Granted Patent B2

US 12,552,783 · App. 17/360,699 · Granted Feb 17, 2026

Inventors: Andrew P. Crew (Chester, CT); Keith R. Hornberger (Southbury, CT); Jing Wang (Milford, CT); Hanqing Dong (Madison, CT)

Assignee: ARVINAS OPERATIONS, INC.

C07D417/14A61P35/00C07D401/14C07D413/14C07D471/04

Abstract

Claims (88)

1 . A compound having the chemical structure:

ULM-L-PTM,

or a pharmaceutically acceptable salt thereof,

wherein:

(a) the ULM has a chemical structure selected from:

wherein:

W is selected from CH 2 , CHR, and C═O;

each X is O:

Z is O;

G is H;

Q 1 , Q 2 , Q 3 , and Q 4 represent an N atom or a C atom substituted with a group independently selected from H and R;

A is H;

n is 1, 2, 3, or 4;

R is selected from H, —CONR′R″, —OR′, —NR′R″, —SR′, —SO 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, —(CR′O) n′ R″, —aryl, —hetaryl, optionally substituted alkyl, —cycloalkyl, —heterocyclyl, —Cl, —F, —CF 3 , —CN, and —CO 2 R′, wherein one R is covalently joined to the L;

R′ and R″ are independently selected from a bond, H, and optionally substituted alkyl;

n′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

represents a bond that is stereospecific or non-stereospecific;

(b) the PTM has a chemical structure that is:

wherein:

 is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, optionally substituted with one or more halo or optionally substituted aryl group;

X PTM is CH or N;

W PTM is selected from optionally substituted C3-C6 cycloalkyl and optionally substituted C3-C6 heterocycloalkyl;

R PTM1A is selected from NR PTM9 R PTM10 , optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted O—(C3-C6 cycloalkyl), optionally substituted-O—C 1-4 alkyl-C 3-6 cycloalkyl, optionally substituted O-C 1-4 alkyl-C 3-6 heterocycloalkyl, optionally substituted aryl, optionally substituted O-aryl, optionally substituted heteroaryl, optionally substituted O-heteroaryl, optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 and optionally substituted

 wherein N* is an N atom of a heterocycloalkyl of the L;

R PTM1B is selected from NR PTM9 R PTM10 , OR PTM9 R PTM10 , H, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted O—(C3-C6 cycloalkyl), optionally substituted-O—C 1-4 alkyl-C3-6cycloalkyl, optionally substituted aryl, optionally substituted O-aryl, optionally substituted heteroaryl, optionally substituted O-heteroaryl, optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 optionally substituted

 and optionally substituted

R PTM9 and R PTM10 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted aliphatic amino, and optionally substituted aliphatic amido;

R PTM2 is H, (C═O)R PTM2 ′, or optionally substituted alkyl;

R PTM2 ′ is optionally substituted alkyl, optionally substituted alkenyl, —N(R PTM8 ) 2 , or —C(OH) 2 ;

R PTM5 is selected from optionally substituted biaryl, optionally substituted biheteroaryl, halogen, H, optionally substituted alkyl, OH, and alkoxy;

R PTM8 is H or alkyl;

t is 0, 1, 2, 3, 4, 5, or 6; and

indicates the site of attachment of the L; and

(c) the L is:

-(A L ) q -,

wherein:

q is an integer greater than or equal to 1;

each A L is independently selected from CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C═C, C 3-11 cycloalkyl optionally substituted with 1-6 R L1 and/or R L2 groups, C 3-11 heterocyclyl optionally substituted with 1-6 R L1 and/or R L2 groups, aryl optionally substituted with 1-6 R L1 and/or R L2 groups, and heteroaryl optionally substituted with 1-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl, each of which is optionally substituted with 1-4 RL5 groups; and

R L1 , R L2 , R L3 , R L4 and R L5 are, each independently, selected from H, halogen, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, OH, NH 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, CN, CF 3 , CHF 2 , CH 2 F, CONHC 1-8 alkyl, and CON(C 1-8 alkyl) 2 .

2 . The compound according to claim 1 , wherein the PTM has a chemical structure that is:

wherein:

R PTM3 is alkyl, alkoxy, or naphthalenyl, each optionally substituted with OH or halogen or a combination thereof;

R PTM4A is 1 or 2 substituents selected from OH, H, halogen, and optionally substituted C1-C6 alkyl;

R PTM4B is OH, H, —CH 2 CN, halogen, or optionally substituted C1-C6 alkyl; and

indicates the site of attachment of the L.

3 . The compound according to claim 1 , wherein the L is selected from:

and

C1-C6 alkyl;

wherein:

*N is an N atom of a heterocycloalkyl that is shared with the PTM; and

each m, n, o, p, q, r, and s is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

4 . The compound according to claim 1 , wherein the L is selected from:

wherein N* is an N atom that is shared with the PTM.

5 . The compound according to claim 1 , wherein the L is polyethylene glycol with 1 to 10 ethylene glycol units, optionally substituted with aryl.

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

or a pharmaceutically acceptable salt thereof.

7 . A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 7 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 7 , R PTM1A is selected from NR PTM9 R PTM10 :

or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 7 , R PTM1A is selected from NR PTM9 R PTM10 :

or a pharmaceutically acceptable salt thereof.

11 . The compound of claim 7 , R PTM1A is selected from NR PTM9 R PTM10 :

or a pharmaceutically acceptable salt thereof.

12 . The compound of claim 1 , wherein the PTM is:

Assignments (2)

Continuity (3)

References Cited (400)