IP Library › Granted Patent US 12,540,143

Granted Patent B2

US 12,540,143 · App. 17/602,345 · Granted Feb 3, 2026

Methods and compositions for targeted protein degradation

Inventors: Weiwen Ying (Lexington, MA); Long Ye (Shanghai, CN); Kevin Foley (Waltham, MA)

Assignee: Ranok Therapeutics (Hangzhou) Co. Ltd.

C07D495/14 A61K31/551 A61K47/545 A61P35/00

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Quick Facts

Patent No.: US 12,540,143
App. No.: 17/602,345
Granted: Feb 3, 2026
Kind: B2

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Abstract

Provided are compounds of Formula I: and pharmaceutically acceptable salts and compositions thereof, which are useful for treating cancers and related conditions.

Claims (61)

1 . A compound of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein

X is C(O) or (C 1 -C 4 )alkylene;

A is

W is 5- or 6-membered heteroaryl optionally substituted with 1 to 3 groups selected from R 2 ;

V is phenyl or 5- to 9-membered heteroaryl optionally substituted with 1 to 3 groups selected from R 3 ;

R 1 is halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or halo(C 1 -C 4 )alkoxy;

R 2 is (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halo(C 2 -C 6 )alkynyl, CN, —C 1-4 alkylOR a , —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —C(O)NR a (C 1-4 alkylene)OR a , —C(O)NR a (C 1-4 alkylene)NR a R b , —C(O)NR a (C 1-4 alkylene)OR, —NR a R b , —O(C 1-4 alkylene)NR a R b , —C 1-4 alkylNR a R b , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR a R b , —SO 2 NR a R b , —NR a (C 1-4 alkylene)OR a , —NR a (C 1-4 alkylene)NR a R b , —C 1-6 alkylC(O)NR a R b , phenyl or 5- to 7-membered heteroaryl, wherein said phenyl and 5- to 7-membered heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R 4 ;

R a and R b are each independently selected from hydrogen and (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is optionally substituted with one or more halo or a 3- to 7-membered heterocyclyl, or both;

R 3 and R 4 are each independently halo, —NR a R b , (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or halo(C 1 -C 4 )alkoxy; and

L is a linker.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

A is

and

Z is N or CH.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein Z is CH.

4 . The compound of claim 1 , wherein each R 3 is independently (C 1 -C 4 )alkyl or halo.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

L is *Het 1 -X 1 —, *Het 1 -X 1 -Het 2 -X 2 —, *Het 1 -X 1 —(C 1 -C 4 )alkylene-Het 2 -X 2 —, *Het 1 -X 1 -Het 2 -X 2 (C 1 -C 4 )alkylene-, *—(CH 2 CH 2 O) o —(CH 2 ) p -Het 1 -X 1 -Het 2 -(CH 2 CH 2 O) n , *—(CH 2 CH 2 O) n —(CH 2 ) m -Het 1 -X 1 -Het 2 -X 2 , *Het 1 -X 1 -Phe-X 2 —NR c —X 3 , *—(CH 2 CH 2 O) o —(CH 2 ) p -Het 1 -X 1 -Phe-X 2 —NR c —(CH 2 CH 2 O) n —, *—(CH 2 CH 2 O) n —(CH 2 ) m —NR c -Phe-X 1 —, *—(CH 2 CH 2 O) o —(CH 2 ) p —NR c -Phe-(CH 2 CH 2 O) n —, *—(CH 2 CH 2 O) o —(CH 2 ) p —NR c —(CH 2 CH 2 O) n —(CH 2 ) m —, *(CH 2 CH 2 O) n —(CH 2 ) m —NR c —(CH 2 CH 2 O) n —(CH 2 ) m —C(O)—NR d —(CH 2 CH 2 O) o —(CH 2 ) p —, *—(CH 2 CH 2 O) o —(CH 2 ) p —NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Het 1 -X 1 -Het 2 -X 2 —, *—(CH 2 CH 2 O) o —(CH 2 ) p —NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Het 1 -X 1 -Het 2 -X 2 —(CH 2 CH 2 O) o , *NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Phe-NH—X 1 -Het 1 -X 2 , *NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Phe-NH—X 1 -Het 1 -X 2 —(CH 2 CH 2 O) o , *—(CH 2 CH 2 O) o —(CH 2 ) p —NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Phe-X 1 —NR c —(CH 2 CH 2 O) o —(CH 2 ) p —, *—(CH 2 CH 2 O) o —(CH 2 ) p —NR c —(CH 2 CH 2 O) n —(CH 2 ) m - Het 1 -X 1 —, *—(CH 2 CH 2 O) o —(CH 2 ) p —NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Het 1 -X 1 —(CH 2 CH 2 O) n —, *—(CH 2 CH 2 O) n —(CH 2 ) m —NR c —(CH 2 ) m —C(O)—NR d -Het 1 -X 1 -Het 2 -(CH 2 CH 2 O) o —(CH 2 ) p , or *NR c —(CH 2 ) m —C(O)—NR d —(CH 2 ) m -Het 1 -X 1 -Het 2 -X 2 ;

* indicates the point of attachment to X;

Het 1 and Het 2 are each independently phenyl, a 4- to 6-membered heterocyclyl, 5- to 7-membered heteroaryl, or a 4- to 6-membered cycloalkyl;

X 1 , X 2 , and X 3 , are each independently C(O) or (CH 2 ) r ;

R c and R d are each independently hydrogen or (C 1 -C 4 )alkyl; and

m, n, o, p, and r are each independently integers selected from 0, 1, 2, 3, 4, 5, and 6.

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

or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is halo or (C 1 -C 4 )alkyl.

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chloro, isopropyl, methyl, propyl, or ethyl.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is isopropyl or ethyl.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —OR a , —SR a , —C(O)NR a R b , or —C(O)NR a (C 1-4 alkylene)NR a R b .

14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a and R b are each independently selected from hydrogen and (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is optionally substituted with 1 to 3 halo or a 6-membered heterocyclyl.

15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is OH, SH, —C(O)NHCH 2 CF 3 , —C(O)NHCH 2 CH 3 , —C(O)NH(CH 2 ) 2 N(CH 2 CH 3 ) 2 , —C(O)NHCH (CH 3 ) 2 , C(O)NH 2 , —C(O)NH(CH 2 ) 2 piperidinyl.

16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —C(O)NHCH 2 CF 3 or OH.

17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the Formula III:

or a pharmaceutically acceptable salt thereof.

18 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein Het 1 and Het 2 are each independently a 4- to 6-membered heterocyclyl.

19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is *Het 1 -X 1 —, *Het 1 -X 1 -Het 2 -X 2 —, *Het 1 -X 1 -Het 2 -(CH 2 CH 2 O) n —, *Het 1 -X 1 -Phe-X 2 —NR c —X 3 —, *Het 1 -X 1 -Phe-X 2 —NR c —(CH 2 CH 2 O) n —, *NR c -Phe-X 1 —, *NR c -Phe-(CH 2 CH 2 O) n —, *NR c —(CH 2 CH 2 O) n —(CH 2 ) m —, *NR c —(CH 2 CH 2 O) n —(CH 2 ) m —C(O)—NR d —(CH 2 CH 2 O) o —(CH 2 ) p —, *NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Het 1 -X 1 -Het 2 -X 2 , *NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Phe-NH—X 1 -Het 1 -X 2 —, *NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Phe-X 1 -Het 1 -X 2 —, *NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Phe-X 1 —NR c —(CH 2 CH 2 O) o —(CH 2 ) p —, *NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Het 1 -X 1 —, *NR c —(CH 2 ) m —C(O)—NR d -Het 1 -X 1 -Het 2 -(CH 2 CH 2 O) o —(CH 2 ) p , or*NR c —(CH 2 ) m —C(O)—NR d —(CH 2 ) m -Het 1 -X 1 -Het 2 -X 2 —.

20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is *Het 1 -X 1 —(CH 2 ) r , *Het 1 -X 1 -Het 2 -(CH 2 ) r —, *Het 1 -(CH 2 ) r -Phe-(CH 2 ) r —NR c —(CH 2 ) r —, *NR c -Phe-(CH 2 ) r —, *NR c —(CH 2 CH 2 O) n —, *NR c —(CH 2 ) m —, *NR c —(CH 2 ) m —C(O)—NR d —(CH 2 ) p —, *NR c —(CH 2 ) m —C(O)—NR d —(CH 2 CH 2 O) o —, *NR c —(CH 2 ) m -Het 1 -X 1 -Het 2 -(CH 2 ) r —, *NR c —(CH 2 ) m -Phe-(CH 2 ) r -Het 1 -(CH 2 ) r —, *NR c -Phe-NH—C(O)-Het 1 -(CH 2 ) r —, *NR c —(CH 2 CH 2 O) n —(CH 2 ) m -Phe-(CH 2 ) o —NR c —(CH 2 ) p —, or *NR c —(CH 2 ) m —C(O)—NR d —(CH 2 ) m -Het 1 -X 1 -Het 2 -(CH 2 ) r —.

21 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein m, n, o, p, and r are each independently integers selected from 0, 1, 2, and 3.

22 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein Het 1 and Het 2 are each independently piperidinyl, piperazinyl, azetidinyl, or pyrrolidinyl.

23 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is

24 . The compound of claim 1 , wherein the compound is of the Formula IV:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is (C 1 -C 4 )alkyl;

R 2 is —C(O)NR a R b or OH;

R a is hydrogen or (C 1 -C 2 )alkyl;

R b is (C 1 -C 4 )alkyl optionally substituted with 1 to 3 halo; and

L is *Het 1 -X 1 -Het 2 -X 2 — or *Het 1 -X 1 -Phe-X 2 —NR c —X 3 .

25 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein R a is hydrogen.

26 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein R b is (C 1 -C 4 )alkyl substituted with 1 to 3 halo.

27 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein L is *Het 1 -(CH 2 ) r -Het 2 -X 2 — or *Het 1 -(CH 2 ) r -Phe-(CH 2 ) r —NR c —(CH 2 ) r .

28 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein each r is independently integers selected from 1 and 2.

29 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein Het 1 and Het 2 are each independently piperidinyl or piperazinyl.

30 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

31 . A method of treating cancer comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

32 . A compound, wherein the compound is (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-1-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

33 . A pharmaceutical composition comprising (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-1-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

34 . A method of treating cancer comprising administering to a subject a therapeutically effective amount of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-1-(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 23, 2022

From: YING, WEIWEN; YE, LONG; FOLEY, KEVIN P.

To: RANOK THERAPEUTICS (HANGZHOU) CO. LTD.

Reel/Frame 059980/0616 →

Priority Claims (1)

WO PCT/CN2019/081919 · Apr 9, 2019 · international

Continuity (1)

Related Publication 20220162228A1 · May 26, 2022

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