Nitrogen-containing heterocyclic compound, preparation method therefor, and use thereof
AssigneeBivision Pharmaceuticals, Inc.
InventorsEric Yanjun WANG, Jinqiu HE, Haihua YU, Kevin Yu WANG, Yueguang SUN, Jian ZHAN, Yaoming YU
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Abstract
Disclosed in the present invention are a nitrogen-containing heterocyclic compound, a preparation method therefor, and a use thereof. Specifically disclosed are a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound can be used for the diagnosis and treatment of FAP-associated tumors, achieves high tumor uptake and long retention, and has a wide application prospect.
Claims21
A compound of formula I or formula V, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof;
- wherein in the compound of formula I:
- R1 and R2 are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, or hydroxyl, and R1 and R2 are not simultaneously C1-6 alkyl, C1-6 alkoxy, or hydroxyl;
- A1 is —CN, —B(OH)2, —CONH2, or —COORa;
- Ra is hydrogen or C1-6 alkyl;
- W1 is hydrogen or C1-4 alkyl;
- L1 is
- wherein the a-terminus is connected to the carbonyl group in the amide bond on the left side;
- X1 and X2 are independently N or CH;
- Y is O, S, or NH;
- Rb and Rc are independently hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy;
- n1, n2, and n3 are independently 0, 1, or 2;
- m1, m2, and m3 are independently 0, 1, or 2;
- p is 1, 2, 3, or 4;
- R3 is independently C1-6 alkylene;
- V1 is a chemical bond, —C(═O)—C1-6 alkylene-NH—, or —C(═O)—CH2—(OCH2CH2)s—NH—, wherein s is 1, 2, 3, or 4, and the —NH— in —C(═O)—C1-6 alkylene-NH— and —C(═O)—CH2—(OCH2CH2)s—NH— is connected to U1;
- U1 is a group containing a radioactive metal ion or a group capable of optical imaging;
- in the compound of formula V:
- R6, R7, R8, and R9 are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, or hydroxyl, and R6 and R7 are not simultaneously C1-6 alkyl, C1-6 alkoxy, or hydroxyl, and R8 and R9 are not simultaneously C1-6 alkyl, C1-6 alkoxy, or hydroxyl;
- A3 and A4 are independently —CN, —B(OH)2, —CONH2, or —COORg;
- Rg is hydrogen or C1-6 alkyl;
- W3 and W4 are independently hydrogen or C1-4 alkyl;
- L3 and L8 are independently phenyl, phenyl substituted by one or more Rh,
- wherein the c-terminus is connected to the carbonyl group in the amide bond;
- Rh, Ri, and Rj are independently hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy;
- X4 and X5 are independently CH or N;
- m5, m6, n5, and no are independently 0, 1, or 2;
- L4 and L7 are independently a chemical bond or C1-6 alkylene:
- L5 and L6 are independently
- wherein the d-terminus is connected to V3;
- V3 is
- wherein the e-terminus is connected to L5 or L6, the f-terminus is connected to L5 or L6, and the g-terminus is connected to U3;
- U3 is a group containing a radioactive metal ion or a group capable of optical imaging.
A compound of formula II or formula VI, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof,
- wherein U1a is a group having a function of chelating a metal ion;
- U3a is a group having a function of chelating a metal ion;
- in the compound of formula II:
- R1 and R2 are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, or hydroxyl, and R1 and R2 are not simultaneously C1-6 alkyl, C1-6 alkoxy, or hydroxyl;
- A1 is —CN, —B(OH)2, —CONH2, or —COORa;
- Ra is hydrogen or C1-6 alkyl;
- W1 is hydrogen or C1-4 alkyl;
- L1 is
- wherein the a-terminus is connected to the carbonyl group in the amide bond on the left side;
- X1 and X2 are independently N or CH;
- Y is O, S, or NH;
- Rb and Rc are independently hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy;
- n1, n2, and n3 are independently 0, 1, or 2;
- m1, m2, and m3 are independently 0, 1, or 2;
- p is 1, 2, 3, or 4;
- R3 is independently C1-6 alkylene;
- V1 is a chemical bond, —C(═O)—C1-6 alkylene-NH—, or —C(═O)—CH2—(OCH2CH2)s—NH—, wherein s is 1, 2, 3, or 4, and the —NH— in —C(═O)—C1-6 alkylene-NH— and —C(═O)—CH2—(OCH2CH2)s—NH— is connected to U1a,
- in the compound of formula VI:
- R6, R7, R8, and R9 are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, or hydroxyl, and R6 and R7 are not simultaneously C1-6 alkyl, C1-6 alkoxy, or hydroxyl, and R8 and R9 are not simultaneously C1-6 alkyl, C1-6 alkoxy, or hydroxyl;
- A3 and A4 are independently —CN, —B(OH)2, —CONH2, or —COORS;
- Rg is hydrogen or C1-6 alkyl;
- W3 and W4 are independently hydrogen or C1-4 alkyl;
- L3 and L8 are independently phenyl, phenyl substituted by one or more Rh,
- wherein the c-terminus is connected to the carbonyl group in the amide bond;
- Rh, Ri, and Rj are independently hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy:
- X4 and X5 are independently CH or N;
- m5, m6, n5, and no are independently 0, 1, or 2;
- L4 and L7 are independently a chemical bond or C1-6 alkylene;
- L5 and L6 are independently
- wherein the d-terminus is connected to V3;
- V3 is
- wherein the e-terminus is connected to L5 or L6, the f-terminus is connected to L5 or L6, and the g-terminus is connected to U3a.
10-25. (canceled)
A compound of formula VII, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof,
- wherein L9 is
- R1 and R2 are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, or hydroxyl, and R1 and R2 are not simultaneously C1-6 alkyl, C1-6 alkoxy, or hydroxyl;
- A1 is —CN, —B(OH)2, —CONH2, or —COORa;
- Ra is hydrogen or C1-6 alkyl;
- W1 is hydrogen or C1-4 alkyl;
- X1 and X2 are independently N or CH;
- Y is O, S, or NH;
- Rb and Rc are independently hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy;
- n1, n2, and n3 are independently 0, 1, or 2;
- m1, m2, and m3 are independently 0, 1, or 2.
Dependencies are inferred from the claim text.