Neurokinin-1 antagonist

Abstract

To provide a compound that is an antagonist of the neurokinin-1 receptor, can be used for the treatment of diseases associated with the neurokinin-1 receptor, can avoid hemolytic action of the drug, and can reduce side effects of drug administration.SOLUTION: The invention provides a compound represented by formula II or a pharmaceutically acceptable salt thereof, and a method for producing the same.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to antagonists of the neuropeptide neurokinin-1 (NK1 or NK-1) receptor.

Background Art

[0002] Tachykinins are peptide ligands of the neurokinin receptors. Neurokinin receptors such as NK1, NK2 and NK3 are involved in various biological processes. They are found in the mammalian nervous system and cardiovascular system, and in surrounding tissues. Therefore, the regulation of such receptors has been studied for the possible treatment or prevention of various mammalian diseases. Examples of typical neurokinin receptor agonists and their uses include US5760018 (1998) (pain, inflammation, migraine and vomiting), US5620989 (1997) (pain, nociception and inflammation), WO95 / 19344 (1995), WO 94 / 13639 (1994) and WO 94 / 10165 (1994). Other types of NK1 receptor antagonists include Wu et al., Tetrahedron 56, 3043-3051 (2000); Rombouts et al., Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al., Tetrahedron 57, 8971-8981 (2001).

[0003] US7049320 provides an effective and selective NK1 antagonist, (5S,8S)-8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]dec-2-one (compound represented by formula (I)), which can be in the form of a free base or a pharmaceutically acceptable salt and is suitable for formulations for parenteral administration, having advantageous therapeutic and pharmacological properties and good metabolic stability.

Chemical Formula

[0004] US9101615 provides prodrugs of compounds of formula (I), i.e., prodrugs and salts thereof, in which the free amine (or two amines) of the compounds of formula (I) are replaced by a group selected from -Y and -X, wherein Y is -P(O)(OH)2, -S(O) n1 R 1 , -C(O)(C 1-6 alkyl)X, -C(O)(C 1-6 Alkyl)(aryl) and -C(O)OR 4 X is selected from the group consisting of -NR 2 R 3 , -P(O)(OH)2 and -S(O) n1 R is selected from the group consisting of: 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 n1 is 0-4. The prodrugs can be used in appropriate liquid formulations (with or without a parenteral carrier for delivery) to treat patients in need thereof. Summary of the Invention [Problem to be solved by the invention]

[0005] In another aspect, drug-induced hemolysis is caused by massive destruction of red blood cells induced by immune factors after the drug enters the human body. Clinically manifested hemolytic symptoms include anemia, jaundice, soy sauce-like urine, etc. Drug-induced hemolytic anemia can be classified into the following three types: (1) leading to drug-induced immune, antibody-mediated hemolytic reactions; (2) the action of drugs on red blood cells with genetic enzyme deficiencies (e.g., G6PD deficiency); (3) drug-induced hemolytic reactions to abnormal hemoglobin. The key to treating such diseases is to stop using the relevant drugs and control the occurrence of hemolysis in order to prevent the occurrence of complications. To solve the problem of the low solubility of the compound represented by formula (I) at physiological pH, researchers used a co-solvent-based formulation containing captisol, propylene glycol, and ethanol to significantly improve the solubility of compound 1. However, the co-solvent-based formulation shows a significant hemolytic effect after intravenous administration. CN102573475 discloses an improved formulation containing polyethylene glycol 15-hydroxystearate and medium-chain triglycerides. However, even when the compound represented by formula (I) is prepared as a prodrug containing phosphate, the hemolytic effect of the pharmaceutical composition has not been completely solved.

Means for Solving the Problems

[0006] The present application provides a new NK1 antagonist prodrug compound that is effective in treating various physiological disorders, conditions, and diseases and has minimal side effects.

[0007] Summary of the Invention The present disclosure relates to formula (II):

Chemical formula

Chemical formula

Chemical formula

[0008] The compound represented by formula (II) of the present disclosure has better solubility than the compound represented by formula (I) which is a prodrug, and is thus suitable for intravenous administration. Further, when the above compound is formulated into an intravenous preparation, it is decomposed under physiological conditions when entering the human body to release the prodrug, which delays the release of the drug and extends the drug release period.

[0009] In another embodiment of the present disclosure, in the compound represented by formula (II), X is hydrogen, heterocyclyl, aryl, heteroaryl, -C(O)O[C(R 1 )(R 2 )(O) p m R 3 、-C(O)NR 4 [C(R 1 )(R 2 )(O) p m R 3 、-[C(R 1 )(R 2 )(O) p m C(O)[C(R 1 )(R 2 )(O) p n R 3 、-[C(R 1 )(R 2 )(O) p m [C(R 1 )(R 2 )]C(O)[(O) q C(R 1 )(R 2 )] n R 3 、-[C(R 1 )(R 2 )(O) p ​​​​​​m C(O)NR 4 [C(R 1 )(R 2 )(O) p n R 3 and -[C(R 1 )(R 2 )(O) p m R 5 selected from the group consisting of, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is alkyl (preferably, but not limited to, selected from the group consisting of C 1-12 alkyl such as methyl, ethyl or isopropyl), cycloalkyl (preferably selected from C 1-12 cycloalkyl such as cyclohexyl and cyclopentanyl), alkoxyl (preferably selected from C 1-12 alkoxyl), hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, cyano, hydroxyl, halogen, SR', NR'(R''), COOR' and CONR'(R'') and is optionally substituted by one or more groups selected from the group consisting of; Y is hydrogen, -C(O)O[C(R 1 )(R 2 )(O) p m R 3 , -C(O)NR 4 [C(R 1 )(R 2 )(O) p m R 3 , -[C(R 1 )(R 2 )(O) p m C(O)[C(R 1 )(R 2 )(O) p n R 3 , -[C(R 1 )(R 2 )(O) p m C(O)[(O) q C(R 1 )(R​​​​​​​2 )] n R 3 ,-[C(R 1 )(R 2 )(O) p m C(O)NR 4 [C(R 1 )(R 2 )(O) p n R 3 and -[C(R 1 )(R 2 )(O) p m R 5 selected from the group consisting of; and X and Y are not hydrogen simultaneously.

[0010] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C(R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )N] m C(O)[C(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )(R 2 )]​​​n R 3 、 [C(R 1 )(R 2 )N] m C(O)[NC(R 1 )(R 2 )] n R 3 、 -[C(R 1 )(R 2 )(O) p m C(O)NR 4 [C(R 1 )(R 2 )(O) p n R 3 and -[C(R 1 )(R 2 )(O) p n R 5 selected from the group consisting of, and X is hydrogen or a 3- to 6-membered heterocyclyl.

[0011] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is -C(O)O[C(R 1 )(R 2 )] m R 3 、 -C(O)NR 4 [C(R 1 )(R 2 )] m R 3 、 -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 、 -[C(R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 、 -[C(R 1 )(R 2 )N] m C(O)[C(R 1 )(R 2 )] n R 3 ​​​, [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[NC(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )(O) p m C(O)NR 4 [C(R 1 )(R 2 )(O) p n R 3 and -[C(R 1 )(R 2 )(O) p n R 5 selected from the group consisting of; X is hydrogen or a 3- to 6-membered heterocyclyl; m, n, and o are each independently selected from the group consisting of 1, 2, 3, 4, 5, and 6; p and q are each independently selected from 0.

[0012] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C(R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )] m C(O)[OC(R 1 )(R​​​2 )] n R 3 、 -[C(R 1 )(R 2 )N] m C(O)[C(R 1 )(R 2 )] n R 3 、 [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )(R 2 )] n R 3 、 [C(R 1 )(R 2 )N] m C(O)[NC(R 1 )(R 2 )] n R 3 、 -[C(R 1 )(R 2 )(O) p m C(O)NR 4 [C(R 1 )(R 2 )(O) p n R 3 and -[C(R 1 )(R 2 )(O) p n R 5 selected from the group consisting of; X is hydrogen or a 3 - to 6 - membered heterocyclyl; m, n, and o are each independently selected from the group consisting of 1, 2, 3, 4, 5, and 6; p and q are each independently selected from 1.

[0013] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is -C(O)O[C(R 1 )(R 2 )]R 3 、 -C(O)NR 4 [C(R 1 )(R 2 )]R 3 、 -[C(R 1 )(R 2 )O]C(O)[C(R 1 )(R​​​2 )]R 3 ,-[C(R 1 )(R 2 )]C(O)[OC(R 1 )(R 2 )]R 3 ,-[C(R 1 )(R 2 )N]C(O)[C(R 1 )(R 2 )]R 3 ,[C(R 1 )(R 2 )N]C(O)[OC(R 1 )(R 2 )]R 3 ,[C(R 1 )(R 2 )N]C(O)[NC(R 1 )(R 2 )]R 3 ,-[C(R 1 )(R 2 )(O) p C(O)NR 4 [C(R 1 )(R 2 )(O) p R 3 and -[C(R 1 )(R 2 )(O) p R 5 selected from the group consisting of, and X is hydrogen or a 3- to 6-membered heterocyclyl.

[0014] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is -C(O)O[C(R 1 )(R 2 )]2R 3 , -C(O)NR 4 [C(R 1 )(R 2 )]2R 3 , -[C(R 1 )(R 2 )O]2C(O)[C(R 1 )(R 2 )]2R 3 , -[C(R 1 )(R 2 )]2C(O)[OC(R 1 )(R 2)]2R 3 ,-[C(R 1 )(R 2 )N]2C(O)[C(R 1 )(R 2 )]2R 3 ,[C(R 1 )(R 2 )N]2C(O)[OC(R 1 )(R 2 )]2R 3 ,[C(R 1 )(R 2 )N]2C(O)[NC(R 1 )(R 2 )]2R 3 ,-[C(R 1 )(R 2 )(O) p 2C(O)NR 4 [C(R 1 )(R 2 )(O) p 2R 3 and -[C(R 1 )(R 2 )(O) p 2R 5 selected from the group consisting of, and X is hydrogen or a 3- to 6-membered heterocyclyl.

[0015] In another embodiment of the present disclosure, in the compound represented by formula (II), X is -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C(R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3and -[C(R 1 )(R 2 )] n R 5 is selected from the group consisting of, and Y is hydrogen.

[0016] In another embodiment of the present disclosure, in the compound represented by formula (II), X is -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C(R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 and -[C(R 1 )(R 2 )] n R 5 is selected from the group consisting of; Y is hydrogen; m, n, and o are each independently selected from the group consisting of 1, 2, 3, 4, 5, and 6; and p and q are each independently selected from 0.

[0017] In another embodiment of the present disclosure, in the compound represented by formula (II), X is -[C(R 1 )(R 2 )]C(O)[OC(R 1 )(R 2 )]R 3 , -C(O)O[C(R 1 )(R 2 )]R 3 , -C(O)NR 4 [C(R 1 )(R 2 )]R 3 , -[C(R1 )(R 2 )O]C(O)[C(R 1 )(R 2 )]R 3 、 -[C(R 1 )(R 2 )]C(O)NR 4 [C(R 1 )(R 2 )]R 3 and -[C(R 1 )(R 2 )]R 5 selected from the group consisting of, and Y is hydrogen.

[0018] Furthermore, in another embodiment of the present disclosure, in the compound represented by formula (II), R 3 is hydrogen, poly(oxyethyleneoxy)

Chemical formula

Chemical formula

[0019] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C(R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R2 )] n R 3 、 -[C(R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 、 -[C(R 1 )(R 2 )N] m C(O)[C(R 1 )(R 2 )] n R 3 、 [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )(R 2 )] n R 3 、 [C(R 1 )(R 2 )N] m C(O)[NC(R 1 )(R 2 )] n R 3 、 -[C(R 1 )(R 2 )(O) p )] m C(O)NR 4 [C(R 1 )(R 2 )(O) p )] n R 3 and -[C(R 1 )(R 2 )(O) p )] n R 5 selected from the group consisting of; X is hydrogen or a 3 - to 6 - membered heterocyclyl; R 3 is hydrogen, poly(oxyethyleneoxy)

Chem.

Chem.

[0020] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is [C(R 1 )(R 2 )(O) p n R 5 selected from, R 5 is C 6-10 heterocyclyl, OPO(R 6 ) 2, OSO2R 6 , SR', SO2R',

Chemical formula

[0021] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is [C(R 1 )(R 2 )] n R 5 selected from, R 5 is C 6-10 heterocyclyl, OPO(R 6 ) 2, OSO2R 6 , SR', SO2R',

Chemical formula

[0022] In another embodiment of the present disclosure, in the compound represented by formula (II), Y is [C(R 1 )(R 2 )O] n R 5 selected from, R​5 is selected from the group consisting of C 6-10 heterocyclyl, OPO(R 6 )2, OSO2R 6 , SR', SO2R', [Chemistry] , OC(O)R 7 and NR'(R'').

[0023] In another embodiment of the present disclosure, in the compound represented by formula (II), R 5 is selected from the group consisting of C 6-10 heterocyclyl, OPO(R 6 )2, OSO2R 6 , SR', SO2R', [Chemistry] , OC(O)R 7 and NR'(R'').

[0024] Furthermore, in the compound represented by formula (II), the R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl (such as piperidine), OR' and NR'(R''), and R' and R'' are as defined in the compound represented by formula (II).

[0025] In another embodiment of the present disclosure, in the compound represented by formula (II), R' and R'' are selected from the group consisting of hydrogen and alkyl, and the alkyl is preferably selected from C 1-10 alkyl, more preferably selected from C 1-6 alkyl such as methyl, ethyl, propyl and isopropyl.

[0026] In another embodiment of the present disclosure, in the compound represented by formula (II), m = 1, 2, 3 or 4, n = 1, 2, 3 or 4, and o = 1 to 8.

[0027] In some embodiments, in the compound represented by formula (II), R 6 and R 7 are as follows: [Chemical formula] each independently selected from the group consisting of, where R' and R'' are selected from the group consisting of hydrogen and alkyl, and the alkyl is preferably C 1-10 alkyl selected from, more preferably C such as methyl, ethyl, propyl and isopropyl 1-6 alkyl selected from.

[0028] In some embodiments, R 3 is selected from OPO(R 6 )2, R 6 is selected from hydroxyl, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy and 3- to 7-membered heterocyclyl, and compound (II) is provided.

[0029] In some other embodiments, compound (II) is provided where m = 1, 2, 3 or 4.

[0030] In some other embodiments, R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-7 cycloalkyl, and compound (II) is provided.

[0031] In some other embodiments, the compound represented by formula (II) is [Chemical formula] [wherein, R 1 and R 2are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from the group consisting of alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, cyano, hydroxyl, halogen, SR', NR'(R"), COOR', and CONR'(R"); R' and R'' are each independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, and acyl; m=1, 2, 3 or 4] or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof, or a deuterated form thereof.

[0032] In some embodiments, in the compound of Formula (II), R 6 is the following: [ka] wherein R' and R'' are selected from the group consisting of hydrogen and alkyl, said alkyl being preferably selected from the group consisting of C 1-10 alkyl, more preferably C such as methyl, ethyl, propyl and isopropyl 1-6 selected from alkyl.

[0033] In some other embodiments, the compound of Formula (III) is [ka] [In the formula, R 1 and R 2is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more groups selected from the group consisting of alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, cyano, hydroxyl, halogen, SR', NR'(R''), COOR' and CONR'(R''); R 6 each of which is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, hydroxyalkyl and NR'(R''), and the alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more groups selected from the group consisting of alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, cyano, hydroxyl, halogen, SR', NR'(R''), COOR' and CONR'(R''); R' and R'' are each independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, alkenyl and acyl] or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof, or a deuterated product thereof.

[0034] Furthermore, in another embodiment, in the compound represented by formula (IV), R 6 is C 1-12 alkyl (but not limited to, such as methyl, ethyl, propyl or isopropyl), C 3-12 cycloalkyl (but not limited to, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.), 3- to 12-membered heterocyclyl (but not limited to, such as pyrrolyl, etc.), C 6-12 aryl (but not limited to, such as phenyl, naphthyl, etc.), 3- to 12-membered heteroaryl (but not limited to, such as pyridine, piperidine, etc.), C1-12 alkoxy (such as, but not limited to, methoxyl, ethoxyl, propoxyl or isopropoxyl), C 1-12 selected from the group consisting of hydroxyalkyl and NR'(R''), wherein said alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, C 1-12 alkoxy, C 1-6 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 6-10 aryl, 3- to 10-membered heteroaryl, nitro, cyano, hydroxyl, halogen, SR', NR'(R''), COOR' and CONR'(R''), and is optionally substituted by one or more groups selected from the group consisting of; R' and R'' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkenyl, C 1-6 alkanoyl (such as acetyl, formyl, etc.), benzoyl and p-toluoyl, respectively.

[0035] In a preferred embodiment of the present disclosure, in the compound represented by formula (II), said R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl (such as piperidine, etc.), OR' and NR'(R'').

[0036] In another embodiment of the present disclosure, in the compound represented by formula (IV), R' and R are selected from the group consisting of hydrogen and alkyl, and said alkyl is preferably C 1-10 selected from alkyl, more preferably C 1-6 selected from alkyl such as methyl, ethyl, propyl and isopropyl.

[0037] In some embodiments, in the compound represented by formula (IV), R 6 is as follows:

Chemical formula

[0038] In a preferred embodiment of the present disclosure, in the compound represented by formula (II), the R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl (such as piperidine), OR' and NR'(R'').

[0039] In another embodiment of the present disclosure, in the compound represented by formula (IV), R' and R" are selected from the group consisting of hydrogen and alkyl, and the alkyl is preferably C 1-10 alkyl selected from, more preferably C such as methyl, ethyl, propyl and isopropyl 1-6 alkyl selected from.

[0040] In some other embodiments, in the compound represented by formula (IV), R 6 is as follows:

Chemical formula

[0041] Typical compounds represented by formula (II) include the following: [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, rotamer or tautomer thereof, but not limited thereto.

[0042] Furthermore, the compound represented by formula (IA) is [Chemistry] or a pharmaceutically acceptable salt thereof.

[0043] In another aspect, the compounds of the present disclosure have higher solubility and better in vivo conversion compared to known compounds. In some embodiments, the compounds of the present disclosure have low hemolytic activity, few side effects after drug administration, and are beneficial for improving patient compliance with drug administration.

[0044] The present disclosure also provides a pharmaceutical composition comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier, diluent or excipient.

[0045] In another aspect, the hydrogen of the functional group of the compounds of the present disclosure can be deuterated to obtain the corresponding deuterated compounds, which retain selectivity and potential comparable to the hydrogen analogs. Deuterium bonds are more stable and lead to different "ADME", i.e., "Toxicokinetics", thereby providing clinically beneficial effects.

[0046] Toxicokinetics refers to the processes of absorption, distribution, metabolism, and excretion of exogenous chemicals by the body.

[0047] The present disclosure also relates to the use of a compound according to the above embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, in the manufacture of a medicament for treating a physiological disorder, condition or disease of a patient, wherein the physiological disorder, condition or disease is a respiratory disease, cough, inflammatory disease, skin disorder, ophthalmic disorder, depression, anxiety disorder, phobia, bipolar disorder, alcohol dependence, drug abuse that seriously affects the nerves, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDS-related dementia, Tourette's disease, stress-related disorder, obsessive / compulsive disorder, bulimia nervosa, anorexia nervosa, polyphagia, mania, premenstrual syndrome, gastrointestinal dysfunction, atherosclerosis, fibrotic disorder, obesity, type 2 diabetes, headache, neuropathic pain, postoperative pain, chronic pain syndrome, bladder disorder, urogenital disorder or vomiting or nausea, and further the present disclosure relates to the use for the manufacture of a medicament for treating asthma, vomiting, nausea, depression, anxiety disorder, cough or migraine.

[0048] In another aspect, the pharmaceutically acceptable salts of the compounds are selected from the group consisting of inorganic salts and organic salts. The compounds according to the present disclosure react with acids such as trifluoroacetic acid to form the corresponding salts. The acids are selected from the group consisting of, but not limited to, acetic acid, hydrochloric acid, salicylic acid, malic acid, ascorbic acid, phosphoric acid, citric acid, benzoic acid, fumaric acid. The compounds according to the present disclosure react with bases such as N-methyl-D-glucamine or dicyclohexylamine to form the corresponding salts. The bases are selected from the group consisting of, but not limited to, sodium, alkaline earth metals and amino acids (such as arginine, lysine).

[0049] In another aspect, the present disclosure also includes isotopically labeled compounds of the present application that are the same as those described in the present disclosure, but one or more atoms are replaced by atoms having an atomic weight or mass number different from that generally found in nature. 2 H 3 H 11 C 13 C 14 C 13 N 15 N 15 O 17 O 18 O 31 P 32 P 5 S 18 F 123 I 125 I and 36 Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine such as Cl are included.

[0050] The compounds of the present disclosure can contain an unnatural proportion of atomic isotopes in one or more atoms constituting the compound. For example, the compound can be tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14It can be labeled with radioisotopes such as C). As another example, hydrogen can be replaced with deuterium to form a deuteride. The bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon. Compared with the non-deuterated compound, the deuterated compound has advantages such as reduction of toxicity and side effects, improvement of drug stability, improvement of efficacy, and extension of biological half-life. All changes in the isotope composition of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0051] Furthermore, substitution with heavier isotopes (such as deuterium (i.e., 2 H), etc.) can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dosage), and thus may be preferred under certain circumstances where deuterium substitution may be partial or complete. Partial deuterium substitution is shown by replacing at least one hydrogen with at least one deuterium.

[0052] Explanation of Terms "Alkyl" refers to a saturated aliphatic hydrocarbon group containing a straight-chain or branched group having 1 to 20 carbon atoms, preferably alkyl having 1 to 12 carbon atoms, more preferably alkyl having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers thereof. Alkyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available bonding point. The substituent is preferably one or more groups independently selected from the group consisting of aryl, heteroaryl, and halogen.

[0053] "Alkenyl" refers to a branched or straight-chain olefin having 2 to 20 carbon atoms, or an olefin containing an aliphatic hydrocarbon group. For example, "C"2-6 "Alkenyl" means an alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.

[0054] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Examples of polycyclic cycloalkyl include cycloalkyl having a spiro ring, a fused ring or a bridged ring.

[0055] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, where the ring attached to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. Cycloalkyl can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl or carboxylate.

[0056] The term "heterocyclyl" contains 3 to 20 ring atoms, and one or more ring atoms are nitrogen, oxygen and S(O) mA heteroatom selected from the group consisting of (where m is an integer from 0 to 2), provided that the moiety while being -O-O-, -O-S- or -S-S- is excluded, and the remaining ring atoms are carbon atoms, represents a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The heterocyclyl preferably contains 3 to 12 ring atoms, where 1 to 4 atoms are heteroatoms, and more preferably contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., and piperidinyl and pyrrolidinyl are preferred. Examples of polycyclic heterocyclyl include heterocyclyl having a spiro ring, a fused ring or a bridged ring.

[0057] The heterocyclic ring can be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocyclyl. Non-limiting examples include

Chemical formula

[0058] The heterocyclyl can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthiol, heterocyclylthiol, oxo, carboxyl or carboxylate.

[0059] "Alkynyl" includes branched or straight-chain alkynyl or olefins containing an aliphatic hydrocarbon group having 2 to 12 carbon atoms, or, when the number of carbon atoms is specified, it means a specific number such as ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl.

[0060] The term "aryl" refers to a monocyclic ring of all carbon atoms having 6 to 14 members or a polycyclic condensed ring having a conjugated π electron system (i.e., each ring shares an adjacent pair of carbon atoms), and 6 to 12 members, such as phenyl or naphthyl, are preferred. The aryl ring can be condensed to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring. As non-limiting examples, the following:

Chemical formula

[0061] Aryl can be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thio, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxyl and carboxylate, and preferably phenyl.

[0062] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl is preferably a 6- to 12-membered heteroaryl, more preferably a 5- or 6-membered heteroaryl, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc.; preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. As non-limiting examples, the following:

Chemical formula

[0063] Heteroaryl can optionally be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thio, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxyl and carboxylate.

[0064] The term "alkoxy" refers to an -O-(alkyl) or -O-(unsubstituted cycloalkyl) group, where alkyl is as defined above. Non-limiting examples of alkoxy include methoxyl, ethoxyl, propoxyl, butoxyl, cyclopropoxyl, cyclobutoxyl, cyclopentyloxyl, cyclohexyloxyl. Alkoxy can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thio, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxyl or carboxylate.

[0065] The term "hydroxyalkyl" refers to alkyl substituted with one or more hydroxyl groups, where alkyl is as defined above.

[0066] The term "haloalkyl" refers to alkyl substituted with one or more halogen atoms, where alkyl is as defined above.

[0067] The term "deuterated alkyl" refers to alkyl substituted with one or more deuterium atoms, where alkyl is as defined above.

[0068] The term "hydroxyl" refers to an -OH group.

[0069] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0070] The term "amino" refers to -NH2.

[0071] The term "cyano" refers to -CN.

[0072] The term "nitro" refers to -NO2.

[0073] "Optional" or "optionally" means that the events or situations described below may occur, but do not have to occur, and the detailed description includes the situations where the events or situations occur or do not occur. For example, "heterocyclyl optionally substituted by alkyl" means that alkyl may or may not be present, and the detailed description includes the situations where heterocyclyl is substituted by alkyl and the situations where heterocyclyl is not substituted by alkyl.

[0074] "Substituted" refers to one or more hydrogen atoms in one group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted by the corresponding number of substituents. Needless to say, the substituents are only present at their possible chemical positions. A person skilled in the art can determine whether substitution is possible or impossible by experiment or theory without undue effort. For example, the bonding of an amino or hydroxyl having free hydrogen to a carbon atom having an unsaturated bond (such as an olefin) may be unstable.

[0075] "Pharmaceutical composition" refers to a mixture containing one or more of the compounds described in this specification, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism, which promotes the absorption of the active ingredient so as to exhibit biological activity.

[0076] The known starting materials in the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from Acros Organics or Aldrich Chemical Company and other companies, or can be obtained by the methods described in CN102775401A.

[0077] The structure of the compound is identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). NMR is determined using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvents for determination are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). A FINNIGAN LCQ Ad (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX for ESI-MS determination) is used. LCMS is determined by high performance liquid chromatography (manufacturer: Agilent, model: 1200) using gradient elution, positive ion scan mode, and a quality scan range of 100 - 1500.

Brief Description of the Drawings

[0078]

Figure 1

Modes for Carrying Out the Invention

[0079] Detailed Description The present disclosure will be further described with reference to the following examples, which should not be regarded as limiting the scope of the present disclosure.

[0080] The experimental methods under unspecified conditions in the examples of the present disclosure generally follow conventional conditions or the conditions recommended by the manufacturer of the raw materials or products. Reagents for which the source is not specified are commercially available conventional reagents.

Examples

[0081]

Chemical Formula

[0082] Step 1:

Chem.

[0083] Step 2:

Chem.

[0084] Step 3:

Chem.

[0085] 1 1H-NMR (400 MHz, CD3OD): δ (ppm) 7.89 (s, 2H), 7.86 (s, 1H), 7.41 - 7.27 (m, 5H), 5.66 (d, J = 12 Hz, 1H), 5.50 - 5.47 (m, 1H), 4.60 (d, J = 8 Hz, 1H), 4.20 - 3.88 (m, 3H), 2.51 - 2.10 (m, 5H), 1.86 - 1.66 (m, 3H), 1.44 - 1.31 (m, 4H).

[0086] Step 4:

Chem.

Example

[0087]

Chem.

[0088] Step 1:

Chem.

[0089] Step 2:

Chemical formula

[0090] Step 3:

Chemical formula

[0091] Step 4:

Chemical formula

[0092] 1 1H-NMR (400 MHz, CD3OD): δ 7.90 - 7.84 (m, 3H), 7.32 - 7.25 (m, 5H), 4.14 - 3.61 (m, 25H), 2.81 (m, 5H), 2.47 - 2.29 (m, 12H), 1.79 - 1.63 (m, 5H), 1.46 - 1.29 (m, 3H), 1.21 - 1.12 (m, 6H).

Example

[0093]

Chem.

[0094] 11H-NMR (400 MHz, CDCl3): δ = 7.79 (s, 1H), 7.72 (s, 2H), 7.42 - 7.40 (d, J = 8 Hz, 2H), 7.31 - 7.27 (m, 2H), 7.27 - 7.21 (m, 1H), 5.58 (s, 1H), 4.55 - 4.53 (m, 1H), 4.06 - 3.99 (m, 2H), 3.69 - 3.67 (d, J = 8 Hz, 1H), 3.53 - 3.49 (d, J = 16 Hz, 1H), 3.25 - 3.21 (d, J = 16 Hz, 1H), 2.77 - 2.74 (d, J = 12 Hz, 1H), 2.59 - 2.57 (d, J = 8 Hz, 1H), 2.34 - 2.31 (m, 3H), 1.97 - 1.71 (m, 7H), 1.46 - 1.45 (d, J = 4 Hz, 3H).

Example

[0095]

Chemical formula

[0096] Step 1:

Chemical formula

[0097] Step 2:

Chemical formula

[0098] 1 1H-NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.73 (s, 2H), 7.37 - 7.26 (m, 5H), 6.56 (s, 1H), 4.44 - 4.40 (m, 1H), 4.29 - 4.24 (m, 2H), 4.10 - 4.07 (m, 1H), 3.90 - 3.87 (d, J = 12 Hz, 1H), 3.79 - 3.76 (d, J = 12 Hz, 1H), 3.01 - 2.97 (d, J = 16 Hz, 1H), 2.52 - 2.32 (m, 15H), 1.93 - 1.65 (m, 6H), 1.29 - 1.28 (d, J = 4 Hz, 3H).

Example

[0099]

Chemical formula

[0100] Step 1:

Chemical formula

[0101] Step 2:

Chemical formula

[0102] 147 mg of Compound 3 and 203 mg of sodium iodide were added to 2 ml of dimethylformamide, and then 136 mg of potassium bicarbonate was added. The reaction mixture was stirred at room temperature for 30 minutes, and then 400 mg of Compound 2 dissolved in 10 ml of dimethylformamide was added dropwise. The mixture was reacted overnight. Water was added to stop the reaction. The reaction mixture was extracted twice with ethyl acetate. The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 450 mg of Compound 4 as an oil.

[0103] Step 3:

Chemical formula

[0104] 1 H-NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.72 (s, 1H), 7.63 (s, 2H), 7.40 - 7.28 (m, 5H), 6.19 (s, 1H), 5.68 - 5.67 (d, J = 4 Hz, 1H), 4.30 - 4.29 (d, J = 4 Hz, 1H), 4.20 - 4.17 (d, J = 12 Hz, 1H), 3.99 - 3.91 (m, 2H), 3.79 (s, 1H), 2.70 - 2.67 (d, J = 12 Hz, 1H), 2.49 - 2.21 (m, 8H), 1.83 - 1.70 (m, 4H), 1.29 - 1.28 (m, 3H), 1.09 - 1.07 (m, 6H).

Example

[0105]

Chem.

[0106] Step 1:

Chem.

[0107] Step 2:

Chem.

[0108] Step 3:

Chemical formula

[0109] 1 1H-NMR (400 MHz, CDCl3) δ = 7.72 (s, 1H), 7.57 (s, 2H), 7.50 - 7.41 (m, 5H), 4.80 - 4.59 (m, 3H), 4.17 - 4.13 (d, J = 16 Hz, 1H), 3.83 - 3.80 (d, J = 12 Hz, 1H), 3.62 - 3.59 (d, J = 12 Hz, 1H), 3.26 - 3.22 (d, J = 16 Hz, 1H), 2.60 - 2.47 (m, 4H), 2.26 - 2.18 (m, 2H), 1.85 - 1.80 (m, 2H), 1.45 - 1.43 (d, J = 8 Hz, 3H), 0.89 - 0.83 (m, 1H).

Example

[0110]

Chemical formula

Chem.

Example

[0111]

Chem.

Chem.

[0112]

Chem.

Example

[0113]

Chem.

Chem.

[0114]

Chem.

[0115]

Chem.

Example

[0116]

Chem.

Example

[0117]

Chem.

Example

[0118]

Chem.

[0119] Boc-L-valine was replaced with N-Boc-glycine, and the target compound was synthesized according to the method of Example 5. LCMS: 632 [M+1].

Example

[0120]

Chem.

[0121] Boc-L-valine was replaced with N-Boc-alanine, and the target compound was synthesized according to the method of Example 5. LCMS: 646 [M+1].

Example

[0122]

Chem.

Example

[0123]

Chem.

Example

[0124]

Chem.

Example

[0125]

Chem.

Example

[0126]

Chem.

[0127] Test Example 1: Water Solubility Data and Chemical Stability 1.1. Preparation of reagents Reagent: NaH2PO4·2H2O

[0128] 1.2. Preparation method 100 mL of strength reagents were prepared as follows: pH = 3.0: Phosphate buffer: 100 ml of 20 mmol / L NaH2PO4, 0.1 M H3PO4, adjusted to pH 3.0. pH = 4.0: Phosphate buffer: 100 ml of 20 mmol / L NaH2PO4, 0.1 M H3PO4, adjusted to pH 4.0. pH = 7.0: Ultra-pure water pH = 9.0: Phosphate buffer: 100 ml of 20 mmol / L Na2HPO4, 0.1 M NaOH solution, adjusted to pH 9.0.

[0129] 1.3. Test method An appropriate amount of the test compound was accurately weighed. The solution was added in small portions several times and stirred until the compound was dissolved, and the content of the compound in the solution was measured. The data are shown in Table 1.

[0130] 2.1 Solubility test of the compound Approximately 1 mg of the sample was weighed into a vial, and then the vial was placed in a vacuum bag, and the bag was evacuated. Next, the bag was placed in a container containing discolored silica gel and sealed. Two parallel samples were prepared. Sufficient samples were prepared according to the sampling time points and placed at 4°C and room temperature respectively. The data are shown in Table 1.

[0131] Table 1

Table 1

[0132] Test Example 2: Plasma Stability Test Test Protocol 1.1 Test Drug The compound of Example 5 and the compound represented by formula (I). 1.2 Test Plasma Human fresh plasma was provided by volunteers who gave informed consent. 1.3 Preparation of Compound Solutions A certain amount of the compound of Example 5 was weighed, DMSO was added to prepare a 30 mM stock solution. A certain amount of the stock solution was diluted with DMSO to prepare Solution I with a concentration of 1600 μM. Next, a certain amount of 1600 μM Solution I was diluted with 45% methanol to prepare Working Solution II with a concentration of 16 μM. Also, a 30 mM stock solution and 1600 μM Solution II for the compound represented by formula (I) were prepared by the above method.

[0133] 1.4 Sample Incubation 5 μL of a 16 μM diluted standard solution of the compound of Example 5 was added to 75 μL of plasma at a final concentration of 1 μM. The sample was incubated in a 37 °C water bath for 0, 15, 30, 60, 90, 120 - 180 minutes. After the incubation was completed, 240 μL of internal standard containing acetonitrile was added to the sample, then shaken on a shaker at 800 rpm for 10 minutes and centrifuged at 3700 rpm at 4 °C for 20 minutes. The supernatant was analyzed by LC-MS, and the injection volume was 2 μL.

[0134] 1.5 Preparation of Standard Curve The aforementioned 1600 μM solution I was diluted with acetonitrile to prepare standard curves at concentrations of 160, 400, 1600, 4000, 8000, 16000, and 32000 ng / mL. The concentrations of the QC dilutions were 480, 1920, and 25600 ng / mL. 5 μL of the standard curve dilution standard solutions and QC dilution standard solutions were added to 75 μL of plasma to obtain standard curve samples at final concentrations of 10, 25, 100, 250, 500, 1000, and 2000 ng / mL, and QC samples at final concentrations of 30, 120, and 1600 ng / mL. Next, 240 μL of acetonitrile containing the internal standard was quickly added to the samples, which were then shaken at 800 rpm for 10 minutes on a shaker and centrifuged at 3700 rpm at 4 °C for 20 minutes. The supernatant was collected and analyzed by LC-MS, and the injection volume was 2 μL.

[0135] The standard curves of the compound represented by formula (I) and the QC samples were prepared by the above method.

[0136] 2. Results The conversion of the compound of Example 5 of the present invention in fresh human plasma was as follows, and the data are shown in Table 2:

[0137] Table 2 [Table 2] Conclusion: The compound was completely converted to the compound represented by formula (I) in fresh human plasma in about 30 minutes.

[0138] Test Example 3: Plasma Stability Test 1.1 Test drugs The compounds of Example 4, Example 6, Example 10, and Example 11. 1.2 Test plasma Fresh human plasma was provided by volunteers who gave informed consent.

[0139] 1.3 Experimental steps 1) The test compounds in Table 3 were each prepared in a 30 mM stock solution containing DMSO for later use. 2) The 30 mM stock solution was diluted to Solution I at a concentration of 1600 μM with a DMSO solution. Next, the 1600 μM Solution I was diluted to the diluted standard solution II at a concentration of 16 μM with acetonitrile (ACN). 3) In this experiment, seven time points of 0, 15, 30, 60, 90, 120, and 180 minutes were set, and two parallel samples were used at each time point. For each compound, two sample groups were set. 75 μL of plasma and 5 μL of the diluted solution II prepared above at a concentration of 16 μM were added to each group. The reaction system was incubated at 37 °C until the set time to stop the reaction with 300 μL of an ACN solution containing an internal standard. The reaction mixture was centrifuged at 3700 rpm for 10 minutes, and the supernatant was collected for analysis. 4) Preparation of the standard curve: The pre-diluted 1600 μM Solution I was diluted to Solution III at 1.5 μM / mL with acetonitrile as the standard curve to be used later. The standard curve concentrations were set at 0.32, 0.8, 1.6, 4.0, 8, 12, 16, and 42 μM. After dilution of each concentration of the standard curve, 75 μL of plasma was added to each concentration point of 5 μL at final concentrations of 0.02, 0.05, 0.1, 0.25, 0.75, 1.0, and 1.5 μM, respectively. Next, 300 μL of the stop solution was quickly added to the samples, followed by centrifugation at 3700 rpm for 10 minutes, and the supernatant was collected for LC-MSMS analysis. The data are shown in Table 3.

[0140] Table 3

Table 3

[0141] Conclusion: The compounds of Example 4, Example 10, and Example 11 are relatively stable in plasma and have a relatively long half-life in plasma, but only a small part of these three compounds is metabolized in plasma to become loperitant. The compound of Example 6 is metabolized in plasma to become loperitant, but it can be seen from the above data that the amount of metabolism in plasma is relatively small.

[0142] Test Example 4: The metabolism of the compounds of Example 1, Example 2 and Example 8 in mouse, rat and human plasma was determined by referring to the test method of Test Example 2. The data are shown in Table 4.

Chemical formula

[0143] Table 4

Table 4

[0144] Conclusion: In mouse, rat and human plasma, the compound of Compound 8 can be converted into loperitant. In particular, the conversion rate in human plasma is about 46%. On the other hand, the compounds of Example 1 and Example 2 basically had no conversion into loperitant or only slight conversion in human plasma.

[0145] Test Example 5: In Vivo Pharmacokinetics Test in Rats Rats were used as test animals. Plasma drug concentrations at different time points after administration of the compounds of Example 1 and Example 2 by injection were determined using the LC / MS / MS method. The in vivo pharmacokinetics of the compounds in rats were studied and the pharmacokinetic properties were evaluated.

[0146] Drug Preparation A certain amount of the compounds of Example 1 and Example 2 was weighed and prepared into a solution with pH = 4.0 by using 20 mmol / L sodium dihydrogen phosphate for later use.

[0147] 1.1 Drug Administration The drug was administered by intravenous bolus injection with an injection time of about 5 minutes, a dose of 2 mg / kg, a dosing concentration of 0.4 mg / ml and a dose volume of 5 ml / kg.

[0148] 1.2 Operation Blood samples were collected from the orbital vein before administration and at 5 minutes, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 24 hours, and 48 hours after administration. For each sample that was anticoagulated using sodium heparin, approximately 0.6 mL was collected and placed on ice immediately after collection. After blood collection, the blood samples were placed into labeled centrifuge tubes, and plasma was separated by centrifugation (centrifugation conditions: centrifugal force 2200 g, centrifugation at 2 - 8 °C for 10 minutes).

[0149] 1.3 Results of Pharmacokinetic Parameters Table 5

Table 5

[0150] Conclusion: The compound of Example 1 is basically not metabolized to the active substance loperitant in vitro, especially not in human plasma, but shows excellent pharmacokinetic data of loperitant in rats, indicating that the compound of Example 1 is metabolized to loperitant in vivo. Furthermore, from the data of AUC 0-∞ 、AUC 0-t and T 1 / 2 , the in vivo metabolism cycle of Compound 1 after administration is long, and the absorption and exposure levels of Compound 1 are comparable to those of loperitant.

[0151] Test Example 6: Pharmacokinetics Test of the Compound in Cynomolgus Monkeys Cynomolgus monkeys were used as test animals. Plasma drug concentrations at different time points after intravenous administration of the compound of Example 5 were determined using the LC / MS / MS method. The in vivo pharmacokinetics of the compound of the present invention in cynomolgus monkeys were studied, and the pharmacokinetic characteristics were evaluated.

[0152] Preparation of the Drug A certain amount of the compound of Example 5 was weighed and prepared into a solution with pH = 4.0 by using 20 mmol / L sodium dihydrogen phosphate for later use.

[0153] 1.1 Drug Administration The drug was administered by intravenous injection with an injection time of approximately 30 minutes, a dosage of 2 mg / kg, an administration concentration of 0.4 mg / ml, and a dosage volume of 5 ml / kg.

[0154] 1.2 Procedures Blood was collected from the femoral vein before administration and at 5 minutes, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 24 hours, and 48 hours after administration. For each sample subjected to anticoagulation treatment using sodium heparin, approximately 0.6 mL was collected and placed on ice immediately after collection. After blood collection, the blood samples were placed in labeled centrifuge tubes, and plasma was separated by centrifugation (centrifugation conditions: centrifugal force 2200 g, centrifugation at 2 - 8°C for 10 minutes).

[0155] The contents of Compound 5 and loperitant in the plasma samples were determined by LC / MS / MS.

[0156] 1.3 Results of Pharmacokinetic Parameters Table 6 [Table 6] Conclusion: In the pharmacokinetic study of the compound of Example 5 in cynomolgus monkeys, most of the compound was rapidly converted to the active metabolite loperitant, which has good pharmacokinetic properties, in cynomolgus monkeys.

Example

[0157] According to Step 1-2 of Example 1, the target compound was prepared. Next, under a nitrogen atmosphere, Compound 3 (6.65 g, 8.67 mmol, 1 equivalent) was dissolved in dichloromethane (200 mL) in a 500 mL one-neck flask, and trifluoroacetic acid (9.89 g, 86.7 mmol, 10.0 equivalents) was slowly added while cooling with ice water. The reaction mixture was stirred until the reaction was complete. The reaction mixture was concentrated to obtain 2.29 g of an oily substance, which was purified by a reverse-phase silica gel column (C18) (Solution A: 20 mmol aqueous solution of NH4HCO3, Solution B: acetonitrile), then adjusted to pH = 1-2 with 1 M phosphoric acid, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.7 g of the target product.

[0158]

Chemical formula

[0159] Test Example 7: Solubility By referring to the solubility test method of Test Example 1, the solubility of the compound of Example 19 at different pH values was measured. The data are as follows: Table 7

Table 7

[0160] Test Example 8: Hemolytic effect Red blood cells (RBC) were collected from the jugular vein or central ear artery of rabbits (10 ml of EDTA whole blood). The blood was placed in an Erlenmeyer flask containing glass beads and shaken for 10 minutes to remove fibrinogen, obtaining defibrinated blood. Approximately 10 times the volume of sodium chloride solution was added to the defibrinated blood, then shaken well and centrifuged at 1500 rpm for 10 minutes. The supernatant was removed, and the precipitated red blood cells were washed 3 times with sodium chloride injection according to the above method until the supernatant was observed to be colorless. The obtained red blood cells were prepared into a 2% (v / v) suspension by injecting sodium chloride for later use.

[0161] Test samples (the compound of Example 5 and the compound of Example 19) were each dissolved in PBS (pH 7.4 or pH 5), filtered, and solutions of 0.4 mg / ml, 0.8 mg / ml, 1.2 mg / ml, 1.6 mg / ml, and 2 mg / ml were prepared for later use.

[0162] To test with the supernatant, a certain amount of the test sample solution was added to the above hemoglobin.

[0163] When the solution in the test tube is transparent and red, and there are no cells remaining at the bottom of the test tube or only a small amount of red blood cells remaining, it indicates that hemolysis has occurred. When all red blood cells have settled and the supernatant is colorless and transparent, it indicates that no hemolysis has occurred. If there is a brownish-red or reddish-brown flocculent precipitate in the solution and it does not disperse even after gently inverting 3 - 5 times, it indicates that red blood cell coagulation may occur. If the sample is further observed under a microscope and the red blood cells appear to be aggregated, coagulation has occurred. The hemolytic effect of the compounds of the present disclosure was determined by using this method.

[0164] Conclusion: The compound of Example 19 has no hemolytic effect at a concentration up to 2 mg / ml, and the compound of Example 5 has a hemolytic effect at a concentration of 0.04 mg / ml or higher.

[0165] Test Example 9: Hemolytic Action of Rolapitant Emulsion By referring to the method described in CN102775401A, loperitant emulsion was prepared (formulation: 4.4% polyethylene glycol 15 hydroxystearate, 1.1% medium-chain triglyceride, and 0.66% soybean oil), and for later use, it was adjusted to 0.18 mg / ml, 0.09 mg / ml, 0.045 mg / ml, 0.023 mg / ml, 0.011 mg / ml, 0.056 mg / ml, and 0.028 mg / ml with PBS.

[0166] The hemolytic effect was determined by referring to the method of Test Example 8.

[0167] Conclusion: Rolapitant emulsions showed hemolytic effects at all concentrations.

[0168] Test Example 10: Pharmacokinetics Test in Cynomolgus Monkeys Cynomolgus monkeys were used as test animals. Plasma drug concentrations at different time points after administration of the compound prepared by referring to Example 19 by injection were determined using the LC / MS / MS method. The in vivo pharmacokinetics of the compound of the present invention in cynomolgus monkeys were studied and the pharmacokinetic properties were evaluated.

[0169] Preparation of the drug A certain amount of the test compound was weighed and prepared into a solution with pH = 4.0 by using 20 mmol / L sodium dihydrogen phosphate for later use.

[0170] 1.1 Drug administration The drug was administered by intravenous drip with an injection time of about 30 minutes, a dose of 3.54 mg / kg, an administration concentration of 2 mg / ml, and a dose of 5 ml / kg.

[0171] 1.2 Operations Blood was collected from the femoral vein before administration and at 5 minutes, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration. For each sample treated with anticoagulation using sodium heparin, about 0.6 mL was collected and placed on ice immediately after collection. After blood collection, the blood samples were put into labeled centrifuge tubes and the plasma was separated by centrifugation (centrifugation conditions: centrifugal force 2200 g, centrifugation at 2 - 8 °C for 10 minutes).

[0172] The contents of Example 24 and rolapitant in the plasma samples were determined by LC / MS / MS.

[0173] 1.3 Results of pharmacokinetic parameters Table 8

Table 8

[0174] Conclusion: In the pharmacokinetic study of the above compound in cynomolgus monkeys, most of the compound was rapidly converted to the active metabolite rolapitant in cynomolgus monkeys, and the compound has good pharmacokinetic properties. Furthermore, compared with the compound of Example 5, the compound has higher in vivo bioavailability in cynomolgus monkeys.

Claims

1. Formula (III): 【Chemical 1】 [In the formula, R 1 and R 2 is hydrogen, C 1-6 are each independently selected from the group consisting of alkyl; m=1, 2, 3 or 4] or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof.

2. The compound of formula (III) is 【Chemistry 2】 2. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof, a stereoisomer, a rotamer or a tautomer thereof, or a deuterated form thereof.

3. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1-2, and a pharmaceutically acceptable carrier, diluent or excipient.

4. 10. Use of a compound according to any one of claims 1 to 2 or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for the treatment of a physiological disorder, condition or disease in a patient, wherein the physiological disorder, condition or disease is a respiratory disorder, cough, inflammatory disease, skin disorder, ophthalmological disorder, depression, anxiety, phobia, bipolar disorder, alcoholism, neurological substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDS-related dementia, Town's disease, stress-related disorder, obsessive / compulsive disorder, bulimia, anorexia nervosa, bulimia, mania, premenstrual syndrome, gastrointestinal dysfunction, atherosclerosis, fibrotic disorder, obesity, type 2 diabetes, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorder, genitourinary disorder or vomiting or nausea.

5. 5. The use according to claim 4, wherein the use is for treating selected from the group consisting of asthma, vomiting, nausea, depression, anxiety, cough and migraine.

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