Granted Patent B2

US 12,454,521 · App. 17/351,935 · Granted Oct 28, 2025

Inventors: Andrew J. Phillips (Arlington, MA); Christopher G. Nasveschuk (Stoneham, MA); James A. Henderson (Watertown, MA); Katrina L. Jackson (Weston, MA); Minsheng He (Andover, MA); Yanke Liang (Belmont, MA); Mark E. Fitzgerald (Newton, MA); Victoria Garza (Chelsea, MA)

C07D401/14C07D239/22C07D401/04C07D401/10

Abstract

Claims (58)

1. A compound of Formula

or a pharmaceutically acceptable salt thereof;

wherein:

m is 1, 2, 3, or 4;

n is 1, 2, 3, 4, 5, or 6;

R 1 and R 2 are hydrogen;

= is a single bond;

R 3 is independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycle, aryl, heteroaryl, —OR 4 , —N(R 4 )(R 4 ′), —SR 4 , —C(O)R 6 , —S(O)R 6 , —S(O) 2 R 6 , F, Cl, cyano, azido, nitro, and R 5 ;

wherein at least one of R 3 is selected from R 5 ;

R 4 and R 4 ′ are independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycle, aryl, heteroaryl, —C(O)R 6 , —C(S)R 6 , —C(═NH)R 6 , —S(O) R 6 , and —S(O) 2 R 6 ;

R 5 is-Linker-Targeting Ligand;

R 6 is independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycle, aryl, heteroaryl, hydroxyl, C 1 -C 6 alkoxy, thio, C 1 -C 6 thioalkyl, —NH 2 , —NH(C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycle, aryl, or heteroaryl), and -N(independently C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycle, aryl, or heteroaryl) 2 ;

XA is CH or N, wherein if XA is N then

and if XA is CH then

wherein if X A is substituted with R 3 , then XA is CR 3 ;

X B is selected from NH and CH 2 ;

wherein if X B is substituted with R 3 , then X B is NR 3 or CHR 3 ;

Linker is

X 1 and X 2 are independently selected from bond, NR 4 , CH 2 , CHR 4 , C(R 4 ) 2 , O, and S;

R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from 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(—NR 4 R 4 ′)—, —C(—O—R 26 )alkyl-, —C(—NR 4 R 4 ′)alkyl-, —C(R 40 R 40 )—, -alkyl(R 27 )-alkyl (R 28 )—, —C(R 27 R 28 )—, —NR 4 C(O)NR 4 —, alkene, haloalkyl, alkoxy, aryl, arylalkyl, heterocycle, heteroaryl, carbocycle;

each of which R 20 , R 21 , R 22 , R 23 , and R 24 is optionally substituted with one or more, two, or three substituents selected from R 101 ,

R 101 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO 2 , F, Cl, CF 3 , NH 2 , NHalkyl, and N(alkyl) 2 , aliphatic, and heteroaliphatic;

R 26 is selected from hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocyclic;

R 27 and R 28 are independently selected from hydrogen, alkyl, 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, or form a 1 or 2 carbon bridged ring;

R 40 is selected at each instance from: hydrogen, alkyl, alkene, alkyne, F, Cl, hydroxyl, alkoxy, azide, amino, cyano, —NH(alkyl), —N(alkyl) 2 , —NHSO 2 (alkyl), —N(alkyl)SO 2 alkyl, —NHSO 2 (aryl, heteroaryl or heterocyclic), —N(alkyl)SO 2 (aryl, heteroaryl or heterocyclic)-NHSO 2 alkenyl, —N(alkyl) SOzalkenyl,-NHSOzalkynyl,-N(alkyl) SOzalkynyl, haloalkyl, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic; and

Targeting Ligand is a means for binding a Target Protein that mediates a disorder, wherein the Target Protein is selected from the group consisting of AKT1, ABL1, ABL2, AKT2, AP1, AP2, ASH1L, ATAD2, androgen receptor, ATF2, BMX, BCR-ABL, Bcl-2, Bcl-XL, BRPF1, CSF1R, CECR2, DDR1, DOT1L, EPHA2, EPHA3, EPHA4, EPHA7, EPHB4, EZH2, EED, EHMT1, EHMT2, estrogen receptor, FLT3, FES, FYN, FKBP, factor Xa, FLAP, GSG2, HDM2, IGF1R, INSR, IDO1, IDH1, KDM4, KDM5, KDM6, KIT, KSR1, LSD1, L3MBTL3, LCK, LYN, mPGES-1, MERTK, MEK1, MDM2, MDM4, MEN1, MTH1, MCL-1, MER, MET, MST1R, NTRK, NTRK1, NTRK2, NTRK3, PHIP, protein S100-A7, PAK1, PAK4, PPAR-gamma, PDGFR receptor, ROS1 receptor, SETD2, SETD7, SETD8, SETDB1, SMYD2, SMYD3, SUV4-20H1, Sec7, TNIK, TRIM24, TAF1, TAF1L, mTORC1, mTORC2, TANK1, TRKB, tie 2 receptor, VEGF receptor, and YES.

2. The compound of claim 1 , wherein the Target Protein is ABL1 or ABL2.

3. The compound of claim 1 , wherein the Target Protein is the androgen receptor.

4. The compound of claim 1 , wherein the Target Protein is the estrogen receptor.

5. The compound of claim 1 , wherein the Target Protein is NTRK1, NTRK2, or NTRK3.

6. The compound of claim 1 , wherein the Target Protein is AKT1 or AKT2.

7. The compound of claim 1 , wherein the Target Protein is Bcl-XL.

8. The compound of claim 1 , wherein the Target Protein is DDR1.

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

is selected from the group consisting of:

13. The compound of claim 1 , wherein

is selected from the group consisting of:

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

or a pharmaceutically acceptable salt thereof.

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

16. The pharmaceutical composition of claim 15 , wherein the composition is suitable for delivery to a human.

17. A method for treating a patient with a disorder mediated by the Target Protein comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier to degrade the Target Protein.

18. The method of claim 17 , wherein the disorder is abnormal cellular proliferation.

19. The method of claim 18 , wherein the abnormal cellular proliferation is a cancer.

20. The method of claim 19 , wherein the cancer is selected from the group consisting of multiple myeloma, squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, bowel cancer, cervix cancer, colon cancer, esophagus cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck, cancer ovary cancer, pancreatic cancer, prostate cancer, stomach cancer, 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.

21. The compound of claim 1 , wherein

is selected from the group consisting of:

22. The compound of claim 1 , wherein

is selected from the group consisting of

23. The compound of claim 9 , wherein the Linker is selected from the group consisting of

and wherein R 21 and R 24 are both bond.

24. The compound of claim 10 , wherein the Linker is selected from the group consisting of

and wherein R 21 and R 24 are both bond.

25. The compound of claim 11 , wherein the Linker is selected from the group consisting of

and wherein R 21 and R 24 are both bond.

Assignments (1)

Continuity (3)

References Cited (237)