Granted Patent B2

US 12,729,213 · App. 17/442,666 · Granted Sep 8, 2026

Inventors: Shaomeng Wang (Superior Township, MI); Haibin Zhou (Ann Arbor, MI); Renqi Xu (Ann Arbor, MI); Longchuan Bai (Ann Arbor, MI); Donna McEachern (Ann Arbor, MI); Jeanne Stuckey (Fenton, MI); Chao-Yie Yang (Ann Arbor, MI)

Assignee: THE REGENTS OF THE UNIVERSITY OF MICHIGAN

C07F9/3882A61P35/00

Abstract

Claims (122)

1 . A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1a and R 1b are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —CH 2 OC(═O)R 1e ;

R 1e is C 1 -C 6 alkyl;

M is selected from the group consisting of —O— and —C(R 2a )(R 2b )—;

R 2a and R 2b are independently selected from the group consisting of hydrogen and fluoro; or

R 2a and R 2b taken together with the carbon atom to which they are attached form a —C(═O)— group;

A is selected from the group consisting of:

wherein the bond designated with an “*” is attached to —C(═O)-E-Q A ,

G 1 is selected from the group consisting of —O—, —S—, and —NR 17 —;

G 2 is —CR 18a ═;

G 3 is —CR 18b ═;

G 4 is —CR 18c ═;

G 5 is —CR 18d ═;

G 6 is —CR 18e ═;

G is selected from the group consisting of —N═ and —CR 18f ═;

R 3 is hydrogen;

R 3b is C 1 -C 4 alkyl;

R 3c is hydrogen;

R 17 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

R 18a , R 18b , R 18c , R 18d , R 18e , and R 18f are hydrogen;

E is:

wherein the bond designated with an “*” is attached to Q A ;

R 3g is hydrogen;

X A is selected from the group consisting of —N(R 8 )CH 2 —, —CH 2 N(R 8 )—, and —CH 2 CH 2 —;

R 8 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (optionally substituted 5- to 8-membered heterocyclo)C 1 -C 6 alkyl-, C 1 -C 6 alkylsulfonyl, —C(═O)R 9 , and -L-B;

R 9 is selected from the group consisting of C 1 -C 6 alkyl, amino, C 1 -C 6 alkoxy, optionally substituted 4- to 8-membered heterocyclo, and optionally substituted 5- to 10-membered heteroaryl;

Q A is selected from the group consisting of:

X 1 is selected from the group consisting of —CH 2 —, —O—, and —N(R 11a )—; or

X 1 is absent;

R 10 is hydrogen;

R 11a is hydrogen;

s is 2 or 3;

X 2 is selected from the group consisting of —CH 2 —, —O—, and —N(R 11b )—; or

X 2 is absent;

t is 2 or 3;

R 11b is hydrogen;

R 12a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 -cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, and (amino)(C 6 -C 14 aryl)C 1 -C 6 alkyl-;

R 12b is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, optionally substituted C 6 -C 14 aryl, and (optionally substituted C 6 -C 14 aryl)C 1 -C 6 alkyl; or

R 12a and R 12b taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo,

R 12c is hydrogen;

X 4 is —CH 2 —; or

X 4 is absent;

v is 0, 1, or 2;

R 12d is hydrogen;

R 13a is selected from the group consisting of hydrogen, optionally substituted C 6 -C 14 aryl, (optionally substituted C 6 -C 14 aryl) C 1 -C 6 alkyl-, (optionally substituted C 3 -C 6 cycloalkyl)C 1 -C 6 alkyl-, and optionally substituted 5- to 9-membered heteroaryl;

R 13b is hydrogen;

R 13c is hydrogen; or

R 13a and R 13b taken together form an optionally substituted C 3 -C 8 cycloalkyl or an optionally substituted C 4 -C 9 heterocyclo; or

R 13b and R 13c taken together form an optionally substituted 4- to 9-membered heterocyclo;

A 2* is selected from the group consisting of —C(R 14b )— and —N—;

R 14b is hydrogen;

g is 2;

h is 2;

X 5 is —CH 2 —; or

X 5 is absent;

y is 1 or 2;

R 15 is optionally substituted C 6 -C 14 aryl;

L is -J 1 -Y 1 -J 2 -Y 2 -J 3 -Z—;

J 1 is selected from the group consisting of C 1-12 alkylenyl, 4- to 8-membered heterocyclenyl, and 5- to 9-membered heteroarylenyl; or

J 1 is absent;

Y 1 is selected from the group consisting of —(CH 2 ) m — and —C≡C—;

m is 0, 1, or 2;

J 2 is C 1-12 alkylenyl; or

J 2 is absent;

Y 2 is selected from the group consisting of —(CH 2 ) n —;

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

J 3 is C 1-12 alkylenyl, 4- to 8-membered heterocyclenyl, and 5- to 9-membered heteroarylenyl; or

J 3 is absent;

Z is selected from the group consisting of —(CH 2 ) d —, —C≡C—, and, —N(R 16c );

d is 0, 1, 2, or 3;

R 16c is hydrogen;

wherein Z is attached to B;

B is selected from the group consisting of:

A 5 is —C(R 19a )═;

A 2 is —C(R 19a )±;

A 3 is —C(R 19a )═;

A 4 is —C(R 19a )═;

Z 1 is —CH 2 and —C(═O)—;

R 5a is selected from the group consisting of hydrogen, methyl, and fluoro;

R 5b is selected from the group consisting of hydrogen and methyl;

R 19a , R 19b , R 19c , and R 19d are each hydrogen;

R 20 is C 4 alkyl;

R 21 is C 1 alkyl;

R 23 is C 1 -C 6 alkyl; and

R 24 is selected from the group consisting of, optionally substituted C 3 -C 6 cycloalkyl and optionally substituted 5- to 14-membered heteroaryl,

with the provisos:

(1) when X A is —CH 2 CH 2 —, then Q A is selected from the group consisting of Q-3, Q-5, Q-6, and Q-7;

(2) when X A is —N(R 8 )CH 2 — or —CH 2 N(R 8 )—, and R 8 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (optionally substituted 5- to 8-membered heterocyclo)C 1 -C 6 alkyl-, C 1 -C 6 alkylsulfonyl, and —C(═O) R 9 , then Q A is selected from the group consisting of Q-3, Q-4, Q-5, Q-6, and Q-7; and

(3) when X A is —N(R 8 )CH 2 — or —CH 2 N(R 8 )—, and R 8 is-L-B, then Q A is selected from the group consisting of Q-1 and Q-2.

2 . The compound of claim 1 , wherein the compound is Formula II:

3 . The compound of claim 1 , wherein A is selected from the group consisting of:

4 . The compound of claim 1 , wherein E is:

or

5 . The compound of claim 1 , wherein X A is —N(R 8 )CH 2 — or —CH 2 N(R 8 )—, R 8 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (optionally substituted 5- to 8-membered heterocyclo) C 1 -C 6 alkyl-, C 1 -C 6 alkylsulfonyl, and —C(═O)R 9 , and Q A is Q-6.

6 . The compound of claim 5 , wherein Q A is Q-6-1 or Q-6-2:

7 . The compound of claim 1 , wherein L is —Y 1 -Y 2 —Z—.

8 . The compound of claim 7 , wherein Y 1 is selected from the group consisting of —(CH 2 ) m — and —C(═O)—; m is 1, 2, or 3; Y 2 is —(CH 2 ) n —; n is 1, 2, 3, or 4; and Z is selected from the group consisting of —(CH 2 )—, —C≡C—, and —N(H)—.

9 . The compound of claim 8 , wherein Z is —C≡C—.

10 . The compound of claim 1 , wherein:

L is selected from the group consisting of:

wherein the bond designated with an “*” is attached to B;

w is 1, 2, 3, 4, 5, 6, 7, or 8; and

x is 1, 2, 3, 4, 5, or 6.

11 . The compound of claim 1 , wherein B is B-1.

12 . The compound of claim 1 , wherein the compound is Formula VII-E:

or a pharmaceutically acceptable salt or solvate thereof.

13 . The compound of claim 12 , wherein:

R 13a is:

R 25e is selected from the group consisting of hydrogen, halo, C 1 -C 6 alkyl, —C(═O)NR 50c R 50d , C 1 -C 6 alkylsulfonyl, C 6 -C 14 arylsulfonyl, —N(R 56c )S(═O) 2 R 56d , and —S(═O) 2 R 58 ;

R 25f is selected from the group consisting of hydrogen and halo;

R 50c is selected from the group consisting of C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, (optionally substituted C 6 -C 14 aryl)C 1 -C 6 alkyl-, (optionally substituted 5- to 14-membered heteroaryl)C 1 -C 4 alkyl-, and (3- to 14-membered heterocyclo)C 1 -C 4 alkyl-;

R 50d is selected from the group consisting of hydrogen and C 1 -C 3 alkyl; or

R 50c and R 50d taken together with the nitrogen to which they are attached form an optionally substituted 3- to 8-membered heterocyclo group;

R 56c is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;

R 56d is selected from the group consisting of optionally substituted C 3 -C 6 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl; and

R 58 is optionally substituted C 3 -C 6 cycloalkyl.

14 . The compound of claim 12 , wherein R 8 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 6 alkylsulfonyl, and —C(═O)R 9 ; and R 9 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 6 alkylamino, diC 1 -C 6 alkylamino, and C 1 -C 4 alkoxy.

15 . The compound of claim 1 , wherein each of R 1a and R 1b is hydrogen.

16 . A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

17 . A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier.

Continuity (3)

References Cited (104)