# US 11,992,531 B2 · C3-carbon linked glutarimide degronimers for target protein degradation

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- Number: US 11,992,531 B2
- Document ID: US11992531B2
- Status: Granted
- Kind: B2
- Application number: 17/107,781
- Filed: 2020-11-30
- Published: 2022-10-06
- Granted: 2024-05-28
- Earliest claimed: 2016-05-10
- Assignees: C4 Therapeutics, Inc.
- Applicants: C4 Therapeutics, Inc.
- Inventors: Andrew J. Phillips; Christopher G. Nasveschuk; James A. Henderson; Yanke Liang; Minsheng He; Kiel Lazarski; Gesine Kerstin Veits; Harit U. Vora
- Web page: https://patentgrep.com/patent/US11992531B2

## CPC

- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 31/45: having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- C07D 211/86: Oxygen atoms
- C07D 211/88: attached in positions 2 and 6, e.g. glutarimide
- C07D 211/90: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 221/22: Bridged ring systems
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- C07D 487/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 495/14: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07K 14/47: from mammals
- C07K 14/72: for hormones {(for neuromediators C07K14/70571)}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

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.

## Claims

### Claim 1

A compound of Formula:
or a pharmaceutically acceptable salt thereof;
wherein:
W1 is C═O;
W2 is C═O;
X is NH;
n is 0, 1, 2, or 3;
is a single or double bond;
R6 is selected from:
Y is independently selected from N, CH, and CR11, wherein 0, 1, or 2 instances of Y are selected to be N;
R7, R8, and R15 are independently selected from hydrogen, alkyl, heterocyclic, carbocyclic, aryl, heteroaryl, hydroxyl, halo, azide, CN—, alkoxy, amine, —NHalkyl, and Nalkyl2;
or R7 and R8 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 R15 and R7 form a 3, 4, 5, or 6 carbon fused ring;
or R15 and R5 form a 3, 4, 5, or 6 carbon fused ring wherein R5 is on the carbon alpha to R15 or a 1, 2, 3, or 4 carbon bridged ring wherein R5 is not on the carbon alpha to R15;
R5 is selected at each instance from: alkyl, alkene, alkyne, heterocyclic, aryl, heteroaryl, halogen, hydroxyl, alkoxy, azide, amino, —NH(alkyl), —N(alkyl)2, —NHSO2(alkyl), —N(alkyl)SO2(alkyl), —NHSO2aryl, —N(alkyl)SO2aryl, —NHSO2alkenyl, —N(alkyl)SO2alkenyl, —NHSO2alkynyl, —N(alkyl)SO2alkynyl, and halo(alkyl);
or two R5 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring;
R10 is a linker-targeting ligand;
linker is selected from:
wherein:
X1 and X2 are independently selected from the group consisting of bond, NH, NR25, CH2, CHR25, C(R25)2, O, and S;
R20, R21, R22, R23, and R24 are independently selected from the group consisting of heteroarylalkyl, aryl, arylalkyl, heterocycle, heteroaryl, carbocycle, bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —SO2—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R26)—, —CH(—NHR25)—, —CH(—NH2)—, —CH(—NR252)—, —C(—O—R26)alkyl-, -alkyl(R27)-alkyl(R28)—, —C(R27R28)—, —NHC(O)NH—, —N(R25)C(O)N(R25)—, —N(H)C(O)N(R25)—, polyethylene glycol, alkene, haloalkyl, alkoxy, and alkyne, each of which is optionally substituted with one or more substituents independently selected from R101;
R25 is selected at each instance from the group consisting of alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl;
R26 is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, or heterocyclic;
R27 and R28 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═CH2, a C3-C6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
R101 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, and N(alkyl)2;
R11 is selected at each instance from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, hydroxyl, heterocyclic, heteroalkyl, carbocyclic, alkoxy, aryl, heteroaryl, alkylamino, alkylhydroxyl, —NHalkyl, —Nalkyl2, amino, cyano, nitro, thioalkyl, thiol, and haloalkyl;
targeting ligand is a means for binding the targeted protein that mediates a disorder;
wherein the targeted protein selected from the group consisting of AKT1, AXL, ABL, ABL1, ABL2, AKT2, AP1, AP2, ASH1L, ATAD2, androgen receptor, ATF2, BMX, BCR-ABL, Bcl-2, Bel-XL, BAZ2A, BAZ2B, BRPF1, BMX, CSF1R, CECR2, cathepsin, cyclin dependent kinase, DDR1, DOT1L, dihydrofolate reductase, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, EZH2, EED, EHMT1, EHMT2, estrogen receptor, FLT3, FES, FYN, FKBP, fatty acid binding protein, factor Xa, FLAP, GSG2, HIV integrase, HIV reverse transcriptase, HIV protease, HCV protease, HDM2, HBV, HCK, histone deacetylase, histone acetyltransferase, heat shock protein, IGF1R, INSR, IDO1, IDH1, ITK, KIT, KSR1, kringle domain V, 4BVV, kallikrein 7, KSR receptor, lactoylglutathione lyase, 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, PHIP, protein S100-A7, PAK1, PAK4, PPAR-gamma, PDGFR receptor, PNET, ROS1 receptor, RCC receptor, RAML receptor, SETD2, SETD7, SETD8, SETDB1, SMYD2, SMYD3, SUV4-20H1, saposin-B, Sec7, SH2 domain, SEGA receptor, TNIK, TRIM24, TAF1, TAF1L, mTORC1, mTORC2, TANK1, TRKB, tie 2 receptor, TEC, SF6D, U09-CX-5279, VEGF receptor, and YES.

### Claim 2 (depends on 1)

The compound of claim 1, wherein n is O.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R7 and R8 are hydrogen.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R15 is hydrogen.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R6 is

### Claim 10 (depends on 1)

The compound of claim 1, wherein R11 is F, Cl, Br, alkyl, or haloalkyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein linker is selected from:

### Claim 12 (depends on 1)

The compound of claim 1, wherein the linker is selected from the group consisting of:

### Claim 13 (depends on 1)

The compound of claim 1, wherein the linker is selected from the group consisting of:

### Claim 14 (depends on 1)

The compound of claim 1, wherein X1 is bond.

### Claim 15 (depends on 1)

The compound of claim 1, wherein X2 is bond.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R21 is bond.

### Claim 17 (depends on 16)

The compound of claim 16, wherein R22 is bond.

### Claim 18 (depends on 17)

The compound of claim 17, wherein R23 is bond.

### Claim 19 (depends on 1)

The compound of claim 1, wherein one of R20, R21, R22, R23, and R24 is aryl, heterocycle, or heteroaryl each of which is optionally substituted with one or more substituents independently selected from R101.

### Claim 20 (depends on 1)

The compound of claim 1, wherein two of R20, R21, R22, R23, and R24 are independently selected from aryl, heterocycle, and heteroaryl each of which is optionally substituted with one or more substituents independently selected from R101.

### Claim 21 (depends on 1)

The compound of claim 1, wherein three of R20, R21, R22, R23, and R24 are independently selected from aryl, heterocycle, and heteroaryl each of which is optionally substituted with one or more substituents independently selected from R101.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the targeted protein is the estrogen receptor or androgen receptor.

### Claim 23 (depends on 1)

The compound of claim 1, wherein the targeted protein is selected from AKT1, AXL, ABL, ABL1, ABL2, AKT2, AP1, AP2, ASH1L, ATAD2, ATF2, BMX, BCR-ABL, Bcl-2, Bcl-XL, BAZ2A, and BAZ2B.

### Claim 24 (depends on 1)

The compound of claim 1, wherein the targeted protein is selected from BRPF1, BMX, CSF1R, CECR2, cathepsin, cyclin dependent kinase, DDR1, DOT1L, dihydrofolate reductase, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, EZH2, EED, EHMT1, and EHMT2.

### Claim 25 (depends on 1)

The compound of claim 1 wherein the targeted protein is selected from FLT3, FES, FYN, FKBP, fatty acid binding protein, factor Xa, FLAP, GSG2, HIV integrase, HIV reverse transcriptase, HIV protease, HCV protease, HDM2, HBV, HCK, histone deacetylase, histone acetyltransferase, heat shock protein, IGF1R, INSR, IDO1, IDH1, and ITK.

### Claim 26 (depends on 1)

The compound of claim 1 wherein the targeted protein is selected from KIT, KSR1, kringle domain V, 4BVV, kallikrein 7, KSR receptor, lactoylglutathione lyase, 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, and NTRK3.

### Claim 27 (depends on 1)

The compound of claim 1 wherein the targeted protein is selected from PDZ, phospholipase A2 domain, PB1, PHIP, protein S100-A7, PAK1, PAK4, PPAR-gamma, PDGFR receptor, PNET, ROS1 receptor, RCC receptor, RAML receptor, SETD2, SETD7, SETD8, SETDB1, SMYD2, SMYD3, SUV4-20H1, saposin-B, Sec7, SH2 domain, and SEGA receptor.

### Claim 28 (depends on 1)

The compound of claim 1 wherein the targeted protein is selected from TNIK, TRIM24, TAF1, TAF1L, mTORC1, mTORC2, TANK1, TRKB, tie 2 receptor, TEC, SF6D, U09-CX-5279, VEGF receptor, and YES.

### Claim 29 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 1)

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

### Claim 31 (depends on 1)

A method for treating a patient with a disorder mediated by the targeted protein comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, wherein the disorder mediated by the targeted protein is a tumor or cancer.