Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—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

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.
• BACKGROUND Cereblon (CRBN) is a protein which associates with DDB1 (damaged DNA binding protein 1), CUL4 (Cullin-4), and RBX1 (RING-Box Protein 1).
• CRL4 CRBN Cullin RING Ligase
• 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.
• the antitumor activity of cereblon modulators is mediated by: 1) inhibition of cancer cell proliferation and induction of apoptosis, 2) disruption of trophic support from tumor stroma, 3) stimulation of immune cells, resulting in proliferation of T-cells, cytokine production and activation of NK (natural killer) cells (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). It has been demonstrated that chemically-modified thalidomide-based derivatives can significantly modify the substrate specificity of CRL4 CRBN ubiquitin ligase.
• Chemically-modified thalidomide-based derivatives such as pomalidomide and lenalidomide, induce degradation of various neosubstrates, such as IKZF1, IKZF3, and/or CK1 ⁇ . While degradation of IKZF1 and IKZF3 might be beneficial in the treatment of some cancer types (such as multiple myeloma), it may also contribute to dose-limiting toxicity of those compounds. Side effects resulting from lenalidomide’s activity include neutropenia, thrombocytopenia, and hemorrhagic disorders (see: Sun X et al. PROTACs: great opportunities for academia and industry.
• a compound of Formula (Ia) or (Ib): L X 1 X 1 or a pharmaceutically acceptable salt or tautomer thereof, wherein each of X 1 and X 2 is independently O or S; Z is O, S or NR 2 ; T is C O or SO 2 ; each of Y 1 , Y 2 , Y 3 , and Y 4 is independently N or CR, wherein at least one of Y 1 , Y 2 and Y 3 in Formula (Ia) is CR, and at least one of Y 1 , Y 2 and Y 4 in Formula (Ib) is CR; n is 0, 1 or 2; L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, halo
• each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR’’, -NR’’ 2 , -NR’’C(O)R’’, - NR’’C(O)CH(OH)R’’, -NR’’C(O)OR’’, -NR’’SO 2 R’’, -NO 2 , -CN, -C(O)R’’, -C(O)OR’’, -C(O)NH 2 , -C(O)NHR’’, - C(O)NR’’ 2 ,
• 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, L is -OR’’, -NR’’ 2 , or -S(O) 2 R’’ In some embodiments, L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl. In some embodiments, L is hydrogen, alkyl, alkenyl, or aryl. In some embodiments, L is hydrogen, alkyl, or alkenyl. In some embodiments, L is hydrogen or alkyl. In some embodiments, L is hydrogen.
• R 2 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, - NR’’ 2 , -NR’’C(O)R’’, -N[C(O)R’’] 2 , -NR’’C(O)OR’’, -C(O)R’’, -C(O)OR’’, -OR’’, -OC(O)R’’, -OC(O)OR’’, - OC(O)NH 2 , -OC(O)NHR’’, or -OC(O)NR’’ 2 .
• the compound is of Formula (Ia), wherein one of Y 1 , Y 2 and Y 3 is CR; the remaining two of Y 1 , Y 2 and Y 3 are each N; and Z is S.
• Y 1 is CR; Y 2 and Y 3 are N.
• Y 2 is CR; Y 1 and Y 3 are N.
• Y 3 is CR, and Y 1 and Y 2 are N.
• the compound is of Formula (Ia) and Y 1 , Y 2 and Y 3 are each CR.
• Y 1 is -C-NHC(O)R’’
• Y 2 is CH
• Y 3 is CH or CCl.
• Y 1 is N, and Y 2 and Y 4 are CR.
• Y 2 is N, and Y 1 and Y 4 are CR.
• Y 4 is N, and Y 1 and Y 2 are CR.
• the compound is of Formula (Ib), wherein one of Y 1 , Y 2 and Y 4 is CR and the remaining two of Y 1 , Y 2 and Y 4 are each N, and wherein Z is S.
• Y 1 is CR
• Y 2 and Y 4 are N.
• Y 2 is CR
• Y 1 and Y 4 are N.
• Y 4 is CR
• Y 1 and Y 2 are N.
• the compound is of Formula (Ib) and Y 1 , Y 2 and Y 4 are each CR.
• each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, -OR’’, -N[C(O)R’’] 2 , -NR’’C(O)R’’, -NHC(O)OR’’, -NHR’’, -NH 2 , or -NHSO 2 R’’CN.
• each R’’ is independently alkyl, cycloalkyl, aryl or benzyl.
• each R’’ is independently alkyl, cycloalkyl, aryl or benzyl.
• Y 1 is CH;
• Y 2 is CH or CCl; and
• Y 4 is C-OR’’ or C-NH 2 , optionally C-OMe or C-NH 2 .
• each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, -NR’’C(O)R’’, NR’’C(O)OR’’, - NR’’C(O)CH(OH)R’’, -NHR’’, -NH 2 , -OR’’, -CN, -C(O)NR’’ 2 , or -NR’’SO 2 R’’.
• each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, -OR’’, -CN, -NHC(O)R’’, -NHC(O)OR’’, - NHR’’, -NH 2 or -NHSO 2 R’’.
• each R’’ is independently alkyl, cycloalkyl, aryl or benzyl.
• X 1 is O and X 2 is S.
• X 1 is S and X 2 is O.
• X 1 and X 2 are S.
• n is 0.
• a compound of Formula (IIa) or (IIb): L X 1 X 1 or a pharmaceutically acceptable salt or tautomer thereof, wherein each of X 1 and X 2 is independently O or S; T is C O or SO 2 ; Y 3 is N or CR; Y 4 is N or CR; indicates a single or double bond, wherein en each is a double bond, each of W 1 , W 2 , W 3 and W 4 is independently N or CR’, wherein at of W 1 , W 2 , W 3 and W 4 is N, and when each is a single b CR’ 2 and Y 4 is 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
• the compound is of Formula (IIb).
• the compound of Formula (IIa) or (IIb) has the structure: L or
• the compound of Formula (IIa) or (IIb) has the structure: L X 1 or L X 1
• Z is O.
• Z is S. In other embodiments, Z is NR 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 , -NR’’ 2 , or -S(O) 2 R’’; optionally wherein L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -NR’’ 2 , or -S(O) 2 R’’’
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, -NR’’ 2 , or -S(O) 2 R’’’
• 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’’, 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, or aryl.
• L is hydrogen, alkyl, or alkenyl.
• L is hydrogen or alkyl.
• L is hydrogen.
• W4 indicates a double bond between W 3 and W 4 , and W 3 and W 4 are each independently N or CR’.
• each is a double bond or each is a single bond.
• 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’.
• one of W 1 , W 2 and W 3 is N, and W 4 is CR’.
• W 1 is N
• W 2 , W 3 and W 4 are each CR’.
• W 2 is N, and W 1 , W 3 and W 4 are each CR’.
• W3 is N, and W1, W2 and W4 are each CR’.
• W4 is N, and W1, W 2 and W 3 are each CR’.
• W 1 and W 2 are each N, and W 3 and W 4 are each CR’.
• W 1 and W 3 are each N, and W 2 and W 4 are each CR’.
• W 1 and W 4 are each N, and W 2 and W 3 are each CR’. In other such embodiments, W 2 and W 3 are each N, and W 1 and W 4 are each CR’. In other such W 4 are each N, and W 1 and W 2 are each CR’. In other embodiments wherein each is a double bond, one of W 1 , W 2 , W 3 and W 4 is CR’, and the remaining three of W 1 , W 2 , W 3 and W 4 are In some such embodiments W 1 is CR’, and W 2 , W 3 and W 4 are each N. In other such embodiments, W 2 is CR’, and W 1 , W 3 and W 4 are each N.
• W 3 is CR’, and W 1 , W 2 and W 4 are each N. In other such embodiments, W 4 is CR’, and W 1 , W 2 and W 3 are each N. In some embodiments, at least one R’ is not hydrogen.
• each is a single bond.
• each R is independently hydrogen, halogen or -NR’’C(O)R’’. In some embodiments of the compound of Formula (IIa) or (IIb), 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. In some embodiments of the compound of Formula (IIa) or (IIb), n is 0. In other embodiments of the compound of Formula (IIa) or (IIb), n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.
• the present invention provides a compound of Formula (Ia), Formula (Ib), Formula (IIa) or Formula (IIb) selected from: HN HN S H O O O
• 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, or a compound selected from
• the invention also provides a compound or composition according to any of the above aspects of the present invention, or a compound selected from S H O S H O S H O N N N f
• the invention also provides a compound or composition according to any of the above aspects of the present invention, or a compound selected from S O S O S O 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 TNF ⁇ related disorders.
• the compound is a compound of any one of the first to third aspects of the present invention, or a compound selected from S O H S O O H S H N N N In some embodiments, the compound is a compound of any one of the first to third aspects of the present invention.
• 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 TNF ⁇ 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, or a compound selected from S H O S O S O . 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 peptide, an antibody, a corticosteroid, or a combination thereof. In some embodiments, the at least one additional active agent is at least one of bortezomib, dexamethasone, and rituximab. In some embodiments, an effective amount of a compound or composition according to any of the above aspects of the present invention is administered to the patient.
• the present invention also provides a combined preparation of a compound of any one of the first to third aspects of the present invention, or a compound selected from S O H S O O H S H N N N and at least one additional active agent, for simultaneous, separate or sequential use in therapy.
• the present invention also provides a combined preparation of a compound of any one of the first to third 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 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 therapy is the treatment of cancer, autoimmune diseases, macular degeneration (MD) and related disorders, diseases and disorders parasitic diseases and disorders, immunodeficiency disorders, atherosclerosis and related conditions, hemoglobinopathy and related disorders, or TNF ⁇ 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.
• the benzyl group is an unsubstituted benzyl group. In some embodiments, all alkyl, cycloalkyl, heterocycolalkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl groups are unsubstituted.
• Figure 1 is an assay showing the effect of various compounds of the invention and various reference compounds CK1 ⁇ 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.
• DETAILED DESCRIPTION OF THE INVENTION As discussed above, the present invention provides compounds of Formulas (Ia), (Ib), (IIa) and (IIb): L X 1
• X 1 X 1 wherein L, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4, W 1 , W 2 , W 3 , W 4 , R 1 and Z are as defined above.
• 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.
• 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 in the following general procedure (carried out under Synthetic Conditions A or Synthetic Conditions B, as set out below: H H A or B O N O R x Reaction Scheme 1: General procedure Synthetic Conditions A An appropriate acid (R x COOH in the above reaction scheme) (1.1 eq), DMAP (0.04 eq), and EDC (1.2 eq) were added to a solution of 3-aminopiperidine-2,6-dione (1 eq) and N-hydroxybenzotriazole (1.2 eq) in DMF (0.5 M).
• Example method 1 formation of chlorinated R x group of R x COOH (or its ester R x COOR y ) NCS (1.1 eq) was added to a solution of an appropriate starting material (1 eq) in DMF (0.5 M) and the reaction mixture was stirred for 2 h at room temperature (20-25°C). The reaction mixture was poured into water (2 x DMF volume) and occurred precipitate was filtered. The solids were washed with water and dried in vacuum to give the acid, ROOH.
• Example method 3 formation of acetylated R x group of R x COOR y
• a mixture of an appropriate amine (1 eq.), Ac 2 O (3 eq.), and DMAP (0.2 eq.) in dioxane (0.2 M) was heated to 80°C for 2 h. Upon completion, the mixture was cooled down to room temperature (20-25°C) and concentrated under reduced pressure. The residue was diluted with water (1 x dioxane volume) and extracted with EtOAc (3 x dioxane volume). The organic layers were washed with water, brine, dried over Na 2 SO 4 , and evaporated to dryness to afford an acylated product typically used without further purification.
• Some examples of compounds of the present invention are shown below:
• 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): 1) Cancer.
• the compounds provided herein can be used for treating, preventing or managing either primary or metastatic tumors.
• 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 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-related acute myeloid leukemia, prolymphocytic leukemia, and chronic myelomono
• 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
• cryoglobulinemia essential mixed cryoglobulinemia, evans syndrome, felty syndrome, fibromyalgia, gastritis, gestational pemphigoid, giant cell arteritis, goodpasture syndrome, Graves' disease, graves ophthalmopathy, Guillain–Barré syndrome, hashimoto's encephalopathy, hashimoto thyroiditis, Henoch-Schonlein purpura, hidradenitis suppurativa, idiopathic inflammatory demyelinating diseases, igG4-related systemic disease, inclusion body myositis, inflamatory bowel disease (IBD), intermediate uveitis, interstitial cystitis, juvenile arthritis, kawasaki's disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, ligneous conjunctivitis, linear IgA disease, lupus nep
• 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, 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; 4) Macular Degeneration ("MD”) and related syndromes, such as: atrophic (dry) MD, exudative
• Examples of 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-Trélat, warty dyskeratoma (WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV), ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneous melanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma, confluent and reticulated papillomatosis (CRP), acrochordons, cutaneous horn, cowden disease (multiple hamartoma syndrome), dermatosis papulosa nigra (DPN), epiderma
• 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 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, chronic obstructive pulmonary disease, interstitial lung disease, sleep- disordered breathing, alveolar hypoventilation disorder, chronic exposure to high altitude, neonatal lung disease, alveolar
• volvulus.Other diseases and disorders caused by non-human intracellular parasites such as, but not limited to,Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp.,andTheileria ssp.,are also encompassed.
• 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 immuno
• the compounds of the present invention may also inhibit the production of certain cytokines including, but not limited to, TNF- ⁇ , IL-1 ⁇ , IL-12, 1L-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 immunomodulatory and/or cytotoxic, and thus may be useful as chemotherapeutic agents.
• the compounds of the present invention are advantageous in terms of their synthetic feasibility.
• the synthesis of the compounds can be summarized in the following general procedure (carried out under Synthetic Conditions A or Synthetic Conditions B, as set out below: An appropriate acid (RCOOH in the above reaction scheme) (1.1 eq), DMAP (0.04 eq), and EDC (1.2 eq) were added to a solution of 3-aminopiperidine-2,6-dione (1 eq) and N- hydroxybenzotriazole (1.2 eq) in DMF (0.5 M). The reaction mixture was stirred overnight at room temperature (20-25°C). Water (2 x DMF volume) was added and the obtained solution was extracted with dichloromethane (3 ⁇ DMF volume).
• Example method 1 formation of chlorinated R group of RCOOH (or its ester RCOOR’) N-chlorosuccinimide(1.1 eq) was added to a solution of an appropriate starting material (1 eq) in DMF (0.5 M) and the reaction mixture was stirred for 2 h at room temperature (20-25°C). The reaction mixture was poured into water (2 x DMF volume) and occurred precipitate was filtered. The solids were washed with water and dried in vacuum to give the acid, ROOH.
• Example method 3 formation of acetylated R group of RCOOR’
• a mixture of an appropriate amine (1 eq.), Ac 2 O (3 eq.), and DMAP (0.2 eq.) in dioxane (0.2 M) was heated to 80°C for 2 h. Upon completion, the mixture was cooled down to room temperature (20- 25°C) and concentrated under reduced pressure. The residue was diluted with water (1 x dioxane volume) and extracted with EtOAc (3 x dioxane volume). The organic layers were washed with water, brine, dried over Na 2 SO 4 , and evaporated to dryness to afford an acylated product typically used without further purification.
• Example 1 Synthesis of tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2- yl)carbamate (1) H O S N NH T sing the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (52% yield) using 2-((tert-butoxycarbonyl)amino)thiophene-3- carboxylic acid (43 mg) as a starting material.
• Step B Acetic anhydride (0.265 g, 2.60 mmol) and DMAP (0.026 g, 0.213 mmol) were added to a solution of N-(2,6-dioxopiperidin-3-yl)-2-(methylamino)thiophene-3-carboxamide (0.579 g, stirred at 60°C for 16 h, washed with water and extracted with EtOAc (3 x 10 mL), dried over Na 2 SO 4 , concentrated under reduced pressure and purified by HPLC to give N-(2,6-dioxopiperidin-3- yl)-2-(N-methylacetamido)thiophene-3-carboxamide (11% yield).
• Step C methyl 2-acetamido-4-methoxythiophene-3-carboxylate was obtained in 73% yield using Example Method 3, above, with methyl 2-amino-4-methoxythiophene-3-carboxylate as a starting material.
• Step D 2-acetamido-4-methoxythiophene-3-carboxylic acid was obtained in 20% yield using Example Method 2, above, with methyl 2-acetamido-4-methoxythiophene-3-carboxylate as a starting material. synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (47% yield), and 2-acetamido-4-methoxythiophene-3-carboxylic acid as a starting material.
• Step C Ethyl 5-cyano-2-acetamidothiophene-3-carboxylate (9.45 g, 39.7 mmol) was dissolved in EtOH:THF solution (120 mL:360 mL), the solution was cooled to +5°C and lithium hydroxide monohydrate (11.7 g, 278 mmol) in H 2 O (120 mL) was added dropwise over 20 min. The reaction mixture was stirred ar RT for 18h, concentrated under reduced pressure and acidified with 15% citric acid. The product was extracted with EtOAc, dried over Na 2 SO 4 and evaporated under reduced pressure to give 5-cyano-2-acetamidothiophene-3-carboxylic acid (57% yield).
• Step B Triethylamine (3.3 g, 32.6 mmol), DMAP (0.13 g, 1.06 mmol) and acetic acid (1.67 g, 27.8 mmol) were added to a solution of tert-butyl 2-amino-5-(methylcarbamoyl)thiophene-3-carboxylate (2.8 g, 10.9 mmol) in dry MeCN (30 mL).
• Step C 10% HCl in dioxane (20 mL) was added to a solution of tert-butyl 2-acetamido-5- (methylcarbamoyl)thiophene-3-carboxylate (3.1 g, 10.4 mmol) in DCM (20 mL) and the reaction mixture was stirred for 3 days at RT.
• Step D N 4 -(2,6-dioxopiperidin-3-yl)-5-acetamido-N 2 -methylthiophene-2,4-dicarboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (44% yield), and 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxylic acid as a starting material.
• Step B 3-Aminopiperidine-2,6-dione hydrochloride (0.655 g, 3.98 mmol) and triethylamine (0.483 g, 4.77 mmol) were added to a solution of 6-chloro-1-methyl-1H,2H,4H-thieno[2,3- d][1,3]oxazine-2,4-dione (0.865 g, 3.97 mmol) in ethanol (20 mL) and the reaction mixture was refluxed for 18h, concentrated under reduced pressure and diluted with water.
• Step C 10% aqueous solution of LiOH (6 mL) was added to a solution of crude methyl 2-[(2S)-2- [(tert-butyldimethylsilyl)oxy]propanamido]-5-chlorothiophene-3-carboxylate (2.42 g, 6.40 mmol) in THF (12 mL) and the mixture was stirred at RT for 3 days.
• the reaction mixture was concentrated under reduced pressure, diluted with water and acidified with 10% HCl.
• the product was extracted into DCM, dried over Na 2 SO 4 , concentrated under reduced pressure and crystallized to give (S)-5- chloro-2-(2-hydroxypropanamido)thiophene-3-carboxylic acid (25% yield).
• Step B 5-chloro-N-(2,6-dioxopiperidin-3-yl)-3-acetamidothiophene-2-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions A, above (40 % yield), and 5-chloro-3-acetamidothiophene-2-carboxylic acid as a starting material.
• Step B 4-chloro-5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid was obtained in 78% yield using Example Method 2, above, with methyl 4-chloro-5-cyclopropyl-2-acetamidothiophene-3- carboxylate as a starting material.
• Step C HATU (0.370 g, 0.973 mmol) was added to the solution of 4-chloro-5-cyclopropyl-2- acetamidothiophene-3-carboxylic acid (0.211 g, 0.812 mmol), 3-aminopiperidine-2,6-dione (0.134 g, 1.05 mmol) and N-methylmorpholine (0.205 g, 2.03 mmol) in DMF (5 mL) at 0°C.
• Step B To a solution of tert-butyl N-( ⁇ 4-[(2,6-dioxopiperidin-3-yl)carbamoyl]-5-methoxythiophen-2- yl ⁇ methyl)carbamate) (8.7 mg, 0.022 mmol, 1 eq.) in dioxane (2 mL) was added 36% HCl (0.2 mL). The reaction was stirred at rt for 3h and concentrated under reduced pressure to give a 5- (aminomethyl)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide hydrochloride (100% yield).
• Step D 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (76% yield) using 5-cyclopropyl-2-methoxythiophene-3-carboxylic acid (20 mg) as a starting material.
• n ry ( m ) was a e 2.5M n-BuLi hexane solution (6.47 mL, 16.2 mmol) at -78 °C under argon atmosphere and the solution was stirred for 1h.
• Tri-n-butyl borate (8.35 mL, 29.42 mmol) was added to the reaction mixture, the mixture was stirred for 1.5h and warmed to RT.20% Na 2 CO 3 (33.6 mL), iodobenzene (1.65 mL, 14.71 mmol), and Pd(PPh 3 ) 4 (0.85 g, 0.73 mmol) were added and the reaction mixture was refluxed for 16h.
• Step C Benzyl 2-methoxy-5-phenylthiophene-3-carboxylate (230 mg, 0.71 mmol) was dissolved in THF (5 mL). MeOH (5 mL) and 50% NaOH solution (10 mL) were added and the reaction mixture was stirred at RT for 16h and acidified with 6 M HCl.
• Step C To a stirred solution of benzyl 5-(tert-butyl)-2-methoxythiophene-3-carboxylate (450 mg, 1.47 mmol) in THF (8 mL) and methanol (8mL) at 5 °C was added 50 % aq. NaOH (16 mL). The reaction mixture was stirred at RT for 16h and acidified with 6 M HCl.
• Step D 5-(tert-butyl)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (75% yield) using 5-(tert-butyl)-2-methoxythiophene-3-carboxylic acid (20 mg) as a starting material.
• Step 2 synthesis of N- ⁇ 3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen-2-yl ⁇ acetamide Fe (0.47 g, 8.42 mmol) was added to a solution of N-(2,6-dioxopiperidin-3-yl)-2-nitrothiophene-3- sulfonamide (0.895 g, 2.80 mmol) in acetic acid (6 mL). The reaction mixture was stirred for 3 h at 50°C. Acetic anhydride (0.315 g, 3.09 mmol) was added under room temperature and the resulting mixture was stirred for 16 h at 50°C.
• Step 3 P synthesis of N- ⁇ 5-chloro-3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen-2-yl ⁇ acetamide NCS (0.161 g, 1.21 mmol) was added to a solution of N- ⁇ 3-[(2,6-dioxopiperidin-3-yl)sulfamoyl]thiophen- 2-yl ⁇ acetamide (0.362 g, 1.09 mmol) in DMF (2 mL). The reaction mixture was stirred for 16 h at room temperature, then it was diluted with water and extracted with EtOAc (3 x 10 mL).
• Step B Tert-butyl N- ⁇ 5-chloro-3-[(2,6-dioxopiperidin-3-yl)carbamoyl]thiophen-2-yl ⁇ carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions A, above (81% yield), and 2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -5-chlorothiophene-3-carboxylic acid as a starting material.
• Step B 10% solution of LiOH (0.081 g, 3.4 mmol) was added to a solution of ethyl 2-acetamido-5- (trifluoromethyl)thiophene-3-carboxylate (0.911 g, 3.24 mmol) in THF (15 mL) and the resulting mixture was stirred for 5 days at RT. The solvents were evaporated under reduced pressure, the residue was diluted with water and washed with MTBE.
• Step C N-(2,6-dioxopiperidin-3-yl)-2-acetamido-5-(trifluoromethyl)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions A, above (26% yield), and 2-acetamido-5-(trifluoromethyl)thiophene-3-carboxylic acid as a starting material.
• Step B POCl 3 (1.05 g, 6.85 mmol) was added to a suspension of methyl 2-acetamido-4-oxo-4,5- dihydrothiophene-3-carboxylate (0.74 g, 3.44 mmol) in dioxane (10 mL) and refluxed for 2 h. The reaction mixture was cooled and poured into iced water, the product was extracted with EtOAc, dried over Na 2 SO 4 and concentrated under reduced pressure to give methyl 4-chloro-2- acetamidothiophene-3-carboxylate (26% yield).
• Step C 4-chloro-2-acetamidothiophene-3-carboxylic acid was synthesized using Example Method 2, above, with methyl 4-chloro-2-acetamidothiophene-3-carboxylate as a starting material.
• Step D 4-chloro-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (17% yield), and 4-chloro-2-acetamidothiophene-3-carboxylic acid as a starting material.
• Step C 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (56% yield), and 5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid as a starting material.
• Step B 2-benzamido-5-chlorothiophene-3-carboxylic acid was synthesized using Example Method 2, above (70% yield), using methyl 2-benzamido-5-chlorothiophene-3-carboxylate as a starting material.
• Step C 2-benzamido-5-chloro-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions A, above (50% yield), and 2-benzamido-5-chlorothiophene-3-carboxylic acid as a starting material.
• Step B 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylic acid was synthesized using Example Method 2, above (82% yield), using methyl 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylate as a starting material.
• Step C 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(2-phenylacetamido)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions A, above (15% yield), with 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylic acid as a starting material.
• Step B n-butyllithium (3.37 ml, 5.43 mmol, 1.6 M in hexane) was added slowly to a THF (30 ml) solution of tert-butyl (3-bromofuran-2-yl)(methyl)carbamate (1.5 g, 5.43 mmol) at -78°C under nitrogen. After 15 min of stirring, a stream of dry CO 2 was bubbled into the solution for 30 min. The under reduced pressure to give 2-((tert-butoxycarbonyl)(methyl)amino)furan-3-carboxylic acid 500 mg (38% yield).
• Step C tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)furan-2-yl)(methyl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above, (59% yield) using 2-((tert-butoxycarbonyl)(methyl)amino)furan-3-carboxylic acid (20 mg) as a starting material.
• Step B ((4-bromo-3-methoxythiophen-2-yl)methoxy)(tert-butyl)dimethylsilane (1.5 g, 4.45 mmol) was dissolved in THF (20 mL) and cooled to -78 °C. n-BuLi (3.7 mL, 6.67 mmol) was added dropwise and the reaction mixture was stirred for 30 min. Methyl chloroformate (0.62 mL, 8.0 mmol) was added and stirring was continued for 2h at -78 °C.
• Step C methyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxythiophene-3-carboxylate (0.8 g, 2.52 mmol) was dissolved in THF (10 mL) and TBAF (1M solution in THF) (5.06 mL, 5.0 mmol) was added at 0 °C.
• Step D methyl 5-(hydroxymethyl)-4-methoxythiophene-3-carboxylate (0.2 g, 1.0 mmol) was dissolved in toluene (3 mL) and cooled to 0 °C. DBU (0.19 mL, 1.3 mmol), and DPPA (0.26 mL, 1.2 mmol) were added and reaction mixture was stirred at RT for 16h.
• Step E methyl 5-(azidomethyl)-4-methoxythiophene-3-carboxylate (40 mg, 0.176 mmol) was dissolved in MeOH (5 mL) and 10% Pd/C (20 mg) was added.
• Step G To 5-(((tert-butoxycarbonyl)amino)methyl)-4-methoxythiophene-3-carboxylate (200.0 mg, 0.66 mmol) in THF (1.0 mL) was added methanol (1.0 mL) and 50% aqueous NaOH (2 mL), the reaction mixture was stirred at RT for 16h, diluted with water and acidified with citric acid. The product was extracted with ethyl acetate, concentrated and triturated with diethyl ether to give 5- (((tert-butoxycarbonyl)amino)methyl)-4-methoxythiophene-3-carboxylic acid (83% yield).
• Step H tert-butyl ((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-methoxythiophen-2- yl)methyl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (23% yield), and 5-(((tert-butoxycarbonyl)amino)methyl)-4- methoxythiophene-3-carboxylic acid (30mg) as a starting material.
• Step B 1M NaOH in H 2 O (10 eq.) was added to a solution of methyl 2-((tert- butoxycarbonyl)(methyl)amino)thiophene-3-carboxylate (52.0 mg, 1.eq.) in methanol and was stirring at room temperature for 18 hours.
• the reaction was completed, to the acidified with 1M HCl, concentrated under reduced pressure and partitioned between ethyl acetate and water. Organic layer was washed with brine, dried over Na 2 SO 4 and evaporated.2-((tert- butoxycarbonyl)(methyl)amino)thiophene-3-carboxylic acid (100%) was used without further purification in the next step.
• Step C tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)(methyl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (57% yield) using 2-((tert-butoxycarbonyl)(methyl)amino)thiophene-3-carboxylic acid (49.4 mg) as a starting material.
• Step B N-(2,6-dioxopiperidin-3-yl)-5-phenyl-2-(2-(pyrrolidin-1-yl)acetamido)thiophene-3- carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (15% yield) using 5-phenyl-2-(2-(pyrrolidin-1- yl)acetamido)thiophene-3-carboxylic acid (18 mg) as a starting material.
• Step B Tert-butyl ((3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)methyl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (37% yield) using 2-(((tert-butoxycarbonyl)amino)methyl)thiophene-3-carboxylic acid (30 mg) as a starting material.
• Step C To a stirring solution of methyl 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4- carboxylate (300 mg, 1.042 mmol, 1eq) in THF:MeOH:H 2 O 3:2:1 (12 mL) was added LiOH ⁇ H 2 O (131 mg, 3.125 mmol, 3eq).
• Step E To a solution of tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazol-2- yl)carbamate (19.6 mg, 0.051 mmol, 1 eq.) in water (3 mL) and dioxane (3 mL) was added 36% HCl amino-N-(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxamide hydrochloride (100% yield).
• Step C To a solution of methyl 2-bromo-5-methoxythiazole-4-carboxylate (1.0 g, 3.968 mmol, 1 eq) in THF (30 mL) and water (15 mL) was added triethylamine (2.701 ml, 19.841 mmol, 5eq) and the solution was purged with argon for 10 min.
• Step D To a solution of 5-methoxy-4-(methoxycarbonyl)thiazole-2-carboxylic acid (300 mg, 1.382 mmol, 1 eq) in tert-butanol (15 mL) was added 2-tert-butyl-1,3-diisopropylisourea (829 mg, 4.147 mmol, 3 eq) and the reaction mixture was stirred at RT for 16h, diluted with ethyl acetate and washed by water, . dried over Na 2 SO 4 , concentrated under reduced pressure and purified by flash column chromatography to give 2-tert-butyl 4-methyl 5-methoxythiazole-2,4-dicarboxylate (31% yield).
• Step E To a solution of 2-tert-butyl 4-methyl 5-methoxythiazole-2,4-dicarboxylate (220 mg, 0.806 mmol, 1 eq) in DCE (5 mL) was added trimethyltin hydroxide (728 mg, 4.029 mmol, 5 eq). Reaction mixture was stirred at 90 °C for 6h, filtered, the filtrate was concentrated under reduced pressure and purified by HPLC to give 2-(tert-butoxycarbonyl)-5-methoxythiazole-4-carboxylic acid (11% yield).
• Step F tert-butyl 4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazole-2-carboxylate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (39% yield) using 2-(tert-butoxycarbonyl)-5-methoxythiazole-4-carboxylic acid (16.5 mg) as a starting material.
• Step G tert-butyl 4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazole-2-carboxylate (6 mg, 0.016 mmol) was dissolved in DCM (0.5 mL) and trifluoroacetic acid (0.092 mL) was added. The Reaction was stirred at RT for 2h and concentrated under reduced pressure to give 4-((2,6- dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazole-2-carboxylic acid (71% yield).
• Example 78 Synthesis of 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)thiazole-4-carboxamide (82) S O H T p y hesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (67% yield) using 5-cyclopropyl-1,3-thiazole-4-carboxylic (20 mg) as a starting material.
• Example 80 Synthesis of 2-benzamido-N-(2,6-dioxopiperidin-3-yl)-4,5-dimethylthiophene-3- carboxamide (87) H O S T s co pou was sy es e using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (27% yield) using 2-benzamido-4,5-dimethylthiophene-3-carboxylic acid (20 mg) as a starting material.
• Step B N-(2,6-dioxopiperidin-3-yl)-2,4-dimethylthieno[3,4-b]pyridine-7-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above (53% yield), and 2,4-dimethylthieno[3,4-b]pyridine-7-carboxylic acid (23.4 mg) as a starting material.
• Step B N-(2,6-dioxopiperidin-3-yl)-4-hydroxy-2-(trifluoromethyl)thieno[3,4-b]pyridine-7- carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above (24% yield), and 4-hydroxy-2-(trifluoromethyl)thieno[3,4-b]pyridine- 7-carboxylic acid (28 mg) as a starting material.
• Step B A solution of methyl 2- ⁇ [(2-bromopyridin-3-yl)methyl]sulfanyl ⁇ acetate (4.5 g, 16.295 mmol) in THF (25 mL) was added slowly to a suspension of KH (1.307 g, 32.591 mmol) and stirred for 20 min at room temperature.
• Step C To the stirred solution of methyl 5H,7H-thieno[3,4-b]pyridine-7-carboxylate (3 g, 15.385 mmol) in CHCl 3 (25 mL) was added activated MnO 2 (13.375 g, 153.846 mmol) and the reaction mixture was stirred at RT for 16h, filtered through celite bed, concentrated under reduced pressure and purified by flash column chromatography to give methyl thieno[3,4-b]pyridine-7-carboxylate (46% yield).
• Step E Synthesis of N-(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above (69 % yield), and thieno[3,4-b]pyridine-7-carboxylic acid (25.0 mg) as a starting material.
• 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.
• CK1 ⁇ degradation assay – Kelly cell line The effect of various compounds of the invention and various reference compounds on CK1 ⁇ 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% CO2), 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.
• FBS Fetal Bovine Serum
• CK1 ⁇ protein reduction is provided based on normalized densitometry values.
• Table 4 CK1 ⁇ degradation in Kelly cell line. Cells were treated with the compounds: 22, 21, 108, 110 at 20 ⁇ M concentration for 24h. % of CK1 ⁇ protein reduction is provided based on normalized densitometry values.
• Example 102 IKZF1 degradation assay – H929 cell line
• 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%.
• Densitometry values are normalized to the loading control ( ⁇ -ACTIN) and presented as % of DMSO control, using the following labels: ⁇ 25% for 0-25% of IKZF1 protein reduction, >25% for 26-74% of IKZF1 protein reduction, ⁇ 75% for 75-100% of IKZF1 protein reduction.
• Figure 2 and Tables 5a and 5b. The remaining compounds are presented in Table 6. As illustrated with these results, the compounds of the present invention present no or low IKZF1 degradation capabilities, in contrast to the LENALIDOMIDE and even more effective POMALIDOMIDE and CC-122. Tables 5a and 5b. IKZF1 degradation in H929 cell line.
• % of IKZF1 ⁇ protein reduction is provided based on normalized densitometry values.
• Table 5a % of IKZF1 protein reduction, based on densitometry values
• Table 5b % of IKZF1 protein reduction based on densitometry values
• Table 6 IKZF1 degradation in H929 cell line. Cells were treated with the compounds at 20 ⁇ M concentration for 24h. % of IKZF1 protein reduction is provided based on normalized densitometry values.
• Example 103 IKZF3 degradation assay – H929 cell line
• 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%.
• % of IKZF3 protein reduction is provided based on normalized densitometry values.
• Table 7a % of IKZF3 protein reduction, based on densitometry values
• Table 7b % of IKZF3 protein reduction, based on densitometry values
• the compounds of invention are capable of potent degradation of CK1 ⁇ , a disease relevant protein kinase.
• Y 1 is CH; Y 2 is CH or CCl; and Y 4 is C-OR’’ or C-NH 2 , optionally C-OMe or C-NH 2 .
• each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, -NR’’C(O)R’’, NR’’C(O)OR’’, -NR’’C(O)CH(OH)R’’, -NHR’’, - NH 2 , -OR’’, -CN, -C(O)NR’’ 2 , or -NR’’SO 2 R’’. 35.
• any one of embodiments 73-76 wherein 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 TNF ⁇ related disorders.
• MD macular degeneration
• 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 TNF ⁇ related disorders.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Endocrinology (AREA)
• Mycology (AREA)
• Immunology (AREA)
• Microbiology (AREA)
• Pulmonology (AREA)
• Dermatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=69024571

Family Applications (1)

Country Status (4)

Cited By (7)

Citations (15)

• 2020
  • 2020-11-27 WO PCT/EP2020/083597 patent/WO2021105335A1/en not_active Ceased
  • 2020-11-27 EP EP20838351.3A patent/EP4065576A1/en active Pending
  • 2020-11-27 US US17/780,894 patent/US20230065745A1/en active Pending
  • 2020-11-27 JP JP2022532095A patent/JP7760167B2/ja active Active

Patent Citations (16)

Non-Patent Citations (13)

Also Published As

Similar Documents

Legal Events