Classifications

• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients

Definitions

• CRBN cereblon
• Cereblon is a 442-amino acid multifunctional protein located in the cytoplasm, nucleus and peripheral membrane of the human brain and other tissues (Wada et al ., Biochem. & Biophys. Res. Comm. 477:388-94 (2016)). It interacts with the DNA damage-binding protein-l (DDB1), Cullin 4 (Cul4A and Cul4B), and regulator of Cullins 1 (RoCl) to form the functional E3 ubiquitin ligase complex, which is known as the CRL4 CRBN E3 ubiquitin ligase complex.
• DDB1 DNA damage-binding protein-l
• Cul4A and Cul4B Cullin 4
• RoCl regulator of Cullins 1
• Cereblon s role as part of this complex includes targeting proteins for proteolysis (degradation) via a ubiquitin- proteasome pathway. See , e.g, Chang et al, Int. J. Biochem. Mol. Biol. 2(3): 287-94 (2011).
• Cereblon is closely associated with the metabolism and proliferation of normal cells as well as tumor cells. On one hand, its existence ensures normal metabolic function and normal physiological function of ion channels, which are important to maintaining cell growth and proliferation. On the other hand, cereblon is also involved in the occurrence of many diseases, such as cancer. See, generally, Shi et al., J. Immunol. Res. Article ID 9130608 (2017).
• Immunomodulatory drugs are a new class of anti-cancer drugs that are derived from thalidomide, a drug which has been approved by the FDA for treatment of multiple myeloma.
• thalidomide a drug which has been approved by the FDA for treatment of multiple myeloma.
• two thalidomide analogs, lenalidomide and pomalidomide have been approved by the FDA (and are being marketed under the names REVLIMID® and POMALYST®, respectively) for treatment of multiple myeloma (among other diseases).
• REVLIMID® thalidomide analogs
• POMALYST® two thalidomide analogs, lenalidomide and pomalidomide, respectively
• one of the first known properties of IMiDs was their immunomodulatory capacity, including cytokine modulation and T cell co-stimulation (Schafer et al ., J.
• IMiDs were shown to have pleiotropic effects on a wide range of immune cells including natural killer (NK) cell activation and B cell and monocyte inhibition (Corral et al ., J. Immunol. 763:380-6 (1999)).
• Cereblon has been identified as a common primary target for IMiDs. For example, it has been reported that members of the Ikaros family of transcription factors, Ikaros and Aiolos (encoded by the genes Ikaros family zinc finger protein 1 ( IKZF1 ) and IKZF3 respectively) are recruited as protein substrates for CRL4 CRBN in T cells in response to treatment with lenalidomide and pomalidomide, resulting in enhanced production of IL-2 and other cytokines that regulate T cell function. See , Vogel et al. , Br. J. Hematol. 764:811-21 (2014).
• lenalidomide but not pomalidomide, induces the degradation of the protein kinase, casein kinase la (CKla), which exploits CKla haploinsufficiency associated with 5q-deletion associated myelodysplastic syndrome.
• CKla casein kinase la
• Structural studies have shown that these IMiDs bind in a shallow hydrophobic pocket on the surface of cereblon, and that the binding is mediated by the glutarimide ring that is common to thalidomide, lenalidomide and pomalidomide.
• CRBN-binding compounds named“cereblon modulators” have been developed.
• CC-122 a new chemical entity termed‘pleiotropic pathway modifier’, binds cereblon and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro , in vivo , and in patients, resulting in both cell autonomous as well as immunostimulatory effects.
• DLBCL diffuse large B-cell lymphoma
• CC-885 another new cereblon modulator, has been reported to possess anti-tumor activity which is broader than that of thalidomide, lenalidomide and pomalidomide.
• CC-885 is mediated by cereblon-dependent ubiquitination and degradation of the translation termination factor glutathione S-transferase pi gene (GSTP1). See , Matyskiela et al, Nature 535:252-7 (2016).
• a first aspect of the present invention is directed to a compound having a structure represented by formula (I):
• X and Xi independently represent C or N, provided that one of X and Xi represents N; wherein Ri is absent if Xi represents N, and if Xi represents C, Ri represents H, or together with
• R2 and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g ., an optionally substituted phenyl group) or an optionally substituted 5- or 6-membered heterocyclic group (e.g., an optionally substituted 5- or 6-membered heteroaryl group);
• R2 represents H, halo, hydroxy, optionally substituted C1-C4 alkoxy, l-benzyl-4-piperidinoxy, optionally substituted 5- or 6-membered carbocyclic group, optionally substituted 5- or 6- membered heterocyclic group, optionally substituted aryl (which as defined herein embraces aralkyl and aralkoxy), optionally substituted heteroaryl (which as defined herein embraces heteroaralkyl and heteroaralkoxy), or NR 6 R7, wherein each of R6 and R7 independently represents H or a substituent ( e.g ., optionally substituted amine (e.g., NH2), optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl), or R2 together with Ri and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, an optional
• R3 is absent, and if X represents C, R3 independently represents H, halo, optionally substituted amine (e.g., NH2), hydroxy, optionally substituted C1-C4 alkoxy, l-benzyl-
• optionally substituted amine e.g., NH2
• hydroxy optionally substituted C1-C4 alkoxy
• 5- or 6-membered heterocyclic group optionally substituted aryl, optionally substituted heteroaryl, or NR 6 R7, or wherein R2 and R3, or R3 and R 4 , together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, an optionally substituted phenyl group) or an optionally substituted 5- or 6-membered heterocyclic group (e.g, an optionally substituted 5- or 6-membered heteroaryl group);
• R 4 , and R5 each independently represents H, halo, optionally substituted amine (e.g., NH2), hydroxy, optionally substituted C1-C4 alkoxy, l-benzyl-4-piperidinoxy, an optionally substituted 5- or 6-membered carbocyclic group, an optionally substituted 5- or 6-membered heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, or NR 6 R7, or wherein R 4 and R5, together with the atoms to which they are bound form an optionally substituted 5- or 6- membered carbocyclic group (e.g, an optionally substituted phenyl group) or an optionally substituted 5- or 6-membered heterocyclic group (e.g, an optionally substituted 5- or 6-membered heteroaryl group);
• optionally substituted amine e.g., NH2
• hydroxy optionally substituted C1-C4 alkoxy
• R9 represents H, halo (e.g, Cl or F), optionally substituted C1-C4 alkyl, optionally substituted amine (e.g., NH2), hydroxy, optionally substituted C1-C4 alkoxy, or an optionally substituted 5- or 6-membered carbocyclic group (e.g, an optionally substituted phenyl group) or an optionally substituted 5- or 6-membered heterocyclic group (e.g, an optionally substituted 5- or 6-membered heteroaryl group);
• Rio represents H, optionally substituted C1-C4 alkyl, optionally substituted amine (e.g ., NH2), optionally substituted Cl -C4 alkoxy, optionally substituted aryl, or an optionally substituted heteroaryl group
• R11, R12, R13, R14, and R15 each independently represents H, halo, hydroxy, optionally substituted C1-C4 alkoxy, optionally substituted aryl (which as defined herein embraces aralkyl and aralkoxy), optionally substituted heteroaryl (which as defined herein embraces heteroaralkyl and heteroaralkoxy), or NR 6 R7, wherein each of R6 and R7 independently represents H or a substituent (e.g., optionally substituted amine (e.g., NH2), optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl), or R11
• R1 ⁇ 2, R17, Rix and R19 independently represent H or a substituent, (e.g, optionally substituted amine (e.g., NH2), hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl) or wherein R1 ⁇ 2 and R17 together with the atoms to which they are bound form an optionally substituted 5- or 6- membered carbocyclic group (e.g, optionally substituted phenyl group), an optionally substituted 5- or 6-membered heterocyclic group (e.g, an optionally substituted 5- or 6-membered heteroaryl group), or wherein R17 and Rix together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, a phenyl group), an optionally substituted 5- or 6-membered heterocyclic group (e.g, a 5- or 6-membered
• R20, R21, R22 and R23 independently represent H or a substituent (e.g, optionally substituted amine (e.g., NH2), hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl), or wherein R20 and R21 together with the atoms to which they are bound form an optionally substituted 5- or 6- membered heterocyclic group, or wherein R21 and R22 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, a phenyl group), an optionally substituted 5- or 6-membered heterocyclic group (e.g, a 5- or 6-membered heteroaryl group), or wherein R22 and R23 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, a phenyl group), or where
• R2, R3, R4, and Rs represents H.
• R2, R3, R4, and Rs represents a substituted benzyloxy group (e.g, 4- [[4(oxymethyl)phenyl]methyl]morpholine) or halo (e.g, Cl).
• Rx is H or methyl
• R9 is H, hydroxy, NH2 or halo (e.g, Cl).
• A is A3, Rio is H or methyl, and R11 and R12 together with the atoms to which they are bound form an optionally substituted 5-membered heterocyclic group.
• one of R2, R3, R4, and Rs represents C5-C6 heterocyclic substituted benzyl or l-benzyl-4-piperidinoxy.
• A is A4
• R1 ⁇ 2 and R17 together with the atoms to which they are bound form an optionally substituted phenyl group.
• R17 and Rix together with the atoms to which they are bound form an optionally substituted phenyl group.
• Ris and R19 together with the atoms to which they are bound form an optionally substituted phenyl group.
• the phenyl group is unsubstituted.
• R20 is H, methyl, phenyl or benzyl, and R21, R22, and R23 are H.
• Another aspect of the present invention is directed to a pharmaceutical composition that includes a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.
• a further aspect of the present invention is directed to a method for making a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof .
• a further aspect of the present invention is directed to methods of treating diseases or disorders involving aberrant (e.g ., dysregulated) protein activity, that entails administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof to a subject in need thereof,.
• aberrant e.g ., dysregulated
• the inventive compounds lack the pyrrolidine-2-one or pyrrolidine-2, 5-di one ring that is common to thalidomide, lenalidomide, and pomalidomide. Applicant has surprisingly and unexpectedly discovered that even without the pyrrolidine-2-one or pyrrolidine-2, 5-dione ring, the inventive compounds have affinity for cereblon and may thus exhibit cereblon modulatory activity and function as immunomodulatory therapeutics. Without intending to be bound by any particular theory of operation, Applicant believes that the compounds effect binding to cereblon at least in part due to intramolecular hydrogen bonding between the NH group and the N atom of the pyridine ring.
• compounds of the present invention may indirectly target a host of different substrates for cereblon-dependent ubiquitination and degradation.
• substrates may include, for example, family with sequence similarity 83 member F (FAM83F), DTW domain containing 1 (DTWD1), IKZF2, IKZF4, IKZF5, zinc finger protein 91 homolog (ZFP91), ZFP62, ZFP36 ring finger protein like (ZFP36L2), ring finger protein 166 (RNF166), Ras-related protein Rab-28 (RAB28), glutathione S-transferase pi 1 (GSTP1), GSPT2, mitochondrial import inner membrane translocase subunit Tim 10 (TIMM 10), GDNF inducible zinc finger protein 1 (GZF1), early growth response 1 (EGR1), hypermethylated in cancer 1 (HIC1), HIC2, insulinoma-associated protein 2 (INS
• inventive compounds may be further advantageous relative to the cereblon-targeted degraders which due to their large flexible linkers can cause pharmacokinetic challenges.
• FIG. 1 A is a graph that shows cereblon binding (expressed in polarization mP) by various inventive immunomodulatory compounds (inventive compounds 2-6) as compared to a control (lenalidomide).
• FIG. 1B is a graph that shows cereblon binding (expressed in polarization mP) by various inventive immunomodulatory compounds (inventive compounds 23, 24 and 26) as compared to a control (lenalidomide).
• the term“about” means within 10% (e.g, within 5%, 2% or 1%) of the particular value modified by the term“about.”
• transitional term “comprising,” which is synonymous with “including,” “containing,” or“characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
• the transitional phrase“consisting of’ excludes any element, step, or ingredient not specified in the claim.
• the transitional phrase“consisting essentially of’ limits the scope of a claim to the specified materials or steps“and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.
• aliphatic refers to a non-cyclic hydrocarbon group and includes branched and unbranched, alkyl, alkenyl, or alkynyl groups.
• alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical.
• the alkyl radical is a Ci-Cis group.
• the alkyl radical is a Co -C6, C 0 -C5, C 0 -C3, C1-C12, Ci-Cs, C1-C 6 , C1-C5, C1-C4 or Ci- C 3 group (wherein Co alkyl refers to a bond).
• alkyl groups include methyl, ethyl, 1- propyl, 2-propyl, i-propyl, 1 -butyl, 2-methyl- 1 -propyl, 2-butyl, 2-methyl-2-propyl, 1 -pentyl, n- pentyl, 2-pentyl, 3 -pentyl, 2-methyl-2 -butyl, 3-methyl-2-butyl, 3 -methyl- 1 -butyl, 2-methyl- 1- butyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3- methyl-3 -pentyl, 2-methyl-3 -pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl
• alkylene refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to 12 carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
• the alkylene chain may be attached to the rest of the molecule through a single bond and to the radical group through a single bond.
• the alkylene group contains one to 8 carbon atoms (Ci-Cs alkylene).
• an alkylene group contains one to 5 carbon atoms (C1-C5 alkylene).
• an alkylene group contains one to 4 carbon atoms (C1-C4 alkylene). In other embodiments, an alkylene contains one to three carbon atoms (C1-C3 alkylene). In other embodiments, an alkylene group contains one to two carbon atoms (C1-C2 alkylene). In other embodiments, an alkylene group contains one carbon atom (Ci alkylene).
• haloalkyl refers to an alkyl group as defined herein that is substituted with one or more (e.g ., 1, 2, 3, or 4) halo groups.
• alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical with at least one carbon-carbon double bond.
• An alkenyl includes radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
• the alkenyl radical is a C2-C18 group.
• the alkenyl radical is a C2-C12, C2-C10, C2-C8, C2-C6 or C2-C3 group.
• Examples include ethenyl or vinyl, prop-l-enyl, prop-2-enyl, 2- methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2-methylbuta- 1,3 -diene, hex-l-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-l,3-dienyl.
• alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond.
• the alkynyl radical is a C2-C18 group.
• the alkynyl radical is C2-C12, C2-C10, C2-C8, C2-C6 or C2-C3. Examples include ethynyl prop-l-ynyl, prop-2 -ynyl, but-l-ynyl, but-2-ynyl and but-3-ynyl.
• aldehyde is represented by the formula— C(0)H.
• alkoxyl or“alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
• Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
• An“ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.
• halogen refers to fluorine, chlorine, bromine, or iodine.
• carboxylic acid is represented by the formula— C(0)0H
• a“carboxylate” is represented by the formula— C(0)0-.
• the term“ester” is represented by the formula— 0C(0)Z 1 or— C(0)0Z 1 , where Z 1 may be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all as described herein.
• ether is represented by the formula Z'OZ 2 , where Z 1 and Z 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all as described herein.
• ketone is represented by the formula Z ⁇ (0)Z 2 , where A 1 and A 2 independently represent alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all as described herein.
• sulfonyl refers to the sulfo-oxo group represented by the formula— S(0)2Z 1 , where Z 1 may be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all as described herein.
• sulfonyl amino (or“sulfonamide”) is represented by the formula— S(0)2NH 2 .
• cyclic group broadly refers to any group that used alone or as part of a larger moiety, contains a saturated, partially saturated or aromatic ring system e.g ., carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl and heteroaryl groups. Cyclic groups may have one or more (e.g, fused) ring systems. Thus, for example, a cyclic group can contain one or more carbocyclic, heterocyclic, aryl or heteroaryl groups.
• carbocyclic refers to a group that used alone or as part of a larger moiety, contains a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms, that is alone or part of a larger moiety (e.g, an alkcarbocyclic group).
• carbocyclyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof. In one embodiment, carbocyclyl includes 3 to 15 carbon atoms (C3-C15). In one embodiment, carbocyclyl includes 3 to 12 carbon atoms (C3-C12).
• carbocyclyl includes C3-C8, C3-C10 or C5-C10.
• carbocyclyl, as a monocycle includes C3-C8, C3-C6 or C5-C6.
• carbocyclyl, as a bicycle includes C7-C12.
• carbocyclyl, as a spiro system includes C5-C12.
• monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, l-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1 -cyclohex- l-enyl, l-cyclohex-2-enyl, 1 -cyclohex-3 -enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, such as for example bicyclo[
• spiro carbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.
• carbocyclyl includes aryl ring systems as defined herein.
• carbocycyl also includes cycloalkyl rings ( e.g ., saturated or partially unsaturated mono-, bi-, or spiro-carbocycles).
• carbocyclic group also includes a carbocyclic ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g, aryl or heterocyclic rings), where the radical or point of attachment is on the carbocyclic ring.
• carbocyclic also embraces carbocyclylalkyl groups which as used herein refer to a group of the formula— R c -carbocyclyl where R c is an alkylene chain.
• carbocyclic also embraces carbocyclylalkoxy groups which as used herein refer to a group bonded through an oxygen atom of the formula— O— R c -carbocyclyl where R c is an alkylene chain.
• heterocyclyl refers to a “carbocyclyl” that used alone or as part of a larger moiety, contains a saturated, partially unsaturated or aromatic ring system, wherein one or more (e.g, 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g, O, N, N(O), S, S(O), or S(0) 2 ).
• heterocyclyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof.
• a heterocyclyl refers to a 3 to 15 membered heterocyclyl ring system.
• a heterocyclyl refers to a 3 to 12 membered heterocyclyl ring system. In some embodiments, a heterocyclyl refers to a saturated ring system, such as a 3 to 12 membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl refers to a heteroaryl ring system, such as a 5 to 14 membered heteroaryl ring system.
• the term heterocyclyl also includes C3-C8 heterocycloalkyl, which is a saturated or partially unsaturated mono-, bi-, or spiro-ring system containing 3-8 carbons and one or more (1, 2, 3 or 4) heteroatoms.
• a heterocyclyl group includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and Spiro ring systems, wherein the ring atoms are carbon, and one to 5 ring atoms is a heteroatom such as nitrogen, sulfur or oxygen.
• heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
• heterocyclyl includes 4- to 6-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
• heterocyclyl includes 3-membered monocycles.
• heterocyclyl includes 4-membered monocycles.
• heterocyclyl includes 5-6 membered monocycles. In some embodiments, the heterocyclyl group includes 0 to 3 double bonds. In any of the foregoing embodiments, heterocyclyl includes 1, 2, 3 or 4 heteroatoms. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g ., NO, SO, SO2), and any nitrogen heteroatom may optionally be quatemized (e.g., [NR.4] + Cl , [NR.4] + OH ).
• heterocyclyls include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2- dithietanyl, l,3-dithietanyl, pyrrolidinyl, dihydro-lH-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, l,l-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperid
• Examples of 5- membered heterocyclyls containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including l,3,4-thiadiazol- 5-yl and l,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4- oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl.
• Example 5-membered ring heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as l,3,4-triazol-5-yl; l,2,3-triazol-5-yl, l,2,4-triazol-5-yl, and tetrazolyl, such as lH-tetrazol-5-yl.
• Representative examples of benzo-fused 5-membered heterocyclyls are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
• Example 6-membered heterocyclyls contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid- 4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as l,3,4-triazin-2-yl and l,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl.
• pyridyl such as pyrid-2-yl, pyrid-3-yl, and pyrid- 4-yl
• pyrimidyl such as pyrimid-2-yl and pyrimid-4-yl
• triazinyl such as l,3,4-triazin-2-yl and l,3,5-
• a heterocyclic group includes a heterocyclic ring fused to one or more (e.g ., 1, 2 or 3) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heterocyclic ring, and in some embodiments wherein the point of attachment is a heteroatom contained in the heterocyclic ring.
• heterocyclic embraces N-heterocyclyl groups which as used herein refer to a heterocyclyl group containing at least one nitrogen and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a nitrogen atom in the heterocyclyl group.
• Representative examples of N-heterocyclyl groups include l-morpholinyl, l-piperidinyl, 1- piperazinyl, l-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl.
• heterocyclic also embraces C-heterocyclyl groups which as used herein refer to a heterocyclyl group containing at least one heteroatom and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group.
• C- heterocyclyl radicals include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3- pyrrolidinyl.
• heterocyclic also embraces heterocyclylalkyl groups which as disclosed above refer to a group of the formula — R c -heterocyclyl where R c is an alkylene chain.
• heterocyclic also embraces heterocyclylalkoxy groups which as used herein refer to a radical bonded through an oxygen atom of the formula— O— R c -heterocyclyl where R c is an alkylene chain.
• aryl used alone or as part of a larger moiety (e.g ., "aralkyl", wherein the terminal carbon atom on the alkyl group is the point of attachment, e.g., a benzyl group), "aralkoxy” wherein the oxygen atom is the point of attachment, or "aroxy alkyl” wherein the point of attachment is on the aryl group) refers to a group that includes monocyclic, bicyclic or tricyclic, carbon ring system, that includes fused rings, wherein at least one ring in the system is aromatic.
• the aralkoxy group is a benzoxy group.
• aryl may be used interchangeably with the term "aryl ring".
• aryl includes groups having 6-18 carbon atoms.
• aryl includes groups having 6-10 carbon atoms.
• Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, l,2,3,4-tetrahydronaphthalenyl, lH-indenyl, 2,3-dihydro-lH-indenyl, and the like, which may be substituted or independently substituted by one or more substituents described herein.
• a particular aryl is phenyl.
• an aryl group includes an aryl ring fused to one or more (e.g, 1, 2 or 3) different cyclic groups (e.g, carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the aryl ring.
• aryl embraces aralkyl groups which as disclosed above refer to a group of the formula— R c -aryl where R c is an alkylene chain such as methylene or ethylene.
• the aralkyl group is an optionally substituted benzyl group.
• aryl also embraces aralkoxy groups which as used herein refer to a group bonded through an oxygen atom of the formula— O— R c — aryl where R c is an alkylene chain such as methylene or ethylene.
• heteroaryl used alone or as part of a larger moiety
• heteroaryl alkyl also“heteroaralkyl”
• heteroarylalkoxy also“heteroaralkoxy”
• heteroaryl refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom.
• heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted.
• heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen.
• Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5-b]pyridazinyl, purinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl,
• heteroaryl also includes groups in which a heteroaryl is fused to one or more cyclic (e.g ., carbocyclyl, or heterocyclyl) rings, where the radical or point of attachment is on the heteroaryl ring.
• Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
• a heteroaryl group may be mono-, bi- or tri-cyclic.
• a heteroaryl group includes a heteroaryl ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g, carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heteroaryl ring, and in some embodiments wherein the point of attachment is a heteroatom contained in the heterocyclic ring.
• heteroaryl embraces N-heteroaryl groups which as used herein refer to a heteroaryl group as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group.
• heteroaryl also embraces C-heteroaryl groups which as used herein refer to a heteroaryl group as defined above and where the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group.
• heteroaryl also embraces heteroarylalkyl groups which as disclosed above refer to a group of the formula— R c -heteroaryl, where R c is an alkylene chain as defined above.
• heteroaryl also embraces heteroaralkoxy (or heteroarylalkoxy) groups which as used herein refer to a group bonded through an oxygen atom of the formula— O— R c -heteroaryl, where R c is an alkylene group as defined above.
• any of the groups described herein may be substituted or unsubstituted.
• substituted broadly refers to all permissible substituents with the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e. a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
• substituents include halogens, hydroxyl groups, and any other organic groupings containing any number of carbon atoms, e.g ., 1-14 carbon atoms, and which may include one or more (e.g, 1 2 3, or 4) heteroatoms such as oxygen, sulfur, and nitrogen grouped in a linear, branched, or cyclic structural format.
• substituents may thus include alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyclic, substituted cyclic, carbocyclic, substituted carbocyclic, heterocyclic, substituted heterocyclic, aryl (e.g, benzyl and phenyl), substituted aryl (e.g, substituted benzyl or phenyl), heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, halo, hydroxyl, aryloxy, substituted aryloxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino (e.g, NH2), substituted amino, amido, substituted amido, morpholino,
• the present invention is directed to a compound having a structure represented by formula (I):
• X and Xi independently represent C or N, provided that one of X and Xi represents N; wherein Ri is absent if Xi represents N, and if Xi represents C, Ri represents H, or together with R2 and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g ., an optionally phenyl group) or an optionally substituted 5- or 6-membered heterocyclic group (e.g., an optionally substituted 5- or 6-membered heteroaryl group);
• an optionally substituted 5- or 6-membered carbocyclic group e.g ., an optionally phenyl group
• an optionally substituted 5- or 6-membered heterocyclic group e.g., an optionally substituted 5- or 6-membered heteroaryl group
• R.2 represents H, halo, hydroxy, optionally substituted C1-C4 alkoxy, l-benzyl-4-piperidinoxy, optionally substituted 5- or 6-membered carbocyclic group, optionally substituted 5- or 6- membered heterocyclic group, optionally substituted aryl (which as defined herein embraces aralkyl and aralkoxy), optionally substituted heteroaryl (which as defined herein embraces heteroaralkyl and heteroaralkoxy), or NR 6 R7, wherein each of R.6 and R independently represents H or a substituent (e.g, optionally substituted amine (e.g., NFb), optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl), or R 2 together with Ri and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, an optionally substitute
• R3 is absent, and if X represents C, R3 independently represents H, halo, hydroxy, optionally substituted amine (e.g., NH2), optionally substituted C1-C4 alkoxy, l-benzyl-
• 5- or 6-membered heterocyclic group optionally substituted aryl, optionally substituted heteroaryl, or NR 6 R7, or wherein R2 and R 3 , or R 3 and R 4 , together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, an optionally substituted phenyl group) or an optionally substituted 5- or 6-membered heterocyclic group (e.g, an optionally substituted 5- or 6-membered heteroaryl group);
• R 4 , and R5 each independently represents H, halo, hydroxy, optionally substituted amine (e.g., NH2), optionally substituted C1-C4 alkoxy, l-benzyl-4-piperidinoxy, optionally substituted
• 5- or 6-membered carbocyclic group optionally substituted 5- or 6-membered heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, or NR 6 R7, or wherein R 4 and Rs, together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, an optionally substituted phenyl group) or an optionally substituted 5- or
• 6-membered heterocyclic group e.g, an optionally substituted 5- or 6-membered heteroaryl group
• Rx represents H, optionally substituted C1-C4 alkyl, optionally substituted amine (e.g., NH2), optionally substituted C1-C4 alkoxy, optionally substituted aryl, or an optionally substituted heteroaryl group
• R9 represents H, halo (e.g, Cl or F), hydroxy, optionally substituted C1-C4 alkyl, optionally substituted amine (e.g., NFh), optionally substituted C1-C4 alkoxy, optionally substituted 5- or 6-membered carbocyclic group (e.g, an optionally substituted phenyl group), or an optionally substituted 5- or 6-membered heterocyclic group (e.g, an optionally substituted 5- or 6-membered heteroaryl group);
• Rio represents H, optionally substituted C1-C4 alkyl, optionally substituted amine, (e.g., NH2) optionally substituted C1-C4 alkoxy, optionally substituted aryl, or an optionally substituted heteroaryl group
• R11, R12, R13, R14, and R15 each independently represents H, halo, hydroxy, optionally substituted C1-C4 alkoxy, optionally substituted aryl (which as defined herein embraces aralkyl and aralkoxy), optionally substituted heteroaryl (which as defined herein embraces heteroaralkyl and heteroaralkoxy), or NR 6 R7, wherein each of R6 and R7 independently represents H or a substituent (e.g, optionally substituted amine (e.g., NFh), optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl), or R11 together with R
• R1 ⁇ 2, R17, Rix and R19 independently represent H or a substituent (e.g, optionally substituted amine (e.g., NH2), hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl), or wherein Ri 6 and R17 together with the atoms to which they are bound form an optionally substituted 5- or 6- membered carbocyclic group (e.g, optionally substituted phenyl group), an optionally substituted 5- or 6-membered heterocyclic group (e.g, an optionally substituted 5- or 6-membered heteroaryl group), or wherein R17 and Rix together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, a phenyl group), an optionally substituted 5- or 6-membered heterocyclic group (e.g, a 5- or 6-membered heteroaryl
• R20, R21, R22 and R23 independently represent H or a substituent (e.g., optionally substituted amine (e.g., NH2), hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl), or wherein R20 and R21 together with the atoms to which they are bound form an optionally substituted 5- or 6- membered heterocyclic group, or wherein R21 and R22 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, a phenyl group), an optionally substituted 5- or 6-membered heterocyclic group (e.g, a 5- or 6-membered heteroaryl group), or wherein R22 and R23 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group (e.g, a phenyl group),
• R2, R3, R4, and Rs represents H.
• all of Ri, R2, R4 and Rs represents H.
• Xi represents N
• all of R2, R3, R4 and Rs represents H.
• one of R2, R3, R4, and Rs represents a substituted benzyloxy group (e.g, 4- [[4(oxymethyl)phenyl]methyl]morpholine), or halo (e.g, Cl).
• Ri and R2 together with the atoms to which they are bound form an optionally substituted 6-membered heteroaryl group such as a pyridyl group.
• Rx is H or methyl
• R9 is H, hydroxy, NH2 or halo (e.g, Cl).
• A is A3
• Rio is H or methyl
• R11 and R12 together with the atoms to which they are bound form an optionally substituted 5-membered heterocyclic group.
• R1 ⁇ 2 and R17 together with the atoms to which they are bound form an optionally substituted 6-membered aryl ring.
• R17 and Ri8 together with the atoms to which they are bound form an optionally substituted 6-membered aryl ring.
• Rix and R19 together with the atoms to which they are bound form an optionally substituted 6-membered aryl ring.
• the aryl group formed by Ri6 and Rn, or by R17 and Ris, or by Ris and R19 is a phenyl group.
• the 6-membered aryl group is unsubstituted.
• R20 is H, methyl, phenyl or benzyl, and R21, R22, and R23 are H.
• Compounds of the present invention may be in the form of a free acid or free base, or a pharmaceutically acceptable salt.
• pharmaceutically acceptable refers to a material which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects (such as dizziness or gastric upset) or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• pharmaceutically acceptable salt refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base.
• Examples of pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts.
• suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulf
• the compound of formula (I) is an isotopic derivative in that it has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
• the compound includes deuterium or multiple deuterium atoms. Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in some circumstances.
• stereoisomer may be in the form of a stereoisomer, which as used herein, embraces all isomers of individual compounds that differ only in the orientation of their atoms in space.
• stereoisomer includes mirror image isomers (enantiomers which include the (R-) or (S-) configurations of the compounds), mixtures of mirror image isomers (physical mixtures of the enantiomers, and racemates or racemic mixtures) of compounds, geometric (cis/trans or E/Z, R/S) isomers of compounds and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
• the chiral centers of the compounds may undergo epimerization in vivo ; thus, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Accordingly, the compounds of the present invention may be made and used in the form of individual isomers and substantially free of other isomers, or in the form of a mixture of various isomers, e.g ., racemic mixtures of stereoisomers.
• the compounds of the present invention embrace the use of N-oxides, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, tautomers, and unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, of the compounds.
• solvated forms of the conjugates presented herein are also considered to be disclosed herein.
• the present invention is directed to a method for making a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.
• inventive compounds or pharmaceutically-acceptable salts or stereoisomers thereof may be prepared by any process known to be applicable to the preparation of chemically related compounds.
• the compounds of the present invention will be better understood in connection with the synthetic schemes that are described in various working examples and which illustrate non limiting methods by which the compounds of the invention may be prepared.
• compositions that includes a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
• Suitable carriers may include, for example, liquids (both aqueous and non-aqueous alike, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g, semi-solids), and gases, that function to carry or transport the compound from one organ, or portion of the body, to another organ, or portion of the body.
• a carrier is“acceptable” in the sense of being physiologically inert to and compatible with the other ingredients of the formulation and not injurious to the subject or patient.
• the composition may include one or more pharmaceutically acceptable excipients.
• compounds of formula (I) may be formulated into a given type of composition in accordance with conventional pharmaceutical practice such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, e.g. , Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
• the type of formulation depends on the mode of administration which may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), and intrasternal injection, or infusion techniques, intra-ocular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation) and topical (e.g, transdermal).
• enteral e.g., oral, buccal, sublingual and rectal
• parenteral e.g, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.)
• intrasternal injection e.g., intrasternal injection, or infusion techniques, intra-ocular, intra-arterial, intramedullary,
• parenteral (e.g, intravenous) administration may also be advantageous in that the compound may be administered relatively quickly such as in the case of a single-dose treatment and/or an acute condition.
• compositions are formulated for oral or intravenous administration (e.g, systemic intravenous injection).
• compounds of the present invention may be formulated into solid compositions (e.g, powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g, solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs); semi-solid compositions (e.g, gels, suspensions and creams); and gases (e.g, propellants for aerosol compositions).
• solid compositions e.g, powders, tablets, dispersible granules, capsules, cachets, and suppositories
• liquid compositions e.g, solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate and an additional carrier or excipient such as a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as crosslinked polymers (e.g, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate, agar-agar, calcium carbonate, potato or tapio
• a carrier such as
• the dosage form may also include buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings. They may further contain an opacifying agent.
• compounds of the present invention may be formulated in a hard or soft gelatin capsule.
• Representative excipients that may be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystalline cellulose and croscarmellose sodium.
• Gelatin shells may include gelatin, titanium dioxide, iron oxides and colorants.
• Liquid dosage forms for oral administration include solutions, suspensions, emulsions, micro-emulsions, syrups and elixirs.
• the liquid dosage forms may contain an aqueous or non-aqueous carrier (depending upon the solubility of the compounds) commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• Oral compositions may also include an excipients such as we
• Injectable preparations may include sterile aqueous solutions or oleaginous suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• the effect of the compound may be prolonged by slowing its absorption, which may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility.
• Prolonged absorption of the compound from a parenterally administered formulation may also be accomplished by suspending the compound in an oily vehicle.
• compounds of formula (I) may be administered in a local rather than systemic manner, for example, via injection of the conjugate directly into an organ, often in a depot preparation or sustained release formulation.
• long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• injectable depot forms are made by forming microencapsule matrices of the compound in a biodegradable polymer, e.g ., polylactide-polyglycolides, poly(orthoesters) and poly(anhydrides). The rate of release of the compound may be controlled by varying the ratio of compound to polymer and the nature of the particular polymer employed.
• Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
• the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody.
• the liposomes are targeted to and taken up selectively by the organ.
• inventive compounds may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges and gels.
• the compounds may be formulated for administration by inhalation.
• Various forms suitable for administration by inhalation include aerosols, mists or powders.
• Pharmaceutical compositions may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
• a suitable propellant e.g, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit of a pressurized aerosol may be determined by providing a valve to deliver a metered amount.
• capsules and cartridges including gelatin for example, for use in an inhaler or insufflator, may be formulated containing a powder mix of the compound and a suitable powder base such
• Bispecifc compounds of formula (I) may be formulated for topical administration which as used herein, refers to administration intradermally by application of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.
• compositions for topical application include solvents (e.g ., alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline).
• Creams for example, may be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl, or oleyl alcohols. Creams may also contain a non-ionic surfactant such as polyoxy-40-stearate.
• the topical formulations may also include an excipient, an example of which is a penetration enhancing agent.
• an excipient an example of which is a penetration enhancing agent.
• these agents are capable of transporting a pharmacologically active compound through the stratum comeum and into the epidermis or dermis, preferably, with little or no systemic absorption.
• a wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers. Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla.
• penetration enhancing agents include triglycerides (e.g, soybean oil), aloe compositions (e.g, aloe-vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g, isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.
• triglycerides e.g, soybean oil
• aloe compositions e.g, aloe-vera gel
• ethyl alcohol isopropyl alcohol
• octolyphenylpolyethylene glycol oleic acid
• polyethylene glycol 400 propylene glycol
• N-decylmethylsulfoxide e.g, isopropy
• excipients that may be included in topical as well as in other types of formulations (to the extent they are compatible), include preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, skin protectants, and surfactants.
• Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols.
• Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid.
• Suitable moisturizers include glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol.
• Suitable buffering agents include citric, hydrochloric, and lactic acid buffers.
• Suitable solubilizing agents include quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.
• Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.
• Transdermal formulations typically employ transdermal delivery devices and transdermal delivery patches wherein the compound is formulated in lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Transdermal delivery of the compounds may be accomplished by means of an iontophoretic patch. Transdermal patches may provide controlled delivery of the compounds wherein the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
• Absorption enhancers may be used to increase absorption, examples of which include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
• Ophthalmic formulations include eye drops.
• Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
• compositions for rectal or vaginal administration may also be formulated as suppositories which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.
• suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.
• the term "therapeutically effective amount” refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof that is effective in producing the desired therapeutic response.
• the term “therapeutically effective amount” thus includes the amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, that when administered, induces a positive modification in the disease or disorder to be treated, or is sufficient to prevent development or progression of the disease or disorder, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject, or which simply kills or inhibits the growth of diseased ( e.g ., cancer) cells.
• the total daily dosage of the compounds and usage thereof may be decided in accordance with standard medical practice, e.g., by the attending physician using sound medical judgment.
• the specific therapeutically effective dose for any particular subject will depend upon a variety of factors including the disease or disorder being treated and the severity thereof (e.g, its present status); the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", lOth Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001).
• the total daily dosage (e.g, for adult humans) may range from about 0.001 to about 1600 mg, from 0.01 to about 1600 mg, from 0.01 to about 500 mg, from about 0.01 to about 100 mg, from about 0.5 to about 100 mg, from 1 to about 100-400 mg per day, from about 1 to about 50 mg per day, and from about 5 to about 40 mg per day, and in yet other embodiments from about 10 to about 30 mg per day.
• Individual dosage may be formulated to contain the desired dosage amount depending upon the number of times the compound is administered per day.
• capsules may be formulated with from about 1 to about 200 mg of compound (e.g, 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg).
• individual dosages may be formulated to contain the desired dosage amount depending upon the number of times the compound is administered per day.
• the compounds of the present invention may be useful in the treatment of diseases and disorders characterized or mediated by an aberrant (e.g., dysfunctional or dysregulated) protein that can be targeted for degradation by cereblon, and which participates in the inception, manifestation of one or more symptoms or markers, severity or progression of the disease or disorder), and where the degradation of the targeted protein may confer a therapeutic benefit.
• aberrant protein activity e.g ., expression of mutated form of the protein or elevated levels of wild-type protein relative to a non-pathological state).
• the disease may also be characterized by a particular dependence/sensitivity to the removal of the protein, in this case by proteasomal degradation, while itself not necessarily being mutated or over expressed.
• a "disease” is generally regarded as a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject's health continues to deteriorate.
• a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
• subject includes all members of the animal kingdom prone to or suffering from the indicated disease or disorder.
• the subject is a mammal, e.g., a human or a non-human mammal.
• the methods are also applicable to companion animals such as dogs and cats as well as livestock such as cows, horses, sheep, goats, pigs, and other domesticated and wild animals.
• a subject“in need of’ treatment according to the present invention may be“suffering from or suspected of suffering from” a specific disease or disorder may have been positively diagnosed or otherwise presents with a sufficient number of risk factors or a sufficient number or combination of signs or symptoms such that a medical professional could diagnose or suspect that the subject was suffering from the disease or disorder.
• subjects suffering from, and suspected of suffering from, a specific disease or disorder are not necessarily two distinct groups.
• compounds of formula (I) may be useful in the treatment of cell proliferative diseases and disorders characterized or mediated by a protein selected from the group consisting of casein kinase 1 alpha (CKla)-, family with sequence similarity 83 member F (FAM83F)-, DTW domain containing 1 (DTWD1)-, zinc finger protein 91 homolog (ZFP91)-, ZFP62-, ZFP36 ring finger protein like (ZFP36L2)-, ring finger protein 166 (RNF166)-, Ikaros family zinc finger protein 1 (IKZF1)-, IKZF2-, IKZF3-, IKZF4-, IKZF5-, Ras-related protein Rab- 28 (RAB28)-, glutathione S-transferase pi 1 (GSTP1)-, GSPT2-, mitochondrial import inner membrane translocase subunit Tim 10 (TIMM 10)-, GDNF inducible zinc finger protein 1 (GZF
• compounds of formula (I) may be useful in the treatment of cell proliferative diseases and disorders (e.g ., cancer or benign neoplasms).
• cell proliferative disease or disorder refers to the conditions characterized by unregulated or abnormal cell growth, or both, including noncancerous conditions, precancerous conditions and cancer.
• non-cancerous diseases or disorders that may be amenable to treatment with the compounds of the present invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, and allergic and genetic diseases.
• Non-cancerous diseases and disorders include rheumatoid arthritis, alopecia areata, lymphoproliferative conditions, autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, anhidrotic ecodermal dysplasia, pure red cell anemia and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin associated periodic syndrome (CAPS), endotoxic shock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, chronic graft rejection, hidradenitis suppurativa, inflammatory bowel disease,
• the methods are directed to treating subjects having cancer.
• the compounds of the present invention may be effective in the treatment of carcinomas (solid tumors including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers affecting blood including lymphocytes, bone marrow and/or lymph nodes) including leukemia, lymphoma and multiple myeloma.
• carcinomas solid tumors including both primary and metastatic tumors
• sarcomas sarcomas
• melanomas hematological cancers
• hematological cancers cancers affecting blood including lymphocytes, bone marrow and/or lymph nodes
• leukemia lymphoma
• lymphoma multiple myeloma
• adults tumors/cancers and pediatric tumors/cancers are included.
• the cancers may be vascularized, or not yet substantially vascularized, or non-vascularized tumors.
• cancers includes adenocortical carcinoma, AIDS-related cancers (e.g ., Kaposi’s and AIDS-related lymphoma), appendix cancer, childhood cancers (e.g ., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, brain cancer (e.g., gliomas and glioblastomas such as brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumors, visual pathway and hypothalamic glioma), breast cancer, bronchial adenomas/carcinoids, car
• Sarcomas that may be treatable with compounds of the present invention include both soft tissue and bone cancers alike, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing’s sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelial sarcoma or mesothelioma (membranous lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), mesenchymous or mixed mesodermal tumor (mixed connective tissue types), and histiocy
• methods of the present invention entail treatment of subjects having cell proliferative diseases or disorders of the hematological system, liver (hepatocellular), brain, lung, colorectal (e.g, colon), pancreas, prostate, skin, ovary, breast, skin (e.g, melanoma), and endometrium.
• lymphoma As used herein,“cell proliferative diseases or disorders of the hematologic system” include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia.
• hematologic cancers may thus include multiple myeloma, lymphoma (including T- cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma) (e.g, B-cell non-Hodgkin’s lymphoma selected from diffuse large B-cell lymphoma (e.g, germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma), Burkitt’s lymphoma/leukemia, mantle cell lymphoma, mediastinal (thymic) large B- cell lymphoma, follicular lymphom
• cell proliferative diseases or disorders of the liver include all forms of cell proliferative disorders affecting the liver.
• Cell proliferative disorders of the liver may include liver cancer (e.g, hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma), a precancer or precancerous condition of the liver, benign growths or lesions of the liver, and malignant growths or lesions of the liver, and metastatic lesions in tissue and organs in the body other than the liver.
• Cell proliferative disorders of the brain may include hyperplasia, metaplasia, and dysplasia of the liver.
• Cell proliferative diseases or disorders of the brain include all forms of cell proliferative disorders affecting the brain.
• Cell proliferative disorders of the brain may include brain cancer (e.g, gliomas and glioblastomas), a precancer or precancerous condition of the brain, benign growths or lesions of the brain, and malignant growths or lesions of the brain, and metastatic lesions in tissue and organs in the body other than the brain.
• Cell proliferative disorders of the brain may include hyperplasia, metaplasia, and dysplasia of the brain.
• cell proliferative diseases or disorders of the lung include all forms of cell proliferative disorders affecting lung cells.
• Cell proliferative disorders of the lung include lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, and metastatic lesions in the tissue and organs in the body other than the lung.
• Lung cancer includes all forms of cancer of the lung, e.g, malignant lung neoplasms, carcinoma in situ typical carcinoid tumors, and atypical carcinoid tumors.
• Lung cancer includes small cell lung cancer (“SLCL”), non-small cell lung cancer (“NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma.
• Lung cancer can include “scar carcinoma”, bronchoalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma.
• Lung cancer also includes lung neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).
• colon cancer includes sporadic and hereditary colon cancer, malignant colon neoplasms, carcinoma in situ , typical carcinoid tumors, and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma.
• Colon cancer can be associated with a hereditary syndrome such as hereditary nonpolyposis colorectal cancer, familiar adenomatous polyposis, MYH associated polyposis, Gardner’s syndrome, Peutz-Jeghers syndrome, Turcot’s syndrome and juvenile polyposis.
• a hereditary syndrome such as hereditary nonpolyposis colorectal cancer, familiar adenomatous polyposis, MYH associated polyposis, Gardner’s syndrome, Koz-Jeghers syndrome, Turcot’s syndrome and juvenile polyposis.
• Cell proliferative disorders of the colon may be characterized by hyperplasia, metaplasia, or dysplasia of the colon.
• cell proliferative diseases or disorders of the pancreas include all forms of cell proliferative disorders affecting pancreatic cells.
• Cell proliferative disorders of the pancreas may include pancreatic cancer, a precancer or precancerous condition of the pancreas, hyperplasia of the pancreas, and dysplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, and metastatic lesions in tissue and organs in the body other than the pancreas.
• Pancreatic cancer includes all forms of cancer of the pancreas, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, and pancreatic neoplasms having histologic and ultrastructural heterogeneity (e.g, mixed cell types).
• ductal adenocarcinoma adenosquamous carcinoma
• pleomorphic giant cell carcinoma mucinous adenocarcinoma
• osteoclast-like giant cell carcinoma mucinous cystadenocarcinoma
• acinar carcinoma unclass
• Cell proliferative diseases or disorders of the prostate include all forms of cell proliferative disorders affecting the prostate.
• Cell proliferative disorders of the prostate may include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in tissue and organs in the body other than the prostate.
• Cell proliferative disorders of the prostate may include hyperplasia, metaplasia, and dysplasia of the prostate.
• cell proliferative diseases or disorders of the ovary include all forms of cell proliferative disorders affecting cells of the ovary.
• Cell proliferative disorders of the ovary may include a precancer or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, and metastatic lesions in tissue and organs in the body other than the ovary.
• cell proliferative diseases or disorders of the breast include all forms of cell proliferative disorders affecting breast cells.
• Cell proliferative disorders of the breast may include breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast.
• cell proliferative diseases or disorders of the skin include all forms of cell proliferative disorders affecting skin cells.
• Cell proliferative disorders of the skin may include a precancer or precancerous condition of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma or other malignant growths or lesions of the skin, and metastatic lesions in tissue and organs in the body other than the skin.
• Cell proliferative disorders of the skin may include hyperplasia, metaplasia, and dysplasia of the skin.
• cell proliferative diseases or disorders of the endometrium include all forms of cell proliferative disorders affecting the endometrium.
• Cell proliferative disorders of the endometrium may include endometrial cancer, a precancer or precancerous condition of the endometrium, benign growths or lesions of the endometrium, and malignant growths or lesions of the endometrium, and metastatic lesions in tissue and organs in the body other than the endometrium.
• Cell proliferative disorders of the endometrium may include hyperplasia, metaplasia, and dysplasia of the endometrium.
• the compounds of the present invention may be administered to a patient, e.g ., a cancer patient, as a monotherapy or by way of combination therapy, and as a front-line therapy or a follow-on therapy for patients who are unresponsive to front line therapy.
• Therapy may be "first- line", i.e., as an initial treatment in patients who have undergone no prior anti -cancer treatment regimens, either alone or in combination with other treatments; or "second-line", as a treatment in patients who have undergone a prior anti -cancer treatment regimen, either alone or in combination with other treatments; or as "third-line", "fourth-line”, etc. treatments, either alone or in combination with other treatments.
• Therapy may also be given to patients who have had previous treatments which have been partially successful but are intolerant to the particular treatment. Therapy may also be given as an adjuvant treatment, i.e ., to prevent reoccurrence of cancer in patients with no currently detectable disease or after surgical removal of a tumor.
• the compound may be administered to a patient who has received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy or any combination thereof.
• the methods of the present invention may entail administration of compounds of the invention or pharmaceutical compositions thereof to the patient in a single dose or in multiple doses (e.g ., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses).
• the frequency of administration may range from once a day up to about once every eight weeks. In some embodiments, the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments entails a 28-day cycle which includes daily administration for 3 weeks (21 days).
• Compounds of formula (I) may be used in combination with at least one other active agent, e.g., anti-cancer agent or regimen, in treating diseases and disorders.
• active agent e.g., anti-cancer agent or regimen
• the term“in combination” in this context means that the agents are co-administered, which includes substantially contemporaneous administration, by the same or separate dosage forms, or sequentially, e.g, as part of the same treatment regimen or by way of successive treatment regimens.
• the first of the two compounds is in some cases still detectable at effective concentrations at the site of treatment.
• the sequence and time interval may be determined such that they can act together (e.g, synergistically to provide an increased benefit than if they were administered otherwise).
• the therapeutics may be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they may be administered sufficiently close in time so as to provide the desired therapeutic effect, which may be in a synergistic fashion.
• the terms are not limited to the administration of the active agents at exactly the same time.
• the treatment regimen may include administration of a compound of formula (I) in combination with one or more additional therapeutics known for use in treating the disease or condition (e.g, cancer).
• the dosage of the additional anticancer therapeutic may be the same or even lower than known or recommended doses. See, Hardman et al, eds., Goodman & Gilman's The Pharmacological Basis Of Therapeutics, lOth ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006.
• Anti-cancer agents that may be used in combination with the inventive compounds are known in the art. See, e.g. , U.S. Patent 9, 101,622 (Section 5.2 thereof) and U.S.
• Patent 9,345,705 B2 (Columns 12-18 thereof).
• additional active agents and treatment regimens include radiation therapy, chemotherapeutics (e.g, mitotic inhibitors, angiogenesis inhibitors, antihormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti -microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g, mono-specific and bispecific antibodies) and CAR-T therapy.
• chemotherapeutics e.g, mitotic inhibitors, angiogenesis inhibitors, antihormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti -microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitor
• the compound of the invention and the additional (e.g., anticancer) therapeutic may be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.
• the two or more therapeutics may be administered within the same patient visit
• the compound of the present invention and the additional agent or therapeutic are cyclically administered.
• Cycling therapy involves the administration of one anticancer therapeutic for a period of time, followed by the administration of a second anti-cancer therapeutic for a period of time and repeating this sequential administration, i.e., the cycle, in order to reduce the development of resistance to one or both of the anticancer therapeutics, to avoid or reduce the side effects of one or both of the anticancer therapeutics, and/or to improve the efficacy of the therapies.
• cycling therapy involves the administration of a first anticancer therapeutic for a period of time, followed by the administration of a second anticancer therapeutic for a period of time, optionally, followed by the administration of a third anticancer therapeutic for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the anticancer therapeutics, to avoid or reduce the side effects of one of the anticancer therapeutics, and/or to improve the efficacy of the anticancer therapeutics.
• kits or pharmaceutical systems may be assembled into kits or pharmaceutical systems.
• Kits or pharmaceutical systems according to this aspect of the invention include a carrier or package such as a box, carton, tube or the like, having in close confinement therein one or more containers, such as vials, tubes, ampoules, or bottles, which contain a compound of formula (I) or a pharmaceutical composition that contains a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier.
• the kits or pharmaceutical systems of the invention may also include printed instructions for using the compound and composition.
• Example 1 Synthesis of 6-(benzyloxy)-/V-(2.6-dioxopiperidin-3-vnpicolinamide (1).
• reaction mixture was stirred at 45 °C for 2 days. Upon cooling to rt, the reaction mixture was diluted with CH2CI2, washed with saturated aq. NH 4 Cl, saturated aq. NaHCCb, water, and brine. The organic layer was collected, dried over Na2S0 4 , filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (0-80% EtOAc/CThCh) yielded partially purified picolinamide compound 1. Further purification by HPLC, then silica flash chromatography (0-20% 1.5 N ME in MeOFl/CFhCh) yielded compound 1 (72 mg, 48%) as a white solid.
• 6-fluoropicolinic acid 1.5 g, 10.9 mmol
• CH2CI2 0.5 M
• Diisopropylethylamine 5.7 mL, 32.6 mmol, 3.0 equiv
• propylphosphonic anhydride T3P, >50 wt%, 13 mmol, 1.2 equiv
• amino glutarimide 2.14 g, 13 mmol, 1.2 equiv
• Example _ 10 _ Synthesis _ of _ N- dioxopi peri din-3 -yl)-5-(Y4-
• HATU (408 mg, 1.8 mmol, 1.2 eq) was added to a mixture of compound Int-6 (500 mg, 1.5 mmol, 1.0 eq), 3-aminopiperidine-2,6-dione hydrochloride (300 mg, 1.8 mmol, 1.2 eq) and DIEA (348 mg, 3.0 mmol, 2.0 eq) in DMF (2 mL) at 0 ⁇ 5 °C. The resulting mixture was allowed to warm to room temperature and was stirred for 1 h. Water was added and the mixture was extracted with EtOAc (2x 15 mL).
• HATEG (988 mg, 2.6 mmol, 1.2 eq) was added to a mixture of compound Int-12 (460 mg, 2.1 mmol, 1.0 eq), 3-aminopiperidine-2,6-dione hydrochloride (429 mg, 2.6 mmol, 1.2 eq) and DIEA (703 mg, 5.5 mmol, 2.5 eq) in DMF (2 mL) at 0 ⁇ 5 °C.
• DMF 703 mg, 5.5 mmol, 2.5 eq
• the resulting mixture was allowed to warm to room temperature and was stirred for 3 h. Water was added and the resulting suspension was filtered. The filtrate cake was washed with H2O and was dried to afford compound 22 (578 mg, 78.1%) as an off-white powder.
• HATU (646 mg, 1.7 mmol) was added slowly to a solution of compound 1-18 (250 mg, 1.2 mmol), 3-aminopiperdine-2,6-dione (275 mg, 1.7 mmol) and DIEA (6l mg, 2.8 mmol) in DMF (5 mL) at 0 °C in portions.
• the reaction was stirred at room temperature for 10 h. Water was added and the aqueous layer was extracted with EtOAc (2 c 50 mL). The combined organic layers were washed with EhO and brine, and dried over Na2S0 4 . The solvent was removed under reduced pressure and the residue was purified by column chromatography (dichloromethane/methanol:30/l) to afford compound 1-19 (300 mg) as a yellow solid.
• Example 17 Synthesis of 3-Amino-N- dioxopiperidin-3-vDquinoline-8- carboxamide (25).
• HATU (258 mg, 0.68 mmol, 1.0 eq) was added to a mixture of compound Int-25 (220 mg, 0.68 mmol, 1.0 eq), 3-aminopiperidine-2,6-dione hydrochloride (110 mg, 0.68 mmol, 1.0 eq) and DIEA (175 mg, 1.36 mmol, 2.0 eq) in DMF (5 mL) at 0 ⁇ 5 °C.
• DMF 5 mL
• the resulting mixture was allowed to warm to room temperature for 3 h. Water was added to the reaction mixture and the resulting suspension was filtered. The filtrate cake was washed with H2O and was dried to afford compound Int-26 (202 mg, 70.6%) as an off-white solid.
• Example 22 Synthesis of N-(2.6-dioxopiperidin-3-yl)indoline-7-carboxamide(30).
• HATU (1.26 g, 3.32 mmol, 1.2 eq) was added to a mixture of compound Int-37 (700 mg, 2.76 mmol, 1.0 eq), 3-aminopiperidine-2,6-dione hydrochloride (546 mg, 3.32 mmol, 1.2 eq) and DIEA (1070 mg, 8.30 mmol, 3.0 eq) in DMF (15 mL) at 0 °C. The resulting mixture was allowed to warm to room temperature and was stirred for 3 h. Water was added and the aqueous layer was extracted with EtOAc (3 c 50 mL). The combined organic layers were washed with water and brine, dried over Na2S0 4 . The solvent was removed under reduced pressure and the residue was purified by column chromatography (dichloromethane/methanol:50/l) to afford compound Int- 38 (730 mg, 73%) as a yellow solid.
• Example _ 24 _ Synthesis _ of _ N- dioxopi peri din-3 -yl )-6-(Y4-
• HATEG (136 mg, 0.36 mmol, 1.0 eq) was added to a mixture of the compound Int-47 (100 mg, 0.36 mmol, 1.0 eq), 3-aminopiperidine-2,6-dione hydrochloride (60 mg, 0.36 mmol, 1.0 eq) and DIEA (116 mg, 0.9 mmol, 3.0 eq) in DMF (2 mL) at 0 ⁇ 5 °C. The resulting mixture was allowed to warm to room temperature for 1 h. Water was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over NaiSOr, and concentrated under reduced pressure. The obtained residue was purified by prep-HPLC to afford compound 32 (72 mg, 54%).
• Example 25 Lenalidomide displacement assay.
• Atto565-Lenalidomide displacement assay were dispensed in a 384-well microplate (Corning, 4514) using D300e Digital Dispenser (HP) normalized to 1% DMSO into 10 nM Atto565-Leanlidomide, 100 nM DDB 1 B-CRBN, 50 mM Tris pH 7.5, 200 mM NaCl, 0.1% Pluronic® F-68 solution (Sigma). Compound titrations were incubated for 60 min at RT. The change in fluorescence polarization was monitored using a PHERAstar® FS microplate reader (BMG Labtech) for 1 h in 120 s cycles.
• HP Digital Dispenser
• lenalidomide as a control is illustrated in FIG. 1 A.
• the ICso values in [mM] for lenalidomide and compound 5 are shown in the Table 2.
• compound 23 resulted in ICso of 2.9 mM, a significant improvement over that of lenalidomide (ICso 5.19 mM in Table 2), an FDA approved binder to CRBN.
• Compound 24, which is a close analog of compound 23 showed a similar binding affinity (IC50 7.7 mM in Table 2) to that of lenalidomide.
• 4-NH2 in quinoline of compound 24 to 4-OH substitution in compound 26 significantly reduced the binding affinity from 7.7 mM to weak 50% of probe displacement at 100 mM respectively, as shown in Table 1 and FIG. 1B..

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