WO2022255890A1 - Composés se liant au céréblon et leur utilisation - Google Patents

Composés se liant au céréblon et leur utilisation Download PDF

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WO2022255890A1
WO2022255890A1 PCT/PL2021/000034 PL2021000034W WO2022255890A1 WO 2022255890 A1 WO2022255890 A1 WO 2022255890A1 PL 2021000034 W PL2021000034 W PL 2021000034W WO 2022255890 A1 WO2022255890 A1 WO 2022255890A1
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compound
hydrogen
nhr
alkyl
benzyl
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PCT/PL2021/000034
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English (en)
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Sylvain Cottens
Katarzyna Kaczanowska
Roman PLUTA
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Captor Therapeutics S.A.
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Priority to PCT/PL2021/000034 priority Critical patent/WO2022255890A1/fr
Publication of WO2022255890A1 publication Critical patent/WO2022255890A1/fr

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    • 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

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
  • the antitumor activity of cereblon modulators is mediated by:
  • each of X 1 and X 2 is independently 0 or S;
  • each R is independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -CH 2 NR" 2 , - NR"C(0)R", - NR"C(0)CH 2 NR" 2 , -NR"C(0)CH 2 -heterocycloalkyl, -NR"C(0)CH(0H)R", -CH 2 NR"C(0)0R", - NR"C(0)0R", -NR"C(0)0R", -NR"
  • R 2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NR"C(0)R", -N[C(0)R”] 2 , -NR"C(0)OR", -NO3 ⁇ 4 -CN, -C(0)R", -C(0)OR", - C(0)NH 2 , -C(0)NHR", -C(0)NR” 2 , -OR", -OC(0)R", -OC(0)OR", -OC(0)NH 2 , -OC(0)NHR", -0C(O)NR” 2 , - SR", or -S(0) 2 R",-S(0) 2 0R", -S(0) 2 NH 2 , -S(0) 2 NHR", or -S(0) 2 NR" 2 ;
  • R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
  • R 3 is hydrogen, deuterium or alkyl; each R 4 is independently deuterium or hydrogen;
  • R 5 is hydrogen, deuterium or alkyl; wherein when Z is O, then Y 2 is CR'.
  • the compound is of Formula (la) or (lb). In some such embodiments, the compound has the structure: In other such embodiments, the compound has the structure:
  • the compound is of Formula (lla) or (lIb). In other embodiments, the compound is of Formula (Ilia) or (lllb).
  • each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NFI2, -NHR", -NR"2, -NR"C(0)R”, - NR"C(0)CH(0H)R", -NR"C(0)0R", -NR"S0 2 R", -NO2, -CN, -C(0)R", -C(0)0R", -C(0)NH 2 , -C(0)NHR", - C(0)NR” 2 , -OR", -0C(0)R", -0C(0)0R", -0C(0)NH 2 , -0C(0)NHR", -0C(0)NR” 2 , -SR", or -S(0) 2 R",- S(0) 2 0R", -S(0) 2 NH 2 , -S(0) 2 N
  • Z is S or NR 2 . In some embodiments, Z is S. In other embodiments, Z is NR 2 . In some embodiments, R 2 is alkyl, benzyl, or -N[C(0)R"] 2 . In certain embodiments, R 2 is hydrogen.
  • Y 1 is not C- NHC(0)R" or -C(0)OR.
  • L is alkyl, benzyl, -C(0)Me, or -C(O) t Bu. In other embodiments, L is hydrogen.
  • each R 4 is deuterium. In other embodiments, each R 4 is hydrogen.
  • R 3 is deuterium
  • R 5 is deuterium. In other embodiments, R 5 is hydrogen.
  • R 1 is hydrogen
  • the compound is of Formula (la), wherein one of Y 1 , Y 2 and Y 3 is N, and the remaining two of Y 1 , Y 2 and Y 3 are each CR.
  • the compound is of Formula (la), 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; or
  • Y 3 is CR, and Y 1 and Y 2 are N.
  • the compound is of Formula (la) and Y 1 , Y 2 and Y 3 are each CR.
  • the compound is of Formula (lb), wherein one of Y 1; Y 2 and Y 4 is N and the remaining two of Y 1 , Y 2 and Y 4 are each CR, and wherein Z is S.
  • 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 (lb), 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, and Y 2 and Y 4 are N
  • Y 2 is CR
  • Y 1 and Y 4 are N
  • Y 4 is CR, and Y 1 and Y 2 are N.
  • each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, -OR", -N[C(0)R") 2 , -NR"C(0)R", -NHC(0)OR", -NHR", -NH 2 , or -NHS0 2 R"CN.
  • each R" is independently alkyl, cycloalkyl, aryl or benzyl.
  • each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, heteroaryl, -NR"C(0)R", NR"C(0)OR", -NR"C(0)CH(OH)R", -NHR", -NH 2 , -OR", -CN, -C(0)NR” 2 , or - NR"S0 2 R".
  • each R is independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, -OR", -CN, -NHC(0)R", -NHC(0)OR", -NHR", -NH 2 or -NHS0 2 R".
  • each R" is independently alkyl, cycloalkyl, aryl or benzyl.
  • the compound is of Formula (la), wherein:
  • R 1 is hydrogen
  • L is hydrogen
  • Z is S, wherein, when Y 1 and Y 3 are CR, then
  • Y 1 is CH
  • Y 3 is CH
  • Y 2 is C-OH or C- CH 2 NHC(0)0R";
  • Y 1 is CH, Y 2 is CH, and Y 3 is C-CH 2 NHC(0)0R"; and when Y 2 is N, then Y 3 is C-NHC(0)0R" or C-NH 2 .
  • R 1 is hydrogen
  • L is hydrogen
  • Z is S
  • Y 2 and Y 4 are CR, wherein: when Y 1 is N, then Y 2 is CH, C-NH 2 or C- CH 2 NHC(O)OR" and Y 4 is CH or C-OR", wherein at least one of Y 2 and Y 4 is not CH; and when Y 1 , Y 2 and Y 4 are each CR, then Y 1 is CH, C-alkyl, C-CI or C-OR"
  • Y 2 is CH, C-halogen, C-cycloalkyl, C-haloalkyl, C-aryl, C-CONH(R"), or C-CN
  • Y 4 is CH, C-NH 2 , C-NHR", C-NR"C(0)R", C-NR"S0 2 R", or C-OR"; at least one of Y 1 , Y 2 and Y 4 is CH or C-CI; and (a) when Y 1 and Y 2 are CH, then Y 4 is C-NHCOR", C-IMHSO 2 R", C-OR", or C-NH 2 ,
  • Y 3 is N or CR
  • Y 4 is N or CR; indicates a single or double bond, wherein when each is a double bond, each of W 1 , W 2 , W 3 and W 4 is independently N or
  • CR' wherein at least one of W 1 , W 2 , W 3 and W 4 is N, and when each is a single bond, W 1 , W 2 , W 3 and W 4 are each CR' 2 and Y 4 is CR; n is 0, 1 or 2;
  • L is hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH 2 OC(O) t Bu, - C(0)OR", -C(0)R"-C(0)NH 2 , -C(0)NHR", -C(0)NR” 2 , -OR", -NR" 2 , -S(0) 2 R” or P(0)(OR")(OR”); each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NR"C(0)R", -NR"C(0)CH 2 R", - NR"C(0)CH(0H)R", -NR"C(0)0R", -NR"S0 2 R", -NO2,
  • R 2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH 2 , -NHR", -NR" 2 , -NR"C(0)R", -N[C(0)R”] 2 , -NR"C(0)0R", -N0 2 , -CN, -C(0)R", -C(0)0R", - C(0)NH 2 , -C(0)NHR", -C(0)NR” 2 , -OR", -0C(0)R", -0C(0)0R", -0C(0)NH 2 , -0C(0)NHR", -0C(O)NR” 2 , - SR", or -S(0) 2 R",-S(0) 2 0R", -S(0) 2 NH 2 , -S(0) 2 NHR", or -S(0) 2 NR"
  • R 3 is hydrogen, deuterium or alkyl; each R 4 is independently deuterium or hydrogen;
  • R 5 is hydrogen, deuterium or alkyl
  • R 1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; wherein when each is a double bond, Z is NR 2 , R 2 is hydrogen, and each R' is hydrogen, then W 4 is CR'.
  • the compound is of Formula (IVa) or (IVb). In some such embodiments, the compound has the structure: In other such embodiments, the compound has the structure:
  • the compound is of Formula (Va) or (Vb). In other embodiments, the compound is of Formula (Via) or (Vlb). In other embodiments, the compound is of Formula (IVa) or (Va).
  • Z is NR 2
  • R 2 is hydrogen
  • Y 3 and Y 4 are
  • 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', then at least one R' is not hydrogen.
  • Z is 0. In other embodiments, Z is S. In other embodiments Z is NR 2 .
  • L is alkyl, benzyl, -C(0)Me, or -C(0)‘Bu. In other embodiments, L is hydrogen.
  • each R 4 is deuterium. In other embodiments, each R 4 is hydrogen.
  • R 3 is deuterium. In other embodiments, R 3 is hydrogen.
  • R 5 is deuterium. In other embodiments, R 5 is hydrogen.
  • R 1 is hydrogen
  • Y 3 is N. In other embodiments, Y 3 is CR.
  • Y 4 is N. In other embodiments, Y 4 is CR. In some embodiments, each is a double bond or each is a single bond.
  • each is a double 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'.
  • two of W 1 , W 2 , W 3 and W 4 is N, and the remaining two of W 1 , W 2 , W 3 and W 4 are each CR'.
  • 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 each N.
  • each is a single bond.
  • each R is independently hydrogen, halogen or -NR"C(0)R".
  • At least one R' is not hydrogen. In other embodiments, each R' is hydrogen.
  • each is a double bond
  • W 1 is N
  • W 2 is C-Me
  • W 3 and W 4 are C-H
  • Z is S
  • Y 3 is C-H.
  • the compound is selected from:
  • R 3 when R 3 is hydrogen, at least one R 4 is deuterium.
  • R 3 is hydrogen
  • X 1 is 0. In other embodiments, X 1 is S.
  • X 2 is O. In other embodiments, X 2 is S. In some embodiments of any of the above aspects, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.
  • the alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups are all unsubstituted.
  • the present invention also provides compound of any of the above aspects and embodiments, for use as a cereblon binder.
  • the present invention also provides a pharmaceutical composition comprising a compound the invention.
  • a compound or composition 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, or TNFa 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, or TNFa related disorders.
  • MD macular degeneration
  • the method further comprises administering at least one additional active agent to the patient.
  • 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 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
  • Example compounds of the present invention are: In accordance with a third aspect of the invention, there is provided 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 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, 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 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.
  • 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 anticancer 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 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.
  • 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.
  • the alkyl group is an unsubstituted alkyl group.
  • the alkyl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 -NHR W , -NR W 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • 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.
  • the alkyl group is a linear alkyl group. In some embodiments the alkyl group is an unsubstituted linear alkyl group.
  • the alkyl group is a linear alkyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR W , -NR W 2 , -SO 2 R w , - C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the alkyl group is a branched alkyl group.
  • the alkyl group is an unsubstituted branched alkyl group.
  • the alkyl group is a branched alkyl group which is substituted by one or more groups selected from -OH, - OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • alkenyl is intended to include both unsubstituted alkenyl groups, and alkenyl groups which are substituted by one or more additional groups.
  • the alkenyl group is an unsubstituted alkenyl group.
  • the alkenyl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR W , -NR W 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • 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.
  • the alkenyl group is a linear alkenyl group.
  • the alkenyl group is an unsubstituted linear alkenyl group.
  • the alkenyl group is a linear alkenyl group which is substituted by one or more groups selected from -OH, - OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the alkenyl group is a branched alkenyl group.
  • the alkenyl group is an unsubstituted branched alkenyl group.
  • the alkenyl group is a branched alkenyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR w , -NR w 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • alkynyl is intended to include both unsubstituted alkynyl groups, and alkynyl groups which are substituted by one or more additional groups.
  • the alkynyl group is an unsubstituted alkynyl group.
  • the alkynyl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR W , -NR W 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • 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.
  • the alkynyl group is a linear alkynyl group.
  • the alkynyl group is an unsubstituted linear alkynyl group.
  • the alkynyl group is a linear alkynyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR W , -NR W , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the alkynyl group is a branched alkynyl group.
  • the alkynyl group is an unsubstituted branched alkynyl group. In some embodiments the alkynyl group is a branched alkynyl group which is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR W , -NR W 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • aryl is intended to include both unsubstituted aryl groups, and aryl groups which are substituted by one or more additional groups.
  • the aryl group is an unsubstituted aryl group.
  • the aryl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR W , -NR W 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the aryl group is a C 6 -Cio 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.
  • the heteroaryl group is an unsubstituted heteroaryl group.
  • the heteroaryl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR W , -NR W 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the heteroaryl group is a C 6 -C 10 heteroaryl, a C 6 -Cg 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.
  • the benzyl group is an unsubstituted benzyl group.
  • the benzyl group is substituted by one or more groups selected from -OH, -OR w , -NH 2 , -NHR W , -NR W 2 , -SO 2 R w , -C(0)R w , -CN, and -N0 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • all alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups in the compounds are unsubstituted.
  • the present invention provides compounds of Formulas (la), (lb), (lla), (lib), (Ilia), (lllb), (IVa), (IVb), (Va), (Vb), (Via) and (Vlb):
  • Biotransformation of thalidomide-based drugs in humans includes chiral inversion, hydroxylation, and slow non-enzymatic hydrolysis (see Chen N et al.: Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide. Clin Pharmacokinet 2017; 56(139)).
  • Disclosed cereblon ligands contain structural modifications of the glutarimide that are designed to alleviate the ligand's chemical and biochemical instability resulting in improved in vitro and in vivo stability. These modifications include for example application of compatible protecting groups, deuteration, or incorporation of an oxetane ring as a bioisostere of a carbonyl group .
  • Most chiral drugs are developed as single enantiomers to limit the undesired enantiomer's impact on the drug development processes. Unfortunately, some chirally pure drug molecules, such as thalidomide, are hampered by rapid in vivo racemization.
  • Some examples of compounds of the present invention include:
  • 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:
  • R 1 is as defined in Formulas (la) - (Vlb) above, R v is
  • R X SO 2 CI may be used in place of R x COOH.
  • Binding of the compounds of the present invention 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 compounds of the present invention 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 may possess pharmaceutically advantageous properties, such as increased stability and improved ADMET (absorption, distribution, metabolism, excretion, and/or toxicity) properties.
  • ADMET absorption, distribution, metabolism, excretion, and/or toxicity
  • 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; 4 Macular Degeneration ("MD”) and related syndromes, such as: atrophic (dry) MD, exudative (wet) MD, age-related maculopathy (ARM), choroidal neovascularisation (CNVM), retinal pigment epithelium detachment (
  • 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-Trelat, 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 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, chronic obstructive pulmonary disease, interstitial lung disease, sleep
  • 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 immunode
  • the compounds of the present invention may also inhibit the production of certain cytokines including, but not limited to, TNF ⁇ , IL-Ib, IL-12, 1L-18, GM-CSF, IL-10, TGF-b 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- b and/or IFN-y.
  • 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.
  • the compounds of the present invention may be synthesized by the method shown in Reaction Scheme 1, below:
  • DIPEA (2-3 eq) was added to a solution of an appropriate acid (R x COOH in the above reaction scheme), DMAP (0-0.1 eq), HATU (1.0-1.5 eq) and appropriate amine (free base or salt - R 1 R y NH in the above reaction scheme) (1.2-3.0 eq) in DMF (0.1-0.5 M).
  • the reaction mixture was stirred overnight at room temperature (20-25°C). After removal of the solvent under reduced pressure, the crude product was purified by preparative HPLC, flash column chromatography or preparative TLC.
  • Example methods of R x COOH synthesis Example method 1: formation of chlorinated R x group of R x COOH (or its ester R x COOR')
  • R x COOH which can be made from the corresponding ester R x COOR' is 4-chloro-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxylic acid (the corresponding ester being thieno[3,4-b]pyridine-7-carboxylic acid, 4-chloro-2-(trifluoromethyl)-, methyl ester):
  • Step B To a suspension of 30% KH in mineral oil (576 mg, 4.31 mmol) in THF (10 ml) was added methyl 2-(((2-chloro-6-methylpyridin-3-yl)methyl)thio)acetate (500 mg, 2.16 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 20 minutes, then cooled to -78°C and quenched with NH4CI solution.
  • Step C To a solution of methyl 2-methyl-5,7-dihydrothieno[3,4-b]pyridine-7-carboxylate (190 mg, 0.909 mmol) in chloroform (5 mL) was added MnO 2 (781 mg, 9.09 mmol) and the reaction mixture was stirred at room temperature for 16hrs. The reaction mixture was filtered through a celite pad, the solids were washed with dichloromethane, filtrates were concentrated under reduced pressure and the residue was triturated with ether/pentane (1:1) to give methyl 2-methylthieno[3,4- b]pyridine-7-carboxylate 140 mg (74% yield) as a white solid.
  • Step D To a solution of methyl 2-methylthieno[3,4-b]pyridine-7-carboxylate (30 mg, 0.145 mmol) in THF (1.5 mL) was added 1M LiOH (0.290 mL, 0.290 mmol) followed by triethylamine (0.403 mL, 2.895 mmol). The reaction mixture was stirred for 18hrs at room temperature and then acidified with 10% KHSO4. The mixture was evaporated to afford 2-methylthieno[3,4-b]pyridine-7-carboxylic acid. It was used as crude in the next step.
  • Step E 2-methyl-N-(6-oxo-2-oxa-5-azaspiro[3.5]nonan-9-yl)thieno[3,4-b]pyridine-7-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1, above, (39% yield) using 2-methylthieno[3,4-b]pyridine-7-carboxylic acid and 9-amino-2-oxa-5-azaspiro[3.5]nonan-6-one (1 eq) as starting materials.
  • N-(2,6-dioxopiperidin-3-yl-3,5,5-d 3 )-2-methylthieno[3,4-b]pyridine-7-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1, above, (19% yield) using 2- methylthieno[3,4-b]pyridine-7-carboxylic acid and 3-aminopiperidine-2,6-dione-3,5,5-d3 (1 eq) as starting material.
  • Step A Methyl 5-chloro-2-pentanamidothiophene-3-carboxylate was synthesized using Example Method 1, above (65% yield), using methyl 2-pentanamidothiophene-3-carboxylate as a starting material.
  • Step B 5-chloro-2-pentanamidothiophene-3-carboxylic acid was synthesized using Example Method 2, above (69% yield), using methyl 5-chloro-2-pentanamidothiophene-3-carboxylate as a starting material.
  • Example 4 5-chloro-2-cvclopropaneamidothiophene-3-carboxylic acid
  • Step A Methyl 5-chloro-2-cyclopropaneamidothiophene-3-carboxylate was synthesized using Example Method 1, above (80% yield) using methyl 2-cyclopropaneamidothiophene-3-carboxylate as a starting material.
  • Step B 5-chloro-2-cyclopropaneamidothiophene-3-carboxylic acid was synthesized using Example Method 2, above (86% yield) using methyl 5-chloro-2-cyclopropaneamidothiophene-3-carboxylate as a starting material.
  • Step A H 2 SO 4 (1 mL) was added dropwise to a stirred suspension of methyl 2-( ⁇ [(9H-fluoren-9- yl)methoxy]carbonyl ⁇ amino)-4-oxo-4,5-dihydrothiophene-3-carboxylate (9.65 g, 24.4 mmol) in MeOH (200 mL). The reaction mixture was refluxed for 16 h, cooled to RT and filtered to give 2- ( ⁇ [(9H-fluoren-9-yl)methoxy]carbonyl ⁇ amino)-4-methoxythiophene-3-carboxylate (63% yield).
  • Step B Morpholine (13.5 g, 155 mmol) was added to a solution of methyl 2-( ⁇ [(9H-fluoren-9- yl)methoxy]carbonyl ⁇ amino)-4-methoxythiophene-3-carboxylate (6.3 g, 15.4 mmol) in dichloromethane (100 mL) and the reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, diluted with MTBE, filtered, and rinsed with small amount of MTBE. The filtrate was evaporated in vacuo to give crude methyl 2-amino-4-methoxythiophene-3- carboxylate, which was used in the next step without further purification.
  • 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.
  • Step A Ethyl 2-acetamidothiophene-3-carboxylate (11 g, 51.6 mmol) was dissolved in AcOH (110 mL) and solution of bromine (3.2 mL, 61.9 mmol) in AcOH (55 mL) was added dropwise over 15 min at RT. The reaction mixture was stirred at RT for 18h, concentrated under reduced pressure and diluted water. The precipitate was filtered, washed with water and dried to give ethyl 5-bromo- 2-acetamidothiophene-3-carboxylate (93% yield).
  • Step B Zn(CN)2 (8.45 g, 72 mmol) and Pd(dppf)Cl2-DCM (3.92 g, 4.8 mmol) were added to a solution of ethyl 5-bromo-2-acetamidothiophene-3-carboxylate (14 g, 48 mmol) in DMF (120 mL). Argon was bubbled through the reaction mixture for 10 min, then the reaction mixture was stirred at 150°C for 16 h, cooled to RT, filtered and washed with EtOAc.
  • 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 H2O (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).
  • Example 7 4.5-Dichloro-2-acetamidothiophene-3-carboxylic acid Step A: methyl 4,5-dichloro-2-acetamidothiophene-3-carboxylate was prepared in 90% yield using Example Method 1, above, with methyl 4-chloro-2-acetamidothiophene-3-carboxylate as a starting material.
  • Step B 4,5-Dichloro-2-acetamidothiophene-3-carboxylic acid was prepared in 70% yield using Example Method 2, above, with methyl 4,5-chloro-2-acetamidothiophene-3-carboxylate as a starting material.
  • Step A 4-tert-butyl 2-ethyl 5-aminothiophene-2,4-dicarboxylate (3.71 g, 13.7 mmol) was added to 20% solution of methylamine in methanol (20 mL) and the reaction mixture was stirred for 5 days at
  • 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% HCI 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. The precipitate was filtered, washed with DCM and dried to give 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxylic acid (60% yield).
  • Example 9 (S)-5-chloro-2-(2-hvdroxypropanamido)thiophene-3-carboxylic acid Step A: Oxalyl chloride (9.24 g, 72.8 mmol) and a drop of DMF were added to a solution of (25)-2- [(tert-butyldimethylsilyl)oxy]propanoic acid (11.9 g, 58.2 mmol) in dry DCM (150 mL), The resulting mixture was stirred at RT for 2 h, concentrated under reduced pressure, dissolved in DCM (50 mL) and added dropwise to a cooled solution of methyl 2-aminothiophene-3-carboxylate (4.58 g, 29.1 mmol) and DIPEA (11.3 g, 87.4 mmol) in DCM (150 mL).
  • Step B N-chlorosuccinimide (1.03 g, 7.71 mmol) was added to a solution of methyl 2-[(2S)-2-[(tert- butyldimethylsilyl)oxy]propanamido]thiophene-3-carboxylate (2.4 g, 6.99 mmol) in DMF (30 mL) and the mixture was stirred at RT for 18h. The reaction mixture was poured into water and extracted with EtOAc, dried over Na 2 SO 4 and concentrated under reduced pressure to give methyl 2-[(2S)-2-[(tert-butyldimethylsilyl)oxy]propanamido]-5-chlorothiophene-3-carboxylate (91% yield).
  • 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% HCI.
  • the product was extracted into DCM, dried over Na 2 S0 4 , concentrated under reduced pressure and crystallized to give (S)-5- chloro-2-(2-hydroxypropanamido)thiophene-3-carboxylic acid (25% yield).
  • Example 10 5-chloro-3-acetamidothiophene-2-carboxylic acid
  • Step A 5-chloro-3-acetamidothiophene-2-carboxylic acid was obtained in 72% yield using Example Method 2, above, with methyl 5-chloro-3-acetamidothiophene-2-carboxylate as a starting material.
  • Example 11 4-chloro-5-cvclopropyl-2-acetamidothiophene-3-carboxvlic acid Step A: SO2CI2 (0.207 g, 1.53 mmol) was added to a solution of methyl 5-cyclopropyl-2- acetamidothiophene-3-carboxylate (0.306 g, 1.28 mmol) in CHCI3 (15 mL). The reaction mixture was refluxed for 2 h, concentrated under reduced pressure and diluted with water. The product was extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure to give methyl 4-chloro-5-cyclopropyl-2-acetamidothiophene-3-carboxylate (81% yield).
  • 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 A To a stirred solution of 3,5-dibromo-2-methoxythiophene (500.0 mg, 1.845 mmol) in toluene (9 mL) was added cyclopropyl boronic acid (206 mg, 2.399 mmol) and K 3 PO 4 (784 mg, 3.69 mmol) in water (3 ml), the reaction mixture was purged with argon for 15 min and then Pd(PPh3)4 (320 mg, 0.277 mmol) was added. The reaction was stirred at 90 °C for 20h, filtered through celite bed, concentrated under reduced pressure and purified by flash column chromatography to give 3- bromo-5-cyclopropyl-2-methoxythiophene (34% yield).
  • Step B To a stirred solution of 3-bromo-5-cyclopropyl-2-methoxythiophene (700 mg, 3 mmol) in THF (20 mL) was added n-BuLi (1.8 M in THF) (3.4 mL, 6.005 mmol) dropwise at -78°C. Reaction mixture was stirred for 1h at -78°C and benzyl chloroformate (0.86 mL, 6 mmol) was added dropwise. The reaction was continued for lh, quenched with water, extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by flash column chromatography to give benzyl 5-cyclopropyl-2-methoxythiophene-3-carboxylate (23% yield).
  • Step C To a stirred solution of benzyl 5-cyclopropyl-2-methoxythiophene-3-carboxylate (350 mg, 1.215 mmol) in THF (6 mL) and methanol (6 mL) at 5-10 °C was added 50 % aq. NaOH (12 ml). The reaction mixture was stirred at RT for 16h and acidified with 6 M HCI. The solids were filtered, washed with pentane and dried to give 5-cyclopropyl-2-methoxythiophene-3-carboxylic acid (76% yield).
  • Example 13 2-methoxy-5-phenylthiophene-3-carboxylic acid
  • Step A To 3,5-dibromo-2-methoxythiophene (4.0 g, 14.71 mmol) in dry THF (30 mL) was added 2.5M n-BuLi hexane solution (6.47 mL, 16.2 mmol) at -78 °C under argon atmosphere and the solution was stirred for Ih. 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.
  • Step B 3-Bromo-2-methoxy-5-phenylthiophene (900 mg, 3.34 mmol) was dissolved in THF (15 mL) and cooled to -78 °C. 1.8M n-BuLi in hexane (3.7 mL, 6.68 mmol) was added dropwise at -78°C. Reaction mixture was stirred for lh at -78°C and benzyl chloroformate (0.95 mL, 6.68 mmol) was added dropwise. The reaction was continued for lh, quenched with water, extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by flash column chromatography to give benzyl 2-methoxy-5-phenylthiophene-3-carboxylate (23% yield).
  • 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 HCI. The solids were filtered, washed with pentane and dried to give 2-methoxy-5-phenylthiophene-3-carboxylic acid (130 mg, 78%) as off white solid.
  • Example 14 5-(tert-butyl)-2-methoxythiophene-3-carboxylic acid Step A: To stirred solution of AlCl 3 (2.1 g, 15.544 mmol) in DCM (20 mL) at -78° C was added tert- butyl bromide (1.9 g, 13.472 mmol) in DCM (10 mL) dropwise at -78°C and stirred for 20 min. 3- bromo-2-methoxythiophene (2 g, 10.363 mmol) in DCM (10 mL) was added dropwise stirred for 2h. The reaction mixture was warmed to RT and stirred for another 16 h. The reaction mixture was quenched with water and extracted with DCM, concentrated under reduced pressure and purified by flash column chromatography to give 3-bromo-5-(tert-butyl)-2-methoxythiophene (31% yield).
  • Step B To a stirred solution of 3-bromo-5-(tert-butyl)-2-methoxythiophene (900 mg, 3.614 mmol) in THF (22 mL) was added n-BuLi (1.8 M in THF) (4ml, 7.229 mmol) dropwise at -78°C. Reaction mixture was stirred for lh at -78°C and benzyl chloroformate (1.03 ml, 7.229 mmol) was added dropwise. The reaction was continued for lh, quenched with water, extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by flash column chromatography to give benzyl 5-(tert-butyl)-2-methoxythiophene-3-carboxylate (220 mg, 20% yield) as light yellow oil.
  • 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 HCI. The solids were filtered, washed with pentane and dried to give 5-(tert-butyl)-2-methoxythiophene-3-carboxylic acid (69% yield).
  • Example 15 2- ⁇ [(terf-butoxy)carbonyl)amino ⁇ -5-chlorothiophene-3-carboxylic acid
  • Step A N-chlorosuccinimide (2.2 g, 16.5 mmol) was added to a solution of 2 -((tert- butoxycarbonyl)amino)thiophene-3-carboxylic acid (3.3 g, 13.6 mmol) in DMF (20 mL) and the reaction mixture was stirred at RT for 2 h. The mixture was diluted with water and filtered. The solids were washed with water and dried to give 2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -5- chlorothiophene-3-carboxylic acid (84% yield).
  • Step A Triethylamine (0.397 g, 3.92 mmol) and acetic anhydride (0.400 g, 3.92 mmol) were added to a solution of ethyl 2-amino-5-(trifluoromethyl)thiophene-3-carboxylate (0.852 g, 3.56 mmol) in MeCN (15 mL). The reaction mixture was stirred overnight at 50°C, cooled to rt, concentrated under reduced pressure, and extracted with DCM, dried over Na 2 SO 4 concentrated to give ethyl 2- acetamido-5-(trifluoromethyl)thiophene-3-carboxylate (91% yield).
  • 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. The aqueous layer acidified by citric acid and the precipitate was filtered, washed with water, and dried to give 2-acetamido-5- (trifluoromethyl)thiophene-3-carboxylic acid (28% yield).
  • Example 17 4-chloro-2-acetamidothiophene-3-carboxylic acid Step A: A solution of methyl 4-chloroacetoacetate (13.3 g, 88.3 mmol) in THF (30 mL) was added dropwise to a suspension of 60% NaH (4.45 g, 111 mmol) in THF (150 mL) at 0°C. After addition was completed, the reaction mixture was warmed to RT and stirred for 20 min. Then, the reaction mixture was cooled to 0°C and a solution of acetyl isothiocyanate (8.92 g, 88.2 mmol) in THF (30 mL) was added dropwise.
  • Step B POCI3 (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 A methyl 5-cyclopropyl-2-acetamidothiophene-3-carboxylate was synthesized in 69% yield using Example Method 3, above, using 2-amino-5-cyclopropylthiophene-3-carboxylate as a starting material.
  • Step B 5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid was synthesized in 57% yield using Example Method 2, above, and methyl 5-cyclopropyl-2-acetamidothiophene-3-carboxylate as a starting material.
  • Example 19 2-benzamido-5-chlorothiophene-3-carboxylic acid
  • Step A methyl 2-benzamido-5-chlorothiophene-3-carboxylate was synthesized using Example Method 1, above (69% yield), using methyl 2-benzamidothiophene-3-carboxylate 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.
  • Example 20 Synthesis of 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylic acid
  • Step A Methyl 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylate was synthesized using Example Method 1, above (75% yield), using methyl 2-(2-phenylacetamido)thiophene-3-carboxylate 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.
  • Example 21 2-((tert-butoxycarbonyl(methyl)amino)furan-3-carboxylic acid
  • Step A To a solution of tert-butyl (3-bromofuran-2-yl)carbamate (2 g, 7.6 mmol) in DMF (40 ml) was added sodium hydride (0.28 g, 11.5 mmol) at 0°C under nitrogen and the reaction mixture was stirred at RT for 1 h. It was then re-cooled at 0°C, methyl iodide (1.42 ml, 23 mmol) was added and the reaction mixture was stirred for an additional 1 h at RT.
  • 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.
  • Example 22 5-(((tert-butoxycarbonyl)amino)methyl)-4-methoxythiophene-3-carboxylic acid Step A: (4-Bromo-3-methoxythiophen-2-yl)methanol (0.8 g, 3.58 mmol) was dissolved in DCM (10 mL).
  • 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. Reaction mixture was stirred at rt for 4h, diluted with ethyl acetate and washed with water. Organic phase was dried over Na 2 S0 4 and concentrated under reduced pressure to give methyl 5-(hydroxymethyl)-4-methoxythiophene-3-carboxylate (88% yield).
  • 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. The mixture was diluted with ethyl acetate, washed with water, dried over Na 2 S0 4 , concentrated under reduced pressure and purified by flash column chromatography to give methyl 5-(azidomethyl)-4-methoxythiophene-3- carboxylate (78% yield).
  • 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. Reaction mixture was stirred under H 2 atmosphere at RT for 3h, filtered through celite bed and concentrated under reduced pressure to give methyl 5-(aminomethyl)-4-methoxythiophene-3-carboxylate that was used directly in the next step.
  • Step F methyl 5-(aminomethyl)-4-methoxythiophene-3-carboxylate (215 mg, 1.06 mmol ) was dissolved in a dioxane-water (1:1; 6 mL).
  • 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 A methyl 2-((tert-butoxycarbonyl)amino)thiophene-3-carboxylate (100 mg, 1 eq.) was added to a stirred mixture of 60% NaH (1.2 eq.) suspended in mineral oil in dry DMF in an inert atmosphere, next was added Mel (1.2 eq.). The resulting mixture was stirred at room temperature for 18 hours, solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give methyl 2-((tert-butoxycarbonyl)(methyl)amino)thiophene-3- carboxylate (49% yield).
  • 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, l.eq.) in methanol and was stirring at room temperature for 18 hours. When the reaction was completed, to the acidified with 1M HCI, concentrated under reduced pressure and partitioned between ethyl acetate and water. Organic layer was washed with brine, dried over Na 2 S0 4 and evaporated.
  • Example 24 5-phenyl-2-(2-(pyrrolidin-l-ylacetamido)thiophene-3-carboxylic acid
  • Step A To the solution of ethyl 5-phenyl-2-(2-(pyrrolidin-l-yl)acetamido)thiophene-3-carboxylate (20 mg, 0.056 mmol) in EtOH (0.6 mL) was added H 2 O (0.1 mL) followed by NaOH (4 eq). Reaction was stirred at 50°C for 3h. The reaction mixture was acidified with 1M HCI, and concentrated under reduced pressure.
  • Example 25 2-(((tert-butoxycarbonyl)amino)methyl)thiophene-3-carboxylic acid Step A: To the solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)thiophene-3-carboxylate (35 mg, 0.129 mmol, l.eq.) in THF (1.0 mL) was added H 2 O (0.3 mL) followed by NaOH (6 eq). Reaction was stirred at RT for 18h and at 50 °C for 4h.
  • reaction mixture was acidified with 1M HCI, extracted with EtOAc, dried over Na 2 S0 4 and concentrated to give 2 -(((tert- butoxycarbonyl)amino)methyl)thiophene-3-carboxylic acid (86% yield).
  • Step A To a stirred solution of ethyl 5-bromothiazole-4-carboxylate (2.0 g, 8.475 mmol, leq) in methanol (24 mL) was added NaOMe (25% in MeOH) (3.8 ml, 16.95mmol, 2eq). The reaction mixture was refluxed for 2h, cooled to RT and quenched by saturated ammonium chloride solution (10 mL). The mixture was concentrated under reduced pressure and purified by flash column chromatography to give methyl 5-methoxythiazole-4-carboxylate (27% yield).
  • Step B To a stirring solution of methyl 5-methoxythiazole-4-carboxylate (100 mg, 0.578 mmol, leq) in a solution of THF, MeOH, H 2 O (4:2:1) (7 mL) was added LiOH, H 2 O (73 mg, 1.734 mmol, 3eq). The reaction mixture was stirred at RT for 16h, evaporated, redissolved in water and washed with ethyl acetate. The aqueous layer was acidified by 0.5 M HCI, extracted with 10% MeOH in DCM!, dried over Na 2 S0 4 , concentrated under reduced pressure and purified by flash column chromatography to give 5-methoxythiazole-4-carboxylic acid (32% yield).
  • Example 27 2-(tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylic acid
  • Step A To a stirring solution of methyl 2-amino-5-bromothiazole-4-carboxylate (1 g, 4.255 mmol, leq) in methanol (30 ml.) was added NaOMe (25% in MeOH) (2.3 ml, 10.638 mmol, 2.5 eq). The reaction mixture was refluxed for 1.5 h, cooled to RT and quenched by saturated ammonium chloride solution (10 mL). The mixture was concentrated under reduced pressure and purified by flash column chromatography to give methyl 2-amino-5-methoxythiazole-4-carboxylate (50% yield).
  • Step B Methyl 2-amino-5-methoxythiazole-4-carboxylate (400 mg, 2.128 mmol, leq.) was dissolved in DCM then were added triethylamine (0.532 mmol, 2eq.) and Boc 2 O (0.532 mmol, 2 eq). The reaction mixture was stirred at RT for 18h, diluted with DCM and washed successively with water and brine, dried over Na 2 S0 4 , concentrated under reduced pressure and purified by flash column chromatography to give methyl 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-car boxylate (49% yield).
  • Step C To a stirring solution of methyl 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4- carboxylate (300 mg, 1.042 mmol, leq) in THF:MeOH:H 2 03:2:1 (12 mL) was added LiOH ⁇ H 2 O (131 mg, 3.125 mmol, 3eq). The reaction mixture was stirred at RT for 16h, evaporated, redissolved in water and washed with ethyl acetate.
  • the aqueous layer was acidified by 0.5 M HCI, extracted with 10% MeOH in DCM, dried over Na 2 S, 0 co 4 ncentrated under reduced pressure and triturated with ether and pentane to give 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylic acid (49% yield).
  • Example 28 2-(tert-butoxycarbonyl)-5-methoxythiazole-4-carboxylic acid Step A: To a stirred solution of ethyl 5-bromothiazole-4-carboxylate (2.0 g, 8.475 mmol) in methanol (24 mL) was added NaOMe (25% in MeOH) (3.8 ml, 16.95 mmol, 2 eq). Reaction mixture was then refluxed for 2h, cooled to RT and quenched by ammonium chloride solution. The product was extracted with ethyl acetate, dried over Na 2 S0 4 , concentrated under reduced pressure and purified by flash column chromatography to give methyl 5-methoxythiazole-4-carboxylate (27% yield).
  • Step B To a solution of methyl 5-methoxythiazole-4-carboxylate (70 mg, 0.405 mmol, 1 eq) in THF (5 mL) was added N-bromosuccinimide (288 mg, 1.618 mmol, 4 eq) and the reaction mixture was stirred at RT for 24h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na 2 S0 4 , concentrated under reduced pressure and purified by flash column chromatography to give methyl 2-bromo-5-methoxythiazole-4-carboxylate (73% 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.
  • Xantphos (0.115 g, 0.198 mmol, 0.05 eq) and Pd(OAc) 2 (44 mg, 0.198 mmol, 0.05 eq) were added and the reaction mixture was stirred at 60 °C under CO (50 psi) for 16h.
  • reaction mixture was cooled to RT, diluted with water and washed with ethyl acetate.
  • the aqueous layer was acidified by 2M HCI solution, extracted with 15% MeOH in DCM, dried over Na 2 S0 4 and concentrated under reduced pressure to give 5-methoxy-4- (methoxycarbonyl)thiazole-2-carboxylic acid (30% yield).
  • 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-l,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 S0 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).
  • Example 29 2.4-dimethylthienof3,4-b)pyridine-7-carboxylic acid
  • Step A To a solution of methyl 2,4-dimethylthieno[3,4-b]pyridine-7-carboxylate (25.0 mg, 0.113 mmol, 1.000 eq) in a mixture of H2O (1.0 mL), THF (1.0 mL) and MeOH (1.0 mL) was added 1M LiOH (2.0 mL, 2.000 mmol, 17.7 eq) and the reaction was stirred at RT for 24h and neutralized with 1M
  • Example 30 4-hydroxy-2-(trifluoromethyl)thieno[3,4-d)pyridine-7-carboxylic acid
  • Step A To a solution of methyl 4-hydroxy-2-(trifluoromethyl)thieno[3,4-b]pyridine-7-carboxylate (30.0 mg, 0.108 mmol, 1.000 eq) in MeOH (2.0 mL) was added NaOH (216 mg, 5.411 mmol, 50 eq). The reaction was stirred at RT for 24h and neutralized with 1M HCI, and concented under reduced pressure.
  • Example 31 Thieno[3.4-b)pyridine-7-carboxylic acid
  • Step A To an ice-cold solution of 2-bromo-3-(bromomethyl)pyridine 2 (10.5 g, 42.0 mmol) in THF (100 mL) was added methyl thioglycolate (4.089g, 18.124mmol) followed by Et3N under stirring. The mixture was warmed to RT and stirred for further 30 min. The reaction mixture was diluted with water and extracted with DCM, dried over Na 2 S0 4 concentrated under reduced pressure and purified by flash column chromatography to give methyl 2- ⁇ [(2-bromopyridin-3- yl)methyl]sulfanyl ⁇ acetate (53% yield).
  • 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. The reaction mixture was then cooled to -78°C and treated with saturated aqueous NH4CI solution, warmed to RT, extracted with DCM, dried over Na, 2 S0 4 concentrated under reduced pressure and purified by flash column chromatography to give methyl 5H,7H-thieno[3,4-b]pyridine-7-carboxylate (56% yield).
  • Step C To the stirred solution of methyl 5H,7H-thieno[3,4-b]pyridine-7-carboxylate (3 g, 15.385 mmol) in CHCI3 (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 D To a stirred solution of methyl thieno[3,4-b]pyridine-7-carboxylate (1.5 g, 7.772 mmol) in THF:MeOH:H 2 0, 4:2:1 (14 mL) was added LiOH-H 2 O (1.304g, 31.088 mmol) at 0°C and then ice-bath was removed and the mixture was stirred at RT for 2.5h. Saturated aqueous citric acid solution was added and the product was extracted with 10% MeOH in DCM, dried over Na, 2 S co0n 4 centrated under reduced pressure and purified by HPLC to give thieno[3,4-b]pyridine-7-carboxylic acid (72 mg, 5%).
  • Example 32 5-(((tert-butoxycarbonyl)amino)methyl)-2-methoxythiophene-3-carboxylic acid
  • Step A To a solution of methyl 2-methoxythiophene-3-carboxylate (300.0 mg, 1.74 mmol) in DCM (10 mL) was added AcOH (9 mL). Reaction mixture was to 0 °C and N-iodosuccinimide (391.0 mg, 1.74 mmol) was added portionwise. After complete addition the reaction mixture was stirred at RT for 2h, then diluted with DCM and washed with water and NaHC03. Organic layer was concentrated under reduced pressure and purified by flash column chromatography to give methyl 5-iodo-2- methoxythiophene-3-carboxylate (300 mg, 57% yield).
  • Step B To a solution of methyl 5-iodo-2-methoxythiophene-3-carboxylate (400 mg, 1.34 mmol) in DMF (6 mL) was added CuCN (240 mg, 2.68 mmol) and the reaction mixture was stirred at 120°C for 24h, cooled to RT, diluted with ethyl acetate and washed with cold water and brine. Organic layer was concentrated under reduced pressure and purified by flash column chromatography to give methyl 5-cyano-2-methoxythiophene-3-carboxylate (150 mg, 56% yield).
  • Step C To a solution of methyl 5-cyano-2-methoxythiophene-3-carboxylate (100.0 mg, 0.507 mmol) in ethanol (5 mL) was added Raney Nickel (50 mg) followed by Boc20 (0.14 mL, 0.608 mmol) and the reaction mixture was stirred under hydrogen atmosphere at RT for 16h. The reaction mixture was filtered through Celite, solids were washed with ethyl acetate, the filtrate was concentrated under reduced pressure and purified by flash column chromatography to give methyl 5-(tert- butoxycarbonyl)amino)methyl)-2-methoxythiophene-3-carboxylate (40 mg, 26% yield).
  • Step D To a solution of methyl 5-(((tert-butoxycarbonyl)amino)methyl)-2-methoxythiophene-3- carboxylate (90.0 mg, 0.299 mmol) in THF/methanol (2/1 v/v, 6 mL) was added LiOH (50 mg, 1.2 mmol) in water (1 mL) and the reaction mixture was stirred at RT for 16h. The reaction mixture was diluted with water and neutralized with citric acid to pH ⁇ 7.
  • 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 K, values.
  • the K, 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
  • CRBN binding Ki [mM] is indicated as follows:
  • 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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Abstract

La présente invention concerne de nouveaux composés qui se lient au céréblon et des procédés d'utilisation de ceux-ci. Ces composés sont représentés par les formules (la), (lb), (lla), (lib), (Ilia), (lllb), (IVa), (IVb), (Va), (Vb), (Via) et (Vlb).
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