Granted Patent B2

US 12,747,233 · App. 18/613,714 · Granted Sep 29, 2026

Inventors: Wenqiang Zhai (Zhejiang, CN); Zhimin Zhang (Zhejiang, CN); Zhe Wang (Zhejiang, CN); Hao Pan (Zhejiang, CN); Liubin Guo (Zhejiang, CN); Qian Wang (Zhejiang, CN)

Assignee: HANGZHOU ZHONGMEIHUADONG PHARMACEUTICAL CO., LTD.

C07D405/14

Abstract

Claims (182)

1 . A compound of Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

represents a single or double bond;

W is selected from the group consisting of O, N, and NH;

X 3 and X 4 are independently selected from the group consisting of CH, N, and C;

Y 1 is selected from the group consisting of CH and N;

Y 2 is selected from the group consisting of CH, N, and C;

Y 3 is selected from the group consisting of CH, N, and C;

R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

R 2 is R z —C 1-3 alkylene-;

R 4 is independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, cyano, hydroxy, amino, amido, sulfonyl, and sulfonamido;

R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-3 alkyl, C 1-3 alkoxy, and C 3-6 cycloalkyl;

R 0 is independently selected from the group consisting of hydrogen, hydroxyl, and halogen;

n is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

p is 0, 1, 2, or 3;

q is 0, 1, 2, 3, or 4;

when m is not 0 and p is not 0, any R 4 and any R 5 may, together with the ring atoms of ring B and ring C therebetween, form a 5- to 8-membered ring, wherein the 5- to 8-membered ring may optionally be substituted 1 to 3 times by C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, cyano, oxo, or C 1-3 alkoxy, if the valence permits;

R z is selected from the group consisting of C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, wherein R z may be optionally substituted 1 to 3 times by C 1-3 alkyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, halogen, cyano, oxo, C 1-3 alkoxy, or 3- to 6-membered heterocyclyl.

2 . The compound according to claim 1 , wherein:

R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, and C 1-6 alkoxy; and/or

R 4 is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, cyano, hydroxy, and amino; and/or

R 5 is independently selected from the group consisting of hydrogen and halogen; and/or

R 0 is independently selected from the group consisting of hydrogen and halogen; and/or

R z is selected from selected from the group consisting of C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O and S, wherein R z may be optionally substituted 1 to 3 times by C 1-3 alkyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, halogen, cyano, oxo, C 1-3 alkoxy, or 3- to 6-membered heterocyclyl.

3 . The compound according to claim 1 , wherein:

X 3 is CH, and X 4 is N; or

X 3 is N, and X 4 is CH; or

X 3 and X 4 are each N; or

X 3 and X 4 are each CH.

4 . The compound according to claim 1 , wherein:

n is 1; and/or

and/or

R 2 is selected from —CH2—R z ; and/or

W is O; and/or

q is 1; and/or

5 . The compound according to claim 1 , wherein the compound has:

the structure of Formula II-1:

wherein X 3 , X 4 , Y 1 , Y 2 , Y 3 , R z , R 0 , R 1 , R 4 , R 5 , m and p are as defined in claim 1 ;

or the structure of Formula II-2:

wherein Y 1 , Y 2 , Y 3 , R z , R 0 , R 1 , R 4 , R 5 , m and p are as defined in claim 1 .

6 . The compound according to claim 1 , wherein R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, and C 1-3 alkoxy.

7 . The compound according to claim 1 , wherein

8 . The compound according to claim 1 , wherein R z is selected from the group consisting of C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O and S, wherein R z may optionally be substituted one time by C 1-3 alkyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, halogen or cyano.

9 . The compound according to claim 1 , wherein:

R 1 is independently selected from the group consisting of halogen and C 1-3 alkoxy; and/or

R 4 is hydrogen; and/or

R z may optionally be substituted one time by C 1-3 haloalkyl, cyano-C 1-3 alkyl or halogen.

10 . The compound according to claim 1 , wherein:

R 1 is independently selected from the group consisting of F, Cl, CH 3 O—, CH 3 CH 2 —O—, CH 3 CH 2 CH 2 —O—, or (CH 3 ) 2 CH—O; and/or

R z may optionally be substituted one time by halomethyl, cyanomethyl, halogen.

11 . The compound according to claim 1 , wherein:

R 1 is independently selected from the group consisting of F, Cl, and CH 3 O—; and/or

R z is selected from the group consisting of

12 . The compound according to claim 1 , wherein:

R z is selected from the group consisting of

13 . The compound according to claim 1 , wherein:

R z is selected from the group consisting of

14 . The compound according to claim 1 , wherein R 2 or

is selected from the group consisting of

15 . The compound according to claim 1 , wherein:

Y 2 is Cor CH; and/or

Y 3 is Cor N.

16 . The compound according to claim 1 , wherein:

Y 2 is CH, Y 3 is N, p is 0, and or

or

Y 2 is C, Y 3 is C, p is an integer of 1, 2 or 3, and

17 . The compound of claim 16 , wherein:

Y 2 is CH, Y 3 is N, p is 0, and

18 . The compound of claim 1 , wherein the compound has:

a structure of Formula II-3:

wherein X 3 , X 4 , Y 1 , R z , R 0 , R 1 , R 4 , and m are as defined in claim 1 ;

or a structure of Formula II-4:

wherein Y 1 , R z , R 0 , R 1 , R 4 , and m are as defined in claim 1 .

19 . The compound according to claim 18 , wherein:

R z is selected from unsubstituted 3- to 6-membered heterocycloalkyl having one O heteroatom;

m is 0;

R 1 is F, Cl, CH 3 O—, CH 3 CH 2 —O—, CH 3 CH 2 CH 2 —O—, or (CH 3 ) 2 CH—O—; and

R 0 is hydrogen, F, or Cl.

20 . The compound according to claim 18 , wherein:

R z is selected from unsubstituted 3- to 4-membered heterocycloalkyl having one O heteroatom; and/or

R 1 is F, Cl, or CH 3 O—; and/or

R 0 is hydrogen or F.

21 . The compound according to claim 18 , wherein:

R z is

22 . The compound according to claim 18 , wherein:

23 . The compound according to claim 18 , wherein:

R z is C 3-6 cycloalkyl optionally substituted with one substituent selected from the group consisting of C 1-3 haloalkyl, cyano-C 1-3 alkyl, and halogen,;

m is 0;

R 1 is F, Cl, CH 3 O—, CH 3 CH 2 —O—, CH 3 CH 2 CH 2 —O—, or (CH 3 ) 2CH—O—; and

R 0 is hydrogen, F, or Cl.

24 . The compound according to claim 18 , wherein:

R z is C 3-4 cycloalkyl optionally substituted with one substituent selected from the group consisting of halomethyl, cyanomethyl, F and Cl; and/or

R 1 is F or Cl; and/or

R 0 is hydrogen.

25 . The compound according to claim 18 , wherein:

R z is

26 . The compound according to claim 18 , wherein:

R z is

27 . The compound of claim 16 , wherein:

Y 2 is C, Y 3 is C, p is 1, and

28 . The compound of claim 1 , wherein:

is

wherein R 5 is at the ortho position of Y 3 .

29 . The compound of claim 1 , wherein the compound has:

a structure of Formula II-5:

wherein X 3 , X 4 , Y 1 , R z , R 0 , R 1 , R 4 , R 5 , and m are as defined in claim 1 ;

or a structure of Formula II-6:

wherein Y 1 , R z , R 0 , R 1 , R 4 , R 5 , and m are as defined in claim 1 .

30 . The compound according to claim 29 , wherein:

R 5 is hydrogen or halogen; and/or

R 0 is hydrogen, F, or Cl; and/or

Y 1 is N; and/or

R 4 is hydrogen.

31 . The compound according to claim 30 , wherein:

R 5 is F or Cl; and/or

R 0 is hydrogen.

32 . The compound according to claim 30 , wherein:

R 5 is F.

33 . The compound according to claim 1 , wherein:

m is not 0 and p is not 0, any R 4 and any R 5 , together with the ring atoms of ring B and ring C therebetween, form a 5- to 8-membered ring, wherein the 5- to 8-membered ring has 0, 1, or 2 ring heteroatoms independently selected from N, O, and S, and the ring heteroatoms are not the ring atoms of ring B and ring C, and wherein the 5- to 8-membered ring may be optionally substituted 1 to 3 times by C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy, if the valence permits.

34 . The compound according to claim 1 , wherein:

m is 1 and p is 1, R 4 and R 5 , together with the ring atoms of ring B and ring C therebetween, form a 5- to 8-membered ring, wherein the 5- to 8-membered ring has 0, 1, or 2 ring heteroatoms independently selected from N, O, and S, and the ring heteroatoms are not the ring atoms of ring B and ring C, and wherein the 5- to 8-membered ring may be optionally substituted 1 to 3 times by C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy, if the valence permits.

35 . The compound according to claim 1 , wherein the compound has:

a structure of Formula II-7:

wherein:

ring D

is a 5- to 8-membered ring;

represents a single or double bond;

Y 1 , Y 2 and Y 3 are each as defined in claim 1 ;

R y is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, cyano, oxo, and C 1-3 alkoxy; and

r is 1, 2, or 3;

or a structure of Formula II-8:

36 . The compound according to claim 35 , wherein:

r in the formula II-7 is 1; and/or

R y is hydrogen.

37 . The compound according to claim 35 , wherein ring D

is selected from the group consisting of

38 . The compound according to claim 35 , wherein ring D

is selected from the group consisting of

39 . The compound according to claim 35 , wherein ring D

is

40 . The compound according to claim 1 , wherein the compound has a structure of Formula II-9:

41 . The compound according to claim 35 , wherein:

Y 3 is N; and/or

Y 1 is N.

42 . The compound according to claim 40 , wherein

is selected from the group consisting of:

43 . The compound according to claim 35 , wherein:

R z is selected from unsubstituted 3- to 6-membered heterocycloalkyl having one O heteroatom;

R 1 is F, Cl, CH 3 O—, CH 3 CH 2 —O—, CH 3 CH 2 CH 2 —O—, or (CH 3 ) 2CH—O—; and

R 0 is hydrogen, F or Cl.

44 . The compound according to claim 35 , wherein:

R z is selected from unsubstituted 3- to 4-membered heterocycloalkyl having one O heteroatom; and/or

R 1 is F or Cl; and/or

R 0 is hydrogen.

45 . The compound according to claim 35 , wherein:

R z is

46 . The compound according to claim 35 , wherein:

47 . The compound according to claim 1 , wherein:

represents a single bond;

W is O;

X 3 and X 4 are independently CH;

Yis N;

Y 2 is CH;

Y 3 is N;

R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy;

R 2 is R z —C 1-3 alkylene-;

R 4 is independently hydrogen;

R 5 is independently hydrogen;

R 0 is independently selected from the group consisting of hydrogen, hydroxyl, and halogen;

n is 0, or 1;

m is 0, or 1;

p is 0, or 1;

q is 0, or 1;

when m is not 0 and p is not 0, R 4 and R 5 may, together with the ring atoms of ring B and ring C therebetween, form a 5- to 8-membered ring, wherein the 5- to 8-membered ring has 1, or 2 ring heteroatoms independently selected from N, O, and S, and the ring heteroatoms are not the ring atoms of the ring B and the ring C;

R z is selected from the group consisting of C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O and S, wherein R z may be optionally substituted 1 to 3 times by C 1-3 haloalkyl, cyano-C 1-3 alkyl, halogen, and cyano.

48 . The compound according to claim 1 , which is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

49 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

50 . A method for treating a GLP-1 receptor mediated or related disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said GLP-1 receptor mediated or related disease or disorder is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, and hyperinsulinemia.

Continuity (3)

References Cited (17)