Granted Patent B2

US 12,310,975 · App. 17/073,135 · Granted May 27, 2025

Inventors: Michael Berlin (Flemington, NJ); Hanqing Dong (Madison, CT); Dan Sherman (Madison, CT); Lawrence Snyder (Killingworth, CT); Jing Wang (Milford, CT); Wei Zhang (Madison, CT)

Assignee: Arvinas Operations, Inc.

A61K31/551A61K31/496A61K31/4985A61K31/506A61K31/5355A61K31/5377A61K31/55C07D401/14C07D405/14C07D413/14C07D417/14C07D471/10C07D487/04C07D487/08C07D487/10

Abstract

Claims (101)

1. A compound having the chemical structure:

ULM-L-PTM,

or a pharmaceutically acceptable salt thereof,

wherein:

(a) the ULM is:

wherein:

W 3 is selected from optionally substituted aryl, optionally substituted heteroaryl, and

R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9 and R 10 , together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl;

R 11 is selected from optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R 12 is H or optionally substituted alkyl;

R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, or optionally substituted aralkyl;

R 14a and R 14b , are each independently selected from H, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, aminomethyl, alkylaminomethyl, alkoxymethyl, optionally substituted hydroxyl alkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, CONR 27a R 27b , CH 2 NHCOR 26 , and (CH 2 )N(CH 3 )COR 26 ; or R 14a and R 14b , together with the carbon atom to which they are attached, form an optionally substituted 3 to 6 membered cycloalkyl, heterocycloalkyl, spirocycloalkyl or spiroheterocyclyl, wherein the spiroheterocyclyl is not epoxide or aziridine;

W 5 is phenyl or 5-10 membered heteroaryl optionally substituted with one or more halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy;

R 15 is H; halogen; CN; OH; NO 2 ; NR 14a R 14b ; OR 14a ; CONR 14a R 14b ; NR 14a COR 14b ; SO 2 NR 14a R 14b ; NR 14a SO 2 R 14b ; optionally substituted alkyl; optionally substituted haloalkyl; optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted cycloheteroalkyl;

each R 26 is independently selected from H, optionally substituted alkyl or NR 27a R 27b ;

each R 27a and R 27b is independently H, optionally substituted alkyl, or R 27a and R 27b together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

each R 16 is independently selected from CN, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, and optionally substituted haloalkoxy;

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

R 18 is H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy;

p is 0, 1, 2, 3, or 4; and

wherein the dashed line indicates the site of attachment of the chemical linker moiety coupling the PTM to the ULM;

(b) the PTM is:

wherein:

Q 6 , Q 7 , Q 8 , Q 9 , Q 12 , Q 13 , Q 14 , and Q 15 are each independently N, O, or C, each optionally substituted with one R PTMI ;

Q 16 is CH;

each R PTMI is independently H, halogen, CN, OH, NO 2 , NH 2 , C 1-6 alkyl, or

t 1 is 1, 2, 3, 4, or 5;

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

R PTM1a and R PTM2a are independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and CH 2 OCH 3 ; or R PTM1a and R PTM2a are joined together to form a 3-10 membered ring;

X is O, S, or CH 2 ;

is a single bond or a double bond;

n is an integer from 0 to 10; and

of the PTM indicates the point of attachment with a chemical linker group; 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 the group consisting of 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 substituted with 0-6 R L1 groups, C 5-13 spirocycloalkyl substituted with 0-9 R L1 groups, C 3-11 heterocyclyl substituted with 0-6 R L1 groups, C 5-13 spiroheterocyclyl substituted with 0-8 R L1 groups, aryl substituted with 0-6 R L1 groups, and heteroaryl substituted with 0-6 R L1 groups; and

R L1 , R L2 , R L3 , and R L4 are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OH, NH 2 , SH, SO 2 C 1-8 alkyl, 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, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, or CON(C 1-8 alkyl) 2 .

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is:

wherein:

W L1 and W L2 are each independently absent or a 4-8 membered ring with 0-4 heteroatoms, wherein the 4-8 membered ring is optionally substituted with RQ;

each RQ is independently a H, halo, OH, CN, CF 3 , unsubstituted or substituted linear or branched C1-C6, unsubstituted or substituted linear or branched C1-C6 alkoxy, or 2 RQ groups taken together with the atom they are attached to form a 4-8 membered ring system containing 0-4 heteroatoms;

Y L1 is each independently a bond, unsubstituted or substituted linear or branched C1-C6 alkyl optionally having one or more C atoms are replaced with O; or unsubstituted or substituted linear or branched C 1 -C 6 alkoxy;

n is 0-10; and

indicates the attachment point to the PTM or the ULM.

3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

4. A compound selected from

Ex. #

49

50

51

53

54

55

56

58

70

78

82

83

86

108

114

115

116

117

122

123

124

133

141

144

159

or a pharmaceutically acceptable salt thereof.

5. A compound selected from

Ex. #

49

50

51

53

54

55

56

58

70

78

82

83

86

108

114

115

116

117

122

123

124

133

141

144

159

Assignments (1)

Continuity (2)

References Cited (272)