TWI322144B - Tetrahydroquinoline derivatives - Google Patents

Description

1322144 A7 _______B7 V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) The invention relates to a compound having FS Η modulation activity, in particular a tetrahydromorphine derivative, a pharmaceutical derivative containing the same, and The use of such compounds for medical treatment. Inventive heat: Gonadotropin has many important functions in the human body, including metabolism, temperature regulation and reproduction. Gonadotropin acts on specific types of gonadal cells to cause ovarian and sputum differentiation and steroid production. For example, the gonadotropin FS Η (follicle stimulating hormone) of the pituitary gland plays an important role in stimulating the development and maturation of follicles. Role; L Η (luteal voxel) can cause ovulation (Sharp, RMClin Endocrinol. 33: 787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res. 35:301 -3 42,19 79) »In recent years, FSH has been used clinically, in combination with L Η to stimulate the ovaries, such as high ovarian stimulation during artificial insemination (IVF) and ovulation in involuntary infertile women (Insler, V_ , Int. J. Fertility 33: 85-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5: 3- 1 3, 1 98 8 ), and used to treat male hypogonadism and male infertility. The gonadotropin F S steroid is affected by gonadotropin-releasing hormone and estrogen during early adolescence and is released from the placenta during pregnancy. In females, F SH acts on the ovary to promote follicular development and is the most important hormone regulating estrogen secretion. In males, F SH is responsible for the integration of the vas deferens and acts on Sertoli cells to support gametes (the standard paper size applies to the Chinese National Standard (CNS) Α4 specification (210Χ297 mm) (please read the notes on the back first) Fill in this page) • Re-filling ΐ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print -4- 1322144 A7 £7_ V. Invention Description (2) Sub) Formation. Purified F SH is clinically used to treat female infertility and certain types of infertility in men who are unable to produce sperm. Therapeutic gonadotropins can be isolated from human urea fluids but are of low purity (Morse et al, Amer. J. Reproduet. Immunol. And Microbiology 17: 143, 1988). Alternatively, they can be prepared using recombinant gonadotropins. Recombinant human F S Η is commercially available and used to aid fertility (Olijve et al. Mol. Hum. Reprod. 2: 37 1, 1996; Devroey et al. Lancet 339: 1 170, 1992). The action of the F S H hormone is modulated by a special plasma membrane receptor, a member of the family of G-protein coupled receptors. These receptors consist of a single polypeptide and seven transmenbrane domains and interact with the G protein to cause activation of adenylate cyclase. The F S receptor is a highly specific target during the growth of ovarian follicles and is exclusively expressed in the ovary. Blocking this receptor or suppressing the signal often induced by F S Η -modulated receptor activation will interfere with the development of follicles, thus affecting ovulation and conception. Therefore, low molecular weight F S antagonists form the basis of novel contraceptive methods. These F S Η antagonists can reduce the development of follicles (no ovulation) but still maintain sufficient estrogen production to avoid undesirable side effects such as bone loss. OBJECTS AND 槪沭 = The present invention is directed to the preparation of low molecular weight hormone analogs which selectively modulate activity for F S receptors. The compound of the present invention can be applied to the Chinese National Standard (CNS) Α4 specification (210X297 mm) on the paper scale (please read the note on the back and then fill in the page), and then fill in the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1322144 A7 B7 V. INSTRUCTIONS (3) A (partial) agonist or (partial) antagonist of the FSH-receiver. Therefore, the present inventors have now found that a tetrahydro-1 porphyrin compound of the following formula 1 or a pharmaceutically acceptable salt has F S Η -modulating activity:

(Please read the notes on the back first. · Printed by the Intellectual Property Office of the Ministry of Economic Affairs, where R1 is methyl ketone, (1-6C) alkylcarbonyl or (1-6C) alkanesulfonyl; R2 and R3 are Η or (1-4C)alkyl; R4 is phenyl which may be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, amine, halogen, nitro, trifluoromethyl, cyano Base, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl(1-4C)alkoxy, (1-4C)(di)alkylamino. Preferred substitution The position is in the para position. R5 is (1-4C) alkyl; Υ - Χ is C (0) - ◦, S (◦) 2-〇, NHC (0) - 〇, NHC (S)-0, 0C (0)-〇, bonding—0,C (Ο) -NH,S (0)2 — NH, NHC (0) - NH - NHC (S) - NH > OC(〇)-NH, bonding An NH, NH-C(0), 〇-C(0) 'NH-S(0) 2, or 0-S(0) 2, or X-Y represents a bond; item refilling-loading--writing This page) -5 4 This paper scale applies to Chinese national standards (CNS > A4 specification (210X297 mm) -6- ^144

DESCRIPTION OF THE INVENTION (4) A7 B7 R6 is hydrogen, trifluoromethyl, (1 - 6C) alkyl, 1- or 2-alkyl (1 - 4C) alkyl, (2 - 6) alkenyl, (2~ Base, (6_l〇c) aryl '(3~9C)heteroaryl~6c)cycloalkyl' (2-6C)heterocycloalkyl, sulfur-burning (1-4C)alkyl, (6-l〇 c) aryl (1 1 alkyl '(3 - 9C)heteroaryl(1-4C)alkyl, 6 6C)cycloalkyl(1-4C)alkyl' (2-6C) hetero (1~4C) ), rb, R9 - amine carbonyl (i_4C, R8, R9-amino (1 - 4C) alkyl, r8 - oxycarboxy 4C) fluorenyl, R8_oxy (1-4C),

R ring base Jingang!| C ) (3 C ) 4 C 3 - alkylalkyl (1 carbonyl ~ 4 C ) alkyl;

If R is R 6 , it should be noted that χ - γ cannot be 6 as a phenyl group, except for the definition of a bond. In addition to the substituents which may have a (6-0C) aryl group, the substituents may also be optionally (6-C printed by the Ministry of Economic Affairs, 8th C.). 4 oxy group, group, (two

10C) aryl, (6-10C) aryloxy, (6 - 1 aryl (1-4C) alkoxy, 9C) heteroaryloxy, (3-9, (1-4C) alkylcarbonyl) 3-6C) cycloalkylcarbonyloxy, (C) alcoxy, (1 - 4C (6-10C) arylcarbonyloxy (3-9C) heteroaryl, (C) heteroaryl (1 - 4) C) (1 - 4 C ) 1 - 4 C ) alkoxy)alkoxy (1 - 4 (1-4C) alkanesulfonyloxy, (1 - 4 C )(di)alkylaminecarbamyl, ( 6-) arylamine-carbamyl, (2-6C)heterocycloalkylamine alkylcarbonyloxycarbonyl (1 C)oxycarbonyl aryl aryloxy sulfonyloxy 1 0 c ) formazan, ,. Install and order (please read the note on the back and fill in this page) This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1322144 Α7 Β7 V. Invention description (5) (6-10C) 2) an arylamino group, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl, (2-6C)heterocycloalkane Base (1 - 4 C ) alkyl. R7 is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogen, trifluoromethyl, cyano, nitro, hydroxy; R8 and/or R9 are hydrogen, (1-4C) Base, (2-4C) ruthenium, (2 - 4C) alkynyl, (6 - 10C) aryl, (3 - 9 c) heteroaryl, (6 - 10C) aryl (1-4C) alkyl '( 3 - 9C)heteroaryl(1-4C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl(1-4C)alkyl, (1 - 4C) (di)alkylamino (1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylthio(1-4C)alkyl (1-4C)alkylcarbonylamino (1-4 C)alkyl, (1-4C) alkoxycarbonyl (1-4C)alkyl, (1-4C) alkoxycarbonylamino (1-4C) Alkyl, (3-6C)cycloalkyl, (2-6C)heterocycloalkyl or R8 and R9 may be combined to form a ring of (2-6C)heterocycloalkyl. The compounds of the present invention have the function of modulating FS receptors, and if they function as agonists, they can be used for the same clinical purpose as natural FS ,, in addition to having altered stability and can be different The advantages of the route to the drug. If these compounds block the F S receptor, they can be used, for example, for contraception purposes. Therefore, the FS Η-receiver modulator of the present invention can be used for treating infertility, contraception and treatment of hormone-related abnormalities such as breast cancer 'prostate cancer and sub-paper scale applicable to China National Standard (CNS) A4 specification (210X297 public)厘) (Please read the notes on the back and fill out this page) Refill ☆ Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed -8- 1322144 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed V. Invention Description ( 6) Endometritis. Preferably, the compounds of the invention are used to deactivate the FSH-receptor. The term (1 - 4 C )alkyl is used in the definition to mean a branched or unbranched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, Dibutyl and tert-butyl. When the term (1 - 6 C )alkyl is used in the definition, it means a branched or unbranched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl' Dibutyl, tert-butyl and hexyl, and the like. Preferably, it is preferably a (1 - 5 C) alkyl group and a (1-4C) alkyl group. 3, 1 or 2 - King Kong (1 - 4 C ), means that an adamantyl group is attached to the first or second position of an alkyl group having 1 to 4 carbon atoms, wherein the alkyl group Has the same meaning as defined above. The term (2 - 4 C ) is intended to mean a branched or unbranched alkenyl group having 2 to 4 carbon atoms such as a vinyl group and a 2-butenyl group. The term (2 - 6 C )alkenyl means a branched or unbranched alkenyl group having 2 to 6 carbon atoms such as a vinyl group, a 2-butenyl group and a n-pentenyl group. The term (2 - 4C) alkynyl means a branched or unbranched alkenyl group having 2 to 4 carbon atoms such as an ethynyl group and a propynyl group. The term (2-6 C)alkynyl means a branched or unbranched alkenyl group having 2 to 6 carbon atoms such as ethynyl 'propynyl and n-pentynyl. The term (3 - 6 C )cycloalkyl means a cycloalkyl group having 3 to 6 carbon atoms which may be a cyclopropyl 'cyclobutyl group, a cyclopentyl group and a cyclohexyl group. The heterocyclic alkyl group having 2 to 6 carbon atoms, which preferably has 3 to 5 carbon atoms, and at least includes (please read the back of the note first) I# • Refilling · Loading — , writing to buy) Φ. This paper scale applies to China National Standard (CNS) Α 4 specification (210X297 mm) -9 - 1322144 A7 _B7 V. Invention description (7 ) (Please Read the precautions on the back and fill out this page. A hetero atom selected from N, ◦ and/or S, if appropriate, can be attached via a hetero atom or carbon atom. Preferred heteroatoms are nitrogen or oxygen. The most preferred examples are piperidine, morpholine and pyrrolidine. The term (1-4C)alkoxy means an alkoxy group having 1 to 4 carbon atoms, wherein the alkyl moiety has the same meaning as defined above. The (1_2C) alkoxy group is preferred. The term (6-10C) aryl means an aromatic hydrocarbon having 6 to 10 carbon atoms, such as a phenyl group, a naphthyl group, a tetrahydronaphthyl group or a benzyl group, which may be optionally Substituted by one or more substituents selected from the group consisting of hydroxyl, amine, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, 2 - 4C) alkynyl, (1-4C)alkoxy '(1-4C)(di)alkylamino group having the same meaning as defined above. A preferred aromatic hydrocarbon group is a phenyl group. The term (3-9C)heteroaryl means an aromatic radical having 3 to 9 carbon atoms which may be substituted or unsubstituted and which includes at least one hetero atom selected from nitrogen oxides and/or sulfur, such as imidazolyl. , thiadiazolyl, pyridyl, (benzo)thienyl, (benzo)furanyl, quinolyl, tetrahydroporphyrinyl, Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, printing 0 quinoline or hydrazine哚基. The substituent on the heteroaryl group may be selected from the group listed as an aryl substituent. If appropriate, the heteroaryl group can be attached via a carbon atom or a hetero atom. Preferred heteroaryl groups are thienyl, furyl and pyridyl. The term (6-10C) aryloxy means that an aryl group of 6 to 10 carbon atoms as defined above is attached to an oxygen atom. (3-9C) Heteroaryloxy is an analog of a (3 - 10 carbon) aryloxy group containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur. This paper scale applies to China National Standard (CNS) A4 specification (21〇Χ297 mm) -10- 1322144 A7 B7 V. Description of invention (8) Term (1 - 4 C ) alkoxycarbonyl (1 - 4 C ) alkane The base means an alkoxycarbonylalkyl group in which an alkoxy moiety having 1 to 4 carbon atoms has the same meaning as defined above and an alkylene group IJ having 1 to 4 carbon atoms has the same meaning as defined above. The term (1-4C)alkoxy(1-4C)alkyl means an alkoxyalkyl group in which the alkoxy moiety having 1 to 4 carbon atoms has the same meaning as defined above and contains 1 - 4 The alkyl group of one carbon atom has the same meaning as defined above. The term (3 - 6 C)cyclodecyl (1 - 4 C), means that a ring of 3 to 6 carbon atoms is attached to any of the groups of 1 to 4 carbon atoms, wherein the cycloalkyl group (3-6C)cycloalkyl as defined above and the alkyl group is a (1-4C)alkyl group as defined above. The term (2-6C)heterocycloalkyl(1 -4 C)alkyl means that a heterocycloalkyl group having 2 to 6 carbon atoms is attached to an alkyl group of any of 1 to 4 carbon atoms, wherein the heterocyclic ring The alkyl group is a (2 - 6 C)heterocycloalkyl group as defined above and the alkyl group is a (1-4C)alkyl group as defined above. The term (1 - 4 C ) (di)alkylamino means a (di)alkylamino group having an alkyl group having 1 to 4 carbon atoms and having the same meaning as defined above. The term (6-10C)(di)arylamino group means a (di)arylamine group having an aryl group having 6 to 10 carbon atoms and having the same meaning as defined above. The term (1-4C)(di)alkylamino(1-4C)alkyl means a (di)alkylaminoalkyl group having an alkyl group of 1 to 4 carbon atoms and having a paper scale applicable to Chinese national standards ( CNS ) A4 specification (210X297 mm) (Please read the notes on the back and fill out this page) Re-filling the item {! Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives Printing Seal -11 - 1322144 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System 7 Β 7 V. Invention Description (9) has the same meaning as defined above. The term (1-4C)alkylthio(1-4C)alkyl means an alkylsulfanyl group having an alkyl group having from 1 to 4 carbon atoms and having the same meaning as previously defined. The term amine carbonyl (1 -4 C)alkyl as defined in the definition of R8, R9-aminoindenyl (1-4C) means an amine carbonylalkyl group having an alkyl group containing from 1 to 4 carbon atoms and Has the same meaning as defined above. The amine carbonylmethyl group is preferably an amine carbonylalkyl group. The term amine (1 _4 C )alkyl in the definition of R 8, R 9 —amino(1 - 4 C)alkyl means an amine alkyl group having an alkyl group having 1 to 4 carbon atoms and having the former The same meaning of the definition. The term oxycarbonyl(1 -4 C )alkyl in the definition of R8-oxycarbonyl(1-4C)alkyl means an oxycarbonylalkyl group having an alkyl group having 1 to 4 carbon atoms and having the above definition The same meaning. The oxycarbonylmethyl group is preferred as the oxycarbonylalkyl group. The term oxygen (1 -4 C )alkyl in the definition of R 8 -oxy(1 -4 C)alkyl means an oxyalkyl group having an alkyl group of 1 to 4 carbon atoms and having the same meaning as defined above. . The term (1 - 4C)alkyl in the definition of R8 -carbonyl(1 _ 4 C)alkyl means a carbonylalkyl group having an alkyl group of 1 to 4 carbon atoms and having the same meaning as defined above. . The term (6-10C)aryl(1-4C)alkyl means an aralkyl group having 7 to 14 carbon atoms, wherein the same as the above-mentioned formula is (1 - 4C) alkyl and aromatic The base is a (6 - 1 0C) aryl group. For Benzene paper scale, apply to China National Standard (CNS) Α4 (2丨Ο X 297 mm) III*—II — Installation — II — II — IIII (please read the notes on the back and fill out this page) -12 - 1322144 A7 B7 V. INSTRUCTIONS (0 (Please read the note on the back and fill out this page) (1 - 4C) Alkyl is the preferred aralkyl group, such as benzyl. (3 - 9 c a heteroaryl (1-4C)alkyl group is an analog of a (6-10C) aryl(1-4C)alkyl group containing at least one hetero atom selected from nitrogen, oxygen and/or sulfur, if appropriate A heteroaryl group can be attached via a carbon atom or a hetero atom. In the definition of NR8R9 the term "bonds to a ring of (2-6C)heterocycloalkyl", wherein R8 and R9 together form a ring with the nitrogen to which they are attached , which means a nitrogen-containing ring and which additionally contains up to 2 to 6 carbon atoms. The ring may additionally contain one or more heteroatoms selected from nitrogen, oxygen and/or sulfur. Examples of such rings are Butyridine, pyrrolidine, piperidine, piperazine and (thia)morpholine. The term halogen means fluorine, chlorine, bromine or iodine. · The term (1-6C) alkane It means an alkylcarbonyl group having an alkyl group having 1 to 6 carbon atoms and having the same meaning as defined above. Preferably, the (1 - 4 C ) alkylcarbonyl group is printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (1) A 4 C )alkylcarbonylamino (1 - 4 C )alkyl group means an alkylcarbonylamine alkyl group having an alkyl group having 1 to 4 carbon atoms and having the same meaning as defined above. Term (6 - 1 0C) Aryl (1-4C) alkoxy means that an aryl group of 6 to 10 carbon atoms as defined above is attached to a (1-4C) alkoxy group as defined above. (3 - 9C) The aryl (1-4C) alkoxy is a (6-10C) aryl (1-4C) oxo analog containing at least one hetero atom selected from nitrogen, oxygen and/or sulfur, if appropriate The heteroaryl group can be attached via a carbon atom or a hetero atom. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 public Chu) 1322144 A7 B7 V. Invention Description (11) (Please read the back of the note first) Matters re-fill in this page) The term (1 - 4C) alkoxycarbonyl (1_4C) alkoxycarbonyl means one (1 - 4 C) alkoxycarbonyl group attached to a The alkyl moiety contains 1 to 4 carbon atoms in the oxy group, and its alkoxy has the same meaning as defined above. The term (1 - 4 C ) alkoxy (1 - 4 C hospital carbonyloxy means An alkoxy group of 1 to 4 carbon atoms is attached to an alkylcarbonyloxy group of 1 to 4 carbon atoms, and the alkoxy group and the alkyl group have the same meanings as defined above. The term (1 - 4 C ) alkylcarbonylamine The base means an alkylcarbonylamino group having an alkyl group having 1 to 4 carbon atoms. The term (1-4C) alkoxycarbonylamino (1-4C)alkyl means that an alkoxycarbonyl group having from 1 to 4 carbon atoms as defined above is attached to an amine alkyl group having from 1 to 4 One carbon atom and has the same meaning as defined above. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. The term (6_1 0C) arylcarbonyloxy means an aryl group having 6 to 10 carbon atoms. A preferred arylcarbonyloxy group is a phenylcarbonyloxy group. (3-9 C ) Heteroarylcarbonyloxy is an analog of (6 - 1 0 C )arylcarbonyloxy which contains at least one hetero atom selected from nitrogen, oxygen and/or sulfur and, if appropriate, via carbon An atom or a hetero atom is attached. The term (1 - 4 C) alkanesulfonyl means an alkanesulfonyl group having an alkyl group having 1 to 6 carbon atoms and having the same meaning as defined above. It is preferred to use (1-3C) alkanesulfonyl. The term (1 - 4 C) alkanesulfonyloxy means an alkanesulfonyloxy group whose alkyl group has 1 to 4 carbon atoms and has the same meaning as defined above. (1 - 3 C) alkanesulfonyloxy The base is good. This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -14- 1322144 A7 B7 V. Description of invention (1 uniform term (6 - 1 0 C) Aromatic sulfonyloxy means an aryl sulfonate An oxy group having an aryl group of 6 to 10 carbon atoms and having the same meaning as defined above. Preferably, a benzenesulfonyloxy group is used. (3-9C) a heteroarylsulfonyloxy group is (6 - 10 C) An analogue of an arylsulfonyloxy group containing at least one hetero atom selected from nitrogen, oxygen and/or sulfur, and if appropriate, may be attached via a carbon atom or a hetero atom. The term (1 - 4C) (di) alkane The carbazide group means a (di)alkylaminecarbamyl group having an alkyl group having 1 to 4 carbon atoms and having the same meaning as defined above. The term (6 - 1 0 C ) (di)arylamine A fluorenyl group means a (di)arylaminecarbamyl group having an aryl moiety having 6 to 10 carbon atoms and having the same meaning as defined above. The term (2-6C)heterocycloalkylamine A The fluorenyl group means a heterocyclic compound amidomethyl group having a heterocycloalkyl group having 2 to 6 carbon atoms and having the same meaning as defined above. Is a compound of formula I, wherein Y - X is C(0) - NH, 0C (〇) - NH or C (〇.) - 〇. The most preferred compound is one in which Y - X has no c(0) - NH. More preferably, R1 is (1 _4 C)alkylcarbonyl, preferably ethyl hydrazide and/or R2 and/or R3 and R5 are each (1-4C)alkyl, preferably methyl. Preferably, it is a bulky group. Preferred compounds are those wherein R6 is (6-10C) aryl, (3-9C)heteroaryl, (6-1 〇C) aryl (1-4C) The alkyl or (3-9C) heterogeneous paper scale applies to the Chinese national standard (CNS > Α4 specification (210X297 mm) (please read the notes on the back and fill out this page) • Refill the Ministry of Economics Property Bureau employee consumption cooperative printing -15- 1322144 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 _____B7_ five, invention description (1 Ling aryl (1 4 C) alkyl. The best compound is R6 The (6 - 10C) aryl group is preferably a phenyl group. Preferred R7 groups are hydrogen, (1 - 4 C) alkyl or (1-4C) alkoxy. The most preferred is hydrogen or (1 - 4 C ) alkyl, preferably hydrogen or methyl The most preferred compound is r7 which is η. According to the invention, in the most preferred compound, R 1 is (1 _ 4 C )alkylcarbonyl, R 2 , R 3 ' R 5 are each (1-4C)alkyl, and R 4 is phenyl. And Υ - Χ is C (〇) - ΝΗ and R7 is Η. The best compound is where R1 is ethyl acetyl, R2, R3, R5 are each methyl, R4 is phenyl and Υ-Χ is C (〇 ) - ΝΗ and R7 is Η. As explained in the definition of the group, substitution of the above preferred compounds is permitted. The phenyl group in R 6 may be further substituted as described for the definition of R 6 . ··· • 1 丨.· The compound excluded in the present invention is 1-ethenyl-6-benzamideamino-4-(4-methylphenyl)-1,2,3,4-tetrahydrogen 2 '2,4-trimethylquinoline, 1 -ethylindolyl-4-phenyl- 1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinoline, 1 Ethyl 4-phenyl-1,2,3,4-tetranitro-2,2,4,6,8-pentamethyl-α-quinoline, 1-ethenyl-6-methoxy-4 Phenyl-1,2'3,4-tetrahydro-2,2,4-trimethylquinoline, 1-ethenyl-6-trifluoroacetamido- 4-(4-tolyl) 1 , 2 , 3 ' 4 —tetrahydro-2,2,4-trimethyl π-quinoline, 1 -ethylindolyl-6-trifluoroacetamido-4-phenyl- 1, 2, 3, 4-tetrahydro-2' 2,4-trimethyl d-quinoline, 1-ethenyl- 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4 , 6_ This paper scale applies to China National Standard Rate (CNS) Ba Gu ^ (210Χ297 mm) (please read the notes on the back and fill out this page) Ι Φ Refills 装·订-16- 1322144 A7 B7 5 Invention (Tetramethyl d-quinoline and 1-ethenyl_4-(4-bromophenyl), 3,4-tetrahydro-2,2,4,6-tetramethylquinoline. 1 ,2 These Exclusions regarding Ref.Zh., Khim, Abstr. No.lZh311, 1 972; Khim.Geterosikl.Soedin.7:795,1 97 l; Ambinter.Screening Collection.order nrs 28020-A0839/0039328 (CAS 3 10456- 97-4) and -A0705/0032919 (CAS 327981-38-4); ChemDiv Inc. order nr 8005-9747 (CAS360760-14-l); ChemStar.Product.list, nr. CHS 006 5 4 1 3 (CAS 2994 1 8 - 67 - 0); Asi nex Compound Collection, order nr BAS0068990 (CAS 299970-20-0). Appropriate methods for preparing the compounds of the invention are generally shown herein: R7

(Please read the notes on the back and fill in. : Write this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print II-a: A = 0Alkyl II-b: A = NH (protection base) II-c: A = C(0)〇Alkyl II-d:A = S(0)2〇Alkyl ne:A = (substituted)alkyl, aryl III-a: A = 0Alkyl III-b:A = NH(protecting group) III-c: A = C(0)0Alkyl III-d: A = S(0)2〇Alkyl III-e: A = (substituted) alkyl, a compound of the basic invention, wherein R2 and R3 are methyl From the formula II a - e (protected) aniline wherein R7 is defined as the starting compound as the starting material. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) -17 1322144 A7 B7 V. Description of the invention (1$ is prepared by the Skraup reaction described in Chu, which produces the 1,2-dihydro-2,2,4-trimethylhydrazine quinone derivative of formula III-a-e. (Read first Note on the back side of this page.) The relevant Skraup cyclization can be found in the literature: A. Knoevenagel, Chem. Ber. 54:1 726,1 92 1 ; RL Atkins and DE Bliss, J. Org.Chem .43: 1975, 1978; JV Johnson, BS Rauckman, DP Baccanari and B. Roth, J. Med. Chem. 32: 1942 , 1989; WCLin, S.-T. Huang and S.-T. LinJ. Chin. Chem. Soc. 43: 497, 1996; JPED Edwards, SJ West, KB Marschke, DE Mais, MMGottardis and TK Jones, J.Med.Chem. 41:303, 1998. The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints the above reaction generally at elevated temperatures in acetone, oxidized or ethyl acetamidine in the presence of iodine or protonic acid. Such as hydrochloric acid, p-toluenesulfonic acid or hydrogen iodide aqueous solution. In addition, Formula III _ a - e 1,2 - dihydro-2,2,4-trimethylquinoline can be corresponding The aniline of formula I I_a — e is reacted with acetone in the presence of magnesium sulfate, 4-tert-butylcatechol and iodine (LG Hamann, RI Higuchi, L. Zhi, JPED Edwards and X.-N. Wand, J. Med. Chem., 41: 623, 199 8). The starting materials can be purchased directly from commercial sources or by the aromatic ring substitution reaction known in the art, as disclosed in H. Cerfontain, Y, Zou and BHBakker, Recl. Trav. Chim. Pays-Bas , 1 1 3 : 403, 1994; A. Coppock, J. Org. Chem. 22: 325, 19 57; M. Schlosser, JH Choi and S. Takagishi, Tetrahedron, 46: 5633, 1990. Further, a compound of the formula VI _a - e wherein R 2 and R 3 are (2 - 4 C) alkyl and R 7 is as defined above, generally by cyclization of the aniline of the formula IV - a - e with the appropriate ketone of the formula V synthesis. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -18 - 1322144 A7 B7 V. Description of invention (堉

+

0 R2^^R3 IV-a: A = 〇Alkyl IV-b: A = NH (protecting group) IV-c: A = C(0)0Alkyl IV-d: A = S(0)2〇Alkyl IV- e: A = (substituted) alkyl, aryl VI-a: A = 0 Alkyl VI-b: A = NH (protecting group) VI-c: A = C(0)0Alkyl VI-d: A = S (0) 2 〇 Alkyl VI-e: A = (substituted) alkyl, aryl (please read the back note first and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed IV - a 2 The reaction is generally carried out in an inert solvent such as toluene at a relatively high temperature using a protic acid or a Lewis acid such as, but not limited to, p-toluenesulfonic acid or boron trifluoride to promote cyclization (11. 31161', 11.531^[ 311(1>1\\^1^161",^17· Chim.Acta., 75:1274, 1992; H. Walter, Helv. Chim. Acta, 77:608> 1 994; H. Walter and J. Schneider, Heterocycles, 41:1251, 1995; JP Edwards, JDRinggenberg and TK Jones, Tetrahedron Lett. 39: 5139, 1998).

The necessary building units can be prepared by the Wittig reaction of the ketones of formula VII. The introduction of a substituent A on an aromatic ring can be accomplished by the aromatic ring substitution conventionally known in the art in the aniline stage or in the 1,2,2,4-trimethylquinoline stage as described in the formula compound. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -19- 1322144 A7 B7 V. Description of invention (1

(Please read the notes on the back and fill out this page) VII-a: A = 〇Alkyl VII-b: A = NH (protecting group) VII-c: A = C(0)0Alkyl VII-d: A = S (0) 2 〇 Alkyl ▽ 11^: hexa = (substituted) alkyl, aryl in another strategy, formula VI - a - e compound wherein r2 = R3 = H can be from formula II a a - e The aniline is prepared by reacting 1-methylstyrene and formaldehyde with acetonitrile at room temperature or higher. The related cyclization is described in the literature: J. M. Mellor and G. D. Merriman, Tetrahedron, 51: 6115, 1995. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed the subsequent compound of formula VI (where R2, R3, R7 and A are as defined above) 1 _ N - deuteration or 1 - N - sulfonation can be used by those skilled in the art Conventional standard conditions are used. In a typical experiment, the compound of formula VI is in a solvent such as dichloromethane, tetrahydrofuran, toluene or pyridine with a mercapto halide or anhydride or sulfonium chloride in the presence of a base such as, but not limited to, N,N-di Reaction with propylethylamine, triethylamine, piperidine or sodium hydride to form N-deuterated or N-sulfonated 1,2-dihydro-4-methyl groups of formula VIII-a and VIII-b, respectively D-quinoline derivative. This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) -20- 1322144 A7 B7 V. Invention Description (1 Ling

VI VIII-a: R' = C(0)Alkyl VIII-b: R1 = S(0)2Alkyl The N-deuteration of the dihydroquinoline skeleton printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs can be found in the following literature. : Zh.V.Shmyreva, Kh.S.Shikhaliev and E · B. S hpa nig, I zv · V yss h. Uchebn.Zaved., Khim.Khim.Tekhnol.3 1:45,1988;Zh.V. Shmyreva, Kh.S.Shikhaliev, LPZalukaec, YAIvanov, YSRyabokobylko and IEPokrovskaya,Zh.Obshch.Khim.59:1391,1989 0 1 A N-methylation can be achieved by the dihydrogen D of the formula VI Quinoline reacts with formic acid in the presence of trifluoroacetic acid at elevated temperatures (see, for example, P. Bouyssou, C. Le Goff and J. Chenault, J. Heterocycl. Chem. 29: 895, 1992) or in the presence of ethyl formate. This is achieved by a reaction under sodium acetate (for example, N. Atanes, s. Perez, E. Guitan. L. Castedo and JMSaa, Tetrahedron, 50:1 1 257, 1994). The introduction of a suitable phenyl group into the 4th position of the dihydroporphyrin skeleton can be carried out by Friedel-Crafts alkylation via a (substituted) benzene derivative with a compound of the formula VIII wherein R1, R2 'R3, R7 and A are as defined above. Achieved. (Please read the notes on the back and fill out this page.) Refill the paper. This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -21 1322144 A7 B7

VIII IX The latter reaction is usually carried out at a higher temperature under only (substituted) benzene or in a suitable solvent such as heptane or hexane with benzene as a reagent, by Lewis acid (such as AlCl3, AlBr3, FeCl3 or

The catalytic action of SnC 14) is carried out. Friedel-Crafts alkylation with 1,2-dihydro-2,2,4-trimethyl alpha-quinoline is described in BA Lugovik, LG Yudin and ANKost, Dokl. Akad. Nauk SSSR, 1 70: 340 , 1 966; BA Lugo vik, LG Yudin, S. M. Vinogrado va and ANKost, Khim. Geterosikl. Soedin, 7: 795, 1971. The compound of the formula XII of the present invention (wherein R5爹Me and R1, R2, R3, R4, R7 and A are as defined above) can be synthesized starting from the tetrahydro D quinolinone of the formula X. Therefore, the ketone of formula X is treated with a suitable Wittig reagent.

The Wittig reaction can produce an unsaturated derivative of the formula X I which can then be used as the starting material for the Friedel-Crafts alkylation of (substituted) benzene via the same procedure as described above for the preparation of the compound of formula IX. (Please read the notes on the back and fill out this page.) Printed by the Consumer Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs.

X

XI

XII This paper scale applies to Chinese national standards (CNS>A4 specification (210X29*7 mm) -22- 1322144 A 7 B7 V. Description of invention (4 The Wittig reaction above is known to those skilled in the art. Appropriate formula X The ketone can be prepared by reacting aniline of formula II with 3-chloro-3-methyl-1-butyne (XIII) in diethyl ether/water in the presence of copper powder and triethylamine. XIV alkyne. Hydrogen-halogen exchange can be deprotonated by adding a compound of formula XIV to an inert solvent such as tetrahydrofuran and n-butyllithium at a temperature below -50 ° C to form p-toluenesulfonyl chloride to form formula XV. Finally, the cyclization catalyzed by an acid such as sulfuric acid can be carried out at a higher temperature in a solvent such as polyethylene glycol to produce a compound of formula XVI as described above for the derivative of formula VI. Deuterated or sulfonated. (Please read the notes on the back and fill out this page.)

II XIII: B = H XIV: B = H XVI: C = H XV: B = C1 X: C = R' Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. The above reaction sequence is described in the literature: P. Barmettler and HJ Hansen, Helv. Chim. Acta, 73: 1515, 1990 (and references cited herein). The functionalization of the sixth position of tetrahydromorphine of formula XII can be accomplished via a deprotection-coupling step as is known in the art: a compound of formula I - a of the invention (where X = 0 and Y = C (0) This paper rhyme uses Chinese national standards (c called Na (7) 0X2 Saki) 1322144 A7 B7 V. Invention description (21), S(0)2>NHC(0), nhc(s), oc(o) or bond) It is prepared from 6-methoxytetrahydromorpholine of the formula x 1 I - a. Demethylation has been known to those skilled in the art.

XII-a: Z = Me XVII: Z = Η R6,

Ia (please read the notes on the back and fill out this page) XVIII-ag Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed in a typical experiment, demethylation can be done by formula XII-a compound and BB r 3 The reaction is carried out in an inert solvent such as, but not limited to, dichloromethane or tetrahydrofuran at low temperature to give the deprotected compound of formula XVII. Alternatively, demethylation can be carried out by reacting a compound of the formula XII-a with a B F3·Me 28 complex at room temperature in the inert solvent used for the demethylation of the B B r 3 described above. 〇Re^^ci ο Re^^oH R6〆, CI XVIII-a XVIII-b XVIII-c This paper size applies to Chinese National Standard (CNS) A4 specification (2丨Ο X 297 mm) -24-1322144 A7 B7 V. Invention Description (Hong

χνΠΙ-d XVIII-e XVIII-f XVIII-g Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Subsequent Functionalization of Free OH Groups in Formula XVII Derivatives is well known to those skilled in the art and can be used with Formula XVIII — a - g reagent is easily achieved. For the halogen-containing reagent of formula XVIII, the foregoing reaction is typically carried out at room temperature in a suitable solvent such as an aprotic solvent such as N,N-dimethylformamide, dichloromethane or tetrahydrofuran in the presence of a base. For example but not limited

This is carried out in N,N-diisopropylethylamine or sodium hydride. Additives such as N'N-dimethylaminopyridine or tetrabutylammonium iodide promote the latter reaction. Further, by reacting an isocyanate or an isothiocyanate of the formula XVIII-d and XVIII-e in an inert solvent at room temperature or at a higher temperature, respectively, a compound of the formula I-a can be produced wherein Y = NHC (0 Or an NHC (S) hydrazine compound wherein Y = c (0) can also be obtained by another method using a carboxylic acid of the formula XVIII-b, using a coupling agent such as hydrazine-(benzotriazole-1-yl) )—N,N,N, > N ' _tetramethyluronium tetrafluoroborate (TBTU), 0_(7-azabenzotriazol-1-yl)-N'N'N, ,N, - tetramethylurea hexafluorophosphate (HATU) or bromopyrrolidine phosphate hexafluorophosphate (pybr 0P ) and a tertiary base such as N,N-diisopropylethylamine in a solvent such as hydrazine 'N-Dimethylformamide or dichloromethane is carried out at room temperature or at elevated temperature. This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) I ^ ^ 1 IJ - order 11111 (please read the note on the back and fill out this page) -25- 1322144 A7 B7 V. Description of invention ( Compounds of the formula I-b-C (wherein W=R8, R9N or R8〇) can be synthesized by reacting a compound of the formula Χγπ with a compound of the formula XIX, respectively, under standard conditions.

_ R5 R4

XIX: n=l-4 Ib: W = R8, R9N Ic: W = R8 〇 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed another option, formula I — b - c compound can be derived from formula XVII and The sulfhydryl group of XIX (wherein W=〇et) starts, followed by saponification with a base (such as sodium hydroxide) and subsequent condensation of the free carboxylic acid with an amine of the formula R8, R9NH or an alcohol of the formula R8〇H The compound of formula I - d_e is prepared by reacting a coupling agent such as TBTU, HATU or PyB r 0P mentioned earlier and a tertiary base such as N,N-diisopropylethylamine (wherein V = R8, R9N) Or R80) can be obtained by a nucleophilic substitution of a halogen such as bromine, respectively, in the presence of a compound of the formula XXI with an amine of the formula R8, R9NH or an alcohol of R8OH. Next, a suitable tetrahydroquinoline of the formula XXI can be synthesized from the compound of the formula XVII and the bromofluorenyl chloride of the formula XX using a synthetic procedure known in the art to synthesize XVII +

Id: V = R8, R9N Ie: V = R80 ϊ~ J Install - Ί I n {Please read the notes on the back and fill out this page) XX : n = 1-4 This paper scale applies to Chinese national standards (CNS A4 size (210X297 mm) -26 1322144 A7 B7 V. Description of the invention (2) This formula I-f-g compound (where u=(substituted) heteroaryl or (substituted)phenyl) can be respectively A (substituted) iodobenzylidene derivative of XXII is used in combination with a Mitsubishi coupling of boric acid of the formula XXIII-a-b.

-Β(ΟΗ),

(Please read the notes on the back and fill out this page)

XXII XXIII-a U = (Substituted) Heteroaromatic XXIII-b U = (Substituted) Aromatic Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed in a typical experiment, the iodide system of formula XXII will be of formula XXIII- The boric acid of a-b is used in a solvent mixture such as dimethoxyethane/ethanol using a fluorination absolute catalyst such as decyltriphenylphosphine or bis(phenylene phenylacetate) at a higher temperature in a nitrogen atmosphere. In the middle of the reaction. The addition of triphenylphosphine promotes the reaction and increases yield. The foregoing reactions have been described in detail in the literature. For example, A. Suzuki, Acc. Chem. Res. 15: 178, 1982; N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh and A. Suzuki, J. Am. Soc. 111: 314, 1989. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -27- 1322144 A7 __B7 V. Description of invention (2 leads similarly to formula I-h compound (where χ = ΝΗ and Y is as defined above) It can be synthesized by the method described in the synthesis of a compound of formula I-a (where χ = 〇). R5 R4 R6,

Compounds of formula I-I-j (wherein X=C(0) or S(0)2 and Y=NH or 0) may be respectively passed through the corresponding mercapto chloride or sulfonyl chloride of formula XXV with an amine of formula R6NH2 or The alcohol of the formula R6〇H is obtained by the same method as described earlier for the preparation of the compound of the formula I-a. (Please read the notes on the back and fill out this page) R5 R4

XXIV: Q = 0H XXV: Q = C1 R5 R4 R6,

Ii: Y = NI Ij: Y = 0 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed XXV Appropriate hydrazinyl or sulfonium chloride can be used from the corresponding formula χχιν compound by P0C 13, PC 15, grass 醯 chlorine , phosgene or SOC 12 treatment, prepared in a solvent such as toluene, acetonitrile or N,N-dimethylformamide, as described in detail in the literature. For example, the paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 28- 1322144 Α7 Β7 V. Invention description (2 and M. B on na t, M. Bra die y and JDKilburn, Tetrahedron Lett. 37:5409, 1996; JG Montana, GMBuckley, N. Copper, HJ Dyke and L. Gowers, Bioorg. Med. Chem. Lett, 8: 2635, 1998; J. Hayler, PDKane, D. LeGrand, F. Lugrin, K. Menear, R. Price, M. Allen, X. Cockcroft, J. Ambler, K. Butler and K. Durren, Bioorg. Med. Chem. Le11.1 0: 1 567, 2000. The compound of the formula XXIV (wherein X = C (〇)) can be directly used as a starting material for the preparation of the derivative of the formula I-I j, by using the aforementioned coupling agent to prepare the derivative. The k-p compound (where X = C (◦) or S(〇) 2 and Y = NH or 0 and n = l - 4) can be prepared according to the synthetic steps known in the art. (Please read the back first) Note on this page)

I-k: W = R8, R9N I-l: W=R80 I-m: W = R8, R9N I-n: W = R8〇 I-o: W = R8, R9N I-p: W = R80 Printed by the Intellectual Property Office of the Ministry of Economic Affairs

XXVI

XXVII

XXIII Therefore, the preparation of tetrahydroquinoline of formula I-k-1 can be applied to Chinese national standards by using the amine or alcohol of formula XXVI (Υ = ΝΗ or 0, respectively) and the chlorinated paper of formula XXV. CNS ) /U Specifications (210X297 mm) -29- 1322144

Iq Α7 Β7 V. Description of the invention (prepared by condensation under standard conditions. In a similar strategy, an amine or alcohol of formula XXVII can be used to prepare a compound of formula I - m η. Finally, use earlier mentioned The boronic acid of the formula XXIII can be prepared by the aforementioned Mitsubishi coupling reaction to prepare a compound of the formula I-〇ρ. The compound of the formula I_q of the present invention (wherein X-oxime is a bond) can be commercially obtained commercially or easily from the formula. XXVIII aniline is prepared by the reaction sequence Skraup, deuteration and Friedel-Crafts alkylation.

XXVIII In another strategy, a compound of formula I-r (wherein X-γ is a bond and U = (substituted) heteroaryl or (substituted) phenyl) can be passed through the corresponding 6-iodoyl group of formula XXIX The tetrahydroquinoline derivative is obtained by the aforementioned Mitsubishi condensation of a boronic acid of the formula χχπι. 11 n Ί— 1« —^Ί n n I Ί-1 n (Please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

2

+ XXIX ·Γ

XXIII This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) '30- 1322144 Α7 Β7 5. Inventive Note (蹭 Appropriate formula XXIX iodide can be made from the corresponding amine by the conventional Sandmeijer reaction (Please read the back y note first and then fill out this page) Certain compounds of the invention, which are in the form of the free base, are isolated as pharmaceutically acceptable salts from the reaction mixture. Salts can be obtained by reacting the free base of formula I with an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid 'propionic acid, glycolic acid, maleic acid, malonic acid, Prepared by treatment with methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, etc. The compound of the present invention has at least one palmitic carbon atom and thus may be a pure enantiomer, A mixture of enantiomers or a mixture of diastereomers is obtained. Methods for obtaining pure enantiomers are known in the art, for example from optically active acids and salts in racemic mixtures. get on Crystallization, or by chromatography with a palm column. For diastereomers, vertical phase column or reverse phase column can be used. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative prints the compound of the invention. It is known to those skilled in the art that the compound may form a hydrate when the charged compound is lyophilized with water, or may form a solvated species when concentrated in a solution with a suitable organic solvent. Including the hydrates and solvates of the listed compounds. In order to select the active compound, the activity of the test compound when tested at 1 〇 5 m must be greater than 20% of the maximum activity when FS Η is used as the control group. It is regarded as an active compound. Another condition can be considered by E C5. EE C5〇値 must be < 1 〇-5Μ, preferably < 1 0 _ 7 Μ. This paper scale applies to Chinese national standard (CNS) A4 size (210X297 mm) -31 - 1322144 A7 B7 V. Invention description (2 bow (please read the back note first and then fill out this page) Those who are familiar with this technology should know the required EC 5 D値 will depend on the test compound. For example, a compound having an EC 50 値 less than 1 〇 5 Μ is generally considered to be a suitable choice for the drug. Preferably, the 値 is less than 10 7 Μ. However, if one Compounds, although having a higher E C5 oxime but being selective for a particular receptor, may be a better choice. Measuring the binding of gonadotropins to the receptor, as well as measuring the biological activity of the in vitro and live In vivo assays are common. In general, the expression receptor is contacted with the test compound, and then the binding sensation and the stimulation or inhibition of the functional response are measured. In order to measure the functional response, the FS is encoded. The DNA of the gene, preferably the human receptor, is expressed in a suitable host cell. These host cells may be Chinese hamster ovary cells, although other cells are also suitable. Preferred cells are cells derived from mammalian sources (Jia et al, Mol. Endocrin, 5: 759-776, 1991). The method of constructing a recombinant FSH expressing cell strain by the Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative is known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, recent edition) ). The performance of the receptor is obtained by expressing the DNA encoding the desired protein. Now, all of these techniques are known to those skilled in the art for mutation techniques for specific sites, joining additional sequences, P C R, and constructing appropriate performance systems. The DNA encoding part or all of the desired protein can be synthetically constructed using standard solid phase techniques, preferably including a restriction enzyme recognition site for easy ligation. The D N A coding sequence can also be provided with control elements suitable for transcription and translation of the contained coding sequences. For example, this paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) -32- 1322144 A7 _B7 V. Invention description (3〇 (please read the note on the back and fill in this page) There are many expression systems that are compatible with many hosts, including prokaryotic hosts such as bacteria and eukaryotic hosts such as yeasts, plant packets, insect packets, mammalian cells, avian cells, etc. Cells that exhibit receptors The test compound is then contacted to observe its binding or stimulatory or inhibitory effects of the functional response. Alternatively, a separate cell membrane containing the expression receptor can be used to measure the binding of the compound. Use radiolabeled or fluorescently labeled compounds. Human recombinant FS Η can be used as a control compound. In addition, competitive binding assays can be performed. Another assay involves the accumulation of c A Μ 调制 accumulated by the receiver. Screening of FS receptor agonist compounds. Therefore, this method involves expressing the receptor on the surface of the host cell membrane and will Exposure to the test compound. The amount of c AMP is then measured. The amount of c AMP may increase or decrease depending on the inhibitory or stimulating effect of the test compound after binding to the receptor. Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperative Printing In addition to directly measuring the amount of c AMP in exposed cells, the cell line used can be transfected with the DNA encoding the second receptor gene in addition to the DNA encoding the receptor, and the expression of the gene is Responding to the amount of c AMP. These receptor genes may be primed by c AMP or constructed to be linked to a novel c AMP response element. Generally, the expression of the acceptor gene may be c AMP by the reaction of any combination. Appropriate receptor genes are controlled by changing reaction elements such as LacZ, basic phosphatase, firefly luciferase, fluorescent protein, etc. The paper size of these transactivation assays is applicable to the Chinese National Standard (CNS) A4 specification ( 2丨〇><297 mm) -33- 1322144 A7 __B7 V. Description of the invention (3, Principles are known to the art and are detailed, for example, in Strat〇wa, Ch. Himmler, A. Czernilofsky, AP, (i995) Curr. Opin. Biotechnolo. 6: 574 » (Please read the notes on the back and fill out this page) The invention also relates to a pharmaceutical composition comprising a tetrahydroquinoline derivative of the formula I Or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant and optionally other therapeutic agents. The adjuvant must be "acceptable" in the sense that it is compatible with the other ingredients of the composition and does not The recipient may have a bad influence. The pharmaceutical composition may also contain tetrahydrofurfuryl quinoline-derived hexamethylene-6-benzamide- 4-(4-tolyl)_1, 2,3,4 —tetrahydro-2' 2 ,4-trimethylquinoline, 1-ethenyl- 4-phenyl-1,2,3,4-tetrahydro-2,2,4,6-tetramethylquina Porphyrin, 1-ethenyl- 4-phenyl- 1 ,2,3,4-tetrahydro-2,2,4,6,8-pentamethyl-α-quinoline, 1-ethylindenyl- 6-A Oxygen 4- 4-phenyl- 1 , 2 , 3 , 4 - tetrahydro - 2 , 2 , 4 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing _ trimethylquinoline, 1-ethyl sulfonyl one 6 - three Fluoroacetamido- 4-one (4-tolyl)-1,2,3,4-tetrahydro-2,2,4-trimethyl sinine, 1-ethylidene-6-trifluoroacetamido- 4-phenyl- 1 , 2 , 3 , 4 - tetrahydro - 2 , 2 , 4 - trimethyl π - quinoline , 1 - ethyl - 4 - ( 4 - chlorophenyl ) - 1,2,3,4 - tetrahydrogen — 2,2,4,6-tetramethylquinoline and 1-ethylindolyl-4—(4-bromophenyl)-1,2,3,4_tetrahydro-2,2,4,6- Tetramethylquinoline. Compositions, including, for example, those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, topical or rectal administration, are all pharmaceutically acceptable unit dosage forms. When administered orally, the active ingredient may be in discrete units, such as tablets, paper size applicable to Chinese National Standard (CNS) Α4 size (210X297 mm) -34 - 1322144 A7 B7 V. Invention Description (all capsules, powders) , nine doses, solutions and suspensions, etc. When administered parenterally, the pharmaceutical composition of the present invention may be administered in a unit dose or in a multi-agent container, for example, in a sealed vial or a watch glass vial, and It can be stored in lyophilized form by adding a sterile liquid carrier such as water prior to use. It can be mixed with pharmaceutically acceptable adjuvants such as those described in standard references, Gennaro, AR et al., Remington: The Science and Practice of Pharmacy (20th Edition. . Lippincott Willians & Wilkins, 2000, with particular reference to Section 5: Pharmaceutical Manufacturing), the active ingredient can be compressed into solid dosage units, such as tablets, lozenges, or processed into Capsule or suppository. The active agent can be administered in the form of a liquid composition, for example, an injection preparation, in the form of a pharmaceutically acceptable liquid. Suspension 'emulsions or sprays, for example in the form of nasal sprays. In the manufacture of solid dosage units, the use of conventional additives such as tanning materials, colorants, polymeric binding agents, etc., generally any pharmacy which does not interfere with the function of the active compound Acceptable additives can be used. The carrier can be used in a suitable amount to allow the active agent of the present invention to be administered as a solid composition, including lactose, starch, cellulose derivatives, etc., or In the case of parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be employed which may contain pharmaceutically acceptable dispersing agents and/or wetting agents such as propylene glycol or butylene glycol. Further included is a pharmaceutical composition which, as hereinbefore described, may be combined with a packaging material suitable for the solid composition, the packaging material may include instructions indicating the use of the composition in the foregoing. National Standard (CNS) A4 Specification (210X297 mm) (Please read the note on the back and fill out this page) - Install. Bureau employee consumption cooperative printing -35- 1322144 Α7 Β7 V. Invention description (both (please read the back note first and then fill out this page) The tetrahydroquinoline derivative of the present invention can also be implanted in the form of a pharmacy device. For administration, the device consists of a layer of outer membrane that regulates the release rate and a core of active material placed in the membrane. These implants can be administered subcutaneously or locally, and can be administered over a relatively long period of time. The active ingredient is released at a nearly constant rate over the course of several weeks. Methods of preparing implantable pharmacy devices are known in the art and are described, for example, in European Patent No. 0,303,306 (AKZO Nobel N.V.). The exact dose and administration schedule of the active ingredient or its pharmaceutical composition will necessarily depend on the desired therapeutic effect (treatment of infertility; contraception) and may be due to the particular compound used, the route of administration, and the patient to whom the drug is administered. The age and condition of the individual vary. Printed by the Ministry of Economic Affairs, the Intellectual Property Office, the Consumer Cooperative, the dose required for parenteral administration is lower than that required for other absorption-dependent methods of administration. However, the dose for human use is preferably an amount of from 0. 00 to 155 mg per kilogram of body weight. The required dose may be provided by a single dose or by sub-division of multiple doses of the agent at appropriate intervals within one day, or in the case of a female user, the required dose may be administered at appropriate intervals in the menstrual cycle. provide. This dose and dosing schedule may vary between female and male takers. Thus, the compounds of the invention may be used therapeutically. A further aspect of the invention relates to the use of a tetrahydro π-quinoline derivative of the formula I for the manufacture of a medicament which can be used to treat an abnormal disease responsive to the path modulated by the FS receptor, which is preferably used to control pregnancy, More preferably used to treat infertility or prevent pregnancy. The compounds of the invention may also be used to treat hormone-related abnormalities such as breast cancer, prostate cancer and endometriosis. This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) -36- 1322144 A7 ___ B7 V. Description of the invention (The present invention is shown in the following example. (Please read the notes on the back and fill in the form) This Example 1 Example Ethyl-R-(Third T-Carbonyl) Amino- 4-Leic- 1 -1, 2, 4, 4, 2, 2, 4 Methyl porphyrin (a) 6 - (t-butoxycarbonyl) amine 1 , 2 - bis-?, _2_, 4 - trimethyl porphyrin N- Boc-1, 4-phenylenediamine (5 · 0 g) and iodine (1.3 g) in a mixture of oxidized radicals (25 ml) at 1 Torr. (: stirring for 2 hours. The reaction mixture was concentrated under vacuum and the residue was at A 1 2 〇3 (aluminum oxide b, act. III) was chromatographed eluting with Heptane / methylene chloride = 8/2. (b) _1. _ 醯 -6 -6 - (Third argon carbonyl) amine - 1 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing - dihydro - 2,2,4 -trimethylquinoline Ethyl chloroform (11. 1 ml) and acetic anhydride (11. 丄Add dropwise to 6-(t-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (8.5 g) in pyridine (22 ml) and dichloro In a solution of methane (2 1 2 mL). After stirring for 18 hours, the reaction mixture was washed with 2M EtOAc and water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Gengben paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -37- 1322144 A7 __________B7_ V. Description of invention (1 2 3$ alkane / ethyl acetate = 8/2 (v / v) as a wash Deprotection to chromatography. Yield: 6 · 7 g. (Please read the notes on the back and fill out this page) MS-ESI : [M + H]+=331.2 (c ) 1 A 4-Benzene-1, 2,3, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printed - 38-1, 4, 2, 2, 4 - Trimethyl, a quinoline, 1-ethylenyl-6_ (third Butoxycarbonyl)amino-2,2,4-trimethyl-1,2-dihydroπ-quinoline (2 · 4 g) and A1C13 (9 · 5 g) in benzene (150 ml) mixture at 70 ° Stir for 1 hour at C. Mix the reaction It was cooled (0 t) and quenched with water and EtOAc EtOAc EtOAc EtOAc EtOAc. v) Chromatography as an eluent. Yield: 1.6 g. 2 MS — ESI : [M+H]+=309.2 (d) 1—Ethyl _ 6 —(2nd butyloxy)amino _ 4 Benzene 3 ——1 , 2, 3, 4- 4氤—2,2,4 —trimethyl morpholine 1 ethoxycarbonyl-6-amino-4_phenyl_1, 2,3, 1322144 A7 _B7___ V. Description of the invention (about eluent layer Yield: 8 mg. (Please read the notes on the back and fill out this page.) MS-ESI : [M+H]+=409.2 Example 2 ft-amine one-1—Ding醯—4-Benzene a 1, 2, 3, 4 - 4, 2, 2, 4 - trimethyl porphyrin (a) 6_ (third butyl carbonyl) amine 1 - butyl sulfhydryl - 1,2 - bismuth - 2, 2,4 - Trimethyl porphyrin Adds butyl hydrazine chloride (185 μl) dropwise to 6 -(t-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (5 Omg) and a catalytic amount of N,N-dimethylaminopyridine in a solution of pyridine (4 ml). After stirring for 18 hours, the reaction mixture was concentrated in vacuo. The ester was washed with water. The organic layer was separated, dried (MgSO4) and evaporated. Chromatography with heptane/ethyl acetate = 1/0 = > 7/3 (v/v) as eluent. Yield: 4 7 mg. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, MS-ESI : [Μ+Η]+=359·4 (b) 6—Amino-]-butyne-—4—Benzene—1,9,q,4—four gas_2,2,4-trimethyl Rotary porphyrin will be 1-butyryl-6-(t-butoxycarbonyl)amino-1, 2,2-di-2,2,4-trimethylquinoline (47 mg) and A1C1; China National Standard (CNS) A4 Specification < 210X297 mm) -39- 1322144 A7 B7 V. Description of Invention ((Please read the note on the back and fill out this page) 5 2mg) Mixture of Benzene (2ml) at 60 After stirring for 6 hours at ° C. The reaction mixture was cooled (0 ° C) and quenched with water and EtOAc EtOAc EtOAc (EtOAc m. Purification by PLC. Production: 10 mg. MS - ESI: [M + H] + = 337. 2; 1^? B (:: 111 = 6_97 minutes (method 1) Example 3 醯 -6 - Amino-4-(4-indolyl)_1,2, 1,4_ 4氤2,2,4—三甲晬晬1_乙醯基_6 —(Tertidinoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylporphyrin (25 mg) and a mixture of AlCh (35 mg) in chlorobenzene (2 ml) were stirred for 1 hour. The reaction mixture was quenched with water and an additional 2M aqueous solution of EtOAc and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. MS-ESI: [M+H]+=343.4; HPLC: Rt = 6 · 16 minutes (Method 1) Example 4 1 - Ethyl- 6-Amino- 4 One (4-aminophenyl)-1, 2,3,4-tetradecyl-2,2,4-trimethyl-rotorine according to the method described in Example 3 in the presence of A 1 C 1 3 with fluorobenzene (2 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -40- 1322144 A7 B7___ V. Description of invention (3$ ml) and 1_Ethyl- 6-(t-butoxycarbonyl)amino group —1 , (Please read the note on the back and then fill out this page) 2 —Dihydro-2,2′ 4-trimethyl π-quinoline (25mg) for Friedel-Craft hospitalization. Yield: 15 mg. MS - ESI : [Μ+Η]+=327·4; HPLC: Rt = 5 . 6 3 minutes (method 1) Example 5 _1 1-ethylidene- 6 - limbs-1, ~ soil, 4 _四氤—4 _ ( j —tolyl) — a 2, 2, 4 — trigram — _ queline according to the method described in Example 3 in the presence of A 1 c 1 3 (3 5 mg) with a copy (2竜; 升) with 1 _ acetyl group ~ 6 _ (t-butoxycarbonyl) amine group - 1 2 - Dihydro-2,2,4-trimethyl d-quinoline (25 mg) for Friedel-Craft alkylation Yield: 2 2 mg. MS - ESI: [M+H]+ = 323. 2 Economy Ministry of Intellectual Property, Staff Consumer Cooperatives, Printing Example 6 J—B with the base-6 —__( 4 chlorobenzidine) amine 4 phenyl _ -i~^—2_:__3__1 4 —four 氤A 2,2_trimethyl p-quine will be 1-ethyl aryl-6-amino- 4~~phenyl-i, 2,3, 4-tetrahydro- 2,2,4-trimethyl-methyl % (1 mg), 4-chlorobenzhydryl chloride (1 lmg) and N'N-diisopropylethylamine (22 μl) in a mixture of tetrahydrofuran (1 ml) 8 hours. This paper scale applies to Chinese national standard (CNS } A4 specification (2丨0><297 mm_^ ' -41 - 1322144 A7 B7__ V. Invention description (please read the notes on the back and fill in the form) The reaction mixture was concentrated in vacuo and the residue was taken in ethyl acetate and washed with EtOAc EtOAc EtOAc Magnesium is dehydrated and concentrated in vacuo. The residue is on silicone. Heptane / ethyl acetate = 1/0 = > square / 1 (v / v) as the eluent for chromatography. Yield: 9.5 mg. MS - ESI : [M+H] + =447. 4 ; HPLC : Rt = 10. 87 minutes (method 1) Example 7 1 _ 醯 醯 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 , p, Q, 4 - four gas - 2, 2, 4 - trimethyl porphyrin according to the method described in Example 6 with 1-ethyl fluorenyl-6-amine 4 _ phenyl- 1 , 2 , 3 , 4 - four gas 2,2,4-trimethyl [I-quine (10 mg)' of the present brewyl chloride (9.img) and diisopropylethylamine (22 microliters) in tetrahydrofuran (i ml The mixture is subjected to a deuteration reaction. Yield: 1.2 mg β Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed MS-ESI: [Μ + Η]+=413.4; HPLC: Rt=10. 01 min (method) Example 8 1-Ethyl 4-41-phenyl-1, 2,4-tetraindole-β-(4-mono[trifluoromethyl]benzylidene)-amino-2, 2 basic paper scales applicable to Chinese National Standard (CNS) Α4 Specifications (210Χ297 mm) -42- 1322144 A7 B7 V. Description of the invention (岣p-quinoline (please read the back note first and then fill out this page) According to the method described in Example 6 with 1 _ acetyl- 6-amine 4-Phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 4-trifluoromethylbenzimidyl chloride (14 mg) and N , N-diisopropylethylamine (2 2 μL) was subjected to oximation in tetrahydrofuran (1 mL). Yield: 8.9 mg. MS - ESI: [M+H]+=481_4; HPLC: Rt = l〇. 76 minutes (method 1) Example 9 1 - Ethyl- 6-(4-nitrobenzidine) Amine-4-Benzene-1, 2, 3, 4 - 4 gas-2 , 2,4-trimethylquinoline according to the method described in Example 6 with 1-acetamidine - 6 -Amino-4-phenyl- 1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 4-nitrobenzoguanidino chloride (12 mg) and N,N-diisopropylethylamine (2 2 μL) was subjected to deuteration reaction in tetrahydrofuran (1 ml). Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed yield: 8.2 mg. MS — ESI: 〔 M+H]+ = 458. 4; HPLC: Rt = 1 〇. 02 min (Method 1) Example 1 0 1 -Ethylamino-4-phenyl- 6-(4-propenylbenzylidene) The size of the amine paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -43- 1322144 A. Rosin A7 B7 V. Invention Description (4 Jinji 1 ' 2 ' 3 ' 4 — £3 Μ ~ According to the method described in Example 6, 1 ~ ng _ 6 amine _ 4 phenyl - 1 , 2, 3 , 4 - tetrahydro - 2, 2, Lin (10 mg) ' 4 - n-propyl benzene Metformyl chloride (1 2 mg) and ...-diisopropylethylamine (2 2 μl) were subjected to a oximation reaction in tetrahydrofuran < cc. Yield: 6.7 mg. 4 _ trimethyl alpha quinone MS — ESI : [ M + Η ] 4 5 4 ;

Η P L C

R 1 9 minutes (method (please read the note on the back and then fill out this page) Example 1 1 1 - Ethyl 6 - (3 - bromo - 2 ) Amino - 4 - Benzene - 1 ~ ~ A A certain scorpion scorpion scorpion scorpion scorpion scorpion scorpion sulphur porphyrin 1 - acetyl sulfonyl 6 - 4 - tetrahydro - 2 , 2 , 4 - bromo 2 , 6 - dimethoxybenzene Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed aza-benzotrisyl hexafluorophosphate, isopropylethyl, 1 8 small ethyl acetate solution, water and residue in the oxazol-1 -yl acid salt HA Τ Amine (3 2 μL. Mix the reaction and wash with 0.5 Μ brine. 矽 上 庚 庚 庚 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- (25 mg), 3_ formic acid (23 mg), 〇_(7 — —N,N,n, > n '-tetramethylhydrazine) (68 mg) and ν,Ν-di) in dichloromethane (4 ml) The mixture was concentrated under vacuum, and the residue was dissolved in EtOAc (EtOAc). Water, EtOAc, EtOAc. Applicable to China National Standard (CNS) Α4 Specifications (210Χ297 PCT) -44- 1322144 A7 B7 V. Description of the invention (Voice (V/V) as eluent for chromatography. Yield: 2 8 mg. (Please read the notes on the back and fill out this page) MS — ESI: [M + H]+ = 551. 4; HPLC: Rt = 3 . 75 min (Method 2) Example 1 2 1 _Ethyl 4-ylphenyl-6-(4-phenylbenzylidene) Amino-1,2,3,4-tetradecyl 2,2,4-trimethylquinoline according to the method described in Example 6 with 1 _ acetyl group -6-amino group 4 - phenyl- 1 , 2,3,4-tetrahydro-2,2,4-trimethylquinoline (11 mg), 4-diphenylcarbonyl chloride (16 mg) and N,N-diisopropylethylamine (2 2 The oximation reaction was carried out in tetrahydrofuran (1 ml). Yield: 1' 0 mg. MS - ESI: [M+H]+ = 489.4; HPLC: Rt = l 1 . 62 min (method 1) Example 1 3 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1 Ethyl ketone-6 (4 - ί 4 - chlorobenzene 1 benzylidene) Amine _ 4 phenyl-1, 2, 3, 4氤2,2,4-trimethyl D-quinoline a) 1-ethyl fluorenyl _6_(4_iodobenzylidene)amino group _4_phenyl fluorene 2,3,4-tetrahydro-2,2,4-trimethylporphyrin 1-Ethylamino-6-amino-4-phenyl_1,2,3, this paper size is applicable to China Standard (CNS) A4 size (210X 297 mm) -45- 1322144 A7 __B7_ V. Invention description (4$ (please read the note on the back and fill out this page) 4 —Tetrahydrogen 2,2 ' 4 —3 A mixture of methylquinoline (300 mg), 4-iodobenzylidene chloride (52Omg) and a catalyst portion of N,N-dimethylaminopyridine in pyridine (4 ml) was stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dehydrated (MgSO4) and concentrated in vacuo. Yield: 460 mg. MS — ESI : [M+H]+=539.4; HPLC: Rt = l 〇. 98 min (method 1) (b) 1 -ethinyl-6 (4 - 1:4 - chlorobenzene 1 benzamidine) A) 4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl porphyrin 1_ethyl hydrazine _6 — (4_iodobenzylidene) Amino- 4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline C 2 5 mg ), 4-chlorophenylboronic acid (22 mg), fluorinated planing Intellectual Property Bureau employee consumption cooperative printed 14 mg), triphenylsulfonium (5. Omg) and ginseng (diphenylacetone) dipalladium (0) (4.3 mg) in dimethoxyethane/ethanol 4: A mixture of 1 (5 ml) was stirred under nitrogen for 15 minutes through a solution of bubbling nitrogen. After being placed at 80 ° C for 3 hours, the reaction mixture was concentrated in vacuo. EtOAc m m m m m m m m . The organic layer was dehydrated with magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1 / 0 = > 0/1 (v / v) as eluent. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -46 - 1322144 A7 B7 V. Description of invention (44 Yield: 16 mg. MS-ESI: (M + H) +=523 . 4 ; (Please read the precautions on the back and fill out this page.) HPLC : Rt = 4 · 40 minutes (method 2) Example 1 4 1 - Ethyl 4- 4 -phenyl - 6 (4_[3_pyridyl) Benzoquinone a certain amine 1, 2, 3, 4 - tetradecyl 2, 2, 4 - trimethyl η quinoline according to the method described in Example 13, 1-ethylidene- 6-(4 Iodophenylmercapto)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg), acridine-3-borate-1 3-propanediol-cyclic ester (23mg), fluorinated planing (14 mg), triphenylsulfonium (5.0 mg) and ginseng (diphenylacetone) dipalladium (〇) (4.3 mg) in dimethoxy Methyl ethane / . ethanol 4: 1 (v / v) (5 ml) for the Mitsubishi cross-coupling reaction. Yield: 1 7 mg. MS - ESI : [M + H] + = 490.4; ^1? 1 ^ <;::1^ = 7.11 minutes (method 1) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example 1 5 Ί 一乙醯基一一一Base_6_(2_phenyl_5_methoxybenzoindolyl)amino-1,2,3,4-tetra--2,2,4-trimethylquinoline (a) 1 _ acetamidine Base 6—(2-Bromo-5-methoxybenzoquinone) This paper scale applies to Chinese National Standard (CNS) A4 Specification (210X297 mm) -47 - 1322144 A7 B7 V. Description of Invention (4$ Amine 4--4-phenyl-1,2,3,4-tetraindole-2,2,4-trimethylquinoline (please read the back note first and then fill out this page) according to the method described in Example 1 , 1-ethyl fluorenyl-6-amino-4-phenyl-1,2,3,4-tetraamino-2,2,4-dimethylquinoline (25 mg) and 2-bromo-5 -Methoxybenzoic acid (21 mg) was condensed under a medium of HATU (6 8 mg) and N,N-diisopropylethylamine (32 μL) in dichloromethane (4 mL). Yield: 31 mg. MS - ESI : [M+H]+ = 521 · 4 ; HPLC : Rt = 3 · 74 min (method 2) (b) 1 -ethinyl-4-phenyl-7-(2) -Phenyl-5-methoxybenzoguanidino)amine 1 , 2,3,4_tetraki- 2,2,4-trimethyl d-quinoline economic ministry The property bureau employee consumption cooperative printed according to the method described in Example 1 3 '1 乙 一 一 -4- phenyl 1-6-(2-bromo-5-methoxybenzhydryl)amine _1, 2 , 3,4_tetrahydro-2,2,4-trimethylquinoline (30mg), phenylboronic acid (25mg), fluorinated planer (21mg), triphenylsulfonium (7 · Omg) and ginseng (diphenyl) Fork acetone) dipalladium (0) (6 · 0 mg) in dimethoxyethane / ethanol 4: 1 (v / v) (5 ml) for Mitsubishi cross coupling reaction. Yield: 2 3 mg. MS-ESI: [Μ + Η]+=519·4; This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) -48- 1322144 A7 B7 V. Description of invention (4$ HPLC : Rt = L〇. 87 minutes (method 1) (Please read the notes on the back and fill out this page) Example 1 6 1 -Ethyl-4 - Benzene 6-(2-phenyl-3-methylbenzene Aβ group) Amino group 1 9 2 > 3 j 4 —tetraki- 2 2 9 4 dimethyl porphyrin ( a ) 1 — acetyl _ 4 — yl 1 - ( 2 bromo _ 3 _ Methylglycidyl) Limb 1 > 2 > 3 ,4 -tetrahydro 2 2 9 4 Dimethyl D-quinoline 1 - Ethyl-6-amine according to the method described in Example 1 Base - 4 - phenyl - 1 5 2 5 3 f 4 - tetrahydro - 2 j 2 ) 4 - trimethyl hydroxyquinoline (25 g: g) with 2 - bromo-3-methylbenzhydrazide Acid (19 mg) was condensed in a medium of ΗATU (6 8 m S ) and N, N-diisopropylethylamine (32 μL) in a solution of dichlorocarbyl (4 ml) Yield; 1 6 • 3 mg 〇Μ S — ESI ; [Μ + η : 1 + = 5 0 5 . 2 t Η PLC * R t 2: 3 • 8 0 minutes (method 2) ( b ) 1 acetyl group 4 propyl-6-(2 benzyl 3-methyl-p-methyl)amino 1 2 > 3, 4 -tetrahydro 2 j 2 9 4 - mono-methyl quinone 1 咐 according to the method described in Example 1 3 , 1 - Ethyl 4- 4 - phenyl-6-(2-bromo-3-methylbenzhydryl)amine- 1 , 2, 3 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed this paper The scale applies to China National Standard (CNS) A4 specification (210X 297 mm) -49- 1322144 A7 B7 V. Invention description (邛 (please read the note on the back and fill in this page), 4 —Tetrahydrogen-2,2 , 4-trimethylquinoline (16mg), benzoic acid (25mg), fluorinated (21mg), triphenylsulfonium (7.0mg) and ginseng (diphenylacetone) dipalladium (0) (6.0 mg The Mitsubishi cross-coupling reaction was carried out in dimethoxyethane/ethanol 4:1 (v/v) (5 ml). Yield: 4.9 mg. MS - ESI: [M + H] + = 503. 3; HPLC: Rt = 4.61 min (Method 2) Example 1 7 1-Ethyl- 4 -phenyl-1,2,3,4 - -6-(α-toluenesulfonyl)amino- 2,2,4-trimethylporphyrin according to the method described in Example 6 with 1-ethenyl-6-amino-4-phenyl-1 , 2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) and toluenesulfonyl chloride (1 2 mg) and hydrazine, N-diisopropylethylamine (2 2 μl of sulfonation reaction in tetrahydrofuran (25 ml). Yield: 9.8 mg. MS-ESI: [Μ + Η]+=463·4; HPLC: Rt = 9 · 49 minutes (method 1) Example 1 8 1 _Ethyl 4- 4 - benzene Base-6-(anilinecarbonyl)amine A 1,3,4-tetrahydro-2,2,4-trimethylquinoline paper size applicable to China National Standard (CNS) A4 specification (210X 297 mm) -50 - 1322144 A7 ___B7_ V. INSTRUCTIONS INSTRUCTIONS (1 醯 醯 一 -6-amino- 4-phenyl- 1 , 2, 3, (please read the notes on the back and fill out this page) 4 Hydrogen-2'2 '4-trimethylquinoline (10 mg), phenyl isocyanate (8 · Omg) and N,N-diisopropylethylamine (22 μL) in tetrahydrofuran ( 1 ml) The mixture was stirred for 18 hours. The reaction mixture was concentrated in vacuo. EtOAc EtOAc m. The organic layer was dried over MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Mg. M S-ESI: CM + H) + = 428 . 4 ; ^^? 2 (:: 1^ = 1 〇. 39 minutes (method 1) Example 1 9 1 醯 醯 _6_ (Third butyl sulphide羯 ) ) — — 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济 经济Method: 1-Ethyl-6-amino-4-phenyl-1,2,3,4-tetrahydro, 2,4-trimethylquinoline (10 mg) and tributyl isocyanate The ester (7.5 mg) and N,N-diisopropylethylamine (22 μL) were subjected to thiourea formation in tetrahydrofuran (1 ml). Yield: 0.50 mg. MS-ESI: ??? M + H]+=424.4; 1^?]^(:: Ruler 1 = 5.90 minutes (method 1) This paper scale applies to Chinese national standards (CNS > A4 specification (210X297 mm) -51 - 1322144 A7 __B7___ V. Description of the invention (4 Orders Example 2 0 (please read the notes on the back and fill in the page again) 1 - Ethyl-6-(T-T benzene) Amine- 4 Benzene _1 2,2,4 —tetrakis-2,2,4-trimethylporphyrin. Tri-argon-hydrogen hydrazine 1-ethoxyphenyl-6-amino-4-phenylene a 1,2,3,4-tetrahydro-2,2,4-trimethylporphyrin (10 mg), 4-(t-butyl)phenyl chloride (6.5 mg) and N,N-II Isopropylethylamine (10 μL) was stirred in a mixture of tetrahydrofuran (1 mL) at 50 ° C for 18 h. The reaction mixture was concentrated in vacuo. EtOAc m. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = I / O = > 0/1 (v / v) as eluent. Yield: 3.1 mg. MS-ESI: [M + H]+=455.4; HPLC: Rt = 10 · 00 min (method 1) Example 2 1 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 1 乙_基—4_苹基— gT_. (3 diphenylpropanoid) marinate a certain ·| , 2 , 3 , 4_ tetrahydro - 2 , 2 , 4 - trimethyl per u - quinoline according to the method described in Example 6 with 1-ethylenyl - 6-Amino-4-phenyl-1,2,3,4-tetrahydro-2' 2,4-trimethyl π-quinoline (10 mg) and 3-phenylpropenyl chloride (1 img) And hydrazine, N-diisopropylethylamine (2 2 μl) in tetrahydrofuran (25 ml) This paper scale is suitable for Laijia standard (coffee) A4 specification (2 cut 297 dong) 1322144 A7 B7 five The invention is described as the deuteration reaction. Yield: 1.2 mg. (Please read the notes on the back and fill out this page.) MS — ESI : 〔Μ + Η〕+=441·4; HPLC : Rt=10 25 minutes (method 1) Example 2 2]-Ethyl-6-(2-furanylmethyl)amine 4- 4-phenyl-], 2,3,4-tetraindole-2,2, 4-trimethyl porphyrin according to the method described in Example 6 with 1-ethyl fluorenyl-6-amino-4-phenyl-1,2 , 3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-furylmethyl chlorohydrin (8 · 5 mg) and N,N-diisopropylethylamine (2 2 liters of the oximation reaction in tetrahydrofuran (1 ml). Yield: 7. 7 mg. MS - ESI: [M+H]+ = 403. 4; HPLC: Rt = 8.91 min (Method 1) Example 2 3 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1_ 醯 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 Methylquinoline according to the method described in Example 6 as 1-ethinyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with isoamyl chloride (7.8 mg) and N,N-diisopropylethylamine (22 μL) in tetrahydrofuran (1 ml) for this paper scale applicable to Chinese national standard (CNS) A4 size (210X 297 mm) -53- 1322144 A7 B7 V. Description of invention (5) Deuteration reaction. Yield: 5 · 3 mg. (Please read the notes on the back and fill out this page) MS — ESI : [Μ + Η]+=393·4; 1^ 尸1^(::1^ = 9.35 minutes (method 1 Example 2 4 1 -Ethylamino-6-(3 - ί adamantane-1-yl)propanyl)amino-4-phenyl- 1, 2, 3, 4-tetra--2,2 , 4-trimethylquinoline, according to the method described in Example 11, 1 1-ethylindolyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4 - Trimethyl morphine (10 mg) and 3 (adamantane-1-yl)propionic acid (1 Omg) in HATU (25 mg) and hydrazine, hydrazine-diisopropylethylamine (2 2 μL) The condensation was carried out under a medium of dichloromethane (1 ml). Yield: 6.7 mg. MS-ESI: [Μ+Η] + =499 · 4 ; HPLC: Rt = 12.43 minutes (method 2) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example 2 5 1 _ 醯 醯 - (B a certain amine, a certain 1,4-phenylene, a 1, 2, 3, 4 _ tetra- 2, 2, 4 _ trimethyl porphyrin according to the method described in Example 6 with 1-ethyl fluorenyl-6-amine Base - 4 -phenyl-1 , 2 , 3 , 4 - tetrahydro - 2,2 , 4 - trimethyl sulfonium paper scale applicable to Chinese National Standard (CNS ) A4 specification (210X297 mm) -54 - ^22144 A7 —--- B7 ___________ V. INSTRUCTIONS (Pelin (1,500 mg) and ethylpropanediyl chloride (1,7 mg) and N'N-diisopropylethylamine (3 1 4 μl) deuteration reaction in tetrahydrofuran (8 ml) (Please read the note on the back and fill out this page) Yield: 1 6 3 mg. MS-ESI: [M + h]+=423_2; ^(::Ι11 = 8.48 minutes (method 1) Example 2 6 丄_二乙醯基_6_ ( ί 4 4~ arginylamino)carbonyl carbonyl carbonyl, β right: y: d — pingji II 1 , 2,3 , 4-tetrazole — 2, 2, d — dimercapto basal beer _ (a ) 1 —ethylenyl hydroxycarbonyl Carbonyl)amine bis-1,2,3,4,tetrahydro-, ,4-trimethyl porphyrin, Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, printing 2M Na〇H solution dropwise to ι_B Sulfhydryl- 6-(ethylpropanediyl)amine- 4-phenyl-1,2,3,4-tetrahydro-2,2,4-dimethyl quinolate (i6img) 4/1 (v/v) (12 ml) of the stirred solution until the pH reached 14. After stirring for 3.5 hours, the reaction mixture was poured into water and the ethyl acetate was used under ρ Η 2 The organic layer was washed with water and brine, dried (MgSO.sub.sub.sub.sub.sub.sub.sub.sub. 43 minutes (method 1) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -55- 1322144 A7 B7 The method described as '4-methoxyphenylamine phenyl 2 V. Description of the invention (5$ (b) 1 ~ ^ - 6 茏 茏 ] ] 羰 羰 羰 一 一 一 4 4 , _4 - four 氤 - 2, 2, 4 _ trimethyl PF quinolin according to Example 1 2mg) 1-Ethyl fluorenyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-tetrahydro-2,2,4-trimethyl D-quinoline (103⁄4 g) in HATU (l9mg) and N,N - diiso The propylethylamine (16 μL) was condensed under a medium of tetrahydrofuran (2 ml). Yield: 7.3 mg. (Please read the notes on the back and fill out this page) MS — ESI : [M + H] 5 4.4; Intellectual Property Intelligence Bureau Staff Consumer Cooperative Printed HPLC: Rt = 8. 80 minutes (Method Example 2 7 1 -乙醯基一6 — Γ "7. Oxycarbonylmethylamine, a certain carbonyl, a certain amine, a certain amine - 4 - phenyl - 1, 2, 3, 4 - four 氤 one?., 2, 4 - three Base D-quinoline according to the method described in Example 11, glyceryl ethyl ester. HC1 (5 _ 3 mg) and 1-ethyl fluorenyl-6-(hydroxycarbonylmethylcarbonyl)amino group 4-phenyl- 1 , 2, 3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) in HATU (19 mg) and N,N-diisopropylethylamine (16 μl) in tetrahydrofuran (2 ml) The condensation is carried out under the medium. Yield: 4 · 6 mg. This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1322144 A7 B7 V. Invention description (5 MS-ESI: [M + H] + =480 · 6 ; 1^卩1^(::1^ = 7.94 minutes (method 1) (Please read the notes on the back and fill out this page) Example 2 8 ]_乙醯基_6— ( Ν -ethyl-N-anilino)carbonylmethylcarbonyl Amino- 4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl D-quinoline oxime-ethylaniline according to the method described in Example 11. 2 mg) with 1-ethyl fluorenyl _6_(hydroxycarbonylmethylcarbonyl)amino _4_phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg Condensation was carried out in a medium of HATU (19 mg) and N,N-diisopropylethylamine (16 μL) in tetrahydrofuran (2 mL). Yield: 7 · 3 mg. MS-ESI: [Μ+ Η]+=512· 6 ; HPLC: Rt=9.36 minutes (method 1) Example 2 9 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 1-Ethyl-( ί2 ,4-difluoroanilino)methylcarbonyl Amino- 4-phenyl-1,2,3,4-tetraindole-2,2,4-trimethyl-p-quinoline (a) 1-acetoxy-6-(y odorantyl)amine Benzyl 4-phenyl- 1 , 2,3,4-tetradecyl 2,2,4-trimethyl porphyrin according to the method described in Example 6 with 1-ethyl fluorenyl-6-amino-4 Paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) -57 - 1322144 A7 B7 ___ V. Invention description (5$ (please read the back) Note: Please fill in this page) —Phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl-11-quinoline (1,300 mg) and bromoethylidene chloride (6 9 μm) The oximation reaction was carried out with methylene chloride (10 mL) in N,N-diisopropylethylamine (1 2 1 μL). Yield: 151 mg. MS-ESI: 〔Μ + Η〕+=431·2 (b) 1 —Ethyl 6-( ί2 ,4-diarsenylamine 1 A-decyl)Amino-4-phenyl-1,2 , 3,4 -tetrakis, 2,._ 4 _ trimethyl hydrazine quinone 1_ethyl fluorenyl-6-(bromoethenyl)amine- 4-phenyl- 1 ' 2 , 3 , 4 - tetrahydro-2,2,4-trimethylquinoline (1 〇 mg), 2,4 difluoroaniline (6.0 g) and N,N-diisopropylethylamine (10 μL) The mixture in di-alkane (2 ml) was stirred at 40 ° C for 18 hours. The reaction mixture was concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol = 1 / s = > 9 5 /5 (v/v) as eluent. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed output: 5 · 5 mg. MS-ESI: [Μ + Η]+=492 HPLC: Rt = 6.74 min (Method Example 3 0

~ 58« Call 144 A7

According to the method described in Example 29, 1 _ phenylpiperazin ((Please read the back of the note before refilling this page) 7 _ 0 μl) and 1-ethyl sulfonyl- 6-(bromoacetamidine) Amino-4-yl-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl d-quinoline (1 Omg) and N,N-diisopropylethylamine (i N-alkylation was carried out in dioxane (2 mL). Calving: 8.4 mg. MS — ESI: [M + H]+ = 511. 4; HPLC: Rt = 7 _ 〇 1 min (method i) Example 3 1 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 丄二二乙醯基二II-I....[N-morpholinium carbamoyl)amine 1/1 — shame~~1,2,3'.4_tetrahydro-2_1_2,4—three _ 卩 卩 啉 根据In the method described in Example 2, the morpholine (4. 〇 microliter) and 1-ethyl fluorenyl-6-(bromoethenyl)amine group are 4-phenylene, 2, 3, 4-14 Hydrogen 2,2,4-trimethylporphyrin (1 〇 mg) and N,N-isopropylethylamine (9 μL) were subjected to N-alkylation in dichloromethane (2 mL). Yield: 10 mg. MS-ESI: [M + H]+=436.4; HPLC: Rt = 5 · 64 min (method 1) Example 3 2 1 -ethylthiol-6-(2-dithiopheneamine) 锶一一~ Ping 1 — This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -59- 1322144 A7 _B7_ V. Description of invention (1,?,,3,4—four gas one 2,2,4 — Trimethyl porphyrin (a) 1 , 2 - dihydro - 2 , 2 , 4 - trimethyl porphyrin mono-carboxy (please read the back of the note before refilling this page) methyl ester according to the method described in Example 1. The Skraup reaction was carried out with methyl 4-aminobenzoic acid ester (5.0 g) and iodine (1.7 g) in yttrium oxide (25 ml). Yield: 2.3 g. MS-ESI: [M + H] + = 232 · 2 (b) 1 - ethyl hydrazino - 1 , 2 - diterpene - 2 , 2, 4 - trimethyl morphine - 6 - carboxylic acid methyl ester will be 1, 2 - dihydro - 2 , a mixture of 2,4-trimethylquinolin-6-carboxylate (2·3 g) and a catalytic amount of N,N-dimethylaminopyridine in acetic anhydride (60 ml) at 1 0 0 Stir for 18 hours at ° C. The reaction mixture was concentrated in vacuo. The organic layer was dehydrated (magnesium sulphate) and concentrated in vacuo. The residue was purified by heptane / ethyl acetate = 1 / 1 = printed by the Intellectual Property Office of the Ministry of Economic Affairs. >1/9 (v/v) as an eluent for chromatography. Yield: 2. 3 g (c) 1 - B-- 4 Benzene 1 , 2 , 3, 4 - 4 - 2 , 2 , 4_trimethylquinoline monocarboxylic acid methyl ester according to the method described in Example 3 in the presence of A 1 C 13 (4.4 g) with benzene (60 ml) and 1-ethylenyl-1, 2 - Dihydrogen-2, the paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) -60-1322144 Α7 Β7 V. Invention description (5$ 2,4 - trimethyl 0 quinine - 6_ Residual methyl ester (2.3 g)

Friedel-Craft alkylation. Yield: 1.2 g. MS-ESI: [M + H]+ = 352. 4; HPLC: Rt = 9. 72 min (method) (d) _1 - acetonitrile - phenyl - 1 , ? ., q , 4 — 四氤一 2 , 2, 4 — Trimethyl porphyrin — 6 — Heteroquinone Add 2M NaOH solution dropwise to 1_Ethyl _4_phenyl-1, 2, 3 ' 4 a stirred solution of tetrahydro-2' 2,4-trimethyl ti quinolin-6-carboxylate (1.2 g) in dioxane/water 4:1 (v/v) (50 ml) Until the PH 1 2 is reached. After stirring for 18 hours, the reaction mixture was poured into water and extracted with ethyl acetate (EtOAc). The organic layer was washed with water and brine, dried (MgSO4) Yield: 8 9 1 mg. MS - ESI: [M + H]+ = 338. 2 (e ) 丄 · ~ B - yl - 6 - _L2 - thiophene methylamine) forging base _ 4 _ base -~~~~~2__:_3__: _4-tetrahydro-2,2,4~di-methyl [1 quinine] according to the method described in Example 11, 1 2-thiophenemethylamine (5. 〇mg) and 1_acetamidine_4_phenyl _1, 2,3,4-tetrahydro-2,2,4-trimethylmorpholine-6-carboxylic acid (1 mg) in HATU (2 3 mg) and hydrazine, N-diisopropylethyl Amine (1 g of this paper size is applicable to ^^^ (CNS) 八4 threat (21〇χ297 mm) (Please read the notes on the back and fill out this page) [Installation · Ministry of Economic Affairs Intellectual Property Bureau employees Consumer Cooperatives Printed -61 - 1322144 A7 B7 V. Description of the invention (5 microliters) Condensation in a medium of dichloromethane (2 ml) Yield: 3 · 0 mg. (Please read the notes on the back first) MS-ESI: [M+H]+=433.4; HPLC: Rt = 9 . 28 min (Method 1) Example 3 3 1 -ethylamino-6-(2 - [4-methoxy] Phenyl]ethylamine) carbonyl some 4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline according to Example 1 1 method, 2-(4-methoxyphenyl)ethylamine (6 · lmg) and 1-ethylindole-4-phenyl-1,2,3,4-tetrahydro-2,2,4 Condensation of a trimethylquinoline-6-carboxylic acid (10 mg) in a medium of HATU (23 mg) and N,N-diisopropylethylamine (19 μL) in dichloromethane (2 mL) Yield: 9. 9 mg MS-ESI: [Μ+Η]+=457·4; HPLC: Rt = 9 · 34 minutes (Method 1) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Example 3 4 1 _ 醯 醯 _6_ (3 -isopropyl amphetamine) carbonyl a 4-benzene certain 1, 2, 3, 4 - tetrahydro - 2, 2, 4 - trimethyl p-quinoline according to the embodiment 1 1 method, 3 - isopropoxypropylamine ( 5.2 mg) and 1- acetyl -4-phenyl -1, 2, 3, 4 paper size applicable to China National Standard (CNS) A4 specifications (210X 297 mm) -62- 1322144 A7 B7 V. Description of the invention (6〇tetrahydro-2,2,4-trimethyl d-quinoline-6-carboxylic acid (1〇mg) in HATU ( 2 3mg ) And n,N-diisopropylethylamine ((Please read the back of the note before you fill out this page) 19 micro ) For condensation at a square Yield hospital chloroformate (2 ml) Media: 8.8 mg. MS - ESI: [Μ + Η]+=437·4; HPLC: Rt = 8 . 80 min (method i) Example 3 5 1 - ethyl hydrazine - 6 - (2 - [methylthiol 1 ethylamine ) Carbonyl - 4 - A group - "_, 2 '_3 ' 4 - Tetrahydrogen 2,? , 4 - trimethyl a dark porphyrin according to the method described in Example 1 '2 - (methylthio) ethylamine (4.1 mg) and 1 acetoin-4-phenyl-1, 2, 3, 4 a tetrahydro-2,2,4-trimethyl d-quinoline-6-carboxylic acid (1 mg) in HATU (2 3 mg) and hydrazine, N-diisopropylethylamine (19 μL) The condensation was carried out under a medium of dichloromethane (2 ml). Yield: 10 mg. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed MS — ESI : [M + H]+=4ll . 4; HPLC : Rt = 3 . 33 minutes (Method 2) Example 3 6 1 - Ethyl group 6 - ( Methoxyphenoxy) _ -4- benzene a certain 1, 2, 3, 4 - tetrahydro-2, 2, 4 - 〒 A certain acetaine according to the method described in Example 1-1, 4 - Methoxol (6.2) This paper scale applies to National Standards (CNS) Α4 (210Χ297 mm) -63- 1322144 A7 ____ B7 V. Inventions (6) (Please read the notes on the back first) Complete this page) mg) with 1-ethylindole 4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl alpha quinolate-6-carboxylic acid (1 mg) The condensation was carried out in a medium of HATU (2 3 mg) and hydrazine, hydrazine-diisopropylethylamine (19 μL) in dichloromethane (2 mL). Yield: 7.2 mg. MS-ESI: [M+H]+ = 458. 4; HPLC: Rt = 3 . 90 min (method 2) Example 3 7 ethyl hydrazide - ft - (4 - phenyl benzophenone) oxygen - 4—Pinger 2, 2, 3, 4-14, 2, = A 啐瞅L a ) 1 , __2 — 氤 6 6 — methoxy 2,2,4- = D quinoline according to The method described in Example 1 carried out a Skraup reaction with 4 ~ anisidine (5.0 g) and hydrazine (1.7 g) in cerium oxide (25 ml). Yield: 2.3 g. MS- ESI :[M+H]+ =204. 2 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Consumers' Cooperatives (b) _1_—Ethylene-based 1' 2 — one gas-R-methoxy- 2m, 2,4 - a triterpenoid, a solution of ethyl chloroform (8 ml) was added dropwise to 1,2-dihydro-6-methoxy-2,2,4-trimethyl d-quinoline (1.7 g) and catalyst. A solution of a portion of N,N-dimethylaminopyridine in pyridine (60 mL) cooled (〇 ° C). After stirring for 18 hours, the reaction mixture is diluted under vacuum to the Chinese National Standard (CNS) A4 specification (210X297 mm) 64 - 1322144 A7 _B7_ V. Invention description (呦 (Please read the back of the note first) The residue is dissolved in dichloromethane and washed with 1M HCl, water, 5% aqueous sodium bicarbonate, water and brine. The residue was chromatographed on silica gel eluting with dichloromethane. Yield: 1.8 g. MS-ESI: (M+H) + =246. 2 (c) 1 -ethylhydrazine-6 —Methoxy—4 Benzene—1,2,卩,4-tetradecyl-2,2,4-dimethyl [1 quinoline according to the method described in Example 3 for A 1 C 1 3 (3 . In the presence of 〇克), this (25 liters) and 1 ethane-based 1,2-dihydro-6-methoxy-2,2,4-trimethylmorpholine (1 · 8g)

Friedel-Craft alkylation. Yield: 1 · 9 grams. HPLC : Rt = 9 . 62 minutes (method 1) (d ) 1 —ethylidene-hydroxy- 4-benzox-1 , 〇, 〇 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 4 - tetrahydro 2 , 2,4—Dimethyl p-quinoline, boron tribromide (1·30 ml) was added dropwise to 1-ethylidene-6-methoxy-4-phenyl-1, 2,3 A solution of 4~tetrahydro-2,2'4-trimethylhydrazine quinine (0.9 g) in dichloromethane (〇〇c). After stirring for 18 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, aq. This paper scale applies to China National Standard (CNS) VIII 4 specifications (210X297 mm) -65- 1322144 A7 B7 V. Description of invention (钤 yield: 950 mg. MS — ESI: [M+H]+ =310.2 : (Please read the precautions on the back and fill out this page) HPLC : Rt = 8 . 41 minutes (method 1) (e ) 1 - ethyl hydrazine _6_ (4 phenylbenzimidyl)oxy _4 —Phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinine according to the method described in Example 6 as 1-ethyl fluorenyl-6-hydroxy-4-phenyl-1. 2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-diphenylcarbonyl chloride (14 mg) and N,N-diisopropylethylamine (2 The oximation reaction was carried out in tetrahydrofuran (1 ml). Yield: 8.2 mg. MS - ESI: CM + H] + = 490 · 4 ; HPLC : Rt = 12. 81 minutes (method 1) 3 8 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1 - Ethyl-based 6 _ (Tertiary butyl ethinyl)oxy _ 4 _ Phenyl-1, 2, 3, 4 - 4 氤 1 2,4-Trimethylquinoline according to the method described in Example 6 with 1-ethylenyl _6 _ A group 4 - phenyl _ 1, 2, 3, 4 _ tetrahydro-2,2 a, 4 - trimethyl quinoline

The porphyrin (10 mg) was tritylated with tert-butylethenyl chloride (9.0 μl) and N,N-diisopropylethylamine (28 μL) in tetrahydrofuran (1 mL). This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -66 - 1322144 A7 _B7_ ___ V. Description of invention (Hungarian production: 3 · 9 mg. MS - ESI : [M + H] + =408 4; (Please read the notes on the back and fill out this page) HPLC : Rt=l 1 · 28 minutes (method 1) Example 3 9 1 One B loses a certain 6-(cyclopropylmethyl) gas —4 — 青一—1 ' 2 , 3 , 4·—four gas one 2 , 2 ' 4 — dimethyl d quinine will be 1-ethenyl- 6-hydroxy- 4-phenyl- 1 , 2, 3, 4-tetrahydro-2,2,4-trimethylquinoline (20 mg), carbonic acid (6 3 mg) 'tetrabutylammonium bromide (29 mg) and chloromethylcyclopropane (8 · 4 μl The mixture was stirred at 5% EtOAc (1 mL) over EtOAc (EtOAc)EtOAc. (v/v) Chromatography as eluent. Yield: 10 mg. MS - ESI: [M + H]+ = 364. 2; HPLC: Rt = 1 〇 · 73 min (method 1) Ministry of Economics Property Bureau Staff Consumer Cooperative Printed Example 4 〇-J-6-(3-pyridine a) argon group] -~-~~~2; __4 - four gas_2, 2, 4 - trimethyl y ku 咐 according to the method described in Example 39, with 1-ethyl fluorenyl -6 ~ 4 a base —1 , 2 , 3 , 4 — tetrahydro 2 , 2 ' 4-dimethylwine (2〇mg), and 3-pyridine methyl chloride. He 1 (is? This paper scale applies Til National County (CNS) eight 4 test (2丨0&gt;&lt;297 public Chu) -67- 1322144 A7 _____B7_ V. Description of the invention (mg), carbonic acid (63mg) and tetrabutylammonium bromide (29mg) Alkylation was carried out in acetonitrile (1 mL). Yield: 10 mg ◊ MS-ESI: </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; _7, fluorenyl-6-ethyl-4, Acer, 2, 2, 3, 4 - 4

The Skraup reaction was carried out according to the method described in Example 1 with p-ethylaniline (1 · gram) and iodine (0.33 g) in oxidized (5 ml). Yield: 800 mg. 2 0 2.2 (Please read the notes on the back and then fill out this page) MS-ESI : [M+H] (b ) 1 一乙醯4 — 四气一 2 Printed by the Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives_B a certain 1, 2, 2, 4 -trimethylquinoline according to the method described in Example 37, with 1,2-dihydro-6-ethyl-2,2,4-trimethyl π-quinoline ( 800 mg) and a catalytic amount of N,N-dimethylaminopyridine were subjected to a oximation reaction in pyridine (25 ml). Yield: 4 10 mg. This paper scale applies to China National Standard (CNS) Μ Specifications (2丨0 X 297 mm) 68- 1322144 A7 B7 V. Invention Description (6$ MS — ESI : [M + H]+ =244. 2 (Please Read the precautions on the back and fill out this page. (c) 1-Ethyl-6-ethyl-4-phenyl-1,2,3,4-tetragen, 2,4-trimethylquinoline The method described in Example 3 is in the presence of A 1 C 1 3 (7 10 mg) in benzene (10 ml) and 1-ethylindenyl-6-ethyl-1,2,3,4-tetrahydro-2 , 2,4-trimethylquinoline (410 mg) was subjected to Friedel-Craft laboratoryization. Yield: 407 mg. MS-ESI: [M+H]+ = 322.4 Example 4 2 1 -ethylhydrazine 6-(1 ,1'-diphenyl)-4-benzene a 1,2,3,4_tetrahydro-2,2,4-trimethylquinoline (a) 1 -ethyl hydrazine - 6 - Iodo-I, 2,2,3,4-tetradecane-2,2,4_trimethylquinoline Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Sodium Nitrate Solution (3 1 mg) Dropped to 1 _Ethyl benzyl-6-amino-4-phenyl- 1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (1 28 mg) and sulfuric acid (82 mg) (2 ml) in a cooled (CKC) solution. After stirring at 0 ° C for 15 minutes, a potassium iodide solution (105 mg) was added. After stirring for 18 hours, the reaction mixture was poured into dichloromethane. Wash with 5% aqueous sodium thiosulfate solution and water, dehydrate (magnesium sulfate) and concentrate in vacuo. This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -69- 1322144 A7 B7 V. Description of the invention (6? Yield: 1 60 mg. MS-ESI: [M+H]+ = 420.0 (Please read the back note first and then fill out this page) (b) 1-Ethyl _6_ (1, 1'-diphenyl)-4-phenyl- 1 ,2,3,4-tetrahydro-2,2,4-trimethylquinoline according to the method described in Example 13 a 6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl d-quine (2〇mg), (1,1-phenyl-4 _) decanoic acid (28 mg), fluorinated (15 mg), triphenyl sulfonium (5.0 mg) and ginseng (diphenylacetone) dipalladium (〇) (4.5 mg) in dimethoxyethane/ethanol 4 : 1 (v/v) (5 ml) for Mitsubishi cross-coupling reaction Yield: 16 mg. MS-ESI: (M+H) + = 446 · 4; HPLC: Rt = 6 · 84 min (Method 2) Example 4 3 1 -ethylamino-6-(4-chlorophenyl)-4-phenyl _1 , 2, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 3,4, 4,4,2,4-trimethylquinoline, according to the method described in Example 1-3, with 1-ethyl fluorenyl -6 _Iodo-4-yl-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20mg), 4-chlorophenylboronic acid (22mg), gasification (15mg ), triphenylsulfonium (5.0mg) and ginseng (diphenylacetone) dipalladium (0) (4.5mg) applied to China National Standard (CNS &gt; A4 specification) on dimethoxyethane/b paper scale (210X297 mm) -70 - 1322144 A7 B7__ V. Description of the invention (alcohol 4:1 (v/v) (5 ml) for Mitsubishi cross-coupling reaction 请 (please read the notes on the back and fill out this page) Yield: 8.6 sm. MS-ESI: [M + H] + = 404 . 4 ; HPLC: Rt = 5.94 min (Method 2) Example 4 4 - Ethyl--amine 4- 4-benzene Base—1,?.,3,4—four氤一?.,2,4,7—tetramethyl porphyrin (a) 1 ethyl sulfonyl -6-amine 1, 2 - 2 gas - 2, 2, 4, 7 - tetramethyl porphyrin N- Boc-2 - methyl-1,4-phenylenediamine (2.3 g), magnesium sulfate (6.3 g) , a mixture of 4 - butyl catechol (100 mg) and iodine (3 mM) in acetone (15 ml) was stirred at reflux for 20 h. The reaction mixture was cooled to room temperature and filtered. The material was concentrated under vacuum and the residue was chromatographed with cerium chloride and was washed with heptane/ethyl acetate = 1/0 = &gt; 3/1 (v/v) as the consumer property cooperative of the Ministry of Economic Affairs. Deprotection. The product, 6-(t-butoxycarbonyl)amino-1,2-dihydro-2,2,4,7-tetramethylti-quinoline, with ethyl chloroform (1 · 0 mL) The mixture was deuterated in a mixture of pyridine (1.0 ml) and toluene (10 ml). After stirring for 1 hour, the reaction mixture was washed with 3% aqueous citric acid and water. Concentrate in vacuo. The residue was chromatographed eluted with EtOAc/EtOAc (EtOAc/EtOAc). Specifications (210X2 97 mm) 1322144 A7 B7 Five 'Inventive Description (Production 50 mg. MS-ESI: [M+H] 3 4 5 (b) 1 乙乙醯_______ Benzene-1 2

A 2,2,4,7-tetramethylquinoline A 1 C 13 (266 mg) is added to 1-ethylenyl-6-amino~1,2-dihydro-2,2,4,7_ Tetramethyl π-quineline (100 mg) in a heated (70 ° C) solution of benzene (10 ml). After 3 hours, the mixture was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried (MgSO4) The residue was chromatographed on silica gel eluting with heptane / ethyl acetate = 1 / s = &gt; 3/1 (v/v). Yield: 7 5 mg. MS - ESI : [Μ+Η]+=323.4 Example 4 5 1 -Ethyl- 6-(4-phenylbenzylidene)-amino-benzene (please read the notes on the back and fill in the form) Page) Ministry of Economic Affairs Intellectual Property Officer X Consumer Cooperative Printed - 1 2 4 - 4 氤 2, 2, 4, 7_ tetramethyl porphyrin according to the method described in Example 6 as 1-ethyl fluorenyl-6-amine 4-yl-phenyl- 1 ' 2 , 3 , 4 - tetrahydro - 2 , 2 , 4 , 7 - tetramethyl - morphine ( 20 mg ) and 4 - diphenylcarbonyl chloride ( 10 〇 mg ) Pyridine (100 μl) in tetrahydrofuran (5 ml) for deuteration reaction yield: 2 4 halo paper scale applicable to Chinese national standard (CNS) A4 specification (210X297 mm) 72 1322144 A7 B7 V. Description of invention (Μ (Please read the precautions on the back and fill out this page) MS — ESI : [M+H]+ =503. 4 Example 4 6 1_Ethyl _6_(4-Phenylbenzylidene) Amino-8-methoxy-4-phenyl-1,2,3,4 tetradecano-2,2,4-trimethylquinoline (a) 1 _ acetyl group 6-amino group _ 8-methoxy-4-phenylene_ 1 , 2, 3, 4 — four gas one 2, 2 4-trimethyl P-quinoline according to the method described in Example 44, using N_Bo c - 3 -methoxy-1,4-phenylenediamine (450 mg), magnesium sulfate (1.0 g), 4 Skraup reaction of tert-butyl catechol (10 mg) and iodine (20 mg) in acetone (10 ml) using ethyl chloroform (250 μL) and pyridine (250 μl) Purified in toluene (10 ml) and then subjected to Friedeb Crafts with A 1 C 13 (26 6 mg). Yield: 71 mg. MS — ESI : [M + H]+=339.4 Ministry of Economics Intellectual Property Printed by the Bureau of Staff Consumer Cooperatives (b) 1 Ethyl- 6-(4-phenylbenzhydryl)amino-8-methoxy-4-phenyl- 1, 2, 3, 4_4氤-2,2,4 _trimethylquinoline according to the method described in Example 6 as 1-ethenyl-6-aminol-8-methoxy-4-phenyl-1,2,3,4 - tetrahydro-2,2,4-trimethylquinoline (20 mg) and 4_diphenylcarbonyl chloride (100% paper size applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) - 73- 1322144 A7 B7 V. INSTRUCTIONS (7) mg ) and pyridine (1 The oximation reaction was carried out in tetrahydrofuran (5 ml). (Please read the notes on the back and fill out this page) Yield: 2 5 mg. MS - ESI : [M+H]+ = 519. 4 Example 4 7 1 _Ethyl -6 - (2 - furanyl) Amino 1, 2, 3, 4 - 4 - 4_ Tolyl-2,2,4-trimethylquinoline according to the method described in Example 6 as 1-ethylindolyl-6-amino-4-methylphenyl-1,2,3,4-tetrahydro-2 , 2,4-trimethylsodium morpholine (10 mg) with 2-furopyryl chloride (8 · 1 mg) and N,N-diisopropylethylamine (20 μL) in tetrahydrofuran (1 ml) The deuteration reaction is carried out. Yield: 12 mg. MS - ESI: [M+H]+ = 417. 4; HPLC: Rt = 4.90 min (Method 2) Example 4 8 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed Ί_乙醯基_6_ (4_Benzene Benzobenzhydryl)amino-1,2,3,4 tetrahydro-4-yl-tolyl-2,2,4-trimethylquinoline according to the method described in Example 6 with 1-ethylenyl- 6-Amino-4-tolyl-1,2,3,4-tetrahydro-2,2,4-trimethyl d-quinoline (10 mg) and 4-diphenylcarbonyl chloride (1 4 mg) And Ν, N-diisopropylethylamine (20 μl) in tetrahydrofuran (1 ml) This paper scale applies to Chinese national standards (CNS &gt; A4 specification (210X297 mm) -74 - 1322144 A7 B7 V. DESCRIPTION OF THE INVENTION (The deuteration reaction was carried out. Yield: 9.3 mg. (Please read the notes on the back and fill out this page.) MS-ESI : [M+H]+=503.4; HPLC: Rt = 6 · 08 min ( Method 2) Example 4 9 1_Ethylamino-6-(ethylpropanediyl)aminol-1,2,3,4_tetradecyl-4-tolyl-2,2,4-trimethyl Quinoline according to the method described in Example 6 as 1-ethylindolyl-6-amino-4-tolyl-1,2,3,4-tetra Hydrogen-2,2,4-trimethylquinoline (10 mg) and ethylpropanediyl chloride (9.4 mg) and N,N-diisopropylethylamine (20 μl) in tetrahydrofuran ( 1 ml) The deuteration reaction was carried out. Yield: 12 mg. MS - ESI : [M + H] + = 437 · 4 ; HPLC : Rt = 4 . 71 min (method 2) Example 5 0 Ministry of Economic Affairs Intellectual Property Office Employees' Consumption Cooperatives Printed 1-Ethyl sulfonyl-6-(3,5-dibromobenzylidene)amino-4-phenyl- 1,2,3,4-tetrahydro-2,2,4 — Trimethylquinoline according to the method described in Example 11 to give 1-ethylindolyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl Base quinoline (10 mg) with 3,5-dibromobenzoic acid (10 mg) and N,N-diisopropylethylamine (22 μL) in tetrahydrofuran (1 paper scale applicable to Chinese national standard ( CNS ) A4 size (210X297 mm) -75- 1322144 A7 B7 V. Description of the invention (ml) for HATU condensation. Yield: 15.9 mg. (Please read the notes on the back and fill out this page) MS- ESI : [M+H]+=470.9; 11?]^(::1^=1 .11 minutes (method 1) Example 5 1 1 -ethyl hydrazine 6-(5-bromo-2-methylamine benzothymidine)amino-4-phenyl- 1, 2, 3, 4- Tetrahydrate- 2,2,4-trimethylquinoline according to the method described in Example 11 to give 1-ethylamino-6-amino-4-phenyl-1,2,3,4-tetrahydrogen a 2,2,4-trimethylquinoline (10 mg) with 5-bromo-2-methylaminobenzoic acid (8.4 mg) and N,N-diisopropylethylamine (2 2 micron) HCl was subjected to HATU condensation in tetrahydrofuran (1 ml). Yield: 13.2 mg. MS — ESI : 〔Μ + Η〕+=522· 1 ; 11卩1^(::1^ = 8.95 minutes (method 1) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Example 5 2 1 _Ethyl a 6-(3,4,5-trimethoxybenzylidene)amino-4-phenyl-1,2,3,4-tetradecane-2,2,4-trimethylquinoline according to the implementation The method described in Example 6 is applied to the Chinese country on the scale of 1-acetamido-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline paper. Standard (CNS) Α4 size (210X 297 mm) -76- 1322144 A7 B7 V. Description of the invention (74 morphine (10 mg) and 3,4,5-trimethoxybenzimidyl chloride (please read the back first) Note: Refill this page) 1 2 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) for purification. Yield: 1 4 · 5 mg. MS - ESI : [M + H]+=5〇3.2; HPLC: Rt=l 1 . 26 min (method i) Example 5 3 1-ethyl-trans-yl-6-(3,5-dichlorodi 2,6-dimethyl Aminobenzidine)Amino-4_Phenyl-1__' 2"3,4-tetraindole-P!, ?.,4-Trimethyl The porphyrin was subjected to the method described in Example 11 to give 1~ethylhydrazine- 6-amino- 4-phenyl- 1 , 2 , 3 , 4 - tetrahydro - 2 , 2 , 4 - trimethyl - Q - quinoline (10 Mg) with 3,5-dichloro-2,6-dimethoxybenzoic acid (9 〇mg) and N,N-diisopropylethylamine (22 μL) in tetrahydrofuran (1 ml) for HatU Condensation. Yield: 15.1 mg. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed MS — ESI : [M+H]+=54l . 1 ; HPLC : Rt = 10 · 92 minutes (method 丄) Example 5 4 1 —B —基一_6_ (2_Ethyloxy_polymethylidene)Amino- 4_Phenyl-1,2_ι 3,4-tetrahydro-2;_2,4-trimethyl porphyrin according to implementation The method described in Example 1 1 makes the i-ethinyl- 6-amine basic paper scale applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ' -- -77- 1322144 A7 B7 V. Description of invention (7 Today (please read the notes on the back and fill out this page) -4 - Phenyl-1,2,3,4 tetrahydro-2,2,4-trimethylhydrazine (10 mg) and 2_ Ethyloxybenzoic acid (6 · Omg ) and N, N - II Isopropylethylamine (22 μL) was subjected to HATU condensation in tetrahydrofuran (1 mL). Yield: 1.1 mg. MS-ESI: (M+H)+=471. 2; HPLC: Rt = 14 · 35 min (method 1) Example 5 5 1 -ethyl hydrazino-6 - (2-ethylamino--5-bromo Benzyl hydrazino)amino-4-yl-phenyl-1,2,3,4-tetradecane-2,2,4-trimethylquinoline according to the method described in Example 1 1 to give 1-ethylidene _ 6 -Amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl π-quinoline (10 mg) with 2-ethylamino--5-bromo Benzoic acid (6. Omg) and N,N-diisopropylethylamine (22 μL) were subjected to HATU condensation in tetrahydrofuran (1 mL). Yield: 2.3 mg. MS-ESI: [Μ+Η]+=530·2; HPLC: Rt=12. 01 minutes (method 1) Example 5 6 1 One 醯 6 6 6 5-Bromo- 2_N,N-dimethylamine-mercaptobenzylidene)Amino-4-phenyl-1,2,3,4_tetraindole - This paper scale applies to Chinese National Standard (CNS) Eight 4 specifications (210X297 mm) -78- 1322144 A7 B7 V. Description of the invention (2,2,4-trimethyl d-quine (please read the note on the back and fill out this page). According to Example 11 Method, 1-ethylamino-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylsodium morpholine (10 mg) and 5-bromine water Salicylic acid (8. Omg) and N,N-diisopropylethylamine (22 μL) were subjected to HATU condensation in tetrahydrofuran (1 ml). Yield: 3.0 mg. MS-ESI: [M+ H]+=580.2; HPLC: Rt=12 · 53 min (Method 1) Example 5 7 1 Ethyl (2_ 44_tolyloxy) benzhydryl) Amino-4-phenyl-1 , 2,3,4, a tetrahydro-2,2,4-trimethyl ti-quinoline according to the embodiment 1 Method for making 1-ethylindolyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 5-bromo A 2-methylaminobenzoic acid (Printed by the Ministry of Economic Intelligence, Employees' Consumer Cooperative, 8.4 mg) and N,N-diisopropylethylamine (22 μL) in tetrahydrofuran (1 mL) for HATU condensation Yield: 13.2 mg. MS - ESI : [M + H]+ = 522.1; HPLC: Rt = 8.95 min (method l) Example 5 8 The paper scale applies to the Chinese National Standard (CNS) A4 size (210X297 mm) -79- 1322144 Α7 ________Β7 V. Description of the invention (丄2~7, 峥基-6-(2-methyloxybenzyl benzoquinone) Amino-phenyl-" __' 2,3 '_4~~4,-2,2,4-Trimethyl (please read the notes on the back and fill out this page) (a) 1 Ethyl-based 6-(2-methoxy a certain benzamidine, an amine, a benzene, a 1, 2, 3, 4 - 4 gas - 2, 2, 4 - trimethyl hydrazine, according to the method described in Example 11, 1 -amino- 4-phenyl- 1 , 2 , 3 , 4~ tetrahydro-2,2,4_ trimethyl 0 quinolin (0 · 6 g) and 2-methoxybenzhydryl chloride (1. 〇g) and N 'N-diisopropylethylamine (1.7 ml) in four gas 咲 (6 0 HCl) for HATU condensation. Yield: 0.65 grams. MS - ESI : [Μ + Η]+=443.4 (b) 1-Ethyl- 6-(2-hydroxybenzhydrazide)amine-4-phenyl--1,2,3,4-tetra —2 , 2 , 4 -: BBr3 (〇. 69 ml) was added dropwise to 1 Ethyl ketone-6-(2-methoxybenzhydryl) by the Intellectual Property Office of the Ministry of Economic Affairs. Amino-tetraphenyl- 1 , 2 , 3 , 4 -tetrahydro-2,2,4-dimethyl π-quinoline (〇. 64 g) in dichloromethane (40 mL). After stirring for 4 hours, TL C indicated complete conversion. Water was added to the reaction mixture and stirring was continued for 15 minutes. The mixture was washed with a 5% aqueous sodium hydrogencarbonate solution and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting product was used without further purification. This paper scale applies to China National Standard (CNS) A4 specification (21〇Χ: 297 mm) ~ 1322144 A7 B7 V. Description of invention (yield: 0.62 g. MS-ESI: [M+H]+= 429.4 Intellectual Property Office of the Ministry of Economic Affairs, Staff and Consumer Cooperatives, India (C) 1 — Ethyl- 6 — C 2 — Methylsulfonyloxymethylcarbendyl” Amine 4 phenyl—1 2 5 3 j 4 Tetrahydrogen 2 &gt; 2 4 dimethyl Q quinolinate 1 - ethoxymethyl 6 - ( 2 - hydroxybenzimidyl) amino - 4 - phenyl - 1 &gt; 2, 3 9 4 - tetrahydro-2 9 2 3 4 —Dimethyl Q-quinoline (12 mg) and methylsulfonyl chloride (6 • 5 μl) were sulfonated in pyridine. After stirring for 1 6 hours, Τ L C analysis showed conversion to a more fluid product 〇 Concentration of the mixture &gt; The residue was dissolved in the dichlorocarbazone and washed with water. The organic layer was dehydrated (sodium sulfate) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel column chromatography. Gengyuan / ethyl acetate = 8 / 2 (V / / V ) 1 C &gt; Yield 8 • 0 ί mg 〇Μ S — Ε SI : [Μ - Η Η ] + = 5 0 7 * 4 t Η Ρ LCR t = 5 • 0 3 minutes (Method 2) Example 5 9 1 — Ethyl _ 6 — ( 2 _ c 3 5 _ dimethylisoxazole — 4 醯 醯 1 1 氧基 ) 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Base; 〇1 according to the method described in Example 58, with 1-ethylidene-6-(2-hydroxybenzhydryl)amino-4-phenyl-1, 2,3, 4-14 (please Read the precautions on the back page and fill in this page. This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -81 - 1322144 A7 B7 V. Invention description (7 orders (please read the notes on the back first) Fill in this page) Hydrogen-2,2,4-trimethylquinoline (20mg) and 3,5- Methylisoxazole-4-sulfonyl chloride (27 mg) in pyridine (2 ml) sulfonation yield: 14 mg. MS-ESI: [M+H]+=588.4; HPLC: Rt=14 · 46 minutes (method 1) Example 6 0 1 -Ethyl fluorenyl-6-(2-methoxycarbonylethyl oxooxy benzophenone) Amino-4 Tephenyl-1,2,3,4- Tetrahydro-2,2,4-trimethyl [1 quinoline according to the method described in Example 6. 1-Ethyl fluorenyl-6-(2-hydroxybenzylidene)amino-4-phenyl group 1, 2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with methyl mercaptopropyl chloride (14 mg) and N,N-diisopropylethylamine (40 μL) was subjected to deuteration reaction in tetrahydrofuran (2 ml). Yield: 2 1. 4 mg. MS - ESI: [M+H]+ = 543. 6; Printed by the Intellectual Property Office of the Ministry of Economic Affairs 1^卩1^(::111 = 6.98 minutes (method 1) Example 6 1 1 ethyl hydrazino _6_ (2_ ί5_methylisoxazole-3 carbonyl) oxybenzimidamide _4_Phenyl-1,2,3,4_tetrakis-2,2,4_trimethylhydrazine quinine This paper scale applies to China National Standard (CNS) Α4 Grid (210X 297 mm) -82- 1322144 A7 B7 V. Inventive Note (Please read the back note first and then fill out this page) According to the method described in Example 6 with 1-ethyl ketone-6 - (2 -Hydroxybenzhydryl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) and 5-methylisoxazole -3 - Carbonyl chloride (1Omg) and N,N-diisopropylethylamine (30 μL) were subjected to a oximation reaction in tetrahydrofuran (1 mL). Yield: 4.0 mg. MS - ESI : [M+H]+=538.4; HPLC: Rt = 9 · 84 min (method 1) Example 6 2 1 - ethyl hydrazine - 6 - (2_ ί2 - oxazolidinone - [5 - A a gas-based benzoylamino)amino-4-yl-phenyl-1,2,3,4-tetraindole-2,2,4-trimethyl porphyrin according to the method described in Example 39 Mercapto-6-(2-hydroxybenzimidyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylhydrazine (20 mg) 5_Chloromethyl-Ministry of Economics, Intellectual Property Office, Staff Consumer Cooperative, 2 oxazolidinone (7mg), carbonated (63mg) and tetrabutylammonium bromide (3Omg) in acetonitrile (1ml) Alkylation. Yield: 2 5 mg. MS - ESI : [M + H]+ = 542. 4; ^1?匕(::1^ = 8.21 min (method 1) Example 6 3 1 - Ethyl _6_ (2-[morpholine-4 —carbonyl]oxybenzamide This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) -83- 1322144 A7 B7 V. Description of invention (8) Base) Amino-4_phenyl- 1 , 2,3,4_tetrakis-2,2, 4-trimethylporphyrin (please read the note on the back and fill out this page). According to the method described in Example 6, 1-Ethyl-based 6_ (2-hydroxybenzhydryl)amino- 4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) and morpholine_4_ The oximation reaction of carbonyl chloride (12 μL) and N,N-diisopropylethylamine (30 μL) in tetrahydrofuran (1 mL). Yield: 5.4 mg. MS - ESI: [Μ+ Η]+=542·4; HPLC: Rt=10 · 02 min (Method 1) Example 6 4 1 -Ethylamino-6-(2-anilinobenzylidene)amino- 4-phenyl- 1 , 2, 3, 4- four gas - 2,2,4-trimethylquinoline Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing according to Example 1 1 Method for 1 - ethyl fluorenyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) with N-phenyl Anthranilic acid (2 lmg) and N,N-diisopropylethylamine (3 3 μl) were subjected to HATU condensation in tetrahydrofuran (1 ml). Yield: 5.8 mg. MS-ESI: Μ+ Η]+=504·4; HPLC: Rt = 13 42 minutes (method 1) Example 6 5 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) -84- 1322144 A7 _B7_ V. Invention Description: 珣1 - acetyl -6 - (2 - pyrrolidinone - N - ethyl carbonyl) amine - 4 - phenyl - 1 ' 2, 3, 4 - 4 - 2, 2, 4 Dimethyst (please read the note on the back and fill out this page) Porphyrin (3) 1 - B-based 6-propane-burning amine ~ 4 A benzene a 1, 2, : ^}, 4氤, 2, 4, 4, a trimethyl porphyrin according to the method described in Example 6 as 1-ethyl fluorenyl-6-amino-4-phenyl-1,2'3,4-tetrahydro-2 , 2 '4-trimethyl [I-quinoline (0.12 g) with acryloyl chloride (39 μg) and N,N-diisopropylethylamine (0.21 ml) was subjected to a deuteration reaction in tetrahydrofuran (1 ml). Yield: 0.13 g. MS - ESI : [M + H]+=363.2 (b) 1-Ethyl-(2-pyrrolidone-N-?-, a fluorenyl)amine _4-phenylene-1' 2 3, 4_四氤—2,2, 4—Trimethylquinoline Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed in 2-pyrrolidone (19mg) and sodium hydride (18mg, 60% in oil) in THF (1 ml) a mixture of 1-ethyl fluorenyl-6-acrylamido-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl π-quinoline (8 mg) ) in THF (1 ml). After 18 hours of stirring, TLC analysis showed conversion to a higher fluidity product. The mixture was diluted with ethyl acetate and washed with water, 〇 5 N HCl 1 and water. The organic layer was dried (sodium sulfate) and concentrated in vacuo. Purified by helium gel column chromatography, using heptane / ethyl acetate. This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) -85- 1322144 A7 B7 V. Description of invention = 8/ 2 = &gt;l/l (v/v) as eluent. Yield: 4.6 mg. (Please read the note on the back and fill out this page) MS — ESI : 〔M + H〕+ HPLC: Rt = 4.51 min (Method 2) Example 6 6 1 Ethyl thiol-6-(ethoxyethoxycarbonyl) amine _4 - Benzene 1 , 2, 3, 4- 4-gas-2,2,4-trimethylquinoline according to the method described in Example 6 5, with 2-ethoxyethanol (1 9 mg) and 1-ethylindolyl-6-acrylamidoamine-4 Monophenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (8 mg) was subjected to Michael addition in THF (1 ml). Yield: 1.0 mg. MS - ESI: [Μ + Η]+=453·4; HPLC: Rt = 5 . 03 min (Method 2) Example 6 7 1 -Ethyl- 6-(2-pyrrolidone-N-methoxycarbonyl) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Carbon Economy. Amino- 4-phenyl-1, 2, 3 4-tetrahydro-2,2,4-trimethyl p-quinoline N-hydroxymethyl-2-pyrrolidone (22 mg) and 1-ethylindenyl-6-(6) according to the method described in Example 11. Hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4

Methylquinoline (15 mg) in HATU (29 mg) and N, N This paper scale applies to Chinese national standards (CNS &gt; A4 specification (210X297 mm) ~ -86 - 1322144 A7 ____B7 V. Invention description (of - Diisopropylethylamine (33 μL) was condensed under a medium of tetrahydrofuran (2 ml). Yield: 1 1 mg. (Please read the back note and fill out this page again) MS-ESI : 〔 M + H]+ = 538.4 ; HPLC : Rt = 5 · 32 min (Method 2) Example 6 9 _1_-Ethyl- 6-(2-furanmethoxycarbonyl carbonyl) a certain amine基基-1' 2,3,4-tetrahydro~2,?.,4-dimethylhydrazine Φ_ According to the method described in Example 11, sterol (17 μL) and 1-ethylidene group- 6 —(Organyl-carbonyl)amino-4-yl-phenyl-1, 2,3,4-tetrahydro-2, 2,trimethylquinoline (15 mg) in HATU (29 mg) and N,N - Diisopropylethylamine (33 μL) was condensed under a medium of tetrahydrofuran (2 ml). Yield: 7.1 mg. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, MS-ESI: CM+H]+ =475 . 4 ; HPLC : Rt = 5 3 〇 minutes (method 2) Example 7 〇-(cyclopropylmethylamine carbonyl) amine -4- benzene, 4 氤 4 氤-2, 2, 4 — trimethyl porphyrin According to the method described in Example 29, cyclopropylmethylamine (4.0 paper size is applied to the Chinese National Standard (CNS) from the threat (2丨〇&gt;&lt;297 mm) -87- 1322144 A7 B7 V. Description of the invention (microliter) and 1-ethyl fluorenyl-6-(bromoethenyl)amine- 4-phenyl-1,2,3,4-tetrahydro-2,2,4_ Trimethylquinoline ((Please read the note on the back and fill out this page) 1 Omg) and N,N - isopropylethylamine (iv 3 μl) in methylene chloride (1 ml) for alkylation Yield: 6.8 mg MS - ESI : [Μ + Η) += 535 . 6 ; HPlC : Rt = 6 · 29 minutes (method 2) Example 7 1 丄 醯 -4 4 - (2 _Methoxyethyl _) —6 — (4-phenylphenyl phenyl) Amino-1,2,3,4-I7q氤-2,2,4-trimethylporphyrin (a) 1_ Ethyl yl- 6-(4-phenylene benzoquinone 2 - bismuth 2, 2, 4 1-3, a 1-ethyl fluorenyl-6-(t-butoxycarbonyl)amine _ι,2 Dihydrogen-2,2 '4 Trimethyl porphyrin (1 · 〇克) Dissolved in the Ministry of Finance, Intellectual Property Bureau, Intellectual Property Bureau, Consumer Cooperative, Printing Acetic Acid/CH2C 12 (1/1 'v/v , 25 ml) of the mixture and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and rinsed with EtOAc. The organic layer was separated &apos; dehydrated (MgSO4) and concentrated. The residue was dissolved in CH2C12 (25 mL), N,N-diisopropylethylamine (5. 2 mL) and 4-phenylbenzhydryl chloride (2 · gram) were added and the mixture was stirred 1 6 hours. The mixture was concentrated and chromatographed on silica gel eluting with heptane / ethyl acetate = &lt;RTI ID=0.0&gt;&gt; This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -88 - 1322144 A7 _B7___ V. Description of invention (8Φ Production: 0 · 6 3 g. MS — ESI : [M+H]+ =411 2 (Please read the note on the back and fill out this page) (b) 1 - Ethyl ketone 4- (2-methoxybenzoyl)-fi-f/i-phenylbenzylidene) Amino —1 , 2,3,4 —tetrakis-2,2,4-trimethylquinoline and 1-ethenyl-4—(4-methoxyphenyl)-6-(4-phenylbenzene Mercapto)amino-1,2,3,4-tetraki-2,2,4-trimethyloxime according to the method described in Example 3, in the presence of A 1 C 13 (〇. 5 g) Anisole (25 ml, stored on a 3 angstrom molecular sieve) and 1-ethylidene-6-(4-phenylbenzhydryl)amino-1,2-dihydro-2' 2' 4 -3 Methyl D-quinoline (〇·5 g) was subjected to friedel-Crafts alkylation. Purification by oxime oxygen gel chromatography (eluent: heptane / ethyl acetate = 1 / 〇 = &gt; 〇 /1, v / v) to give 2-methoxyphenyl substituted derivatives as their trace products And producing a 4-methoxyphenyl substituted derivative as its main product. Yield: 4 6 mg. MS-ESI: [μ+Η]+ = 518·0 (2-methoxyphenyl) Yield 0 · 2 gram. MS - ES I : [μ+Η]+ = 518. 1 (4-methoxyphenyl) Example 7 2 4 — (4-Phenylphenyl)_6-(4-Phenylbenzoylase-棊_" 1 ,?,卩,4,4,4,4,4,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3 Co-operatives printed A7 B7 V. Inventions (碁 碁 1) 1 啾 啾 under nitrogen atmosphere in 1 - ethyl aryl - 4 - (4-methoxyphenyl) - 6 - (4-phenylbenzhydryl) Amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.46 g) was added to a cooled (0 ° C) solution of dichloromethane to add BBr3. After complete stirring at room temperature for 3 hours, complete conversion was achieved. The mixture was cooled, 1 Μ N a Ο 加入 was added until it became basic Ρ Η値, then ethyl acetate was added and the mixture was acidified with 1 M HCl 1. The organic layer was separated and dried. (MgSO4 and concentrated. The residue was chromatographed on a hydrazine gel column with heptane / ethyl acetate = 1 /0 = &gt; 0/1 (v/v) as eluent. Yield 0. 1 3克. MS-ESI : [Μ+Η]+ =504.0 Example 7 3 1 —6-(5-methyl nicotine decyl)amine _4_phenyl-1,2,3,4_tetraindole 2,2,4-trimethyl porphyrin according to Example 11. Method of making 1 _ acetyl -6-amino-4-phenyl- 1,2,3,4-tetrahydro-2,2,4-trimethyl η-quinoline (0.1 g) with 5 _Methylnicotinic acid (0.1 g) was carried out in a medium of HATU (0 · 18 g) and hydrazine, hydrazine-diisopropylethylamine (0 · 28 mL) in dichloromethane (2 mL) Condensation. Yield: 0.12 g. MS-ESI: [M + H]+ = 427.0 This paper scale applies to Chinese national standards (CNS &gt; A4 size (210x297 mm) &quot; (Please read the back Precautions Please fill out this page) -t _ l·- · - Packing. Book 1322144 A7 B7 V. INSTRUCTIONS (Arsenic Example 7 4 - F SH The F SH activity of the bovine material in the test tube is stable Tested on Chinese hamster ovary cells (CHO) transfected with human F SH receptors and co-transfected with c AMP response element (CRE) / indicative of firefly enzyme photoreceptor gene expression. G s - coupled FS Η receiver can add CAMP Which will induce back to the luciferase construct was higher in receptor activation turn. The luciferase signal using fluorescent-based quantitative counter. For test compounds, E C 50 値 was evaluated (the concentration required to test the compound for one of the maximum stimulatory reactions (50%)). For these purposes, the software program GraphPad PRISM, Third Edition (GraphPad software Inc., San Diego) was used. All of the example compounds are active below 10_5M ((Please read the back note first and then fill out this page) EC 2 4 5 3 3 0 5 5 Example 1,6 — 13,15,16,21 - 3 6 5 7 37,45,46,48,50 — 5 8,6 1 ' 6 3 and 6 4 show low opinion. The Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, prints the paper scale for Chinese national standards ( CNS ) Α 4 Specifications (210Χ297 mm) -91 -

Claims (1)

1322144 A8 B8 C8 D8 VI. Application for Patent Scope 1 Attachment 3: Patent Application No. 9 1 1 1 1 887 Patent Application Replacement of this patent ^^年继正正产1 ·—蒱田于坊法丨丨4r杳々 々 &; 护, 芦 恬 T 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 Wherein R1 is indolyl, (1-6C)alkylcarbonyl or (1-6C)alkylsulfonyl; R2 and R3 are deuterium or (1 -4C)alkyl; R4 is phenyl, optionally Substituted by one or more substituents selected from the group consisting of hydroxyl, amine, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2 - 4C) alkynyl, (1 - 4C) alkoxy, (1-4C) (di)alkylamino; R5 is (1-4C)alkyl; Υ - X is c(o)-〇, s(o)2-o, NHC (〇) - 〇' NHC (S) - 0 · 0C (0) - 0 , key _〇, C (〇)-NH,S ( 0 ) 2 - N Η -NHC (〇) - ΝΗ 'NHC (S) - ΝΗ, i The paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm). (Please read it first, and then fill in the back of this page) -'s 4. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed J 1322144 8 8 8 8 ABCD VII. Patent Application 2 〇C ( 〇) — N Η , Key - -Ν Η, Ν Η -C ( 0 j 〇 - C ( 〇 ) Ν Η — S (0 ); 1 » or 0 a S ( 〇) 2 5 or X — Y means the key » R 6 is (but exclude Y-X as a bond) Trifluoromethyl, :1 - 6 C ) Alkyl&gt; 1 — or 2 — King Kong - Dean (1 -4 C ) Institute, ( 2 - 6 C ) Alkene Base f ( 2 - 6 C ) alkynyl 5 (3 - 9 C ) Heteroaryl, ( 3 - 6 C ) ΤΞΙ Bad Institute J ( 2-6 C ) Heterocycloalkyl, ( 1 - 4 • C ) Alkyl sulfide ( 1 - 4 C ), (6 - -1 0 C ) aryl ( 1 - 4 C ) (3 - 9 c ) heteroaryl (1 - 4 C ) — 6 C ) cycloalkyl ( 1 — 4 C ), fen, ( 2 — 6 C ) heterocycloalkyl ( 1 — 4 C ), R 8 , R 9 —amine carbonyl ( 1 — 4 C ) Alkyl R 8 , R 9 —amino( 1-4 C ), R 8 —oxyindolyl ( 1 - 4 C )alkyl, R —oxy( 1 4 C )alkyl R 8 — γμ&gt ; fSk group ( 1 - 4 C ) or (6 - 10 C ) aryl y However, if ( 6 - 1 0 C ) aryl is phenylphenyl optionally hydroxy > amine » m ' Halogen nitro y difluoromethyl cyano, ( 1 - 4 C ) alkyl, ( 2 - 4 C ) alkenyl ( 2 - 4 C ) alkynyl, ( 1 4 C ) alkoxy group (1 - 4 C ) (-) alkylamino group, (6 - 1 0 C) arylji 'trim base> (6 - 1 0 C) aryloxy, (6 -1 0 C) aryl (1 huicai-4 C) alkoxy&gt; (3-9C) heteroaryl j (3-9C) hydroxyaryl (3-9C) heteroaryl, ( 1 - 4 C ) oxime &gt; X consumption ( 1 _ 4 C ) oxime-based, (1 _ 4 C ) alkoxycarbonyl (co- 3-6 C) cycloalkane moxy 5 (1 - 4 C ) alkoxy oxane (1 - 4C printed by ASD) alkoxyoxy, ( 1 -4 C ) alkoxy ( 1 4 C ) This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) (Please note the back of the arm before filling in this page) -2- to 144 A8 B8 C8 'Application for patent range 3 Institute of oxy-(6-10C) arylcarbonyloxy, (3-9C) heteroaryl oxy '(1-4C) alkanesulfonyloxy, (6-10 C) (please first Read the precautions on the back page and fill in this page) ^Acetyloxy, (3-9C) Heteroarylsulfonyloxy, (1-4 Q \ - (di)alkylcarbamoyl' (6 - 10C (2) aryl@amino&lt; mercapto, (2-6C)heterocycloalkylcarbamoyl, (g~10C)(di)arylamino, (3-6C)cycloalkyl, (^ 6C)cycloalkyl(1-4C)alkyl' (2-6C) heterocyclic or (2-6C)heterocycloalkyl(1-4C)alkyl substituted, 'and yet all of R6 The aryl and heteroaryl groups may be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, amine, halogen, nitro 'trifluoromethyl, cyano, (1-4C)alkyl , (2 - 4 C) Jingji' (2 - 4C) alkynyl, (1 - 4C) alkoxy or (1 ~ 4 c ) (di)alkylamino; R7 is hydrogen '(1 - 4C) alkyl , (1-4C) alkoxy, halogen 'trifluoromethyl, cyano, nitro, hydroxy; and Ministry of Economic Affairs Intellectual Property Bureau R&D Co., Ltd. printed R8 and/or R9 as hydrogen, (1-4C)alkyl, (2-4C)alkenyl '(2-4C)alkynyl, (6-10C)aryl, (3-9 C Heteroaryl, (6 - i〇c) aryl (1-4C)alkyl, (3-9C)heteroaryl(1-4C)alkyl, (3-6C)cycloalkyl (1-4C) Alkyl, (2-6C)heterocycloalkyl(1-4C)alkyl, (1-4C)(di)alkylamino(1-4C)alkyl, (1-4C)alkoxy (1) a 4C) alkyl group, (1-4C)alkylthio(1-4C)alkyl, (1-4C)alkylcarbonylamino (1-4C)alkyl, (1-4C)alkoxycarbonyl (1) — 4C) Alkyl, (This paper scale uses Chinese National Standard (CNS) A4 specification (210X297 mm) -3- 1322144 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Α8 Β8 C8 D8 VI. Patent application scope 4 1—4C) oxycarbonylamino (i-4C) alkyl, (3-6C) cycloalkyl '(2-6 C)heterocycloalkyl or R8 and R9 may be combined into one (2-6C) a ring of a heterocycloalkyl group, wherein each -(3_9(:)heteroaryl means imidazolyl, thiadiazolyl, pyridyl, thienyl, benzothienyl, furanyl, Benzofuranyl, quinolinyl, tetrahydroquinolinyl, quinoxalinyl, or indolyl, and each of the (2 - 6 C) heterocycloalkyl means a piperidinyl, morpholinyl or pyrrolidinyl. 2 - a tetrahydroquinoline derivative of the following formula I or a pharmaceutically acceptable salt thereof, 6 R3 2 Formula i wherein R1 is indolyl, (1-6C)alkylcarbonyl or (1-6C)alkylsulfonyl; R2 and R3 are deuterium or (1-4C)alkyl; R4 is phenyl' Optionally substituted with one or more substituents selected from the group consisting of hydroxy 'amine, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C) olefin Base, (2 - 4C) alkynyl, (1 - 4C) alkoxy, (1 - 4C) (di) alkylamine; This paper scale applies to Chinese National Standard (CNS) Α 4 specification (210X297 mm) - — — — — — Install IIII Set III line (please smell the first note on the back page) -4- 1322144 A8 B8 C8 D8 VI. Patent application scope 5 R5 is (1-4C) alkyl; Y — X is C(0)-0, S(0)2-0, (please read the note on the back of the section first.) NHC (〇)〇, NHC (S) — 0, 〇C (0 )_0, key one 〇, C (0) - NH, S (〇) 2-NH, NHC (O)-NH &gt; NHC (S) - NH &gt; OC (〇)-NH, bond-NH, NH — C (0), 0 - C ( 0 ) , 1^11-3(0) 2, or 〇 3 (〇) 2, or X _ Y represents a bond; R6 is hydrogen (but exclude YX as a bond), trifluoromethyl, (1 - 6C) alkyl, 1 or 2 - adamantyl (1_4C) alkyl, (2_6 C)alkenyl, (2_6C) alkynyl, 3_9C)heteroaryl, (3-6C)cycloalkyl, (2-6C)heterocycloalkyl, (1-4C)alkylthio(1-4C)alkyl,(6-10C)aryl (1— 4 C) alkyl, (3 - 9C)heteroaryl (1-4C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl (1 - 4C) alkyl, R8, R9-amine carbonyl (1-4C)alkyl, R8, R9-amino (1 - 4C) alkyl, 'R8 - oxycarbonyl (Ministry of Commerce, Intellectual Property Office, Staff Consumer Cooperative, Printed 1 — 4C)alkyl, R 8 —oxy(1-4C)alkyl, R 8 —carbonyl(1-4C)alkyl or (6—10C)aryl, whereas (6—10 C)aryl is phenyl, The phenyl group may be optionally hydroxy, amine, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1 — 4C) alkoxy, (1 - 4 C ) (di)alkylamino, (6 - 10C) aryl, (6 - 10C) aryloxy, (6 - 10C) aryl, (1 a paper Zhang scale Applicable to China National Standard (CNS) A4 Specification (210X297 mm) -5- 1322144 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed VI. Application Patent Range 6 1 1 4 C ) College Oxygen, (3 - 9 C ) Heteroaryl, ( 3 — 9 C ) hetero 1 1 aryloxy &gt; ( 3 - 9 C ) Heteroaryl ( 1 - 4 C ) alkoxy, ( 1 I 1 - 4 C ) alkylcarbonyl Amino ( 1 - 4 C ) alkane W. oxy (3 s 1 first 1 _ 6 C ) oxime ore, ( 1 _ 4 C ) alkoxycarbonyl ( 1 - 4 read 1 1 C ) alkoxy W. oxy (1 - 4 C ) alkoxy ( 1 _ 4 C ) alkane back 1 I 1 f m. oxy &gt; ( 6 - 1 0 C ) aryl·¥, hawthorn oxy, (3 — 9 C ) Heterofang Notes 1 Μ oxy ( 1 - 4 C ) alkane sulfonyloxy, ( 6 — 1 0 C ) aryl term again 1 % 1 sulfonyloxy, (3 - 9 C ) heteroaryl Alkyl sulfonyloxy&gt; (1 - 4 C Write a page 1) (b) Alkylaminomethyl hydrazino) (6 -10 C ) (b) aryl 1 Amino Mercapto, ( 2 - 6 C ) heterocycloalkylcarbamoyl ( 6 1 1 - 1 0 C ) (di) arylamine 5 ( 3-6 C ) cycloalkyl ( 1 1 3 - 6 C) cycloalkyl (1 - 4 C ) alkyl, ( 2 - 6 C ) miscellaneous I rm bad alkyl or ( 2 - 6 C ) heterocycloalkyl (1 - 4 C ) alkyl substituted 1 1 I And, however, all of the aryl and heteroaryl groups in R 6 may be optionally substituted with one or more I 1 substituents selected from the group consisting of a white hydroxy group, an amine halogen 5 nitro 1 1 dimethyl difluoromethyl group, Cyano, ( 1-4 C )alkyl 5 ( 2 ^v 4 C 线 | ) alkenyl ( 2 - 4 C ) alkynyl ( 1-4 C ) alkoxy or ( 1 I 1 - 4 C ) ( 2) alkylamino group » 1 1 IR 7 is hydrogen, ( 1 - 4 C ) alkyl 5 ( 1 - 4 C ) alkoxy J halogen 1 1 &gt; difluoromethyl, cyano, nitro, hydroxy And 1 1 R 8 and/or R 9 are hydrogen, ( 1 _ 4 C) alkyl, ( 2 - 4 C ) olefin 1 | group) ( 2 - 4 C ) alkynyl group > (6 - -1 0 C ) aryl &gt; ( 3 — 9 1 IC ) Heteroaryl, ( 6 -1 3 C ) aryl (1 - 4 C ) alkyl &gt; ( 1 1 3 — 9 C ) Heteroaryl (1 - i 4 C ) alkyl, ( 3 — 6 C ) naphthenic 1 1 1 This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm) -6 - 1322144 A8 B8 C8 D8 Patent Application No. 7 base (1-4C) alkyl, (2-6C)heteroalkyl (1-4C)alkyl, (1-4C)(di)alkylamine (1 — 4C) alkyl, (1-4C)alkoxy(1-4C)alkyl'(1-4C)alkylthio(1-4C)alkyl, (1-4C)alkylcarbonylamine (1 -4) C) alkyl, (1-4C) alkoxycarbonyl (1-4C)alkyl, (1-4C) alkoxycarbonylamino (1-4-C)alkyl' (3-6C) group, (2 - 6C) Heterocycloalkyl or R8 and R9 may be combined to form a ring of -6 C)heterocycloalkyl, cycloalkane (2 wherein each (3-9 C)heteroaryl means imidazolylridyl, thiophene Benzo, benzothienyl, furyl 'benzotetrahydroquinolyl, quinoxalinyl or fluorenyl, and thiadiazolyl, pyrrolyl, porphyrin (2-6C) heterocycloalkane Base means piperidinyl, morpholinyl or pyrrolidinylbenzimidylamine, provided that the derivative is not 1 _ethyl fluorenyl- 6 4-(4-methylphenyl)-1,2,3'4-tetrahydro-2,2,4-trimethyl-11-quinoline, 1-ethenyl_4_phenyl-1' 2 4-tetrahydro-2,2,4,6-tetramethyl D-quine, 1-B, please read the note first I. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, employee consumption cooperative, 3 thiol-4-phenyl _1,2,3,4-tetrahydro-2,2 6, ki- 1 - -1 - ethane 4 - 4 8 -pentamethyl D-quinoline ' 1 -ethyl keto-methoxy- 4- benzene 1 , 2 , 3 , 4 - tetrahydro - 2 , 2 , 4 - trimethylquinine , ethyl aryl - 6 - trifluoroethylamino _ 4 - ( 4 - methylphenyl ) , 2 , 3 , 4 tetrahydro-2,2,4-trimethylquinoline, 1 fluorenyl-6-trifluoroacetamido- 4-phenyl- 1,2,3, tetrahydro- 2' 2 ' 4 Trimethyl 11 quinolin ' 1 -acetate - 4 - This paper scale applies to China National Standard (CNS) A4 specification (210 &gt;&lt; 297 public) 7 - 1322144 A8 B8 C8 D8 VI. Patent application scope 8 (4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4 6-tetramethylporphyrin, 1-ethylindolyl-4(4-bromophenyl)- 4 tetrahydrogen-2,2 6-tetramethyl D-quinoline-ethenyl-6-amino- 4-(4-aminophenyl)- 1,2,3 ' 4-tetrahydro- 2,2 , 4-trimethylquinoline, 6-amino-1-ethylcarbonyl-4-ylphenyl-1,2,3,4-tetrahydro-2, 2'4-trimethylquinoline, 1 -Ethylamino-6-amino _4_phenyl-1 2 4 -tetrahydro-2,2,4_trimethyl π quinine Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 3 . The quinone hydrogen quinolin derivative or a pharmaceutically acceptable salt thereof, wherein Y - X is C (0) _NH, 0C ( 〇) - N Η or C ( 0 ) - 〇. 4. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein γ_χ is C(0)-oxime. 5. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein ri is (1-4C)alkylcarbonyl. 6. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein each of R2, R3 and R5 is (1 _ 4 C )alkyl. 7. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein R6 is (6-10C) aryl, (3-9C)heteroaryl 6- 10C) an aryl (1-4C) alkyl group or a (3-9C) heteroaryl (1-4C) alkyl group, whereas if the (6-100C) aryl group is a phenyl group, the phenyl group may be optionally a hydroxy group. , Amine, halogen, paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back and fill out this page) -8- 1322144 A8 B8 C8 D8 VI. Apply for a patent Range 9 'nitro", trifluoromethyl, cyano, (1-4C)alkyl, -4C)alkenyl, (2 - 4C)alkynyl, (1 - 4c)yl' (1-4C) ( 2) alkylamino, (6 - l〇c) aryl, (6-10C) aryloxy, (6-10C) aryl (4C) alkoxy, (3-9C) heteroaryl, (3 — 9C aryloxy '(3-9C)heteroaryl(1-4C)alkoxy-1-4C)alkylcarbonylamino, (1-4C)alkylcarbonyloxy, 6C)cycloalkylcarbonyloxy, (i_4C) alkoxycarbonyl (1 C) alkoxycarbonyloxy, (1-4C) alkoxy (1-4C (2 alkoxy 1 - hetero) (3 -4 Please read the notes on the back of the carbonyloxy group, carbonyloxy group, sulfonyloxy 6 - 10C) arylcarbonyloxy 1-4C) alkanesulfonyloxy 3 - 9 C ) 6 - 1 〇 c 3 — 9 C) Heteroarylsulfonyloxy (6 - 1 0 C ) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Carbamoyl, (2-6C) Heterocycloalkylcarbamyl, — 10C) (di)arylamino, (3-6C)cycloalkyl 3-6C)cycloalkyl(1-4C)alkyl, (2-6c cycloalkyl or (2-6)heterocycloalkyl (1 _4C)alkyl group. However, all aryl and heteroaryl groups in R6 may be optionally substituted by one or a substituent which is selected from the group consisting of a hydroxyl group, an amine group, a halogen group, a fluoromethyl group, and a cyano group. 1 - 4 C ) Alkyl, (2 _ 4 C ) alkynyl-4 C) (di)alkylamino. Alkane aryl) aryl 4 C aryl cleavage 2 4 ) heterogeneous, nitro C, 1-4C alkoxy or 8 · tetrahydroquinoline derivative as claimed in claim 2 Salts are acceptable for use in fertility control. The standard of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -9