HETEROCYCLIC DEGRONIMERS FOR TARGET PROTEIN DEGRADATION
This invention provides heterocyclic compounds that bind to E3 Ubiquitin Ligase (typically through cereblon) (“Degrons”), which can be used as is or linked to a Targeting Ligand for a selected Target Protein for therapeutic purposes 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:
A is C═O or CR 8 R 9 ;
R 10 is Linker-Targeting Ligand;
Q 1 , Q 2 , Q 3 , and Q 4 are independently selected from the group consisting of CH, CR 12 , and N;
R 8 and R 9 are hydrogen;
R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(alkyl), —C(O)O(alkyl), —NH(alkyl), —N(alkyl) 2 , —NHSO 2 (alkyl), —N(alkyl)SO 2 (alkyl), —NHSO 2 (aryl or hetereoaryl), —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, cyano, nitro, nitroso, —SH, —S-alkyl, haloalkyl, aryl, heteroaryl, and heterocycle;
Linker is
X 1 and X 2 are independently selected from the group consisting of 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 the group consisting of bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —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 2 )alkyl-, —C(—NR 25 2 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —CR 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 )—, alkenyl, haloalkyl, alkoxy, alkynyl, aryl, heterocycle, heteroaryl, lactic acid, and glycolic acid;
R 25 is selected at each instance from the group consisting of alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;
R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocycle;
R 27 and R 28 are independently selected from the group consisting of 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 the group consisting of N and O, or form a 1 or 2 carbon bridged ring;
Targeting Ligand is a small molecule means for binding a Targeted Protein that mediates a disease; and
Targeted Protein is selected from the group consisting of 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, and YES.
2 . The compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , wherein the Linker is a moiety selected from the group consisting of Formula LVIII, LIX, and LX:
7 . The compound of claim 1 , wherein the Linker is selected from the group consisting of
8 . The compound of claim 1 , wherein the Linker is selected from the group consisting of
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 Linker is selected from the group consisting of
15 . The compound of claim 1 , wherein the Targeted Protein is selected from the group consisting of 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, CSFIR, cyclin dependent kinase, DDR1, dihydrofolate reductase, DOT1L, EED, EHMT1, EHMT2, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, estrogen receptor, and EZH2.
16 . The compound of claim 1 , wherein the Targeted Protein is selected from the group consisting of 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, and KSR1.
17 . The compound of claim 1 , wherein the Targeted Protein is selected from the group consisting of 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, and ROS1 receptor.
18 . The compound of claim 1 , wherein the Targeted Protein is selected from the group consisting of saposin-B, Sec7, SEGA receptor, SETD2, SETD7, SETD8, SETDB1, SF6D, SH2 domain, SMYD2, SMYD3, SUV4-20H1, TAF1, TAFIL, TANK1, TEC, tie 2 receptor, TNIK, mTORC1, mTORC2, TRKB, TRIM24, U09-CX-5279, VEGF receptor, and YES.
19 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20 . A method for treating a patient with a medical disorder that can be treated by degrading a Targeted Protein that binds to a Targeting Ligand, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
21 . The method of claim 20 , wherein the disorder is selected from abnormal cellular proliferation, a tumor, a cancer, an immune disorder, an autoimmune disorder, arthritis, lupus, diabetes, cardiovascular disease, an infectious disease, or an inflammatory condition.
22 . The method of claim 21 , wherein the disorder is a tumor.
23 . The method of claim 21 , wherein the disorder is a cancer.
24 . The method of claim 23 , wherein the cancer is selected from the group consisting of squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, cancer of the bladder, bowel, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreatic, prostate, stomach, leukemia, lymphoma, Burkitt's lymphoma, Non-Hodgkin's lymphoma; melanoma; myeloproliferative disease; sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; breast cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma.