Neurokinin-1 antagonist

Abstract

A compound represented by formula II or a pharmaceutically acceptable salt thereof, and a preparation method therefor. The compound represented by formula II is an antagonist of a neurokinin-1 receptor, can be used for treating diseases related to the neurokinin-1 receptor, and can avoid hemolytic effects of drugs and reduce the side effects of drug administration.

Description

Neurokinin-1 antagonists TECHNICAL FIELD

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

[0002] Tachykinins are peptide ligands for neurokinin receptors. Neurokinin receptors, such as NK1, NK2 and NK3, are involved in a variety of biological processes. They can be found in the nervous and circulatory systems of mammals, as well as in peripheral tissues. Modulation of such receptors has therefore been investigated for the potential treatment or prevention of a variety of diseases in mammals. Exemplary neurokinin receptor antagonists and their uses include: US5760018 (1998) (pain, inflammation, migraine and emesis), US5620989 (1997) (pain, nociception and inflammation), WO95 / 19344 (1995), WO 94 / 13639 (1994) and WO 94 / 10165 (1994). Other classes 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, selective, and well metabolically stable NK1 antagonist, (5S,8S)-8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7- diazaspiro[4.5]decane-2-one (Compound of Formula I), which can be in free base form or in pharmaceutically acceptable salt form, in a formulation suitable for parenteral administration,

[0004]

[0005] US9101615 provides prodrugs of the compound of Formula I, i.e., prodrugs of the compound of Formula I in which the hydrogen of the free amine (or both amines) is replaced by a group selected from -Y, -X, and salts thereof, wherein Y is selected from -P(O)(OH)2, -S(O) n1 R 1 , -C(O)(C 1-6 alkyl)X, -C(O)(C 1-6 alkyl)(aryl), -C(O)OR 4 ; X is selected from -NR 2 R 3 , -P(O)(OH)2, or -S(O)n1 R1; R 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 alkyl; n1 is 0-4. The prodrug can be used in a suitable liquid formulation (including or excluding the parenteral delivery vehicle) to treat a patient in need thereof.

[0006] On the other hand, drug hemolysis is the massive destruction of red blood cells caused by immune factors after the drug enters the human body, and clinically presents hemolytic phenomena such as anemia, jaundice, soy sauce and urine. Drug-induced hemolytic anemia can be divided into the following three types: (1) drug-induced immunity, leading to antibody-mediated hemolytic reaction; (2) drugs acting on red blood cells with genetic enzyme defects (such as G6PD deficiency); (3) drug hemolytic reaction on abnormal hemoglobin. The key to treating this disease is to stop using related drugs and control the occurrence of hemolysis to prevent the occurrence of complications. In order to solve the problem of low solubility of the compound of formula I in physiological pH solvents, the researchers used a co-solvent-based formulation containing Captisol, propylene glycol and ethanol to significantly improve the solubility of compound 1, but the co-solvent formulation has obvious hemolytic effect after intravenous administration. CN102573475 discloses an improved prescription containing polyethylene glycol 15-hydroxystearate, medium-chain triglyceride. However, the hemolytic effect of the drug composition has not been completely solved, even if the compound of formula I is prepared into a prodrug containing a phosphate ester.

[0007] The present application provides a new prodrug compound of NK1 antagonist which is effective for treating various physiological disorders, symptoms and diseases with minimal side effects.

[0008] SUMMARY

[0009] The disclosure provides a compound shown in formula II:

[0010] or a pharmaceutically acceptable salt thereof or a stereoisomer, rotamer or tautomer thereof or a deuterated compound thereof,

[0011] wherein X is selected from hydrogen, heterocyclyl, aryl, heteroaryl, -C(O)OA m R 3 , -C(O)NR 4 A m R 3 , -A m [C(R 1 )(R 2 )]C(O)OAn R 3 , m OC(O)[C(R 1 )(R 2 )]A n R 3 , m C(O)NR 4 A n R 3 , m NR 4 C(O)A n R 3 or -A m R 5 , said heterocyclyl, aryl or heteroaryl group being optionally substituted by one or more substituents selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, SR', NR'(R"), COOR' or CONR'(R");

[0012] Y is selected from hydrogen, -C(O)OA m R 3 , 4 -C(O)NR m A 3 R m , 1 [C(R 2 )(R n )]C(O)OA 3 R m , 1 OC(O)[C(R 2 )(R n )]A 3 R m , 4 C(O)NR n A 3 R m , 4 NR n C(O)A 3 R m or -A 5 R 1 ;

[0013] A is independently selected from -C(R 2 )(R p )(B) q - or -(B) 1 C(R 2 )(R 1 )-,

[0014] R 2 or R4 each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR', or CONR'(R");

[0015] R 3 selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, poly(oxaethylene) poly(ethyleneoxy) OPO(R 6 )2, PO(R 6 )2, OSO2(R 6 )2, SO2(R 6 )2, OC(O)R 6 , or C(O)OR 6 , said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR', or CONR'(R");

[0016] R 5 selected from heterocyclyl, heteroaryl, OSO2R 7 , OC(O)R 7 , SR', SO2R', or NR'(R");

[0017] R 6 each independently selected from hydrogen, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, hydroxyalkyl, or NR'(R"), said alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR', or CONR'(R");

[0018] R 7 each independently selected from alkyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, or NR'(R"), said alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR', or CONR'(R");

[0019] R' or R" is independently selected from hydrogen, hydroxyl, alkyl (preferably selected from C 1-12 alkyl, including but not limited to methyl, ethyl or isopropyl), alkoxy (preferably selected from C 1-12 alkoxy), alkenyl, acyl;

[0020] B is each independently selected from O, N, SC(O)

[0021] m, n, o are each independently selected from 1 to 10, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p, q are each independently selected from 0 or 1;

[0022] and X and Y are not simultaneously hydrogen.

[0023] The compound of Formula II has a solubility superior to the parent compound of Formula I, and thus, can be suitable for intravenous administration. In addition, the aforementioned compound, when administered intravenously to a human, degrades under physiological conditions and releases the parent drug, delaying the release of the drug and extending the release period of the drug.

[0024] In alternative embodiments of the present disclosure, the compound of Formula II, wherein X is selected from 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 or -[C(R 1 )(R 2 )(O) p ] m R 5 , said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more substituents selected from alkyl (preferably selected from C 1-12 alkyl groups, including but not limited to methyl, ethyl or isopropyl), cycloalkyl (preferably selected from C 1-12 cycloalkyl groups, such as cyclohexyl, cyclopentyl), alkoxy (preferably selected from C 1-12 alkoxy groups), hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, SR', NR'(R"), COOR' or CONR'(R");

[0025] Y is selected from 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 )(R2 )(O) p ] n R 3 or -[C(R 1 )(R 2 )(O) p ] m R 5 , and X and Y are not both hydrogen.

[0026] In alternative embodiments of the disclosure, the compound of Formula II, wherein Y is selected from -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 ] mC(O)NR 4 [C(R 1 )(R 2 )(O) p ] n R 3 or -[C(R 1 )(R 2 )(O) p ] n R 5 , X is hydrogen, 3- to 6-membered heterocyclyl.

[0027] In alternative embodiments of the disclosure, the compound of Formula II, wherein Y is selected from -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 )(R2 (O) p ] m C(O)NR 4 [C(R 1 (R) 2 (O) p ] n R 3 or -[C(R 1 (R) 2 (O) p ] n R 5 X is hydrogen, a 3 to 6-membered heterocyclic group; m, n, o are each independently selected from 1, 2, 3, 4, 5 or 6; p, q are each independently selected from 0.

[0028] In an optional embodiment of this disclosure, the compound represented by Formula II, wherein Y is selected from -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(R1 (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 or -[C(R 1 (R) 2 (O) p ] n R 5 X is hydrogen, a 3 to 6-membered heterocyclic group; m, n, o are each independently selected from 1, 2, 3, 4, 5 or 6; p, q are each independently selected from 1.

[0029] In an optional embodiment of this disclosure, the compound represented by Formula II, wherein Y is selected from -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 or -[C(R 1 )(R 2 )(O) p ]R 5 , X is hydrogen, 3- to 6-membered heterocyclyl.

[0030] In alternative embodiments of the disclosure, the compound of Formula II, wherein Y is selected from -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 or -[C(R 1)(R 2 )(O) p ]2R 5 , X is hydrogen, 3- to 6-membered heterocyclyl.

[0031] In alternative embodiments of the disclosure, the compound of Formula II, wherein X is selected from -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 or -[C(R 1 )(R 2 )] n R 5 , Y is hydrogen.

[0032] In alternative embodiments of the disclosure, the compound of Formula II, wherein X is selected from -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 R3 or -[C(R 1 )(R 2 )] n R 5 ; Y is hydrogen; m, n, o are each independently selected from 1, 2, 3, 4, 5 or 6; p, q are each independently selected from 0.

[0033] In alternative embodiments of the disclosure, the compound of Formula II, wherein X is selected from -[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(R 1 )(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 or -[C(R 1 )(R 2 )]R 5 , Y is hydrogen.

[0034] Further, in alternative embodiments of the disclosure, the compound of Formula II, wherein R 3 is selected from hydrogen, poly(oxaethyleneoxy) poly(ethyleneoxy) OPO(R 6 )2, PO(R 6 )2, OSO2(R 6 )2, SO2(R 6 )2, OC(O)R 6 or C(O)OR 6 , R 6 is as defined in the compound of Formula II.

[0035] In alternative embodiments of the disclosure, the compound of Formula II, wherein Y is selected from -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 or -[C(R 1 )(R 2 )(O) p ] n R 5 , X is hydrogen, 3- to 6-membered heterocyclyl; R 3 is selected from hydrogen, poly(oxaalkylene) poly(ethyleneoxy) OPO(R 6 )2, PO(R 6 )2, OSO2(R 6 )2, SO2(R 6 )2, OC(O)R 6 or C(O)OR 6 , R 6 is as defined in the compound of formula II.

[0036] In an alternative embodiment of the present disclosure, the compound of formula II, wherein Y is selected from [C(R 1 )(R 2 )(O) p ] n R 5 , R 5 is selected from C 6-10 heterocyclyl, OPO(R 6 )2, OSO2R 6 , SR', SO2R', OC(O)R 7 or NR'(R").

[0037] In an alternative embodiment of the present disclosure, the compound of formula II, wherein Y is selected from [C(R 1 )(R 2 ] n R 5 , R 5 is selected from C 6-10 heterocyclyl, OPO(R 6 )2, OSO2R 6 , SR', SO2R', OC(O)R 7 or NR'(R").

[0038] In an alternative embodiment of the present disclosure, the compound of formula II, wherein Y is selected from [C(R 1 )(R 2 )O] n R 5 , R 5 is selected from C 6-10 heterocyclyl, OPO(R 6 )2, OSO2R 6 , SR', SO2R', OC(O)R 7 or NR'(R").

[0039] In an alternative embodiment of the present disclosure, the compound of formula II, wherein R 5 is selected from C 6-10 heterocyclyl, OPO(R6 )2, OSO2R 6 , SR', SO2R', OC(O)R 7 or NR'(R").

[0040] Further, the compound of formula II, wherein R 6 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl (e.g. piperidine), OR' or NR'(R"), R', R" are defined as in the compound of formula II.

[0041] In alternative embodiments of the present disclosure, the compound of formula II, wherein R', R" are selected from hydrogen or alkyl, said alkyl is preferably selected from C 1-10 alkyl, more preferably from C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl.

[0042] In alternative embodiments of the present disclosure, the compound of formula II, wherein m = 1, 2, 3 or 4, n = 1, 2, 3 or 4, o = 1 to 8.

[0043] In some embodiments, the compound of formula II, wherein R 6 and R 7 are each independently selected from

[0044] wherein R', R" are selected from hydrogen or alkyl, said alkyl is preferably selected from C 1-10 alkyl, more preferably from C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl.

[0045] Some embodiments provide the compound of formula II, wherein R 3 is selected from OPO(R 6 )2, R 6 is selected from hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy or 3 to 7 membered heterocyclyl.

[0046] Some embodiments provide the compound of formula II, wherein m = 1, 2, 3 or 4.

[0047] Some embodiments provide the compound of formula II, wherein R 1 or R 2 are each independently selected from hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl.

[0048] In other embodiments, the compound of Formula II is

[0049] or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer or a tautomer thereof or a deuterated derivative thereof,

[0050] wherein R 1 or R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more substituents selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR' or CONR'(R");

[0051] R' or R" are independently selected from hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, acyl;

[0052] m = 1, 2, 3 or 4.

[0053] In some embodiments, the compound of Formula II is wherein R 6 is selected from

[0054] wherein R', R" are selected from hydrogen or alkyl, said alkyl being preferably selected from C 1-10 alkyl, more preferably from C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl.

[0055] In other embodiments, the compound of Formula III is

[0056] or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer or a tautomer thereof or a deuterated derivative thereof,

[0057] wherein R 1 or R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more substituents selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR' or CONR'(R");

[0058] R 6each independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, hydroxyalkyl, or NR'(R"), said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, SR', NR'(R"), COOR', or CONR'(R");

[0059] R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, acyl.

[0060] Further, in an alternative embodiment, the compound of Formula IV, wherein R 6 is selected from C 1-12 alkyl (including but not limited to methyl, ethyl, propyl, or isopropyl), C 3-12 cycloalkyl (including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), 3- to 12-membered heterocyclyl (including but not limited to pyrrolyl), C 6-12 aryl (including but not limited to phenyl, naphthyl), 3- to 12-membered heteroaryl (including but not limited to pyridine, pyridine), C 1-12 alkoxy (including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), C 1-12 hydroxyalkyl, or NR'(R"), said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more selected from 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, nitrile, hydroxy, halogen, SR', NR'(R"), COOR', or CONR'(R"); R' or R" is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkenyl, C 1-6 alkanoyl (such as acetyl, formyl), benzoyl, p-toluoyl.

[0061] In a preferred embodiment of the present disclosure, the compound of Formula IV, wherein the R 6 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl (such as pyridine), OR', or NR'(R").

[0062] In an alternative embodiment of the present disclosure, the compound of Formula IV, wherein R' and R" are selected from hydrogen or alkyl, said alkyl is preferably selected from C1-10 alkyl, more preferably C1-C6alkyl, most preferably methyl. 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl.

[0063] In some embodiments, the compound of Formula IV, wherein R 6 is selected from the group consisting of

[0064] wherein R', R" is selected from hydrogen or alkyl, the alkyl is preferably C1-C6alkyl, most preferably methyl. 1-10 alkyl, more preferably C1-C6alkyl, most preferably methyl. 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl.

[0065] In preferred embodiments of the disclosure, the compound of Formula IV, wherein the R 6 is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, 3- to 6- membered heterocyclyl (such as pyrrolidine), OR' or NR'(R"). 1-6 alkyl, C3-C6cycloalkyl, 3- to 6- membered heterocyclyl (such as pyrrolidine), OR' or NR'(R"). 3-6 cycloalkyl, 3- to 6- membered heterocyclyl (such as pyrrolidine), OR' or NR'(R").

[0066] In alternative embodiments of the disclosure, the compound of Formula IV, wherein R', R" is selected from hydrogen or alkyl, the alkyl is preferably C1-C6alkyl, most preferably methyl. 1-10 alkyl, more preferably C1-C6alkyl, most preferably methyl. 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl.

[0067] In some embodiments, the compound of Formula IV, wherein R 6 is selected from the group consisting of

[0068] wherein R', R" is selected from hydrogen or alkyl, the alkyl is preferably C1-C6alkyl, most preferably methyl. 1-10 alkyl, more preferably C1-C6alkyl, most preferably methyl. 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl.

[0069] Exemplary compounds of Formula II include, but are not limited to:

[0070]

[0071]

[0072]

[0073]

[0074] or a pharmaceutically acceptable salt thereof or a stereoisomer, rotamer or tautomer thereof.

[0075] Further, the compound of Formula IA is:

[0076] or pharmaceutically acceptable salts thereof.

[0077] In another aspect, the compounds of the present disclosure have higher solubility, superior in vivo conversion compared to known compounds. In some embodiments, the compounds of the present disclosure have low hemolytic effect, reduce side effects of the drug when administered, and facilitate improved patient compliance.

[0078] Also provided in the present disclosure is a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier, diluent or excipient.

[0079] In another aspect, the hydrogen in the functional groups of the compounds of the present disclosure can be replaced by deuterium to obtain the corresponding deuterated compounds, which retain comparable selectivity and potential to the hydrogen analogs; the deuterium bond is more stable, resulting in different "ADME", i.e. "drug pharmacokinetics", thereby providing clinically beneficial effects.

[0080] Drug pharmacokinetics refers to the processes of absorption, distribution, metabolism and excretion of exogenous chemicals by the body.

[0081] The present disclosure also relates to the use of the compounds described in the above schemes or pharmaceutically acceptable salts thereof, or pharmaceutical compositions 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 disease, cough, an inflammatory disease, a skin disorder, an ophthalmic disorder, depression, anxiety, phobia, a bipolar disorder, alcohol dependence, abuse of substances that have a pronounced effect on the nervous system, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, dementia associated with AIDs, Towne's disease, a disorder associated with stress, obsessive / compulsive disorder, bulemia, anorexia nervosa, binge eating, mania, premenstrual syndrome, a gastrointestinal functional disorder, atherosclerosis, a fibrotic disorder, obesity, type II diabetes, a headache, neuropathic pain, post-movement pain, chronic pain syndrome, a bladder disorder, a urogenital disorder, emesis or nausea. Further, the use in the manufacture of a medicament for the treatment of asthma, emesis, nausea, depression, anxiety, cough or migraine.

[0082] In another aspect, pharmaceutically acceptable salts of the compounds are selected from inorganic or organic salts, the compounds of the present disclosure are reacted with an acid such as trifluoroacetic acid to form the corresponding salt, the acid is selected from, but not limited to, acetic acid, hydrochloric acid, salicylic acid, malic acid, ascorbic acid, phosphoric acid, citric acid, benzoic acid or fumaric acid. The compounds of the present disclosure are reacted with a base such as N-methyl-D-glucamine or dicyclohexylamine to form the corresponding salt, the base is selected from, but not limited to, sodium, alkaline earth metal, amino acid (such as arginine, lysine).

[0083] In another aspect, the present disclosure also includes isotopically-labeled compounds of the present application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc.

[0084] The compounds of the present disclosure can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterium- containing drugs. Deuterium-containing drugs have advantages over their non-deuterium- containing counterparts because deuterium is denser than hydrogen, and thus deuterium- containing drugs can have increased stability or efficacy, or decreased toxicity, as compared to their non-deuterium-containing counterparts. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0085] Furthermore, substitution with heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In certain instances, deuterium substitution can be preferred wherein deuterium substitution can be partial or complete.

[0086] Terminology:

[0087] "Alkyl" refers to saturated aliphatic hydrocarbon radicals including straight chain and branched chain groups of 1 to 20 carbon atoms. Preferred alkyl groups contain 1 to 12 carbon atoms, more preferred 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, preferably one or more groups independently selected from aryl, heteroaryl, halo, substituted. "Alkenyl" includes branched and straight chain alkenyl groups or aliphatic hydrocarbon groups containing alkenyl groups having 2 to 12 carbon atoms. For example "C 2-6 "Alkenyl" means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl.

[0088] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

[0089] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring that is attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0090] The term "heterocyclyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents containing 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) mheteroatoms, but not including a ring moiety of -0-0-, -0-S- or -S-S-, the remaining ring atoms being carbon. Preferred are monocyclic heterocyclyl groups containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferred are monocyclic heterocyclyl groups containing 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like, preferably piperidinyl, pyrrolidinyl. Polycyclic heterocyclyl groups include spiro, fused and bridged ring heterocyclyl groups.

[0091] The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is connected together with the parent structure is a heterocyclyl ring, non-limiting examples of which include:

[0092] and the like.

[0093] The heterocyclyl group can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0094] "Alkynyl" includes branched and straight-chain alkynyl groups having from 2 to 12 carbon atoms or aliphatic hydrocarbon groups containing alkenes, or if a specified number of carbon atoms is given, then that specific number is intended. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl.

[0095] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share pairs of adjacent carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring that is connected together with the parent structure is an aryl ring, non-limiting examples of which include:

[0096]

[0097] The aryl group can be substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.

[0098] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 membered, more preferably 5 or 6 membered, for example imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0099]

[0100] The heteroaryl group can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0101] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy. The alkoxy group can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0102] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, wherein alkyl is as defined above.

[0103] The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0104] The term "deuteroalkyl" refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.

[0105] The term "hydroxyl" refers to the -OH group.

[0106] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0107] The term "amino" refers to -NH2.

[0108] The term "cyano" refers to -CN.

[0109] The term "nitro" refers to -NO2.

[0110] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus such phrases include instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclic group optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

[0111] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be possible (experimentally or theoretically) determined by a person skilled in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0112] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism, to facilitate absorption of the active ingredient, and to facilitate the biological activity of the active ingredient.

[0113] Known starting materials in the present disclosure can be synthesized or purchased from Acros Organics or Aldrich Chemical Company or the like or obtained by the methods described in the reference CN102775401A, or synthesized according to methods known in the art.

[0114] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in 10-6 (ppm) units. NMR is determined by a Bruker AVANCE-400 nuclear magnetic instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the determination solvent, and tetramethylsilane (TMS) as the internal standard; ESI-MS is determined by a FINNIGAN LCQ Ad (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX), and LCMS is performed by gradient elution using high performance liquid chromatography (manufacturer: Agilent, model: 1200) in positive ion mode scanning, with a mass scan range of 100-1500. BRIEF DESCRIPTION OF DRAWINGS

[0115] Figure 1: Trend chart of the conversion of the compound of Example 5 in human plasma. DETAILED DESCRIPTION

[0116] The present disclosure is further described in the following examples, but the examples are not intended to limit the scope of the present disclosure.

[0117] The experimental methods in the examples of the present disclosure, unless otherwise specified, were generally performed according to conventional conditions, or according to the conditions recommended by the manufacturer of the raw materials or commercial products. The reagents, unless otherwise specified, were commercially available reagents.

[0118] Example 1:

[0119]

[0120] First step:

[0121]

[0122] Under N2protection, compound 1 (2.43 g, 4.86 mmol, 1 eq) was dissolved in dichloromethane (36 mL) in a 100 mL three-necked flask, diisopropylethylamine (5 g, 38.76 mmol, 8 eq) was added, and the solution was cooled to -30 °C. Trimethylsilyl chloride (1.36 g, 12.52 mmol, 2.6 eq) was added, and the solution was stirred at room temperature for 2 h. The solution was cooled to -25 °C, and chloromethyl chloroformate (0.77 g, 6 mmol, 1.23 eq) in dichloromethane was added dropwise. The solution was stirred at -20 °C to -5 °C until the reaction was complete. The reaction solution was poured into ice water, and the solution was separated. Dichloromethane was added, and the solution was separated. Water and 1 N hydrochloric acid solution were added, and the solution was separated. The solution was sequentially washed with brine, saturated sodium bicarbonate aqueous solution, and brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.0 g of a yellow gum, with a yield of 104%.

[0123] Second step:

[0124]

[0125] Under N2protection, compound 2 (2.8 g, 4.53 mmol, 1 eq), tetrabutylammonium iodide (1.68 g, 4.55 mmol, 1 eq), potassium di-tert-butyl phosphate salt (5.63 g, 22.67 mmol, 5 eq), and dioxane (84 mL) were added to a 500 mL three-necked flask, and the solution was heated to 55 °C and stirred for 4 h. The reaction solution was cooled, poured into ethyl acetate and water, and the solution was separated. The solution was extracted with ethyl acetate, washed with an aqueous sodium sulfite solution, and sequentially washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.73 g of a yellow foam, with a yield of 107%.

[0126] Third step:

[0127]

[0128] Into a 100 mL single neck flask was placed compound 3 (1.95 g, 2.543 mmol, 1 eq) dissolved in dichloromethane (40 mL) under N2protection, trifluoroacetic acid (1.45 mL, 19.52 mmol, 8 eq) was added slowly under ice water cooling, stirred until the reaction was completed, concentrated to get 2.29 g of oil, separated and purified to get 1.39 g of white foamy solid, yield 83.5%.

[0129] 1 H-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).

[0130] Fourth step:

[0131]

[0132] Into a 50 mL single neck flask was placed compound 4 (111 mg, 0.17 mmol), meglumine (59.6 mg, 0.305 mmol) dissolved in methanol (5 mL), stirred at room temperature for 1.5 h, concentrated to get 174 mg of white solid salt.

[0133] Example 2:

[0134]

[0135] First step:

[0136]

[0137] Into a 250 mL three neck flask was placed compound 1 (5 g, 10 mmol, 1 eq), 50 mL of dichloromethane was added, replaced by N2, diisopropyl ethyl amine (5.1 g, 40 mmol, 4 eq) was added, cooled to 0 °C, chloroformic acid-3-chloropropyl ester (4.71 g, 30 mmol, 3 eq) was added slowly drop by drop, stirred until the reaction was completed, the reaction liquid was washed with 20 mL x 2 water, dried with anhydrous sodium sulfate, concentrated, the crude product was slurried with 20 mL of t-butyl methyl ether, filtered and dried to get 5.3 g of product, white solid, yield 85.5%, HPLC purity 95.2%.

[0138] Second step:

[0139]

[0140] Compound 2 (500 mg, 0.833 mmol, 1 eq) was placed in a 25 mL round bottom flask, 5 mL of dimethylformamide, 5 mg of potassium iodide and tetrabutylammonium phosphate dibutylate (564 mg, 1.25 mmol, 1.5 eq) were added, and the reaction was completed by warming to 100 °C, concentrated, and 370 mg of product was obtained by high performance liquid chromatography preparation, with a yield of 57.8%, HPLC purity of 97%.

[0141] Third step:

[0142]

[0143] Compound 3 (2 g, 2.52 mmol) was dissolved in a hydrochloric acid dioxane solution (25 mL, 4 M), and after stirring at room temperature for 30 min, it was evaporated under reduced pressure to obtain compound 4 (1.4 g, 2.05 mmol) with a yield of 81%.

[0144] Fourth step:

[0145]

[0146] Compound 4 (700 mg, 1.025 mmol) and meglumine (310 mg, 2 mmol) were dissolved in methanol (10 mL) at 25 °C, stirred for 1 h, and concentrated under reduced pressure to obtain compound 5 crude (1.1 g), which was slurried with methyl tert-butyl ether and filtered to obtain pure compound 5 (1 g, 0.932 mmol) with a yield of 91%.

[0147] 1 H-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).

[0148] Example 3:

[0149]

[0150] In a 25 ml flask, 2 ml of acetone and 100 mg of compound 1 were added, and stirring was started; after adding solid potassium carbonate (42 mg, 0.3 mmol, 1.5 eq) in batches, stirring was carried out at room temperature for half an hour; 36 mg of compound 2 was added to the reaction bottle, and the reaction was completed by stirring at room temperature for about 18 hours, and 50 mg of 3 was obtained by column chromatography purification (yield 40.8%).

[0151] 1H-NMR (400 MHz, CDC13): δ = 7.79 (s, IH), 7.72 (s, 2H), 7.42-7.40 (d, J = 8 Hz, 2H), 7.31-7.27 (m, 2H), 7.27-7.21 (m, IH), 5.58 (s, IH), 4.55-4.53 (m, IH), 4.06-3.99 (m, 2H), 3.69-3.67 (d, J = 8 Hz, IH), 3.53-3.49 (d, J = 16 Hz, IH), 3.25-3.21 (d, J = 16 Hz, IH), 2.77-2.74 (d, J = 12 Hz, IH), 2.59-2.57 (d, J = 8 Hz, IH), 2.34-2.31 (m, 3H), 1.97-1.71 (m, 7H), 1.46-1.45 (d, J = 4 Hz, 3H).

[0152] Example 4:

[0153]

[0154] First step:

[0155]

[0156] Under nitrogen atmosphere, 750 mg of compound 1, 2.1 ml of diisopropylethylamine were added into a three-necked flask, then 12 ml of anhydrous dichloromethane was added, and the temperature was lowered to -40 °C. After 0.5 ml of trimethylsilyl chloride was added dropwise, the reaction was stirred at room temperature for two hours. Then the temperature was lowered to -30 to -20 °C, 0.024 ml of chloroethyl chloroformate was dissolved in 3 ml of anhydrous dichloromethane, and was added dropwise into the reaction solution. After the addition was completed, the reaction was stirred at -20 to 5 °C until it was completed. Water was added to quench the reaction, and the mixture was separated. The resulting solution was washed with 1 N hydrochloric acid, saturated brine, saturated sodium bicarbonate solution, and saturated brine in sequence. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried in vacuum to obtain 1 g of white solid 2.

[0157] Second step:

[0158]

[0159] 1 g of compound 2 and 0.99 g of sodium iodide were dissolved in 10 ml of dimethylformamide, 1.15 ml of diisopropylethylamine and 0.75 ml of methylpiperazine were added, and the mixture was heated to 90 °C and stirred until the reaction was completed. The reaction solution was directly concentrated, and 430 mg of compound 3 was obtained by high performance liquid chromatography.

[0160] 1H-NMR (400 MHz, CDC13): 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).

[0161] Example 5:

[0162]

[0163] First step:

[0164]

[0165] Under nitrogen atmosphere, 750 mg of compound 1 and 2.1 ml of diisopropylethylamine were dissolved in 13 ml of anhydrous dichloromethane, cooled to -10°C, and 0.5 ml of trimethylsilyl chloride was added dropwise. After the addition was completed, the temperature was raised to room temperature and stirring was continued for three hours. The temperature was again lowered to -10°C, and 3 ml of chloromethyl chloroformate (0.288 g) in dichloromethane was added dropwise. After the addition was completed, the reaction was completed at -10°C. The reaction was quenched with water, and the mixture was separated. The organic phase was washed successively with dilute hydrochloric acid, saturated brine, saturated sodium bicarbonate solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification gave 400 mg of compound 2 as a white solid.

[0166] Second step:

[0167]

[0168] Compound 3 (147 mg) and sodium iodide (203 mg) were added to 2 ml of dimethylformamide, followed by the addition of potassium bicarbonate (136 mg). The mixture was stirred at room temperature for half an hour, and then compound 2 (400 mg) dissolved in 10 ml of dimethylformamide was added dropwise to the reaction system. The reaction was carried out overnight. The reaction was quenched with water, and the mixture was extracted twice with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification on a silica gel column gave 450 mg of compound 4 as an oil.

[0169] Third step:

[0170]

[0171] 405 mg of compound 4 was dissolved in 18 ml of dichloromethane, and 4.5 ml of trifluoroacetic acid was added dropwise under ice bath cooling. After the addition was complete, the reaction was brought to room temperature and stirred for two hours. After concentration, the product compound 5 was purified by column chromatography to obtain 330 mg of product compound 5, with a yield of 80%.

[0172] 1 H-NMR (400MHz, CDCl3): δ8.34(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=4Hz,1H),4.30-4.29(d, J=4Hz,1H),4.20-4.17(d,J=12Hz,1H),3.99-3.91(m,2H),3.79(s,1H),2.70-2.67(d,J=12Hz,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).

[0173] Example 6:

[0174]

[0175] first step:

[0176]

[0177] 1.294 g of triphosgene was dissolved in 7.5 ml of anhydrous tetrahydrofuran, cooled in an ice bath, and purged three times with nitrogen. Then, 0.33 ml of pyridine was added dropwise. After the addition was complete, a solution of 500 mg of compound 1 dissolved in 7.5 ml of anhydrous tetrahydrofuran was added dropwise to the reaction mixture. The reaction was then stirred at 5°C for 3 hours. The solution was diluted with 30 ml of dichloromethane, washed successively with dilute hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 700 mg of crude product.

[0178] Step Two:

[0179]

[0180] To 128 mg of compound 3 in 2 mL of dry THF, was bubbled through three times under N2. The reaction was cooled to -65 °C and 0.28 mL of lithium hexamethyldisilazide (1 M in hexanes) was added dropwise and stirred for half an hour. Another 60 mg of compound 2 from the previous step was dissolved in 1 mL of dry THF, bubbled through three times under N2and cooled to -65 °C. The lithium salt from the previous step was transferred to the reaction flask containing compound 2. The reaction was stirred at -65 °C until completion. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated and purified directly on a column to give 62 mg of compound 4.

[0181]

[0182] To 62 mg of compound 4 and 31 mg of 20% wet palladium hydroxide in 1.5 mL of ethyl acetate was bubbled through three times under N2. The reaction was stirred at room temperature for 5 hours. The reaction was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated and purified to give 41 mg of compound 5 as a white solid.

[0183] 1 H-NMR (400 MHz, CDC13) 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).

[0184] Example 7:

[0185]

[0186] Potassium carbonate (11.7 g, 84.66 mmol, 8.47 eq) was dissolved in water (40 mL) and used as such. Compound 1 (5.55 g, 10 mmol, 1 eq) was suspended in ethyl acetate (80 mL) and cooled in an ice bath. The above potassium carbonate solution was added dropwise to the reaction mixture under N2. After the addition was complete, Cbz-Cl (1.7 mL, 12 mmol, 1.2 eq) was added dropwise and stirred for 10 min. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give 4.3 g of compound 2 as a white solid in 56% yield.

[0187] Example 8:

[0188]

[0189]

[0190] In a 50 mL vial, was added compound 1 (317 mg, 0.5 mmol) and THF (7.2 mL) under N2protection, stirred to dissolve and cooled to -20 °C. NaHMDS (2 M, 0.5 mL, 1 mmol) was added dropwise, stirred until the reaction was complete, quenched with saturated ammonium chloride, extracted with methyl tert-butyl ether, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound 2 (250 mg) in 68% yield.

[0191]

[0192] In a 50 mL vial, was added compound 2 (250 mg, 0.34 mmol), methanol (10 mL), palladium on carbon (10%, 250 mg), stirred at room temperature under hydrogen atmosphere until the reaction was complete, filtered, and concentrated to give compound 3 (150 mg) in 74% yield.

[0193] LCMS: 601 [M+1].

[0194] Example 9:

[0195]

[0196] In a 50 mL vial, was added compound 1 (215 mg, 0.339 mmol, 1 eq), anhydrous potassium carbonate (55 mg, 0.396 mmol, 1.1 eq), paraformaldehyde (37 mg, 1.23 mmol, 3.3 eq), and THF (5 ml) under N2protection, heated and stirred until the reaction was complete, filtered, and concentrated to give a crude product, which was purified by column chromatography to give 216 mg of oil 2 in 95% yield.

[0197]

[0198] In a 50 mL vial, was added compound 2 (66 mg, 0.1 mmol, 1 eq) and THF (5 ml) under N2protection, and LiHMDS (1 M in THF, 0.2 ml, 0.2 mmol, 2 eq) was added dropwise under ice bath cooling, followed by the addition of compound 3 (40 mg, 0.37 mmol, 3.7 eq), stirred until the reaction was complete, extracted with ethyl acetate, and concentrated to give a crude product, which was purified by column chromatography to give 27 mg of oil 4 in 36% yield.

[0199]

[0200] To a reaction flask was added compound 4 (27 mg, 0.367 mmol, 1 eq), Pd / C (33 mg) and methanol (5 ml) at room temperature, stirred under hydrogen atmosphere until the reaction was completed, filtered, concentrated to get the crude product, which was purified by column chromatography to get 13 mg of oil 5 in 58.8% yield.

[0201] LCMS: 602 [M+1].

[0202] Example 10:

[0203]

[0204] This target compound was synthesized according to the procedure of Example 5, using chloroformic acid chloropropyl ester instead of chloromethyl chloroformate. LCMS: 702 [M+1].

[0205] Example 11:

[0206]

[0207] This target compound was synthesized according to the procedure of Example 5, using chloroformic acid chloroethyl ester instead of chloromethyl chloroformate. LCMS: 688 [M+1].

[0208] Example 12:

[0209]

[0210] This target compound was synthesized according to the procedure of Example 5, using N-Boc-glycine instead of Boc-L-valine. LCMS: 632 [M+1].

[0211] Example 13:

[0212]

[0213] This target compound was synthesized according to the procedure of Example 5, using Boc-L-alanine instead of Boc-L-valine. LCMS: 646 [M+1].

[0214] Example 14:

[0215]

[0216] This target compound (isomers about 1 / 1) was synthesized according to the procedure of Example 5, using 1-chloroethyl chloroformate instead of chloromethyl chloroformate. LCMS: 688 [M+1].

[0217] Example 15:

[0218]

[0219] This compound was synthesized according to the procedure of Example 5, substituting Boc-L-proline for Boc-L-valine. LCMS: 672 [M+l].

[0220] Example 16:

[0221]

[0222] This compound was synthesized according to the procedure of Example 5, substituting Boc-L-proline for Boc-L-valine. LCMS: 672 [M+l].

[0223] Example 17:

[0224]

[0225] This compound was synthesized according to the procedure of Example 5, substituting (S)-2,6-di-tert-butylcarbonylamino hexanoic acid for Boc-L-valine. LCMS: 703 [M+l].

[0226] Example 18:

[0227]

[0228] This compound was synthesized according to the procedure of Example 5, substituting Boc-D-valine for Boc-L-valine. LCMS: 674 [M+l].

[0229] Test Example 1: Water solubility data and chemical stability

[0230] 1.1 Preparation of reagents

[0231] Reagent: NaH2PO4.2H2O

[0232] 1.2 Preparation method

[0233] Prepare the following in 100 ml scale:

[0234] pH = 3.0: Phosphate buffer solution: 100 ml 20 mmol / L NaH2PO4, 0.1 M H3PO4 to adjust pH to 3.0.

[0235] pH = 4.0: Phosphate buffer solution: 100 ml 20 mmol / L NaH2PO4, 0.1 M H3PO4 to adjust pH to 4.0.

[0236] pH = 7.0: Ultra-pure water

[0237] pH = 9.0: Phosphate buffer solution: 100 ml 20 mmol / L Na2HPO4, 0.1 M NaOH solution to adjust pH to 9.0

[0238] 1.3 Test method

[0239] Accurately weigh the appropriate amount of the test compound, add a small amount of solution to stir and wait for the compound to dissolve, and determine the compound content in the solution. The data are shown in Table 1.

[0240] 2.1 Compound stability experiment

[0241] Weigh about 1 mg of sample into a vial, place it in a vacuum bag, vacuum, and then place it in a container containing color-changing silica gel, seal, and prepare two copies in parallel. Prepare enough copies according to the sampling time points, and place them at 4 degrees and room temperature respectively. The data are shown in Table 1.

[0242] Table 1

[0243] Serial number Water-soluble chemical stability Example 1 > 10 mg / ml (PH = 5) better Example 2 9.05 mg / ml (PH = 5) better Example 3 < 0.1 mg / ml (PH = 5) better Example 4 2.08 mg / mL (PH = 3) better Example 5 > 10 mg / ml (PH = 4) better Example 6 1.12 mg / mL (PH = 3) better Example 7 NANA Example 8 1.37 mg / ml (PH = 5) moderate Example 9 < 0.1 mg / ml (PH = 3) better Example 10 1.86 mg / mL (PH = 3) better Example 11 2.81 mg / mL (PH = 3) better Example 12 NA worse Example 13 NA moderate Example 14 4.5 mg / ml (PH = 4) better Example 15 NA worse Example 16 NA worse Example 17 NA moderate Example 18 2.62 mg / mL (PH = 4) better

[0244] Note: better, 7 days of storage, purity reduction < 0.5%; moderate, 7 days of storage, purity reduction 0.5% ~ 2.0%; worse, 7 days of storage, purity reduction > 2.0%

[0245] Test Example 2: Plasma Metabolic Evaluation

[0246] Test scheme

[0247] 1.1 Test drug

[0248] Example 5 compound and formula I compound.

[0249] 1.2 Test plasma

[0250] Human fresh plasma was donated by volunteers with their consent.

[0251] 1.3 Preparation of compound solution

[0252] An amount of the compound of Example 5 was weighed and dissolved in DMSO to prepare a 30 mM stock solution. A certain volume of the stock solution was diluted with DMSO to prepare a solution I with a concentration of 1600 μM. A certain volume of the solution I with a concentration of 1600 μM was diluted with 45% methanol to prepare a working solution II with a concentration of 16 μM. The 30 mM stock solution and the 1600 μM solution II of the compound of Formula I were prepared by the above method.

[0253] 1.4 Incubation of sample

[0254] 5 μL of the working solution of the compound of Example 5 with a concentration of 16 μM was added to 75 μL of plasma to make the final concentration of the compound 1 μM. The sample was incubated in a water bath at 37°C for 0, 15, 30, 60, 90, 120, 180 min. After incubation, 240 μL of acetonitrile containing an internal standard was added, and then the sample was shaken at 800 rpm for 10 min, centrifuged at 3700 rpm for 20 min at 4°C. The supernatant was analyzed by LC-MS with a sample injection volume of 2 μL.

[0255] 1.5 Preparation of standard curve

[0256] The previously diluted 1600 μM solution I was diluted with acetonitrile to prepare a working solution for standard curve with concentrations of 160, 400, 1600, 4000, 8000, 16000, 32000 ng / mL, and the QC working solution had a concentration of 480, 1920, 25600 ng / mL. 5 μL of the standard curve and the QC working solution was added to 75 μL of plasma to make the final concentrations of the standard curve samples 10, 25, 100, 250, 500, 1000, 2000 ng / mL and the final concentrations of the QC samples 30, 120, 1600 ng / mL. Then 240 μL of acetonitrile containing an internal standard was added, and then the sample was shaken at 800 rpm for 10 min, centrifuged at 3700 rpm for 20 min at 4°C. The supernatant was analyzed by LC-MS with a sample injection volume of 2 μL.

[0257] The standard curve and the QC sample of the compound of Formula I were prepared by the above method.

[0258] 2. Results

[0259] The conversion of the compound of Example 5 in human fresh plasma was as follows, and the data are shown in Table 2.

[0260] Table 2

[0261] Time point (min) Example 5 compound (μM) Formula I compound (μM) 0 0.0015 0.53 0.78 300.12 1.186 0.01 1.229 0.00 1.31 200.00 1.28 1800.00 1.02

[0262] Conclusion: In human fresh plasma, all of the compounds are converted into Formula I compound in about 30 min.

[0263] Test Example 3: Plasma stability test

[0264] 1.1 Test drug

[0265] Example 4, Example 6, Example 10 and Example 11 compounds

[0266] 1.2 Test plasma

[0267] Human fresh plasma was donated by volunteers with informed consent

[0268] 1.3 Experimental procedure

[0269] 1) The compounds to be tested in Table 3 were prepared into 30 mM stock solutions with DMSO for standby.

[0270] 2) The stock solution with a concentration of 30 mM was diluted with a DMSO solution to a solution I with a concentration of 1600 μM, and then acetonitrile (ACN) was used to dilute the solution I with a concentration of 1600 μM to a working solution II with a concentration of 16 μM.

[0271] 3) The experiment was set up at 7 time points of 0, 15, 30, 60, 90, 120, and 180 min, with two parallel samples at each time point. The reaction system was divided into two groups for each compound, and 75 μL of plasma and 5 μL of the prepared working solution II with a concentration of 16 μM were added. Incubation was performed at 37°C, and the reaction was terminated with a solution of ACN containing an internal standard at 300 μL at the time. Centrifugation was performed at 3700 rpm for 10 min, and the supernatant was analyzed.

[0272] 4) Standard curve configuration: The previously diluted solution I with a concentration of 1600 μM was diluted with acetonitrile to a solution III with a concentration of 1.5 μM / mL for standby as a standard curve. The standard curve concentrations were set as 0.32, 0.8, 1.6, 4.0, 8, 12, 16, and 42 uM. After dilution, 75 μL of plasma was added to 5 μL of each concentration point to make the final concentrations 0.02, 0.05, 0.1, 0.25, 0.75, 1.0, and 1.5 uM, respectively. Then, 300 μL of termination liquid was quickly added, and centrifugation was performed at 3700 rpm for 10 min. The supernatant was analyzed by LC-MSMS. The data are shown in Table 3.

[0273] Table 3

[0274]

[0275] Note: a Concentration of compound in plasma, b Concentration of lormetigene in plasma after metabolism of compound in example.

[0276] Conclusion: The compounds in example 4, example 10 and example 11 are stable in plasma and have long metabolism time, but only a small amount of the three compounds are metabolized to lormetigene in plasma. The compound in example 6 can be metabolized to lormetigene in plasma, but the overall metabolism of the compound in plasma is small according to the above data.

[0277] Test Example 4:

[0278] The metabolism of the compounds in example 1, example 2 and example 8 in the plasma of mice, rats and humans was tested according to the test method in test example 2, and the data is shown in table 4.

[0279] Example 1 Example 8

[0280] Table 4

[0281]

[0282] Note: a Concentration of compound in plasma, b Concentration of lormetigene in plasma after metabolism of compound in example.

[0283] Conclusion: The compound in example 8 can be converted to lormetigene in the plasma of mice, rats and humans, especially in human plasma, with a conversion rate of nearly 46%, while the compounds in example 1 and example 2 are not converted to lormetigene in human plasma, or only slightly converted.

[0284] Test Example 5: Pharmacokinetic test in rats

[0285] The drug concentration in the plasma of rats at different times after injection of the compounds in example 1 and example 2 was determined by LC / MS / MS method. The pharmacokinetic behavior of the compounds in rats was studied, and the pharmacokinetic characteristics were evaluated.

[0286] Drug preparation

[0287] A certain amount of the compounds in example 1 and example 2 was weighed and prepared into a pH = 4.0 solution with 20 mmol / L sodium dihydrogen phosphate for use.

[0288] 1.1 Administration

[0289] Intravenous bolus, bolus time about 5 min, dose 2 mg / kg, concentration 0.4 mg / ml, volume 5 ml / kg.

[0290] 1.2 Operation

[0291] Before administration and 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h and 48 h after administration, blood was collected from the orbital vein, about 0.6 mL of each sample, anticoagulated with sodium heparin, and placed on ice immediately after collection. The blood sample was placed in a labeled centrifuge tube after collection, and the plasma was separated by centrifugation (centrifugation conditions: centrifugal force 2200 g, centrifugation for 10 min, 2-8°C).

[0292] 1.3 Pharmacokinetic parameter results

[0293] Table 5

[0294]

[0295] Note: a Pharmacokinetic parameters of the compound in Example 1 in rats, b Pharmacokinetic parameters of the metabolite of the compound in Example 1 in rats.

[0296] Conclusion: Although the compound in Example 1 is not metabolized to loranatide in vitro, especially in human plasma, it can exhibit excellent loranatide pharmacokinetic data in rats, indicating that the compound in Example 1 has been metabolized to loranatide in vivo, and from the AUC 0-∞ , AUC 0-t and T 1 / 2 data, the compound 1 has a long in vivo metabolism period after administration, and the absorption and exposure level are equivalent to loranatide.

[0297] Test Example 6: Pharmacokinetic test of the compound in cynomolgus monkeys

[0298] Cynomolgus monkeys were used as test animals, and LC / MS / MS was used to determine the drug concentration in plasma at different times after injection of the compound in Example 5. The pharmacokinetic behavior of the compound in cynomolgus monkeys was studied, and its pharmacokinetic characteristics were evaluated.

[0299] Drug preparation

[0300] A certain amount of the compound in Example 5 was weighed and prepared into a pH = 4.0 solution with 20 mmol / L sodium dihydrogen phosphate for use.

[0301] 1.1 Administration

[0302] Intravenous infusion, bolus time about 30 min, dose 2 mg / kg, concentration 0.4 mg / ml, volume 5 ml / kg.

[0303] 1.2 Procedure

[0304] Blood samples were collected from the femoral vein before dosing and at 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h and 48 h after the end of dosing, with approximately 0.6 mL of blood collected per sample. The blood was anticoagulated with sodium heparin and placed on ice immediately after collection. The blood samples were placed in labeled centrifuge tubes immediately after collection and centrifuged to separate the plasma (centrifuge conditions: 2200 g for 10 min at 2-8 °C).

[0305] The content of the compound of Example 5 and loranapitant in the plasma samples was determined using LC / MS / MS.

[0306] 1.3 Pharmacokinetic parameter results

[0307] Table 6

[0308] Compound Compound of Example 5 Loranapitant (compound of Formula I) Tmax (h) 0.11 ± 0.12 0.14 ± 0.10 Cmax (ng / mL) 2.28 ± 0.39 315.25 ± 97.08 AUC (ng / mL*h) 0.77 ± 0.29 426.87 ± 182 0.65 0-t (ng / mL*h) 0.77 ± 0.29 426.87 ± 182 0.65

[0309] Conclusion: The compound of Example 5 was rapidly converted to the active metabolite loranapitant in cynomolgus monkeys in the pharmacokinetic study in cynomolgus monkeys, and it has good pharmacokinetic properties.

[0310] Example 19:

[0311] Compound 3 was prepared according to the procedure described in Step 1-2 of Example 1, and then under N2protection, compound 3 (6.65 g, 8.67 mmol, 1 eq) was dissolved in dichloromethane (200 mL), trifluoroacetic acid (9.89 g, 86.7 mmol, 10.0 eq) was added slowly under ice water cooling, and the reaction was stirred until completion. The reaction mixture was concentrated to obtain 2.29 g of an oil, which was purified by reverse-phase silica gel column (C18) (A solution: 20 mmol NH4HCO3 aqueous solution, B solution: acetonitrile), and then the pH was adjusted to 1-2 with 1 M phosphoric acid, and the target product was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.7 g of the target product.

[0312]

[0313] Test Example 7: Solubility

[0314] Parameter Test Example 1 Solubility Test Method

[0315] Table 7

[0316] pH Solubility Saturation Solubility 7.4 26 mg / ml 19.8 mg / ml

[0317] 9.028 mg / ml 21.4 mg / ml

[0318] Test Example 8: Hemolysis

[0319] Red blood cells (RBC) were taken randomly from rabbit jugular vein or ear central artery (EDTA whole blood) 10 ml, put into a triangular flask with glass beads, shaken for 10 minutes, remove fibrinogen, make into defibrinated blood. Add about 10 times the amount of sodium chloride injection, shake well, centrifuge at 1500 rpm for 10 minutes, remove the supernatant, the precipitated red blood cells are washed 3 times with sodium chloride injection according to the above method, until the supernatant is not red. The resulting red blood cells are suspended in 2% (v / v) sodium chloride injection for use.

[0320] Take the test sample (compound of Example 5 and compound of Example 19) respectively dissolved in PBS (pH 7.4 or pH 5), filter, prepare 0.4 mg / ml, 0.8 mg / ml, 1.2 mg / ml, 1.6 mg / ml and 2 mg / ml for use.

[0321] Take a certain amount of test sample solution to test the above hemoglobin in the supernatant.

[0322] If the solution in the test tube is clear red, there is no cell residue or a small amount of red blood cell residue at the bottom of the tube, indicating that hemolysis has occurred; if the red blood cells all sink, the supernatant is colorless and clear, indicating that no hemolysis has occurred. If there is a brown or red-brown flocculent precipitate in the solution, which does not disperse after gently inverting 3-5 times, it indicates that red blood cell aggregation may occur; further observation under a microscope shows that red blood cells are aggregated into aggregates. The compound provided in the disclosure is used to determine hemolysis by this method.

[0323] Conclusion: The compound of Example 19 does not have hemolysis at a concentration as high as 2 mg / ml, and the compound of Example 5 has hemolysis at a concentration of 0.04 mg / ml and above.

[0324] Test Example 9: Hemolytic effect of lorcaserin emulsion

[0325] The rolapitide emulsion (formulation: 4.4% macrogol-15-hydroxystearate, 1.1% medium-chain triglyceride and 0.66% soybean oil) was prepared according to the method in CN102573475, and was prepared into 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.

[0326] The hemolysis was determined according to the method in Test Example 8.

[0327] Conclusion: The rolapitide emulsion at all concentrations has hemolysis.

[0328] Test Example 10: Pharmacokinetic test in cynomolgus monkeys

[0329] The drug concentration in plasma at different time after injection of the compound prepared according to the method in Reference Example 19 was determined in cynomolgus monkeys as test animals by LC / MS / MS method. The pharmacokinetic behavior of the compound in cynomolgus monkeys was studied, and the pharmacokinetic characteristics were evaluated.

[0330] Drug preparation

[0331] A certain amount of the test compound was weighed and prepared into a pH = 4.0 solution with 20 mmol / L sodium dihydrogen phosphate for use.

[0332] 1.1 Administration

[0333] Intravenous infusion, push injection time about 30 min, administration dose 3.54 mg / kg, administration concentration 2 mg / ml, administration volume 5 ml / kg.

[0334] 1.2 Operation

[0335] Blood was collected from femoral vein before administration and at 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h and 24 h after administration, about 0.6 mL of each sample was collected, anticoagulated with heparin sodium, and placed on ice immediately after collection. The blood sample was placed in a labeled centrifuge tube after collection, and the plasma was separated by centrifugation (centrifugation condition: centrifugal force 2200 g, centrifugation for 10 min, 2-8°C).

[0336] The content of the compound of Example 24 and rolapitide in the plasma sample was determined by LC / MS / MS.

[0337] 1.3 Pharmacokinetic parameter results

[0338] Table 8

[0339]

[0340] Note: a Pharmacokinetic parameters of the compound in Example in cynomolgus monkey, b Pharmacokinetic parameters of the compound metabolized to rolapitant in cynomolgus monkey.

[0341] Conclusion: In the pharmacokinetic study of the compound in cynomolgus monkeys, most of the cynomolgus monkeys rapidly converted to the active metabolite rolapitant, and the compound had good pharmacokinetic properties. In addition, compared with the compound in Example 5, the compound has higher bioavailability in cynomolgus monkeys.

Claims

1. Compound of formula II, Or its medicinal salts or its stereoisomers, rotational isomers or tautomers or their deuterated derivatives, in, X is selected from hydrogen, heterocyclic group, aryl group, heteroaryl group, and -C(O)OA group. m R 3 -C(O)NR 4 A m R 3 -A m [C(R 1 (R) 2 )]C(O)OA n R 3 -A m OC(O)[C(R 1 (R) 2 A n R 3 -A m C(O)NR 4 A n R 3 -A m NR 4 C(O)A n R 3 or -A m R 5 The heterocyclic, aryl, or heteroaryl group may optionally be replaced by one or more groups selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R”), COOR', or CONR'(R”); Y is selected from hydrogen, -C(O)OA m R 3 、-C(O)NR 4 A m R 3 、-A m [C(R 1 )(R 2 )]C(O)OA n R 3 、-A m OC(O)[C(R 1 )(R 2 )]A n R 3 、-A m C(O)NR 4 A n R 3 、-A m NR 4 C(O)A n R 3 or -A m R 5 ; A is independently selected from -C(R) 1 (R) 2 (B) p -or-(B) q C(R 1 (R) 2 )-, R 1 R 2 Or R 4 Each is independently selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally replaced by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R”), COOR' or CONR'(R”); R 3 Selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and poly(ethoxy) groups. Poly(ethylene oxide) OPO(R 6 )2、PO(R 6 )2、OSO2(R 6 2. SO2(R) 6 2. OC(O)R 6 or C(O)OR 6 The alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally replaced by one or more groups selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R”), COOR' or CONR'(R”); R 5 Selected from heterocyclic groups, heteroaryl groups, and OSO2R 7 OC(O)R 7 ,SR', SO2R' or NR'(R”); R 6 Each is independently selected from hydrogen, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, hydroxyalkyl or NR'(R”), wherein the alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally replaced by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R”), COOR' or CONR'(R”); R 7 Each is independently selected from alkyl, hydroxy, cycloalkyl, heterocyclic, aryl, heteroaryl, hydroxyalkyl or NR'(R”), wherein the alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally replaced by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R”), COOR' or CONR'(R”); R' or R” is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, and acyl groups; B is selected independently from O, N, and SC(O); m, n, o are each independently selected from 1 to 10; p, q are each independently selected from 0 or 1; Furthermore, X and Y are not both hydrogen.

2. The compound of claim 1, wherein X is selected from hydrogen, heterocyclic, 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 or -[C(R 1 (R) 2 (O) p ] m R 5 The cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally replaced by one or more groups selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R”), COOR', or CONR'(R”); Y is selected from 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 or -[C(R 1 (R) 2 (O) p ] m R 5 Furthermore, X and Y are not both hydrogen.

3. The compound of claim 1 or 2, wherein Y is selected from -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 or -[C(R 1 (R) 2 (O) p ] n R 5 X is hydrogen or a 3- to 6-membered heterocyclic group.

4. The compound according to any one of claims 1-3, wherein X is selected from -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 or -[C(R 1 (R) 2 )] m C(O)NR 4 [C(R 1 (R) 2 )] n R 3 or -[C(R 1 (R) 2 )] m R 5 Y represents hydrogen.

5. The compound according to any one of claims 1-4, wherein R 3 Selected from hydrogen and poly(ethylene oxide) OPO(R 6 )2、PO(R 6 )2、OSO2(R 6 2. SO2(R) 6 2. OC(O)R 6 or C(O)OR 6 R 6 As described in claim 1.

6. The compound according to any one of claims 1-5, wherein R 3 Selected from OPO(R) 6 )2, R 6 Selected from hydroxyl, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Alkoxy or 3 to 7-membered heterocyclic groups.

7. The compound according to any one of claims 1-4, wherein m = 1, 2, 3 or 4.

8. The compound according to any one of claims 1-3, wherein R 1 Or R 2 Each is independently selected from hydrogen and C. 1-6 Alkyl or C 3-7 Cycloalkyl.

9. The compound of claim 1, wherein m = 1, 2, 3 or 4, n = 1, 2, 3 or 4, and o = 1 to 8.

10. The compound according to claims 1-9, wherein the compound represented by formula II is: Or its medicinal salts or its stereoisomers, rotational isomers or tautomers, wherein... m = 1, 2, 3 or 4; R 1 R 2 As described in claim 1.

11. The compound according to any one of claims 1-10, wherein the compound of formula II is selected from: Or its medicinal salts, stereoisomers, rotational isomers or tautomers or their deuterated derivatives.

12. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound as claimed in any one of claims 1-11, and a pharmaceutically acceptable carrier, diluent, or excipient.

13. The use of the compound of any one of claims 1-11, or the pharmaceutical composition of claim 12, in the preparation of a medicament for treating a physiological disorder, symptom, or disease in a patient, wherein the physiological disorder, symptom, or disease is a respiratory disorder, cough, inflammatory disease, skin disorder, ophthalmic disorder, depression, anxiety, phobia, bipolar disorder, alcohol dependence, substance abuse with significant neurological effects, epilepsy, nociceptive disorder, psychosis, schizophrenia, Alzheimer's disease, dementia associated with AIDs, Towne's disease, stress-related disorder, obsessive-compulsive disorder, bulemia, anorexia nervosa, binge eating, mania, premenstrual syndrome, gastrointestinal dysfunction, atherosclerosis, fibrotic disorder, obesity, type II diabetes, headache, neuropathic pain, post-movement pain, chronic pain syndrome, bladder disorder, genitourinary disorder, or vomiting or nausea.

14. The use as claimed in claim 13, wherein the ingredient is selected for the treatment of asthma, vomiting, nausea, depression, anxiety, cough, or migraine.