (2-chloroethyl) -? / - (2-methylbutyl) chloride ammonium. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl) -1,3 -thiazolidine.

Entry 15 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give thiazolidine, which was reacted with 4-bromobut-1-ene according to Method D2a to give 2- (2-methyl-4-nitrophenlimin) -3- (but-1-en-4-ylo) -1,3-thiazolidine.

Entry 16 Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give thiazolidine, which was reacted with 1-bromobut-2-yn, according to Method D2a to give 2- (2-methyl-4-nitrophenynylamino) -3- (but-2-yn-1-ylo) -1,3-thiazolidine.

Entry 17 The 2-chloroethylammonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give the thiazolidine, which was reacted with 2-ethylbutyl bromide according to Method D2a to give 2- ( 2-methyl-4-nitrophenylmethyl) -3- (2-ethyl-1-butyl) -1,3-tiazolidine.

Entry 18 The 2-chloroethylammonium chloride (Step 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C1a to give the thiazolidine, which was reacted with 2-methylbutyl bromide according to the Method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-methyl-1-butyl) -1,3-thiazolidine.

Entry 19 The 2-chloroethyl ammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give thiazolidine, which was reacted with 1-nonyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenynylamino) -3- (1-nonyl) -1, 3-tiazolidine.

Entry 20 The 2-chloroethylammonium chloride (Entradal) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give the thiazolidine, which was reacted with 2-dimethylpropyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenlimin) -3- (2,2-dimethylpropyl) -1,3-thiazolidin.

Entry 21 ^ k Me 2-Butylamine was converted to? / - (2-hydroxyethyl) -? / - (2-butyl) amine according to Method B5a. The amine was reacted with SOCI2, according to Method B7a to give? / - (2-chloroethyl) -N- (2-butyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1 a to give 2- (2-methyl-4-nitrphenylimino) -3- (2-butyl) -1,3-thiazolidine.

Entry 22 The 3-pentylamine was converted to N- (2-hydroxyethyl) -N- (3-pentyl) amine according to Method B5a. The amine was reacted with SOCI2, according to the Method B7a to give? / - (2-chloroethyl) -N- (3-pentyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenolimino) -3- (3-pentyl) -1, 3 -thiazolidine.

Entry 23 The 2-chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C1a to give thiazolidine, which was reacted with 1-heptyl bromide according to Method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (1-heptyl) -1,3-t-azole dina.

Entry 24 The d-2-chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl socianate according to Method C1a to give thiazolidine, which was reacted with 8-bromo-1-ketene according to the Method D2a to give 2- (2-methyl-4-nitrophenylimino) -3- (oct-1-en-8-yl) -1,3-tiazole.

Entry 25 1-Propyl-1-hydroxypentane was converted to 1-bromo-2-propylpentane according to Method B2b, Step 2. 2-Chloroethylammonium chloride (Entry) was reacted with 2-methyl-4-nitrophenyl isothiocyanate, according to Method C1a to give thiazolidine, which was reacted with 1-bromo-2-propylpenta or according to Method D2a to give 2- (2-methyl-4-nitrophenyl) -3- (2 -propyl-1-pentyl) -1, 3-thiazolidine.

Entry 26 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to the method C1a to give the thiazolidine, which was reacted with 1,1-dicyclopropylbutyl-1-bromide in -4-according to Method D2a to give 2- (2-methyl-4-nitrophenyl-m -no) -3- (1, 1-dicyclopropyl-1-en-4-ylo) - 1,3-thiazolidine.

Entry 27 Cl Cl Sthiocyanate of 2,6-dichloro-4-nitrophenyl with 2-butylamine was reacted followed by chloroacetic acid according to the C8a method to provide 2- (2,6-dichloro-4-nitrophenimethyl) -3 - (2-butyl) -1,3-t-azolidin-4-one.

Entry 28 The 2-chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C1 a to give the thiazolidine, which was reacted with (EZ) -1,3-dibromopropane according to with Method D2a to give 2- (2-methyl-4-nitrophenlimine) -3- (bromoprop-1-en-3-yl) -1,3-thiazole as an EZ mixture. The mixture was separated using a preparative TLC to give 2- (2-methyl-4-nitrophenyl-amino) -3 - ((Z) -bromoprop-1-en-3-yl) -1,3-thiazole.

Entry 29 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanant according to Method C1a to give thiazolidine, which was reacted with (£) -1,3-dichloropropene according to Method D2a to give 2- (2-metll-4-nitrophenylimino) -3 - ((£) -chloroprop-1-en-3-yl) 1,3-thiazolidine.

Entry 30 } = N? CHO2: - I Me and 2-chloroethylammonium chloride (Entry 1) was reacted with isothiocyanant 2-methyl-4-nitrophenyl according to Method C1a to give thiazolidine, which was reacted with 3-chloro-1-propino according to Method D2a to give 2- (2-methyl-4-nitrophenolimino) -3-prop-1-yn-3-yl) 1,3-tlazolidine. Entry 31 2-Chloroethylammonium chloride (Entry 1) was reacted with isothiocyanant 2-methyl-4-nitrophenyl according to Method C1 a to give thiazolidine, which was reacted with (EZ) -1,3-dibromopropene according to the Method D2a to give 2- (2-methyl-4-nitrophenynylamino) -3- (bromoprop-1-en-3-yl) -1,3-thiazolidine ran an E / Z mixture. The mixture was separated using preparative TLC to give 2- (2-methyl-4-nitrophenylimino) -3 - ((E) -bromoprop-1-en-3-yl) -1,3 thiazolidine.

Entry 32 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanant according to Method C1a to give thiazolidine, which was reacted with (Z) -4-chloro-3-ethoxybut-2-enoate according to Method D2a to give 2- (2-methyl-4-nitrophenylmethyl) -3- (1-ethoxycarbonyl-2-ethoxyprop-1-en-3-ylo) -1, 3-thiazolidine.

Entry 33 2-Chloroethylammonium chloride (Entry 1) was reacted with 21-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give thiazolidine, which was reacted with methyl 4-bromobutanoate according to Method D2a' to give 2- (2 -methyl-4-nitrophenylimino) -3- (1-methoxycarbonyl-3-propyl) -1,3-thiazolidine.

Entry 34 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanant according to Method C1a to give thiazolidine, which was reacted with methyl chloroacetate according to Method D2a to give 2- ( 2-methyl-4-nitrophenylimino) -3- (methoxycarbonylmetho) -1,3-thiazolidine.

Entry 35 2-Chloroethylammonium chloride (Entry 1) was reacted with isothiocyanant 2-methyl-4-nitrophenyl according to Method C1a to give thiazolidine, which was reacted with a-chloroacetophenone according to Method D2a to give 2- ( 2-methyl-4-nitrophenylimino) -3- (1-oxo-1-phenyl-2-ethyl) -1,3-thiazolidine. The ketone was reduced according to Method D5a to obtain 2- (2-methyl-4-nitrophenylylamine) -3- (1-hydroxy-1-phenyl-2-ethyl) -1,3 thiazolidine.

Entry 36 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C1a to give thiazolidine, which was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to give 2- (2-methyl-4-nitrophenylmethyl) -3- (2-oxo-3,3-dimethyl-1-butyl) -1, 3- Thiazolidine Method 37 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give thiazolidine, which was reacted with 1-chloro-2-butanone according to Method D2a for obtain 2- (2-methyl-4-nitrophenlimine) -3- (2-oxo-1-butyl) -1,3-thiazolidine.

Method 38 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give thiazolidine, which was reacted with 1-chloro-2-butanone according to Method D2a for obtain 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-1-butyl) -1,3-thiazole dina. The ketone was reduced according to Method D5a to give 2- (2-methyl-4-nitrophenylimin) -3- (2-hydroxy-1-butyl) -1,3-thiazolidine.

Method 39 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give thiazolidine, which was reacted with 1-chloro-3,3-dimethyl-2-butanone from according to Method D2a to obtain 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidine. The ketone was reduced according to Method D5a to give 2- (2-methyl-4-nitrophenylimino) -3- (2-hydroxy-3,3-dimethyl-1-butyl) -1, 3 -t¡azol¡dina.

Entry 40 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C1a to give thiazolidine, which was reacted with 5-bromo-2-pentanone according to Method D2a to obtain 2- (2-methyl-4-nitrophenylimino) -3- (2-oxo-5-pentanyl) -1,3-tiazolidine.

Entry 41 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C1a to give thiazolidine, which was reacted with 1, 1, 3-trichloro-1-propene according to with Method D2a to obtain 2- (2-methyl-4-nitrophenylimino) -3- (1,1-dichloroprop-1-en-3-yl) -1,3-thiazolidine.

Entry 42 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C a to give thiazolidine, which was reacted with propionyl chloride according to Method D2a to obtain - (2-methyl-4-nitrophenolimino) -3- (1-oxo-1-propyl) -1,3-thiazolidine.

Entry 43 2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give thiazolidine, which was reacted with (E) -1-chloro-5-methoxy-2 -pentene according to the Method 'D2a to obtain 2- (2-methyl-4-nitrophenylimino) -3 - ((E) -5-methoxypent-2-en-1-yl) -1, 3 -thiazolidine.

Entry 44 2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to achieve 4-aza-1-oxaspiro [4.4] nonane. The oxazolidine was reduced according to Method B4b, Step 2 to obtain? / - cyclopentyl -? / - (2- x hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / -cyclopentyl- / V- (2-chloroethylol) amine. The amine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1d to obtain 2- (2-methyl-4-nitrophenylimino) -3-cyclopentyl-1,3-thiazole. Na Entry 45 2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to achieve 4-aza-1-oxaspiro [4.4] nonane. The oxazolidine was reduced according to Method B4b, Step 2 to obtain? / -cyclopentyl -? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclopentyl -? / - (2-chloroethyl) amine. The amine was reacted with 2-methoxy-4-nitrophenyl sothiocyanate according to Method C1d to obtain 2- (2-methoxy-4-nitrophenylmethyl) -3-cyclopentyl-1, 3- Thiazolidine Entry 46 2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to achieve 4-aza-1-oxaspiro [4.4] nonane. Oxazolidine was reduced according to Method B4b, Step 2 to get? -cyclopentyl- / V- (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclopentyl -? / - (2-chloroethyl) amine. The amine was reacted with 2,3-dichlorophenyl isothiocyanate according to Method C1d to obtain 2- (2,3-dichlorophenylimino) -3-cyclopentyl-1,3-thiazolidine.

Entry 47 Cyclohex-2-en-1-was reduced according to Method B2b, Step 1 to obtain cyclohex-2-en-1-ol. The alcohol was converted to 3-bromo-1-cyclohexene according to Method B2b, Step2. The halide was converted to α / - (cyclohex-2-en-1-yl) -? / - (2-hydroxyethyl) amine according to Method B2b, Step 3. The alcohol was reacted with SOCI2 in accordance with Method B7a to obtain N- (cyclohex-2-en-1-yl) -? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method x C1a to obtain 2- (2-methyl-4-nitrophenolyl) -3- (cyclohex-) 2-en-1-ylo) -1, 3-thiazolydin.

Entry 48 2-Hydroxyethylamine and cyclohexanone were reacted according to Method B4a, Step 1 to achieve 4-aza-1-oxaspiro [4.5] decane. The oxazolidine was reduced according to Method B4a, Step 2 to obtain? / -cyclohexyl- / V- (2-hydroxyethyl) amine. Was the alcohol reacted with SOCI2 according to Method B7c to obtain? -cyclohexyl-? - (2-chloroethyl) amine. The amine was reacted with 2-methoxy-4-nitrophenol isothiocyanate according to Method C1d to obtain 2- (2-methyl-4-nitrophenylimino) -3-cyclohexyl-1,3-t. Azolidina.

Entry 49 The? / - (2-Hydroxyethyl) aniline was reacted with SOCI2 according to Method B7a to give? / - (2-chloroethyl) anionium chloride. The chloroethylamine was reacted with 2-methyl-4-nii? -enhenyl isothiocyanate according to Method C1a to obtain 2- (2-methyl-4-nitrophenylamino) -3-phenyl-1,3-thiazolidine.

Entry 50 The 2-hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to give? / -cycloheptyl -? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cycloheptyl- / V- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenynylamino) -3-cycloheptyl-1,3-thiazolidine.

Entry 51 The 2-hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-α / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclooctyl -? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenlimino) -3-cyclooctyl-1,3-thiazolidine.

Entry 52 The 2-hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give? / - c? Cl? Octyl -? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 in accordance with Method B7c to obtain? / - cyclooctyl -? / - (2-chlornethyl) ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2- (2-methoxy-4-nitrophenolimino) -3-cyclooctyl-1,3-thiazolidine.

Entry 53 The 2-hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give? / -cyclooctyl -? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclooctyl -? / - (2-chloroethyl) ammonium chloride. The chloroethiamine was reacted with x isothiocyanate 2,3-dichlorophenyl to give 2- (2,3-dichlorophenylimino) -3-cyclooctyl-1,3-thiazolidine.

Entry 54 The 2-hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give? / - cyclopropylmethyl -? / - ('2-hydroxyethyl) amyria. The alcohol was reacted with SOCI2 in accordance with Method B7c to obtain? / - cyclopropylmethyl-? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl sothiocyanate to give 2- (2,3-dichlorophenimlimino) -3- (cyclopropylmethyl) -1,3-thiazole dirane.

Entry 55 The 2-hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give? / - cyclopropylmethyl -? / - ('2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclopropylmethyl-? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-metii-4-nitrophenol sothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine .

Entry 56 The 2-hydroxyethyl amine was reacted with cyclopropylmethyl bromide according to Method B2a to give / V-cyclopropylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 in accordance with Method B7c to obtain? / - cyclopropylmethyl-? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl sothiocyanate to give 2- (2,4-dichlorophenyl-1,4-yl) -3- (cyclopropylmethyl) -1,3-thiazolidin.

Entry 57 The 2-hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl- / V-2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclopropylmethyl- / V- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino) -3- (cyclopropylmethyl) -1,3-thiazolidine.

Entry 58 The 2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl- (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclobutylmethyl -? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,2-dichlorophenyl isothiocyanate to give 2- (2,2-dichlorophenylimin) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Entry 59 The 2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give? / - cyclobutylmethyl -? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain / V-cyclobutylmethyl-1 / - (2-chloroethyl) arnonium chloride. Chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Entry 60 The 2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give? / - cyclobutylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclobutylmethyl -? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimino) -3- (cyclobutylmethyl) -1,3-thiazolidine.

Entry 61 The 2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give? / - cyclobutylmethyl-N-2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclobutylmethyl -? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2- (2,3-dimethylphenylimino) -3- (cyclobutylmethyl) -1,3-thiazolinidine.

Entry 62 The 2-hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give / V-cyclobutylmethyl-N-2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 in accordance with Method B7c to obtain A / -cyclobutylmethyl-1 / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methyiphenyl sothiocyanate to give 2- (3-chloro-2-methylphenylamino) -3- (cyclobutylmethyl) -1,3-thiazole dine.

Entry 63 The 2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl- / V- (-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclopentylmethyl-? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl sothiocyanate to give 2- (2,3-dichlorophenolinylamino) -3- (cyclopentylmethoxy) -1,3-tiazole. Na Entry 64 The 2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give? / - cyclopentylmethyl-? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain A / - cyclopentylmethyl -? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3,4-dichlorophenyl sothiocyanate to give 2- (3,4-dichlorophenylammon) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Entry 65 The 2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give? / -cyclopentylmethyl -? / - ('2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7ó to obtain? / - cyclopentylmethyl-? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2- (2-4-nitrophenylimin) -3- (cyclopentylmethyl) -1,3-tiazole. . Entry 66 The 2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclopentylmethyl-? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,4-dichlorophenyl sothiocyanate to give 2- (2,4-dichlorophenyl) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Entry 67 The 2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give? / - cyclopentylmethyl -? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain A / -cyclopentylmethyl-1 / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2- (2,3-dimethylphenylamino) -3- (cyclopentylmethyl) -1,3-thiazolidine isothiocyanate.

Entry 68 The 2-hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give? / - cyclopentylmethyl -? / - 2-hydroxyethanol) amine. The alcohol was reacted with SOCI2 in accordance with Method B7c to obtain? / - cyclopentylmethyl- / V- (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2- (3-chloro-2-methylphenylimin) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Entry 69 The 2-hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclopentylmethane-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 in accordance with Method B7 to obtain? / - cyclopentylmethyl-? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3- (dichlorophenylimin) -3- (cyclohexylmethyl) -1,3-tiazolidine.

Entry 70 The 2-hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give? / - cyclohexylmethyl-? / - 2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclopentylmethyl-? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl sothiocyanate to give 2- (2-methyl-4-nitrophenylimino) -3- (cyclopentylmethyl) -1,3-thiazolinidine.

Entry 71 The 2-hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give? / - cyclopentylmethyl -? / - 2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cyclohexylmethyl-? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl sothiocyanate to give 2- (2-methoxy-4-nitrophenolimino) -3- (cyclohexylmetho) -1, 3- thiazolidine.

Entry 72 The 1-cyclohexylamine was converted to? / - (2-hydroxyethyl) -N- (1-cyclohexyl-1-ethyl) amine according to Method 5a. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - (2-chloroethyl) -N- (1-cyclohexyl-1-ethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C1a to give 2- (2-methyl-4-nitrophenolimino) -3- x (1-cyclohexyl- 1-etl) -1, 3-thiazolidine.

Entry 73 Bn Me Cl The 2-hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give? / -benzyl-? / - 2-hydroxyethanol) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain N-benzyl-? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl sothiocyanate to give 2- (3-chloro-2-methylphenylimin) -3-benzyl-1,3-thiazolidine.

Entry 74 The 2-hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain N-benzyl-? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2- (3,4-dichlorophenylimin) -3-benzyl-1,3-thiazolidine.

Entry 75 The 2-hydroxyethylamine was reacted with bromide of 1-achenyl according to Method B2a to give? / -benzyl-? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain N-benzyl-? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2- (2,4-dichlorophenylimino) -3-benzyl-1,3-thiazoiidine.

Entry 76 The 2-hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give? / -benzyl-? / - (2-hydroxyethyl) amine. The alcohol was reacted. with SOCI2 in accordance with Method B7c to obtain N-benzyl-? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2-methylphenyl-4-nitrophenyl isothiocyanate to give 2- (2-methyl-4-nitrophenolimino) -3-benzyl-1, 3-x thiazolidine.

Entry 77 The 2-hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give? / -benzyl-? / - (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain N-benzyl-? / - (2-chloroethyl) ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl sothiocyanate to give 2- (2,3-dichlorophenylimino) -3-benzyl-1,3-thiazolidin.

Entry 78 The 2-hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give? / - (4-chlorobenzyl) -? / - ('2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - (4-chlorobenzyl-? / - (2-chloroethyl) ammonium chloride.Cycloethylamine was reacted with 4-cyano-2 isothiocyanate. -ethylphenyl to give 2- (4-cyano-2-ethylphenylimino) -3- (4-chlorobenzyl) -1,3-thiazolidine.

Entry 79 The 2-hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give? / - (4-chlorobenzyl) -? / - 2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 according to Method B7c to give? / - (4-chlorobenzyl- / V- (2-chloroethyl) ammonium chloride.Cl chlorethylamine was reacted with 2-chloro-4 isothiocyanate. -cyanophenyl to give 2- (2-chloro-4-cyano-phenyl-1-yl) -3- (4-chlorobenzyl) -1,3-thiozo-idine.

Entry 80 The 2-hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give / V-cycloheptyl-1-methyl-2-hydroxyethyl amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cycloheptylmethyl -? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrophenol-2-thiocyanate to give 2- (2-methyl-4-nitrophenylmethyl) -3- (cyclopentylmethyl) -1,3-thiazolidine.

Entry 81 The 2-hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptyl-1-yl- (2-hydroxyethyl) amine. The alcohol was reacted with SOCI2 in accordance with Method B7c to obtain? / - cycloheptylmethyl-? / - (2-chloroethylene) ammonium chloride. Chloroethylamine was reacted with 2-methoxy-4-nitrophenyl sothiocyanate to give 2- (2-methoxy-4-nitrophenylimino) -3- (cycloheptylethyl) -1,3-thiazolidine.

Entry 82 The 2-hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give / V-cycloheptyl-1-N- (2-hydroxyethyl) amine. The alcohol was reacted with SOCI. according to Method B7c to obtain? / - cycloheptylmethyl-1 / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2- (2,3-dichlorophenylimino) -3- (cycloheptylmethyl) -1,3-thiazolidine.

Entry 83 The 2-hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give / V- cyclohep.ylmethyl-? / - (2-hydroxyethanol) amine. The alcohol was reacted with SOCI2 according to Method B7c to obtain? / - cycloheptylmethyl -? / - (2-chloroethyl) ammonium chloride. Chloroethylamine was reacted with 4-cyanophenyl sothiocyanate to give 2- (4-cyano-phenyl-1-yl) -3- (cycloheptylmethyl) -1,3-thiazole.

Entry 84 The methyl cyclododecanocarboxylate was reduced according to Method B2b, Step 1 to give, cyclododecylmethanol. The alcohol was converted to cyclododecylmethylbromide according to Method B2b of Step 2. The halide was reacted with 2-hydroxyethylamine according to Method B2b, Step 3 to obtain? / - (2-hydroxyethyl) -? / - (cyclododecylmethyl) amine The alcohol was reacted with SOCI2 according to Method B7a to give? / - (2-chloroethyl) -? / - (cyclododecylmethyl) ammonium chloride. Chloroethylamine was reacted with 2-methyl-4-nitrofc-n-isothiocyanate according to Method C1 to give 2- (2-methyl-4-nitrophenyl-1-yl) -3- (cyclododecylmethyl) -1 , 3-thiazolidine.

Entry 85 The 2-chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to achieve 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine , which was reacted with 3- (chloromethyl) -6,6-dimethyl-cyclo [3.1.1] hept-2-ene, according to Method D2a to obtain 2- (4-nitrophenolimine) -3 - ((6,6-dimethylbicyclo [3.1.1] hept-2-en-3-yl) methyl) -1,3-thiazolidine.

Entry 86 The 2-chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to obtain 2- (2-methyl-4-nitrophenylimino) -1,3-thiazolidine, to which it was reacted with 5- (bromomethyl) -bicyclo [2.2.1] hept-2-ene, according to Method D2a to obtain 2- (4-nitrophenyl) -3 - ((bicyclo [2.2 .1] hept-2-en-5-yl) methylo) -1,3-thiazolidine.

Entry 87 The 3-Aminoquinoline was converted to 3-quinoline isothiocyanate according to Method A2c. (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from methyl ester () -leucine as described in Method B1 b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to? / - (1 S) -1- (chloromethyl) -3-methylbutyl-? / - (butyl) ammonium chloride as described in Method B7c. The 3-quinoline isothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) -3-methylbutyl-? / - (isobutyl) ammonium chloride according to Method C1f to obtain 2- (3-quinolylim) No) -3,5-d¡-butyl-1, 3-thiazolidine.

Entry 88 It was made at (1 S) -1- (Hydroxymethyl) -3-methylbutylamine from the methyl (L) -leucine ester, as described in Method B1b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentanol, as described in Method B4c, Steps 1-2. The alcohol was converted to? / - (1 S) -1- (chloromethyl) -3-methylbutyl-? / - (isobutyl) ammonium chloride as described in Method B7c. The 4-Nitrophenyl isothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) -3-methyl-butyl-? / - (sobutyl) ammonium chloride according to the Method C1f to give 2- (4-nitrophenylimin) -3,5-diisobutyl-1,3-thiazolidine.

Entry 89 (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl (L) -leucine ester, as described in Method B1b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutyllamine) pentanol, as described in Method B4c, Steps 1-2. The alcohol was converted to α / - (1S) -1- (chloromethyl) -3-methylbutyl-A / - (butyl) ammonium chloride as described in Method B7c. He 4-Cyanophenyl sothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) -3-methylbutyl) -? / - (sobutyl) ammonium chloride according to Method C1f to give - (4-cyanophenyl-1,4-yl) -3,5-diisobutyl-1,3-thiazolidine.

Entry 90 (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was converted to (S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1 S) -1 - (chloromethyl) -3-methylbutanoammonium chloride according to Method C1 a to give (4S) -2- (2- methylene-4-nitrophenylimino) -4-butyl-1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain the salt of HCl (4S) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1, 3-tiazolidin.

Entry 91 The (1S) -1- (H &ldroxymethyl) -3-methylbutyllamine was converted to (1R) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2-Methyl-4-nitrophenyl isothiocyanate was reacted with the (1) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4R) -2- (2-methyl- 4-Nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain the salt of HCl (4R) -2- (2-methyl-4-nitrophenolimide) -3,4-d Isobutyl-1, 3-thiazolidine.

Entry 92 The (1 S) -1- (H -droxymethyl) -3-methylbutylamine was converted to (1R) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2-Methyl-5-n-trophonyl isothiocyanate was reacted with (1 R) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4R) -2- ( 2-methyl-5-nitrophenylimino) -4-isobutyl-1,3-tiazole. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain the salt of HCl (4'R) -2- (2-methyl-5-nitrophenolimino) -3,4-di sobutl-1, 3-tiazolidin.

Entry 93 The (1S) -1- (Hydroxymethyl) -3-methylbutylamine was converted to (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride as described in Method B7a. The 2-Methyl-5-nitrophenyl isothiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (2 -methyl-5-nitrophenylmethyl) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain the salt of HCl (4S) -2- (2-methyl-5-nitrophenylimino) -3,4-diisobutyl-1 , 3-tiazolidine.

Entry 94 (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was converted to (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride as described in Method B7a. The 2-Methyl-4-nitrophenol isothiocyanate was reacted with the (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a to give (4R) -2- (2-methyl-) 4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to obtain the salt of HCl (4R) -2- (2-methyl-4-nitrophenolimide) -4-isobutyl- 3-methyl-1,3-thiazolidine.

Entry 95 (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The isothiocyanate 2-Methylene-4-nitrophenyl was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4) -nitrophenylimino) -4 -sobutyl-1, 3-tiazolidin. The thiazolidine was reacted with methyl iodide according to Method D2a to obtain the salt of HCl (4S) -2- (2-methyl-4-nitrophenylmethyl) -4-isobutyl-3-methyl -1, 3-thiazolidine.

Entry 96 The (1S) -1- (Hydroxymethyl) -3-methylbutyllamine was converted to (1R) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2-Methyl-5-nitrophenyl isothiocyanate was reacted with the (1R) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a to give (4R) -2- (2- methylene-5-nitrophenolimino) -4-isobutyl-1,3-thiazolidin. The thiazolidine was reacted with methyl iodide according to Method D2a to obtain the salt of HCl (4R) -2- (2-methyl-5-nitro, renylimino) -4-SOBUT 1-3-methyl-1,3-thiazolidine.

Entry 97 The (1 S) -1- (Hydroxymetyl) -3-methylbutylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutaneammonium chloride as described in Method B7a. The isothiocyanate 2-Methyl-4-nitrophenyl was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-) nitrophenolimino) -4-isobutyl-1,3-thiazolidin. The thiazolidine was reacted with 1-bromo-2-ethylbutane according to Method D2a to obtain the salt of HCl (4S) -2- (2-methyl-4-nitrophenylimino) -4 -sobutyl-3- (2-ethyl-1-butyl) -1,3-thiazolidine.

Entry 98 The (1S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl () -leucine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutaneamonium chloride as described in Method B7a. 2-Methyl-4-Nitrophenyl isothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (2-methyl-) 4-N -trofenylamino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to obtain (4S) -2- (2-methyl-4-nitrophenylimino) -4 -sobutyl-3- (2-oxo-3, 3-dimethyl-1-butyl) -1,3-thiazolidine.

Entry 99 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl () -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride in accordance with Method C1a to give (4S) -2- (2-methyl-4-nitrophenolimino) -4-butyl-1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to obtain (4S) -2- (2-ethyl-4-cyanophenimlimino) -4-isobutyl-3- (2-oxo-3, 3-dimethyl-1-butyl) -1,3-thiazolidine.

Entry 100 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the ester of (L) -rucyryl as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2-methyl-4-N-trophenyl isothiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1 a to give (4S) -2- (2 -methyl-4-nitrophenylimino) -4 -sobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2a to obtain (4S) -2- (2-methyl-4-nitrophenylmethyl) -4 -sobutyl-3- (c) Chlopropylmethyl) -1, 3-tiazolidine.

Entry 101 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl (L) -leucine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (2- methylene-4-n-phenylphenyliron) -4-isobutyl-1,3-thiazoylidene. The thiazolidine was reacted with cyclobutylmethyl bromide according to Method D2a to obtain (4S) -2- (2-methyl-4-nitrophenylmethyl) -4-isobutyl-3- (cyclobutylmethyl) - 1,3-tiazolidine.

Entry 102 Ai (1 S) -1- (Hydroxymethyl) -3-methylbulylamine was made from the methyl (/.) - leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The isothiocyanate 2-methyl-4-Nitrophenyl was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride in accordance with Method C1a to give (4S) -2- (2-methyl-4-n) Trophenylymino) -4-isobutyl-1,3-thiazole dina. The thiazolidine was reacted with 2-chloro-3,3-dimethyl-2-butanone according to Method D2a to obtain (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl -3- (2-Oxo-3,3-dimethyl-1-butyl) -1,3-thiazolidin. The ketone was reduced according to Method D5a to obtain (4S) -2- (2-methyl-4-nitrophenlimine) -4-isobutyl-3- (3,3-dimethyl-2-hydroxy). 1-butyl) -1, 3-thiazolidine.Entry 103 The (1S) -1- (Hydroxymethyl) -3-methylbutylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2,6-dimethyl-4-nitroaniline was converted to 2,6-dimethyl-4-nitrophenyl sothiocyanate according to Method A2b. The 2,6-Dimethyl-4-nitrophenol isothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenlimin) -4 -sobutyl-1,3-thiazolidin. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain the salt of HCl (4S) -2- (2-methyl-4-nitrophenolinylamino) -3,4-diisobutyl-1, 3 -thiazolidine.

Entry 104 It was made at (1S) -1- (H &sub1; xmethyl) -3-methylbutylamine from the methyl (L) -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. 2,3-Dichlorophenyl isothiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenol) No) -4-butyl-1, 3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to obtain (4S) -2- (2,3-dichlorophenylimino) -4-isobutyl-3- (3-pentyl) -1,3-t Azol¡d¡na Entry 105 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl (L) -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The isothiocyanate 2-Methyl-4-nitrophenyl was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) ) -4-isobutyl-1,3-thiazolidin. The thiazolidine was reacted with 5-iodopentane according to Method D2a to obtain (4S) -2- (2-methyl-4-nitrophenylimino) -4-isobutyl-3- (5-heptyl) -1 , 3-thiazolidine.

Entry 106 It was made at (1 S) -1- (Hydroxymethyl) -3-methylbutylamine from the methyl () -leucine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. 2,3-Dichlorophenol isothiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) - 4-isobutyl-1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (2,3-dichlorophenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Entry 107 It was made at (1S) -1- (Hydroxymethyl) -3-methylbutylamine from the methyl (L) -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The isothiocyanate 2 (Trifluoromethyl) -4-nitrophenyl was reacted with (1 S) -1- (chloromethyl) -3-methylbutane ammonium chloride in accordance with Method C1c to give a trifuoroacetate salt (4S) - (2- (trifluoromethyl) -4-nitrophenolimino) -4-isobutyl-1,3-thiazolidine.

Entry 108 The (1 S) -1- (Hydroxymethyl) -3-methylbutyllamine was made from the methyl () -leucine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2- (Trifluoromethyl) -4-nitrophenol isothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1c to give (4S) -2- (2-trifluorom tyl) -4-nitrophenyl-amino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to obtain a trifluoroacetate (4S) -2- (2-trifluoromethyl) -4-nitrophenolimide salt) -3.4- diisobutyl-1,3-thiazolidine.

Entry 109 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl (L) -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 4-cyano-2- (trifluoromethyl) phenothio isotiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1c to give (4S) -2- (4-cyano-2- (trifluoromethyl) phenlimino) -4 -sobutyl-1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to obtain a trifluoroacetate (4S) -2- (4-cyano-2- (trifluoromethyl) phenylimino) -3,4-diisobutyl-1 salt, 3-thiazolidine. Entry 110 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl ester () -leucine as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 2-chloro-4-cyano-6-methylphenyl isothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1c to give (4S) -2- (2-chloro) -4-cyano-6-methylphenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to obtain a trifluoroactetate salt (4S) -2- (2-chloro-4-cyano-6-methylphenylamino) -3,4-d So-butyl-1, 3-tiazolidine.

Entry 111 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl (L) -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 4- (methoxycarbonyl) -2-methylfenyl sothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (4- (methoxycarbonyl) -2-methylphenlimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4- (methoxycarbohyl) -2-methylenephosphine) -3,4-diisobutyl-1 , 3-tiazolidine. Entry 112: The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl () -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride as described in Method B7a. 3,5-Dimethyl-4-nitroaniline was converted to isothiocyanant 3,5-Dimethyl-4-nitrophenyl, according to Method A2a, Step 3. The 3,5-Dimethyl-4-nitrophen-isothiocyanate It was reacted with (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride in accordance with Method C1a to give (4S) -2- (3,5-dimethyl-4-nitrophenylimino) -4-isobutyl -1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide anoacid according to Method D2a to obtain (4S) -2- (3,5-dimethyl-4-nitrophenylmethyl) -3,4-diisobutyl-1 , 3-thiazolidine.

Entry 113 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl ester (L) -leucine as described in Method B1 b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. 4- (Methoxycarbonyl) -2-methylphenol isothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (4- ( methoxycarbonyl) -2-methylphenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-methoxycarbonyl) -2-methylphenylimin) -3,4-diisobutyl-1, 3- Thiazolidine The thiazolydin was saponified according to Method D6a, Step 1 to obtain (4S) -2- (4-carboxy-2-methylphenylamino) -3,4-diisobutyl-1,3-thiazolidine. The acid was bound with ammonia as described in Method D6a, Step 2 to achieve (4S) -2- (4-carbamoyl-2-methylphenylimin) -3,4-diisobutyl-1,3-thiazolidine .

Entry 114 The (1 S) -1- (Hydroxymethyl) -3-methylbutylamine was made from the methyl (L) -leucine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The isothiocyanate Fluor-2-methylphenyl was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride in accordance with Method C1a to give (4S) -2- (4-fluoro-2-methylphenylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-butylbutyromide according to the M all D 2a to obtain (4S) -2- (4-fluoro-2-methylphenylimino) -3,4-diisobutyl-1, 3-thiazolidine.

Entry 115 It was made to (1 S) -1- (Hydroxymethyl) -3-methylbutyllamine from the methyl (L) -leuclna ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 4-chloro-2-methylphenyl isothiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride in accordance with Method C1a to give (4S) -2- (4-Chloro-2-methylphenylamino) -4-isobutyl-1,3-thiazole dina. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-chloro-2-methylphenimlimino) -3,4-diisobutyl-1, 3 -thiazolidine.

Entry 116 [J ^ k -k B- i-Bu Me It was made to (1 S) -1- (H -droxymethyl) -3-methylbutylamine from the ester of ryrimethyl (L) -leucine as described in Method B1 b . The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanoammonium chloride as described in Method B7a. The 4-Bromo-2-methylfenyl isothiocyanate was reacted with (1S) -1- (chloromethyl) -3-methylbutane ammonium chloride according to Method C1a to give (4S) -2- (4- bromo-2-methylphenylamino) -4-isobutyl-1,3-thiazolidipa. The thiazolidine was reacted with tert-butyl bromide according to Method D2a to obtain (4S) -2- (4-bromo-2-methylphenylmethyl) -3,4-diisobutyl-1 , 3-thiazolidine.

Entry 117 (1 S) -1- (Hydroxymethyl) -3-methylbutyllamine was reacted with SOCI2 x followed by 4-cyano-2-ethylphenyl ester according to Method C2a, to give (4S) -2- (4-cyano-2-ethyl-vinyl) -4 -sobutyl-1,3-thiazolidine. Thiozolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-cyano-2-ethylphenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Entry 118 It was made to (1 S) -1- (Hydroxymethyl) -3-methylbutyllamine from the methyl () -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol chloride as described in Method B4c. The resulting 2-hydroxyethylamine was converted to? / - (1 S) -1- (chloromethyl) -3-methylbutyl) -? / - (isobutyl) ammonium chloride according to Method B7c. The 2-methyl-4-nitrophenol isothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) -3-methylbutyl) -? / - (isobutyl) ammonium chloride according to the Method C1b to give (4S) -2- (2-methyl-4-nitrophenylmethyl) -3,4-diisobutyl-1,3-thiazolidine.

Entry 119 It was made to (1S) -1- (Hydroxymethyl) -3-methylbutylamine from the methyl (/.) - leucine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol chloride as described in Method B4c. The resulting 2-hydroxyethylamine was converted to? - (1 S) -1- (Chloromethyl) -3-methylbutyl) -? / - (isobutyl) ammonium according to Method B7c. The 4-amine-3-methylpyridine was converted to 3-methyl-4-pyridylisocyanate was reacted according to Method A2b. The 3-methyl-4-pyridyl isothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) -3-methylbutyl) -? / - (isobutyl) ammonium chloride in accordance to Method C1 b to give (4S) -2- (2-methyl-4-nitrophenylimin) -3,4-d, 1-butyl-1, 3-thiazolidine.

Entry 120 It was made to (1 S) -1- (Hydroxymethyl) -3-methylbutyllamine from the methyl (L) -leucine ester as described in Method B1b. The 4-Nitro-naphthyl was converted to 4-nitro-1-naphthyl sothiocyanate according to Method A2b. The 4-nitro-1-naphthyl isothiocyanate was reacted with (1 S) -1-hydroxymethyl-3-methylbutylamine according to Method C2a to give (4S) -2- (4-nitride-1-naphthylimino) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S) -2- (4-nitro-1-naphthlimino) -3,4-d¡¡sobutyl-1, 3- v thiazolidine.

Entry 121 It was made to (1 S) -1- (Hydroxymethyl) -3-methylbutylamine from the methyl ester (L) -leucine as described in Method B1 b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to? / - (1 S) -1- (chloromethyl) -3-methylbutyl) - / V- (isobutyl) ammonium chloride according to Method B7c. The 4-nitrophenyl isothiocyanate was reacted with? / - (1 S) -1 - (chloromethyl) -3-methylbutyl) -? / - (isobutyl) ammonium chloride according to Method C1f to give (4S) ) -2- (4-nitrophenylmethyl) -3,4-diisobutyl-1,3-thiazolidine.

Entry 122 It was made to (1 S) -1- (hydroxymethyl) -3-methylbutylamine from the methyl () -leucine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to A / - (1 S) -1- (chloromethyl) -3-methyl-butyl) -? / - (isobutyl) ammonium chloride according to Method B7c. The 4-cyanophenyl isothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) -3-methylbutyl) -? / - (isobutyl) ammonium chloride according to Method C1f to give ( 4S) -2- (4-cyanophenylimino) -3,4-diisobutyl-1,3-thiazolidine.

Entry 123 It was made to (1 S) -1- (Hydroxymethyl) -3-methylbutyl amine from the methyl (L) -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to? / - (1 S) -1- (chloromethyl) -3-methylbutyl) -? / - (isobutyl) ammonium chloride in accordance with Method B7c. The 4-amino-3-methylpyridine was converted to 3-methyl-4-pyridyl isocanate according to Method A2b. The 3-methyl-4-pyridyl isothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) -3-methylbutyl) -? / - (isobutyl) ammonium chloride. according to Method C1 b to give (4S) -2- (2-methyl-4-nitrophenylmethyl) -3,4-diisobutyl-1,3-thiazolidine. The thiazolidine was oxidized according to Method D4a to obtain (4S) -2- (2-methyl-4-nitrophenimyl) -3,4-diisobutyl-1,3-thiazolidine 1- oxide.

Entry 124 The (1S, 2S) -1- (Hydroxymethyl) 23-methylbutylamine was converted to (1S, 2S) -1- (Chloromethyl) -2-methylbutanemonium as described in Method B7a. The isothiocyanate 2-Methyl-4-nitro was reacted with (1 S, 2S) -1- (chloromethyl) -2-methylbutanemonium chloride according to Method C1 a to give (4S) -2- (2-methyl-) 4-N -trofenylamino) -4 - ((2S) -2-butyl) -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain an HCl salt of (4S) -2- (2-methyl-4-nitrophenolimide) -4- ((2S) - 2-butyl-3-isobutyl-1,3-thiazolidine.

Entry 125 The γ (t-Butoxycarbomoyl) - (1 S, 2 R) -1- (hydroxymethyl) -2-methylbutylamine was prepared from the? - Ie / t-butoxycarbamoyl) - () -alo-sulfin as described in Method B1 a, Step 2. The carbamate was converted to (1 S, 2R) -1- (chloromethyl) - 2-Methylbutane ammonium as described in the Method B7b. The 2-methyl-4-nitrophenol-isothiocyanate was reacted with (1S, 2R) -1- (chloromethyl) -2-methylbutanoammonium chloride of Method C1e to give an HCl salt of (4S) - 2- (2-methyl-4-nitrophenylimino) -4 - ((2R) -2-butyl) -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain an HCl salt of (4S) -2- (2-methyl-4-nitrophenylimino) -4- ((2S) -2-butyl-3-isobutyl -1, 3-thiazolidine.

Entry 126 The α / (te / t-Butoxycarbamoyl) - (1 S) -1-cyclohexyl-2-hydroxyethylbutylamine was prepared from the α / - (re-butoxycarbamoyl) - () -cyclohexylglycine as described in the Method B1a, Step2. The carbamate was reacted with SOCI2 as described in Method B1 b, and the resulting material was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenynylamino) -4-cyclohexyl-1,3-thiazolidin. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain a HCl salt of (4S) -2- (2-methyl-4-nitrophenynylamino) -4-cyclohexyl-3-isobutyl) -1, 3-thiazolidine.

Entry 127 It was made to (1 S) -1- (Hydroxymethyl) -2-methylbutylamine from the methyl (_) - isoleucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanoammonium chloride, as described in Method B7a. The 4-methoxycarbonyl-2-methylphenyl isothiocyanate was reacted with (1 S) -1- (chloromethyl) -2-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (4-methoxycarbonyl- 2-methylphenyl amino)) - 4- (2-butyl) -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-methoxycarbonyl-2-methylenephenyl) -4- (2-butyl) -3 -sobutyl-1,3-thiazolidine.

Entry 128 The (1 S) -1-lsopropyl-2-hydroxyethylamine was converted to (1 S) -2-chloro-1-isopropylethylammonium chloride as described in Method B7a. The 2-methyl-4-nitrophenyl isothiocyanate was reacted with the (1S) -2-chloro-1-isopropylthiolammonium chloride according to Method C1a to give (4S) -2- (2- methylene-4-nitrophenylimino) -4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain the salt of HCl (4S) -2- (2-rriethyl-4-nitrophenylimino) -4-isopropyl-3-isobutyl 1, 3-tiazolidin.

Entry 129 It was made to (1 S) -1- (H &subdex; methyl) -2-methylbutyllamine from the methyl (L) -lucycin ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -2-methylbutane ammonium chloride, as described in Method B7a. The 5-aminonoin-1-one was converted to 1-oxo-5-indanyl-isothiocyanate according to Method A2a. The isothiocyanate was reacted with (1 S) -1- (chloromethyl) -2-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (1-oxo-5-indanylmno) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (1-oxo-5-indamino) -4- (2-butyl) -3-SOBUTY L-1, 3-tiazolidin. x Entry 130 It was made to (1 S) -1- (Hydroxymethyl) -2-methylbutylamine from the methyl (L) -soleucine ester as described in Method B1b. The 2-hydroxyethyl amine was converted to (1 S) -1- (chloromethyl) -2-methylbutanoammonium chloride, as described in Method B7a. 4-Chloro-3- (trifluoromethyl) aniline was converted to isothiocyanate 4-Chloro-3- (trifluoromethyl) according to Method D2a, Step 3. To the isothiocyanate 4-Chloro-3- (trifluoromethyl) phenol it was reacted with (1S) -1- (chloromethyl) -2-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (4-chloro-3- (trifluoromethyl) phenylimino) -4- (2-butyl) -1,3-thiazolidine The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-chloro-3- (trifluoromethyl) phenolimino) -4- (2-butyl) -3-isobutyl-1,3-thiazolidine.

Entry 131 It was made to (1 S) -1- (Hydroxymethyl) -2-methylbutylamine from the methyl (L) -isoleucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanoammonium chloride, as described in Method B7a. 4-Cyano-3- (trifluoromethyl) aniline was converted to the isothiocyanato4-cyano-3- (trifluoromethyl) phenol according to Method A2a, Step 3. The isothiocyanate was reacted with (1 S) chloride. ) -1- (Chloromethyl) -2-methylbutane ammonium according to Method C1a to give (4S) -2- (4-cyano-3- (trifluoromethyl) phenyl) -4- (2-butyl) -1, 3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-cyano-3- (trifluoromethyl) phenylimino) -4- (2-butyl) -3-isobutyl-1 , 3-thiazolidine.

Entry 132 (1S) -1- (Hydroxymethyl) -2-methylbutylamine was made from the methyl (L) -isoleucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -2-methylbutanoammonium chloride, as described in Method B7a 4-nitro-1-naphthylamine was converted to 4-nitro-1 isothiocyanate. -naftil according to Method A2b. The 4-nitro-1-naphthyl isothiocyanate was reacted with (1S) -1- (chloromethyl) -2-methylbutanamide chloride according to Method C1a to give (4S) -2- (4 -n-1-naphthylamino) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-nitro-1-naphthylamino) -4-butyl-3-isobutyl-1,3-thiazolidine.

Entry 133 It was made to (1 S) -1- (Hydroxymethyl) -2-methylbutylamine from the methyl (L) -isoleucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanoammonium chloride, as described in Method B7a. The 4-cyano-2-ethylphenyl aniline isothiocyanate was reacted with (1 S) -1- (chloromethyl) -2-methylbutanoammonium chloride according to Method C1a to give (4S) -2- (4-cyano-2) -ethylphenylmethyl) -4- (2-butyl) -1,3-thiazole. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-cyano-2-ethylphenyl) -4-butyl-3-isobutyl. l-1, 3-thiazolidine.

Entry 134 The (1 S) -1- (Hydroxymethyl) -2-methylbutylamine was made from the methyl (/ _) - isoleucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -2-methyl butanoammonium chloride, as described in Method B7a. 4-Cyano-2-methylaniline was synthesized as described in Method A1a. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate as described in Method A2a, Step 3, 4-Cyano-2-methylphenol isothiocyanate was reacted with (1S) -1- chloride (chloromethyl) -2-methylbutanoammonium according to Method C1a to give (4S) -2- (4-cyano-2-methylphenyl) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to obtain (4S) -2- (4-cyano-2-methylphenylimino) -4-butyl-3-isobutyl-1,3-thiazolidine.

Entry 135 (1 S) - (Hydroxymethyl) -2-methylbutylamine was made from the methyl ester of () -isoleucine as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -2-methylbutanemonium chloride as described in Method B7a. The 2,5-dimethyl-4-nitrobenzonitrile was converted to 4-cyano-2,5-methylaniline according to Method A1a. The aniline was converted to 4-cyano-2,5-dimethylphenyl isothiocyanate as described in Method A2a, Step 3. The isothiocyanate of 4-cyano-2,5-dimethylphenyl was reacted with (1 S) -chloride. chloromethyl) -2-methylbutanamide in accordance with Method C1a to give (4S) -2- (4-cyano-2,5-dimethylphenylimino) -4- (2-butyl) -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a. To give (4S) -2- (4-cyano-2,5-d-methylpropyl) -4-butyl-3-yls, obutil-1,3-taizolidine.

Entry 136 (1 S) - (Hydroxymethyl) -2-methylbutylamine was made from the methyl ester of () -isoleucine as described in Method B1b. The 2-hydroxyethylamine was converted to (1S) -1- (chloromethyl) -2-methylbutanemonium chloride as described in Method B7a. The 2,5-methylaniline was converted to 2,5-dimethyl-4-nitrophenyl sothiocyanate according to Method A2a. The 2,5-dimethyl-4-nitrophenyl isothiocinate was reacted with (1S) -1- (chloromethyl) -2-methylbutanamyl chloride as described in Method C1a to give (4S) -2- (2,5- dimethyl-4-nitrophenolinylamino) -4- (2-butyl) -1,3-tiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a. To give (4S) -2- (2,5-dimethyl-4-nitrophenlimin) -4-butyl-3-isobutyl-1,3-thiazolidine.

Entry 137 ^ ks N khN ° > I i-Bu Me The (1R) -1-isopropyl-2-hydroxyethylamine was reacted with SOCL2, followed by 2-methyl-4-nitrophenyl sothiocyanate according to Method C2a. to give (4R) -2- (2-methyl-4-nitrophenylammon) -4-isopropyl-1,3-tiazole. Thiazolidine was reacted with isobutyl bromide according to Method D2a to deliver (4R) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-isobutyl-1,3-thiazolid Na Entry 138 The (1 S) -1-isopropyl-2-hydroxyethylamine was reacted with SOCL2, followed by 2-methyl-4-nltriphenyl isothiocyanate according to Method C2a. To give (4S) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-1,3-thiazolidin. The thiazolidine was reacted with cyclopentyl bromide according to Method D2a to deliver (4S) -2- (2-methyl-4-nitrophenylimino) -4-isopropyl-3-cyclopentyl-1, 3- Thiazolidine Entry 139 The (1 S) -1-benzyl-2-hydroxyethylamine was converted to (1 S) -2-chloro-1-benzylethylammonium chloride according to Method B7b. The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1S) -2-chloro-1-benzylethylammonium chloride according to Method C1a to give (4S) -2- (2-methyl-4-nitrophenylimino) - 4-benzyl-1,3-thiazolidine. Thiazolidine was reacted with isobutyl bromide according to Method D2a to provide HCl salt (4S) -2- (2-methyl-4-nitrophenylimino) -4-benzyl-3-isobutyl-1,3-thiazolidine .

Entry 140 The (1 S) -1-phenyl-2-hydroxyethyl amine was converted to (1 S) -2-chloro-1-phenylethylammonium chloride according to Method B7b. The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1 S) -2-chloro-1-benzylethylammonium according to Method C1 a to give (4S) -2- (2-methyl-4-nitrophenylimino) - 4-phenyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to deliver salt of HCl (4S) -2- (2-methyl-4-nitrophenylimino) -4-phenyl-3-isobutyl-1,3-thiazolidine.

Entry 141 The 2-piperidenemethanol was made from the methyl pipecolinate as described in Method B1b. The 2-hydroxyethylamine was converted to 2-chloromethylpiperidinium chloride according to Method B7a. 2-methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloromethylpiperidinium chloride according to Method C1a to give 9- (2-methyl-4-nitrophenlimine) -1-aza-8-tiabic Clo [4.3.0] nonane.

Entry 142 2-pyrrolidinemethanol was made from methyl proline ester as described in Method B1 b. The 2-hydroxyethylamine was converted to 2-chloromethylpyrrolidinium chloride according to Method B7a. 2-methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloromethylpyrrolidinium chloride according to Method C1a to give 3- (2-methyl-4-nitrophenylimino) -2,5,6,7,7a-pentahydro- 2-thiapyrrolizine.

Entry 143 The (1S) -1- (4-hydroxyphenylmethyl) -2-hydroxyethylamine was made from the methyl () tyrosine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (4S) -2-isopropyl-4- (4-hydroxyphenylmethyl) -1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to? / - (( 1 S) -1- (4-hydroxyphenylmethyl) -2-hydroxyethyl) -? / - isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCI2, in accordance with Method B7c to give? / - ((1 S) -1- (4-hydroxyphenylmethyl) -2-chloroethyl) -? / - lsobutylammonium chloride. The 2-ethyl-4-cyanophenium isothiocyanate was reacted with? / - ((1 S) -1- (4-hydroxyphenylmethyl) -2-chloroethyl) -? / - isobutylammonium chloride according to Method C1b for give a salt of HCl (4S) -2- (2-ethyl-4-cyanophenolimino) -4- (4-hydroxyphenylmethyl) -3-isobutyl-1, 3 -thiazolidine.

Entry 144 (1 S) -1- (4-chlorophenylmethyl) -2-hydroxyethylamine was made from the methyl () -4-chlorophenylalanine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (4S) -2-isopropyl-4- (4-chlorophenylmethyl) -1,3-oxazolidine according to Method B4c, Step 1. Oxazolidine was reduced to A / - ((1S) -1- (4-chlorophenylmethyl) -2-hydroxyethyl) -? / - isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOGI2, according to Method B7c to give? / Chloride - ((1 S) -1- (4-chlorophenylmethyl) -2-chloroethyl) -? / - isobutylammonium. The 2-ethyl-4-cyanophenyl isothiocyanate was reacted with? / - ((1 S) -1- (4-chlorophenylmethyl) -2-chloroethyl) -? / - sobuylmonium chloride. according to Method C1b to give a salt of HCl (4S) -2- (2-etl-4-cyanophenylimino) -4- (4-chlorophenylmethyl) -3-isobutyl-1, 3-t, azol¡d¡na Entry 145 The (1 S) -1- (benzylthiomethyl) -2-hydroxyethylamine was made from the methyl () -S-benzylcysteine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (4S) -2-isopropyl-4- (benzylthiomethyl) -1,3-oxazolidine according to Method B4c, Step 1. Oxazolidine was reduced to α / - ((1 S) - 1- (benzylthiomethyl) -2-hydroxyethyl) -? / - isobutylamine according to the Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCI2, according to Method B7c to give? / - ((1 S) -1- (benzylthiomethyl) -2-chloroethyl) - / V-isobutylammonium chloride. The 2-ethyl-4-cyanophenyl isothiocyanate was reacted with A / - ((1 S) -1- (benzylthiomethyl) -2-chloroethyl) -? / - isobutylammonium chloride according to Method C1b to give a salt of HCl (4S) -2- (2-ethyl-4-cyanophenylimino) -4- (benzylthiomethyl) -3-isobutyl-1,3-thiazolidin Entry 146 The HCl (R) -? / - isobutylserin salt was made from the methyl serine ester (D) as described in Method B3a. The ester was reacted with SOCI2, followed by 2-methyl-4-nitrophenol isothiocyanate according to Method C2a to provide HCl (4S) -2- (2-methyl-4-nitrophenylmethane) salt. -4- (methoxycarbonyl) -3-isobutyl, 3-tiazole dina.

Entry 147 The salt of HCl (S) -? / - isobutylserine was made from the ester of metll serine- (L) as described in Method B3a. The ester was reacted with SOCI2, followed by 2-methyl-4-nitrophenyl sothiocyanate according to Method C2a to provide HCl salt (4R) -2- (2-methyl-4-nitrophenylmethyl) - 4- (methoxycarbonyl) -3-isobutyl-1,3-thiazolidine.

Entry 148 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (re-butoxy) propanammonium chloride was made from the salt of () - (1 S, 2R) -? / - (benzyloxycarbonyl) -0-terf-but Threonine dicyclohexylamine as described in Method B8a. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (fe t -butoxy) propanemonium chloride was reacted with 2-methyl-4-nitrophenyl sothiocyanate followed by isobutyl bromide according to the Method C5b to supply (4R) -2- (2-methyl-4-nitrophenylimin) -4 - ((1R) -1-fe /? -butoxyethyl) -3-isobutyl-1,3-t-azolid Na Entry 149 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (feri-butoxy) propanammonium chloride was made from the salt of () - (1 S, 2R) -? / - (benzyloxycarbonyl) -0- Re-butythreonine dicyclohexylamine as described in Method B8a. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (te / t-butoxy) propanemonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to supply (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1R) -1-te / t-butoxyethyl) -3-cyclopentyl-1,3-t! azol¡d¡na.

Entry 150 The (1R, 2S) -1-methanesulphonyloxymethyl-2- (t-butoxy) propanamonium chloride was made from the salt of (L) - (1S, 2S) -N- (benzyloxycarbonyl) -O -te / t-butyltreonine dicyclohexylamine as described in Method B8a. Chloride (1R, 2S) -1-methanesulfonyloxymethyl-2- (fe / t-butoxy) propanemon was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to deliver ( 4R) -2- (2-methyl-4-nitrophenynylamino) -4 - ((1S) -1-fe / f-butoxyethyl) -3-cyclopentyl-1,3-thiazole; dina Entry 151 (1R, 2S) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was made from the salt of (L) - (1 S, 2S) -? / - (benzyloxycarbonyl) -0-te f- butyltronone dicyclohexylamine as described in Method B8a. The (1R, 2S) -1-methanesulfonyloxymethyl-2- (te -butoxy) propanemonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to deliver (4R) -2- (2-methyl-4-nitrophenolimino) -4 - ((»1 S) -1-re-butoxyethyl) -3-isobutyl-1,3-thiazolidine Entry 152 (1R, 2S) -1-methanesulfonyloxymethyl-2- (re / t-butoxy) propanammonium chloride was made from the salt of (L) - (1 S, 2S) -? / - (benzyloxycarbonyl) -O-enf -butyltreonine dicyclohexlamine as described in Method B8a. (1, 2S) -1-Methanesulfonylmethyl-2- (ferph-butoxy) propanemonium chloride was reacted with 4-cyano-2-methylphenium isothiocyanate followed by cyclopentyl bromide according to Method C5b for supply (4R) -2- (4-cyano-2-methylphenyl) -4- ((1 S) -1 -.er.-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine Entry 153 The (1R, 2S) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was made from the salt of (/ -) - (1S, 2S) -? / - (benzyloxycarbonyl) -0- re / t-butyltreonine dicyclohexylamine as described in Method B8a. The 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl sothiocyanate according to Method A2b. The (1R, 2S) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthyl sothiocyanate followed by isobutyl bromide according to Method C5b to deliver (4R) - 2- (4-Nitro-1-naphthylamino) -4 - ((1 S) -1-fe-butoxyethyl) -3-isobutyl-1,3-thiazole; Entry 154 The (1R, 2S) -1-methanesulfonyl-oxymethyl-2- (ferph-butoxy) propane chloride was made from the salt of () - (1S, 2S) -? / - (benzyloxycarbonyl) - O-re / -butyltrononium dicyclohexylamine as found in Method B8a. The 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl sothiocyanate according to Method A2b. The (1R, 2S) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthyl sothiocyanate followed by cyclopentyl bromide according to Method C5b to deliver (4R) -2- (4-Nitro-1-naphthylimino) -4 - ((1 S) -1 -ferf-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Entry 155 (1, 2R) -1-methanesulfonylmethyl-2- (fe-butoxy) propanemonium chloride was made from the salt of () - (1 S, 2R) -? / - (benzyloxycarbon) L) -0-yer-butyltrononium dicyclohexylamine as described in Method B8a. The 1-amino-5,6,7,8-tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahydronaphth-1-yl thiocyanate according to Method A2a. The (1, 2R) -1-methanesulfonyloxymethyl) -2- (fe t -butoxy) propanemonium chloride was reacted with 4-nitro-5,6,7,8-tetrahydronaphth-1-yl sothiocyanate, followed by cyclopentyl bromide according to Method C5b to supply (4R) -2- (4-nitro-5,6,7 , 8-tetrahydronaphth-1 -limino) -4 - ((1R) -1-phe-t-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine Entry 156 The (1R, 2R) -1-methanesulfonyloxymethyl-2 - (. EAf-butoxy) propanemonium chloride was made from the salt of () - (1S, 2) -? / - (benzyloxycarbonyl) -O -fe / t-butyltreonine dicyclohexylamine as described in Method B8a. The 1-amino-5,6,7,8-tetrahydronaphthalene was converted to 4-nitro-5,6,7,8-tetrahdironaphth-1-yl isothiocyanate according to Method A2a. The (1R, 2R) -1-methanesulfonyloxymethyl) -2- (te / t-butoxy) propanamonium chloride was reacted with 4-nitro-5,6,7,8-tetrahydronaphthyl isothiocyanate. 1-i, followed by isobutyl bromide according to Method C5b to give (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1 -limino) -4- ( (1 R) -1-teAt-butoxyethyl) -3-isobutyl-1,3-thiazolidine Entry 157 The (1R, 2R) -1-methanesulfonylmethyl-2 - (.alpha.-butoxy) propanemonium chloride was made from the salt of (L) - (1S, 2R) -? / - ( benzyloxycarbonyl) -O-te / t-butyltronone diclclohexylamine as described in Method B8a. The 2-isopropylaniline was converted to 2-isopropyl-4-nitrophenol sothiocyanate according to Method A2a. (1, 2R) -1-Methanesulfonylmethyl-2- (fe / f-butoxy) propanemonium chloride was reacted with 2-isopropyl-4-nitrofepyl isothiocyanate followed by isobutyl bromide according to Method C5b to supply (4R) -2- (2-isopropyl-4-n-phenylphenyl) -4 - ((1R) -1-.e / -butoxyethyl) -3-isobut l-1, 3-thiazolidine Entry 158 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (reAt-butoxy) propanamonium chloride was made from the salt of (L) - (1 S, 2R) - / V- (benzyloxycarbonyl) -O- te / t-butyltronone dicyclohexylamine as described in Method B8a. The 2-isopropylaniline was converted to 2-isoprocyanate 2-isopropyl-4-nitrophenol according to Method A2a. The (1, 2R) -1-methanesulfonylmethyl-2- (te / t-butoxy) propanamonium chloride was reacted with 2-isopropyl-4-nitrophenyl sothiocyanate followed by cyclopentyl bromide according to the Method C5b to supply (4R) -2- (2-isopropyl-4-nitrophenolimino) -4 - ((1R) -1-te / t-butoxyeti) -3-c clopentyl-1,3-thiazolidine Entry 159 (1, 2R) -1-methanesulfon-1-oxymethyl-2 - (. E / t-butoxy) propanemonium chloride was made from the salt of () - (1 S, 2R) -? / - (benz Loxycarbonyl) -O-rerf-butyltreonine dicyclohexylamine as described in Method B8a. The 2,3-dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl sothiocyanate according to Method A2a. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (te / t-butoxy) propanemonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to the Method C5b for supplying (4R) -2- (2,3-dimethyl-4-nitrophenolinylamino) -4 - ((1R) -1-ferr-butoxyethyl) -3-cyclopentyl-1 , 3-thiazolidine.

Entry 160 The (1 R, 2R) -1-methanesulfonyloxymethyl-2- (e / t-butoxy) propanemonium chloride was made from the salt of () - (1 S, 2R) - / V- (benz! Ioxicarbonyl) -0-te / -butyllthenonium dicyclohexylamine as described in Method B8a. The 2,3-dimethyl-4-nitroquinoline was converted to 2,3-dimethyl-4-nitrophenyl sothiocyanate according to Method A2a. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (fe / -butoxy) propanemonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl sothiocyanate followed by isobutyl bromide in accordance with Method C5b for supplying (4R) -2- (2,3-dimethyl-4-n -trofenylamino) -4 - ((1R) -1-fe / -butoxyeti) -3- sobutil-1, 3-tiazolidin.

Entry 161 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (re / -butoxy) propanammonium chloride was made from the salt of (L) - (1 S, 2R) - / V- (benzyloxycarbonyl) -0-tert.-butyltrimonium dicyclohexylamine as described in Method B8a. The 2,3-dimethyl-4-nitroaniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2a. The (1, 2R) -1-methanesulfonyloxymethyl-2- (feri-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl sothiocyanate followed by 2-ethyl-1-butyl bromide. according to Method C5b for supplying (4R) -2- (2,3-dimethyl-4-n -trofemylimino) -4- ((RI) - '/ - ie -butoxyethyl) - 3- (2-ethyl-1-butyl) -1,3-thiazolidine.

Entry 162 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was made from the salt of (L) - (1 S, 2R) -? / - (benzyloxycarbonyl) -0 -te.-butyltonione dicyclohexylamine as described in Method B8a. The 1-amino-4-cyano-5,6,7,8-tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphtyl sothiocyanate according to Method A2b. Chloride of x (1,2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propane ammonium was reacted with 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate followed by cyclopentyl bromide according to with Method C5b to supply (4R) -2- (4-cyano-5, 6,7,8-tetrahydronaphthylimino) -4 - ((1 R) -1-yer-butoxylet) -3-cyclopentyl -1, 3-thiazolidine.

Entry 163 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was made from the salt of () - (1S, 2R) -? / - (benzyloxycarbonyl) -0-feri butynthreonine dicyclohexylamine as described in Method B8a. The 1-amino-4-cyano-5,6,7,8-tetrahydronaphthalene was converted to 4-cyano-5,6,7,8-tetrahydronaphtyl isothiocyanate according to Method A2b. (1, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was reacted with 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate followed by bromide of isobutyl according to Method C5b to supply (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4 - ((1R) -1 -te / t-butoxylethyl) -3 -isobutyl-1, 3-tlazolidine.

Entry 164 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (te / t-butoxy) propanammonium chloride was made from the salt of (L) - (1 S, 2R) -? / - (benzyloxycarbonyl) ) -0-tert-butyltreonine dicyclohexylamine as described in Method B8a. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (ferf-butoxy) propanemonium chloride was reacted with 2-methyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b for supply (4R) -2- (2-methyl-4-nltrofen¡l¡m¡no) -4 - ((1) -1-te / t-butoxyethyl) -3 -sobutyl-1, 3- tzolzolidine. The tert-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (2-methyl-4-nitrophenylimido) -4 - ((1R) -1-hydroxyethyl) -3-isobutyl-1, 3-thiazole Entry 165 (1, 2S) -1-methanesulfonyloxymethyl-2- (te / t-butoxy) propanammonium chloride was made from the salt of (L) - (1S, 2R) -? / - (benzyloxycarbonyl) -O- The dicyclohexylamine is described as described in Method B8a. The 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. The (1R, 2S) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to deliver (4R) -2- (4 -nitro-1-naphthylamino) -4 - ((1 S) -1-te / -butoxyethyl) -3-cyclopentyl-1,3-tiazole dina. The tert-butyl ether was deprotected according to Method D3a to provide (4R) -2- (4-nitro-1-naphthylamino) -4 - ((1 S) -1-hydroxyethyl) -3-cyclopentyl -1, 3-tzolidine.

Entry 166 The (1R, 2S) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was made from the salt of () - (1S, 2S) -? / - (benzyloxycarbonyl) -O-tert-butyltronone dicyclohexylamine as described in Method B8a. The (1, 2S) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was reacted with 2-methyl-4-n-tronaphthio-2-thiocyanate followed by cyclopentyl bromide in accordance with Method C5b for supplying (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1 S) -1-te / t-butoxyethyi) -3-cyclopentyl-1,3-thiazolinidine. The tert-butyl ether was deprotected according to Method D3a to provide (4R) -2- (2-methyl-4-nltrofenilimino) -4 - ((1S) -1-hydroxyethyl) -3-cyclopentyl-1, 3-tiazolidin.

Entry 167 The (1, 2R) -1-methanesulfonyl-oxoxymethyl-2- (tert-butoxy) propanemonium chloride was made from the salt of (L) - (1S, 2R) -? / - (benzyloxycarbonyl) -0- te / f-butyltronone dicyclohexylamine as described in Method B8a. (1, 2R) -1-methanesulfonyloxymethyl-2- (te / -butoxy) propanemonium chloride was reacted with 2-methyl-4-nitronaphthyl isothiocyanate followed by acyl cyclopentyl bromide with Method C5b to give (4R) -2- (2-methyl-4-nltrofen¡l¡m¡no) -4 - ((1R) -1-te / t-butoxyethyl) -3-cyclopentyl-1,3-t! azolidina. The tert-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (2-methyl-4-nitrophenylymino) -4 - ((1R) -1-hydroxyethyl) -3- cyclopentyl-1,3-tiazolidine.

Entry 168 The (1R, 2S) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was made from the salt of () - (1S, 2S) - / V- (benzyloxycarbonyl) -0- dicyclohexylamine ferf-butyltreonine as described in Method B8a. The (IR ^ RJ-l-methanesulfonyloxymethyl ^ -tete-butoxy-Jpropanammonium chloride was reacted with 2-methyl-4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2- methyl-4-nitrophenylimino) -4 - ((1S) -1-te / t-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine The tert-butyl ether was deprotected in accordance with Method D3a for supplying (4R) -2- (2-methyl-4-nitrophenylimino) -4 - ((1 S) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Entry 169 Ef (1R, 2R) -1-methanesulfonyloxymethyl-2- (te / t-butoxy) propanammonium chloride was made from the salt of (L) - (1 S, 2R) -? / - (benzyloxycarbonyl) -0-te / -butiitreonine dicyclohexylamine as described in Method B8a. 2-Terr-butyl-4-cyanoaniline was converted according to Method A2b. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (ten-butoxy) propanammonium chloride was reacted with 2-te / -butyl-4-cyanophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (2-Fet-butyl-4-cyanophenylimino) -4 - ((1 S) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to deliver (4f?) -2- (2-te / f-butyl-4-cyanophenylimino) -4 - ((1R) -1-hydroxyethyl) -3 -cyclopentyl-1,3-thiazolidine.

Entry 170 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (te / f-butoxy) propanamonium chloride was made from the dicyclohexylamine salt (L) - (1S, 2R) - / V- (benzydrocarbonyl) - 0-tert-butyltreonine as described in Method B8a. The 2-tert.-butyl-4-cyanoaniline was converted to 2-tert-butyl-4-cyanophenyl isothiocyanate according to Method bA2a. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (te / t-butoxy) propanamonium chloride was reacted with 2-tert-butyl-4-cyanophenyl isothiocyanate followed by isobutyl bromide according to with Method C5b to provide (4R) -2- (2-te / r-butyl-4-cyanophenylimino) -4 - ((1R) -1-te-butoxyethyl) -3-isobutyl-1, 3-ylazolidine. The tert-butyl ether was deprotected according to Method D3a to provide (4R) -2- (2-tert-butyl-4-cyanophenylimino) -4 - ((1 R) -1-hydroxyethyl) -3-isobutyl -1, 3-thiazolidine.

Entry 171 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was made from the dicyclohexylamine (L) - (1S, 2R) - / V- (benzylcarbonyl) salt. ?) - 0-te / t-butyltreonine as described in Method B8a. The 4-nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. The chloride (1R), 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium was reacted with 4-nitronaphthyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to deliver (4R) -2- (4-nitro-1 - x naphthylimino) -4 - ((1R) -1-te / t-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (4-nitro-1-naphthylimino) -4 - ((1 R) -1-hydroxyethyl) -3-cyclopentyl- 1,3-thiazolidine.

Entry 172 (1, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was made from the dicyclohexylamine (L) - (1 S, 2R) -? / - (benzyloxycarbonyl) -0- salt terf-butyltreonine as described in Method B8a. It was converted to 1-amino-5,6,7,8-tetrahydronaphthalene in 4-nitro-5,6,7,8-? Or tetrahydronaphthyl-1-yl isothiocyanate according to Method A2a. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was reacted with 4-nitro-5,6,7,8-tetrahydronaphth-1-yl isothiocyanate followed by cyclopentyl bromide according to with Method C5b to supply (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1 -limino) -4 - ((1R) -1-te / 1-butoxyethyl) -3- cyclopentyl-1, 3- 15 thiazolidine. The tert-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1-ylimino) -4 - ((1 R) - 1-hydroxyethyl) -3-cyclopentyl-1,3-tiazolidine.

Entry 173 20 - - -. m ^ * ~ ~? > ^^^ - MU "(1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was made from the dicyclohexylamine (L) - (1 S, 2R) -? (benzyloxycarbonyl) -0-tert-butyltreonipa as described in Method B8a, converted to 1-Amino-5,6,7,8-tetrahydronaphthalene in 4-nitro-5,6,7,8-tetrahydronaphthyl isothiocyanate. -1-yl according to Method A2a: (1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was reacted with 4-nitro-5,6,7,8-tetrahydronaft isothiocyanate -1-yl followed by cyclopentyl bromide according to Method C5b to give (4R) -2- (4-nitro-5,6,7,8-tetrahydronaphth-1 -limino) -4 - ((1R) - 1-te-butoxyethyl) -3-isobutyl-1,3-thiazolidine The tert-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (4-ntr-5, 6,7,8-tetrahydronaphth-1 -limino) -4 - ((1R) -1-hydroxyethyl) -3-isobutyl-1, 3-thiazolydin.

Entry 174 (1R, 2R) -1-methanesulfonyloxymethyl-2- (fe.t-butoxy) propanemonium chloride was made from the dicyclohexylamine (L) - (1S, 2R) - / V- (benzyloxycarbonyl) -0- salt terf-butyltreonine as described in Method B8a. It was converted to 2-isopropylaniline in 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a. The (1, 2R) -1-methanesulfonyloxymethyl-2- (te / t-butoxy) propanamonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to the Method. C5b for supplying (4R) -2- (2-isopropyl-4-nitrophenylimino) -4 - ((1 R) -1-phe / t-butoxyethyl) -3-issbutyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to give (4R) -2- (2-isopropyl-4-nitrophenylimino) -4 - ((1 R) -1-hydroxyethyl) -3-isobutyl-1 , 3-thiazolidine.

Entry 175 (1R, 2R) -1-methanesulfonyloxymethyl-2- (te / f-butoxy) propanemonium chloride was made from the dicyclohexylamine salt (£.) - (1S, 2R) -? / - (benzyloxycarbonyl) -0 -tertt-butyltreonine as described in Method B8a. It was converted to 2-Isopropylaniline in 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a. (1R, 2R) -1-methanesulonyloxymethyl-2- (tert-butoxy) propanemonium chloride was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b to deliver (4R ) -2- (2-isopropyl-4-nitrophenylimino) -4 - ((1 R) -1-te / f-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to provide (4R) -2- (2-isopropyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-cyclopentyl lo-1, 3-thiazolidine.

Entry 176 The (1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was made from the dicyclohexylamine (L) - (1 S, 2R) -? / - (benzyloxycarbonyl) -0 salt -te / -butyltreonine as described by Method B8a. It was converted to 2,3-Dimethyl-4-nitroaniline in 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (tet-butoxy) propanammonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by 2-ethyl-1-butyl bromide according to Method C5b to supply (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1 R) -1-buto-butoxyethyl) -3- (2-ethyl-1-butyl) -1 , 3-thiazolidine. The te / t-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (2,3-dimethyl-4-nitrophenoliny) -4 - ((1R) -1-hydroxyethyl ) -3- (2-ethyl-1-butyl) -1,3-thiazolidine.

Entry 177 (1R, 2R) -1-methanesulfonyloxymethyl-2- (te / f-butoxy) propanammonium chloride was made from the dicyclohexylamine () - (1 S, 2R) - / V- (benzyloxycarbonyl) -0-te salt - bütiltreonina as it is described in Method B8a. It was converted to 2,3-Dimethyl-4-nitroaniline in 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1, 2R) -1-methanesulfon-oxoxymethyl-2- (te / t-butoxy) propanamonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by isobutyl bromide according to Method C5b to provide (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1 R) -1-methyl-butoxyethyl) -3-isobutyl-1,3-thiazolidine. The te / 1-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3- isobutyl-1, 3-thiazolidine.

Entry 178 (1, 2R) -1-Methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was made from the dicyclohexylamine (L) - (1 S, 2R) -? / - (benzyloxycarbonyl) -0-te salt / f-butyltreonine as described in Method B8a. It became the 2,3-Dimethyl-4-nitroaniline in 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method A2b. (1R, 2R) -1-methanesulfonylmethyl! -2- (tert-butoxy) propanemonium chloride was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate followed by cyclopentyl bromide according to Method C5b for to give (4R) -2- (2,3-dimethyl-4-nitrophenimlimino) -4 - ((1R) -1-te -butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (2,3-dimethyl-4-nitrophenylimino) -4 - ((1R) -1-hydroxyethyl) -3-cyclopentyl- 1,3-thiazolidine. ' Entry 179 (1R, 2R) -1-methanesulfonyloxymethyl-2- (te -butoxy) propanemonium chloride was made from the dicyclohexylamine () - (1S, 2R) -? / - (benzylloxycarbopyl) salt -0-te / f-butyltreonine as described in Method B8a. It was converted to 1-amino-4-cyano-5,6,7,8-tetrahydronaphthalene in 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (tef-butoxy) propanammonium chloride was reacted with 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate followed by cyclopentyl bromide according to the Method C5b for supplying (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4 - ((1R) -1-tert-butoxyethyl) -3-cyclopentyl-1,3-thiazolidine. The tert-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4 - ((1 R) -1-hydroxyethyl) -3-cyclopentyl-1,3-thiazolidine.

Entry 180 (1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanemonium chloride was made from the dicyclohexylamine (_) - (1S, 2R) -? / - (benzyloxycarbonyl) -0 salt -te / -butyltreonine as described in Method B8a. It was converted to 1-amino-4-cyano-5,6,7,8-tetrahydronaphthalene in 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate according to Method A2b. The (1R, 2R) -1-methanesulfonyloxymethyl-2- (tert-butoxy) propanammonium chloride was reacted with 4-cyano-5,6,7,8-tetrahydronaphthyl isothiocyanate followed by isobutyl bromide according to Method C5b to supply (4R) -2- (4-cyano-5,6,7,8-tetrahydronaphthylimino) -4 - ((1R) -1- / e / 7-butoxyethyl) -3-isobutyl-1,3-thiazolidine . The tert-butyl ether was deprotected according to Method D3a to deliver (4R) -2- (4-cyano-5,6,7-8-tetrahydronaphthylimino) -4 - ((1 R) -1 - hydroxyethyl) -3-isobutyl-1,3-thiazolidine.

Entry 181 2-amino-1,3-propanediol was reacted with excess SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -4- ( chloromethyl) -1,3-thiazolidine. Thiazolidine was reacted with / V-methylamine according to Method D13a to give 2- (2-methyl-4-nitrophenylimino) -4- (V-methylaminomethyl) -1,3-thiazolidipa, which was reacted with bromide of isobutyl according to Method D2a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4 - (? / - isobutyl-β-methylaminomethyl) -1,3-yiazolidine.

Entry 182 2-amino-1,3-propanediol was reacted with excess of SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -4- ( chloromethyl) -1,3-thiazolidine. Thiazolidine was reacted with dimethylamine according to Method D13a to give 2- (2-methyl-4-nitrophenylimino) -4- (isobutyl-? / - methylaminomethyl) -1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4 - (? /,? / - dimethylaminomethyl) -1,3-thiazolidine.

Entry 183 The (L) -Histidinol was reacted with SOCI2 followed by 2-methyl-4-nitrophenyl sothiocyanate according to Method C2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4- ( 1-isobutyl! Imdazolyl) methyl) -1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to provide (4S) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4- (1- (isobutylimidazolyl) methyl) -1, 3-thiazolidine.

Entry 184 The (L) -Hstidinol was reacted with SOCI2 followed by 2-methyl-4-nitrophenyl sothiocyanate according to Method C2a to give (4S) -2- (2-methyl-4-nitrophenylimino) -4- (1-isobutyl-imidazolyl) methyl) -1,3-thiazolidine. The thiazolidipa was 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.

Entry 185 N0 > 2-Hydroxypropylamine was converted to 2-chloroproamylammonium chloride, according to Method B7a. The isothiocyanate 2-methyl-4-nitrophenyl was reacted with 2-chloropropylammonium according to Method C1a to give 2- (2-methyl-4-nitrophenylamino) -5-methyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-ylbromide according to Method D2g to deliver a salt of Hbr 2- (2-methyl-4-nitrophenylimino) -3- (2- methylprop-2-en-1-yl) -5-methyl-1,3-thiazolidine.

Entry 186 2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-2-phenyl-2-hydroxymethylamine. Ethanolamine was reacted with SOCI2 followed by 2-chloro-4- (trifluoromethyl) phenyl isothiocyanate according to Method C2f to give HCl salt 2- (2-chloro-4- (trifluoromethyl) phenylmethane) - 3-isobutyl-5-phenyl-1,3-thiazolidine. ' Entry 187 2-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-phenyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give? / - isobutyl-2-phenyl-2-hydroxyethylamine. Ethanolamine was reacted with SOCI2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to give 2- (2,3-dichlorophenylimino) -3-isobutyl-5-phenyl-1,3-thiazolidine.

Entry 188 HCl 3-Phenyl-2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-benzyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-3-phenyl-2-hydroxypropylamine. Propanolamine was reacted with SOCI2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to provide HCl salt 2- (2,3-dichlorophenylimino) -3-isobutyl-5-be? Ci-1 , 3-thiazolidine.

Entry 189 2-Methyl-2-hydroxypropyl amine was reacted with cyclohexanecarboxaldehyde according to Method B4c, Step 1 to give 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. Oxazolidine was reduced according to Method B4c, Step 2 to give? -cyclohexyl-2-methyl-2-hydroxypropylamine. Propanolamine was reacted with SOCI2 followed by 2,6-dichlorophenyl isothiocyanate according to Method C2f to provide 2- (2,6-dichlorophenylimino) -3-cyclohexyl-5,5-dimethyl-1,3-thiazolidine.

Entry 190 L (1R) -1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give? / - ((1) -1-Cyclohexyl-1-ethyl) - ? / - (2,2, -dimethyl-2-hydroxyethyl) amine. The? / - ((1R) -1-Cyclohexyl-1-ethyl) -? / - (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOCI2 followed by isothiocyanato-2,3-dichlorophenyl according to Method C2f to obtain a HCl salt of 2- (2,3-dichlorophenylimino) -3 - ((1 R) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazolidine Entry 191 (1 S) -1-Cyclohextrl--ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Me B5b to give? - ((1 S) -1-Cyclohexyl-1-ethyl) - / V- (2,2-dimethyl-2-hydroxyethyl) amine. The α / - ((1 S) -1-Cyclohexyl-1-ethyl) -? / - (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOCI2 followed by 2,4-dichlorophenyl isothiocyanate. according to Me C2f to obtain a HCl salt of 2- (2,4-dichlorophenylimino) -3 - ((1 S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1, 3-. thiazolidine Entry 192 The (1 S) -1-cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Me B5b to give? / - ((1 S) -1-Cyclohexyl-1-ethyl ) - / V- (2,2-dimethyl-2-hydroxyethyl) amine. The? / - ((1 S) -1-Cyclohexyl-1-ethyl) -? / - (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOCI2 followed by isothiocyanate 2,3-dichlorophenyl according to with the C2f Me to obtain a HCl salt of 2- (2,3-dichlorophenylimino) -3 - ((1 S) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazolidine .

Entry 193 2-MetiI-2-hydroxypropylamine was reacted with SOCI2 followed by 2,3-dichlorophenyl sothiocyanate according to Me C2f to obtain 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1, 3- Thiazolidine 2- (:, 3- dichlorophenylimino) -5,5-dimethyl-1,3-thiazolidipa was reacted with ethylene oxide according to Me B5b to obtain a salt of 2- (2,3-dichlorophenylimino) HCl -5,5-dimethyl-1,3-thiazolidine.

Entry 194 The 2-Methyl-2-hydroxypropylamine was reacted with SOCI2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Me C1a to obtain 2- (2-methyl-4-nitrophenylimino) -5,5-dimethyl ester. 1,3-thiazolidine.

Entry 195 2-Methyl-2-hydroxypropylamine was reacted with SOCI2 followed by 2-methyl-4-nitrophenyl-isothiocyanate according to Me C1a to obtain 2- (2-methyl-4-nitrophenylimino) -5,5-dimethyl -1, 3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Me D2g to obtain a Hbr salt of 2- (2-methyl-4-nitrophenylimino) -3- (2-methylpropyl). 2-en-1-yl) 5,5-dimethyl-1,3-thiazolidine.

Entry 196 2-Methyl-2-hydroxypropylamine was reacted with SOCI2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Me C1a to obtain 2- (2-methyl-4-nitrophenolimino) - 5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Me D2g to obtain a 2- (2-methyl-4-nitrophenylimino) -3-isobutyl) -5,5-dimethyl-1,3-thiazolidine.

Entry 197 HCl 2-Methyl-2-hydroxypropylamine was reacted with SOCI2 followed by 2,3-dichlorophenyl isothiocyanate according to Me C1a to obtain 2- (2,3-dichlorophenylimino) -5,5-dimethyl-1, 3- Thiazolidine The thiazolidine was reacted with isobutyl bromide according to Me D2g to obtain 2- (2,3-dichlorophenylimino) -3-isobutyl) -5,5-dimethyl-1,3-thiazolidine.

Entry 198 2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Me B4c, Pasol to obtain 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. The oxazolidine was reduced according to Me B4c, Step 2 to give? / - cyclohexyl-2-methyl-2-hydroxypropylamine. The propanolamine was reacted SOCI2 followed by isothiocyanate 2-methyl-4-nitrophenyl according to Me C2f to obtain 2- (2-methyio-4-nitrophenylimino) -3-cyclohexyl-5,5-dimethyl-1, 3- Thiazolidine Entry 199 2-Methyl-2-hydroxypropylamine was reacted with cyclohexanecarboxaldehyde according to Me B4c, Pasol to obtain 2-cyclohexyl-5,5-dimethyl-1,3-oxazolidine. The oxazolidine was reduced according to Me B4c, Step 2 to give V-cyclohexyl-2-methyl-2-hydroxypropylamipa. The propanolamine was reacted SOCI2 followed by isothiocyanate 2-methyl-4-nitrophenyl according to Me C2f to obtain 2- (2,3-dichlorophenylymino) -3-cyclohexyl-5,5-dimethyl-1, 3- Thiazolidine ' Entry 200 1 (R) -1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Me B5b to give / V-1 ((R) -1-cyclohexyl-1-ethyl ) - / V- (2,2-d.methyl-2-hydroxyethyl) amine. The? / - ((1 R) -1-cyclohexyl-1-ethyl) -? / - (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Me C2f to provide a salt of 2- (2-methyl-4-nitrophenylimino) -3 - ((1R) -1-cyclohexyl-1-ethyl) -5,5-dimethyl-1, 3- HCl ThiazolidineEntry 201 I have reacted 1 (S) -1-cyclohexyl-1-ethylamine with 1,2-epoxy-2-methylpropane according to Method B5b to give? / - 1 (S) -1-cyclohexyl-1-eti lamind -? / - (2,2-dimethyl-2-hydroxyethylamine) The? - ((1 S) -1-cyclohexyl-1-ethyl) -? / - (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to give a salt of 2- (2-methyl-4-nitrophenylimino) -3 - ((1 S) -1 HCl -cyclohexyl-1-ethyl) -5,5-dimethyl-1,3-thiazolidine.

Entry 202 Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give? -isopropyl- / V- (2,2-dimethyl-2-hydroxyethyl) amine. The N-isopropyl-A / - (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to give 2- (2-methyl) -4-nitrophenylimino) -3-isopropyl-5,5-dimethyl-1,3 thiazolidine.

Entry 203 The Isopropylamine was reacted with 1,2-epoxy-3-methylpropane according to Method B5b to give N-isopropyl-N- (2,2-dimethyl-3-hydroxyethyl) amine. The N-isopropyl-N- (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to give 2- (2-methyl-) 4-nitrophenylimethyl) -3 - ((1R) -1-isopropyl-5,5-dimethyl-1,3-thiazolidine.

Entry 204 HCl The isobutylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give? / - sobutyl-N- (2,2-dimethyl-2-hydroxyethyl) amine. The? / - SOBUTYL -? / - (2,2-dimethyl-2-hydroxyethyl) amine was reacted with SOCI2, followed by 2,4-dichlorophenyl isothiocyanate according to Method C2f to deliver a salt of HCl 2- (2,4-dichlorophenylimino) -3-isobutyl-5,5-dimethyl-, 3-thiazolidine.

Entry 205 L 1,1-dimethyl-2-hydroxyamine was converted to 1,1-dimethyl-2-chloroethylammonium chloride according to Method B7a. The isothiocyanal 2-methyl-4-nitrophenyl was reacted with 1,1-dimethyl-2-chloroethylammonium chloride according to Method C1a to give 2- (2-methyl-4-nitrophenylimino) -4, 4-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to deliver a salt of HBr 2- (2-methyl-4-nitrophenylimino) -4,4-dimethyl-3 - (2-methylprop-2-en-1-yl) -1,3-thiazolidine.

Entry 206 The methyl aminoisobutyric acid was converted to the salt of HCl methyl aminoisobutyrate according to Method B1c, Step 1. The ester was reduced to 3-hydroxy-2-methyl-2-propylamine according to Method B1c, Step 2. -hydroxyethylamine was treated with SOCI2, according to Method B7b, followed by 2-methyl-3-nitrophenyl isothiocyanate according to Method C1a to give 2 (2-methyl-4-nitrofepilimino) -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.

Entry 207 The 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 1- (cyclohexylamino) -1-hydroxymethylcyclopentane was synthesized as described in Method B4a. The 2-hydroxyethylamine was treated with SOCI2, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to provide 3-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -1-thia. -3-azaspiro [4.4] nonane.

Entry 208 The 2-ethylaniline was converted to 2-ethylacetanolide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. Acetanilide was deprotected according to with Method A2a, Step 3 to supply 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. The 1-amino-1 - (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2- (2-ethyl-4-nitrophenylimino) -1-thia-3-azaspiro [4,4] nonane. The 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.

Entry 209 The 2-n-propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a, Step 1. The aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to the Method A2b. The 1-amino-1 - (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 4-iodo-2-n-propylphenyl isothiocyanate according to Method C a to give 2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro [4 , 4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to provide 3-cyclopentyl-2- (4-iodo-2-n-propylphenylimino) -1-thia-3-azaspiro [4,4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to provide 3-cyclo? Enti-2- (4-cyano-2-A? -propylphimethyl) -1-t-a-3-azaspiro [4.4] nonane » Entry 210 The isopropylaniline was converted to 4-iodo-2- / sopropylaniline according to Method A5a. The aniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. The 1-amino-1 - (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 4-iodo-isopropylphenyl isothiocyanate according to Method C1a to give 2- (4-iodo-2-isopropylphenylimino) -1-thia-3-azaspiro [4,4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to deliver 3-cyclopentyl-2- (4-iodo-2- / sopro-pyl-phenylimino) -1-thia-3-azaspiro [4,4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to provide 3-cyclopentyl-2- (4-cyano-2- / sopro-phenyl-phenyl-1-yl) -1-t-a-3-azaspir [4 , 4] nonane.

Entry 211 The 2-te / t-butylaniline was converted to 4-iodo-2-te -butylaniline according to Method A5a. The aniline was converted to 4-iodo-2-tert-butylphenyl isothiocyanate according to Method A2b. The 1-amino-1 - (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-doroethylamine was reacted with 4-iodo-2-tert-butylphenyl isothiocyanate according to Method C1a to give 2- (4-iodo-2-tert-butylphenyl) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to provide 3-cyclopentyl-2- (4-iodo-2-tert-butylphenylimino) -1-thia-3-azaspiro [4, 4] nonane. The phenyl iodide was reacted with CuCN according to Method D7a to provide 3-cyclopentyl-2- (4-cyano-2-te-butylphenylimino) -1-tia-3-azaspiro [4.4 ] nonane.

Entry 212 The 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The amino alcohol was reacted with 2-methylcyclopentanylone according to Method B4a, Step 1 to give 13-aza-1-methyl-6-oxodispiro [4.2.4.1] tridecane, which was reduced with NaBH4, according to Method B4a, Step 2 to provide 1- (2-methylcyclopentyl) amino-1- (hydroxymethyl) cidopentane. The 2-hydroxyethylamine was reacted with SOCI ?, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to provide 3- (2-methylcyclopentyl) -2- (2-methyl-4-nitrophenylimino) -1 -thia-3-azaspiro [4.4] nonane.

Entry 213 The 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOC, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1 e to give 2- (2-methyl-4-nitrophenolimino) -3-thia-1-azaspiro [4? 4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4,4] nonane.

Entry 214 Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step-1. Acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. Acetanilide was deprotected according to the Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. The 1-amino-1- (hydroxymethyl) cidopentane was synthesized as described in Method B1c. The 2-h / droxyethylamine was reacted with SOCI2, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2- (2-ethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4,4] nonane. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-ethyl-4-nitrophenylimino) -3-tia-1-azaspiro [4,4] nonane.

Entry 215 The 2-n-propylaniline was converted to 2-n-propylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl - /? - propyl-4-nitroacetanilide according to Method A2a, Step 2 The acetanilide was deprotected according to Method A2a, Step 3 to give 2-n-propyl-4-nitroaniline. The aniline was converted to 2-n-propyl-4-nitrophenyl sothiocyanate according to Method A2a, Step 3. The 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCI2l according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 2-rt-propyl-4-nitropheni isothiocyanate according to Method C1a to give 2- (2- / 7-propyl-4-nitrophenylimino) -3-tia-1-azaspiro [4.4] nonane. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-n-propyl-4-nitrophenylimino) -3-tia-1 -azaspiro [ 4.4] nonane.

Entry 216 The 2-isopropylaniline was converted to 2-isopolylacetanilide according to Method A2a, Step 1. Acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to Method A2a, Step 2. Acetanilide was unprotected according to Method A2a, Step 3 to give 2-isopropyl-4-nitroaniline. The aniline was converted to 2-isoprocyanate 2-isoprocyanate-4-nitrophenol according to Method A2a, Step 3. The 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in the Method B1c The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate according to Method C a to give 2- (2-isopropyl-4-nitrophenlimimino) -3-thia-1-azaspiro [4.4] nonane . The thiazolidine was reacted with isobutyl bromide according to Method D2a to provide 1-isobutii-2- (2-isopropyl-4-nitrophenylimino) -3-thia-1-azaspiro [4,4] nonane.

Entry 217 The 2,3-dimethyl-4-nitroaniline was synthesized as described in Method A4a. The aniline was converted to 2,3-dimethyl-4-nitrophenyl isothiocyanate as described in the A2d method. The 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B e. The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7e to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2- (2,3-dimethyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4 ] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (2-methyl-4-nitrophenylimino) -3-thia-1 -azaspiro [4,4] nonane.

Entry 218 The 3-methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. The 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-doroethylamine was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4,4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-butyl-2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4,4] nonane.

Entry 219 The 1-amino-5,6,7,8-tetrahydronaphthaline was converted to 1-acetamino-5,6,7,8-tetrahydronaphthaline according to M 2a, Step 1. The acetanilide was converted to 1-acetamino-5,6,7,8-tetrahydronaphthalene from according to Method A2a, Step 2. Acetanilide was deprotected according to Métqdo A2a, Step 3 to provide 1-amino-4-nitro-5.6.7.8-tetrahydronaphthaline. The aniline was converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method A2a, Step 3. The 1-amino-1 - (hydroxymethyl) cyclopentane was synthesized as described in Method B1 c. The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7a to give a salt of 1-amino-1- (chloromethyl) cyclopentane HCl. The 2-chloroethylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method C1a to give 2- (4-nitro-5,6,7,8-tetrahydro-1-naphthylimino) -3- thia-1-azaspiro [4.4] nonane. Thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (4-nitro-5,6,7,8-tetrahydro-1-naphthylamino) -3-tia-1-azaspiro [ 4.4] nonane.

Entry 220 The 1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCI2, according to Method B7e to give a HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine was reacted with 4-cyanophenyl isothiocyanate according to Method C1 a to give 2- (4-cyanophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give 1-isobutyl-2- (4-cyanophenlimine) -3-thia-1 -azaspiro [4.4] nonanp.

Entry 221 The 4-cyano-2-methylaniline was synthesized as described in Method A1a. The aniline was converted to 4-cyano-2-methylphenyl isothiocyanate according to Method A2a., Step 3. A 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. 2-Hydroxyethylamine was reacted with SOCI2 according to Method B7a to give a HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamipa was reacted with 4-cyano-2-methylphenyl isothiocyanate according to Method C1 a to give 2- (4-cyano-2-methylphenylimino) -1-thia-3-azas? Iro [4, 4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-iodo-2-methylphenylimino) -1-thia-3-azaspiro [4,4] nonane.

Entry 222 The 1-amino-1 - (hydroxymethyl) cyclopentane was synthesized as described in Method B1 c. The 2-hydroxyethylamine was reacted with SOCI2 according to Method B7a to give a HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine was reacted with 4-cyano-2-ethylphenyl sothiocyanate according to Method C1a to give 2- (4-cyano-2-methylphenylimino) -1-thia-3-azaspiro [4.4] nonano The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-cyano-2-methylphenylimino) -1-thia-3-azaspiro [4,4] nonane.

Entry 223 EI-1-amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1 c. The 2-hydroxyethylamine was reacted with SOC according to Method B7a to give a HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 1-amino-4-cyanonaphthalene was converted to 4-cyano-1-naphthyl isothiocyanate, according to Method A2a, Step 3. Chloroethylamine was reacted with 4-cyano-1-naphthyl isothiocyanate according to Method C1a to give 2- (4-cyano-1-naphthylimino) -1-thia-3-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2- (4-cyano-1-naphthylimino) -1-thia-3-azaspiro [4,4] nonane.

Entry 224 2,3-Dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method A2a, Step 3. A 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOC according to Method B7e to give a HCl salt of 1-amino-1- (chloromet / l) cyclopentane. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-iodophenylimino isothiocyanate) according to Method C1e to give 2- (2,3-dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [ 4.4] nonane. Thiazolidine was reacted with isobutyl bromide according to Method D2h to provide 3-isobutyl-2- (4-iodo-2- / 7-propylphenylimino) -1-thia-3-azaspiro [4.4] nonane .

The phenyl iodide was reacted with CuCN according to Method D7a to obtain 3-isobutyl-2- (2,3-dimethyl-4-cyanophenylimino) -1-tia-3-azaspyrro [4]. , 4] nonane.

Entry 225 The 2,3-dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl sothiocyanate according to Method A2a, Step 3. A 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B c. The 2-hydroxyethylamine was reacted with SOCI2 followed by 2,3-dimethy-4-iodophenylimino isothiocyanate) according to Method C2a to give 2- (2,3-dimethyl-4-iodophenylimino) -1-thia-3 -azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to provide 3-isobutyl-2- (4-iodo-2-A? -propylphenylimino) -1-thia-3-azaspiro [4,4] nonane. The phenyl iodide was reacted with trimethylsilylacetylene according to Method D8a, Step 1, to obtain 3-isobutyl-2- (2,3-dimethyl-4- (2-trimethylsilylanethyl) phenolimine. ) -1-thia-3-azaspiro [4.4] nonane. Silyl acetylene was deprotected according to Method D8a, Step 2 to provide 3-isobutyl-2- (2,3-dimethyl-4- (ethylene phenyl) -1-thia-3-azaspiro [4.4] nonane.

Entry 226 The 2,3-dimethylaniline was converted to 2,3-dimethyl-4-iodoaniline according to Method A5a. The aniline was converted to 2,3-dimethyl-4-iodophenyl sothiocyanate according to Method A2a, Step 3. A 1-Amino-1- (hydroxymethyl) cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOC according to Method B7e to give a HCl salt of 1-amino-1- (chloromethyl) cyclopentane. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-iodophenyl isothiocyanate according to Method C1 e to give 2- (2,3-dimethyl-4-iodophenylimino) -1-thia-3-azaspiro [4 , 4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2h to give 3-isobutyl-2- (4-iodome-2-propylphonylamino) -1-t-aa-3. azaspyrro [4.4] nonane.

Entry 227 The 2,3-dimethylaniline was converted to 2,3-dimethyl-6-nitroaniline according to Method A4a. The aniline was converted to 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method A2d. A 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl 1-chloromethylcyclopentanamine salt was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method C1e to give 2- (2,3-dimethyl-6-nitrophenylimino) -3-thia-1 -azaspiro [4.4] nonane. The thiazolidine was reacted with sodiumbutyl bromide according to Method D2b to give 2- (2,3-dimethyl-6-nitrophenylimino) -1-i sobutyl-3-thia-1-azaspiro [4.4] nonane.

Entry 228 The 2-cyano-5-nitrotiofene was converted to 2-amino-5-cyano-1-thiophene according to Method A2b. 1-HydroxymethylcyclopentA1 amine was prepared by Method B1 c aminothiophen was converted to 5-cyano-1-thiophenium isothiocyanate according to Method A2b. The 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a 1-chloromethylcyclopentanamine HCl salt according to Method B7c. The HCl 1-chloromethylcyclopentanamine salt was reacted with 5-cyano-1-thiophene isothiocyanate according to Method C1e to give 2- (5-cyanothienylimino) -3-thia-1-azaspiro [4,4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 2- (5-cyanothienylimino) -1-isobutyl-3-thia-1-azaspiro [4,4] nonane.

Entry 229 The 6-amino-3-cyano-2,3-dimethyl-pyridine was converted to 3-cyano-2,3-dimethyl-6-pyridyl thiocyanate according to Method A2c. The 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a salt of 1-C-oromethylcyclopentanamine HCl according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 3-cians-2,3-dimethyl-6-pyridyl isothiocyanate according to Method C1 e to give 2- (3-cyano-2,3-dimethyl-6) -pyridylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2h to give 2- (5-bromothienylimino) -1-isobutyl-3-thia-1-azaspiro [4,4] nonane.

Entry 230 The 1- (hydroxymethyl) cyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCI2, and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1 -azaspiro [4, 4] nonane. Thiazolidine was reacted with 1-bromo-2-ethylbutapo according to Method D2a to give 2- (2-methyl-4-nitrophenimimino) -1- (2-ethyl-1-butyl) -3-thiazole. 1 -azaspiro [4.4] nonane Entry 231 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1 e to give 2- (4-cyano-2-ethylfinilimino) -3-thia-1-azaspiro [4, 4] nonane. Thiazolidine was reacted with 3-bromopentane, according to Method D2b to provide 2- (4-cyano-2-ethylphenylimino) -1- (3-pentyl) -3-thia-1-azaspiro [4.4] nonane .

Entry 232 The 1-hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethylamine was converted to a 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The salt of 1-cyclo-methylcyclopentanamine HCl was reacted with 4-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [ 4.4] nonane. The thiazolidine was reacted with isopropyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (2-propyl) -3-thia-1 -azaspiro [4, 4] nonane.

Entry 233 The 1-hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethylamipa was converted to a HCl salt of 1-chloromethylcyclopentanamine according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrofepilimino) -3-thia-1 -azaspiro [4.4 ] nonane. The thiazolidine was reacted with 3-bromo-2-methylpropene according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) - '! - (2-methylprop-1-en-3-yl) 3-thia-1 -azaspiro [4.4] nonane.

Entry 234 A 1-hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethylamine was converted to a salt of 1-chloromethylcyclopentanamine HCl according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1 e to give 2- (2-methyl-4-nitrophenimimino) -3-thia-1-azaspiro [4, 4] nonane. Thiazolidine was reacted with allyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1 - (pro? -1-en-3-yl) -3-thia-1 -azaspiro [4.4] nonane.

Entry 235 1-Hydroxymethyl iclopentanamine was prepared according to Method B1c. The 2-hydroxyethyl amine was converted to a salt of 1-chloromethylcyclopethylamine HCl according to Method B7e. The salt of HCl 1 -chloromethylcyclopentaneamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate of acylide with Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4] nona no. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1 (cyclopropylmethyl) -3-thia-1-azaspiro [4,4] nonane.

Entry 236 1-Hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethyl amine was converted to a salt of 1-chloromethylcyclopentanamine HCl according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1 e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1 -azaspiro [4, 4] nonane. The thiazolidine was reacted with cyclohexylmethyl bromide according to Method D2e to give 2- (2-methyl-4-nitrophenylimino) -1- (cyclohexylmethyl) -3-thia-1-azaspiro [4,4] nonane.

Entry 237 The 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1 e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4, 4] nopano. Thiazolidine was reacted with 2- (bromomethyl) tetrahydro-2H-pyran, according to Method D2e, to give 2- (2-methyl-4-nitrophenylimino) -1 - (tetrahydro-2H-pyran-2-ylmethyl) -3-t-a-1 -azaspiro [4.4] nonane.

Entry 238 The 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a salt of HCl '1-chloromethylcyclopentanamine according to Method B7e. The HCl 1-chloromethylcyclopentanamine salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4 ] nonane. Thiazolidine was reacted with 2- (2-bromoethyl) -1,3-dioxane, according to Method D2e, to give 2- (2-methyl-4-nitrophenylimino) -1- (2- (1, 3- dioxane-2-yl) ethyl) -3-thia-1-azaspiro [4.4] nonane.

Entry 239 The 1-hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethylamine was converted to a 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The salt of HCl 1- x chloromethylcyclopentanamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4, 4] nopano. The thiazolium was reacted with cyclobutyl bromide, according to Method D2e, to give 2- (2-methyl-4-nitrophenyl-amino) -1-cyclobutyl-3-thia-1-azaspiro [4,4] nonane.

Entry 240 1 - (Hydroxymethyl) cyclopentanamine was prepared according to the Method B1c The 2-hydroxyethylamine was treated with SOCI2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1 -azaspiro [4.4 ] nonane. The thiazolidine was reacted with cyclopeptyl bromide, according to Method D2b, to give 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 241 1-Hydroxymethylcyclopentanamine was prepared according to Method B1 c.

The 2-hydroxyethylamine was reacted with SOCI2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspyrro [ 4.4] nopane. Thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (2-methyl-4-nitrophenimimino) -1 -2-cyclopentyl-3-thia-1-azaspiro [4,] nonane . The thiazolidine was oxidized with m-d 3A according to Method D4a to give 2- (2-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane 3-oxide.

Entry 242 1-Hydroxyethylamine was prepared according to Method B1c. The 2-hydroxyethylamine was reacted with SOCI2 followed by 2-methyl-4-nitrophenyl ethanocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4 , 4] nonane. Thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (2-methyl-4-nitrophenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. Thiazolidine was oxidized with m-CPBA according to Method D4a to provide 2- (2-methyl-4-nitrophenylimino) -1-cyclopeni / l-3-thia-1-azaspiro [4,4] nonane 3-dioxide .

Entry 243 The 2-ethylamin was protected as 2-ethylacetanilide according to Method A2a, Step 1. Acetamide was converted to 2-ethyl-4-nitroaniline, then it was deprotected according to Method A2a, Step 2. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. The 1-hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethylamine was converted to HCl 1 -chloromethylcyclopentanamine salt according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2- (2-ethyl-4-nitrophenylphenylimino) -3-thia-1-azaspiro [4.4 ] nonane. The 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.

Entry 244 The 3-methyl-4-nitroaniline was converted to isothiocyanate 3-methyl-4-nitrophenyl according to Method A2a, Step 3. The 1-hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethylamine was converted to a salt of 1-chloromethylcyclopentanamine HCl according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2- (3-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4.4 ] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (3-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspyrro [4,4] nonane.

Entry 245 2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, Step 1. Acetamide was converted to 2,3-dimethyl-4-nitroaniline, then unprotected according to Method A2a, Step 2. The aniline was converted to 2-dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. The 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamipa was converted to the 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2- (2,3-dimethyl-4-nitrophenylphenyl) -3 -thia-1 -azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2,3-dimethyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 246 2,3-Dimethylaniline was protected as 2,3-dimethylacetanilide according to Method A2a, Step 1. Acetamide was converted to 2,3-dimethyl-6-nitroaniline, then unprotected according to Method A2a, Step 2. The aniline was converted to 2-dimethyl-6-nitrophenyl isothiocyanate according to Method A2a, Step 3. The 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to HCl 1-chloromethylcyclopentane HCl salt according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method C1e to give 2- (2,3-dimethyl-6-nitrophenylimino) -3-thia-1-azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (2,3-dimethyl-6-nitrophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 247 1-Hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethylamine was converted to a salt of 1-chloromethylcyclopentanamine HCl according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 4-iodophenyl etothiocyanate according to Method C1e to give 2- (4-iodophenylphenylimino) -3-tia-1-azaspiro [4.4 ] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-iodophenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. Phenyl iodide was reacted with CuCN according to Method D2h to give 2- (4-cyanophenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 248 The 4-cyano-2-methylaniline was prepared according to Method A1a. The aniline was converted to 4-cyano-2-methylphenyl sothiocyanate according to Method A2b. The 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to HCl 1-chloromethylcyclopentanamine salt according to Method B7e. The HCl salt 1- chloromethylcyclopentanamine was reacted with 4-cyano-2-methylphenyl sothiocyanate according to Method C1e to give 2- (4-cyanophenylphenylimino) -3-thia-1-azaspiro [4.4] nonane . The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 249 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a salt of 1-chloromethylcyclopentanamine HCl according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 4-cyano-2-ethylphenyl sothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4 , 4] nonane. The thiazolidine was reacted with cyclopentyl bromide, x according to Method D2b, to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 250 U n 4-mud-2-p-propylaniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCI2 and 4-iodo-2- / 7-propylphenyl isothiocyanate according to Method C2a to give 2- (4-iodo-2- / 7-propylphenylimino) -3-ti a-1-azasp! ro [4.4] nonane.

Thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-iodo-2-r? -propylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane . The phenyl iodide was reacted with CuCN according to Method D7a to give 2- (4-cyano-2-p-propylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 251 A 4-iodo-2-isopropylaniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCI2 and 4-iodo-2-isopropylphenyl isothiocyanate according to Method C2a to give 2- (4-iodo-2-isopropyl) -3-thia-1- azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-iodo-2-isopropylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The phenyl was reacted with CuCN in accordance with Method D7a to give 2- (4-cyano-2-isopropylphenylimin) -1-cyclopentyl-3-thia-1-azaspyr. [4.4] nonane. ' Entry 252 A 4-lodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenyl sothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCI2 and 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method C2a to give 2- (4-iodo-2,3-dimethylphenylimino) -3-thia-1- azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-iodo-2,3-dimethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The phenyl was reacted with CuCN according to Method D7a to give 2- (4-cyano-2,3-dimethyphenylimino) -1-cyclopentyl-3-thia-1-azaspyrro [4.4 ] nonane. v Entry 253 1-Hydroxymethylcyclopentanamine was prepared according to Method B1 c. The 2-hydroxyethylamine was converted to a salt of 1-chloromethylcyclopentanamine HCl according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4, 4] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was hydrolyzed according to Method D9a to provide 2- (4-carboxy-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4-nonane] Entry 254 The 4-cyano-2-methylamino was prepared according to Method A1 a. The aniline was converted to 4-cyano-2-methylphenyl isocyanate according to the Method A2b. The hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a salt of 1-chloromethylcyclopentanamine HCl according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 4-cyano-2-methylphenyl isothiocyanate according to Method C1 e to give 2- (4-cyano-cyanophenylphenylimino) -3-thia-1-azaspiro [4, 4] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-cyano-2-methyl-ethyl-pyrimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-methylphenlimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4-nonane.

Entry 255 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4, 4] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4,4-nonane]. The benzoic acid was converted to 2- (4-acetyl-2-ethylphenylphenyl) -1-cidopentyl-3-thia-1-azaspiro [4,4] nonane according to Method D10a.

Entry 256 Methyl 4-amino-3-methoxybenzoate was converted to 4-methoxycarbonyl-2-methylphenyl thiocyanate according to Method A2a. The hydroxymethylcyclopentanamine was prepared according to Method B1c. Hydroxyethylamine was sequentially reacted with SOCI2, and 4-methoxycarbonyl-2-methylphenyl isothiocyanate according to Method C2a to give 2- (4-methoxycarbonyl-2-methylphenylimino) -3-thia-1-azaspiro- [4.4 ] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2h to give 2- (4-methoxycarbonyl-2-methylphenylimin) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 257 1-Hydroxymethylcyclopentanamine was prepared according to Method B1 c.

The 2-hydroxyethylamine was converted to a 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 4-cyano-2-ethylphenyl sothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4 , 4] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was hydrolyzed according to Method D9a to provide 2- (4-carboxy-2-ethylphenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The benzoic acid was reacted with methylamine according to Method D6b to give 2- (4 -? / - methylcarbamoyl) -2-ethylpheniramine] -1-cyclopentyl-3-thia-1 -azaspiro [4.4] nonane .

Entry 258 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to a salt of 1-chloromethylcyclopeptanamine HCl according to Method B7e. The salt of 1-chloromethylcyclopentanamine HCl was reacted with 4-cyano-2-ethylphenyl sotiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [ 4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide, according to Method D2b, to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was hydrolyzed according to Method D9a to give 2- (4-carboxy-2-ethylphenylimino) -1-2-cyclopentyl-3-thia-1-azaspiro [4,4-nonane]. The benzoic acid was reacted with dimethylamine according to Method D6b to give 2- (4-? -? / - dimethylcarbamoyl) -2-ethylphenylimino) -1-cyclopentyl-3-thia-1 -azaspiro [4.4] nonane .

Entry 259 The 2,3-dichloroaniline was converted to 2,3-dichloroformanilide according to Method A3a, Step 1. The formanilide was converted to isocyanide 2,3-dichlorophenyl dichloride according to Method A3a, Step 2. The salt of HCl 1-hydroxymethylcyclopentanamine was synthesized according to Method B1c. The 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro (4.2.4) tridecane according to Method B4d, Step.The oxazolidine was opened reductively according to Method B4d, Step 2 to give 1- (cyclopentylamino) - 1- (hydroxymethyl) cyclopentane The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (acetylthiomethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2, to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane The thioethylamine was reacted with 2,3-dichlorophenyl 1,3-dichlorophenyl dichloride according to Method C6c to give 2- (2, 3-dichlorophenynylamino) -1-cyclopentyl-3-tia-1 -azaspiro [4,4] nonane.

Entry 260 The 2- (trifluoromethyl) aniline was converted to 2- (trifluoromethyl) formallide according to Method A3a, Step 1. The formanilide was converted to isocyanide dichloride (trifluoromethyl) phenyl according to Method A3a, Step 2. The HCl 1 -hydroxymethylcyclopentanamine salt was synthesized according to Method B1 c. The 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro (4.2.4.1) tridecap according to Method B4d, Step 1. Oxazolidine was opened reductively according to Method B4d, Step 2, to give 1- (cyclopentyl amino) ) -1- (hydroxyethyl) cyclopentane The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, Step 1. Thioacetate was hydrolyzed according to Method C6c Step 2 to give 1- (cyclopentylamino) -1- (thiomethyl) cyclopentane The 2-thioethylamine was reacted with 2- (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c to deliver 2- (2- (trifluoromethyl) phenylimin) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane.

Entry 261 The 4- (trifluoromethyl) aniline was converted to 4- (trifluoromethyl) formanilide according to Method A3a, Step 1. The formanilide was converted to dichloride of socianide (trifluoromethyl) phenyl in accordance with Method A3a, Step 2. The salt of HCl 1-hydroxymethylcyclopentanamine was synthesized according to Method B1 c. The 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro (4.2.4.1) tridecane according to Method B4d, Step 1. Oxazolidine was opened reductively according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclo? Entan.The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 .- (cyclopentyllamine) -1- (thiomethyl) cyclopentane The 2-thioethylamine was reacted with 4- (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c to supply 2- (4- (trifluoromethyl) phenylamide) -1-cyclopentyl-3-tia-1-azaspiro [4.4] nonane .

Entry 262 2-Chloro-3-methylaniline was converted to 2-chloro-3-methylformanilide according to Method A3a, Step 1. The formanilide was converted to isocyanide dichloride 2-chloro-3-methylphenyl according to the Method A3a, Step 2. The salt of HCl 1-Hydroxymethylcyclopentanamine was synthesized according to Method B1c.

The 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro (4.2.4.1) tridecane according to Method B4d, Step 1. Oxazolidine was opened reductively according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cidopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamino) -1 - (thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 2-chloro-3-methylphenyl isocyanide dichloride according to Method C6c to give 2- (2-chloro-3-methylphenylimino) -1-cyclopentyl-3-thia-1 - azaspiro [4.4] nonane.

Entry 263 The 3- (trifluoromethyl) aniline was converted to 3- (trifluoromethyl) -silylide according to Method A3a, Step 1. The formanilide was converted to dichloride of socianide (trifluoromethyl) phenyl according to Method A3a, Step 2. The HCl 1-hydroxymethylcyclopentanamine salt was synthesized according to Method B1c. The 2-hydroxyethylamine was converted to 13-eza-6-oxadispiro (4.2.4.1) tridecane according to Method B4d, Step 1. Oxazolidine was opened reductively according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentate or according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1 - (cyclopentylamino) -1 - (thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 3- (trifluoromethyl) phenyl isocyanide dichloride according to Method C6c to give 2- (3- (trifluoromethyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4, 4] nonane.

Entry 264 The 3-chloro-2-methylaniline was converted to 3-chloro-2-methylformamide in accordance with Method A3a, Step 1. The formanilide was converted to isocyanide dichloride 3-chloro-2-methylphenyl according to Method A3a, Step 2. The HCl salt 1-hydroxymethylcyclopentanamine was synthesized according to Method B1c. The 2-hydroxyethylamine was converted to 13-aza-6-oxadispiro (4.2.4.1) tridecane according to Method B4d, Step 1. Oxazolidine was opened reductively according to Method B4d, Step 2 to give 1- (cyclopentylamino) ) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- ( cyclopentylamino) -1- (thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 3-chloro-2-methylphenyl dichloride according to Method C6c to give 2- (3-chloro-2-methylphenylimin) -1-cyclopentyl-3-thia-1 -azaspiro [4.4] nonane.

Entry 265 The 2,3-dichloro-4-methylanaline was converted to 2,3-dichloro-4-methylformanide according to Method A3a, Step 1. The formanilide was converted to isocyanide dichloride 2,3- dichloro-4-methylphenyl according to Method A3a, Step 2. The HCl 1-hydroxymethylcyclopentanamine salt was synthesized according to Method B1 c. 2-Hydroxyethylamine was converted to 13-aza-6-oxadispiro (4.2.4.1) tridecane according to Method B4d, Step '1. Oxazolidine was opened reductively according to Method B4d, Step 2 to give 1- ( cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was converted to 1- (cyclopentylamino) -1- (thioacetylmethyl) cyclopentane according to Method C6c, Step 1. The thioacetate was hydrolyzed according to Method C6c, Step 2 to give 1- (cyclopentylamide) no) -1- (thiomethyl) cyclopentane. The 2-thioethylamine was reacted with 2,3-dichloro-4-methylphenyl isocyanide dichloride according to Method C6c to give 2- (2,3-dichloro-4-methylphenylimin) -1-cyclopentyl-3. -thia-1-azaspiro [4.4] nonane.

Entry 266 A 1-hydroxymethylcyclopentanamine was prepared according to the Method B1c The 2-hydroxyethylamine was subsequently reacted with the SOCI2 and 4-bromo-2-methylfenyl sothiocyanate according to Method C2a to give 2- (4-bromo-2-methylphenylamino) -3-thia-1- azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-bromo-2-methylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane.

Entry 267 A 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to the 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1 -azaspiro [4, 4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1- cyclopentyl-3-thia-1-azaspyrro [4,4] nonane. The nitrile was reduced according to Method D11a to give 2- (4-formyl-2-ethylphepolylamino) -1-cyclopentyl 3-thia-1 -azaspiro [4.4] nonane Entry 268 A 1-hydroxymethylcyclopentanamine was prepared according to the Method B1c - The 2-hydroxyethylamine was converted to HCl 1 -chloromethylcyclopentanamine salt according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4 ] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was reduced according to Method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a to give 2- (2-ethyl-4 - ((1E) -2-ethoxycarbonylvinyl) phenylmethane) -1-cyclopent L-3-tia-1-azaspyrro [4,4] nonane Entry 269 A 1-hydroxymethylcyclopentanamine was prepared as per Method B1c. The 2-hydroxyethylamine was converted to the 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 4-cyano-2-ethylphenyl sothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenimlimino) -3-t-a-1- azaspiro [4.4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was reduced according to Method D11a to give 2- (4-formyl-2-ethenylphenyl) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The aldehyde was reacted with nitromethane in accordance with Method D12b to give 2- (2-ethyl-4 - ((1 E) -2-nitrovinyl) phenlimino) -1-cyclopentyl-S-thia-1- azaspiro ^^ jnonano Entry 270 A 1-hydroxymethylcyclopentanamine was prepared according to the Method B1c The 2-hydroxyethylamine was converted to the 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 4-cyano-2-ethylphenyl sothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4, 4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was reduced according to Method D11a to give 2- (4-formyl-2-ethylphenylamino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a to give 2- (2-ethyl-4 - ((1 £) -2-ethoxycarbonylvinyl) phenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4 , 4] nonane. The ester was saponified according to Method D6a to give 2- (2-etii-4 - ((1 £) -2-carboxyvinyl) phenylimino) -1-dclopentyl-3-thia-1 -azaspiro [4.4] nonano Entry 271 A 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to the 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl salt 1-chloromethylcyclopentanamine was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4.4 ] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to provide 2- (4-cyano-2-etiiphenylimino) -1-c / 'clo? Entyl-3-thia-1-azas? Iro [4.4 ] nonane. The nitrile was reduced according to Method D11a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1- azaspiro [4.4] nonane. The aldehyde was reacted with maloponitrile according to Method D12c to give 2- (2-ethyl-4- (2,2-dicyanovinyl) phenyl, mno) -1-cyclopentyl-3-thia-1-azaspiro [4] , 4] nonane.

Entry 272 A 1-hydroxymethylcyclopentanamine was prepared according to the Method B1c The 2-hydroxyethylamine was converted to the 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl 1 -chloromethylcyclopentanamine salt was reacted with 4-cyano-2-ethylphenyl sothiocyanate according to Method C1 e to give 2- (4-cyano-2-ethylphenylimino) -3-thia-1-azaspiro [4 , 4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was reduced according to Method D1 a to give 2- (4-formyl-2-ethylphenylimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The aldehyde was reacted with diethyl (2-oxopropyl) phosphonate according to Method D12b to give 2- (2-ethyl-4 - ((1 E) -2-acetylvyl) phenylimino) -1-cyclopentyl-3 -t¡a-1-azasp¡ro [4.4] nonane Entry 2 73 A 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to the 1-chloromethylcyclopentanamine HCl salt according to Method B7e. The HCl 1-chloromethylcyclopentanamine salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2- (4-cyano-2-ethylphenylamino) -3-thia-1- azasp ? 'ro [4, 4] nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2- (4-cyano-2-ethylphenylimino) -1- cyclo? Entyl-3-thia-1-azaspiro [4,4] nonane. The nitrile was reduced according to Method D11a to give 2- (4-formyl-2-ethelinimino) -1-cyclopentyl-3-thia-1-azaspiro [4,4] nonane. The aldehyde was reacted with acetonitrile according to Method D12d to provide 2- (2-ethyl-4 - ((1E) -2-cyanovinyl) phenylmethyl) -1-cyclopentyl-3-thia -1-azaspiro [4.4] nonane Entry 274 Na 1 -hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was reacted sequentially with S0Cl2 and 2-methyl-2-nitrophenyl sothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenylmethyl) -3-tia -1-azaspiro [4.4] nonapo. The thiazolidine was reacted with cyclohexyl bromide according to Method D2e to give 2- (2-methyl-4-pyrofenilimino) -1-cyclohexyl-3-thia-1-azaspiro [4,4] nonane.

Entry 275 A 1-hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was reacted sequentially with SOCI2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2- (2-methyl-4-nitrophenyl-amino) -3-t-a-1- azaspiro [4.4] nonane. The thiazolidine was reacted with cycloheptyl bromide according to Method D2e to give 2- (2-methy-4-nitrophenylimino) -1-cycloheptyl-3-thia-1-azaspiro [4,4] nonane.

Entry 276 The 1-aminocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method B1a, Step 1. The 1- (benzyloxycarbonylamino) cyclohexane-1-carboxylic acid was reduced to 1- (benzyloxycarbonylamino) -1- ( hydroxymethyl) cyclohexane according to Method B1a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1- (hydroxymethyl) cyclohexane. The 2-hydroxyethylamine was treated sequentially with SOCI2 and 2-methyl-4-nitrophenyl isothiocyanate according to the Method C2a to give 2- (2-methyl-4-nitrophenylimino) -3-thia-1-azaspiro [4, 5] Dean. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to give 2- (2-methyl-4-nitrophenolimino) -1-cycloheptyl-3-thia-1-azaspyrro [4, 4] nonane.

Entry 277 The 2-methyl-4-nitroaniline was converted to 2-rnethyl-4-nitropormanylide according to Method A3a, Step 1. The formanilide was converted to 2-methyl-4-nitrophenyl isocyanide in accordance with Method A3a, Step 2. The 3-aminotetrahydro-2 - / - pyran-3-carboxylic acid was converted to methyl ester according to Method B1b, Step 1. Methyl 3-aminotetrahydro-2- H-pyran-3-carboxylate was reduced to 3-amino-3- (hydroxymethyl) tetrahydro-2 - / - / - pyran according to Method B1 b, Step 2. The 2-hydroxyethylamine was Reacted with isobutyraldehyde according to Method B4c, Step 1 to deliver 2-isopropyl-1-aza-3,7-dioxaspiro [4.5] decane. The oxazolidine was reduced to 3-isobutylamino-3- (hydroxymethyl) tetrahydro-2-pyran. The 2-hydroxyethylamine was converted to 3-isobutylamino-3- (acetylthiomethyl) tetrahydro-2-H-pyran according to Method C6c, Step 1. The thioacetate was saponified according to Method C6c, Step 2 to give 3- Sobutylamino-3- (thiomethyl) tetrahydro-2H-pyran. The 2-thioethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride to give 2- (2-methyl-4-nitrophenylimino) -1-isobutyl-1-aza-7-oxa-3-t; aspir [4.5) dean.

Entry 278 The 2-methyl-4-nitrcaniline was converted to 2-methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a , Step 2. The 4-aminotetrahydro-2 - / - / -? Iran-3-carboxylic acid was converted to methyl ester according to Method B1 b, Step 1. Methyl 4-aminotetrahydro-2-H- pyran-4-carboxylate was reduced to 4-amino-4- (hydroxymethyl) tetrahydro-2-t'-pyran according to Method B1 b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c , Step 1 to deliver 2- isdpropil-1-aza-3,8-dioxaspiro [4,5] decane. The oxazolidine was reduced to 4-isobutylamino-4- (hydroxymethyl) tetrahydro-2 - / - / - pyran. The substituted 2-hydroxyethylamine was converted to 4-isobutylamino-4- (acetylthiomethyl) tetrahydro-2-H-pyran according to Method C6c, Step 1. The thioacetate was saponified according to Method C6c, Step 2 to give 4 -isobutylamino-4- (thiomethyl) tetrahydro-2 / L-pyran. The 2-thioethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride to give 2- (2-methyl-4-nitrophenolimino) -1-isobutyl-1-aza-8-oxa-3- tiaspiro [4.5) dean.

Entry 279 The 2-amino-2-norbornane-1-carboxylic acid as a mixture of isomers was converted into a? / -benzyloxycarbonyl analogue according to Method B1 a, Step 1. (Benzyloxycarbonylamino) -2-norbornane-1-carboxylic acid was reduced to 1- (benzyloxycarbonylamino) -1- (hydroxymethyl) -2-norbornane according to Method B1 a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to provide 1-amino-1- (hydroxymethyl) -2-norbornane. The 2-hydroxyethylamine was alkylated with isobutyl bromide according to the method B2a to give? -isobutyl-1-amino-1 - (hydroxymethyl) -2-norbornane. The alkylated 2-hydroxyethylamine was treated with SOCI2 in accordance with Method B7a to give HCl salt. / - 2-butyl-2-chloroethylamine. Chloroethylamine was treated with 2-methyl-4-nitrophenyl isothiocyanate. according to Method C1a to provide 2- (2-methyl-4-nitrophenylimino) -3-isobutylspiro [1,3-thiazolidin-4,3'-bicyclo [3.2.1] octane] Entry 280 The N- (tet-butoxycarbonyl) (L) -valin was converted to (S) -3- (tert-butoxycarbonyllamine) -1-diazo-4-methylpntan-2-one according to Method B6a, Step 1. The diazo compound was converted to Methyl (R) -3- (tert-buzoxycarbonylamino) -4-methy1pentanoate according to Method B6a, Step 2. The ester was reduced in accordance with Method B6a, Step 3 to give (R) -3- (te / t-butoxycarbonylamino) -4-methylpentan-1-ol. The carbamate was deprotected and converted to (R) -3-amino-1-chloro-4-methylpentane according to Method B7e. 3-Chloropropylamine was treated with 2-methyl-4-nitrophenyl sothiocyanate according to Method C2a to give (4R) -2 (2-methyl-4-nitrophenylimino) -4-isopropyl-1,3-t! azine. The thiazine was alkylated with isobutyl bromide according to Method D2a to provide (4R) -2 (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1,3-thiazine.

Entry 281 The 3-aminopropanol was reacted with butyraldehyde according to the Method B9a, Step 1 to provide 2-isopropyltetrahydro-1,3-oxazine. The oxazine was reduced according to Method B9a, Step 2 to give / V-isobutyl-3-hydroxypropylamine. The 3-hydroxypropylamine was reacted with SOCI2 according to Method B9a, Step 3 to give HCl salt? -isobutyl-3-chloropropylamine. The 3-chloropropylamine was reacted with 2-methyl-4-n / trophenyl isothiocyanate according to Method C1a, to give 2- (2-metii-4-nitrophenylimino) -3-isobutyltetrahydro-1, 3- thiazine.

Entry 282 The 4-aminobutanol was reacted with butyraldehyde according to Method B9a, Step 1 to deliver 2-isopropyltetrahydro-1,3-oxazepine. The 1,3-oxazepine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxypropylamine. The 3-hydroxypropylamine was reacted with SOCI2 according to Method B9a, Step 3 to give HCl salt? / - isobutyl-3-chlorobutylamine. The 3-chlorobutylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1 a, to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl! Tetrahydro-1,3-thiazepine.

Entry 283 3-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by chloroacetic acid according to Method C8a to give 2- (3-methyl-4-nitrophenylimino) -3-isobutyl-1,3-thiazole. -4-one.

Entry 284 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3- (2- methylbutyl) -1,3-thiazolidin-4-one.

Entry 289 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with benzylamine followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenimlimino) -3- (phenylmethyl) -1, 3 -thiazolidin-4-one.

Entry 290 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by a-chloropropionic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-meityl-1, 3-thiazolidin-4-one.

Entry 291 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with 1-amino-1-cyclohexyl ethane followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3 - (1-cyclohexylethyl) -1,3-thiazolidin-4-one.

Entry 292 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1 S) -1-amino-1-cyclohexyl ethane followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3 - ((1 S) -1-cyclohexylethyl) -1,3-thiazolidin-4-one.

Entry 293 The isothiocyanate of 2-methyl-4-nitrophenyl was reacted with (1) -1-amino-1-cyclohexyl ethane followed by chloroacetic acid according to Method C8a to give '2- 2-methyl-4-nitrophenylimino ) -3 - ((1) -1-cyclohexylethyl) -1,3-thiazolidin-4-one.

Entry 294 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by a-chloro-a-phenylacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl -5-phenyl-1,3-thiazolidin-4-one. Entry 295 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1 R) -1-amino-1-cyclohexyl ethane followed by a-chloropropynic acid according to Method C8a to give 2- (2-methyl) 4-nitrophenylimino) -3 - ((1) -1-cyclohexylethyl) -5-methylene-, 3-thiazolid-n-4-one.

Entry 296 The 2-methyl-4-nitrofenyl isothiocyanate was reacted with (R) -1-amino-1-cyclohexylethane followed by a-chloro-a-phenylacetic acid according to Method C8a to give 2- (2- methyl-4-nitrophenylimino) -3 - ((1) -1-cyclohexylethyl) -5-phenyl-1,3-thiazolidin-4-opa.

Entry 297 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1 S) -1-amino-1-cyclohexyl ethane followed by a-chloropropionic acid according to Method C8a to give 2- (2-methyl-1-nitrophenylimino) -3 - ((1 S) -1-cyclohexylethyl) -5-methyl! -1,3-thiazolidin-4-one.

Entry 298 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1 S) -1-amino-1-cyclohexyl ethane followed by a-chloro-a-phenylacetic acid according to Method C8a to give 2- (2-methyl-) 4-nitrophenylimino) -3 - ((1 S) -1-cyclohexylethyl) -5-phenyl-1,3-thiazolidin-4-one.

Entry 299 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by a-chloropropionic acid according to the method C8a to provide 2- (2-methyl-4-nitrophenylimethyl) -3- (2-ethyl-1-butyl) -5-methyl-1,3-thiazolidin-4-one.

Entry 300 The 2-methyl-4-nitrophenol isothiocyanate was reacted with isobutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl -5-isobutyl-1, 3-thiazolidin-4-one.

Entry 301 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to give 2- (2-methyl-4-) nitrophenolyl) -3-isobutyl-5- (2-ethyl-1-butyl) -1,3-thiazolidin-4-one.

Entry 302 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with methylbutylamine followed by 2-chloro-4-methylpentanoic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3 - (2-butyl) l-5-isobutyl-1,3-thiazolidin-4-one.

Entry 303 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with 2-methylbutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3- (2 -butyl) -5-isopropyl-1,3-thiazolidin-4-one.

Entry 304 The 2-methyl-4-nitrophenyl isothiocyanate reacted with butylamine followed by 2-chloro-3-methano-btanoic acid according to Method C8a to give 2- (2-methyl-4-n-trofenilimino) -3-isobutyl-5-isopropyl-1,3-thiazolidin-4-one Entry 305 The 2-methyl-4-nitrophenol isothiocyanate was reacted with (2S) -2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to give 2- (2-methyl-4-nitrophenylimino) -3 - ((2S) -2-methyl-1-butyl) -1, 3-yiazolidin-4-one.Entry 306 The 2-methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to provide 2- (2-methyl-4-nitrophenylimino) ) -3- (2-et? L-1-butyl) -5-isopropyl-1,3-thiazolid-4-one.

Entry 307 The methyl (R) -? / - isobutylserine ester HCl salt was prepared from the methyl serine ester (D) as described in method B3a. The alcohol was reacted with SOCI2, according to Method B7b, followed by the reaction of 2-methyl-4-nitrophenyl isothiocyanate according to Example C1a to provide 2- (2-methyl-4-nitrophenolimino) - 3-butyl-4-methylene-1,3-thiazolidin-5-one Entry 308 The 2,4,6-trichloroenile isothiocyanate was reacted with 2-butylamine followed by chloroacetic acid according to cor. Method C8a for supplying 2- (2,4,6-trichlorophenyiimino) -3- (2-butyl) -1,3-azolidin-4-one.

Entry 309 The 3,4-dichlorophenyl isothiocyanate was reacted with 2-methylbutylamine followed by chloroacetic acid c > according to Method C8a to provide 2- (3,4-dichlorophenylimino) -3- (2-butyl) -1,3-t-azazolidin-4-one.

Entry 310 The ester of / V-isobutylglycine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C11a to give 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-1,3-tl. azolidin-5-one.

Entry 311 The isothiocyanate of 2-methyl-4-n-trophenol was reacted with 2-ethyl-1-butylamine followed by chloroacetic acid according to Method C8a to give 2- (2-methyl) -4-n? Trophin? L? No) -3- (2-et? L-1 -but? L) -1, 3-t? Aolol d? N-4-one. 10 Entry 312 The ethyl? / - isobutyleucine ester was reacted with 2-methyl-4-nitrophenyl sothiocyanate according to Method C11a to deliver (4S) 2- (2-methyl-4-20 n? Trofenyl? M) no) -3,4-d? -butbutyl-1,3-thiazole? din-5-one.

Entry 313 AND! Ethyl? / - isobutylproline ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C11a to provide 4- (2-methyl-4-nitrophenylimino) -1-oxoperhydro-2-t¡apyrrole 2ina.

Entry 314 The tert-butyl? / - (tert-butoxycarbonyl) glycine ester was reacted with 3-bromo-2-methylpropene according to Method B8b, Step 1 to give te -butyl N- (te / -butoxy) ester. carbonyl) -? / - (2-methylprop-2-enyl) glycine. The ester was reduced according to Method B8b, Step 2 to give? - (tert-butoxycarbonyl) -V- (2-hydroxyethyl) 1-amino-2-methylprop-2-ene. The alcohol was treated with p-toluenesulfonyl chloride according to Method B8b, Step 3 to give / V- (te / f-butoxycarbonyl) -? / - (2-tosyloxyethyl) -1-amino-2 -met¡iprop-2-ene. The carbamate was deprotected according to Method B8b, Step 4 to give? / - (2-tosyloxyethyl) -2-methylprop-2-en-1-ammonium trifluoroacetate. The tosylate was reacted with 2-methyl-4-nitropheni isocyanate! according to Method C5a to provide 2- (2-methyl-4-nitrophenlimine) -3- (2-methylprop-2-enyl) -1,3-oxazolidinone.

Entry 315 The methyl ester Valine - () to (1 S) -1- ^ hid Oxymethyl) -2-methylpropyllamine was reduced according to Method B1 b, Step 2. The hydroxyethylamine was reacted with isobutyraldehyde in accordance with Method B4c, Step 1 to give (4S) -2,4-diisopropyl-1,3-oxazolidine. The oxazolidine was run according to Method B4c, Step 2 to give (1 S) -1- (hydroxymethyl) -? - isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOC according to the Method B7b to give (1S) -1- (chloromethyl) -? / - isobutyl-2-methylpropylamine. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl socianate according to Method C4a to give (4S) -2 (2-methyl-4-nitrophenylimino) -3-isobutyl-4-ysopropyl-1, 3 -oxazolidine.

Entry 316 The methyl leucine- (L) ester was reduced to (1 S) -1- (hydroxymethyl) -3-methylmethylbutylarnine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c , Step 1 to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine. The oxazouedin was reduced according to Method B4c, Step 2 to give (1 S) -1- (hydroxymethyl) -A / -isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine was reacted with STCI2 according to Method B7b to obtain (1 S) -1- (chloromethyl) -? / - isobutyl-3-methylbutylamine. Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to give (4S) -2 (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-oxazolidine.

Entry 317 The methyl leucine ester (i-) was reduced to (1 S) -1- (hydroxymethyl) -3-methylmethylbutylamine according to Method B1b, Step 2. The hydroxyethylamine was reacted with isobutyraldehyde in accordance with Method B4c, Step 1 to give (4S) -2-isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1 S) -1- (hydroxymethyl) -? / - isobutyl-3-methylbutylamine. The 4-amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformanilide according to Method A3a, Step 1. The formanilide was reacted with SOCI2 and SO2CI2 according to Method A3a. Step 2 to provide 4-cyano-2-ethylphenyl dichloride. The substituted 2-hydroxyethylamine was reacted with 4-cyano-2-ethylphenyl isocyanide dichloride according to Method C7b to deliver (4S) -2- (4-cyano-2-ethylpyrimine) -3.4- diisobutyl-1, 3-oxazolidine Entry 318 The 2-amino-2-methyl-1-propanol was reacted with cyclopentanone according to Method B4b, Step 1 to provide 4-aza-3,3-d-methyl-1-oxaspiro [4,4] nonane. The oxazolidine was reduced according to Method B4b, Step 2 to deliver? / -cyclopentyl (1,1-dimethyl-2-hydroxyethyl) amine. The 2-methyl-4-nitroaniline was converted to 2-methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was reacted with SOCI2 and SO2CI2 according to Method A3a, Step 2 to give dichloride of! socianuro 2-methyl-4-nitrophenyl. The Substituted 2-hydroxyethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride according to Method C7a to give 2- (2-methyl-4-nitrophenynylamino) -3-cyclopentyl-4,4-dimet L-1, 3-oxazolidine Entry 319 The 2-amino-2-methyl-1-propanol was reacted with cyclopentanone according to Method B4b, Step 1 to provide 4-aza-3,3-dimethyl-1-oxaspiro [4,4] nonane. The oxazolidine was reduced according to Method B4b, Step 2 to deliver? / -cyclopentyl (1,1-dimethyl-2-hydroxyethyl) amine. 4-Amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethyleneforman in accordance with Method A3a, Step 1. The formanilide was reacted with SOCI2 and S02CI2 according to Method A3a, Step 2 for to give 4-cyano-2-ethylphenyl dichloride. The substituted 2-hydroxyethylamine was reacted with 4-cyano-2-ethylphenyl isocyanide dichloride according to Method C7a to give 2- (4-cyano-2-ethylphenimlimino) -3-cydopentyl-4,4- dimethyl-1,3-oxozolidine Entry 320 1-Aminocyclopentanecarboxylic acid was converted to methyl ester according to Method B1c, Step 1. The ester was reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. Hydroxyethylamine was reacted with cyclopentanone according to the Method B4d, Step 1, to provide 6-aza-12-oxadispiro [4.1.4.2] tridecane. Oxazolidine was reduced according to Method B4d, Step 2 to give 1- (cyclopentylamino) -l- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCI2, according to Method B7b, to 1 - (cyclopentylamino) -1- (chloromethyl) cyclopentane. The 2-chloroethylamine was reacted with isocyanate of 2-methyl-4-nitrophenyl according to Method C4a to give 1-cyclopentyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane Entry 32 ' 1-Aminocyclopentanecarboxylic acid was converted to methyl ester according to Method B1c, Step 1. The ester was reduced to 1-hydroxymethiicyclopentanamine according to Method B1 c, Step 2. The 2-hydroxyethylamine was reacted with cyclobutanone according to with Method B4a, Step 1, to provide 5-aza-12-oxadispiro [3.1.4.2] dodecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1- (cyclobutylamino) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCI2, according to Method B7b, to 1- (cyclobutylamino) -1- (chloromethyl) cyclopentane. 2-Chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to give 1-cyclobutyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1 -azaspiro [ 4.4] nonane Entry 322 The 1-aminocyclopentanecarboxylic acid was converted to methyl ester according to Method B1c, Step 1. The ester * was reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. Hydroxyethylamine was reacted with cyclohexanone according to Method B4a, Step 1, to provide 6-aza-13-oxadispiro [4.1.5.2] tetradecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1- (cyclohexylamine) -1- (hydroxymethyl) cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCI2, according to Method B7b, to 1- (cyclohexylamino) -1 - (chloromethyl) cyclopentane. 2-Chloroethylamine was reacted with 2-meityl-4-nitrophenyl isocyanate according to Method C4a to give 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1-azasp ro [4.4] nonane.

Entry 323 The 1-aminocycloalkanocarboxylic acid was converted to methyl ester according to Method B1c, Step 1. The ester was reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. Hydroxyethylamine was reacted with cyclopentanone according to Method B4d, Step 1, to supply 6-aza-12-oxadispiro [4.1.4.2] trdecane. The oxazolidine was reduced according to Method B4d, Step 2 to give 1- (cyclopentylamino) -1- (hydroxymethyl) cyclopentane. The 4-amino-3-ethylbenzonitrile was converted to 4-cyano-2-ethylformamide according to Method A3a, Step 1. The formanilide was reacted with SOCI2 and SO2CI2 according to Method A3a, Step 2 for to give 4-cyano-2-ethylphenyl isocyanide dichloride The substituted 2-hydroxyethylamine was reacted with isocyanide dichloride 2-methyl-4-nitrofepil, according to the C7a method to supply 1-cyclopentyl-2- (2-methyl) -4-nitrophenylimino) -3-oxa-1-azaspiro [4.4] nonane Entry 324 (1 S) -1 - (hydroxymethyl) -3-methylbutylamine was made from the methyl leucine ester (L) as described in Method B1 b. The 2-hydroxyethylamine was converted to (2S) -4-methyl-2- (isobutylamino) pentanol as described by Method B4c, Steps 1-2. The alcohol was converted to? / - (1 S) -1- (chloromethyl] -3-methylbutyl) -N- (isobutyl) ammonium chloride as described in Method B7c. The 4-nitrophenyl isothiocyanate was reacted with? / - (1 S) -1- (chloromethyl) 3-methylbutyl) - / V- (isobutyl) ammonium chloride according to Method C1f to give 2- (4-nitrophenyl) O) -1,5-d-isobutylmidazoline.

Entry 325 (1 S) -1- (hydroxymethyl) -3-methylbutylamine was made from the methyl leueine ester (L) as described in Method B1 b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1S) -1 - (chloromethyl) -3-methylbutylammonium chloride according to Method C1a to give (4S) -2- (2-methyl) -4-nitrophenylimino) -4-isobutyl-1, 3-thiazolidine.Tiazolidine was reacted with 5-iodoheptane according to Method D2a to give (S) -2 - (? / - (4-heptyl) -? / - (2-methyl-5-nitrophenyl) amino) -4-isobutyl-1,3-thiazoline.

Entry 326 The (1) -1- (hydroxymethyl) -3-methylbutyllamine was made from the methyl (D) -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. The 2-methyl-4-nitrophenyl isothiocyanate was reacted with (1R) -1- (chloromethyl) -3-methyl-butyl ammonium chloride according to Method C1 a to give (4R) -2- (2 -methyl-5-nitrophenylmethyl) -4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give an HCl salt of (4R) -2 - (? / - isobutyl -? / - (2-methyl-5-nitrophenyl) amino) -4- isobutyl-1, 3-thiazoline.

Entry 327 (1 S) -1 - (hydroxymethyl) -3-methylbutylamine was made from the methyl (L) -leucine ester as described in Method B1 b. The 2-hydroxyethylamine was converted to (1S) -1 - (chloromethyl) -3-methylbutanemonium chloride as described in Method B7a. The 2-methyl-4-nitrophenyl isocyanate was reacted with (1S) -1 - (chloromethyl) -3-methylbutyl-ammonium chloride according to Method C1 a to give (4S) -2- (2 -methyl-4-nitrophenylimino) -4-isobutyl-1,3-thiazolidine. Thiazolidine was reacted with neopentyl bromide according to Method D2a to give (4S) -2 - (/ V- (2,2-d.methylpropyl) (2-methyl-4-nitrophenylamino) -4-isobutyl -1, 3-thiazoline.

Entry 328 (1 S) -1- (hydroxymethyl) -3-methylbutyllamine was made from the methyl (L) -leucine ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1 S) -1- (chloromethyl) -3-methylbutanammonium chloride as described in Method B7a. The 2,3-dichlorophenyl isothiocyanate was reacted with (1 S) -1- (chloromethyl) -3-methyl butylammonium chloride according to Method C1a to give (4S) -2- (2,3-dichlorophenylimino) ) -4-isobutyl-1,3-thiazolidin. Thiazolidine was reacted with 3-bromopentane according to Method D2a to give »(4S) -2 - (? / - (3-pentyl) -2-methyl-4-nitrophenylamino) -4-isobutyl-1,3- thiazolin.

TABLES The compounds listed below in Tables 1-4 were synthesized according to the methods described above. Table 1: 2-! Mino-1, 3-thiazolidines and Annular Expanded Homologs 333 355 65 í a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2 x 300 Phenomenex 3 uM C-18 column; the flow rate 1.0 mlJmin .; Shock absorber A: 0.02% TFA / 2% CH3CN / water, Shock absorber B: 0.018% TFA 98% CH 3CN / water; Shock absorber A maintained at 100% for 1 minute, Shock absorber A gradient from 100% to 100% of Shock absorber B for more than 3 min., Shock absorber B maintained at 100% for 1 min., Shock absorber B gradient from 100% to 100% Shock Absorber A at 100% for more than 0.05 min, maintaining Shock Absorber A at 100% for 1.5 min. b) Ranin Dynamax HPLC equipped with dual long wave detector UV-DII (254 and 220 nm) and a Dynamax column 3 uM C-18 of 4 x 100 mm; flow rate 1.5 mL / min; Shock absorber A: 0.5% TFA / water, Shock absorber B: 0.5% - TFA / CH3CN; Shock absorber A gradient from 100% to Shock absorber B at 100% for more than 10 min., Keeping Shock absorber B at 100% for 5 min. c) Hewlett Packard 1090 HPLC equipped with a UV detector (210 nM) and a Nucleosil 3 uM C-18 4x125 mm column; flow rate 2.0 mL / min; Shock absorber A: 0.001 mole percent H3PO4 / water, Shock absorber B: 0.01 mole percent H3PO4 / CH3CN; Shock absorber B at 10% for 1 min, Shock absorber B gradient from 10% to 90% Shock absorber B for more than 8 min., Shock absorber B gradient from 90% to 10% of Shock absorber B for more than 4 min. d) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Dynamax 8 uM C-18 2500 mm column; flow rate 18 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 30% to Shock absorber B at 100% for more than 25 min., Maintained Shock absorber B at-100% for 30 min. e) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Dynamax 8 uM C-18 2500 mm column; flow rate 18 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 50% to Shock absorber B at 60% for more than 25 min., Gradient from 60% to 100% for 32 min. f) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: o.1% -TFA99.9% CH3CN; Shock absorber B gradient from 30% to Shock absorber B at 100% for more than 25 min., Maintained at 100% B 100% for 30 min. g) Ranin Dynamax HPLC equipped with long-wave detector dual UV-DII (254 and 220 nm) and a Microsorb column 5 uM C-'l d 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0. 1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 50% to Shock absorber B at 100% for more than 25 min., Maintained at 100% B '100% for 7 min. h) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0. 1% -TFA 99.9% CH3CN; Shock absorber B gradient from 10% to Shock absorber B at 100% for more than 30 min., Maintained at 100% B 100% for 7 min. i) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-8 column of 4.6 x 100 mm; flow rate 20 mlJmin; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 10% to Shock absorber B at 100% for more than 5 min., Maintained at 100% B 100% for 1.5 min. j) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 20% to Shock absorber B at 100% for more than 30 min., Maintained at 100% B 100% for 7 min.

Table 2: 2-lmino-1,3-thiazolidin-4-ones and 2-lmino-1,3-thiazoidin-5-ones a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2 x 300 Phenomenex 3 uM C-18 column; the flow rate 1.0 mL / min .; Shock absorber A: 0.02% TFA / 2% CH3CN / water, Shock absorber B: 0.018% TFA 98% CH 3CN / water Shock absorber A maintained at 100% for 1 minute, Shock absorber A gradient from 100% to 100% Shock absorber B for more 3 min., Shock Absorber B maintained at 100% for 1 min., Shock Absorber B gradient from 100% to 100% Shock Absorber A at 100% for more than 0.05 min., Shock Absorber A maintained at 100% for 1.5 min. b) Ranin Dynamax HPLC equipped with dual long-wave detectoi UV-DII (254 and 220 nm) and a Dynamax 3 uM C-18 column of 4 x 100 mm; flow rate 1.5 mL / min; Shock absorber A: 0.5% TFA / water, Shock absorber B: 0.5% - TFA / CH3CN; Shock absorber A gradient from 100% to Shock absorber B at 100% for more than 10 min., Keeping Shock absorber B at 100% for 5 min. c) Hewlett Packard 1090 HPLC equipped with a UV detector (210 nM) and a Nucleosil 3 uM C-18 4x125 mm column; flow rate 2.0 mL / min; Shock absorber A: 0.001 mole percent H3P0 / water, Shock absorber B: 0.01 mole percent H3PO / CH3CN; Shock Absorber B at 10% for 1 min, Shock Absorber B gradient from 10% to 90% Shock Absorber B for more than 8 min., Shock Absorber B gradient from 90% to 10% of Shock Absorber B for more than 4 min. d) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Dynamax 8 uM C-18 2500 mm column; flow rate 18 mlJmin; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 30% to Shock absorber B at 100% for more than 25 min., Maintaining Shock absorber B at 100% for 30 min. e) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Dynamax 8 uM C-18 2500 mm column; flow rate 18 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 50% to Shock absorber B at 60% for more than 25 min., Gradient from 60% to 100% for 32 min. f) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 30% to Shock absorber B at 100% for more than 25 min., Maintained at 100% B 100% for 30 min. g) Ranin Dynamax HPLC equipped with dual long wave UV-DIP detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 50% to Shock absorber B at 100% for more than 25 min., Maintained at 100% B 100% for 7 min. h) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mlJmin; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 10% to Shock absorber B at 100% for more than 30 min., Maintained at 100% B 100% for 7 min. i) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-8 column of 4.6 x 100 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0. 1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 10% to Shock absorber B at 100% for more than 5 min., Maintained at 100% B 100% for 1.5 min. j) Ranin Dynamax HPLC equipped with dual long-wave UV-DI detector! (254 and 220 nm) and a Microsorb column 5 uM C-18 of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 20% to Shock absorber B at 100% for more than 30 min., Maintained at 100% B 100% for 7 min. 384 Table 3: 2-lrnino-1,3-oxazolidines Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2 x 300 Phenomenex 3 uM C-18 column; the flow rate 1.0 mL / min .; Shock absorber A: 0.02% TFA / 2% CH3CN / water, Shock absorber B: 0.018% TFA / 98% CH 3CN / water; Shock absorber A maintained at 100% for 1 minute, Shock absorber A gradient from 100% to 100% Shock Absorber B for more than 3 min., Shock Absorber B maintained at 100% for 1 min., Shock Absorber B gradient from 100% to 100% Shock Absorber 100% for more than 0.05 min, keeping Shock Absorber A 100% for 1 .5 min. b) Ranin Dynamax HPLC equipped with dual long wave detector UV-DII (254 and 220 nm) and a Dynamax column 3 uM C-18 of 4 x 100 mm; flow rate 1.5 mlJmin; Shock absorber A: 0.5% TFA / water, Shock absorber B: 0.5% - TFA / CH3CN; Shock absorber A gradient from 100% to Shock absorber B at 100% for more than 10 minutes, keeping Shock absorber B at 100% during min c) Hewlett Packard 1090 HPLC equipped with a UV detector (210 nM) and a Nucleosil 3 uM C-18 4x125 mm column; flow rate 2.0 mlJmin; Shock absorber A: 0.001 mole percent H3PO / water, Shock absorber B: 0.01 mole percent H3PO4 / CH3CN; Shock absorber B at 10% for 1 min, Shock absorber B gradient from 10% to 90% Shock absorber B for more than 8 min., Shock absorber B gradient from 90% to 10% of Shock absorber B for more than 4 min. d) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Dynamax 8 uM C-18 2500 mm column; flow rate 18 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 30% to Shock absorber B at 100% for more than 25 min., Maintaining Shock absorber B at 100% for 30 min. e) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Dynamax 8 uM C-18 2500 mm column; flow rate 18 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 50% to Shock absorber B at 60% for more than 25 min., From 60% to 100% for 32 min. f) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 30% to shock absorber B at 100% for more than 25 min., Maintained at 100% B 100% for 30 min. g) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 50% to Shock absorber E at 100% for more than 25 min., Maintained at 100% B 100% for 7 min. h) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0. 1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 10% to Shock absorber B at 100% for more than 30 min., Maintained at 100% B 100% for 7 min. i) Ranin Dynamax HPLC equipped with dual long-wave detectoi UV-DII (254 and 220 nm) and a Microsorb 5 uM C-8 column of 4.6 x 100 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber E: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 10% to Shock absorber B at 100% for more than 5 min., Maintained at 100% B 100% for 1.5 min. j) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 20% to Shock absorber B at 100% for more than 30 min., Maintained at 100% B 100% for 7 min.

Table 4: Additional Examples a) Hewlett Packard 1100 HPLC equipped with a Finnigan LCQ MS detector and a 2 x 300 Phenomenex 3 uM C-18 column; the flow rate 1.0 mL / min .; Shock absorber A: 0.02% TFA / 2% CH3CN / water, Shock absorber B: 0.018% TFA 98% CH 3CN / water; Shock absorber A maintained at 100% for 1 minute, Shock absorber A gradient from 100% to 100% of Shock absorber B for more than 3 min., Shock absorber B maintained at 100% for 1 min., Shock absorber B gradient from 100% to 100% Shock Absorber A at 100% for more than 0.05 min, maintaining Shock Absorber A at 100% for 1.5 min. b) Ranin Dynamax HPLC equipped with dual long wave detector UV-DII (254 and 220 nm) and a Dynamax 3 uM C-8 column of 4 x 100 mm; flow rate 1.5 mL / min; Shock absorber A: 0.5% TFA / water, Shock absorber B: 0.5% - TFA / CH3CN; Shock absorber A gradient from 100% to Shock absorber B at 100% for more than 10 min., Keeping Shock absorber B at 100% for 5 min. c) Hewlett Packard 1090 HPLC equipped with a UV detector (210 nM) and a Nucleosil 3 uM C-18 4x125 mm column; flow rate 2.0 mL / min; Shock absorber A: 0.001 mole percent H3PO / water, Shock absorber B: 0.01 mole percent H3PO4 / CH3CN; Shock absorber 3 to 10% for 1 min, Shock absorber B gradient from 10% to 90% Shock absorber B for more than 8 min, Shock absorber B gradient from 90% to 10% of Shock absorber B for more than 4 min. d) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Dynamax d uM C-18 2500 mm column; flow rate 18 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 30% to shock absorber B at 100% for more than 25 min., Keeping Shock absorber B aL100% for 30 min. e) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Dynamax 8 uM C-18 2500 mm column; flow rate 18 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 50% to Shock absorber B at 60% for more than 25 min., Gradient from 60% to 100% for 32 min. f) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 30% to Shock absorber B at 100% for more than 25 min., Maintained at 100% B 100% for 30 min. g) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0. 1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 50% to Shock absorber B at 100% for more than 25 min., Maintained at 100% B. 100% for 7 min. h) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mLJmin; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0. 1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 10% to Shock absorber B at 100% for more than 30 min., Maintained at 100% B 100% for 7 min. i) Ranin Dynamax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-8 column of 4.6 x 100 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 10% to Shock absorber B at 100% for more than 5 min., Maintained at 100% B 100% for 1.5 min. j) Ranin Dynarnax HPLC equipped with dual long wave UV-DII detector (254 and 220 nm) and a Microsorb 5 uM C-18 column of 21 x 2500 mm; flow rate 20 mL / min; Shock absorber A: 0.1% TFA / 99.9% water, Shock absorber B: 0.1% -TFA / 99.9% CH3CN; Shock absorber B gradient from 20% to Shock absorber B at 100% for more than 30 min., Maintained at 100% B 100% for 7 min. Biological Protocol The activity of a given compound to bind the progesterone receptor can be assayed routinely according to the procedure disclosed below. This procedure was used to determine the binding activities of progesterone of the compounds of the invention. Progesterone Receptor Binding Assay The binding buffer (100 mL, 50 rpM Tris, pH 7.4, 10 mM molybdic acid, 2 mM EDTA, 150 mM NaCl, 5 mL) was added to the siliceous glass test tubes on an ice bath. % glycerol, 1% DMSO) containing various concentrations of a compound to be tested, the cytosol cell T47D (100 μL of a solution that will give at least 4000 cpm binding) and the 3H-progesterone 50 μL, 10 nM, Net-381 ). The mixture was incubated for 16 hours at 4 ° C, and treated with charcoal (250 μL of a 0.5% mixture of charcoal covered with 0.05% dextran which was washed twice with a binding buffer). The resulting mixture was incubated for 10 minutes at 4 ° C. The tubes were centrifuged (20 minutes at 2800 x g) at 4 ° C. The supernatant was transferred to flasks. The supemaciente was transferred to scintillation flasks containing scintillation fluid (4mL). The remaining 3H-progesterone was determined with Packard 1900TR beta counter. Each trial included the following control groups: 1) total binding group (without compound), 2 nonspecific binding group (with 400 nM progesterone) and 3) a positive control group (with 2 nM progesterone or an inhibitor) known). It was found that the compounds of the present invention cause an inhibition greater than or equal to 30% binding of 3H-progesterone to the progesterone receptor at a compound concentration of 200 nM. The activity oscillations of the compounds of the present invention in the Binding Assay of Progesterone receptor at a compound concentration of 200 nM are listed in Table 5. 393 Table 5. Inhibitory activity of the exemplified compounds The preceding examples can be repeated with similar success by replacing the described reactants in a generic or specific form and / or operating conditions of this invention for those used in the preceding examples. Other embodiments of the invention will be apparent to those skilled in the art from the consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplars only, and the following Claims indicate the true scope and spirit of the invention.

Claims (2)

1 . A compound that has the formula where R is aryl of 6-14 carbons; or heteroaryl of 3-10 carbons and containing 1 - 3 heteroatoms selected from the group consisting of N, O and S, with the proviso that R is other than benzofuran or benzothiophene; R 'is alkyl of 1-10 carbons; 3-12 carbon cycloalkyl and containing 1-3 rings; 4-7 carbon heterocycloalkyl and containing 1 -3 rings and 1 -3 heteroatoms selected from the group consisting of N, O, and S; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons and containing 1 -3 rings; or alkynyl of 3-10 carbons; R, RJ, and R are independently selected from the group consisting of H; alkyl of 1-10 carbons; 400 cycloalkyl of 3-12 carbons; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons; aryl of 6 - 13 carbons; Heteroaryl of 3-9 carbons and containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S; C02R5; wherein R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloaicyl of 3-6 carbons or halocycloalkyl of 3-6-10 carbons; halogen y = O, representing two of the groups R2, R3, and R4; X is O or S (0) y; where y is O, 1, or 2; 15 n is 2, 3,, or 5; p is the sum of H non-substituents R2, R3, and R4; T is a substituent selected from the group consisting of alkyl of 1-4 carbons; 1-4 carbon alkoxy; 20 aryl of 6-10 carbons; CO2H; C02R5; 2-4 carbon alkenyl; 2-4 carbon alkynyl; 25 C (O) C6H5; C (0) N (R6) (R7); where R6 is H or alkyl of 1-5 carbon; Y . R7 is H or alkyl of 1-b carbons; S (O) and R8; where y 'is 1 or 2; and R8 is alkyl of 1-5 carbon; S02F; CHO; OH; N02; CN; - halogen; OCF3; Oxide-N; O-C (R9) 2-0, the oxygens being connected to the adjacent positions in R; and wherein R9 is H, halogen, or alkyl of 1-4 carbons; C (O) NHC (0), the carbons being connected to the adjacent positions in R; and C (O) C6H, the carbonyl carbon and the ortho carbon ring being connected to the adjacent positions in R; t is 1 - 5; provided that when the substituent fraction T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, aryl of 6-10 carbons, C02R5, alkenyl of 2-4 carbons, alkynyl of 2-4 carbons, C (O) C6H5 , C (O) N (R6) (R7), S (O) and R8, 0-C (R9) 2-O, or C (O) C6H4, then T optionally can support secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; 1-4 carbon alkoxy; CO2Rs; CO2H; C (O) N (R6) (R7); CHO; OH; . . DO NOT; CN; halogen; S (O) and R8, or = 0, the amount of said secondary substituents being 1 or 2 with the exception of halogen, which can be used above the level of the perhalo; G is a substituent selected from the group consisting of halogen; OH; OR R5 '= 0, represented by two substituents G; alkyl of 1-4 carbons; ~ alkenyl of 1-4 carbons; 3-7 carbon cycloalkyl; heterocycloalkyl of 3 - 5 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; 5-7 carbon cycloalkenyl; heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; C (O) N (R6) (R7); aryl of 6 - 10 carbons; heterocaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N, O and S, NO2; CN; S (SO) and R ']; SO3R3. and SO2N (R6) (R7); g is O - 4 with the exception of halogen, which can be used up to 403 perhalo level; provided that when the substitute G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, heterocyclalkyl of 3-5 carbon, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then g optionally can support secondary halogen substituents up to the level of the perhalo; and when the substituent G is aryl or heteroaryl, then G optionally can support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties , and up to the perhalo level for halogen; Q is a substituent selected from the group consisting of alkyl of 1-4 carbons; haloalkyl of 1-4 carbons; cycloalkyl of 3-8 carbons; alkoxy of 1-8 carbon; alkenyl of 2-5 carbons; cycloalkenyl of 5-8 carbons; d-0 carbons; heteroaryl of 3-9 carbons and containing from 1 to 3 heteroatoms selected from the group consisting of N, O, and S; CG2R5, = 0, representing two substituyen.es G, OH, halogen; N (R6) (R7); S (0) and R8; S03 R8; and S02 N (R6) (R7); q is O - 4 provided that when the Q substituent is aryl or heteroaryl, then Q optionally can support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3, for alkyl and - to the perhalo level for the halogen; and with the further proviso that: a) two of (Q) qR1, (Q) qR2, (Q) qR3, and (Q) qR4 can be joined and taken together with the atom (s) to which they are attached forming a non-aromatic spiro or non-spiro ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of NO and S; b) when n = 2 or 3, at least one R2, R3 and R4 is other than H; c) when n = 2, and X = O, if t = 1, then T is selected from the list of substituents T above except alkyl, and the -4 position of the 1,3-oxazolidine ring must support a substituent; d) when n = 3 and X = O, and t is equal to or greater than 1, then at least one T is selected from the list of substituents T cited above, except alkyl and alkoxy; e) when n = 2 or 3 and X = O or S, then the sum of non-hydrogen atoms in R1, R2, R3, and R4, is at least 5; f) when n = 2, X = O, position 4- of ring 1, 3 oxazolidine can support a carbonyl group, and R supports halogen in its 2- and 4- positions, then position 5 of R supports H; g) when n = 2 and X = O, the 4- position of the 1,3-oxazolidine ring can support a carbonyl if the fifth position of said ring supports at least one non-H substituent; h) when n = 2; X = S (O) y, the 4- position of the 1,3-thiazolidine ring supports a carbonyl group, R 1 is a substituted methyl group, and G is a phenyl group, then said phenyl group supports a secondary substituent; i) when n = 4, X = S, and G is CO 2R5, then R5 contains at least 2 carbons; and pharmaceutically acceptable salts thereof. A compound that has the formula: where R is phenyl or pyridyl; R1 is alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons and containing 1-3 rings;

2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons and containing 1 -3 rings; or alkynyl of 3-10 carbons; R2, R3, and R4 are independently selected from the group consisting of H; alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons; - = O, representing two of the groups R2, R3, and R4; X is O or S (O) y; where y is O, 1, or 2; n is 2 or 3; p is the sum of H non-substituents R2, R3, and R4; T is a substituent selected from the group consisting of alkyl of 1-4 carbons; 1-4 carbon alkoxy; 2-4 carbon alkenyl; 2-4 carbon alkynyl; N02; CN; and halogen; t is 1 - 5; provided that when the substituent fraction T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, alkenyl of 2-4 carbons or alkynyl of 2-4 carbons, when T optionally can support secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; 1-4 carbon alkoxy; C02R5; where R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons or halocycloalkyl of 3-6 carbons; CO2H, C (O) N (R6) (R7). where R6 is H or alkyl of 1-5 carbon; and R7 is H or alkyl of 1-5 carbon. CHO; OH; NO2; CN: halogen; S (O) and R8; wherein x R8 is alkyl of 1-5 carbon; y = O, representing two secondary substituents; the number of said secondary substituents is 1 or 2, with the exception of the halogen which can be used up to the level of the perhalo. G is a substituent selected from the group consisting of halogen; O R5 'alkyl of 1-4 carbons; alkenyl of 1-4 carbons; 3-7 carbon cycloalkyl; 5-7 carbon cycloalkenyl; aryl of 6 - 10 carbons; and CN; g is 0 - 4 with the exception of halogen, which can be used up to the level of the perhalo; provided that when the substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, -cycloalkenyl of 5-7 carbons, then G optionally can support secondary substituents of halogen up to the level of the perhalo; and when the substituent G is aryl, then G can optionally support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the amount of said secondary substituents being up to 3 fractions for the alkyl, and up to the level of the perhalo for halogen: Q is a substituent selected from the group consisting of alkyl of 1-4 carbons; haloalkyl of 1-4 carbons; cycloalkyl of 3-8 carbons; alkoxy of 1-8 carbon; 2-5 carbon alkenyl; cycloalkenyl of 5-8 carbons; CO2R5; = O, representing two Q substituents; OH; halogen; N (R6) (R7); S (O) and R8; q is 0 - 4 and provided that: a) two of (Q) qR2, (Q) qR3, and (Q) qR4 can be joined together and taken together with the atom (s) to which they are attached they form a ring non-aromatic spiro or non-spiro of 3 - 8 members containing 0 - 2 heteroatoms selected from! group consisting of "NO and S; b) when n = 2 or 3, at least one R2, R3 and R4 is other than H; c) when n = 2, and X = O, if T = 1, then T is selected from the list of substituents T above except alkyl, and the 4- position of the 1,3-oxazolidine ring must support a substituent, d) when n = 3 and X = O, is equal to or greater than 1, then at least one T is selected from the list of substituents T mentioned above, except alkyl and alkoxy; e) when n = 2 or 3 and X = O or S, then the sum of the non-hydrogen atoms in R1, R2, R3, and R4, are at least 5; f) when n = 2, X = O, position 4- of ring 1, 3 oxazolidine can support a carbonyl group, and R supports halogen in its 2- and 4- positions, then position 5 of R supports H; g) when n = 2 and X = O, the 4- position of the 1,3-oxazolidine ring can support a carbonyl if the fifth position of said ring supports at least one non-H substituent; and h) when n = 2; X = S (O) y, the 4- position of the 1,3-thiazolidine ring supports a carbonyl group, R 1 is a substituted methyl group, and G is a phenyl group, then said phenyl group supports a secondary substituent; and pharmaceutically acceptable salts thereof. A compound that has the formula: where R is phenyl or pyridyl; R1 is alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons and containing 1-3 rings; R2, R3, and R4 are independently selected from the group consisting of H; alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons; X is O or S (O) y; where y is O, 1, or 2; n is 2, or 3; p is the sum of H non-substituents R2, R3, and R4; T is a substituent selected from the group consisting of alkyl of 1-4 carbons; 2-4 carbon alkenyl; NO2; CN; and halogen; t is 1 - 5; provided that when the substituent fraction T is alkyl of 1-4 carbons, alkenyl of 2-4 carbons, then T optionally can support secondary substituents selected from the group consisting of alkyl of 1-4 carbons; 1-4 carbon alkoxy; CO2R5; where R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons; CO2H; C (O) N (RQ) (R7); where R6 is H or alkyl of 1-5 carbon; and R7 is H or alkyl of 1-5 carbon CHO; OH; NO2; CN; halogen; S (O) and R8; where R8 is alkyl of 1-5 carbon; y = 0, the amount of said substituents being secondary 1 or 2 with the exception of halogen, which can be used up to the level of the perhalo; G is a substituent selected from the group consisting of halogen; alkyl of 1-4 carbons; alkenyl of 1-4 carbons; 3-7 carbon cycloalkyl; 5-7 carbon cycloalkenyl; aryl of 6 - 10 carbons; g is 0-4 with the exception of halogen, which can be used up to the level of the perhalo; provided that when the substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, cycloalkenyl of 5-7 carbons, then g optionally can support secondary substituents of halogen up to the level of the porhal; and when the substituent G is aryl, then G optionally can support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties, and up to the level of the perhalo for halogen; Q is a substituent selected from the group consisting of alkyl of 1-4 carbons; haloalkyl of 1-4 carbons; cycloalkyl of 3-8 carbons; alkoxy of 1-8 carbon; 2-5 carbon alkenyl; cycloalkenyl of 5-8 carbons; halogen; q is 0 - 4 provided that when a) two of (Q) qR1, (G) qR2, (Q) qR3, and (Q) qR4 can be joined and taken together with the atom (s) to which attached form a non-aromatic spiro or non-spiro ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of NO and S; b) when n = 2 or 3, at least one R2, R3 and R4 is other than H; c) when n = 2, and X = O, if T = 1, then T is selected from the list of substituents T above except alkyl, and the 4- position of the 1,3-oxazolidine ring must support a substituent; d) when n = 3 and X = O, is equal to or greater than 1, then at least one T is selected from the list of substituents T cited above, except alkyl; e) when n = 2 6 3 and X = O or S, then the sum of non-hydrogen atoms in R1, R2, R3, and R4, is at least 5; and pharmaceutically acceptable salts thereof. A compound of Claim 1 selected from the group consisting of: (4s) -2- (2-methyl-4-nitrophenylimino) -3-butyl-4-isopropyl-1,3-thiazole;; (4 s) -2- (2-methyl-4-nitrophenylimino) -3,4-diisobutyl-1,3-thiazolidine; (4 s) -2- (2-methyl-4-nitroienylimino) -3-isobutyl-4- (trifluoromethyl) -1,3-thiazolidine; (45) -2- (2-methyl-4-nitrophenylimino) -3-cyclopentyl-4-isobutyl-1,3-thiazolidine; (4 s) -2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4-isopropyl-1 -3-thiazolidine; (43) -2- (2-methyl-4-nitrophenylimino) -3-cyclopentyl-4-isopropyl-1 I3-thiazolidine; (4?) -2- (2-methyl-4-nitotophenylimino) -3-isobutyl-4-isopropyl tetrahydro-2H-1, 3-thia? Ina; (4 s) -2- (4-Nitro-1-naphthylimino) -3-cyclopeniyl-4 - ((1 tf) -1-hydroxyethyl) -1,3-thiazolidine; 2- (4-cyano-2-methylphenylimino) -1-cyclopentyl-3-thia-1 -azaspiro [4.4] nonane; 2- (4-cyano-2-ethylphenylimino) -1-cyclopentyl-3-thia-1 -azaspiro [4.4] nonane; 2- (4-cyanophenylimino) -1-cyclopentyl-3-thia-1 -azaspiro [4.4] nonane; 2- (4-cyano-2-methylphenylimino) -1-isobutyl-3-thia-1 -azaspiro [4.4] nonane; 2- (4-cyano-2,3-dimethylphenyl) -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-naphthylamino) -1-isobutyl-3-thia-1 -azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino) -1 - (prop-2-en-1-yl) -3-thia-1 -azaspiro [4.4] nonane; 2- (2-methyl-4-nitrophenylimino) -1-isopropyl-3-yia-1 -azaspiro [4.4 J nonane; x 2- (2-methyl-4-nitrophenylimino) -1-isobutyl-3-thia-1-a? aspiro [4,4] nonane; 2- (2-methyl-4-nitrophenylimino) -1-cyclopenyl-3-thia-1 -azaspiro [4.4] nonane; 2- (3-methyl-4-nitrophenylimino) -1-cyclopentyl-3-thia-1-a? Aspiro [4,4] nonane; 2- (2-methyl-4-nitrophenylimino) -1-cyclohexyl-3-thia-1 -azaspiro [4.4] nonane; 2- (2,3-dimethyl-4-nitrcphenylimin) -1-cyclopentyl-3-thia-1-azaspiro [4.4] nonane; Y 2- (4-cyano-2,3-dimethyi-4-nitrophenimimino) -1-cyclopentyl! -3-tia-1 -azaspiro [4.4] nonane; A compound of Claim 1 selected from the group consisting of: 2- (2-meityl-4-niiophenilimino) -3-isobutyl-1,3-thiazolidin-4-one; 2- (3-methyl-4-nitrophenlimino) -3-isobutyl-1,3-thiazolidin-4-one; 2- (2-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidin-4-one; 2- (3-methyl-4-nitrophenylimino) -3-benzyl-1,3-thiazolidin-4-one; 2- (2-methyl-4-nitrophenylmethyl) -3- (2-methyl-1-butyl) -1,3-thiazolidin-4-one; 2- (3-methyl-4-nitrophenylimino) -3- (2-methyl-1 but: l) -1,3-thiazolidin-4-one; 2- (2-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-1-ethyl) -1,3-thiazolidin-4-one; 2- (3-methyl-4-nitrophenylimino) -3- (1-cyclohexyl-1-ethyl) -1,3-thiazolidin-4-one; 2- (2-methyl-4-nitrophenylimino) -3- (2-ethyl-1-butyl) -1,3-thiazolidin-4-one; 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-5-methylene-1,3-tlazolid-4-one; and 2- (2-methyl-4-n-phenylphenyl) -3-isobutyl-5-methyl-1,3-thiazolidin-4-one; 6. A compound of Claim 1 selected from the group consisting of: 2- (2-methyl-4-nitrophenylimino) -3-isobutyl-4,4-dimethyl-1,3-oxazolidine; 1-cyclopentyl-2- (4-cyano-2-ethylphenylimino) -3-oxa-1-azaspiro [4.4] nonane; 1-cyclopentyl-2- (2-methyl-4-nitropheninyl) -3-oxa-1-azaspiro [4.4]; nonane and 1-cyclohexyl-2- (2-methyl-4-nitrophenylimino) -3-oxa-1 -azaspiro [4.4] nonane; 7. A pharmaceutical composition comprising a compound of Claim 1, 2, 3, 4, 5 or 6 and a pharmaceutically acceptable carrier. 8. A method for treating a mammal by administering to said mammal an effective amount of a compound for: A1) increasing bone formation in diseases where there is bone weakening for the treatment or prevention of osteopenia or osteoporosis; A2) improvement in fracture healing; B1) activity as a female contraceptive agent; B2) prevention of endometrial implantation; 416 B3) induction of delivery B4) treatment of luteel deficiency; B5) better recognition and maintenance of pregnancy; B6) counteract pre-eclampsia, eclampsia of pregnancy and early delivery; B7) treatment of infertility, including the promotion of spermatogenesis, induction of the acrosome reaction, maturation of oolociyos or in vitro fertilization of oocytes; C1) treatment of dysmenorrhea; C2) treatment of dysfunctional uterine bleeding; C3) treatment of ovarian hyperandroginism; C4) treatment of ovarian hyperaldosteronism; C5) relief of premenstrual syndrome and premenstrual tension; C6) relief of perimenstrual behavior disorders; C7) treatment of climacteric disturbance including menopausal transition, changes in mood, sleep disturbance and vaginal dryness; C8) increase in female sexual receptivity and male sexual receptivity; C9) treatment of menopausal urinary incontinence; C10) improvement of motor and sensory functions; C1 1) improvement of short-term memory; C12) relief of postpartum depression C13) treatment of genital atrophy; C14) prevention of postoperative adhesion formation; C15) regulation of uterine immune function; C16) prevention of myocardial infarction; DI) hormone replacement therapy; E1) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer and endometrial cancer; E2) treatment of endometriosis; E3) treatment of uterine fibrosis; F1) treatment of hirsutism; F2) inhibition of hair growth; G1) activity as masculine anticoncepetivo; G2) activity as an abortifacient; and H1) promotion of marrow repair; wherein said compound has the following general formula, where R is aryl of 6-14 carbons; or heteroaryl of 3-10 carbons and containing 1-3 heteroatoms selected from the group consisting of N, O, and S, with the proviso that R is other than benzofuran or benzothiophene; R1 is alkyl of 1-10 carbons; 3-12 carbon cycloalkyl and containing 1-3 rings; 4-7-carbon heterocycloalkyl and containing 1-3 rings and 1 -3 heteroatoms selected from the group consisting of N, O, and S; 6-10 carbon aryl; 3-9 carbon heteroaryl and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O and S; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons and containing 1-3 rings; or alkynyl of 3-10 carbons; R2, R3, and R4 are independently selected from the group consisting of H; alkyl of 1-10 carbons; cycloalkyl of 3-12 carbons; 2-10 carbon alkenyl; cycloalkenyl of 5-12 carbons; aryl of 6 - 13 carbons; heteroaryl of 3-9 carbons and containing from 1 - 3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; where R5 is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons or halocycloalkyl of 3-6 carbons; halogen; y = O, representing two of the groups R2, R3, and R4; X is O or S (O) y; where y is O, 1, or 2; n is 2, 3, 4, or 5; p is the sum of non-substituents H, R, R, and R; s represents the number of dooral junctions in the ring y is 0, 1, or 2; T is a substituent selected from the group consisting of alkyl of 1-4 carbons; 1-4 carbon alkoxy; aryl of 6 - 10 carbons; C02H; C02R5; 2-4 carbon alkenyl; "2-4 carbon alkynyl; C (O) C6H5; C (O) N (R6) (R7); wherein R6 is H or alkyl of 1-5 carbon; and R7 is H or alkyl of 1-5 carbon; S (O) R8, where y 'is 1 or 2, and R8 is alkyl of 1-5 carbon, S02F, CHO; OH; N02; CN; halogen; OCF3; Oxide-N; OC (R9) 2-0, the oxygens being connected to the adjacent positions in R; and wherein R9 is H, halogen, or alkyl of 1-4 carbons; C (0) NHC (0), the carbons being connected to the adjacent positions in R; and C (0) C6H, the carbonyl carbon and the ortho carbon ring being connected to the adjacent positions in R; t is I-5; provided that when the substituent fraction T is alkyl of 1-4 carbons; 1-4 carbon alkoxy, 6-10 carbon aryl, C02R5, 2-4 carbon alkenyl, 2-4 carbon alkynyl, C (O) CßH5, C (O) N (R6) (R7), S (O) and.R8, OC (R9) 2-O, or C (O) C6H4i then T optionally can support secondary substituents selected from the group consisting of alkyl of 1 - 4 carbons; 1-4 carbon alkoxy; CO2R5; C02H; C (O) N (R6) (R7); CHO; OH; NO2; CN; halogen; S (O) and R8; or = O, the amount of said secondary substituents being 1 or 2 with the exception of halogen, which can be used up to the level of the perhalo; G is a substituent selected from the group consisting of halogen; OH; OR5; = 0, representing two substituents G; alkyl of 1-4 carbons; alkenyl of 1-4 carbons; 3-7 carbon cycloalkyl; heterocycloalkyl of 3 - 5 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; 421 5-7 carbon cycloalkenyl; heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N, O, and S; CO2R5; C (0) N (R6) (R7); aryl of 6 - 10 carbons; heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N, O and S; NO2; - cN; S (SO) and R8; SO3 R8: and SO2 N (R6) (R7); g is 0-4 with the exception of halogen, which can be used up to the level of the perhalo; provided that when the substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbon, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then G optionally can support secondary halogen substituents up to the level of the perhalo; and when the substituent G is aryl or heteroaryl, then G optionally can support secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for the alkyl moieties, and up to the level of the perhalo for halogen; Q is a substituent selected from the group consisting of 422 alkyl of 1-4 carbons; haloalkyl of 1-4 carbons; cycloalkyl of 3-8 carbons; alkoxy of 1-8 carbon; 2 - 5 carbon aikenyl; cycloalkenyl of 5-8 carbons; aryl of 6 - 10 carbons; heteroaryl of 3-9 carbons and containing from 1 to 3 heteroatoms selected from the group consisting of N, O, and S; - CO2R5; = O, representing two Q substituents; OH; halogen; N (R6) (R7); S (O) and R8; SO3 R8; and SO2 N (R6) (R7); q is 0-4, provided that when the substitute Q is aryl or heteroaryl, then Q optionally can support secondary substituents independently selected from the group consisting of 1-4 carbons and halogen, the number of said secondary substituents being I * sta 3 for alkyl fractions and up to the perhalo level for halogen; and with the further proviso that two of (Q) qR1, (Q) qR2, (Q) qR3, and (Q) qR4 can be joined together and taken together with the atom (s) to which they are attached they form a ring non-aromatic spiro or non-spiro of 3 - 8 H ^^ aa || jirikririugta 423 members containing 0-2 heteroatoms selected from the group consisting of N, O, and S; and the pharmaceutically acceptable salts thereof. The method of Claim 8 wherein said mammal is a human.