Brm targeting compounds and associated methods of use

Abstract

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

What is claimed: 
     
         1 . A compound of Formula (I):
   PTM-ULM  (I)
   or a pharmaceutically acceptable salt or solvate thereof,   wherein
 PTM is a moiety of Formula IA: 
   
       
         
           
           
               
               
           
         
         wherein
 R 1  is a covalent bond, or chemical moiety that links PTM and ULM; 
 * is a point of attachment to ULM; 
 n=0-3; 
 W is optionally substituted —CH 2 —, —C(O)—, —S(O)—, or —S(O) 2 —; wherein when n=2 or 3, only one W may be —C(O)—, —S(O)—, or —S(O) 2 —; 
 R c1  and R d1  are independently H, D, Halo, C 1-3  alkyl, C 1-3  haloalkyl, or C 1-4  alkoxyl; 
 R e3  is H, —C(O)R f , or —P(O)(OR g ) 2 ; wherein R f  and R g  are independently H, C 1-4  alkyl, C 1-4  substituted alkyl, C 3-8  cyclcoalkyl, C 3-8  substituted cyclcoalkyl, C 3-8  heterocyclcoalkyl, or C 3-8  substituted heterocyclcoalkyl; 
 Z and Y are each independently N; CR h  wherein R h ═H or absent; or, if R 1  is attached to Z, then Z is C and Y is N or CR h  wherein R h  is H; or if R 1  is attached to Y, then Y is C and Z is N or CR h  wherein R h  is H; 
 B is an optionally substituted 5-7 membered cycloalkyl ring, an optionally substituted 5-7 membered heteroaryl ring, or an optionally substituted 5-7 membered heterocyclic ring, wherein ring B is fused to ring C through Y and Z; and ULM is a small molecule E3 Ubiquitin Ligase binding moiety that binds a Von Hippel-Lindau E3 Ubiquitin Ligase. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is a covalent bond. 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is a chemical moiety represented by the formula:
   -(A) q -,   wherein:
 q is an integer from 1 to 14; 
 each A is independently selected from the group consisting of CR 1a R 1b  O, S, SO, SO 2 , NR 1c , SO 2 NR 1c , SONR 1c , SO(═NR 1c ), SO(═NR 1c )NR 1d , CONR 1c , NR 1c , CONR 1d  NR 1c C(O)O, NR 1c SO 2 NR 1d , CO, CR 1a ═CR 1b , C≡C, SiR 1a R 1b , P(O)R 1a , P(O)OR 1a  (CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4  NR 1c C(═NCN)NR 1d NR 1c C(═NCN), NR 1c C(═CNO 2 )NR 1d , 3-11 membered cycloalkyl, optionally substituted with 0-6 R 1a  and/or R 1b  groups, 3-11 membered heteocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups, aryl optionally substituted with 0-6 R 1a  and/or R 1b  groups, or heteroaryl optionally substituted with 0-6 R 1a  and/or R 1b  groups, 
 wherein R 1a , R 1b , R 1c , R 1d , and R 1e  are each independently, —H, D, -halo, —C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, —C 1 -C 6 haloalkyl, —S—C 1 -C 8 alkyl, —NHC 1 -C 8 alkyl, —N(C 1 -C 8 alkyl) 2 , 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, —O—(3-11 membered cycloalkyl), —S—(3-11 membered cycloalkyl), NH—(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl) 2 , N-(3-11 membered cycloalkyl)(C 1 -C 8 alkyl), —OH, —NH 2 , —SH, —SO 2 C 1 -C 8 alkyl, SO(NH)C 1 -C 8 alkyl, P(O)(OC 1 -C 8 alkyl)(C 1 -C 8 alkyl), —P(O)(OC 1 -C 8 alkyl) 2 , —C≡C—C 1 -C 8 alkyl, —C≡CH, —CH═CH(C 1 -C 8 alkyl), —C(C 1 -C 8 alkyl)═CH(C 1 -C 8 alkyl), —C(C 1 -C 8 alkyl)═C(C 1 -C 8 alkyl) 2 , —Si(OH) 3 , —Si(C 1 -C 8 alkyl) 3 , —Si(OH)(C 1 -C 8 alkyl) 2 , —C(O)C 1 -C 8 alkyl, —CO 2 H, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NO 2 , —SF 5 , —SO 2 NHC 1 -C 8 alkyl, —SO 2 N(C 1 -C 8 alkyl) 2 , —SO(NH)NHC 1 -C 8 alkyl, —SO(NH)N(C 1 -C 8 alkyl) 2 , —SONHC 1 -C 8 alkyl, —SON(C 1 -C 8 alkyl) 2 , —CONHC 1 -C 8 alkyl, —CON(C 1 -C 8 alkyl) 2 , —N(C 1 -C 8 alkyl)CONH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl)CON(C 1 -C 8 alkyl) 2 , —NHCONH(C 1 -C 8 alkyl), —NHCON(C 1 -C 8 alkyl) 2 , —NHCONH 2 , —N(C 1 -C 8 alkyl)SO 2 NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl)SO 2 N(C 1 -C 8 alkyl) 2 , —NHSO 2 NH(C 1 -C 8 alkyl), —NHSO 2 N(C 1 -C 8 alkyl) 2 , or —NHSO 2 NH 2 ; and where R 1a  or R 1b , each independently may be optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R 1e  groups. 
   
     
     
         4 . The compound according to  claim 3 , wherein q=4 and R 1  is a chemical moiety represented by the formula:-A 1 -A 2 -A 3 -A 4 -, wherein each of A 1-4  is independently selected from the group consisting of O, S, SO, SO 2 , NR 1c  SO 2 NR 1c  SONR 1c , SO(═NR 1c ), SO(═NR 1c )NR 1d , CONR 1c , NR 1c , CONR 1d , NR 1c  C(O)O, NR 1c SO 2 NR 1d , CO, CR 1a ═CR 1b , C≡C, SiR 1a R 1b , P(O)R 1a , P(O)OR 1a , (CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl, and heteroaryl;
 wherein R 1a  and R 1b  are each independently selected from the group consisting of —H, D, -halo, —C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, —C 1 -C 6 haloalkyl —S—C 1 -C 8 alkyl —NHC 1 -C 8 alkyl —N(C 1 -C 8 alkyl) 2 , 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, —O—(3-11 membered cycloalkyl), —S—(3-11 membered cycloalkyl), NH—(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl) 2 , N-(3-11 membered cycloalkyl)(C 1 -C 8 alkyl), —OH, —NH 2 , —SH, —SO 2 C 1 -C 8 alkyl, SO(NH)C 1 -C 8 alkyl, P(O)(OC 1 -C 8 alkyl)(C 1 -C 8 alkyl), —P(O)(OC 1 -C 8 alkyl) 2 , —C≡C—C 1 -C 8 alkyl, —C≡CH, —CH═CH(C 1 -C 8 alkyl), —C(C 1 -C 8 alkyl)═CH(C 1 -C 8 alkyl), —C(C 1 -C 8 alkyl)═C(C 1 -C 8 alkyl) 2 , —Si(OH) 3 , —Si(C 1 -C 8 alkyl) 3 , —Si(OH)(C 1 -C 8 alkyl) 2 , —C(O)C 1 -C 8 alkyl, —CO 2 H, —CN, —NO 2 , —SF 5 , —SO 2 NHC 1 -C 8 alkyl, —SO 2 N(C 1 -C 8 alkyl) 2 , —SO(NH)NHC 1 -C 8 alkyl, —SO(NH)N(C 1 -C 8 alkyl) 2 , —SONHC 1 -C 8 alkyl, —SON(C 1 -C 8 alkyl) 2 , —CONHC 1 -C 8 alkyl, —CON(C 1 -C 8 alkyl) 2 , —N(C 1 -C 8 alkyl)CONH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl)CON(C 1 -C 8 alkyl) 2 , —NHCONH(C 1 -C 8 alkyl), —NHCON(C 1 -C 8 alkyl) 2 , —NHCONH 2 , —N(C 1 -C 8 alkyl)SO 2 NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl)SO 2 N(C 1 -C 8 alkyl) 2 , —NHSO 2 NH(C 1 -C 8 alkyl), —NHSO 2 N(C 1 -C 8 alkyl) 2 , or —NHSO 2 NH 2 ; and 
 R 1c  and R 1d  are each independently selected from the group consisting of H, D, optionally substituted C 1-4  alkyl, C 3-8  cyclcoalkyl, C 3-8  heterocyclcoalkyl, aryl, or heteroaryl. 
 
     
     
         5 . The compound according to  claim 1 , wherein R 1  is a 3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups, 3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups, —(CR 1a R 1b ) 1-5 , —(CR 1a ═CR 1b )—, —(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(CR 1a ═CR 1b )—(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 —(CR 1a ═CR 1b )—(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(C≡C)—(CR 1a R 1b ) 1-5 —, —(CR 1a R 1b ) 1-5 -A-(C≡C)—(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(C≡C)—(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(C≡C)—(CR 1a R 1b ) 1-5 , —(CR 1a R 1b ) 1-5 -A-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-, —(CR 1a R 1b ) 1-5 -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-, -(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 —, -(3-11 membered heterocyclyl optionally substituted with 0-6 Rea and/or R 1b  groups)- (CR 1a R 1b ) 1-5 —, —(CR 1a R 1b ) 1-5 -A-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-A-, —(CR 1a R 1b ) 1-5 -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-A-, —(CR 1a R 1b ) 1-5 , -(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CR 1a R 1b ) 1-5  —(CR 1a R 1b ) 1-5 -A-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-A- wherein A is O, S, or NR 1c —(CR 1a R 1b ) 1-5 -A-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CR 1a R 1b ) 1-5 , —(CR 1a R 1b ) 1-5 -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A- wherein each A is independently O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CR 1a R 1b ) 1-5 -A- wherein each A is independently O, S, or NR 1c , —(CR 1a R 1 ) 1-5 -A-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CO) wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CR 1a ═CR 1b )—(CR 1a R 1b ) 1-5 -A-(CO)— wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(C≡C)—(CR 1a R 1b ) 1-5 -A-(CO)— wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CR 1a R 1b ) 1-5 -A-(CO)— wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CO)-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A-(CO)— wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CO)-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-A-(CO)— wherein each A is independently O, S, or NR 1c , -(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups) 1-5 -(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CR 1a R 1b ) 1-5 -A-(CO)— wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A-(CO)—wherein A is O, S, or NR 1c , -(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 —, or -(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 —, -(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CO)—(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c ; -(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CO)-A-(CR 1a R 1b ) 1-5 — wherein A is O, S, or NR 1c ; -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A- wherein each A is independently O, S, or NR 1c ; -(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CR 1a R 1b ) 1-5 -A-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c ; -(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c ; -(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-A-(CR 1a R 1b ) 1-5 -A- wherein each A is independently O, S, or NR 1c ; -(heteroaryl optionally substituted with 0-4 R 1a  and/or R 1b  groups)-A-(CR 1a R 1b ) 1-5 — wherein A is O, S, or NR 1c ; -(3-11 membered heterocyclyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c ; -(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CO)—(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c ; -(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)-(CO)-A-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c ; —(CO)-(3-11 membered cycloalkyl optionally substituted with 0-6 R 1a  and/or R 1b  groups)- (CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1 c. 
     
     
         6 . The compound according to  claim 1 , wherein the compound of Formula IA is a compound of Formula IA-1: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 1 , wherein the compound of Formula IA is a compound of Formula IA-2: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to  claim 1 , wherein the compound of Formula IA is a compound of Formula IA-3: 
       
         
           
           
               
               
           
         
         wherein m=1 to 3; 
         X is optionally substituted —CH 2 —, or NH; or, if R 1  is attached to X, then X is —CH— or N; and Q is optionally substituted —CH 2 —, optionally substituted —(CH 2 ) 2 —, —C(O)—, optionally substituted —CH 2 C(O)—, —S(O)—, —S(O) 2 —, optionally substituted —CH 2 S(O) 2 —, or optionally substituted —CH 2 S(O)—. 
       
     
     
         9 . The compound according to  claim 1 , wherein the compound of Formula IA is a compound of Formula IA-4: 
       
         
           
           
               
               
           
         
         wherein m=1 to 3; each R k  is independently H, D, F, C 1-3  alkyl, C 1-3  haloalkyl, C 1-4  alkoxyl, substituted C 1-3  alkyl, substituted C 1-3  haloalkyl, or substituted C 1-4  alkoxyl; and s=0-7. 
       
     
     
         10 . The compound according to  claim 9 , wherein the compound of Formula IA-4 is a compound of Formula IA-5: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 8 , wherein m=2. 
     
     
         12 . The compound according to  claim 8 , wherein at least one W is optionally substituted —CH 2 —; and wherein when n=2 or 3, only one W may be —C(O)—, —S(O)—, or —S(O) 2 —. 
     
     
         13 . The compound according to  claim 10 , wherein W is —CH 2 —. 
     
     
         14 . The compound according to  claim 10 , wherein W is —CH(CH 3 )—. 
     
     
         15 . The compound according to  claim 8 , wherein at least one W is —C(O)—. 
     
     
         16 . The compound according to  claim 11 , wherein the compound of Formula IA-5 is a compound of Formula IA-6: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound according to  claim 1 , wherein R e3  is H. 
     
     
         18 . The compound according to  claim 1 , wherein R d1  is H. 
     
     
         19 . The compound according to  claim 9 , wherein s=0. 
     
     
         20 . The compound according to  claim 1 , wherein R c1  is H. 
     
     
         21 . The compound according to  claim 1 , wherein ULM is a moiety having the Formula ULM-I 
       
         
           
           
               
               
           
         
         wherein 
         the dashed line ( ) indicates the position of attachment of ULM-I to R 1 ; 
         V is H or F; 
         R 3  is optionally substituted phenyl, optionally substituted napthyl, or an optionally substituted 5-10 membered heteroaryl; 
         one of R 4  or R 5  is H, D, haloalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, —COR d , CONR e1 R e2 ; 
         the other of R 4  or R 5  is H or D; 
         or R 4  and R 5 , together with the carbon atom to which they are both attached, form an optionally substituted 3-5 membered cycloalkyl or heterocyclyl; 
         W 3  is an optionally substituted aryl, optionally substituted heteroaryl, or 
       
       
         
           
           
               
               
           
         
         R 6  and R 7  are independently H, D, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted haloalkyl, 
         or R 6 , R 7 , and the carbon atom to which they are attached form an optionally substituted cycloalkyl or optionally substituted heterocyclyl; 
         R 8  is an optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, CONR a R b  NR a R b   
       
       
         
           
           
               
               
           
         
         R a  is selected from H or optionally substituted alkyl; 
         R b  is selected from H, —C(O)—* wherein * is a point of attachment to R 1 , optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (cycloalkyl)carbonyl, optionally substituted (heterocyclyl) carbonyl, or optionally substituted aralkyl; 
         each R c  is independently H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; 
         each R d  is independently selected from H, optionally substituted alkyl or NR e1 R e2 ; 
         each R e1  and R e2  is independently H, D, optionally substituted alkyl, 
         or R e1  and R e2  together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl; and 
         p is 0, 1, 2, 3, or 4. 
       
     
     
         22 .- 35 . (canceled) 
     
     
         36 . The compound according to  claim 21 , wherein R 3  is optionally substituted phenyl having the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 9  is H, D, halo, —CN, —OH, —NO 2 , —NR e1 R e2 , —OR e1 , NR e1 COR e2 , —SO 2 NR e1 R e2 , —NR e1 SO 2 R e2  optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted heterocyclyl; 
         R 10  is H, D, halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, —NH(optionally substituted alkyl), —N(optionally substituted alkyl) 2 , optionally substituted alkoxy, or optionally substituted haloalkoxy; and 
         z is 0, 1, 2, 3, or 4. 
       
     
     
         37 . The compound according to  claim 36 , wherein R 9  is —CN, or 
       
         
           
           
               
               
           
         
       
       each optionally substituted. 
     
     
         38 . The compound according to  claim 37 , wherein R 9  is 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound according to  claim 36 , wherein R 10  is H, D, hydroxy, halogen, —NH(C 1 -C 4 alkyl), or C 1 -C 6 alkoxy, and z is 0, 1, 2, 3, or 4. 
     
     
         40 . The compound according to  claim 21 , wherein
 w 3  is   
       
         
           
           
               
               
           
         
         R 6  is H; 
         R 7  is H, or optionally substituted alkyl; 
         R 8  is 
       
       
         
           
           
               
               
           
         
         R a  is H or optionally substituted alkyl; 
         R b  is H, —C(O)—* wherein * is a point of attachment to R 1 , optionally substituted alkyl, 
         optionally substituted alkylcarbonyl, or optionally substituted (cycloalkyl)carbonyl. 
       
     
     
         41 . The compound according to  claim 21 , wherein
 R 7  is H, C 1 -C 6 alkyl, C 1 -C 6 alk-OH, C 1 -C 6 alk-NH 2 , —C 1 -C 6 alk-CONH—*, or —C 1 -C 6 alk-NHCO—*;   R 8  is —NH—*, or —NHCOR 11 ;
 * is a point of attachment of the ULM to R 1 ; and 
   R 11  is   
       
         
           
           
               
               
           
         
       
     
     
         42 . The compound according to  claim 21 , wherein
 W3 is R 8     
       
         
           
           
               
               
           
         
         R 6  is H; 
         R 7  is H, or optionally substituted alkyl; 
         R 8  is 
       
       
         
           
           
               
               
           
         
         R c  is H or optionally substituted alkyl; and p=1. 
       
     
     
         43 . The compound according to  claim 21 , wherein ULM-I is a compound of formula: 
       
         
           
           
               
               
           
         
         * is a point of attachment of the ULM to R 1 . 
       
     
     
         44 . The compound of  claim 43 , wherein
 R 9  is —CN or optionally substituted   
       
         
           
           
               
               
           
         
         and R 10  is H, D, hydroxy, halogen, —NH(C 1 -C 6 alkyl), or —OC 1 -C 6 alkyl. 
       
     
     
         45 . The compound of  claim 44 , wherein
 R 9  is   
       
         
           
           
               
               
           
         
         and R 10  is H, —F, or —OCH 3 . 
       
     
     
         46 .- 93 . (canceled)