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CN-121974842-A - Amine linked C for target protein degradation3Glutarimide degradation determinants

CN121974842ACN 121974842 ACN121974842 ACN 121974842ACN-121974842-A

Abstract

The present invention provides amine-linked C 3 -glutarimide degradation determinants and degradation determinants for therapeutic applications as further described herein, as well as methods and compositions for their use, and methods of their preparation.

Inventors

  • A.J. PHILLIPS
  • C.G. Nasworth Schuk
  • J.A. HENDERSON
  • LIANG YANKE
  • CHEN QILI
  • M. Duplice
  • HE MINSHENG
  • K. Lazarsky

Assignees

  • C4医药公司

Dates

Publication Date
20260505
Application Date
20170510
Priority Date
20160510

Claims (15)

  1. 1. A compound of the formula: (I)、 (II) or (V) Or a pharmaceutically acceptable salt, N-oxide or isotopic derivative thereof; Wherein: W 1 is CR 6 R 7 、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 ; W 2 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 ; X is independently selected from NH, NR 3 、CH 2 、CHR 3 、C(R 3 ) 2 , O, and S; n is 0, 1, 2 or 3; Is a single bond or a double bond; Wherein when When representing a single bond, n is 0,1, 2 or 3; Wherein when When representing a double bond, n is 0, 1 or 2; r 1 is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and R is 1 ; Or R 1 is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 And ; R 2 is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl; Or R 1 and R 2 combine to form a 4,5, 6,7,8, 9, or 10 membered heterocyclic or heteroaryl species, wherein the heterocyclic or heteroaryl species is substituted at any desired position with R 12 , wherein the heterocyclic or heteroaryl species is optionally further substituted with one or more substituents selected from R 5 ; R 1 Selected from: 、 、 、 、 、 、 、 、 、 、 、 And ; R 3 is selected from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) O alkyl, alkene and alkyne, aliphatic, heteroaliphatic, aryl, heteroaryl and heteroalkyl; R 4 is selected from the group consisting of alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, cyano, -NH (aliphatic), -N (aliphatic) SO 2 alkyl, -NHSO 2 (aryl, heteroaryl or heterocyclyl), -N (alkyl) SO 2 (aryl, heteroaryl or heterocyclyl) -NHSO 2 alkenyl, -N (alkyl) SO 2 alkenyl, -NHSO 2 alkynyl, -N (alkyl) SO 2 alkynyl and haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl and carbocyclyl; Or two R 4 substituents together with the carbon atom to which they are attached may form a3, 4, 5 or 6 membered ring; R 5 and R 14 are in each case selected from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, cyano, -NH (aliphatic), -N (aliphatic) 2 、-NHSO 2 (aliphatic), -N (aliphatic) SO 2 alkyl, -NHSO 2 (aryl, heteroaryl or heterocyclyl), -N (alkyl) SO 2 (aryl, heteroaryl or heterocyclyl) -NHSO 2 alkenyl, -N (alkyl) SO 2 alkenyl, -NHSO 2 alkynyl, -N (alkyl) SO 2 alkynyl and haloalkyl, -aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl and carbocyclyl; Or R 5 is independently selected from C (O) R 4 , cyano, aryl, aryloxy, heterocycle, heteroaryl, arylalkyl, alkoxy, hydroxy, O-arylalkyl, or cycloalkyl; R 6 、R 7 、R 8 、R 9 、R 10 and R 11 are independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, hydroxy, alkoxy, amine, -NH (aliphatic), and-N (aliphatic) 2 ; Or R 6 and R 7 together with the carbon to which they are attached 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 together with the carbon to which they are attached 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 10 and R 11 together with the carbon to which they are attached 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 8 form a1 or 2 carbon bridged ring; Or R 6 and R 10 form a1 or 2 carbon bridged ring; Or R 8 and R 10 form a1 or 2 carbon bridged ring; Or R 14 and R 6 form a3, 4,5, or 6 carbon fused ring; Or R 14 and R 10 form a3, 4,5, or 6 carbon fused ring; Or R 14 and R 8 form a1 or 2 carbon bridged ring; Or R 14 and R 4 form a 3, 4, 5, or 6 carbon fused ring, wherein R 5 is on the alpha carbon of R 14 , or a1, 2, 3, or 4 carbon bridged ring, wherein R 5 is not on the alpha carbon of R 14 ; r 12 is a linker-targeting ligand; R 17 is selected from: 、 、 、 、 、 、 、 、 、 、 , Y is independently selected from N, CH or CR 101 , wherein examples of 0,1, 2, or 3Y are selected as N; R 101 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO 2 、F、Cl、Br、I、CF 3 、NH 2 , NH alkyl, N (alkyl) 2 , aliphatic, and heteroaliphatic; The linker is a chemical group that links the degradation determinant to the targeting ligand; and the targeting ligand is selected from those in fig. 1A to 8 PPPPP.
  2. 2. A compound of formula III or formula IV: (III) or (IV) Or a pharmaceutically acceptable salt, N-oxide or isotopic derivative; Wherein: r 13 is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ; Or R 13 and R 2 are combined to form a 4 to 10 membered heterocyclic or heteroaryl species, wherein the heterocyclic or heteroaryl species is optionally further substituted with one or more substituents selected from R 5 , and wherein the heterocyclic or heteroaryl species is optionally further substituted with one or more = O (oxo) at a valence-allowed position.
  3. 3. The compound of claim 1 or 2, wherein W 1 is c=o, W 2 is c=o and X is NH.
  4. 4. A compound according to claim 1, 2 or 3 wherein the linker has a chain of 2 to 20 carbon atoms, wherein one or more carbons may be replaced by heteroatoms such as O, N, S or P, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.
  5. 5. The compound of claim 1, 2 or 3, 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 from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) O alkyl, alkenyl, or alkynyl or alternatively may be aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclyl; R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, and alkyne, or may be selected from aryl, heteroaryl, heterocyclyl, aliphatic, and heteroaliphatic groups in addition to these, and R 27 and R 28 are independently selected from hydrogen, alkyl, amine or taken together with the carbon atom to which they are attached form 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 a1 or 2 carbon bridged ring.
  6. 6. A compound according to claim 1,2 or 3 wherein the linker is a moiety selected from the group consisting of formula LVIII, LIX and LX: wherein the variables are as defined in claim 5.
  7. 7. The compound of claim 1, 2 or 3 wherein the linker is selected from the group consisting of 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 And , Wherein the variables are as defined in claim 5.
  8. 8. The compound of claim 1, 2 or 3, wherein the linker is 、 、 、 、 、 、 And , Wherein the variables are as defined in claim 5.
  9. 9. The compound of claim 1, 2 or 3, 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 -, a, -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.
  10. 10. The compound of claim 1, 2 or 3, wherein the linker is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 And ; R 71 is-O-, -NH, -NMe, -N alkyl N (aliphatic), -N (heteroaliphatic); Representative of And And (C) sum M1, n2, o1, p1, q2 and r1 are independently 1,2, 3,4 or 5.
  11. 11. Use of an effective amount of a compound of claims 1, 3 or 4-10, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for the manufacture of a medicament for treating a patient suffering from a medical condition treatable by degradation of a target protein bound to a targeting ligand.
  12. 12. Use of an effective amount of a compound of claims 2, 3 or 4-10, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of a patient suffering from a medical condition treatable by binding to the protein cereblon in vivo.
  13. 13. The use of claim 11 or 12, 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.
  14. 14. The use of claim 11 or 12, 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, mycosis, protozoa, enteromorpha, helminth, prions or parasites.
  15. 15. The use of claim 11 or 12, wherein the condition is a cancer selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder carcinoma, intestinal cancer, cervical cancer, colon cancer, esophageal carcinoma, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric 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 cancer, and teratoma.

Description

Amine linked C 3 -glutarimide 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 201780036136.X and the application name of 'amine-linked C 3 -glutarimide degradation determinant for target protein degradation'. Cross Reference to Related Applications The present application claims the benefit of U.S. provisional application 62/334,338 filed 5/10/2016. The entire contents of this application are incorporated herein by reference for all purposes. Technical Field The present invention provides amine-linked C 3 -glutarimide degradation determinants (Degronimer) and degradation determinants (Degron) for therapeutic applications as further described herein, as well as methods and compositions for their use and methods of their preparation. 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 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 T