Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/69—Boron compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/545—Heterocyclic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D495/14—Ortho-condensed systems

Definitions

• the present invention relates to novel compounds which bind to the protein cereblon and modulate the substrate specificity of CUL4-DDB1-RBX1-CRBN ubiquitin ligase complex (CRL4 CRBN ).
• Cereblon is a substrate recognition component of CRL4 CRBN . Chemical modulation of cereblon may induce association of novel substrate proteins, followed by their ubiquitination and degradation.
• Cereblon is a protein which associates with DDB1 (damaged DNA binding protein 1), CUL4 (Cullin- 4), and RBX1 (RING-Box Protein 1). Collectively, the proteins form a ubiquitin ligase complex, which belongs to Cullin RING Ligase (CRL) protein family and is referred to as CRL4 CRBN . Cereblon became of particular interest to the scientific community after it was confirmed to be a direct protein target of thalidomide, which mediates the biological activity of cereblon.
• Thalidomide a drug approved for treatment of multiple myeloma in the late 1990s, binds to cereblon and modulates the substrate specificity of the CRL4 CRBN ubiquitin ligase complex. This mechanism underlies the pleiotropic effect of thalidomide on both immune cells and cancer cells (see Lu G et al.: The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins. Science. 2014 Jan 17; 343(6168): 305- 9).
• CMAs Cereblon Modulating Agents
• CMAs in numerous hematologic malignancies, such as multiple myeloma, myelodysplastic syndromes lymphomas and leukemia, has been demonstrated (see Le Roy A et al.: Immunomodulatory Drugs Exert Anti-Leukemia Effects in Acute Myeloid Leukemia by Direct and Immunostimulatory Activities. Front Immunol. 2018; 9: 977).
• the antitumor activity of cereblon modulators is mediated by:
• each of X 1 and X 2 is independently O or S; each of Q 1 and Q 2 is independently N or CR, wherein at least one of Q 1 and Q 2 is N; each of W 1 , W 2 , W 3 and W 4 is independently N or CR'; n is 0, 1 or 2;
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R", -C(O)OR", - C(O)NH 2 , -C(O)NHR", -C(O)NR" 2 , -OR", -NR" 2 , or -S(O) 2 R"; each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NR"C(O)R", -NR"C(O)OR", -NO 2 , -CN, -C(O)R", -C(O)OR", - C(O)NH 2 , -C(O)NHR", -C(O)NR" 2
• the compound of Formula (I) has the structure:
• the compound of Formula (I) has the structure: In some embodiments, one of W 1 , W 2 , W 3 and W 4 is N, and the remaining three of W 1 , W 2 , W 3 and W 4 are each CR'. In some such embodiments, W 1 is N, and W 2 , W 3 and W 4 are CR'. In other embodiments, W 2 is N, and W 1 , W 3 and W 4 are CR'. In yet other embodiments, W 3 is N, and W 1 , W 2 and W 4 are CR'. In other embodiments, W 4 is N, and W 1 , W 2 and W 3 are CR'. In some embodiments, W 1 , W 2 , W 3 and W 4 are each CR'. In some such embodiments, W 2 , W 3 and W 4 are each CH. In other embodiments, W 1 is C-NH 2 , C-NHR" or C-NR" 2 . In certain embodiments, W 1 is C- NH 2 .
• W 1 , W 2 , W 3 and W 4 are N, and the remaining two of W 1 , W 2 , W 3 and W 4 are each CR'.
• W 1 and W 2 are each N
• W 3 and W 4 are each CR'.
• W 1 and W 3 are each N
• W 2 and W 4 are each CR'.
• W 1 and W 4 are each N
• W 2 and W 3 are each CR'.
• W 1 and W 4 are each CR'.
• W 2 and W 4 are each N
• W 1 and W 4 are each CR'.
• W 2 and W 4 are each N
• W 1 and W 3 are each CR'.
• W 3 and W 4 are each N
• W 1 and W 2 are each CR'.
• three of W 4 , W 2 , W 3 and W 4 are N, and the remaining one of W b W 2 , W 3 and W 4 is CR'.
• W 1 , W 2 and W 3 are N, and W 4 is CR'.
• W 1 , W 2 and W 4 are N, and W 3 is CR'.
• W 1 , W 3 and W 4 are N, and W 2 is CR'.
• W 2 , W 3 and W 4 are N, and W 3 is CR'.
• each R is independently hydrogen or alkyl. In some such embodiments, each R is independently hydrogen or C 1 -C 4 alkyl. In some embodiments, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl or n-butyl. In some embodiments, the C 1 -C 4 alkyl is methyl or ethyl. In some embodiments, each R is independently hydrogen or methyl.
• each R' is independently hydrogen, -NH 2 , -NHR" or -NR" 2 . In some such embodiments, each R' is independently hydrogen or -NH 2 . In some such embodiments, each R' is hydrogen.
• X 1 and X 2 are O. In other embodiments, X 1 is O and X 2 is S. In other embodiments, X 1 is S and X 2 is O. In other embodiments, X 1 and X 2 are S.
• n is O. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR" 2 , or -S(O) 2 R".
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R", - C(O)OR", -C(O)NH 2 , -C(O)NHR", or -C(O)NR" 2 .
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR" 2 , or -S(O) 2 R".
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl.
• L is -OR", - NR" 2 , or -S(O) 2 R"
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.
• L is hydrogen, alkyl, alkenyl, or aryl.
• L is hydrogen, alkyl, or alkenyl.
• L is hydrogen or alkyl. In some embodiments of the compound of Formula (I), L is hydrogen.
• the compound of Formula (I) is: In some such embodiments, the compound of Formula (I) is:
• the compound of Formula (I) is:
• the compound of Formula (I) is: In one embodiment, the compound of Formula (I) is:
• each of X 1 and X 2 is independently O or S; each of Q 1 and Q 2 is independently N or CR, wherein at least one of Q 1 and Q 2 is N; each of W 1 , W 2 and W 3 is independently N or CR';
• the compound of Formula (Ila), (llb), or (llc) has the structure:
• the compound of Formula (Ila), (llb), or (llc) has the structure:
• W 1 is N. In some embodiments of the compound of Formula (Ila) or (llb), W 2 is N. In some embodiments of the compound of Formula (llb) or (llc), W 3 is N.
• one of W 1 , W 2 and W 3 is N, and the other of W 1 , W 2 and W 3 is CR'. In some such embodiments, one of W 1 , W 2 and W 3 is N, and the other of W 1 , W 2 and W 3 is CH.
• W 1 , W 2 and W 3 are each CR'.
• W 1 is C-NH 2 , C-NHR" or C-NR" 2 . In some such embodiments, W 1 is C-NH 2 .
• W 1 , W 2 and W 3 are each N.
• Z is O.
• Z is S.
• Z is NH.
• Q 1 is N and Q 2 is CR.
• Q 1 is N and Q 2 is N.
• Q 1 is N and Q 2 is N.
• Q 1 is N and Q 2 is N.
• Q 1 is N and Q 2 is N.
• Q 1 is N and Q 2 is N.
• each R is independently hydrogen or alkyl. In some such embodiments, each R is independently hydrogen or C 1 -C 4 alkyl. In some embodiments, C 1 -C 4 alkyl is methyl, ethyl, n-propyl or n-butyl. In some embodiments, C 1 -C 4 alkyl is methyl or ethyl. In some embodiments, each R is independently hydrogen or methyl.
• each R' is independently hydrogen, -NH 2 , -NHR" or -NR" 2 . In some such embodiments, each R' is independently hydrogen or -NH 2 . In some such embodiments, each R' is hydrogen.
• X 1 and X 2 are O. In other embodiments, X 1 is O and X 2 is S. In other embodiments, X 1 is S and X 2 is O. In other embodiments, X 1 and X 2 are S.
• n is O. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2. In some embodiments of the compound of Formula (Ila), (llb) or (llc), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR" 2 , or -S(O) 2 R".
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R", -C(O)OR", -C(O)NH 2 , -C(O)NHR", or -C(O)NR" 2 .
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR" 2 , or -S(O) 2 R".
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl.
• L is -OR", -NR" 2 , or -S(O) 2 R"
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.
• L is hydrogen, alkyl, alkenyl, or aryl.
• L is hydrogen, alkyl, or alkenyl.
• L is hydrogen or alkyl. In some embodiments of the compound of Formula (Ila), (llb) or (llc), L is hydrogen.
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R", -C(O)OR", - C(O)NH 2 , -C(O)NHR", -C(O)NR" 2 , OR", -NR" 2 , or -S(O) 2 R"; each of R 1 , R 2 and R 3 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NR"C(O)R", -NR"C(O)OR", -NO 2 , -CN, -C(O)R", - C(O)OR", -C(O)NH 2 , -C(O)NHR", -
• the compound of Formula (III) has the structure: In other embodiments, the compound of Formula (III) has the structure:
• X 1 and X 2 are 0. In other embodiments, X 1 is O and X 2 is S. In other embodiments, X 1 is S and X 2 is O. In other embodiments, X 1 and X 2 are S.
• n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR" 2 , or -S(O) 2 R".
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R", - C(O)OR", -C(O)NH 2 , -C(O)NHR", or -C(O)NR" 2 .
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR" 2 , or -S(O) 2 R".
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl.
• L is -OR", - NR" 2 , or -S(O) 2 R"
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl.
• L is hydrogen, alkyl, alkenyl, or aryl.
• L is hydrogen, alkyl, or alkenyl.
• L is hydrogen or alkyl. In some embodiments of the compound of Formula (III), L is hydrogen.
• each of X 1 and X 2 is independently O or S;
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R", -C(O)OR", - C(O)NH 2 , -C(O)NHR", -C(O)NR" 2 , -OR", -NR" 2 , or -S(O) 2 R"; each of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is independently N or CR, wherein at least one of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is N; each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NR"C(O)R", -NR"C(O)OR", -
• the compound of Formula (IV) has the structure:
• the compound of Formula (IV) has the structure:
• X 1 and X 2 are 0. In other embodiments, X 1 is O and X 2 is S. In other embodiments, X 1 is S and X 2 is O. In other embodiments, X 1 and X 2 are S.
• one of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is N, and the remaining four of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are each CR.
• Q 1 is N.
• Q 2 is N.
• Q 3 is N.
• Q 4 is N.
• Q 5 is N.
• two of Q 1 , Q2, Q 3 , Q 4 and Q 5 are N, and the remaining three of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are each CR.
• Q 1 and Q 2 are N
• Q 3 , Q 4 and Q 5 are each CR.
• Q 2 and Q 3 are N
• Q 1 , Q 4 and Q 5 are each CR.
• Q 1 and Q 3 are N
• Q 2 , Q 4 and Q 5 are each CR.
• Q 2 and Q 4 are N
• Q 1 , Q 3 and Q 5 are each CR.
• Q 1 and Q 4 are N
• Q 1 , Q 3 and Q 5 are each CR.
• Q 1 and Q 4 are N
• Q 2 , Q 3 and Q 5 are each CR.
• Q 1 and Q 4 are N
• Q 2 , Q 3 and Q 5 are each CR.
• three of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are N, and the remaining two of Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are each CR.
• each R is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NR"C(O)R", - NR"C(O)OR", -NO 2 , -CN, -C(O)R", -C(O)OR", -C(O)NH 2 , -C(O)NHR", -C(O)NR” 2 , -OR", -OC(O)R", - OC(O)OR", -OC(O)NH 2 , -OC(O)NHR", -OC(O)NR” 2 , -SR", S(O) 2 R".
• each R is independently hydrogen or -NH 2 . In some embodiments, each R is hydrogen. In some embodiments of the compound of Formula (IV), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR" 2 , or -S(O) 2 R".
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R", - C(O)OR", -C(O)NH 2 , -C(O)NHR", or -C(O)NR" 2 .
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -OR", -NR" 2 , or -S(O) 2 R" .
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, or haloalkenyl. In other embodiments of the compound of Formula (IV), L is -OR", - NR" 2 , or -S(O) 2 R" In some embodiments of the compound of Formula (IV), L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments of the compound of Formula (IV), L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments of the compound of Formula (IV), L is hydrogen, alkyl, or alkenyl. In some embodiments of the compound of Formula (IV), L is hydrogen or alkyl. In some embodiments of the compound of Formula (IV), L is hydrogen.
• a pharmaceutical composition comprising a compound according to any of the above aspects of the present invention.
• the invention also provides a compound according to any of the above aspects of the present invention for use as a cereblon binder.
• the invention also provides a compound or composition according to any of the above aspects of the present invention, for use in medicine.
• the invention also provides a compound or composition according to any of the above aspects of the present invention, for use in immune-oncology.
• the invention also provides a compound or composition according to any of the above aspects of the present invention, for use in the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, orTNFa related disorders.
• autoimmune diseases macular degeneration (MD) and related disorders
• diseases and disorders associated with undesired angiogenesis skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, orTNFa related disorders.
• the present invention also provides a method for the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, or TNFa related disorders; wherein the method comprises administering to a patient in need thereof an effective amount of a compound or composition according to any of the above aspects of the present invention.
• MD macular degeneration
• the method further comprises administering at least one additional active agent to the patient.
• the at least one additional active agent is an anti-cancer agent or an agent for the treatment of an autoimmune disease.
• the at least one additional active agent is a small molecule, a peptide, an antibody, a corticosteroid, or a combination thereof.
• the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.
• the present invention also provides a combined preparation of a compound of any one of the first to fourth aspects of the present invention and at least one additional active agent, for simultaneous, separate or sequential use in therapy.
• the at least one additional active agent is an anti- cancer agent or an agent for the treatment of an autoimmune disease.
• the at least one additional active agent is a peptide, an antibody, a corticosteroid, or a combination thereof.
• the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab.
• the therapy is the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders associated with undesired angiogenesis, skin diseases, pulmonary disorders, asbestos-related disorders, parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, or TNFa related disorders.
• alkyl is intended to include both unsubstituted alkyl groups, and alkyl groups which are substituted by one or more additional groups - for example -OH, -OR", -NH 2 , -NHR", -NR'' 2 , - SO 2 R", -C(O)R", -CN, or -NO 2 .
• the alkyl group is an unsubstituted alkyl group. In some embodiments, the alkyl group is a C 1 -C 12 alkyl, a C 1 -C 10 alkyl, a C 1 -C 8 alkyl, a C 1 -C 6 alkyl, or a C 1 -C 4 alkyl group.
• alkenyl is intended to include both unsubstituted alkenyl groups, and alkenyl groups which are substituted by one or more additional groups - for example -OH, -OR", -NH 2 , -NHR", - NR" 2 , -SO 2 R", -C(O)R", -CN, or -NO 2 .
• the alkenyl group is an unsubstituted alkenyl group.
• the alkenyl group is a C 2 -C 12 alkenyl, a C 2 -C 10 alkenyl, a C 2 -C 8 alkenyl, a C 2 - C 6 alkenyl, or a C 2 -C 4 alkenyl group.
• alkynyl is intended to include both unsubstituted alkynyl groups, and alkynyl groups which are substituted by one or more additional groups - for example -OH, -OR", halogen, -NH 2 , - NHR", -NR" 2 , -SO 2 R", -C(O)R", -CN, or -NO 2 .
• the alkynyl group is an unsubstituted alkynyl group.
• the alkynyl group is a C 2 -C 12 alkynyl, a C 2 -C 10 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 6 alkynyl, or a C 2 -C 4 alkynyl group.
• aryl is intended to include both unsubstituted aryl groups, and aryl groups which are substituted by one or more additional groups -for example -OH, -OR", halogen, -NH 2 , -NHR", - NR" 2 , -SO 2 R", -C(O)R", -CN, or -NO 2 .
• the aryl group is an unsubstituted aryl group.
• the aryl group is a C 6 -C 10 aryl, a C 6 -C 8 aryl, or a C 6 aryl.
• heteroaryl is intended to include both unsubstituted heteroaryl groups, and heteroaryl groups which are substituted by one or more additional groups - for example -OH, -OR", halogen, -NH 2 , -NHR", -NR" 2 , -SO 2 R", -C(O)R", -CN, or -NO 2 .
• the heteroaryl group is an unsubstituted heteroaryl group.
• the heteroaryl group is a C 6 -C 10 heteroaryl, a C 6 -C 9 heteroaryl, a C 6 -C 8 heteroaryl, or a C 6 heteroaryl.
• benzyl is intended to include both unsubstituted benzyl groups, and benzyl groups which are substituted by one or more additional groups - for example -OH, -OR", halogen, -NH 2 , - NHR", -NR" 2 , -SO 2 R", -C(O)R", -CN, or -NO 2 .
• the benzyl group is an unsubstituted benzyl group.
• Figure 1 is an assay showing the effect of various compounds of the invention and various reference compounds on SALL4 degradation in the Kelly cell line.
• Figure 2 is an assay showing the effect of various compounds of the invention and various reference compounds on IKZF1 degradation in the H929 cell line.
• Figure 3 is an assay showing the effect of various compounds of the invention and various reference compounds on IKZF3 degradation in the H929 cell line.
• L, X 1 , X 2 , Q 1 , Q 2 , Q3, Q 4 , Q 5 , W 1 , W 2 , W 3 , W 4 , R, R 1 , R 2 , R 3 and Z are as defined above.
• Binding of the above compounds to cereblon may alter the specificity of the CRL4 CRBN complexes, and induce association of novel substrate proteins, followed by their ubiquitination and degradation.
• novel substrate proteins include, but are not limited to, IKZF1 and IKZF3.
• the above compounds may modulate cereblon in a unique way allowing CRL4 CRBN ubiquitin ligase complex to recognise different substrates to those which it would otherwise recognise, and target them for degradation. Consequently, the compounds of the present invention are expected to broaden/modify CRBN's antiproliferative activity, thus extending the range of cancer types sensitive to treatment with CMAs.
• the compounds of the present invention are advantageous in terms of their synthetic feasibility.
• the synthesis of the compounds can be summarized as follows:
• One example of a compound of the present invention is 3-(5-amino-2-methylquinolin-3-yl)piperidine-
• Compound 1 exhibits a similar cereblon binding capability to that of the known CMA, CC-122.
• CMAs such as CC-122
• patients often develop resistance to these compounds.
• novel compounds - such as those of the present invention, as described above - may help to overcome this clinical obstacle.
• CMAs have safety profile.
• the teratogenicity of the CMAs is dependent upon the extent to which the CMAs induce degradation of SALL4 transcription factor.
• Known CMAs induce degradation of several proteins (including SALL4) which bind to CRL4 CRBN ligase only in presence of the CMA.
• SALL4 degradation observed under treatment with CMAs, is responsible (at least partly) for the teratogenicity of the CMAs. Compounds with diminished capability to induce SALL4 degradation may demonstrate an improved safety profile.
• the compounds of the present invention may also possess pharmaceutically advantageous properties, such as increased stability and improved ADMET (absorption, distribution, metabolism, excretion, and/or toxicity) properties.
• the compounds of the present invention may be useful in the treatment of various diseases and disorders, including (but not limited to):
• Cancer The compounds provided herein can be used for treating, preventing or managing either primary or metastatic tumors.
• Specific examples of cancer include, but are not limited to, cancers of the skin, such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages, and AIDS-related cancers and hematological malignancies.
• Hematological malignancies include leukemia, lymphoma, multiple myeloma or smoldering myeloma.
• Leukemia can be selected from: acute leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia, acute myeloid leukemia (AML), adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute megakaryoblastic leukemia, adult acute minimally differentiated myeloid leukemia, adult acute monoblastic leukemia, adult acute monocytic leukemia, adult acute myeloblastic leukemia with maturation, adult acute myeloblastic leukemia without maturation, adult acute myeloid leukemia with abnormalities, adult acute myelomonocytic leukemia, adult erythroleukemia, adult pure erythroid leukemia, secondary acute myeloid leukemia, untreated adult acute myeloid leukemia, adult acute myeloid leukemia in remission, adult acute promyelocytic leukemia with PML- RARA, alkylating agent-
• Lymphoma can be selected from the group consisting of: adult grade III lymphomatoid granulomatosis, adult nasal type extranodal NK/T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous B- Cell non- Hodgkin lymphoma, extranodal marginal zone lymphoma of mucosa- associated lymphoid tissue, hepatosplenic T-cell lymphoma, intraocular lymphoma, lymphomatous involvement of non- cutaneous extranodal site, mature T-cell and K- cell non-Hodgkin lymphoma, nodal marginal zone lymphoma, post-transplant lymphoproliferative disorder, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult grade III lymphomato
• Autoimmune diseases such as: Acute disseminated encephalomyelitis, acute motor axonal neuropathy, Addison's disease, adiposis dolorosa, adult-onset Still's disease, alopecia areata, ankylosing spondylitis, anti-glomerular basement membrane nephritis, anti-neutrophil cytoplasmic antibody-associated vasculitis, anti-N-methyl-D-aspartate receptor encephalitis, antiphospholipid syndrome, antisynthetase syndrome, aplastic anemia, autoimmune angioedema, autoimmune encephalitis, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune polyendocrine syndrome type 2, autoimmune polyendoc
• angiogenesis diseases and disorders associated with, or characterized by, undesired angiogenesis include, but are not limited to: arthritis, endometriosis, Crohn's disease, heart failure, advanced heart failure, renal impairment, endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus replication, wasting, meningitis, silica-induced fibrosis, asbestos- induced fibrosis, veterinary disorder, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q- deletion syndrome, nociceptive pain, neuropathic pain, mixed pain of nociceptive and neuropathic pain, visceral pain, migraine, headache and postoperative pain.
• nociceptive pain examples include, but are not limited to, pain associated with chemical or thermal bums, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.
• neuropathic pain examples include, but are not limited to, CRPS type I, CRPS type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine and velcade;
• RSD reflex sympathetic dystrophy
• reflex neurovascular dystrophy reflex dystrophy
• reflex dystrophy sympathetically maintained pain syndrome
• causalgia Sudeck atrophy of bone
• algoneurodystrophy shoulder hand syndrome
• post-traumatic dystrophy trigeminal neural
• MD Macular Degeneration
• ARM age-related maculopathy
• CNVM choroidal neovascularisation
• PED retinal pigment epithelium detachment
• RPE retinal pigment epithelium
• Skin diseases such as: keratoses and related symptoms, skin diseases or disorders characterized with overgrowths of the epidermis, acne, and wrinkles.
• skin diseases or disorders characterized with overgrowths of the epidermis include, but are not limited to, any conditions, diseases or disorders marked by the presence of overgrowths of the epidermis, including but not limited to, infections associated with papilloma virus, arsenical keratoses, sign of Leser-Trelat, warty dyskeratoma (WD), trichostasis spinulosa (IS), erythrokeratodermia variabilis (EKV), ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneous melanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma, confluent and reticulated papillomatosis (CRP), acrochordons,
• dermatosis papulosa nigra DPN
• ENS epidermal nevus syndrome
• ichthyosis vulgaris molluscum contagiosum
• prurigo nodularis acanthosis nigricans
• Pulmonary disorders such as pulmonary hypertension and related disorders.
• pulmonary hypertension and related disorders include, but are not limited to: primary pulmonary hypertension (PPH); secondary pulmonary hypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonary hypertension; pulmonary arterial hypertension (PAH); pulmonary artery hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary arteriopathy (TPA); plexogenic pulmonary arteriopathy; functional classes I to IV pulmonary hypertension; and pulmonary hypertension associated with, related to, or secondary to, left ventricular dysfunction, mitral valvular disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous drainage, pulmonary venoocclusive disease, collagen vasular disease, congenital heart disease, HIV virus infection, drugs and toxins such as fenfluramines, congenital heart disease, pulmonary venous hypertension,
• Asbestos-related disorders such as: mesothelioma, asbestosis, malignant pleural effusion, benign exudative effusion, pleural plaques, pleural calcification, diffuse pleural thickening, rounded atelectasis, fibrotic masses, and lung cancer;
• Parasitic diseases and disorders caused by human intracellular parasites such as, but not limited to, P. falcifarium, P. ovale, P. vivax, P, malariae, L. donovari, L. infanium, L. aethiopica, L. major, L. tropica, I mexicana, L braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C. parvum, C. cayetanensis, E. histolytica, I. belli, S. monsonii, S. haemolobium, Trypanosoma ssp., Toxoplasma ssp.,andO. volvulus.
• Other diseases and disorders caused by non-human intracellular parasites such as, but not limited to, Babesia bovis, Babesia canis, Banesia
• mice are also encompassed.
• Specific examples include, but are not limited to, malaria, babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis, ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis, toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis, filariasis, schistosomiasis, and dermatitis caused by animal schistosomes;
• Immunodeficiency disorders which include, but are not limited to, adenosine deaminase deficiency, antibody deficiency with normal or elevated Igs, ataxia-tenlangiectasia, bare lymphocyte syndrome, common variable immunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chain deletions, IgA deficiency, immunodeficiency with thymoma, reticular dysgenesis,
• Nezelof syndrome selective IgG subclass deficiency, transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency;
• Atherosclerosis and related conditions such as: all forms of conditions involving atherosclerosis, including restenosis after vascular intervention such as angioplasty, stenting, atherectomy and grafting;
• Hemoglobinopathy and related disorders such as sickle cell anemia, and any other disorders related to the differentiation of CD34+ cells;
• TNFa related disorders such as: endotoxemia or toxic shock syndrome; cachexia; adult respiratory distress syndrome; bone resorption diseases such as arthritis; hypercalcemia;
• the compounds of the present invention may also be useful in preventing, treating, or reducing the risk of developing graft versus host disease (GVHD) or transplant rejection.
• the compounds of the present invention may also inhibit the production of certain cytokines including, but not limited to, TNF- ⁇ , IL-l ⁇ , IL-12, IL-18, GM-CSF, IL-10, TGF- ⁇ and/or IL-6.
• the present compounds may stimulate the production of certain cytokines, and also act as a costimulatory signal for T cell activation, resulting in increased production of cytokines such as, but not limited to, IL-12, IL-2, IL-10, TGF- ⁇ and/or IFN- ⁇ .
• compounds provided herein can enhance the effects of NK cells and antibody- mediated cellular cytotoxicity (ADCC).
• ADCC antibody- mediated cellular cytotoxicity
• compounds provided herein may be immunomodulatory and/or cytotoxic, and thus may be useful as chemotherapeutic agents.
• Step 1 Synthesis of3-bromo-2-methyl-5-nitro-8,8a-dihydroquinoline 2-Methyl-5-nitro-8,8a-dihydroquinoline (19.8 g, 105.3 mmol) was dissolved in dichloromethane (250 mL) and cooled to 5°C in an ice bath. m-CPBA (32.9 g, 133.4 mmol, 70%) was added in portions thereto and the reaction mixture was stirred at room temperature (20-25°C) for 12 hrs. The mixture was washed with 2M NaOH solution (2x150 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to afford a yellow solid (22 g).
• Step A To an ice cold solution of 5-nitro-2-methyl quinoline (2.3 g, 12.22 mmol) in DCM (25 mL) was added m-CPBA (2.3 g, 13.67 mmol). The reaction mixture was warmed to RT and stirred for 16 h. The mixture was filtered and filtrates were washed with 1 M KOH solution, dried over Na 2 SO 4 , and concentrated under reduced pressure to give 2-methyl-5-nitroquinoline 1-oxide (88% yield).
• Step B To an ice cold solution of 2-methyl-5-nitroquinoline 1-oxide (500.0 mg, 2.44 mmol) in DCM (5 mL) was added POBr 3 (1.4 g, 4.9 mmol) in DCM (5 mL). The reaction mixture warmed to RT and stirred for 48 h. Ice water was added, the solution was neutralized with 10% NH 3 solution, extracted with DCM, dried over Na 2 SO 4 , concentrated under reduced pressure and purified by flash column chromatography to give 2-methyl-3-bromo-5-nitroquinoline (14% yield).
• Step C To a solution of 2-methyl-3-bromo-5-nitroquinoline (600 mg, 2.24 mmol) in dioxane (8 mL) was added KOAc (441 mg, 4.49 mmol) followed by l-(tert-butyldimethylsilyloxy)-l-tert- butoxyethylene (2.07 g, 8.98 mmol) and the reaction mixture was degassed for 15 min under N 2 .
• Step D To a solution of tert-butyl 2-(2-methyl-5-nitroquinolin-3-yl)acetate (200 mg, 0.662 mmol) in DMF (10 mL) were added K 2 CO 3 (150.6 mg, 0.662 mmol), benzyltriethylammonium chloride (91.4 mg, 0.662mmol) and acrylonitrile (0.043 mL, 0.662 mmol) and the reaction mixture was stirred at RT for 16h.
• K 2 CO 3 150.6 mg, 0.662 mmol
• benzyltriethylammonium chloride 91.4 mg, 0.662mmol
• acrylonitrile 0.043 mL, 0.662 mmol
• reaction mixture was diluted with water, extracted with ethyl acetate, dried over Na 2 SO 4 , concentrated under reduced pressure and purified by flash column chromatography to give tert-butyl 4-cyano-2-(2-methyl-5-nitroquinolin-3-yl)butanoate (40% yield).
• Step E To an ice cold solution of tert-butyl 4-cyano-2-(2-methyl-5-nitroquinolin-3-yl)butanoate (120.0 mg, 0.338 mmol) in DMSO (5 mL) were added H 2 O 2 (0.052 mL, 1.688 mmol) and K 2 CO 3 (6.533 mg, 0.047 mmol). The reaction mixture warmed to RT and stirred for 16h, diluted with water, extracted with ethyl acetate, dried over Na 2 SO 4 , concentrated under reduced pressure and purified by SFC to give tert-butyl 5-amino-2-(2-methyl-5-nitroquinolin-3-yl)-5-oxopentanoate (51% yield).
• Step F In a vial were placed tert-butyl 5-amino-2-(2-methyl-5-nitroquinolin-3-yl)-5-oxopentanoate (5.0 mg, 0.013 mmol, 1.000 eq), p-toluenesulfonic acid (25.5 mg, 0.134 mmol, 10.000 eq) and acetonitrile (0.5 mL) and the reaction mixture was stirred at 80°C for 2h. The mixture was concentrated under reduced pressure and purified by HPLC to give 3-(2-methyl-5-nitroquinolin-3- yl)piperidine-2, 6-dione (77% yield).
• Step A To a solution of 2-amino-6-fluorobenzaldehyde (1.0 g, 7.19 mmol) in MeOH (20 mL) was added 4-oxopentanoic acid (0.739 mL, 7.194 mmol) followed by 2M NaOH (5.0 mL). The reaction mixture was refluxed for 18 h, concentrated under reduced pressure, neutralized with acetic acid, the solids were filtered and washed with ether and pentane to give 2-(5-fluoro-2-methylquinolin-3- yl)acetic acid (38%).
• Step B To a solution of DCC (1.036 g, 5.023 mmol) in DCM (5.0 mL) were added DMAP (446 mg, 3.653 mmol) and 2-(5-fluoro-2-methylquinolin-3-yl)acetic acid (1.0 g, 4.566 mmol). Tert-butanol (0.406 mL, 13.7 mmol) was added and the reaction mixture was warmed to RT and stirred for 12 h.
• reaction mixture was diluted water, extracted with ethyl acetate, dried over Na 2 SO 4 , concentrated under reduced pressure and purified by flash column chromatography to give tert- butyl 2-(5-fluoro-2-methylquinolin-3-yl)acetate (35% yield).
• Step C To a solution of tert-butyl 2-(5-fluoro-2-methylquinolin-3-yl)acetate (500 mg, 1.816 mmol) in DMF (10 mL) were added K 2 CO 3 (251 mg, 1.816 mmol), benzyltriethylammonium chloride (413.6 mg, 1.816 mmol) and acrylonitrile (0.119 mL, 1.816 mmol) and the reaction mixture was stirred at RT for 16h.
• K 2 CO 3 (251 mg, 1.816 mmol
• benzyltriethylammonium chloride 413.6 mg, 1.816 mmol
• acrylonitrile (0.119 mL, 1.816 mmol
• reaction mixture was diluted with water, extracted with ethyl acetate, dried over Na 2 SO 4 concentrated under reduced pressure and purified by flash column chromatography to give tert-butyl 4-cyano-2-(5-fluoro-2-methylquinolin-3-yl)butanoate (50% yield).
• Step D To an ice cold solution of tert-butyl 4-cyano-2-(5-fluoro-2-methylquinolin-3-yl)buta noate (500 mg, 1.524 mmol) in DMSO (5 mL) were added H 2 O 2 (0.238 mL, 7.77 mmol) and K 2 CO 3 (29.5 mg, 0.14 mmol).
• Step E In a vial were placed tert-butyl 5-amino-2-(5-fluoro-2-methylquinolin-3-yl)-5-oxopentanoate (5.0 mg, 0.014 mmol, 1.000 eq), p-toluenesulfonic acid (27.5 mg, 0.144 mmol, 10.000 eq) and acetonitrile (0.5 mL) and the reaction mixture was stirred at 80°C for 2h. The mixture was concentrated under reduced pressure and purified by HPLC to give 3-(5-fluoro-2-methylquinolin-3- yl)piperidine-2, 6-dione (84% yield).
• CRBN-DDB1 protein complex was mixed with Cy5-labelled thalidomide and a compound to be tested (the "test compound”).
• the test solution was added to a 384-well assay plate. The plate was spun-down (1 min, 1000 rpm, 22”C) and then shaken using a VibroTurbulator for 10 min at room temperature (20-25°C), with the frequency set to level 3.
• the assay plate with protein and the tracer was incubated for 60 min at room temperature (20-25°C) prior to read-out with a plate reader.
• Read-out fluorescence polarization
• the FP experiment was carried out with various concentrations of the test compounds in order to measure Ki values.
• Ki values of competitive inhibitors were calculated using the equation based on the IC 50 values of relationship between compound concentration and measured fluorescence polarization, the K d value of the Cy5-T and CRBN/DDB1 complex, and the concentrations of the protein and the tracer in the displacement assay (as described by Z. Nikolovska-Coleska et al., Analytical Biochemistry 332 (2004) 261- 273). Fluorescence Polarization (FP) Assay - Results
• Table 1 FP assay results for Compound 1 and control compounds CC-122 and Thalidomide As can be seen from Table 1, above, compound Compound 1 of the present invention exhibited similar CRBN binding affinity (Ki in the same concentration range) as the reference compounds, CC-122 and Thalidomide.
• Example 5 SALL4 degradation assay - Kelly cell line
• the effect of various compounds of the invention and various reference compounds on SALL4 degradation in the Kelly cell line was investigated, using the degradation assay protocol below.
• Kelly cells were maintained in RPMI-1640 medium, supplemented with penicillin/streptomycin and 10% Fetal Bovine Serum (FBS). Cells were seeded on 6-well plates, and the compounds to be tested were added at the desired concentration range. Final DMSO concentration was 0.25%. After 24h incubation (37°C, 5% CO 2 ), cells were washed and cell lysates were prepared using RIPA lysis buffer. The amount of protein was determined via BCA assay, and the appropriate quantity was then loaded on the precast gel for the protein separation. After primary and secondary antibody staining, the membranes were washed and signals developed. The densitometry analysis was implemented to obtain the numeric values used later in the protein level evaluation process.
• FBS Fetal Bovine Serum
• the compounds of the invention Induce degradation of SALL4 protein in the Kelly (neuroblastoma) cell line with lower potency than the reference compounds CC-122 and Thalidomide.
• the compounds of the present invention may therefore be more useful in circumstances where degradation of SALL4 protein is not desired.
• H929 cells were maintained in RPMI-1640 medium, supplemented with penicillin/streptomycin, 10% Fetal Bovine Serum (FBS) and 0.05 mM 2-Mercaptoethanol. Cells were seeded on 6- or 12-well plates, and the compounds to be tested were added at the desired concentration range. Final DMSO concentration was 0.25%. After 24h incubation (37°C, 5% CO 2 ), cells were harvested, washed and cell lysates were prepared using RIPA lysis buffer. The amount of protein was determined via BCA assay, and the appropriate quantity was then loaded on the precast gel for the protein separation. After primary and secondary Ab staining, the membranes were washed and signals developed. The densitometry analysis was implemented to obtain the numeric values used later in the protein level evaluation process.
• FBS Fetal Bovine Serum
• the compounds of the invention induce degradation of IKZF1 protein in the H929 cell line with higher potency than the reference compound Thalidomide.
• the compounds of the present invention may therefore be useful as anti-cancer compounds.
• Example 7 IKZF3 degradation assay - H929 cell line
• H929 cells were maintained in RPMI-1640 medium, supplemented with penicillin/streptomycin and 10% Fetal Bovine Serum (FBS) and 0.05 mM 2-Mercaptoethanol. Cells were seeded on 6- or 12-well plates, and the compounds to be tested were added at the desired concentration range. Final DMSO concentration was 0.25%. After 24h incubation (37°C, 5% CO 2 ), cells were harvested, washed and cell lysates were prepared using RIPA lysis buffer. The amount of protein was determined via BCA assay, and the appropriate quantity was then loaded on the precast gel for the protein separation. After primary and secondary Ab staining, the membranes were washed and signals developed. The densitometry analysis was implemented to obtain the numeric values used later in the protein level evaluation process.
• FBS Fetal Bovine Serum
• the compounds of the invention induce degradation of IKZF3 protein in the H929 cell line with higher potency than the reference compound Thalidomide.
• the compounds of the present invention may therefore be useful as anti-cancer compounds.
• Example 8 Viability - CTG assay The effect of compound 1 of the invention on the viability of H929 (myeloma) was investigated, using the CTG assay protocol below.
• the compounds of the invention may be useful in the treatment of cancer.
• room temperature means a temperature of between 20°C and 25°C.
• small molecule means an organic compound with a molecular weight of less than 900 Daltons.

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