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EP-4741406-A1 - NEUROKININ-1 RECEPTOR ANTAGONIST COMPOUND

EP4741406A1EP 4741406 A1EP4741406 A1EP 4741406A1EP-4741406-A1

Abstract

Disclosed in the present invention is a neurokinin-1 receptor antagonist compound, specifically, a compound having a structure represented by the following formula (II), formula (III) or formula (IV), an isomer, or a pharmaceutically acceptable salt or acid thereof or a deuterated compound thereof. The compound of the present invention has suitable solubility, and can be rapidly converted into an active metabolite rolapitant in blood plasma and liver, such that the problem that rolapitant is difficult to develop into a conventional injection formulation due to poor solubility is solved; in addition, hemolysis can be avoided, and the injection risk can be reduced. Compared with an existing prodrug molecule (a compound of formula (I)), the compound of the present invention is converted in vivo to release the active metabolite rolapitant at a much faster rate, has higher in-vivo exposure of the active metabolite rolapitant, and exhibits superior pharmacokinetic properties.

Inventors

  • GE, HUI
  • CHEN, Zhengbang
  • WANG, SHAN
  • LIU, CHUNBO

Assignees

  • Creadev (Nanjing) Pharmaceutical Technology Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240821

Claims (10)

  1. A compound having a structure represented by formula (II), formula (III), or formula (IV), an isomer thereof, or a pharmaceutically acceptable salt or acid thereof, or a deuterated derivative thereof: wherein: in formula (II), L 1 is selected from -[C(R 4 )(R 5 )] m -(A) q -, -[C(R 4 )(R 5 )] m -(A) p -C(O)-[C(R 4 )(R 5 )] n -(A) q -, -[C(R 4 )(R 5 )] m -C(O)-(A) p -[C(R 4 )(R 5 )] n -(A) q -, -[C(R 4 )(R 5 )] m -(A) p -B-(A) q -, - [C(R 4 )(R 5 )] m -C(O)-(A) p -B-(A) q -, -[C(R 4 )(R 5 )] m -(A) p -C(O)-B-(A) q -, -[C(R 4 )(R 5 )] m- (A) p -C(S)-B-(A) q -, -[C(R 4 )(R 5 )] m -C(S)-(A) p -B-(A) q -, -[C(R 4 )(R 5 )] m -B-(A) p -, - [C(R 4 )(R 5 )] m -B-C(O)-(A) p -, -[C(R 4 )(R 5 )] m -B-(A) p -C(O)-(A) q -, -[C(R 4 )(R 5 )] m -B-(A) p -C(S)-(A) q -, -[C(R 4 )(R 5 )] m -B-C(S)-(A) p -, -[C(R 4 )(R 5 )] m - (A) p -S(O) t -B-, - [C(R 4 )(R 5 )] m -S(O) t -(A) p -B-, -[C(R 4 )(R 5 )] m -S(O)=N-[C(R 4 )(R 5 )] n -, and -[C(R 4 )(R 5 )] m -N=S(O)-[C(R 4 )(R 5 )] n -; A is selected from O, S, and N(R 6 ); B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, 6-12 membered fused heterocyclic groups containing N, O, or S, alkenyl, or alkynyl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, and 6-12 membered fused heterocyclic groups containing N, O, or S are optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, hydroxy, SH, and halogen; R 1 is selected from R 2 is selected from the group consisting of hydrogen, hydroxy, SH, alkyl, haloalkyl, alkoxy, -[C(R 4 )(R 5 )] m -N(R 7 ) 3 + , cycloalkyl, heterocyclyl, aryl, heteroaryl, 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, 6-12 membered fused heterocyclic groups containing N, O, or S, alkenyl, alkynyl, or cyano, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, and 6-12 membered fused heterocyclic groups containing N, O, or S are optionally substituted with one or more substituents selected from the group consisting of H, NH 2 , OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; R 3 is selected from the group consisting of hydrogen, SH, alkyl, haloalkyl, alkoxy, -[C(R 4 )(R 5 )] m -N(R 7 ) 3 + , cycloalkyl, heterocyclyl, aryl, heteroaryl, 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, 6-12 membered fused heterocyclic groups containing N, O, or S, alkenyl, or alkynyl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, and 6-12 membered fused heterocyclic groups containing N, O, or S are optionally substituted with one or more substituents selected from the group consisting of H, NH 2 , OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; when L 1 is -[C(R 4 )(R 5 )] m -(A) p -B-(A) q -, -[C(R 4 )(R 5 )] m -S(O)=N-[C(R 4 )(R 5 )] n -, or - [C(R 4 )(R 5 )] m -N=S(O)-[C(R 4 )(R 5 )] n -, R 1 can further be selected from when L 1 is-[C(R 4 )(R 5 )] m -(A) q -, -[C(R 4 )(R 5 )] m -S(O)=N-[C(R 4 )(R 5 )] n -, or - [C(R 4 )(R 5 )] m -N=S(O)-[C(R 4 )(R 5 )] n -, R 1 can further be R 4 and R 5 are independently selected from the group consisting of hydrogen, hydroxy, SH, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, cyano, or halogen, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of H, NH 2 , OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; R 6 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, haloalkyl, C 1 -C 8 cycloalkyl, C 1 -C 8 heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of H, NH 2 , OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; R 7 is selected from the group consisting of C 1 -C 6 alkyl, haloalkyl, alkenyl, alkynyl, and cyano; m is an integer from 0 to 6; n is an integer from 0 to 6; p is 0, 1, or 2; q is 0, 1, or 2; t is 1 or 2; in formula (III), R' is selected from the group consisting of H, alkoxy, alkenyl, alkynyl, nitro, cyano, halogen, acetyl, sulfonyl, C 1 -C 6 alkyl, haloalkyl, C 1 -C 8 cycloalkyl, C 1 -C 8 heterocyclyl, aryl, heteroaryl and R" is selected from the group consisting of NH 2 and groups selected from the substituted or unsubstituted following: 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, 6-12 membered fused heterocyclic groups containing N, O, or S, -[C(R 4 )(R 5 )]m-N(R‴) 3 + , C 2 -C 7 cyclic quaternary ammonium salts (e.g., ), 5-12 membered heterospirocyclic quaternary ammonium salts containing N, O, or S (e.g., ), and 5-12 membered heterobridged quaternary ammonium salts containing N, O, or S (e.g., ), wherein substituents are selected from the group consisting of H, OH, SH, NH 2 , C 1 -C 6 alkyl, haloalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; R 4 and R 5 are as previously defined; m is an integer from 0 to 6; or R' and R" together with the carbon atom to which they are attached form a substituted or unsubstituted group selected from the following: groups containing a 5-12 membered spirocyclic, 5-12 membered heterobridged cyclic, or 6-12 membered fused cyclic system containing N, O, or S, wherein substituents are selected from the group consisting of H, OH, SH, NH 2 , C 1 -C 6 alkyl, haloalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; x is an integer from 1 to 6; R‴ is selected from the group consisting of C 1 -C 6 alkyl, haloalkyl, alkenyl, alkynyl, and cyano; in formula (IV), L 2 is selected from the group consisting of -[C(R b )(R c )] x -, -[C(R b )(R c )] x -Z-[C(R d )(R e )] h -, -[C(R b )(R c )] x -A-C(O)-[C(R d )(R e )] h -, -[C(R b )(R c )] x -A-C(S)-[C(R d )(R e )] h -, -[C(R b )(R c )] x -A-S(O) 2 -[C(R d )(R e )] h -, -[C(R b )(R c )] x -C(O)-A-[C(R d )(R e )] h - -[C(R b )(R c )] x -C(S)-A-[C(R d )(R e )] h -, -[C(R b )(R c )] x -S(O) 2 -A-[C(R d )(R e )] h -, -[C(R b )(R c )] x -ethenyl-[C(R d )(R e )] h -, -[C(R b )(R c )] x -ethynyl-[C(R d )(R e )] h -, -[C(R b )(R c )] x -S(O)(NR k )- [C(R d )(R e )] h -, -[C(R b )(R c )] x -S(O)=N-[C(R d )(R e )] h -, and -[C(R b )(R c )] x -S(O) t -[C(R d )(R e )] h -; R a is selected from the group consisting of -[C(R f )(R g )] n -R j , -Y-[C(R f )(R g )] n -R j , -[C(R f )(R g )] n -N(R p ) 2 + - [C(R h )(R i )] i -R j , -[C(R f )(R g )] n -A-C(O)-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -A-C(S)-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -ethenyl-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -ethynyl-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -S(O)(NR k )-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -S(O)=N-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -S(O) t -[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -C(O)-A-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -C(S)-A-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -ethenyl-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -ethynyl-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -S(O)(NR k )- [C(R h )(R i )] i -R j , [C(R f )(R g )] n -N=S(O)-[C(R h )(R i )] i -R j , -[C(R f )(R g )] n -S(O) t -[C(R h )(R i )] i -R j , and -[C(R f )(R g )] n -N(R p ) 2 + -[C(R h )(R i )] i -R j ; R b , R c , R d , R e , R f , R g , R h and R i are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, cyano, or halogen, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, halogen, acetyl, sulfonyl, or R b and R c , R d and R e , R f and R g , R h and R i together with the carbon atom(s) to which they are attached, respectively form a substituted or unsubstituted group selected from the following: cycloalkyl, heterocycloalkyl, 5-12 membered spirocyclic groups containing N, O, or S, 5-12 membered heterobridged cyclic groups containing N, O, or S, and 6-12 membered fused cyclic groups containing N, O, or S, wherein substituents are selected from the group consisting of H, OH, SH, NH 2 , C 1 -C 6 alkyl, haloalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; R j is selected from the group consisting of H, NH 2 , OH, SH, alkoxy, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, nitro, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 8 cycloalkyl, C 1 -C 8 heterocyclyl, aryl, heteroaryl, 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, 6-12 membered fused heterocyclic groups containing N, O, or S, -N(R p ) 3 + , C 2 -C 7 cyclic quaternary ammonium salts (e.g., ), 5-12 membered heterospirocyclic quaternary ammonium salts containing N, O, or S (e.g., ), and 5-12 membered heterobridged quaternary ammonium salts containing N, O, or S (e.g., ), wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, hydroxy, amino, halogen, acetyl, sulfonyl, R 2 is as previously defined; R k is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, haloalkyl, C 1 -C 8 cycloalkyl, C 1 -C 8 heterocyclyl, aryl, and heteroaryl, wherein the C 1 -C 8 cycloalkyl, C 1 -C 8 heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, hydroxy, amino, SH, and halogen; R p is selected from the group consisting of C 1 -C 6 alkyl, haloalkyl, alkenyl, alkynyl, and cyano; A is selected from O, S, or N(R k ); Y is selected from substituted or unsubstituted C 1 -C 8 cycloalkyl, C 1 -C 8 heterocyclyl, aryl, heteroaryl, 5-12 membered spirocyclic groups, 5-12 membered heterospirocyclic groups containing N, O, or S, 5-12 membered bridged cyclic groups, 5-12 membered heterobridged cyclic groups containing N, O, or S, 6-12 membered fused cyclic groups, and 6-12 membered fused heterocyclic groups containing N, O, or S, wherein substituents are selected from H, NH 2 , OH, SH, C 1 -C 6 alkyl, haloalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; Z is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one substituent selected from H, NH 2 , OH, SH, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, nitro, cyano, and halogen; h is an integer from 0 to 10; i is an integer from 0 to 10; m is an integer from 0 to 6; n is an integer from 0 to 6; x is an integer from 1 to 6; y is an integer from 0 to 10.
  2. The compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof according to claim 1, wherein in formula (II): L 1 is selected from - [C(R 4 )(R 5 )] m -(A) q - or -[C(R 4 )(R 5 )] m -(A) p -C(O)-[C(R 4 )(R 5 )] n -(A) q -; A is selected from O or S; R 1 is selected from R 2 is selected from hydrogen, hydroxy, SH, alkyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; R 3 is selected from hydrogen, SH, alkyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; m is an integer from 0 to 6; n is an integer from 0 to 6; p is 0, 1, or 2; q is 0, 1, or 2; t is 1 or 2.
  3. The compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof according to claim 1, wherein in formula (II): R 1 is selected from R 2 is selected from hydrogen, hydroxy, SH, alkyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; p is 0, 1, or 2.
  4. The compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof according to claim 1, wherein in formula (III): R' is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro, cyano, or halogen; R" is selected from groups substituted or unsubstituted as follows: 5-12 membered heterospirocyclic groups containing N, O, or S, -[C(R 4 )(R 5 )] m -N(R‴) 3 + ; the substituents are selected from H, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, nitro, cyano, or halogen; m is 0, 1, 2, 3, 4, 5, or 6; R 4 and R 5 are independently selected from hydrogen, hydroxy, SH, alkyl, or C 1 -C 4 alkyl; alternatively, R' and R" together with the carbon atom to which they are attached form a substituted or unsubstituted group selected from 5-12 membered spirocyclic groups having N, O, or S, 5-12 membered heterobridged cyclic groups containing N, O, or S, or 6-12 membered fused cyclic groups containing N, O, or S; the substituents are selected from H, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, nitro, cyano, or halogen; x is 1, 2, 3, 4, 5, or 6; R‴ is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, alkenyl, alkynyl, or cyano; preferably, R'is selected from H, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, nitro, cyano, or halogen; R" is selected from NH 2 and groups substituted or unsubstituted as follows: - [C(R 4 )(R 5 )] m -N(R‴) 3 + ; the substituents are selected from H, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, nitro, cyano, or halogen; m is 0, 1, 2, 3, 4, 5, or 6; R 4 and R 5 are independently selected from hydrogen, hydroxy, SH, alkyl, or C 1 -C 4 alkyl; R‴ is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, alkenyl, alkynyl, or cyano; preferably methyl, ethyl, propyl, or isopropyl.
  5. The compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof according to claim 1, wherein in formula (IV), L 2 is selected from-[C(R b )(R c )] x -, -[C(R b )(R c )] x -Z-, -[C(R b )(R c )] x -O-C(O)-[C(R d )(R e )] h -, -[C(R b )(R c )] x -S-C(O)-[C(R d )(R e )] h -, -[C(R b )(R c )] x - O -C(O)-[C(R d )(R e )] h -, -[C(R b )(R c )] x - O -C(S)-[C(R d )(R e )] h -; R b is H or methyl; R c is H or methyl; Z is a C 5 -C 10 aryl or a 5-6 membered heteroaryl, preferably phenyl, naphthyl, or thiophenyl; R d is methyl or ethyl; R e is H, methyl, or ethyl; x is 1, 2, 3, 4, 5, or 6; h is an integer from 0 to 10; preferably, L 2 is selected from -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -; more preferably, L 2 is -CH 2 -; preferably, L 2 is selected from -CH 2 -O-C(O)-(CH 2 ) h -, -CH 2 -S-C(O)-(CH 2 ) h -, - CH 2 -O-C(O)-[C(R d )(R e )] h -, -CH 2 -O-C(S)-[C(R d )(R e )] h -; R d is methyl; R e is H or methyl; h is 0 or an integer up to 10; more preferably, h is an integer from 0 to 6; most preferably, h is 0, 1, 2, 3, or 4.
  6. The compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof according to claim 1, wherein in formula (IV), R a is selected from substituted or unsubstituted groups as follows: C 1 -C 10 alkyl, -(CH 2 ) h CHR x R y , -(CH 2 ) h NR m R n , -(CH 2 ) h N(R p )2 + -R j ; the substituents are selected from NH 2 , -OH, -COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 carboxyalkyl; h or y is an integer from 0 to 10; R x is selected from H, -COOH, or C 1 -C 4 alkyl; R y is selected from H, amino, or C 1 -C 4 alkyl; R m and R n are independently selected from H, amino, -COOH, or C 1 -C 4 alkyl; or R m and R n together with the nitrogen atom to which they are attached form a 5-11 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S; R j is selected from H or C 1 -C 6 alkyl; R p is selected from H or C 1 -C 6 alkyl; preferably, in formula (IV), R a is selected from substituted or unsubstituted groups as follows: C 1 -C 6 alkyl, -(CH 2 ) h CHR x R y , -(CH 2 ) h NR m R n , -(CH 2 ) h N(R p ) 2 + -R j ; the substituents are selected from -NH 2 , -OH, - COOH, y is 1, 2, 3, 4, 5, or 6; h is 0, 1, 2, 3, or 4; R x is selected from H, -COOH, methyl, ethyl, propyl, or isopropyl; R y is selected from H, amino, methyl, ethyl, propyl, or isopropyl; R m and R n are independently selected from H, amino, -COOH, methyl, ethyl, propyl, or isopropyl; or Rm and Rn together with the nitrogen atom to which they are attached form a 5-11 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S; R j is selected from H, methyl, ethyl, propyl, or isopropyl; R p is selected from H, methyl, ethyl, propyl, or isopropyl.
  7. A compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof having the following structure:
  8. A composition comprising the compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof according to any one of claims 1-7, and a pharmaceutically acceptable carrier.
  9. Use of the compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof according to any one of claims 1-7 in the preparation of a neurokinin-1 receptor antagonist.
  10. Use of the compound, isomer, or pharmaceutically acceptable salt, acid, or deuterated derivative thereof according to any one of claims 1-7 in the preparation of a medicament for treating vomiting, nausea, asthma, anxiety, depression, cough, or migraine.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese Patent Application No. 202311086740.7, filed on August 28, 2023. BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the field of medicinal chemistry, and in particular to a neurokinin-1 (NK1 or NK-1) receptor antagonist. Description of Related Art Neurokinins are central neurotransmitters that participate in a variety of physiological activities in the human body. Neurokinins comprise multiple substances, such as substance P, neurokinin A, and neurokinin B. Neurokinin receptors are classified into three types, namely neurokinin receptor 1 (NK1R), neurokinin receptor 2 (NK2R), and neurokinin receptor 3 (NK3R). Among them, NK1R is the most important and the most widely distributed, being present in neurons, the brainstem, vascular endothelium, the gastrointestinal tract, and the urogenital system, and is most abundantly expressed in the vomiting center of the brain. Substance P is the most important neurotransmitter, is widely distributed in the central nervous system and gastrointestinal tract, and has the strongest binding affinity for NK1R. After binding to NK1R, substance P acts on calcium ion channels on the cell membrane via inositol triphosphate, leading to membrane depolarization and changes in protein kinase activity, thereby participating in pain and stress signaling and triggering physiological responses such as vomiting, anxiety, and pain. Neurokinin receptor antagonists and their uses are disclosed in, for example, US5760018 (1998) (pain, inflammation, migraine, and vomiting), US5620989 (1997) (pain, inflammation, and nociception), WO95/19344 (1995), WO94/13639 (1994), and WO94/10165 (1994). Other classes of NK1 receptor antagonists are also reported in, for example, 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). US7049320 discloses an effective and selective NK1 antagonist having beneficial therapeutic and pharmacological properties and good metabolic stability, namely (5S,8S)-8-(((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (rolapitant). This compound, in the free base form or in the form of a pharmaceutically acceptable salt, is suitable for formulations for parenteral administration. Rolapitant has very poor solubility at physiological pH and is difficult to develop into conventional injectable formulations. To address this issue, researchers have employed cosolvent-based formulations containing Captisol, propylene glycol, and ethanol to significantly improve the solubility of rolapitant; however, such formulations exhibit significant hemolytic effects after intravenous administration. Drug-induced hemolysis refers to the extensive destruction of red blood cells caused by immune factors after a drug enters the human body, and clinically manifests as anemia, jaundice, and dark-colored urine. CN102573475 discloses a series of rolapitant prodrugs and an improved formulation containing polyethylene glycol 15-hydroxystearate and medium-chain triglycerides; however, the hemolytic effect of the pharmaceutical composition has not been completely resolved. WO2020259675A1 discloses a series of rolapitant prodrug compounds. The prodrug compounds of this invention (formula (I)) exhibit significantly improved solubility and are largely converted to rolapitant in vivo, thereby avoiding hemolysis of the pharmaceutical composition and reducing side effects during administration. A prodrug refers to a compound obtained by chemical modification of a drug (parent drug) that is inactive or has low activity in vitro, and that releases the active drug through enzymatic or non-enzymatic conversion in vivo to exert pharmacological effects. The prodrug design of rolapitant is mainly intended to improve its water solubility to facilitate the development of injectable formulations. Such prodrugs are rapidly converted in vivo to release the active metabolite rolapitant, and when the in vivo exposure of the active metabolite rolapitant is high, they are considered to possess desirable pharmacokinetic properties and to be ideal rolapitant prodrugs. In view of the above, there is significant clinical value in providing additional prodrug designs of rolapitant to identify prodrug molecules that are converted more rapidly in vivo to release the active metabolite rolapitant, achieve higher in vivo exposure of the active metabolite rolapitant, and are safer and more effective. BRIEF SUMMARY OF THE INVENTION One of the objectives of the present invention is to provide a neurokinin-1 (NK1 or NK-1) receptor antagonist, comprising a compound having a structure represented by formula (II), formula (III), or formula (IV), or an isomer thereof, or a pharmaceutically acceptable salt or acid thereof, or a deuterated derivative thereof: wherein: in formula (II),