C3-carbon linked glutarimide degronimers for target protein degradation
This invention provides Degronimers that have carbon-linked E3 Ubiquitin Ligase targeting moieties (Degrons), which can be linked to a targeting ligand for a protein that has been selected for in vivo degradation, and methods of use and compositions thereof as well as methods for their preparation.
1. A compound of Formula:
or a pharmaceutically acceptable salt thereof;
wherein:
W 1 is C═O;
W 2 is C═O;
X is NH;
n is 0, 1, 2, or 3;
is a single or double bond;
R 6 is selected from:
Y is independently selected from N, CH, and CR 11 , wherein 0, 1, or 2 instances of Y are selected to be N;
Z is NH, O, S, or NR 12 ;
R 7 , R 8 , and R 15 are independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, carbocyclic, aryl, heteroaryl, hydroxyl, halo, azide, CN—, alkoxy, amine, —NHalkyl, —Nalkyl 2 , —NH(aliphatic), and —N(aliphatic) 2 ;
or R 7 and R 8 together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered spiro-carbocycle, or a 4-, 5-, or 6-membered spiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;
or R 15 and R 7 form a 3, 4, 5, or 6 carbon fused ring;
or R 15 and R 5 form a 3, 4, 5, or 6 carbon fused ring wherein R 5 is on the carbon alpha to R 15 or a 1, 2, 3, or 4 carbon bridged ring wherein R 5 is not on the carbon alpha to R 15 ;
R 5 is selected at each instance from: alkyl, alkene, alkyne, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, halogen, hydroxyl, alkoxy, azide, amino, —NH(aliphatic), —N(aliphatic) 2 , —NHSO 2 (aliphatic), —N(aliphatic)SO 2 (aliphatic), —NHSO 2 aryl, —N(aliphatic)SO 2 aryl, —NHSO 2 alkenyl, —N(aliphatic)SO 2 alkenyl, —NHSO 2 alkynyl, —N(aliphatic)SO 2 alkynyl, and halo(aliphatic);
or two R 5 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring;
R 10 is a linker-targeting ligand;
linker is selected from:
wherein:
X 1 and X 2 are independently selected from bond, NH, NR 25 , CH 2 , CHR 25 , C(R 25 ) 2 , O, and S;
R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from heteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocycle, bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R 26 )—, —CH(—NHR 25 )—, —CH(—NH 2 )—, —CH(—NR 25 2 )—, —C(—O—R 26 )alkyl-, —C(—NHR 25 )alkyl-, —C(—NH)alkyl-, —C(—NR 25 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —C(R 27 R 28 )—, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 25 )—, polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, and alkyne;
R 25 is selected at each instance from alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl;
R 26 is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, or heteroaliphatic;
R 27 and R 28 are independently selected from hydrogen, alkyl, and amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a C 3 -C 6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
R 11 is selected at each instance from: hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, hydroxyl, heterocyclic, heteroalkyl, carbocyclic, alkoxy, aryl, heteroaryl, alkylamino, alkylhydroxyl, —NHalkyl, —Nalkyl 2 , —NH(aliphatic), —N(aliphatic) 2 , amino, cyano, nitro, thioalkyl, thiol and haloalkyl;
R 12 is selected at each instance from: hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, heteroaryl, aryl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), —C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne;
R 13 and R 14 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy, amino, —NHalkyl, and —N(alkyl) 2 ;
or R 13 and R 14 together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
targeting ligand binds to a targeted protein selected from the group consisting of AKT1, ALK, AXL, ABL, ABL1, ABL2, AKT2, AP1, AP2, ASH1L, ATAD2, aurora kinase, androgen receptor, ATF2, BMX, BCR-ABL, bromodomain containing protein, Bcl-2, Bcl-XL, BCL6, BAZ2A, BAZ2B, BRD4, BRD9, BRPF1, BMX, CSF1R, CECR2, CBP, CREBBP, CNNTB1, cathepsin, cyclin dependent kinase, DDR1, DOT1L, dihydrofolate reductase, ERBB2, ERBB3, ERBB4, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, EZH2, EED, EHMT1, EHMT2, ERK1, ERK2, estrogen receptor, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, FES, FYN, FKBP, fatty acid binding protein, factor Xa, FLAP, GSG2, HIV integrase, HIV reverse transcriptase, HIV protease, HCV protease, HDAC6, HDAC7, HDM2, HBV, HCK, histone deacetylase, histone acetyltransferase, heat shock protein, HDAC, Her3, IGF1R, INSR, IDO1, IDH1, ITK, KDM4, KDM5, KDM6, KMT5A, KIT, KSR1, kringle domain V, 4BVV, kallikrein 7, KSR receptor, LRRK2, lactoylglutathione lyase, LSD1, L3MBTL3, lysine-specific histone demethylase, lysine methyltransferase, LCK, LYN, mPGES-1, MERTK, MEK1, MDM2, MDM4, MEN1, MTH1, MCL-1, MER, MET, mast/stem cell growth factor receptor, MST1R, NTRK, NTRK1, NTRK2, NTRK3, PDZ, phospholipase A2 domain, PB1, PCAF, PHIP, protein S100-A7, PAK1, PAK4, PPAR-gamma, PDGFR receptor, PNET, PI3Ka receptor, PIK3CA, ROS1 receptor, RCC receptor, RAML receptor, RET, SETD2, SETD7, SETD8, SETDB1, SMYD2, SMYD3, SUV4-20H1, saposin-B, Sec7, SH2 domain, Src-AS1, Src AS2, SEGA receptor, TNIK, TRIM24, TAF1, TAF1L, mTORC1, mTORC2, TANK1, TRKB, tie 2 receptor, TEC, SF6D, U09-CX-5279, VEGF receptor, WDR5, and YES.
2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
3. The compound of claim 1 , wherein n is 0.
4. The compound of claim 1 , wherein R 7 and R 8 are hydrogen.
5. The compound of claim 1 , wherein the targeted protein is the estrogen receptor or androgen receptor.
6. The compound of claim 1 , wherein the compound is selected from:
7. The compound of claim 1 , wherein linker is selected from:
8. The compound of claim 7 , wherein the compound is selected from:
9. The compound of claim 1 , wherein the linker is selected from the group consisting of:
10. The compound of claim 1 , wherein the linker is selected from the group consisting of:
11. The compound of claim 1 , wherein the linker is selected from the group consisting of:
12. The compound of claim 1 , wherein the linker is selected from the group consisting of:
13. The compound of claim 1 , wherein the linker is selected from the group consisting of:
14. The compound of claim 1 , wherein the R 6 is selected from the group consisting of:
15. The compound of claim 1 , wherein the R 6 is selected from the group consisting of:
16. The compound of claim 1 , wherein the R 6 is selected from the group consisting of:
17. The compound of claim 1 , wherein the targeted protein contains a bromodomain.