TWI314861B - Glycine-substituted thieno [2,3-d] pyrimidines with combined lh and fsh agonistic activity - Google Patents

Description

1314861 A7 B7 V. DESCRIPTION OF THE INVENTION (1) The present invention relates to a compound having a glycoprotein hormone agonistic activity, specifically a compound having both agonistic activity of luteinizing hormone (LH) and follicle stimulating hormone (FSH), the present invention It also relates to pharmaceutical compositions containing such compounds and to the use of these compounds in medicine, especially for the purpose of controlling fertility. Gonadotropins have important functions in a variety of bodily functions, including metabolism, temperature regulation, and reproductive processes. For example, pituitary gonadotropins FSH and LH play an important role in stimulating follicular development and maturation, while LH involves ovulation (Sharp) , RM Clin. Endocrinol 3^.: 787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res 35_: 301-342, 1979; Levy et al, Human Reproduction 1_5: 2258-2265, 2000). Currently, clinically, LH is used in combination with FSH for ovarian stimulation, that is, ovarian hyperstimulation for in vitro fertilization (IVF) and ovulation in infertile women who are not ovulating (Insler, V·, Int. J. Fertility 11:85-97, 1 988, Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5_: 3-13, 1 988), and for male reproductive dysfunction and male infertility. Gonadotropin acts on specific gonadal cell types to trigger ovarian and squamous differentiation and steroidogenesis. These hormones in the pituitary gland and placenta are affected by the specific membrane receptors of a large group of G-protein-coupled receptors. It includes a single polypeptide with seven transmembrane regions and is capable of interacting with Gs proteins, resulting in activation of adenylate cyclase. Gonadotropins for medical purposes can be isolated from human urine sources at low purity (Morse et al, Amei_. J. Reproduct. Immunol. And This paper scale applies to Chinese National Standard (CNS) A4 specifications (210X 297) PCT) __________0! (Please read the notes on the back and fill out this page)

1T Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperation Du printing system -4- 1314861 at B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (2) Microbiology Γ7_: 143, 1988), or, it can be prepared In addition to these proteins, gonadotropin receptors can be activated or deactivated via synthetic low molecular weight compounds, and bicyclic heteroaromatic compounds are disclosed in WO 00/61586 via in vitro and in vivo. Experiments showing that it can be used as an LH agonist. In normal women, the release of the pituitary gland LH and FSH is characterized by mid-cycle surges during ovulation. The ovulation is characterized by three distinct physiological phenomena, namely oocyte maturation, follicular rupture and corpus luteum. Although the role of LH-undulation in triggering these phenomena in vivo is undoubted, the role of FSH-fluctuation is less serious, but it has recently been shown that FSH can overcome the hypoxanthine triggering meiosis by triggering cell mound production. The factor induces oocyte maturation in vitro (Lu et al, Mol. Cell. Endocrinol. 164:191-196, 2000), which is a meiotic activated sterol (MAS). The present invention provides a low molecular weight compound exhibiting LH activity, which unexpectedly also has FSH activity in addition to LH activity, usually these compounds are thiazol[2,3-d]pyrimidines which are in the 4-position of the pyrimidine ring. Substituted by a substituted phenyl group at the intermediate position, the substituent includes a spacer of three atoms (NH-C(0)-CH〇, which is also functionalized by a substituted amine group, usually having varying degrees of FSH agonistic activity, but usually lower than Lh agonistic activity. The present invention relates to a glycine-substituted thiazol[2,3-d]pyrimidine derivative according to formula I, --------- __ -: - * a (Please read the notes on the back and fill out this page.) The paper size applies to the Chinese National Standard (CNS) -5-134191

V. Description of the invention (3 R3 R4

Or a pharmaceutically acceptable salt thereof, wherein X is 0 or Η, Η Α is S' NH, N(R6), 〇 or a bond; # R is (1-4C), (2-4C) a dilute, phenyl or (2-5c)heteroaryl or heteroaryl ring which is optionally substituted with one or more substituents: hydroxyhalo, nitro, trifluoromethyl, cyano, amine or (1_4C) (2) Courtamines (please read the notes on the back and fill out this page) f Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed R is H, (1-4C) alkyl, (1-4C Alkoxy (2-4C) alkyl or hydroxy (2-4C) alkyl; R3 and R4 are each independently selected from the group consisting of hydrazine and hydroxy (1-4C); R5 is hydrazine or (1-4C) Alkyl; R6 may be selected from the same group used to describe R1. The term "1-4C" alkyl as used in the definition of formula I refers to a branched or straight-chain alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl. , a second butyl group or a third butyl group. The term "2-4C" alkenyl as used in the definition of formula I refers to a branched or straight-chain alkenyl group having 2 to 4 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, or methyl-vinyl. , 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propene paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) I Order---- --Line _-------^----4-- -6- 1314861 Λ7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (4) alkenyl, 2-methyl- 2-propenyl, benzyl-1-propenyl, ethane-vinyl hydrazine (1-4C) alkoxy (1-4C) alkyl means that an alkyl group having 1 to 4 carbon atoms is bonded via an oxygen atom to Another hospital base with 1 to 4 carbon atoms has the same meaning as previously defined. The noun (1-4C) alkoxy (2-4C) alkyl means that the alkyl group having 1 to 4 carbon atoms is bonded to another hospital base having 2 to 4 carbon atoms via an oxygen atom, and the The same meaning of the definition. The term hydroxy(1-4C)alkyl means that the hydroxy group is bonded to an alkyl group having from 1 to 4 carbon atoms, and the alkyl moiety has the same meaning as previously defined. The term hydroxy(2-4C)alkyl means that the hydroxy group is bonded to an alkyl group having 2 to 4 carbon atoms, and the alkyl moiety has the same meaning as previously defined. The term (1-4C) (di)alkylamino means that one or two previously defined alkyl groups having from 1 to 4 carbon atoms are attached to the nitrogen atom. The term (2-5C)heteroaryl means an aryl group having 2 to 5 carbon atoms and optionally substituted as a hetero atom selected from N, 0 and/or S, such as an imidazolyl group or a thiol group. , furyl or pyridyl. The term halo refers to fluoro, chloro, bromo or iodo. The compound of the above formula I was shown to have LH and FSH agonistic activity, and the EC5 of the LH receptor was found in an in vitro bioassay using CHO cells stably transfected with human LH or FSH receptors, respectively. Below 5.1 (Γ8 molar concentration and EC5 of FSH receptor. Below 10_5 molar concentration, usually FSH activity range is from about 1% LH stimulating stimulus to about 1% LH stimulating activity. Also relates to a pharmaceutical composition containing the formula I and the paper size applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

-7- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (5) [2,3-d] pyrimidine derivative compounds or their salts. Accordingly, the compound according to the present invention can be used in medical treatment, and another aspect of the present invention relates to the use of the Thio[2,3d]pyrimidine compound of the formula I for the production of a medicament for controlling fertility, which is preferably for ovulation induction. The compounds of the invention are useful for activating LH and FSH receptors, and the compounds of the invention are therefore useful in methods of treating fertility problems in women. The Thio[2,3-d]pyrimidine compound of the present invention may contain -or a plurality of palmitic carbon atoms, and the present compound may thus be obtained as a palm pure compound or a non-palphaliomer and/or a pair. A mixture of palmomers to obtain a palmitic pure compound is well known in the art, such as crystallization or chromatography. For medical use, the salt of the compound of formula I wherein the counterion is pharmaceutically acceptable However, acid addition salts of the bases according to formula I are also useful, for example, in the preparation or purification of pharmaceutically acceptable compounds, whether pharmaceutically acceptable or unacceptable, all within the scope of the invention. Examples of the acid addition salt include derivatives derived from inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, preferably hydrochloric acid, and organic acids such as citric acid, tartaric acid, acetic acid, lactic acid, maleic acid, malonic acid, and fumar. Acid, glycolic acid, succinic acid, and the like. Suitable routes of administration of a compound of formula I, or a pharmaceutically acceptable salt thereof, also referred to herein as an active ingredient are intramuscular, subcutaneous, intravenous or intraperitoneal, oral and intranasal, preferably oral The exact dose of this compound, the active ingredient or its pharmaceutical composition, and the size of the paper to be taken apply to the Chinese National Standard (CNS) A4 specification (2) 0X297 mm) I I-'1 I .—^ —Γ "7T I ~ 11 11 Order - (Please read the note on the back and fill out this page) Line ^ min^im · -8- 1314861 A7 __ B7 V. Invention Description (6) The law must be achieved by the medical effect ( Treatment for infertility, contraception) is determined and will vary with the particular compound, the route of administration, and the age and circumstances of the individual patient taking the drug. Usually, the dose required for parenteral administration is lower than other methods of administration, which is more related to absorption, but the dosage for human use is preferably 0.0001-25 mg/kg body weight. The desired dose can be presented as a single dose or multiple doses. The second dose is administered at appropriate intervals throughout the day. In the case of a female patient, the dose can be administered at an appropriate daily interval throughout the menstrual cycle for egg fixation or as a single dose for ovulation, the dose and The birth method can vary between female and male patients. In the case of use in vitro or in vitro, for example, in IVF applications, the compounds of the invention are employed in culture media at concentrations of from about 0.01 to about 5 micrograms per milliliter. The invention therefore also relates to a pharmaceutical composition comprising a Thio[2,3-d]pyrimidine compound according to formula I in admixture with a pharmaceutically acceptable adjuvant and, if desired, other medical agents, the adjuvant must be By "acceptable" is meant to be compatible with the other ingredients of the composition without deteriorating the patient. Medicinal compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal or sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions can be prepared by any of the methods well known in the art of pharmacy, for example using methods disclosed in Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing company, 1990, see, in particular, Part 8: Pharmaceutical Preparations and Their Manufacture). ° The paper size applies to the Chinese National Standard (cns) A4 specification (210X297 mm) (please read the note on the back and fill out this page). Customize the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative Printed -9- 1314861 A7 B7 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printing 5, invention description (7) The steps of this method include mixing the relevant active ingredients with adjuvants, also known as subsidiary ingredients and included in this technique (Gennaro above) Compounds such as gargles, adhesives, diluents, decomposers, lubricants, dyes, flavoring agents and Agent. The pharmaceutical composition suitable for oral administration may be presented as an isolated administration unit such as a nine dose, a tablet or a capsule, or a powder or granule, or a solution or suspension, and the active ingredient may also be presented as a large nine. The agent or paste, the composition can also be used as a suppository or enema for rectal administration. For parenteral administration, suitable compositions include aqueous or non-aqueous sterile injections, which may be presented in unit or multi-dose containers, such as sealed vials and vials, and may be stored in a freeze-dried condition and in use. A sterile liquid carrier such as water is added before. Compositions or preparations suitable for inhalation via the nose include fine dust or mist which is produced via metered administration of a pressurized aerosol, nebulizer or insufflator. The Thio[2,3-d]pyrimidine compound of the present invention can also be administered in the form of an implantable medical device in which the core of the active substance is coated with a membrane having a modified release rate, which is subcutaneously or partially. The use of, and for example, a few weeks to years, the release of the active ingredient at a suitable fixed rate, the preparation of implantable medical devices is known in the art, for example in European patents. 0, 3.03, 306 (AKZO NV). Accordingly, the compounds according to the present invention can be used for the same clinical purpose as native LH, which has the advantage of FSH activity, exhibits altered stability properties and can be administered differently. (Please read the notes on the back and fill out this page.) P., tT. Line size is applicable to China National Standard (CNS) A4 specification (2丨0X297 mm) -10- 1314861 Α7 Β7 V. Invention description (8 The preparation of the compounds of the invention represented by the formula (I) can be carried out generally by reacting a compound of the formula (II) wherein Q = ci or Br with an amine of the formula (III) in a suitable solvent such as N,N-dimethylformamide In the THF, a nucleophilic substitution reaction at room temperature and in the presence of a tertiary base such as N,N-diisopropylethylamine, many of the amines of the formula (III) are commercially available.

R2 R3 R4

'R5

(ΙΠ) Preparation of a derivative of formula (II) wherein Q = C1 or Br can be obtained by reacting an aniline derivative of formula (Va) with a mercapto chloride of formula (IV) wherein Q = C1 or Br is in the tertiary base, for example Stereoselective thiolation in the presence of hydrazine, hydrazine-diisopropylethylamine in a suitable solvent such as dichloromethane or THF. (Please read the notes on the back and fill out this page), ?τ Printed by the Intellectual Property Office of the Ministry of Economic Affairs

+ Cl (Π)

VQ (TV) Compounds of formula (V) may be derivatized with a suitable reducing agent such as hydrogen in the presence of a metal (Pd/Pt), via a reducing formula (VI) known in the art. Acquired, the related reductions are revealed in: P.Μ. :arabateas, PR Brundage, KO Gelotte, MD Gruett, RR .orenz, J. Heterocycl. Chem. 2^1,1 849 (1 984), or yes, This paper scale can be applied to China National Building Standard (CNS) Α4 specifications (2) 〇Χ 297 mm) -11 - 1314861 at Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (9) tin chloride (II) Reduction in a suitable solvent such as ethanol in the presence of hydrochloric acid and at elevated temperature. U. Heilbron, J. Chem. Soc, 1279 (1940)).

(V) The thienopyrimidine of the formula (VI) may be in a coupling agent such as 0-(benzotriazole-i-yl)-1^, heart 1^', ^1'-tetramethylurea tetrafluoroborate Under the influence of salt (butyl 61'11) or bromotripyrrolidinium hexafluorophosphate (PyBrOP) and a tertiary base such as N,N-diisopropylethylamine, via carboxylic acid (VII) and third butyl Obtained by the condensation of a base amine.

The saponification of the corresponding ethyl ester (VIII) with the carboxylic acid (VII) is carried out in the presence of a base such as lithium hydroxide, potassium hydroxide or sodium hydroxide in an aqueous dioxane solution at a high temperature (80 ° C to reflux) get on.

(VII) The bicyclic ring system of the formula (VIII) is a substitution reaction of a chloride of the formula (X) with ethyl thioglycolate in the presence of hydrazine, hydrazine-diisopropylethylamine, followed by the paper scale. China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back and fill out this page) -^1 n · mn, 1T1^1 nn Line N---

•I -12- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed V. Illustrated (10) Formed by a ring-closing reaction catalyzed by a base thioether (IX), such a thiophene [2] , 3-d] pyrimidine ring formation revealed in: SA Abdel-Hady, MA Badawy, YA Ibrahim, Sulfur Lett. 9, 101 (1989) and S. Tumkevicius, Liebigs Ann, 1703 (1995) °

(X) (IX) Suitable for the cyclization reaction is sodium ethoxide in ethanol or N,N-diisopropylethylamine in toluene/ethanol (1/1, V/V) and It is carried out at reflux temperature.

+ r~\ HS OEt (please read the note on the back and fill out this page) -^1. , -!! (IX) (X) Compounds of formula (X) can be synthesized by the following literature methods, for example, revealed in AJA Santilli, DH Kim and SV Wanser, J. Heterocycl. Chem. i, 445, 1971, in a typical experiment, the guanamine of formula (XI) is treated with POCh at elevated temperature (80 ° C to reflux). The addition of a suitable solvent such as dioxane and/or the addition of PC15 or N,N-diisopropylethylamine to the reaction mixture may result in a shortened reaction time or an increase in the yield of chloride (X). This paper scale applies to the national standard (CNS) A4 specification (210X297 mm) line · -13- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperation du printing system 5, invention description (

(X) (XI) General route for the preparation of the lactones of the formula (XI) includes condensation of ethyl cyanoacetate with 3-nitro-benzaldehyde and compound (XII), which may be isothiourea (xn_a), isourea (ΧΙΙ-b), monosubstituted 胍 (XII-c), disubstituted 胍 (ΧΠ-d) or 脒 (ΧΙΙ-e). , no2 NHR1, person, a’, nh2

'Η (XI) (χπ) In a typical experiment, ethyl cyanoacetate, 3-nitrobenzaldehyde and derivatives (XII) are suspended in a suitable solvent such as ethanol, methanol, hydrazine, hydrazine-dimethyl ketone. In the case of decylamine, hydrazine-methylpyrrolidone, tetrahydrofuran or pyridine, and adding a base such as potassium carbonate, sodium acetate, sodium methoxide or sodium ethoxide, the reaction is carried out at a high temperature (70 ° C to reflux), and after filtration, remains. The product (XI) precipitates after being dissolved in water and acidified (pH 2) (S. Kambe, K. Saito and H. Kishi, Synthesis, 287 (1979); AM Abd-Elfattah, SM Hussain and AM El-Reedy, Tetrahedron 39., 3197 (1983); SM Hussain, AA El-Barbary and SA Man sour, J. Heterocycl. Chem. 22_, 16 9 (1985)) « This paper scale applies to the Chinese National Standard (CNS) A4 specification (2) 0X297 mm) (Please read the notes on the back and then fill in this 1) Book-14- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventions (12) R1. ΙΊΠΛ. R1, ΙΝΠ R1. NH NH NH 人~Λ 人J 八NH, , nAnHs R1 I Η 2 I R4 (ΧΠ-a) (XII-b) (XII-c) (XU-d) (XU-e) The compound of the present invention represented by the formula (Ia) wherein A = N can be prepared by reacting a sub-substance of the formula (XIII) with a nucleophilic reaction with an amine nucleophile of the formula (XIV), and the reaction is usually R3 R4 R5 is carried out at elevated temperature in the presence of a tertiary amine base such as N,N-diisopropylethylamine in a suitable solvent such as 1,4-dioxane

R3 R4

R5 (ΧΠΙ) (XIV) Similarly, a compound of the invention represented by the formula (Ib) wherein A = 0 can be nucleophilic from a sub-substance of the formula (XIII) via a nucleophile of the alkoxide of the formula (XV) Prepared by a reaction which is carried out in the presence of potassium t-butoxide and an excess of the alcohol V-OH. (XIII) K—〇 R1 (XV)

'R5 Formula (XIII) sub-small derivatives can be expressed by the oxidation formula (Ι-C). This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the back note first) Please fill out this page again. Order-Line· -15- 1314861 A7 B7 V. Invention Description (13) (Please read the notes on the back and fill out this page) (I) Compounds where R^Me and A = S The oxidation reaction is carried out via 3-chloroperbenzoic acid in trifluoroacetic acid, and the acidic nature of the solvent prevents oxidation of the 5-amine group to the corresponding 5-nitroso derivative. R3 R4

Methods for determining receptor binding and methods for determining the biological activity of gonadotropins in vitro and in vivo are well known and, in general, the receptors present are contacted with a test compound and the stimulation or inhibition of binding or functional response is measured. In order to measure the functional response, the isolated DNA encoding the LH or FSH receptor gene, preferably a human receptor, is expressed in a suitable host cell, which may be a Chinese big hamster ovary cell, but other cells are also suitable, Preferred cells are of mammalian origin (Jia et al, Mol. Endocrin., 5: 759-776. 1991). The Ministry of Economic Affairs, the Intellectual Property Office, and the staff of the Consumers' Association for the production of recombined LH or FSH expressing cell lines are well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Mannul, Gold Spring Harbor Laboratory Press, Cold Spring) Harbor, larest ediion), the expression of the receptor is achieved by the expression of the desired protein encoding the DNA, the mutagenesis site, the ligation of other sequences, PCR and the construction of a suitable expression system are currently well known in the art. Some or all of the DNA-encoded proteins can be used in standard solid paper scales. The Chinese National Standard (CNS) A4 specification (210X 297 mm) -16-1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed V. DESCRIPTION OF THE INVENTION (14) Phase-by-tech synthesis, preferably including restriction sites for easy ligation, suitable control elements for transcription and translation of the contained coding sequences can be provided to DNA-encoded sequences, and it is well known that existing expression systems are now available. Compatible with a variety of hosts, including prokaryotic hosts such as bacteria and eukaryotic hosts Yeast, plant cells, insect cells, mammalian cells, avian cells and the like square cells expressing receptor is then contacted with a test compound to observe binding, or stimulation or inhibition of functional response. Alternatively, the binding of the compound can be measured using an isolated cell membrane containing the expression receptor. Radioactive or camping-labeled compounds can be used to measure binding, either using human recombined LH or FSH as a reference compound or performing competitive binding assays. Another assay involves examining an LH or FSH receptor agonistic compound via stimulation of cAMP accumulation measuring receptor intervening effects, whereby the method comprises expressing a receptor on the cell surface of the host cell and exposing the cell to the test compound, The amount of cAMP is then measured and the amount of cAMP will decrease or increase depending on the inhibitory or stimulatory effect of the test compound binding to the receptor. In addition to directly measuring, for example, the amount of cAMP exposed to cells, the cells can be used to transfect a second DNA in addition to the DNA bound by the transfected receptor, and the expression of the encoded receptor gene is in response to the amount of cAMP, which is The gene may be cAMP priming or constructed by linking to a novel cAMP response element. Typically, receptor gene expression can be controlled by any change in the response element cAMP. Suitable receptor genes are, for example, alkaline phosphatase. , Firefly (please read the precautions on the back and then fill out this page) ^^1. Customize the paper size for the Chinese National Standard (CNS) A4 specification (210Χ297 mm) -17- 1314861 A7 B7 V. Invention Description (15 Firefly luciferase and green fluorescent protein, the principles of this transactivation assay are well known in the art and are disclosed, for example, in Stratowa, Cli, Himmler, A and Czernilofsky, AP (1995) Curr. Opin. Biotechnol. 6 :574. For selective activating compounds on LH or FSH receptors, testing at 10-5 molar concentrations must result in greater than 20% maximum activity when LH or FSH is used as a reference material, and the other standard is EC5.値, it must be <1 (Τ5 molar concentration, preferably <1 (Τ7 molar concentration. Those who are familiar with this artist will know the desired EC5. 値 is determined by the test compound, such as EC5. 値 below 1 (Τ5 Compounds of molar concentration are generally considered candidates for drug selection, preferably less than 10.7 moles, but higher EC5. However, selectivity may be better for specific receptor compounds. Candidates. LH receptor agonistic compounds can also be used in the mouse Ley dig cell bioassay to enter fj (Van Damme, M., Robersen, D. and Diczfalusy, E. (1 974). Acta Endocrinol. 77: 655 -67 1

Mannaerts, B., Kloosterboer, H. and Schuurs, A. (1 987). Neuroendocrinology of reproduction. R. Rolland et al. Eds., Elsevier Science Publishers BV, 49-58). In this test, LH is subject to The production of the stimuli of the interstitial effect of body stimulation can be measured by Leydig cells isolated from male mice. The FSH agonistic activity of the compound can also be determined using the cultured mouse follicles in an in vitro mode according to Nayudu, P. and Osborn, S. (1992, J. Reproduction and Fertility 95: 349-362), according to which the mice are The follicles of the ovary are separated and cultured in the presence of FSH agonistic compounds to induce the paper size to be applied to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page), τ Ministry of Economics Intellectual Property Bureau employee consumption cooperative printing -18-1314861 A7 B7 V. Description of invention (16) Follicle growth, measurement of follicle diameter in culture medium and estradiol can show follicular growth. In order to measure the LH activity of a compound in vivo, the ovulation initiation of immature mice can be investigated. In this test, immature female mice are treated with urinary FSH and treated with LH agonistic compound after about 48 hours. The animals after LH activation were killed and the number of eggs in the fallopian tubes was assessed microscopically. In order to measure the FSH activity of the compound in vivo, immature female voles were treated with FSH agonistic compounds at 0, 8, 24 and 32 hours to initiate follicle length, and 52 hours after the start of the experiment, the animals were injected with hCG to induce ovulation. The experiment was started after 72 hours. The animals were sacrificed and the number of eggs in the fallopian tubes was evaluated by microscopy. In addition, the ovarian weight was measured. The compounds of the present invention can be clinically applied in the current method of using LH or hCG, including LH replacement in patients with hypogonadism of male or female hypogonadism, and intermediate cycle medication to induce ovulation (ovulation initiation (01)) or control Excessive stimulation (COH) or irritation of the corpus luteum. The following examples are intended to illustrate the invention and are not to be construed as limiting the scope of the invention. EXAMPLES Example 1 Tributyl 5-amino-5-methylthio-4-(3-((N-methyl-N-(2-hydroxyethylethylglycosyl)-phenyl)) - Thien and "2.3-dl pyrimidine-6-decylamine" This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 丨ί-ιίί-μη------ (Please read the back first Note: Please fill out this page) Order Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed -19- 1314861 A7 B7 V. Description of Invention (17) (a) . 5-Cyano-4-(3-nitrobenzene )-2-methylthio-6-hydroxy-pyrimidine (please read the notes on the back and fill out this page) S-methylisothiourea sulfate (69.0 g), 3-nitrobenzaldehyde (75.0) a mixture of cyanoacetic acid ethyl ester (56.0 ml) and potassium carbonate (72.5 g) in anhydrous EtOH (1500 ml) was stirred at 60 ° C for 16 hours, and the reaction mixture was cooled to 0 ° C in an ice bath. The resulting precipitate was filtered, washed with anhydrous EtOH and dissolved in hot water (100 ° C). The solution was cooled to room temperature, acidified to pH 2 with 2 eq. HCl and cooled to 0 ° C in an ice bath. The precipitate is filtered and rinsed with ice water, with 1 The residual water in the precipitate was removed by evaporation of 4-di-nf alkane. Yield: 54.0 g MS-ESI: [M + H] + = 289.0 TLC: Rf = 0.3, oxime, DCM/MeOH = 9/l (v/ v) (b) . 6-Chloro-5-cyanide-4-(3-nitrophenyl)-2-methylthio-pyrimidine Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing P0C13 (100 ml) added To 5-cyano-4-(3-nitrophenyl)-2-methylthio-6-hydroxy-pyrimidine (Example 1 (a), 25.0 g) in anhydrous 1,4-dioxane (3 00) After stirring for 3 hours at 90 ° C, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-di- D-hexane (1 mL) The solution was cooled to 〇t, ice water was carefully added, and the obtained precipitate was filtered and washed with water, and the water remaining in the precipitate was removed by evaporation with 1,4-dioxane. Yield: 26.0 g MS-ESI: [M + H] + = 307.0 TLC: Rf = 0_5, silicone, heptane / EtOAc = 3/2 (v/v) This paper wave scale applies to China National Standard (CNS) A4 specification (2) OX 297 mm) -20 - 1314861 A7 B7 V. INSTRUCTIONS INSTRUCTION (彳8) (C). Ethyl 5-aryl-4-(3-nitrophenyl)- 2-Methylthio-6-(ethyl ester thiol)-pyrimidine DIPEA (15.7 ml) was added to ethyl 2-mercaptoacetate (9.3 ml) and 6-chloro-5-cyano-4-(3) - nitrophenyl)-2-methylthio-pyrimidine (Example 1 (b), 26.0 g) in a stirred solution of a mixture of EtOH (250 mL) and DCM (250 mL) To the mixture was added aq. EtOAc (EtOAc)EtOAc. Yield: 28.0 g MS-ESI: [Μ + ΗΓ = 391·4 TLC: Rf = 0.5, oxime, heptane/EtOAc = 3/2 (v/v) (d). 5-amine -4-(3 -Nitrate benzene)-2-methylthio- thia # "2,3-dl pyrimidine-6-carboxylic acid ethyl ester ethyl 5-cyano-4-(3-nitrophenyl)-2 a mixture of methylthio-6-(ethyl ester methylthio)-pyrimidine (Example 1 (c), 28.0 g) and DIPEA (30 mL) in a mixture of toluene (150 mL) and EtOH (150 mL) The mixture was stirred at reflux temperature (100 ° C) for 16 hours, then the mixture was cooled to room temperature and concentrated under reduced pressure, and the residual DIPEA in the precipitate was removed by evaporation with toluene. Yield: 28.0 g MS-ESI: M + H] + = 391.4 TLC: Rf = 0.6, decyl, heptane / EtOAc = 3/2 (v/v) (e). 5-amino-4-(3-amine benzene)-2- Methylthio-thilyl and 2,3-dl pyrimidine-6- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page) Intellectual Property Office Staff Consumer Cooperative Printed - 21 - A7 1314861 ____B7 V. Invention Description (19) Ethyl Carboxylate (Please read the back note first) Fill in this page) Add Et〇H (400 ml) to 5-amino-4-(3-nitrophenyl)-2-methylthio-thiazolo[2,3-d]pyrimidine-6- a mixture of ethyl carboxylate (Example 1 (d), 28.0 g), concentrated aqueous HC1 (15 mL) and tin (II) chloride (41.0 g) in ι, 4- 腭 腭 (400 mL) The mixture was stirred at 90 ° C for 16 hours, then the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in EtOAc ( 1000 mL). The mixture was stirred vigorously and the organic layer was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj /2(v/v) (f). 5-Amino-4-(3-aminophenyl)-2-methylthio-thiophene and "2.3-dl oxime- ή. carboxylic acid economics wisdom The property bureau employee consumption cooperative printed potassium hydroxide (32.4 g) added to 5-amino-4-(3-aminophenyl)-2-methylsulfanyl-thiazolo[2,3-d]pyrimidine Ethyl 6-carboxylate (Example 1 (e), 21.0 g) A solution in a mixture of 1,4-dioxane (300 mL) and water (100 mL). After 1 6 hours at 0 ° C, the mixture was cooled to 10 ° C and 2 eq. aqueous citric acid (300 mL) was added with vigorous stirring, and the resulting precipitate was washed and washed with water (180 mL). Dry in vacuum. Yield: 14.0 g MS-ESI : [M + H] + = 333.0 TLC: Rf = 0.5, silicone, DCM/Me〇H = 9/l (v/v) This paper size applies to the Chinese National Standard (CNS) Α4 (21 297 297 mm) -22- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed V. Inventions (2〇) (g) · Ternyl 5-amino- 4-(3-amine Benzene)-2-methylthio-thiline and 2,3-dl-pyrimidine-6-decylamine added TBTU (16.1 g) to 5-amino-4-(3-aminophenyl)- 2-Methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid (Example 1 (f), 14.0 g), DIPEA (Π. 4 mL) and tert-butylamine (7_3 g) After 3 hours at room temperature, the mixture was diluted with DCM (50 mL) with aq. NaH.sub.2 (aq. (100 ml) and water (1 ml) were washed with EtOAc (EtOAc m.) [Μ + ΗΓ = 3 8 8.2 HPLC : Rt = 30.72 min, Luna C-18 (2), 5 μm, 250x2.0 mm, detection UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash water / ACN / MeOH = 90 / 9.5 / 0.5 to 0 / 95 / 5, operating time =5 0 minutes. (h). Third-butyl 5-amine-2-methylthio-4-(3-(2-bromoethylamino)-phenyl)-thiol and "2.3-dl Pyrimidine-6-decylamine Adds bromoacetic acid chloride (615 mg) to the tert-butyl-5-amino-4-(3-aminophenyl)-2-methylthio-thiol [2,3 -d]A solution of pyrimidine-6-nonylamine (Example 1 (g), 1.08 g) and DIPEA (2.43 ml) in anhydrous DCM (20 mL). Saturated NaHCCh aqueous solution is rinsed, dried (MgSCU) and concentrated under dust reduction, and the crude product is produced (please read the back of the note first and then fill in the page). The paper size is applicable to the Chinese National Standard (CNS) A4 specification ( 210X297 mm) -23- 1314861 A7 B7 V. Inventive Note (21) Purification by chromatography with heptane / EtOAc = 3/2 (v/v) as a stream wash. Yield: 910 mg MS -ESI : [M + H] + = 510.2 TLC: Rf = 0.3, decyl, heptane / EtOAc = 3/2 (v/v) (1) · T-butyl 5-amine -2-methylsulfanyl-4-(3-((N-methyl-N-(2-hydroxyethyl)-glycinyl)-aminophenyl) thiazepine 2,3-dl pyrimidine- 6-decylamine Addition of N-methyl-2-amino-ethanol (250 mg) to tert-butyl 5-amino-2-methylthio- 4-(3-(2-bromoethylamino) a solution of phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine (Example 1 (h), 250 mg) in DCM (5 mL) The mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc.EtOAc. The aqueous solution of %ACN/ACN = 90/10 to 10/90 (v/v) was lyophilized for 30 minutes, then the title compound was lyophilized from a mixture of 1,4-dioxane, 1% aqueous TFA and water. Yield: 112 mg (TFA-salt) MS-ESI: [M + H] + = 503.2 HPLC: R, = 11.45 min, column Luna C-18 (2), 3 micron, 100 x 2.0 mm, detection, UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10/80/10 to 10/10/80 (v/v/v), operation time = 20 minutes This paper is again applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page) <11 Line Ministry of Economics Intellectual Property Bureau Staff Consumer Cooperative Printed - 24-1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (22) Example 2 Third Butyl .5 -Amino-2-Methylthio-Zen -2-methyl-propan-2-()--glycinyl)-amino)-phenyl)-thilyl 2,3-d 1 ll·Midine-oxime--amine 2 -Amino-2-methyl-propanol (250 mg) is added to the third butyl 5-amino-2-methylthio- 4-(3-(2-bromoethinyl)-phenyl) _ 噻 并 [2,3-d] mouth 'steep _ 6- decylamine (example 1 (h), 250 mg) in DCM (5 ml), after 1 6 hours at room temperature The mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc.EtOAc. 1% TFA in water + 10% ACN in water / ACN = 90/10 to 10/90 (v/v) in 30 minutes, then the title compound from ι, 4-dioxane, ο·%% tfa aqueous solution and water The mixture was freeze dried. Yield: 67 mg (TFA-salt) MS-ESI: [Μ + Η] + = 517·2 HPLC: 1^=12.67 min, column Luna C-18(2), 3 μm, 100 x 2.0 mm, Detect UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 5 〇 millimolar pH 2.1 / water / ACN = 10 / 80/10 to 10/10 /80 (v/v/v), operation time = 20 minutes 〇 Example 3 Lithium butyl 5-diamino-2-methylthio-4-(3-((N-(methyl ester) methyl glycine) A paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

-25- 1314861 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (23) Amine V phenyl thiophene and "2.3-d" pyrimidine-6-decylamine methyl glycinate hydrochloride Salt (200 mg) was added to the tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoacetamido)-phenyl)-thiene [2,3-( 1] Pyrimidine-6-nonylamine (Example 1 (h), 250 mg) and hydrazine, hydrazine-diisopropylethylamine (0.20 mL) in DCM (5 mL) The mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc.EtOAc. Aqueous TFA + 10% aqueous solution of ACN / ACN = 90/10 to 10/90 (v/v) at 30 minutes, then the title compound was frozen from a mixture of 1,4-dioxane, 11% aqueous TFA and water. Dry 〇 yield: 133 mg (TFA-salt) MS-ESI: [M + H] + = 517_2 HPLC : Rt = l 1.87 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, Detect UV = 210 nm, furnace temperature = 40 ° C, flow rate = 0.25 ml / min, Washing solution phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10 / 80/10 to 10/10 / 80 (Wv / v), operating time = 20 minutes 〇 Example 4 third butyl 5-amine -2-Shen thio- 4-(3-((N-ethyl-N-(2-methyl)-ethyl)-glycosyl)-amine benzene thiophene and "2.3-dl pyrimidine -6-decylamine is added N-(2-methoxyethyl)-ethylamine (266 mg) to the third butyl 5-- (please read the back of the note first and then fill out this page)

This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -26- 1314861 A7 B7 V. Description of invention (24) Amino-2-methylthio-4-(3-(2-bromoethyl) A solution of guanidino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine (Example 1 (h), 200 mg) in DCM (5 mL) After the mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. Aqueous solution of TFA + 10% aqueous solution of ACN / ACN = 90/10 to 10/90 (v/v) The title compound was then lyophilized from a mixture of 1,4-dioxane, 0.1% aqueous TFA and water. Yield: 84 mg (TFA-salt) MS-ESI: [M + H] + = 531.2 HPLC: R, = 12.62 min, column Luna C-18 (2), 3 micron, 100 x 2.0 mm, UV detection = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10/80/10 to 10/10/80 ( v/v/v), operation time = 20 minutes 〇 Example 5 Third butyl 5-amine-2-methylthio-4-(3-((N-(Rl-methyl ester) is _c. 1 -Glycosylamine a V-amino)-phenyl)-thieno- 2,3-dl-pyrimidine decylamine D-proline methyl ester hydrochloride (250 mg) was added to the third butyl group 5_ Lunyl-2-methylthio-4-(3-(2-bromoacetamido)-phenyl)-thieno[2,3-d] chelate steep-6-decylamine (Example 1 ( h), 250 mg) and N,N-diisopropylethylamine (0.2 ml) in DCM (5 ml), after 16 h at room temperature, the mixture is applied to this paper scale. National Standard (CNS) A4 Specification (210X297 mm) (Please read the note on the back and fill out this page) Customs Department of Intellectual Property Intellectual Property Office Staff Cooperatives Print -27- 1314861 A7 B7 V. Invention Description (2 5) Dilute with DCM (50 mL), EtOAc EtOAc (EtOAc)EtOAc. Aqueous solution of TFA + 10% aqueous solution of ACN / ACN = 9 0/10 to 10/9 0 (v/v) at 30 minutes, then the title compound from a mixture of 1,4-dioxane, 0.1% aqueous TFA and water Freeze-dried mash yield: 77 mg (TFA-salt) MS-ESI: [M + H] + = 559.2

HPLC : Rt = 13.22 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash Phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10 / 80/10 to 10/10 / 80 (v / v / v), operating time = 20 minutes 〇 Example 6 third butyl 5-amine a certain 2-methylthio-4-(3-((1^.^1-zero-(2-methoxyethyl)-glycosylamino)-V-phenyl)-thiazolidine 2 , 3-dl pyrimidine-6-indole, hydrazine, hydrazine-bis-(2-methoxyethyl)-amine (400 mg) added to the tert-butyl-5-amino-2-methylthio-: 4-(3-(2-Bromoethylamino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine (Example Uh), 250 mg) in DCM (5 mL) The solution was diluted with EtOAc (50 mL) EtOAc (EtOAc)EtOAc. 1 8 column is purified by HPLC in the following gradients · 0.1% TFA aqueous solution + 10% ACN aqueous solution / ACN = 90/10 to 10/90 This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) (please Read first Note on the back of the page and fill in this page)

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -28- 1314861 A7 B7 V. Inventive Note (26) (ν/v) at 30 minutes, then the title compound from 1,4-dioxane, 〇1% TF A The mixture of aqueous solution and water is freeze dried. Yield: 166 mg (TFA-salt) MS-ESI · [M + H] + = 561.3 HPLC: R, = 13.62 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, UV detection = 210 nm, furnace temperature = 40 °C, flow rate

= 0.25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2.1/water/ACN=10/80/10 to 10/10/80 (v/v/v), operating time = 20 minutes〇 Example 7 Third-butyl 5-amine-2-methylthio- 4-(3-((2.3-dihydroxy-propyl-1-glycinylamine) V benzene some thiophene and "2, 3-dl pyrimidine-6-decylamine 3-amino-2-hydroxy-propanol (250 mg) was added to the tert-butyl 5-amino-2-methylthio-4-(3-(2- A solution of bromoacetamido)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine (Example 1 (h), 250 mg) in DCM (5 mL) After 16 hours, the mixture was diluted with EtOAc EtOAc EtOAc EtOAc. Purification: 0.1% aqueous solution of TFA + 1096 ACN in water / ACN = 90/10 M 10/90 (Wv), 30 min, then the title compound was lyophilized from a mixture of 1,4-dioxane, 0.1% aqueous TFA and water. : 164 mg (TFA-salt) This paper size applies to Chinese National Standard (CNS) A4 size (210X 297 mm) ~ -29- (Read first Precautions for re-filling this page) Ordering _· Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed 1131861 Λ7 B7 V. Inventions (27) MS-ESI : [Μ + ΗΓ = 519·2 HPLC : Rt = 12.62 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / Minutes, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10/80/10 to 10/10 / 80 (v / v / v), operating time = 20 minutes 〇 example δ third Ding Mou 5-amine-2-methylthio- 4-(3-((1,3-dihydroxy-propan-2--glycinylamine) benzene thiophene and f2.3-dl pyrimidine- 6-decylamine 2-amino-3-hydroxypropanol (250 mg) was added to the tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoethylamino) group -Phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine (Example 1 (h), 250 mg) in DCM (5 mL) Dilute with DCM (50 mL), EtOAc (EtOAc)EtOAc. The following gradient was purified by HPLC: 0.1% aqueous solution of TFA + 10% aqueous solution of ACN / ACN = 90/10 to 10/90 (Wv) at 30 min then the title compound from 1,4-dioxane, 〇. 1 % TFA The mixture of aqueous solution and water is freeze dried. Yield: 117 mg (TFA-salt) MS-ESI: [M + H] + = 519.2 HPLC: Rt = 12.62 min, column Luna C-18 (2), 3 micron, 100 x 2.0 mm, UV detection 210 nm, furnace temperature = 40 ° C, flow rate This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

-30- 1314861 A7 B7 V. Description of invention (28)

= 0.25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2.1/water/ACN=10/80/10 to 10/10/80 (Wv/v), operation time = 20 minutes 〇 (please Read the precautions on the back and then fill out this page. Example 9 Third Ding 5-Amino-2-Benzene-4-(3-((N-Ethyl-N-(2-hydroxyethylethyl ganate) Acid-)-amino)-phenyl)-thio-"2,3-dl-pyrimidine-6-decylamine (a). 5-aryl- 4-(3-nitrophenyl)-2-benzene -6-Ke-Ken-Ming, Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed benzamidine hydrochloride (16.4 g), 3-nitrobenzaldehyde (15.1 g), ethyl cyanoacetate (11.2 ml) And a mixture of potassium carbonate (16.6 g) in anhydrous EtOH (250 ml) was stirred at 60 ° C for 8 hours, and the reaction mixture was cooled to 0 ° C in an ice bath, and the obtained precipitate was filtered and washed with anhydrous EtOH. And heated in water (100 ° C) to obtain a clear solution, the solution was cooled to 50 ° C, acidified to pH 2 by adding 2 equivalents of aqueous HCl solution and cooled to 〇 ° C in an ice bath, the resulting precipitate Filtration and washing with ice water, evaporation in the precipitate by evaporation with 1, 4-dioxane Residual water removal. Yield: 15.0 g MS-ESI ·· [M + H] + = 319.2 TLC: Rf = 0'3, silicone, DCM/Me〇H = 9/l (v/v) (b) . 6-Chloro-5-cyano-4-(3-nitrophenyl)-2-benzene-pyrimidine P0C13 (50 ml) was added to 5-cyano-4-(3-nitrophenyl), 2-Benzene paper scale applicable to China National Standard (CNS) A4 rule earned (210X297 mm) -31 - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1131861 A7 B7 V. Invention Description (29) Base-6-Hydroxy- A stirred solution of pyrimidine (Example 9 (a), 15.0 g) and dimethylaniline (0.5 mL) in anhydrous 1,4-dioxane (200 mL), warmed at 90 ° C for 3 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. EtOAc was evaporated. Evaporation removes residual water from the precipitate. Yield: 15.8 g MS-ESI: [M + H] + = 337.4 TLC: Rf = 0.8, decyl, heptane / EtOAc = 3/2 (v/v) (c) . Ethyl 5-cyano-4-(3-nitrophenyl)-2-benzene-6-(ethyl ester methylthio)-pyrimidine will be DIPEA (8. 71 ml) was added to 2-mercaptoacetate (5.15 ml) and 6-chloro-5-cyano-4-(3-nitrophenyl)-2-phenyl-pyrimidine (Example 9(b), 15.8 g) After stirring a mixture of EtOH (125 ml) and DCM (125 ml) under nitrogen pressure for 2 hours at room temperature, the mixture was diluted with DCM to dissolve completely, rinsed with 0.5 eq. (MgSOO and concentrated under reduced pressure. Yield: 19.7 g of MS-ESI: [M + H] + = 421.2 TLC: Rf = 0.7, decyl, heptane / EtOAc = 3/2 (v/v) (d). 5-amine -4-(3) -Nitrobenzene)-2-Benzene-anthracene and 2,3-dl-pyrimidine-..6-diethyl decanoate. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) (please Read the notes on the back and fill out this page.)

-32- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1131861 A7 B7 V. Description of Invention (30) Add 01? (20.0 ml) to ethyl 5-cyano-4-(3-nitrophenyl) a stirred solution of 2-phenyl-6-(ethyl estermethylthio)-pyrimidine (Example 9(c), 19.7 g) in a mixture of anhydrous EtOH (100 mL) and anhydrous toluene (100 mL) After 48 hours at 100 ° C, the mixture was cooled to 0 ° C, and the obtained precipitate was filtered, washed with cold EtOH and dried under vacuum at 40 ° C. Yield: 17.0 g MS-ESI: [M + H] + = 421.2 TLC: Rf = 0.5, decyl, heptane / EtOAc = 3/2 (v/v) (e). 5-amine -4-(3) -Aminophenyl)-2-phenyl- thio-"2,3-dl-pyrimidine-6-carboxylic acid ethyl ester. Add tin(II) chloride (23.0 g) in EtOH (250 mL) to Ethyl 5-amino-4-(3-nitrophenyl)-2-phenyl-thieno[2,3-d]pyrimidin-6" residue (Example 9(d), 16.6 g) A solution of 1,4-di Df (250 mL), EtOAc (EtOAc) (EtOAc) The residue was suspended in EtOAc (500 mL). EtOAc (EtOAc (EtOAc) Concentration: Yield: 17.0 g MS-ESI: [M + H] + = 421_2 TLC: Rf = 0.5, decyl, heptane / EtOAc = 3/2 (v/v) (1) · 5-amino- 4- ( 3-aminophenyl benzene)-2-phenyl-thiazinopyrene 2,3-dl pyrimidine-6-carboxyl paper size applicable to national standards of the country (〇 八八4 threat (210 father 297 mm)~~ ' " -33- ( Please read the notes on the back and fill out this page.)

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1131861 A7 B7 V. Description of Invention (31) E- Addition of potassium hydroxide (20.0 g) to 5-amino-4-(3-aminophenyl)-2- a mixture of phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (Example 9(e), 17.0 g) in 1,4-dipropane (210 mL) and water (80 mL) The solution was centrifuged at 90 ° C for 16 hours, the mixture was cooled to 0 ° C, the resulting precipitate was filtered, suspended in water (300 mL) and cooled to 0 ° C. The aqueous solution was acidified to pH 3 and stirred at 0 ° C to room temperature for 2 hours. The obtained precipitate was filtered, washed with water and dried under vacuum at 40 ° C. Yield: 13.3 g of MS-ESI: [M + H] + = 363.0 TLC: Rf = 0.2, phthalocyanine, DCM/MeOH = 95/5 (v/v) (g). Third butyl 5-amino-4 -(3-Aminophenyl)-2-phenyl- thiazepine 2,3-dl pyrimidine-6-decylamine DIPEA (15.3 ml), tert-butylamine (9.3 g) and TBTU (14.1 (g) added to 5-amino-4-(3-aminophenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (Example 9(f), 14_0 g After a mixture of DCM (250 ml) and DMF (50 ml) under nitrogen pressure for 3 hours at room temperature, the mixture was diluted with DCM, using saturated NaHCOoJc solution, 0.1 equivalent of aqueous HCl and saturated NaCl. The aqueous solution was washed with water and the organic layer was dried (MgSO.sub.sub.sub.sub.sub.sub. Purification: Yield: 14.7 g This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back and fill out this page)

-34- 1314861 A? B7 Ministry of Economic Affairs, Zhisheng Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (32) MS-ESI : [M + H] + = 418.4 TLC: Rf = 0.4, silicone, heptane / EtOAc = 3/2(v/v) (h). Tert-butyl 5-amino-4-(3-(2-淳7, decyl phenyl)-2-phenyl- thiazepine 2.3- Dl-pyrimidine-6-decylamine was added dropwise to the third butyl 5-amino-4-(3-aminophenyl)-2-phenyl-thiophene [2. , 3-d]pyrimidine-6-decylamine (Example 9 (g), 5.8 g) and DIPEA (12.2 mL) in DCM (50 mL). The mixture was washed with aq. EtOAc EtOAc EtOAc (EtOAc m. To give the third butyl 5-amino-4-(3-(2-bromoethylamino)-phenyl)-2-phenyl-thiazolo[2,3-d]pyrimidin-6-oxime Amine and tert-butyl 5-amino-4-(3-(2-chloroethylamino)-phenyl)-2-phenyl-thieno[2,3-d]pyrimidin-6-oxime 1:1 mixture of amines (mol/mole). Yield: 2.6 g MS-ESI: [M + H] + = 540.2, [M' + H] + = 494.2 TLC : Rr = 0.3, decyl, heptane / EtOAc = 3/2 (v/v) (1) ·: tert-butyl 5-amine, a 2-mercapto, 4-(3-( (N-B-N-(2-hydroxyethyl V-glycine' acid group)-aminophenyl thiophene #丨2.3-dl pyrimidine-6-decylamine in tert-butyl 5-amino-4 -(3-(2-bromoethylamino)-phenyl)-2-phenyl-thieno[2,3-d]pyrimidin-6-decylamine (Example 9(h), 500 mg) Add N-ethyl-2-amino-ethanol (500 mg) to a stirred solution of DCM (5 ml). (Please read the note on the back and fill out this page)

, tT line -3⁄4 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) -35-

1314861 A7 ____B7_5, invention description (33) After stirring at room temperature for 17 hours, the reaction mixture was diluted with DCM (100 ml), washed with NaHCCh aqueous solution (1 molar concentration, 2 x 50 ml), dried (MgSCn) and Concentrate under reduced pressure and the crude material was purified using EtOAc EtOAc EtOAc EtOAc EtOAc Minutes, then the title compound was lyophilized from a mixture of 1,4-difane, 0.1% aqueous TFA and water. Yield · · 271 mg (TFA-salt) MS-ESI : [Μ + Η]+=547·2 HPLC : Rt = 11.88 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, Detect UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10/80/10 to 10/10 / 80 (v/v/v), operation time = 20 minutes 〇 Example 10 Third butyl 5-amino-2-benzene (methyl ester methyl)-glycine V (please read the back) Note: Please fill out this page again. .m— Ding-Minute Line Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing amine-based)-phenyl)-thiol and C2, 3-dl pyrimidine-6-nonylamine in the third 5-Amino-4-(3-(2-bromoethylamino)-phenyl)-2-phenyl-thieno[2,3-d]pyrimidin-6-decylamine (Example 9 ( h), 500 mg) and N,N-diisopropylethylamine (DiPEA, 1 ml), a solution of methyl glycinate (700 mg) in a stirred solution of DCM (5 mL). After stirring for 17 hours, the reaction mixture was diluted with EtOAc EtOAc EtOAc (EtOAc) Concentrated paper & scale applicable to China National Standard (CNS) A4 specification (210X297 mm) '-36- • HTFI. 1314861 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing _ B7 V, invention description (34), will be coarse The product was purified by HPLC using a Luna C-18 column in the following gradient: 0.1% aqueous TFA + 10% aqueous ACN / ACN = 90/10 to 10/90 (v/v) over 30 min. A mixture of 4-di Df alkane, 0.1% aqueous TFA and water was lyophilized. Yield: 321 mg (TFA-salt) MS-ESI: [Μ + Η] + = 547·2 HPLC ·· Rt = 12.54 min, column Luna C-18(2), 3 microns, 100x2.0 mm, UV = 210 nm, oven temperature = 40 t, flow rate = 0.25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2.1 /water/ACN=10/80/10 to 10/10/80 (v/v/v), operation time = 20 minutes 实例. Example 11 Third butyl 5-amino-2-(2-furyl) -4-(3-((N-methyl-N-(2-hydroxyethyl)-glycinyl)-amine) benzophenone and f2,3-dl pyrimidine-6-decylamine (a) 2-mercaptofuran Addition of cooled (0 ° C) and saturated ethanolic HC1 (40 mL) to 2-furfur The nitrile (13 ml) was cooled (ice bath, 〇 ° C) in a reaction vessel, and the resulting solution was allowed to reach ambient temperature and stirred under nitrogen pressure for 48 hours. After the reaction mixture was concentrated in vacuo, the corresponding 2-furanyl group was obtained. The residue of ethyl imidate was again dissolved in ethanol (20 ml) and stirred under a nitrogen pressure of 〇 ° C, followed by the addition of saturated ethanolic ammonia (40 ml) and the reaction mixture was applied to the sealed reaction paper scale. China National Standard (CNS) A4 Specification (210X297 mm) ~ -37- (Please read the notes on the back and fill out this page)

1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventive Note (35) Stir in the vessel for 48 hours, filter the reaction mixture, concentrate the filtrate under reduced pressure, and use the crude compound without purification. One step. (b) . 5-Cyano-4-(3-nitrophenyl)-2-(2-furanyl)- 2-mercaptofuran (Example 11(a), 15 g), 3-nitrate A mixture of benzaldehyde (24 g), ethyl cyanoacetate (17 ml) and potassium carbonate (25 g) in anhydrous EtH (300 mL) was stirred at 60 ° C for 16 hours, and the reaction mixture was taken in an ice bath. Cooled to 0 ° C, the resulting precipitate was filtered, washed with anhydrous EtOH and heated in water (100 ° C) to give a milky suspension, the suspension was cooled to 50 ° C, by adding 2 equivalents of HC1 The aqueous solution was acidified to pH 2 and cooled to 0 ° C in an ice bath, and the obtained precipitate was filtered and washed with ice water, and water remaining in the precipitate was removed by evaporation with 1,4-dioxane. .1 6.0 g MS-ESI : [M + H]+ = 309.2 TLC: Rf = 0.3, oxime, DCM/MeOH = 9/l (ν/ν) (c) . 6-chloro-5-cyano-4 -(3-Nitrophenyl)-2-(2-furyl)-pyrimidine Add P〇Ch (50 ml) to 5-cyano-4-(3-nitrophenyl)-2-(2 -furanyl)-6-hydroxy-pyrimidine (Example 11 (b), 16.0 g) and dimethylaniline (0.5 mL) were dissolved in dry 1,4-dif-hexane (250 mL) After 2 hours at 90 ° C, the warm mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane and added to ice water, and the obtained precipitate was filtered. Wash with water and remove the residual water from the precipitate by evaporation with 1,4-dioxane. This paper scale applies to the Chinese national standard (CNS>A4 specification (210X297 mm) (please read the back note first) Fill in this page) ^1. —订 ------ Line _丨-38- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperation Du Printing wu' invention description (36) Production: 16.0 g MS-ESI : [M + H] + = 327.2 TLC ·· Rf.= 〇.75, grit, Gengyuan / EtOAc = 3/ 2 (ν/ν) (d) . B 5-cyano-4-(3 -N-phenyl)-2-(2-furyl)-6-(ethyl thiol)-pyrimidine DIPEA (9.1 ml) was added to ethyl 2-mercaptoacetate (5.4 ml) and 6- Chloro-5-cyano-4-(3-nitrophenyl)-2-(2-furyl)-pyrimidine (Example 1 1 (c), 16.0 g) in EtH (125 mL) and DCM ( 125 ml) The mixture was stirred under nitrogen pressure, and after 2 hours at room temperature, the mixture was diluted with DCM. Until complete dissolution, washed with 0.5 N aqueous HC1 concentration Qing, dried (MgSOd and concentrated under reduced pressure. Yield: 20.0 g·MS-ESI: [Μ + ΗΓ = 411.2 TLC: Rf = 0.7, decyl, heptane/EtOAc = 3/2 (v/v) (e). 5-amine- 4-(3- Nitrophenyl)-2-(2-indole)-thiazolidine 2.3-(31 thiophene·6-carboxylic acid ethyl ketone DIPEA (20.0 ml) was added to ethyl 5-cyano-4 -(3-Nitrophenyl)-2-(2-furyl)-6-(ethyl estermethylthio)-pyrimidine (Example 11(d), 20 g) in anhydrous EtOH (100 mL) and toluene (100 ml) of the stirred solution in the mixture, after 48 hours at 100 ° C, the mixture was cooled to 〇 ° C, and the resulting precipitate was filtered, washed with cold EtOH and dried under vacuum at 40 ° C. 20 grams (please read the notes on the back and fill out this page) t.-----^---Ί--订-------

•I This paper scale applies to the national standard (CNS) Α4 specification (210X297 mm) -39 - 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (37) MS-ESI : [Μ + Η] + = 411·2 TLC: Rf = 〇.6, 矽, heptane/Et〇Ac = 3/2(v/v) (f) . 5-amine -4-(3-aminobenzene -2-(2-furyl)-thiazide #"2.3-dl^^-6-carboxylic acid ethyl ester added tin (II) chloride (28.0 g) in anhydrous EtOH (250 ml) 5-Amino-4-(3-nitrophenyl)-2-(2-furyl)-thieno[2,3-pyrimidine-6-carboxylic acid ethyl ester (Example 11(e), 20 a solution of 1,4-dioxane (250 ml), a 37% aqueous HCl solution (8.5 ml) was added and the mixture was heated at reflux (90 ° C) for 16 hours, and the mixture was allowed to cool to room temperature and The organic layer was separated and dried (MgSO. Concentration under reduced pressure. Yield: 17.5 g MS-ESI: [M + H] + = 381.2 TLC: Rf = 0.4, silicone Heptane/Et〇Ac = 3/2(v/v) (g) . 5-Amino-4-(3-aminophenyl)-2-(2-furylthio) and 2.3-dl pyrimidine -6-carboxylic acid added potassium hydroxide (23.0 g) to 5-amino-4-(3-aminophenyl)-2-(2-furyl)-thiene [2,3-d] A solution of pyrimidine-6-carboxylate ethyl ester (Example 11 (f), '17.5 g) in a mixture of 1,4-dicrolimin (210 mL) and water (80 mL) after 8 hours at 90 ° C , the mixture is cooled to 〇 ° C, the resulting precipitate is filtered, suspended in water (300 ml) and cooled to 0 ° C, by adding 2 (please read the back of the note before you fill out this page) Paper scale applicable to China National Standard (CNS) A4 specification (210'〆297 mm) -40- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (38) The concentration of citric acid aqueous solution acidified the mixture The mixture was filtered to pH 3 and stirred at rt to room temperature for 2 hrs, filtered, washed with water and dried at 4 vac.. yield: 16.9 g MS-ESI: [M + H] 4 = 3 5 3.2 TLC : Rf=0.2, silicone, DCM/MeOH = 95/5 (v/v) (h) tert-butyl 5 - 4-(3-Aminophenyl)-2-(2-indolyl)-thieno[2,3-dl-pyrimidin-6-decylamine DIPEA (19.2 ml), tert-butylamine ( 11.6 ml) and TBTU (17.7 g) were added to 5-amino-4-(3-aminophenyl)-2-(2-furyl)-thieno[2,3-d]pyrimidine-6- A solution of the ammonium acid (Example 11 (g), 16.9 g) in a mixture of DCM (250 mL) and DMF (50 mL) under nitrogen pressure, after 3 hours at room temperature, formed a large yellow precipitate which was filtered. The residue was washed with diethyl ether and dried under vacuum at 40 °C. Yield: 18.0 g MS-ESI: [M + H] + = 408.2 TLC: Rf = 0.4, decyl, heptane/EtOAc = 3/2 (v/v) (i). 4-(3-(2-bromoacetamido)-phenyl)-2-(2-furylthioindole 2,3-dl-pyrimidine-6-decylamine bromoacetic acid chloride (100 ml) Add dropwise to the third butyl 5-amino-4-(3-aminophenyl)-2-(2-furyl)-thieno[2,3-d]pyrimidin-6-decylamine ( Example 11 (h), 250 mg) and DIPEA (0.5 ml) in DCM (5 ml) This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill in the form) This page) : Booking line ^--------Ί -41 - 1314861 A7 — B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (39), after 3 hours at room temperature, will The mixture was diluted with EtOAc (EtOAc) EtOAc (EtOAc m.jjjjjjjj Purification by analytical method to give the third butyl 5-amino-4-(3-(2-bromoethylamino)-phenyl)-2-(2-furyl)- thiazolidine [2,3- d] pyrimidine-6-decylamine and tert-butyl 5-amino-4-(3-(2-chloroethylamino)-phenyl)-2-(2-furyl)-thiol[ a 1:1 mixture of 2,3-(1)pyrimidin-6-decylamine (mol/mole). Yield: 124 mg MS-ESI: [Μ + ΗΓ = 540.2, [Μ, + Η] + = 494 · 2 TLC: Rf = 0.3, decyl, heptane / EtOAc = 3/2 (v / v) (j). tert-butyl 5-amino-2-(2-furan)-4-(3- ((N-ethyl-N-(2-hydroxyethyl)-glycine)-amino)-phenyl)-thiazide I 2,3-dl pyrimidine-6-decylamine in the third 5-Amino-4-(3-(2-bromoacetamido)-phenyl)-2-(2-furyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example ll (i), 130 mg) EtOAc (EtOAc) (50 ml) was diluted, washed with aq. EtOAc (EtOAc (EtOAc) 〇.i%TFA aqueous solution +10% ACN aqueous solution / ACN = 90/10 to 10/90 (v/v) in 30 minutes, then make the title 1,4-dioxane from the compound of the palate, and the mixture 〇.l% TFA water solution and freeze-dried. Yield: 81 mg (TFA-salt) (Please read the notes on the back and fill out this page) Φ! * I ^ flin ^nt J^l In-, v9 potential

•I This paper scale applies to China National Standard (CNS) A4 specification (2!〇><297 mm) -42- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1131861 A7 _____B7_ _ V. Invention Description (4 〇) MS-ESI ·· [M + H] + = 523.2 HPLC : Rt = 11.01 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, UV detection = 210 nm, oven temperature =40 ° C, flow rate

= 〇·25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2·1/water/ACN=10/80/10 to 10/10/80 (v/v/v), operation time =20 minutes 〇Example 12 簠diyl 5-amino-2-(2-furan)-4-hydroxy-2-methyl-propan-2-ylglycine)-amino)-benzene - thiazolidine "2,3-dl pyrimidine-6-decylamine in tert-butyl 5-amino-4-(3-(2-bromoacetamido)-phenyl)-2-(2) -furanyl)-thilyl-[2,3-d]pyrimidin-6-nonylamine (Example ll(i), 130 mg) in a stirred solution of DCM (5 mL) After the mixture was stirred at room temperature for 17 hours, the reaction mixture was diluted with DCM (50 ml), rinsed with NaHCO^Jc solution (1 molar, 2 x 10 ml), dried (MgSO. Concentrated under reduced pressure, the crude material was purified by HPLC using a Luna C-18 column: 0.1% TFA aqueous solution + 10% ACN aqueous solution / ACN = 90/10 to 10/90 (v/v) in 30 minutes. The title compound was then lyophilized from a mixture of 1,4-di Dfane, EtOAc, <RTI ID=0.0> =11.15 points , Column Luna C-18 (2), 3 microns, this paper scale applicable Chinese National Standard (CNS > Α4 specifications (210Χ297 mm) (Please read the back of the precautions to fill out this page)

-43 - Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1314861 A7 B7 V. Inventions (41)

100x2.0 mm, detection UV = 210 nm, oven temperature = 4 (TC, flow rate two 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10 / 80 / 10 to 10/10/80 (v/v/v), operation time = 20 minutes 〇 Example 13 Third butyl 5-amino- 2-(2-furan)-4-(3-(N-( Methyl ester-methyl-glycine amine A V-phenyl)-thiol and 2,3-dl-pyrimidine-6-decylamine in tert-butyl 5-amino-4-(3-(2-bromo) Acetylamino)-phenyl)-2-(2-furyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example ll(i), 130 mg) and DiPEA (0.5 ml) Add a solution of methyl glycyrate hydrochloride (324 mg) to a stirred solution of DCM (5 mL). After stirring at room temperature for 17 hours, the mixture was diluted with DCM (50 mL). The ear concentration, 2 x 10 ml) was washed, dried (MgSO4 and concentrated under reduced pressure, and crude material was purified by HPLC using Luna C-18 column: 0.1% TFA aqueous solution + 10% ACN aqueous solution / ACN = 90 / 10 to 10/90 (v/v) at 30 minutes, then freeze-dried the title compound from a mixture of 1,4-di Dfane, 〇.l% TFA in water and water Yield: 74 mg (TFA-salt) MS-ESI: [M + H] + = 537.2

HPLC : Rt = 12.09 min, column Luna C-18 (2), .3 micron, 100 x 2.0 mm, UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash Liquid phosphate buffer 50 millimolar pH This paper scale applies to China National Standard (CNS) A4 specification (210 ><29"7 mm) (Please read the note on the back and fill out this page)

-44- 1314861 A7 B7 V. INSTRUCTIONS (42) 2.1/Water/ACN=10/80/10 to 10/10/80 (v/v/v), operation time=20 minutes 〇Example 14 Third T 5-amino-2-(2-thienyl)-4-(3-((N-methyl-N-(2-hydroxyethyl)-glycine), an amine, a phenyl V, and f2 .3-dl pyrimidine-6-decylamine (a). 5-Cyano-4-(3-nitrophenyl)-2-(2-thienyl)-6-hydroxy-pyrimidine thiol thiophene salt A mixture of the acid salt (10.0 g), 3-nitrobenzaldehyde (9.7 g), ethyl cyanoacetate (6.81 ml) and potassium carbonate (10.1 g) in anhydrous EtOH (200 ml) was stirred at 60 ° C for 8 hours. , the reaction mixture was cooled to 0 ° C in an ice bath, filtered, washed with anhydrous EtOH and heated in water (100 ° C) to obtain a clear solution, the solution was cooled to 50 ° C, by adding 2 equivalents The aqueous solution of HC1 was acidified to pH 2 and cooled to 0 ° C in an ice bath, and the obtained precipitate was filtered and washed with ice water, and water remaining in the precipitate was removed by evaporation with 1,4-dioxane. : 10.0 g MS-ESI : [M + H] + = 325.0 TLC: Rf = 0.3, oxime, DCM/MeOH = 9/l (v/v) (b). (S-氡-5-Cyan-4 -(3-nitrate a phenyl)-2-(2-thia-V-pyridine) is added to P0C13 (30 ml) to 5-cyano-4-(3-nitrophenyl)-2-(2-thienyl)- 6-Hydroxy-pyrimidine (Example 14 (a), 10.0 g) and dimethylaniline (several papers are again applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill in the form) This page) Customs Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed -45 - 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau 8 workers consumption cooperatives printed five, invention description (43) drops) in anhydrous 1,4-dioxane ( 150 ml) of the stirred solution, after 3 hours at 90 ° C, the mixture was cooled to room temperature and concentrated under reduced pressure, the residue was dissolved in 1,4-dioxane, and ice water was carefully added. The precipitate was filtered and washed with water, and the water remaining in the precipitate was removed by evaporation with 1,4-dioxane and dried under vacuum at 40 ° C. Yield: 9.8 g MS-ESI: [Μ + Η] + = 343·4 TLC: Rf = 0_8, decyl, heptane / EtOAc = 3/2 (v/v) (c). ethyl 5-cyano- 4-(3-nitrophenyl)-2-( 2-thiam)-6-(ethyl ester a methylthio group)-mouth dense π will be DI PEA (5.57 ml) was added to ethyl 2-mercaptoacetate (3.28 ml) and 6-chloro-5-cyano-4-(3-nitrophenyl)-2-(2-thienyl)-pyrimidine ( Example 14(b), 9.8 g) A mixture of EtOH (80 mL) and DCM (EtOAc) (EtOAc) The aqueous HCl solution was washed with EtOAc (EtOAc) Yield: 12.9 g of MS-ESI: [M + H] + = 427.2 > TLC: Rf = 0.7, decyl, heptane / EtOAc = 3/2 (v/v) (d). 5-amino-4- (3-nitrogen benzene)-2-(2-thiazepine thiophene and f2.3-dl pyrimidine-6-carboxylic acid ethyl ester DIPEA (13.0 ml) was added to ethyl 5-cyano-4 -(3-Nitrophenyl paper size applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back and fill out this page)

-46- 1314861 Λ7 Β7 V. Description of invention (44) (Please read the notes on the back and fill out this page)) -2-(2-Thienyl)-6-(ethyl ester methylthio)-pyrimidine (Example 14(c), 12·9 g) A stirred solution of a mixture of anhydrous EtOH (75 mL) and toluene (75 mL), after a period of 48 hours at 100 ° C, the mixture was cooled to 0 ° C. The precipitate was filtered, washed with cold EtOH and dried under vacuum at 40 °C. Yield: 11.0 g MS-ESI: [M + H] + = 427.2 TLC: Rf = 0.6, decyl, heptane/EtOAc = 3/2 (v/v) (e). 5-amine -4-(3) -aminophenyl)-2-(2-thienyl)-thio-"2,3-dl-pyrimidine-6-carboxylic acid ethyl ester Ministry of Economic Affairs Zhici Property Bureau employee consumption cooperative printing will be in Et〇H Tin (II) chloride (15 g) in (150 ml) was added to 5-amino-4-(3-nitrophenyl)-2-(2-thienyl)-thiol [2, A solution of 3-d]pyrimidine-6-carboxylate (Example 14(d), 10.86 g) in 1,4-dioxane (150 mL). The mixture was heated at reflux for 16 h, then the mixture was cooled to EtOAc EtOAc EtOAc. 11. The mixture was diluted with aq. EtOAc (EtOAc) (EtOAc m. , oxime, heptane / EtOAc = 3/2 (Wv) (1) · iJS-yl-4-(3-amine phenyl)-2-(2-thiol thiophene and f2 .3-dl_ η Macro - This paper size is applicable, National Standard (CNS) Α4 Specification (210Χ: 297 mm) -47- 1314861 A7 B7 V. Description of Invention (45) 6 - Carboxylic Acid (Please read the back first) Precautions by refilling this page) Add potassium hydroxide (13 g) to 5-amino-4-(3-aminophenyl)-2-(2-'thenyl)-thiol [2 , 3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 14(e), 10.1 g) in a mixture of 1,4-dioxane (150 ml) and water (50 ml), at 90 ° C After 16 hours, the mixture was cooled to 〇 ° C, the resulting precipitate was filtered, suspended in water (1 80 mL) and cooled to a mixture, acidified to pH 3 at 0 ° After stirring to room temperature for 2 hours, the obtained precipitate was filtered, washed with water and dried under vacuum over 40 s. Yield · ' 6.3 g MS-ESI · · [M + H] + = 369.2 TLC: Rf = 0.2, silicone , DCM/MeOH = 95/5 (v/v) (g). Tert-butyl 5-amine a 4-(3-aminophenyl)-2-(2-thienyl)-thiol [2.3-dl-pyrimidine-6-醯 pickled Ministry of Economy, Intellectual Property Bureau, employee consumption cooperative, printing will be 01? £8 (7.1 毫), tert-butylamine (4.3 ml) and butyl 31^ (6.6 g) were added to 5-amino-4-(3-aminophenyl)-2-(2-thienyl)-thiol a mixture of [2,3-d]pyrimidine-6-carboxylic acid (Example 14(f), 6.3 g) in DCM (125 mL) and DMF (purum, dimethyl-dimethylformamide) (25 mL) After the reaction at room temperature for 3 hours, the mixture was diluted with DCM, washed with a saturated aqueous solution of NaHCCh, a 0.1 liter aqueous solution of HCl and a saturated aqueous solution of NaCl, and the organic layer was dried (MgS 〇 4) and reduced. Concentration was carried out and the crude product was purified by chromatography using EtOAc EtOAc EtOAc (EtOAc) This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -48- 1314861 A7 B7 V. Description of invention (46) Yield: 6.45 g MS-ESI : [M + H]+ = 424.4 (Read first Note on the back side of this page) D: LC: Rf = 0.3, silicone, heptane / Et 〇 Ac = 3 / 2 (v / v) (h). Third butyl 5-amine -4- (3 -(2-bromoacetamide, a phenyl thiophene and 2,3-dl pyrimidine-6-decylamine, ethyl bromide chloride (2.40 ml) was added dropwise to the tert-butyl 5-amino-4 -(3-Aminophenyl)-2-(2-Thienyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example 14(g), 5.0 g) and DIPEA (10_5 </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Purification by chromatography using heptane / EtOAc = 3 / 2 (v / v) as a stream elute to give the &lt;RTI ID=0.0&gt; Phenyl)- 2-(2-thienyl)-thieno[2,3-(1]pyrimidin-6-decylamine and tert-butyl 5-amino-4-(3-(2-chloro) Acetylamino)-phenyl)-2-(2-thienyl)- Um and [2,3-d] mouth 'steep-6-decylamine mixture. Yield: 3.0 g Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed MS-ESI: [Μ + ΗΓ = 546.2, [M, + H ] + = 500.2 TLC : Rf = 0.2, grit, toluene / EtOAc = 7 / l (ν / ν) (i). Third butyl ' 5-amino-2-(2-thiol)-4 -(3 - "N-By-anthracene-ylethyl"-glycosylamino)-phenyl)-thioindole 2.3-dl-pyrimidine-indole-indole in tert-butyl 5-amine 4-(3-(2-bromoacetamido)-phenyl)_2_(2 sulphonyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example 14(h) , 1〇〇mg) Applicable to Chinese National Standard (CNS) A4 Specification (210X297 mm) at the paper scale 1~~~ '-- -49- 1314861 A7 B7 V. Invention Description (47) (Please read the back Precautions. Fill in the following steps) Add N-ethyl-2-aminoethanol (140 mg) to a stirred solution of DCM (5 mL). After stirring at room temperature for 17 hr, the mixture was diluted with DCM (50 mL) Wash with NaHCCh aqueous solution (1 molar concentration, 2×10 mL), dry (MgSO.sub. Purification by HPLC: 0.1% aqueous solution of TFA + 10% aqueous solution of ACN / ACN = 90/10 to 10/90 (Wv) at 30 min, then the title compound from 1,4-dioxane, 0.1% aqueous TFA and water The mixture is freeze dried. Yield: 59 mg (TFA-salt) MS-ESI ·· [M + H]+ = 539.2 HPLC: Rt = l 1.01 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, detection UV = 210 nm, furnace temperature = 40 ° C, flow rate

= 0.25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2.1/water/ACN=10/80/10 to 10/10/80 (v/v/v), operating time = 20 minutes〇 Example 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed third Ding certain 5-amine-2-(2-thiam)-4-nf (N-(methyl ester-methyl-glycinate)-amine Benzoyl thiophene and 2,3-dl pyrimidine-6-decylamine in tert-butyl 5-amino-4-(3-(2-bromoethylamino)-phenyl)-2-( 2-thiazolidine--thiazolo[2,3-d]pyrimidin-6-nonylamine (Example 14(h), 100 mg) and DiPEA (0.5 mL) in DCM (5 mL) Add methyl glycinate hydrochloride (250 mg) and stir at room temperature for 17 hours. The standard size of the reaction paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -50-1314861 at B7. The title compound (48) was diluted with DCM (50 ml), washed with NaHC.sub.2 (aq. Purified by HPLC in the following gradient: 1.1% TFA in water + 10% ACN in water/ACN = 90/10 to 10/9 0 (v/v) at 3 Torr, then the title compound was lyophilized from a mixture of 1,4-dioxane, 1% TFA aqueous solution, liquid and water. Yield: 74 mg (TFA-salt) MS- ESI : [Μ + ΗΓ = 553.0 HPLC : Rt = 12.57 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, UV = 210 nm, oven temperature = 40 ° C, flow rate

= 0.25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2.1/water/ACN=10/80/10 to 10/10/80 (v/v/v), operating time = 20 minutes〇 Example 16 Third butyl 5-amino-2-(2-thiol)-4-(3-((N,N-di-(2-methyl)7,even)-glycosylamine And phenyl thiophene and 2,3-dl pyrimidine-6-decylamine in tert-butyl 5-amino-4-(3-(2-bromoacetamido)-phenyl)-2 -(2-Thienyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example 14(h), 100 mg) was added to a stirred solution of DCM (5 mL). Di-(2-methoxyethyl)-amine (200 mg), after stirring at rt for EtOAc (3 mL), EtOAc (EtOAc m. Wash, dry (MgSCh) and concentrate under reduced pressure, use the Luna paper size for the Chinese National Standard (CNS) A4 specification (21 OX297 mm) (please read the back note and fill out this page) Ministry of Economy, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Cooperatives, Printed -51 - 1314861 A7 _ B7 V. Description of Invention (49) C-1 8 column is purely HPLC-based : 0.1% aqueous solution of TFA + 10% aqueous solution of ACN / ACN = 90/10 to 10/90 (v/v) at 30 minutes, then the title compound was taken from 1,4-dioxane, 〇.1% TFA aqueous solution and The mixture of water was freeze-dried. Yield · · 59 mg (TFA-salt) MS-ESI : [M + H] + = 597.4 HPLC: Rt = 13.84 min, column Luna C-18 (2), 3 micron, 100x2. 0 mm, detection UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 5 〇 millimolar pH 2.1 / water / ACN = 10 / 80/10 To 10/10/80 (v/v/v), operation time = 20 minutes 〇 Example 17 Third butyl 5-amino-2-ethylamino-4-(3-((N-yl-N) -(2-methyl-ethyl)-glycosyl)-amino)-phenyl)-thioindole 2,3-dlD-pyridine-6-nonylamine (please read the precautions on the back) Fill in this page) Printed by the Ministry of Commerce, Intellectual Property Bureau, Consumer Cooperatives (a). Third butyl 5-amino-2-methylsulfinyl- 4- (3-(7N-B-N-( 2-methoxyethyl)-glycine group)-amine oxime thiophene and "2.Vdl cumene-6-oxime in tert-butyl 5-amino-2-methylthio- 4-(3-((N-ethyl-N-(2-methoxy) Benzyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example 4, 1.0 g) in trifluoroacetic acid (TFA, 25 Add 3-chloroperbenzoic acid (m-CPBA, 1.0 g) to the stirred solution of ML). After 17 hours, the standard size of the reaction paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -52- 1314861 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing _ B7 5, invention description (50) The compound is concentrated under reduced pressure at ambient temperature (20 °C), dissolved again in DCM (100 ml), carefully saturated The aqueous NaHCCh solution (2 x 50 mL) and water (50 mL) was evaporated and evaporated. Yield: 820 mg MS-ESI: [M + H] + = 547.3 TLC: Rf = 0.2, oxime, DCM/MeOH = 9/l (ν/ν) (b). butyl 5-amine 2- -ethylamino-4-(3-((Ν-乙某-Ν-(2-methyl aryl) glycine aminophenyl phenyl hydrazino 2,3-dl pyrimidine-6-fluorene Amine Addition of ethylamine hydrochloride (150 mg) to tert-butyl 5-amino-2-methylsulfinyl-4-(3-((N-ethyl-N-(2-methoxy)) Ethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example 17(a), 100 mg) and DiPEA (0.5 mL) The reaction mixture was heated at 60 ° C for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM (50 ml) (1 molar concentration, 25 ml) and water (25 ml) were rinsed, then the organic layer was dried (MgSO.sub.2) and concentrated in vacuo, and the residue thus obtained was applied to the following gradients by HPLC using a Luna C-1 8 column. Purification: 0.1% aqueous TFA + 10% aqueous ACN / ACN = 90/10 to 10/90 (v/v) at 30 min, then the title compound from 1,4-dipropane, 0.1% aqueous TFA and water The mixture was lyophilized. Yield: 36 mg (TFA-salt) MS-ESI: [M + H] + = 528.4 HPLC: R. = 10.21 min, column Luna C-18(2), 3 micron, paper The scale applies to China National Standard (CNS) A4 specification (2]0χ297 mm) (Please read the note on the back and fill out this page) Zero| Order 3⁄4 -53- 1314861 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print A7 £ 7_5, invention description (51) 100x2.0 mm, detection UV = 210 nm, furnace temperature = 40 °C, flow rate = 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 /water/ACN=10/80/10 to 10/10/80 (v/v/v), operation time = 20 minutes 〇Example 18 Third butyl 5-amino- 2-(N,N-dimethyl A certain amine-N-(2-hydroxyethylglycinylamino)-phenyl V thiophene and 2,3-dl pyrimidine-6-decylamine (a). Second butyl 5-amine Benzyl-2-methylsulfinyl-4-(3-((N-methyl-N-(2-hydroxyethyl))-aminobenzene)-thi-indole 2.3-dl pyrimidine -6-decalamine in tert-butyl 5-amino-2-methylthio-4-(3-((N-methyl-N-(2-hydroxyethyl)-glycinyl)-amine Base)-phenyl)-thiene[2,3- d] Pyrimidine-6-decylamine (Example l(i), 1.0 g). In a stirred solution of trifluoroacetic acid (TFA, 25 mL), 3-chloroperbenzoic acid (m-CPBA, 1.0 g). After </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; It was dried (MgSO.sub. Yield: 910 mg MS-ESI : [M + H] + = 519.6 TLC: Rf = 0.15, decyl, DCM/MeOH = 9/l (Wv) (Please read the note on the back and fill out this page)

This paper scale applies to the national standard (CNS) A4 specification (210X297 mm) -54- 1314861 A7 B7 V. Description of invention (52) (b). Second Ding 5-amine- 2-(N, N-dimethylamine)-4-(3-((N-methyl-N-_(2-hydroxy-7, a certain glycine)-amino)-phenyl)-thiol and i2, 3-dl-pyrimidine-6-nonylamine Addition of dimethylamine hydrochloride (150 mg) to tert-butyl 5-amino-2-methylsulfinyl-4-(3-((N-methyl) -N-(2-hydroxyethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example 18(a), 100 mg And diPEA (0.5 ml) in a stirred solution of 1,4-dioxane (5 ml) and the reaction mixture was heated at 60 ° C for 3 hours, and the residue was dissolved in vacuo. DCM (50 ml) was washed with brine (1 mL, 25 mL) and water (25 mL) and then organic layer dried (MgSCU) and concentrated in vacuo. The residue thus obtained was used Luna C-1 8 The column was purified by HPLC on the following gradient: 0.1% aqueous TFA + 10% aqueous ACN / ACN = 90/10 to 10/90 (v/v) over 30 min. Freeze-dried from a mixture of 1,4-dioxane, 0.1% aqueous TFA and water. Yield: 36 mg (TFA-salt) MS-ESI: [M + H] 4 = 500.2 HPLC : Rt = 10.03 min, column Luna C-18(2), 3 microns, 100x2.0 mm, UV detection = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 50. Concentration pIi 2.1/water/ACN=10/80/10 to 10/10/80 (v/v/v), operation time=20 minutes 〇Example 1 9 This paper scale applies to China National Standard (CNS>A4 specification (210x297) () Please read the notes on the back and fill out this page. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperatives -55- 1314861 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed A7 B7 V. Inventions (53)棊__5-amine_yl·2·ethylamino- 4_(3-((N-(A beer, a certain glycine acid & 丄-amine phenyl)- thia and f2.3-dl Pyrimidine-ft-fermentation ___t-butyl 5-amino-2-methylsulfinyl- 4-(3-((Ν-(methyl 甲甲)-何一胺酸))- Amino)-phenyl thiazolidine and T2,3-dl[^-t--6-decylamine in tert-butyl 5-amino-2-methylthio-4-(3-((N-(methyl ester) Methyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyramid-6-decylamine (Example 3, 1.0 g) in trifluoroacetic acid (TFA, 3 ml of chloroperbenzoic acid (m-CPBA, 1_0 g) was added to the stirred solution of 25 ml). After 17 hours, the reaction mixture was concentrated under reduced pressure at ambient temperature (20 ° C) and dissolved again in DCM. (100 ml), carefully washed with aq. EtOAc (EtOAc) (EtOAc) Yield: 680 mg MS-ESI: [Μ + Η] + = 533·6 TLC: Rf = 0.17, oxime, DCM/MeOH = 9/l (v/v) (b). tert-butyl 5-amino group -2-B-Amino-4-(3-((N-(methyl-methylglycine))-amine)-Benzene)-Thien and 2,3-dl-pyrimidine-6- Indoleamine added ethylamine hydrochloride (150 mg) to tert-butyl 5-amino-2-methylsulfinyl-4-(3-((N-(methyl)methyl)-glycolamine) Acid-)-amino)-phenyl)-thieno[2,3-&lt;1]pyrimidin-6-decylamine (Example 19(3), 100 mg) and 1^?£8 (0.5 ml) In a stirred solution of 1,4-dipropane (5 ml) and heating the reaction mixture at 60 ° C for 3 hours, after concentrating the reaction mixture under reduced pressure, the residual paper size is applied to the Chinese National Standard (CNS). A4 size (2丨0'乂297 mm) (Please read the notes on the back and fill out this page)

-56 - 1314861 A7 B7 V. Inventive Note (54) Dissolve in DCM (50 ml) and rinse with brine (1 molar, 25 mL) and water (25 mL), then dry the organic layer (MgSO. Concentrated in vacuo, the residue thus obtained was purified by HPLC using a Luna C-1 8 column in the following gradient: 0.1% aqueous TFA + 10% aqueous ACN / ACN = 90/10 to 10/90 (v/v) at 30 The title compound was then lyophilized from a mixture of 1,4-dipropane, 0.1% aqueous TFA and water. Yield: 57 mg (TFA-salt) MS-ESI: [M + H] + = 514.2 HPLC : Rt =12.56 minutes, column Luna C-18(2), 3 microns, 100x2.0 mm, UV detection = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer Liquid 50 mM concentration pH 2.1/water/ACN=10/80/10 to 10/10/80 (v/v/v), operating time = 20 minutes 〇 Example 20 Third working group 5-amino group i Alanine-4-(3-((N-ethyl-N-(2-methoxy B) (please read the back note first and then fill out this page) .1· Customize the Ministry of Economic Affairs Intellectual Property Office staff consumption Co-operative printing base) - glycine acid) - amine )-Phenyl)-Thienthene 2.3-dl Pyrimidine-6-decylamine Addition of isopropylamine (150 mg) to tert-butyl 5-amino-2-methylsulfinyl-4-(3- ((N-ethyl-N-(2-methoxyethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]caridine-6-nonylamine (Example 17 (a), 100 mg) and DiPEA (0.5 ml) in a stirred solution of 1,4-di- D-hexane (5 ml) and the reaction mixture was heated at 60 ° C for 3 hr. After the mixture is concentrated, the residue is dissolved in DCM (50 ml) and brine (1 molar concentration, 25 ml paper size applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) -57- 1314861 at B7 V. Invention (55)) and water (25 ml) were rinsed, then the organic layer was dried (MgSCh) and concentrated in vacuo, and the residue thus obtained was purified by HPLC using a Luna C-1 8 column: 0.1% Aqueous TFA + 10% aqueous solution of ACN / ACN = 90/10 to 10/90 (v/v) over 30 min then the title compound was lyophilized from a mixture of 1,4-dioxane, 0.1% aqueous TFA and water. Yield: 57 mg (TFA-salt) MS-ES I : [M + H] + = 542.4 HPLC : Rt = 11.01 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, UV = 210 nm, oven temperature = 40 ° C, Flow rate = 0.25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2.1/water/ACN=10/80/10 to 10/10/80 (v/v/v), operating time = 20 minutes Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printing Example 21 箆三丁, 5-Amine-2-enylamine, a 4-(3-((N-(methyl-methyl)-glycine) Thiophene and "2,3-dl pyrimidine-6-decylamine to add allylamine (200 mg) to tert-butyl 5-amino-2-methylsulfinyl-4-(3-((N) -(carbomethoxymethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example 19(a), 100 mg) and DiPEA (0.5 ml) in a stirred solution of 1,4-di- D-hexane (5 ml) and the reaction mixture was heated at 60 ° C for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM ( 50 ml) and rinsed with brine (1 molar concentration, 25 ml) and water (25 ml), then the organic layer was dried (MgSOd and concentrated in vacuo) With China National Standard (CNS) A4 size (210X297 mm) (Please read the notes and then fill in the back of this page)

-58- 1314861 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, W-Consumer Cooperative, Printed V. Inventive Note (56), the residue thus obtained was purified by HPLC using Luna C-1 8 column in the following gradient·· 0_1% TFA Aqueous solution + 10% aqueous solution of ACN / ACN = 90/10 to 10/90 (v/v) over 30 min, then the title compound was lyophilized from a mixture of ι, 4-dioxane, 0.1% aqueous TFA and water. Yield: 65 mg (TFA-salt) MS-ESI: [M + H] + = 526.4 HPLC: Rt = 13.18 min, column Luna C-18 (2), 3 micron, 100 x 2.0 mm, UV detection = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10/80/10 to 10/10/80 (v /v/v), operation time = 20 minutes 〇 Example 22 tert-butyl 5-amino-2-methoxy-4-(3-((N-ethyl)-N-(2-methoxy) Ethyl)-glycine-based V-amino group V-phenyl V-thiophene and 2,3-dl-pyridyl-6-decylamine added potassium butoxide (100 mg) to the third butyl 5-amine Benzyl-2-methylsulfinyl- 4-(3-((N-ethyl-N-(2-methoxyethyl)-glycosyl)-amino)-phenyl)-thio And [2,3-d]pyrimidin-6-decylamine (Example I7(a),: 200 mg) in a stirred solution of methanol (5 ml) and the reaction mixture was heated at 50 ° C for 3 h, After the reaction mixture was concentrated, the residue was crystallised eluted eluted eluted eluted eluted eluted eluted ) wash, then will The organic layer is dried (MgSOd and concentrated in vacuo, and the residue thus obtained is applied to the paper. The Chinese National Standard (CNS) A4 specification (210×297 mm) 1-59- (Please read the back note first and then fill out this page) ) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1314861 A7 ____B7 V. Invention description (57)

The Luna C-18 column was purified by HPLC on the following gradient: 0.1% aqueous TFA + 10% aqueous ACN / ACN = 90/10 to 10/90 (v/v) over 30 min. A mixture of di Df alkane, hydrazine 1% aqueous TFA solution and water was lyophilized. Yield: 92 mg (TFA-salt) MS-ESI: [M + H] + = 515.4 HPLC: R, = 12.21 min, column Luna C-18 (2), 3 micron, 100 x 2.0 mm, UV detection = 210 nm, oven temperature = 40 °C, flow rate = 0.25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10/80/10 to 10 Π 0/80 (Wv/ v), operation time = 20 minutes Example 23 Third butyl 5-amino-2-allyloxy dn-UN-Z-N-(2-methoxyethyl glucosyl)-amino group )-Benzene)-thiene and "2,3-dl-ranyl-pyridyl-6-decylamine added potassium t-butoxide (100 mg) to tert-butyl 5-amino-2-methylsulfinium 4-(3-((ethylidene-1^-(2-methoxyethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d] Pyrimidine-6-decylamine (Example 17(a), 200 mg), mp. The residue was dissolved in DCM (50 mL) EtOAc (EtOAc) Layer was dried (MgSOd and concentrated in vacuo, the residue thus obtained was applied using the paper scale Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the notes and then fill in the back of this page)

-60- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5, Invention Description (58) Luna C-18 column was purified by HPLC in the following gradient: 0.1% aqueous TFA + 10% ACN aqueous solution / ACN = 90/ 10 to 10/90 (v/v) at 30 minutes, then the title compound was lyophilized from a mixture of 1,4-difane, 〇.1% aqueous TFA and water. Yield: 63 mg (TFA-salt) MS-ESI: [Μ + Η] + = 541·4 HPLC: Rt = 12.71 min, column Luna C-18 (2), 3 μm, 100 x 2.0 mm, detection UV = 210 nm, oven temperature = 40 °C, flow rate = 0.25 ml/min, flow wash phosphate buffer 50 mM concentration pH 2_1 / water / ACN = 10/80/10 to 10/10/80 (v/v/v), operation time = 20 minutes 〇 Example 24. Third butyl 5-amino-2-isopropoxy-4-(3-((N-ethyl-N-(2-) Methoxy(meth)-glycosylamino)-phenyl)- thiazepine 2,3-dl-pyrimidine-6-decylamine potassium butoxide (100 mg) added to the t-butyl group 5-amino-2-methylsulfinyl-4·(3-((Ν-ethyl-N-(2-methoxyethyl)-glycinyl))))) - Thio[2,3-d]pyrimidin-6-decylamine (Example 17(a), 200 mg) in a stirred solution of isopropanol (5 mL) and the reaction mixture was heated at 5 (TC for 3 hours) After concentrating the reaction mixture under reduced pressure, EtOAc m. (25 ml) wash Then, the organic layer was dried (MgSOd and concentrated in vacuo, and the residue thus obtained was used (please read the back note first and then fill out this page)

This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -61 - 1314861 A7 _____B7 V. Invention description (59) &quot; ^

Luna C-18. Column was purified by HPLC on the following gradient: 0.1% aqueous TFA + 10% aqueous ACN / ACN = 90/10 to 10/90 (v/v) at 30 min then the title compound was taken from 1,4 - Two crocodile, 〇. 1% τ FA aqueous solution and water mixture freeze-dried. Yield: 32 mg (TFA-salt) MS-ESI: [M + H] + = 543.4

HPLC: Rt = 12.93 min, column Luna C-18 (2), 3 micron, 100 x 2.0 mm, UV = 210 nm, oven temperature = 4 Torr. (:, flow rate = 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10 / 80/10 to 10/10 / 80 (v / v / v), operating time =20 minutes 〇Example 25 Third butyl 5-amino- 2-(4-3⁄4) -4-(3-((Ν-(Ί-)-yl-2-yl)-glycine ))-amino)-phenyl)-thio-"2.3 - dl-pyrimidine H p-amine (a). 5-cyano-4-(3-nitrophenyl)-2-(4-acridine 4-) Xiang-pyrimidine 4-mercapto-3⁄4 pyridine hydrochloride (16.5 g), 3-nitrobenzaldehyde (15.1 g), cyanoacetic acid ethyl acetate (11.2 ml) and cesium carbonate (16.6) The mixture was stirred at 60 ° C for 16 hours. The reaction mixture was cooled to 0 ° C in an ice bath. The obtained precipitate was filtered, washed with anhydrous EtOH and water (100 °) C) heated to obtain a sputum solution, the solution is cooled to 50 ° C, acidified to pH 2 by adding 2 equivalents of HCI aqueous solution and applied to China National Standard (CNS) Α 4 specifications (2) 0Χ297 mm) (Please read the notes on the back and fill out this page.) -62- 1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventive Note (6〇) Cool down to 0°C, filter the resulting precipitate and wash it with ice water, with 1,4-two The nf alkane was evaporated together to remove residual water from the precipitate. Yield: 18.3 g MS-ESI: [M + H] + = 320.2 TLC: Rf = 0.2, yttrium, DCM/Me 〇H = 9/l (v/v (b) . 6-Chloro-5-cyano-4-(3-nitrobenzoyl)-2-(4-acridine)-pyrimidine Add POCls (50 ml) to 5-cyano-4 -(3-Nitrophenyl)-2-(4-pyridyl)-6-hydroxy-pyrimidine (Example 25(a), 18.3 g) and dimethylaniline (0.5 mL) in anhydrous 1,4-di A stirred solution of decane (200 ml), after 3 hours at 90 ° C, the warm mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane and added to ice. Water, the obtained precipitate was filtered and washed with water, and water remaining in the precipitate was removed by evaporation with 1,4-dioxane. Yield: 17.2 g MS-ESI: [M + H] + = 338.4 TLC :Rf = 0.7, decyl, heptane / EtOAc = 3/2 (v/v) (c) . 5- 5-cyano-4-(3-nitro -2-(4-3⁄4 pyridine)-6-(ethyl ester methylthiopyrimidine DIPEA (9.8 ml) was added to ethyl 2-mercaptoacetate (5.7 ml) and 6-chloro-5- A mixture of cyano-4-(3-nitrophenyl)-2-(4-acridinyl)-pyrimidine (Example 25(b), 17.2 g) in EtOH (125 mL) and DCM (125 mL) Air pressure stirring solution, after 2 hours at room temperature, the mixture is applied to the Chinese National Standard (CNS) A4 specification (210X297 mm) on the paper scale (please read the back note before filling this page) -63- Economy Ministry of Intellectual Property, Staff Consumer Cooperatives Printed 1131861 A7 B7 V. INSTRUCTIONS (61) DCM was diluted to complete dissolution, rinsed with 0.5 equivalent of aqueous HC1 solution, dried (MgS〇4) and concentrated under reduced pressure. Yield: 20.5 g of MS-ESI: [Μ + ΗΓ = 422.0 TLC · Rf = 0.6, oxime, heptane / EtOAc = 3/2 (v/v) (d) . 5-amino-4-(3-nitrate Benzene)-2-(4-Acridine a V 并 and 2,3-cU _ -6-6-carboxylic acid ethyl ester DIPEA (20.0 ml) was added to ethyl 5-cyano- 4- (3-Nitrophenyl)-2-(4-pyridyl)-6-(ethyl estermethylthio)-pyrimidine (Example 25(c), 20.5 g) in anhydrous EtOH (100 mL) and anhydrous toluene (100 ml) of the stirred solution in the mixture, after 48 hours at 100 ° C, the mixture was cooled to 0 ° C, and the resulting precipitate was filtered, washed with cold EtOH and dried under vacuum at 40 ° C. 15.7 g MS-ESI: [M + H] + = 422.2 TLC: Rf = 0.5, decyl, heptane/EtOAc = 3/2 (v/v) (e). 5-amino-4-(3-amine Ethylphenyl)-2-(4-3⁄4-pyridyl)-thieno-f2,3-dl-pyrimidine-6-carboxylic acid ethyl ester Tin chloride (Π) in EtOH (250 ml) (21.0 g) Addition to 5-amino-4-(3-nitrophenyl)-2-(4-3⁄4-pyridyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 25 ( d), 15.7 g) in a solution of 1,4-dipyran (250 ml), adding 37% 11 (:1 aqueous solution (6.9 m) And the mixture is heated at reflux (90 ° 匚) for 16 hours, the mixture is cooled to room temperature and concentrated under reduced pressure, the residual paper scale is applicable, the standard of compensation (CNS) A4 specification (2 like 297 f) (Please read the notes on the back and fill out this page)

-64- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1131861 A7 .B7 V. Inventive Note (62) Residue suspended in EtOAc (500 ml), add 4 equivalents of NaOH aqueous solution to pH 10-11, The mixture was diluted with aq. EtOAc (aq.). Silicone, heptane / EtOAc = 3/2 (v / v) (f) . 5-amine a 4-(3-aminophenyl pyridine) - thiazepine 2,3-dl pyrimidine-6- The carboxylic acid added potassium hydroxide (15.7 g) to 5-amino-4-(3-aminophenyl)-2-(4-pyridyl)-thieno[2,3-d]pyrimidine-6 a solution of ethyl carboxylate (Example 25(e), 12.0 g) in a mixture of 1,4-dioxane (2 10 mL) and water (80 mL). Cool to 0 ° C, filter the resulting precipitate, suspend in water (300 mL) and cool to 0 ° C, acidify the mixture to pH 3 by adding 2 eq. After 2 hours, the resulting precipitate was filtered, washed with water and dried at 40 ° C. Dry: Yield: 12..0 g! MS-ESI : [Μ + ΗΓ = 364·2 TLC: Rf = 0.1, sand, DCM/Me〇H = 95/5 (Wv) (g). Third Ding Mo 5-amino-4-(3-aminophenyl)-2-(4-DH; 晗 噻 并 [2 J-dl pyrimidine-6-decylamine will 01? Ugly six (12.9 ml) , T-butylamine (7.8 ml) and D-61'11 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) — -65- (Please read the note on the back and fill out this page)

1314861 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventive Note (63) (11.9 g) added to 5-amino-4-(3-aminophenyl)-2-(4-pyridyl) -Thiono[2,3-d]pyrimidine-6-carboxylic acid (Example 25(f), 12.0 g) in DCM (250 mL) and DMF (50 mL) After 3 hours, the mixture was diluted with EtOAc EtOAc EtOAc (EtOAc m. Purification of hydrazine by chromatography using methylene chloride/methanol = 1/0 to 95/5 (v/v) as a stream wash: 12.2 g MS-ESI: [M + H] + = 419.4 TLC: Rf =0.3, decyl, heptane/EtOAc = 3/2 (v/v) (h). tert-butyl 5-amine 4-(3-(2-bromoacetamide) (4-Pyridyl)-thilyl 2,3-dl-pyrimidine-6-decylamine A solution of bromoacetic acid chloride (0.59 mL) in THF (25 mL) 4-(3-aminophenyl)-2-(4-b-pyridyl)-thieno[2,3-d]pyrimidin-6-nonylamine (Example 25(g), 2.0 g) N, After a solution of N-dimethylaniline (3.0 ml) in THF (50 ml), EtOAc (EtOAc) , dried (MgSO.sub.sub.sub.sub.sub.sub. EtOAc = 3/2 (v/v) (please read the notes on the back and fill out this page)

This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -66 - 1314861 A7 A7 B7 Ministry of Economic Affairs Zhici Property Bureau employee consumption cooperative printing 5, invention description (64) (1). Third butyl 5 - Amino- 2-(4-pyridyl, 4-(3-((Ν-(1-hydroxy-2-methyl-propan-2-yl))-glycolic acid)丨2,3-dl-pyrimidine-6-oxime in tert-butyl 5-amino-4-(3-(2-bromoethylamino)-phenyl)-2-(4-pyridyl)- 2-Amino-2-methyl-propanol was added to a stirred solution of thieno[2,3-d]pyrimidine-6-nonylamine (Example 25 (h), 200 mg) in DCM (5 mL) After stirring at room temperature for 17 hours, the reaction mixture was diluted w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The product was purified by HPLC using a Luna C-18 column in the following gradient: 0.1% aqueous TFA + 1% aqueous solution of ACN/ACN = 90/10 to 10/90 (Wv) at 30 min. a mixture of di Df alkane, % TFA aqueous solution and water lyophilized. Yield: 73 mg (TFA-salt) MS- ESI : [M + H]+ = 548.2 HPLC ·· R, = 9.65 min, column Luna C-18(2), 3 μm, 100 x 2.0 mm, UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10 / 80/10 to 10/10 / 80 (v / v / v), operating time = 2 〇 minutes 〇 Example 26 Third butyl 5-amine a certain 2-(4-pyridyl)-4-(3-((N,N-bis-(2-methoxy) ethyl group (please read the back first) Note: Please fill in this page) This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -67- 1314861 Λ7 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau 8 Workers Consumption Cooperative Printed 5, Invention Description (65 ))-Glycine group)-Amino)-Benzene)-Thienthene 2.3-dl-pyrimidine-6-indole in the second butyl 5-amino-4-(3-(2-bromoacetic acid) Amino)-phenyl)-2 -(4-oxidenyl)-thieno[2,3-d]pyrimidin-6-decylamine (Example 25(h), 200 mg) in DCM (5 mL To the stirred solution was added bis-(2-methoxyethyl)-amine (300 mg). After stirring at room temperature for 17 h, the mixture was diluted with DCM (100 mL) Aqueous solution of Ch (1 mL, 2×50 mL) was dried, dried (MgSO 4 and evaporated, evaporated,lululululululululululululululululululululu The aqueous solution of ACN/ACN = 90/10 to 10/90 (v/v) was lyophilized over 30 minutes, then the title compound was lyophilized from a mixture of 1,4-dioxane, 1% aqueous TF A and water. Yield: 170 mg (TFA-salt) MS-ESI: [Μ + Η]+ = 592·2 HPLC: Rt = 12.02 min, column Luna C-18 (2), 3 micron, 100 x 2.0 mm, detection UV = 210 nm, oven temperature = 40 ° C, flow rate = 0.25 ml / min, flow wash phosphate buffer 50 mM concentration pH 2.1 / water / ACN = 10/80/10 to 10/10/80 (v/v/v), operating time = 20 minutes 〇 Example 27 CH0-LH and CHO-FSH in vitro bioactivity was stably transfected into human LH receptor and co-transfected with cAMP response element (CE)/accelerator for expression Firefly luciferase receptor gene Chinese big cheeks (please read the back note first and then fill out this page) 1«· The book paper size applies to China National Standard (CNS) Α4 size (210Χ297 mm) -68- 1314861 At Β7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed V. Illustrative (66) LH agonistic activity of test compounds in ovarian (CHO) cells, binding of ligands to Gs-coupled LH receptors will result in increased cAMP, Activation of the luciferase receptor is then initiated, and the luciferase signal is quantified using a fluorescent counter, and for the test compound, EC5 is calculated.値 (resulting in a concentration of half-maximum (50%) stimuli) for the purpose of using the software program GraphPad PRISM, version 3.0 (GraphPad software Inc., San Diego). In a similar manner, the FSH agonistic activity of the test compound was transfected with CHO cells transfected with the luciferase receptor gene and the human FSH receptor, and the results were listed in the in vivo bioactivity of vaccination in immature mice. To test the in vivo activity of LH/FSH receptor agonistic compounds, in this test, immature female mice were treated with urinary FSH (H umeg ο η 1 2.5 IU / animal), and the animals were placed after about 48 hours. Treatment with LH/FSH agonistic compound at a dose of 50 mg/kg was prepared in Examples 1, 4, 9 and 17, after 24 hours of LH/FSH agonistic treatment, the animals were sacrificed and the number of eggs in the fallopian tubes was assessed microscopically. On average, 10-15 animals were tested, except for the compound of Example 17 (which is 〇.4), and the average number of eggs was 8. (Please read the notes on the back and fill out this page)

This paper scale applies, national standard (CNS) Α4 specification (2] 0X297 mm) -69- 1314861 A7 B7 V. Invention description (67) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing table 1 Name example LH EC50 (M) FSH EC50 (M) tert-butyl 5-amino-2-methylthio-4-(3-((N-methyl-N-(2-hydroxyethyl)-glycine)) -amino)·phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 1 2.73E-09 5.69E-08 tert-butyl 5-amino-2-methylthio-4 -(3-((Ν-(1-hydroxy-2-methyl-propan-2-yl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidine -6-decylamine 2 5.42E-09 8.06E-07 tert-butyl 5-amino-2-methylthio-4-(3-((N-(methyl)methyl)-glycine) )-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 3 5.97E-09 1.44E-06 tert-butyl 5-amino-2-methylthio- 4-(3-((N-ethyl-N-(2-methoxyethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidine- 6-decylamine 4 7.00E-09 1.01E-07 tert-butyl 5-amino-2-methylthio-4-(3-((N-(R-1-methyl)-2-methyl) -prop-1-yl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 5. 9.63E-09 3.48E-07 Butyl 5-amino-2-methylthio-4-(3-((N,N-bis-(2-methoxyethyl)-glycosyl)-amino)-phenyl)- Thio[2,3-d]pyrimidin-6-decylamine 6 1.00E-08 1.18E-06 tert-butyl 5-amino-2-methylthio-4-(3-((2,3) -dihydroxy-propan-1-yl)-glycine group)-Alkyl)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 7 1.22E-08 1.13E-06 Third butyl 5-amino-2-methylthio-4-(3-((1,3-dihydroxypropan-2-yl)-glycosyl)-amino)-phenyl)-thio嗯和[2,3-d]pyrimidine-6-decylamine 8 2.64E-08 1.00E-06 (Please read the notes on the back and fill out this page) This paper size applies to the Chinese National Standard (CNS) A4 specification ( 210X297 mm) -70- 1314861 A7 A7 B7 V. INSTRUCTIONS (68) Ministry of Economic Affairs Intellectual Property Office S-Consumer Cooperatives Printed Table 1 (continued) Name Example LH EC50 (M) FSH EC50 (M) Third butyl 5-amino-2-phenyl-4-(3-((N-ethyl-N-(2-hydroxyethyl)-glycosyl)-amino)-phenyl)-thio-[ 2,3-d]pyrimidine-6-nonylamine 9 4.82E-09 6.06E-07 tert-butyl 5-amino-2-phenyl-4-(3-(N-(methyl ester methyl)) -glycosylamino)-phenyl)-thieno[2,3-d]pyrimidin-6-decylamine 10 1.01E-08 2.48E-06 Tert-butyl 5-amino-2-(2-furyl)-4-(3-((N-methyl)(2-hydroxyethyl)-glycine group )-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-acid amine 11 4.00E-09 6.16E-07 tert-butyl 5-amino-2-(2- Furyl)-4-(3-(N-(1-hydroxy-2-methyl-propan-2-yl)-glycosyl)-amino)-phenyl)-thio-[2,3 -d]pyrimidine-6-nonylamine 12 1.18E-08 2.97E-06 tert-butyl 5-amino-2-(2-furyl)-4-(3-(N-(methyl)methyl) )-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-醯 Limb 13 1.21E-08 2.55E-06 tert-butyl 5-amino- 2-(2-Thienyl)-4-(3-((N-methylethyl(2-hydroxyethylglycinyl)-amino)-phenyl)-thio)[2,3- d]pyrimidine-6-nonylamine 14 5.28E-09 1.44E-06 tert-butyl 5-amino group: (2-thienyl)-4-(3-((N-(methyl)methyl) -glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 15 1.82E-08 3.21E-06 tert-butyl 5-amino-2 -(2-Thienyl)-4-(3-((N,N-di-(2-methoxyethyl:l-glycosyl)-amino)-phenyl)-thiol [2,3-d]pyrimidine-6-decylamine 16 2.13E-08 6.81E-06 (Please read the notes on the back and fill in This page applies to the Chinese National Standard (CNS) A4 specification (2丨〇·〆297 mm) -71 - 1314861 A7 B7 V. Description of invention (69) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Table 1 (Continued) Name example LH EC50 (M) FSH EC50 (M) Tert-butyl 5-amino-2-ethylamino-4-(3-((N-ethyl-N-(2-methoxy) Benzyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 17 1.04E-08 1.25E-06 tert-butyl 5- Amino-2-(N,N-dimethylamino)-4-(3-((N-methyl-N-(2-hydroxyethyl)-glycinyl)-amino)-phenyl )-thieno[2,3-d]pyrimidin-6-decylamine 18 1.45E-08 1.63E-06 tert-butyl 5-amino-2-ethylamino-4-(3-(( N-(methyl ester methyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 19 2.29E-08 2.30E-06 Tributyl 5-amino-2-isopropylamino-4-(3-((N-ethyl-N-(2-methoxyethyl)-glycinyl)-amino)-phenyl )-thieno[2,3-d]pyrimidin-6-nonylamine 20 4.24E-08 2.95E-06 tert-butyl 5-amino-2-ylpropanyl-4-(3-((N) -(methyl ester methyl)-glycosyl)-amino)-phenyl)-thien[2,3-d] Pyridin-6-nonylamine 21 5.70E-08 5.60E-07 tert-butyl 5-amino-2-methoxy-4-(3-((N-ethyl-N-(2-methoxy)) Ethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 22 1.16E-08 9.53E-07 tert-butyl 5,amine Benz-2-allyloxy-4-(3-((N-ethyl-N-(2-methoxyethyl)-glycosyl)-amino)-phenyl)-thiol [2,3-d]pyrimidine-6-nonylamine 23 3.68E-08 1.74E-06 tert-butyl 5-amino-2-isopropoxy-4-(3-((N-ethyl-) N-(2-methoxyethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 24 7.82E-08 2.51E- 06 tert-butyl 5-amino-2-(4-pyridyl)-4-(3-((N-(l-hydroxy-2-methyl-propan-2-yl)-glycine)) -amino)-phenyl)-thieno[2,3-d]pyrimidin-6-nonylamine 25 3.47E-08 4.00E-07 Second butyl 5-amino-2-(4-B ratio卩定))-4-(3-((N,N-bis-(2.methoxyethyl)-glycinyl)-amino)-phenyl)-thio-[2,3-d ] Pyrimidine-6-decylamine 26 3.82E-08 1.23E-06 (Please read the note on the back and fill out this page) This paper scale applies to Chinese National Standard (CMS) A4 specification (210X: 297 mm) -72 -

Claims (1)

1314861 Α8 Β8 C8 D8 Month 曰 曰 repair jl. Supplement 6. Patent application scope Attachment 2A: Patent No. 91 115229 Patent application Chinese patent application scope Replacement of the amendment of the Republic of China on February 18, 1994 1. A kind of formula I And [2,3-d] acridine derivatives, R3 R4 〇, R5 (Please read the note on the back ^^ and then fill out this page&gt; • Install. Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs (Form I) or its pharmaceutically acceptable salts, where X is 0 or Η, Η Α is S, ΝΗ, Ν (R6), 0 or a bond; R1 is (1-4C)alkyl, (2-4C)alkenyl, phenyl, furyl, thienyl or pyridyl, the benzene a group, a furyl group, a thienyl group or a pyridyl group may be optionally substituted with one or more substituents: hydroxy, halo, nitro.trifluoromethyl, cyano, amine or (1-4C) (b) Alkylamino group; and 'R2 is H, (1-4C)alkyl, (1-4C)alkoxy(2-4C)alkyl or hydroxy(2-4C)alkyl; R3 and R4 are independent of each other Is selected from H, (1-4C) alkyl or hydroxy (Bu 4C) alkyl; R5 is hydrazine or (1-4C) alkyl; R6 may be the same group selected from R1. Patent application No. 1 of the compound 'where X is Η ' _ Nickel paper size applicable to China National Standard (CNS) A4 specification (210X297 public 13) 1314861 A8 B8 C8 D8 VI. Patent application scope &quot; Η ° 3 · According to the application of patent scope 1 or 2 , Wherein r5 is (1-4C) alkyl {Note Please read smell of the back page and then fill) 2 or 4. A compound of the scope of patent 1, wherein R3 = R4. 5 · A compound according to claim 1 or 2, wherein R3 = R4 = H. 6. A compound according to claim 1 or 2 wherein y is (1-4C)alkyl. 7. A compound according to claim 1 or 2 of the patent application for the manufacture of a medicament for birth control. 8. A compound selected from the group consisting of: tert-butyl 5-amino- 2-methylsulfanyl 4-(3-((N-methyl-N-(2-hydroxyethyl)-glycine) ()-amino)-phenyl)_ thiazepine [2,3-d]pyrimidin-6-carboxamide; tert-butyl 5-amino- 2-methylsulfanyl- 4-(3-(( N-(1 -hydroxy-2-methyl-propan-2-yl)-glycosyl)-amino)phenyl)- thia-[2'3-d-pyrimidine-6-carboxamide Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printing Tert-Butyl 5 - Limb- 2 -Methylthio- 4 - (3-((N-(methoxycarbonylmethyl)-glycinyl)-Amino) )-phenyl)-thilyl[2,3-d]pyrimidin-6-carboxamide; tert-butyl 5-amino-2-methylsulfanyl- 4-(3-((N-ethyl-) N-(2-methoxyethyl)-glycosyl)-amino)-phenyl)-thiazolo[2,3-d]pyrimidin-6-carboxamide; this paper scale applies to China Standard (CNS) A4 size (210X 297 mm) 1314861 A8 Βδ C8 D8 VI. Patent application scope (please read first) Note: Please fill in this page) Tert-butyl 5-amino-2-methylthio-4-( 3-((N-(R-1-methoxycarbonyl)-2-methyl-propan-1) ))-glycosyl)-amino)phenyl- phenyl-[2,3-d]pyrimidine- 6-carboxamide; tert-butyl 5-amino-2-methylsulfanyl-4 One (3 -((N,N-bis-(2-methoxyethyl)-glycosyl)-amino)-phenyl)- thia-[2,3-d-pyrimidine_ 6 _ Carboxylamidine; tert-butyl 5-amino- 2-methylthio-tetra-(3-((2,3-dihydroxy-propyl-1-yl)-glycinyl)-amino)-benzene a thiol-[2,3-d]pyrimidine- 6-carboxamide; tert-butyl 5-amino- 2-methylthio- 4-(3-((1,3-dihydroxypropanol) 2-amino) monoglycolate) monoamino)-phenyl)- thia-[2,3-d-pyrimidine- 6-carboxamide; tert-butyl 5-amino-2-phenyl 4-(3-((N-ethyl-N-(2-hydroxyethyl)-glycosyl)-amino)-phenyl)- thia-[2,3-d-pyrimidine-6-carboxylate Guanidine; tert-butyl 5-aminol-2 _Phenyl- 4-(3-(N-(methoxycarbonylmethyl)-glycosyl)-amino)-phenyl)- thia-[2,3-d]pyrimidine- 6-carboxyindole Amine; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed t-butyl 5-amino-2-(2-furyl)- 4-(3-((N-methyl-N-(2-hydroxyethyl)) Monoglycosyl)-amino)phenyl-yl)-(2,3-d)pyrimidine-6-carboxamide; tert-butyl 5-amino-2-(2-furanyl)- 4-(3-(N-(1-hydroxy-2-methyl-propan-2-yl)-glycosyl)-amino)phenyl)- thia-[2,3-d-pyrimidine A 6-carboxyguanamine; This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -3- 1314861 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A8 B8 C8 D8 々, patent pending range butyl 5-amino- 2-(2-furyl)_4_(3-(N-(methoxycarbonylmethyl)-glycosyl)-amino)phenyl-thio][2,3- d]pyrimidine- 6-carboxyguanamine; tert-butyl 5-amino- 2 - 2-(Thienyl)- 4-(3-((N-methyl-N-(2-hydroxyethyl)-glycosyl)-amino)phenyl)- thiazepine [2,3 — d] pyrimidine-6-carboxyguanamine; tert-butyl 5-amino- 2-(2-thiol)_4_(3-((N-(methoxycarbonylmethyl)-glycine)) Amino)-phenyl)- thia-[2,3-d]pyrimidine- 6-carboxamide; tert-butyl 5-amino- 2-(2-thiol)- 4-(3-( (N,N-di-(2-methoxyethyl)-glycosyl)-amino)phenyl)- thia-[2,3-d]pyrimidine-6-carboxamide; Butyl 5-amino-2-carboxyethyl 4-yl(3-((N-ethyl-N-(2-methoxyethyl)-glycinyl)-amino)-phenyl )-thiazolo[2,3-d]pyrimidine-6-carboxyguanamine; tert-butyl 5-amino-2-(N,N-dimethylamino)-4(3((N) -methyl-N-(2-hydroxyethyl)-glycosyl)-amino)-phenyl)- thia-[2,3-d-pyrimidine- 6-carboxamide; tert-butyl 5 -Amino-2-ethylamino group - 4 one ( 3-((N-(methoxycarbonylmethyl)-glycosyl)-amino)-phenyl)-thieno[2,3-d]pyrimidine- 6-carboxamide; tert-butyl 5 -Amino- 2-isopropylamino- 4-(3-((N-ethyl-N-(2-methoxyethyl)-glycosyl))-amino)-phenyl)- Thio[2,3-d]pyrimidine- 6-carboxamide; (please read the notes on the back and fill out this page) This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -4- 1314861 A8 B8 C8 D8 t, patent pending range butyl 5-amino-2-alkylallyl-4- (3 〜((methoxycarbonylmethyl)-glycosyl)-amino)phenyl)-[2,3-d]-anthranyl-6-cylamine; tert-butyl-5-amino-2 Methoxy- 4_(3-((N-N_(2-methoxyethyl)-glycinyl)-amino)~-嚷^[2,3-d] 卩疋6-6 Residual acid S female, tert-butyl 5-amino-2-phenyleneoxy-4-iso(3~(N~thioethylphenyl)-N-(2-methoxyethyl)-gan Amino acid)-amino)-thiazolo[2,3-d]pyrimidine--6-carboxamide; tert-butyl 5-amino- 2-isopropoxy-4-(3~(yl) N-(2-methoxyethyl)-glycinyl)-amino))-thiazolo[2,3-d]pyrimidine-6-carboxamide; tert-butyl-5-amino-2 — (4 —pyridyl)- 4~—(1—transyl-2-methyl-propan-2-yl)-glycinic acid))-phenyl)_salph[2,3—d] D D-6 - Residual acid amine. Tert-butyl 5-amino-2-(4-pyridyl)_4~(3~ 'N-bis-(2-methoxyethyl)-glycine group (N-Ethyl Phenyl (N-Ethyl Phenyl) (N-Amine or Printed by the Consumers' Cooperatives of the Intellectual Property Office of the Ministry of Economics) - Thio[2,3 - d]pyrimidine -6-Carboxylamamine-based CN 'Benzene L yj — α” pharynx, 哫 _ d - guanamine 9. A pharmaceutical composition for the treatment of fertility disorders, which covers the scope of patents 1-6 of the thiophene [2,3-d a pyrimidine compound or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant. The paper size is applicable to the Chinese National Rate (CNS) A4 specification (21〇χ297 mm) cPlease read first Please fill in the back of this page]