Substituted piperidine Degronimers for Target Protein degradation

Patent metadata

Field	Value
Publication number	US-12048747-B2
Application number	US-202017121389-A
Country	US
Kind code	B2
Filing date	Dec 14, 2020
Priority date	May 10, 2016
Publication date	Jul 30, 2024
Grant date	Jul 30, 2024

Abstract

This invention provides amine-linked C 3 -glutarimide Degronimers for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation, wherein the C 3 -glutarimide Degronimers have the formula:

First claim

We claim:

1. A method for degrading a Targeted Protein via the cereblon E3 Ligase ubiquitin proteasome pathway, wherein the method comprises contacting the Targeted Protein with a compound having an N-acyl glutarimide of the following formula:

or a pharmaceutically acceptable salt thereof,
wherein:
R 12 is a Linker-Targeting Ligand;
Linker is:

X 1 is a bond, —NH—, —NR 25 —, —CH 2 —, —CHR 25 —, —C(R 25 ) 2 —, —O—, or —S—;
X 2 is a bond, —NH—, —NR 25 —, —CH 2 —, —CHR 25 —, —C(R 25 ) 2 —, —O—, or —S—;
R 20 is a bond, —CR 27 R 28 —, —CH(OR 26 )—, poly[CH(OH)CH(OH)], poly[CH 2 CH(OH)CH(OH)], —CH(OH)C(O)O—, —CH 2 CH(OH)C(O)O—, poly(lactic-co-glycolic acid), alkylene, haloalkylene, -alkylene(R 27 )-alkylene(R 28 )—, arylalkylene, heteroarylalkylene, —C(OR 26 )alkyl-, alkenylene, alkynylene, —C(O)—, —C(O)alkylene, —C(O)O—, —C(O)Oalkylene, —C(O)NH—, —C(O)N(alkyl)-, —C(S)—, —NH—, —N(alkyl)-, —NHC(O)—, —N(alkyl)C(O)—, —NHC(O)NH—, —NHC(O)NR 25 —, —NR 25 C(O)NR 25 —, —O—, —O-alkylene, —OC(O)—, —P(O)(OR 26 )—, —P(O)(OR 26 )O—, —S—, —S(O)—, —S(O) 2 —, carbocyclylene, heterocyclylene, arylene, or heteroarylene;
R 21 is a bond, —CR 27 R 28 —, —CH(OR 26 )—, poly[CH(OH)CH(OH)], poly[CH 2 CH(OH)CH(OH)], —CH(OH)C(O)O—, —CH 2 CH(OH)C(O)O—, poly(lactic-co-glycolic acid), alkylene, haloalkylene, -alkylene(R 27 )-alkylene(R 28 )—, arylalkylene, heteroarylalkylene, —C(OR 26 )alkyl-, alkenylene, alkynylene, —C(O)—, —C(O)alkylene, —C(O)O—, —C(O)Oalkylene, —C(O)NH—, —C(O)N(alkyl)-, —C(S)—, —NH—, —N(alkyl)-, —NHC(O)—, —N(alkyl)C(O)—, —NHC(O)NH—, —NHC(O)NR 25 —, —NR 25 C(O)NR 25 —, —O—, —O-alkylene, —OC(O)—, —P(O)(OR 26 )—, —P(O)(OR 26 )O—, —S—, —S(O)—, —S(O) 2 —, carbocyclylene, heterocyclylene, arylene, or heteroarylene;
R 22 is a bond, —CR 27 R 28 —, —CH(OR 26 )—, poly[CH(OH)CH(OH)], poly[CH 2 CH(OH)CH(OH)], —CH(OH)C(O)O—, —CH 2 CH(OH)C(O)O—, poly(lactic-co-glycolic acid), alkylene, haloalkylene, -alkylene(R 27 )-alkylene(R 28 )—, arylalkylene, heteroarylalkylene, —C(OR 26 )alkyl-, alkenylene, alkynylene, —C(O)—, —C(O)alkylene, —C(O)O—, —C(O)Oalkylene, —C(O)NH—, —C(O)N(alkyl)-, —C(S)—, —NH—, —N(alkyl)-, —NHC(O)—, —N(alkyl)C(O)—, —NHC(O)NH—, —NHC(O)NR 25 —, —NR 25 C(O)NR 25 —, —O—, —O-alkylene, —OC(O)—, —P(O)(OR 26 )—, —P(O)(OR 26 )O—, —S—, —S(O)—, —S(O) 2 —, carbocyclylene, heterocyclylene, arylene, or heteroarylene;
R 23 is a bond, —CR 27 R 28 —, —CH(OR 26 )—, poly[CH(OH)CH(OH)], poly[CH 2 CH(OH)CH(OH)], —CH(OH)C(O)O—, —CH 2 CH(OH)C(O)O—, poly(lactic-co-glycolic acid), alkylene, haloalkylene, -alkylene(R 27 )-alkylene(R 28 )—, arylalkylene, heteroarylalkylene, —C(OR 26 )alkyl-, alkenylene, alkynylene, —C(O)—, —C(O)alkylene, —C(O)O—, —C(O)Oalkylene, —C(O)NH—, —C(O)N(alkyl)-, —C(S)—, —NH—, —N(alkyl)-, —NHC(O)—, —N(alkyl)C(O)—, —NHC(O)NH—, —NHC(O)NR 25 —, —NR 25 C(O)NR 25 —, —O—, —O-alkylene, —OC(O)—, —P(O)(OR 26 )—, —P(O)(OR 26 )O—, —S—, —S(O)—, —S(O) 2 —, carbocyclylene, heterocyclylene, arylene, or heteroarylene;
R 24 is a bond, —CR 27 R 28 —, —CH(OR 26 )—, poly[CH(OH)CH(OH)], poly[CH 2 CH(OH)CH(OH)], —CH(OH)C(O)O—, —CH 2 CH(OH)C(O)O—, poly(lactic-co-glycolic acid), alkylene, haloalkylene, -alkylene(R 27 )-alkylene(R 28 )—, arylalkylene, heteroarylalkylene, —C(OR 26 )alkyl-, alkenylene, alkynylene, —C(O)—, —C(O)alkylene, —C(O)O—, —C(O)Oalkylene, —C(O)NH—, —C(O)N(alkyl)-, —C(S)—, —NH—, —N(alkyl)-, —NHC(O)—, —N(alkyl)C(O)—, —NHC(O)NH—, —NHC(O)NR 25 —, —NR 25 C(O)NR 25 —, —O—, —O-alkylene, —OC(O)—, —P(O)(OR 26 )—, —P(O)(OR 26 )O—, —S—, —S(O)—, —S(O) 2 —, carbocyclylene, heterocyclylene, arylene, or heteroarylene;
each R 25 is independently alkyl, alkenyl, alkynyl, —C(O)H, —C(O)alkyl, —C(O)OH, or —C(O)Oalkyl;
each R 26 is independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;
each R 27 is independently H, alkyl, or NH 2 ;
each R 28 is independently H, alkyl, or NH 2 ; or
each R 27 and R 28 , together with the carbon atom to which they are attached, independently forms —C(CH 2 )—, —C(O)—, a C 3 -C 6 spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene, wherein the 4-, 5-, or 6-membered spiroheterocyclylene contains 1 or 2 heteroatoms independently selected from the group consisting of N and O; and
Targeted Protein is 4BVV, ABL1, ABL2, AKT1, AKT2, androgen receptor, AP1, AP2, ASH1L, ATAD2, ATF2, AXL, BAZ2A, BAZ2B, Bcl-2, Bcl-XL, BCR-ABL, BMX, BRPF1, cathepsin, CECR2, CSF1R, cyclin dependent kinase, DDR1, dihydrofolate reductase, DOT1L, EED, EHMT1, EHMT2, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, estrogen receptor, EZH2, factor Xa, fatty acid binding protein, FES, FKBP, FLAP, FLT3, FYN, GSG2, HBV, HCK, HCV protease, HDM2, heat shock protein, histone acetyltransferase, HIV integrase, HIV protease, HIV reverse transcriptase, IDO1, IDH1, IGF1R, INSR, ITK, kallikrein 7, KDM4, KDM5, KDM6, KIT, kringle domain V, KSR1, L3MBTL3, lactoylglutathione lyase, LCK, LSD1, LYN, lysine methyltransferase, lysine-specific histone demethylase, mast/stem cell growth factor receptor, MCL-1, MDM2, MDM4, MEK1, MEN1, MER, MERTK, MET, mPGES-1, MST1R, MTH1, NTRK, PAK1, PAK4, PB1, PDGFR receptor, PDZ, PHIP, phospholipase A2 domain, PNET, PPAR-gamma, protein S100-A7, RAML receptor, RCC receptor, ROS1 receptor, saposin-B, Sec7, SEGA receptor, SETD2, SETD7, SETD8, SETDB1, SF6D, SH2 domain, SMYD2, SMYD3, SUV4-20H1, TAF1, TAF1L, TANK1, TEC, tie 2 receptor, TNIK, mTORC1, mTORC2, TRKB, TRIM24, U09-CX-5279, VEGF receptor, or YES;
wherein the alkylene, each alkylene of -alkylene(R 27 )-alkylene(R 28 )—, alkyl of —C(OR 26 )alkyl-, alkylene of arylalkylene, alkylene of heteroarylalkylene, alkenylene, alkynylene, —C(O)alkylene, —C(O)Oalkylene-, —C(O)N(alkyl)-, —N(alkyl)-, —N(alkyl)C(O)—, or —O-alkylene- of R 20 , R 21 , R 22 , R 23 , and R 24 is optionally and independently substituted with one substituent independently selected from the group consisting of F, Cl, Br, I, —CN, —NO 2 , —C(O)OH, —C(O)Oalkyl, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —O(alkyl), —O(aryl), —O(heteroaryl), heterocyclyl, aryl, and heteroaryl;
wherein the carbocyclylene, heterocyclylene, arylene, or heteroarylene of R 20 , R 21 , R 22 , R 23 , and R 24 is optionally and independently substituted with one substituent independently selected from the group consisting of F, Cl, Br, I, —CN, —NO 2 , alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, —C(O)OH, —C(O)Oalkyl, —NH 2 , —NHI(alkyl), —N(alkyl) 2 , OH, —O(alkyl), —O(aryl), —O(heteroaryl), heterocyclyl, aryl, and heteroaryl;
wherein the compound having an N-acyl glutarimide binds to cereblon;
wherein the compound having an N-acyl glutarimide contains a Targeting Ligand for the Targeted Protein; and
wherein the Targeting Ligand is a small molecule means for binding a Targeted Protein that mediates a disease.

2. The method of claim 1 , wherein the Linker is:

3. The method of claim 1 , wherein the Linker is:

4. The method of claim 1 , wherein the Linker is:

wherein:
(i) -Heteroaryl- is

 or
(ii) -Heteroaryl- is

Assignees

• C4 Therapeutics Inc

Inventors

• Phillips Andrew J
• Nasveschuk Christopher G
• Henderson James A
• Liang Yanke
• Chen Chi-Li
• Duplessis Martin
• He Minsheng
• Lazarski Kiel

Classifications

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/45 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide · CPC title