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CN-121991025-A - Heterocyclic degradation determinants for target protein degradation

CN121991025ACN 121991025 ACN121991025 ACN 121991025ACN-121991025-A

Abstract

The present invention provides heterocyclic compounds ("down-resolution stators") that bind to E3 ubiquitin ligases (typically by cereblon) that can be used as such or linked to targeting ligands for selected target proteins for therapeutic purposes, methods and compositions thereof, and methods of making the same.

Inventors

  • A.J. PHILLIPS
  • C.G. Nasworth Schuk
  • J.A. HENDERSON
  • LIANG YANKE
  • M.E. Fitzgerald
  • HE MINSHENG
  • R.E. Michael

Assignees

  • C4医药公司

Dates

Publication Date
20260508
Application Date
20170510
Priority Date
20160510

Claims (18)

  1. 1. A compound of formula I or formula II: (I) (II) Or a pharmaceutically acceptable salt, N-oxide or isotopic derivative; Wherein: A is CR 8 R 9 、C═O、C═S、C═CH 2 、SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH, P (O) NH 2 ; A' is CR 1 R 2 、C═O、C═S、C═CH 2 、SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH, P (O) NH 2 ; A '' is CR 3 R 4 、C═O、C═S、C═CH 2 、SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH, P (O) NH 2 ; X is independently NH, NR 11 、CH 2 、CHR 12 、C(R 12 ) 2 , O, or S; Z is O, S, CH 2 、CH(C 1 -C 4 alkyl) and C (C 1 -C 4 alkyl) 2 ; n is 0, 1,2 or 3; Is a single bond or a double bond; R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 and R 13 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, amine, -NH (aliphatic), and-N alkyl 2 ; Or R 1 and R 2 form a 3-, 4-, 5-or 6-membered spirocarbocyclic ring, or a 4-, 5-or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O; Or R 3 and R 4 form a 3-, 4-, 5-or 6-membered spirocarbocyclic ring, or a 4-, 5-or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O; Or R 6 and R 7 form a 3-, 4-, 5-or 6-membered spirocarbocyclic ring, or a 4-, 5-or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O; Or R 8 and R 9 form a 3-, 4-, 5-or 6-membered spirocarbocyclic ring, or a 4-, 5-or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O; Or R 1 and R 3 form a 1,2, 3, or 4 carbon bridged ring; or R 1 and R 7 form a1, 2,3, or 4 carbon bridged ring; Or R 3 and R 7 form a1, 2,3, or 4 carbon bridged ring; or R 13 and R 1 form a3, 4, 5, or 6 carbon fused ring; Or R 13 and R 6 form a3, 4, 5, or 6 carbon fused ring; Or R 13 and R 4 form a1, 2,3, or 4 carbon bridged ring; Or R 13 and R 5 form a 3, 4, 5, or 6 carbon fused ring, wherein R 5 is on the alpha carbon of R 13 , or a1, 2, 3, or 4 carbon bridged ring, wherein R 5 is not on the alpha carbon of R 13 ; R 5 is in each case selected from the group consisting of alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, -NH (aliphatic), -N (aliphatic) 2 、-NHSO 2 (aliphatic), -N (alkyl) SO 2 (aliphatic), -NHSO 2( aryl or heteroaryl), -N (aliphatic) SO 2 aryl, -NHSO 2 alkenyl, -N (alkyl) SO 2 alkenyl, -NHSO 2 alkynyl, -N (alkyl) SO 2 alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle and haloalkyl; Or two R 5 substituents together with the carbon atom to which they are bound may form a3, 4,5 or 6 membered ring; r 10 is a linker-targeting ligand; Q 1 、Q 2 、Q 3 and Q 4 are independently selected from CH, CR 12 , N, and wherein in certain embodiments the number of nitrogen atoms in the ring is 0, 1,2, or 3, and when the Q is in a six-membered ring (unfused or fused) and at least one is nitrogen, the ring may be pyridine, diazine, triazine, pyrimidine, pyridazine, pyrazine, triazine, or tetrazine, R 11 is independently selected from alkyl, alkenyl, alkynyl, C (O) H, -C (O) OH, -C (O) alkyl, -C (O) O alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocycle; R 12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azide, amino, -C (O) H, -C (O) OH, -C (O) (aliphatic), -C (O) O (aliphatic), -NH (aliphatic), -N (aliphatic) SO 2 (aliphatic), -NHSO 2( aryl or heteroaryl, -N (aliphatic) 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, and haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocycle; a linker is a chemical group that links the degradation determinant to the targeting ligand; the targeting ligand is a moiety capable of binding or binding to a target protein, and wherein the target protein is selected from those in fig. 1A to 8 PPPPP; Wherein the compound satisfies at least one of a, b, c, d, e, f, g, h, i, j, k, l or m: n, R 1 and R 3 form a 1 or 2 carbon bridged ring; o, R 1 and R 13 form a3, 4, 5 or 6 carbon fused ring; p, R 4 and R 13 form a 1 or 2 carbon bridged ring; q.A is SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH or P (O) NH 2 ; R.A' is SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH or P (O) NH 2 , or S.A″ is SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH or P (O) NH 2 .
  2. 2. The compound of claim 1, selected from the group consisting of: , , , , A kind of electronic device 。
  3. 3. A compound of formula III: (III) Or a pharmaceutically acceptable salt, N-oxide or isotopic derivative, Wherein m is 1 or3 and the other variables are as described in claim 1.
  4. 4. A compound of formula IV or V: (IV) (V) Or a pharmaceutically acceptable salt, N-oxide or isotopic derivative; Wherein: wherein the variables are as described in claim 1 and at least one of claims a, b, c, d, e, f, g, h, i or j is: k. R 1 and R 2 form a 4, 5 or 6 membered spiroheterocycle or a3, 4, 5 or 6 membered spirocarbocycle; l, R 3 and R 4 form a 4, 5 or 6 membered spiroheterocycle or a3, 4, 5 or 6 membered spirocarbocycle; m, R 6 and R 7 form a 4, 5 or 6 membered spiroheterocycle or a3, 4, 5 or 6 membered spirocarbocycle; n, R 8 and R 9 form a 4, 5 or 6 membered spiroheterocycle or a3, 4, 5 or 6 membered spirocarbocycle; o, R 1 and R 3 form a1 or 2 carbon bridged ring; p, R 1 and R 13 form a3, 4, 5 or 6 membered fused ring; q, R 4 and R 13 form a1 or 2 carbon bridged ring; r.A is P (O) Oalkyl, P (O) NHalkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH or P (O) NH 2 ; s.A' is SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH or P (O) NH 2 , or T.A '' is SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH or P (O) NH 2 .
  5. 5. A compound of formula III selected from: , , , , , , A kind of electronic device 。
  6. 6. A compound of formula VI: (VI) Or a pharmaceutically acceptable salt, N-oxide or isotopic derivative; Wherein the variables are as described in claim 1 and in certain embodiments, at least one of claims a, b, c, d, e, f, g, h, i, j, k, l or m is: n, m is 3 and n is not 0; o, R 1 and R 2 form a spiro ring; p, R 3 and R 4 form a spiro ring; q, R 6 and R 7 form a spiro ring; R, R 8 and R 9 form a spiro ring; s, R 1 and R 3 form a 1 or 2 carbon bridged ring; t, R 1 and R 13 form a3, 4, 5 or 6 carbon fused ring; u, R 4 and R 13 form a 1 or 2 carbon bridged ring; v, R 13 and R 5 form a3, 4, 5 or 6 carbon fused ring; w, R 13 and R 5 form a 1 or 2 carbon bridged ring; x, A is SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH, or P (O) NH 2 ; y. A' is SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH or P (O) NH 2 , or Z. A '' is SO 2 , S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl) 2 , P (O) alkyl, P (O) OH or P (O) NH 2 .
  7. 7. The compound of claims 1-6, wherein the linker has a chain of 2 to 20 carbon atoms, wherein one or more carbons may be replaced by a heteroatom such as O, N, S or P or 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.
  8. 8. The compound of claims 1-6, wherein the linker is a moiety selected from the group consisting of formula LI, formula LII, formula LIII, formula LIV, formula LV, formula LVI, and formula LVII: Wherein: 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) O alkyl, -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 2 ) alkyl-, -C (-NR 25 2 ) alkyl-, -C (R 4 R 4 ) - -, -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 acid-co-glycolic acid), alkene, haloalkyl, alkoxy, alkyne, heteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocycle, or-O- (CH 2 ) 1-12 -O-、-NH-(CH 2 ) 1-12 -NH-、-NH-(CH 2 ) 1-12 -O-, or -O-(CH 2 ) 1-12 -NH-、-S-(CH 2 ) 1-12 -O-、-O-(CH 2 ) 1-12 -S-、-S-(CH 2 ) 1-12 -S-、-S-(CH 2 ) 1-12 -NH- or-NH- (CH 2 ) 1-12 -S-; r 25 is selected in each case from alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) O alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocycle; R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic, and R 27 and R 28 are independently selected from hydrogen, alkyl, amine, or form, together with the carbon atom to which they are attached, a C (O), C (S), c=ch 2 、C 3 -C 6 spirocarbocyclic ring, or a 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O, or form a 1 or 2 carbon bridged ring.
  9. 9. The compound of claims 1-6, wherein the linker is a moiety selected from the group consisting of formulas LVIII, LIX, and LX: wherein the variables are as defined in claim 8.
  10. 10. The compound of claims 1-6, wherein the linker is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , A kind of electronic device Wherein the variables are as defined in claim 8.
  11. 11. The compound of claims 1-6, wherein the linker is , , , . , , A kind of electronic device Wherein the variables are as defined in claim 8.
  12. 12. The compound of claims 1-6, wherein the linker is selected from the group consisting of: -NR 61 (CH 2 ) n1 - (lower alkyl) -, -NR 61 (CH 2 ) n1 - (lower alkoxy) -, -NR 61 (CH 2 ) n1 - (lower alkoxy) -OCH 2 -,-NR 61 (CH 2 ) n1 - (lower alkoxy) - (lower alkyl) -OCH 2 -,-NR 61 (CH 2 ) n1 - (cycloalkyl) - (lower alkyl) -OCH 2 -,-NR 61 (CH 2 ) n1 - (heterocycloalkyl) -, -NR 61 (CH 2 CH 2 O) n1 - (lower alkyl) -O-CH 2 -,-NR 61 (CH 2 CH 2 O) n1 - (heterocycloalkyl) -O-CH 2 -,-NR 61 (CH 2 CH 2 O) n1 -aryl-O-CH 2 -,-NR 61 (CH 2 CH 2 O) n1 - (heteroaryl) -O-CH 2 -,-NR 61 (CH 2 CH 2 O) n1 - (cycloalkyl) -O- (heteroaryl) -O-CH 2 -,-NR 61 (CH 2 CH 2 O) n1 - (cycloalkyl) -O-aryl-O-CH 2 -,-NR 61 (CH 2 CH 2 O) n1 - (lower alkyl) -NH-aryl-O-CH 2 -,-NR 61 (CH 2 CH 2 O) n1 - (lower alkyl) -O-aryl-CH 2 ,-NR 61 (CH 2 CH 2 O) n1 -cycloalkyl-O-aryl-, -NR 61 (CH 2 CH 2 O) n1 -cycloalkyl-O-heteroaryl-, -NR 61 (CH 2 CH 2 ) n1 - (cycloalkyl) -O- (heterocycle) -CH 2 ,-NR 61 (CH 2 CH 2 ) n1 - (heterocycle) -CH 2 and-NR 61 - (heterocycle) -CH 2 ; wherein n1 is 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and R 61 is H, methyl or ethyl.
  13. 13. The compound of claims 1-6, wherein the linker is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , A kind of electronic device ; R 71 is-O-, -NH, -NMe, -N alkyl, N (aliphatic), -N (heteroaliphatic); Representative of And And (3) M1, n2, o1, p1, q2 and r1 are independently 1, 2, 3, 4 or 5.
  14. 14. A method for treating a patient suffering from a medical condition treatable by degradation of a target protein bound to a targeting ligand comprising administering an effective amount of a compound of claims 1-13, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  15. 15. A method for treating a patient suffering from a medical condition treatable by binding to the protein cereblon in vivo, comprising administering an effective amount of a compound of claims 1-13, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
  16. 16. The method of claim 14 or 15, wherein the disorder is selected from abnormal cell proliferation, a tumor, a cancer, an immune disorder, an autoimmune disorder, arthritis, lupus, diabetes, a cardiovascular disease, an infectious disease, or an inflammatory disorder.
  17. 17. The method of claim 14 or 15, wherein the infectious disease is selected from HIV, HBV, HCV, HSV, HPV, RSV, CMV, ebola virus, flavivirus, pestivirus, rotavirus, influenza, coronavirus, EBV, viral pneumonia, drug-resistant virus, avian influenza, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus or hepadnavirus, gram negative bacteria, gram positive bacteria, atypical bacteria, staphylococci, streptococci, escherichia coli, salmonella, helicobacter pylori, meningitis, gonorrhea, chlamydiaceae, mycoplasma, fungi, protozoa, enteromorpha, worms, prions or parasites.
  18. 18. The method of claim 14 or 15, wherein the disorder is a cancer selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder carcinoma, bowel cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, leukemia, lymphoma, burkitt's lymphoma, non-hodgkin's lymphoma, melanoma, myeloproliferative disorder, sarcoma, angiosarcoma, kaposi's sarcoma, liposarcoma, myosarcoma, peripheral nerve epithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, meningioma, neurofibroma, and schwannoma, breast cancer, uterine cancer, lymphoma, thyroid cancer, astrocytoma, carcinoma, sarcoma, hodgkin's disease, testicular tumor, and teratoma.

Description

Heterocyclic degradation determinants for target protein degradation The application is a divisional application of Chinese patent application with the application date of 2017, 5, 10, the application number of 201780042416.1 and the application name of heterocyclic degradation determinant for target protein degradation. Cross Reference to Related Applications The present application claims the benefit of priority from U.S. application Ser. No. 62/334,395, filed 5/10/2016, which is incorporated herein by reference for all purposes. Technical Field The present invention provides heterocyclic compounds ("down-resolution stators") that bind to E3 ubiquitin ligases (typically by cereblon) that can be used as such or linked to targeting ligands for selected target proteins for therapeutic purposes, methods and compositions thereof, and methods of making the same. Background Protein degradation is a highly regulated process necessary to maintain cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved by the ubiquitin-proteasome pathway (UPP). UPP is essentially central to the regulation of almost all cellular processes including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, nerve and muscle degeneration, morphogenesis of neural networks, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular modulators, ribosomal biogenesis, and viral infection. A number of ubiquitin molecules label proteins for proteasome degradation by covalent attachment of the E3 ubiquitin ligase to terminal lysine residues, wherein the protein is digested into small peptides and eventually into its constituent amino acids, which serve as building blocks for new proteins. Defective proteasome degradation is associated with a variety of clinical conditions including alzheimer's disease, parkinson's disease, huntington's disease, muscular dystrophy, cardiovascular disease, cancer, and the like. There are over 600E 3 ubiquitin ligases that promote ubiquitination of different proteins in vivo, which can be divided into four families, HECT domain E3, U-box E3, monomeric RING E3 and multi-subunit E3. See generally Li et al (PLOS One, 2008,3, 1487), titled "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.";Berndsen et al (Nat. Structure, mol. Biol., 2014,21, 301-307), titled "NEW INSIGHTS intoubiquitin E3 LIGASE MECHANISM", titled Deshaies et al (Ann. Rev. Biochem., 2009,78, 399-434), titled "RING domain E3 ubiquitin liquids"; spratt et al (biochem. 2014,458, 421-437), titled "RBR E3 ubiquitin ligases: new structures, NEW INSIGHTS, new structures"; and Wang et al (Nat. Rev. Cancer., 2014,14, 233-347), titled "Roles of F-box proteins in cancer". In 1995 Gosink et al (Proc. Natl. Acad. Sci. USA1995,92, 9117-9121) provided in a publication titled "REDIRECTING THE SPECIFICITY of Ubiquitination by Modifying Ubiquitin-Conjugating Enzymes" in vitro proof of concept that an engineered peptide could selectively direct ubiquitination of intracellular proteins. Nawaz et al (Proc. Natl. Acad. Sci. U.S. A.1999,96, 1858-1862) entitled "Proteasome-DEPENDENT DEGRADATION OF THE HUMAN ESTROGEN RECEPTOR" describe ER degradation using the ubiquitin-proteasome pathway. Proteinex, inc 2 in 1999 filed a published patent application as us patent 6,306,663, which claims a method of producing a compound for activating ubiquitination of a target protein comprising covalently linking a target protein binding element capable of specifically binding to the target protein via a ubiquitination recognition element. Proteinex describes that the invention can be used to control protein levels in eukaryotes. While the' 663 patent may be based on the first patent application to describe a high-level concept of how to manipulate a UPP system to degrade a selected protein in the body, the patent does not provide sufficient detail to allow a skilled artisan to easily construct a range of proposed compounds. For example, for ubiquitinated recognition elements, the skilled person is especially informed of drug discovery using standard methods and screens for suitable small molecules that will bind to the binding enzyme. Proteinex also underscores the use of peptides as ubiquitinated recognition elements, which can create significant difficulties for oral drug administration. Since then, therapeutic intervention using the ubiquitin-proteasome pathway has attracted great interest in the scientific community. Zhou et al (mol. Cell2000,6, 751-756) from the Harvard medical institute describe an engineered receptor capable of directing ubiquitination in mammalian and yeast cells in a publication titled "HARNESSING THE Ubiquitination Machinery to TARGET THE Degra