Classifications

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  • 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
  • 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
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • 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
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• Imide molecules such as thalidomide and its analogs, bind to Cereblon (CRBN), a substrate adaptor for the ubiquitously expressed cullin ring ligase 4 (CUL4)-RBX1-DDB1- CRBN (CUL4CRBN) E3 ligase (Kronke et al., Science 343:301-305 (2014); Ito et al., Science 327:1345-1350 (2010)).
• Helios resulted in an enhanced anti-tumor immune response (Kim et al., Science 350:334-339 (2015)). Notably, Helios is highly expressed in regulatory T cells (Elkord et al., Expert Opin. Biol. Ther.12:1423-1425 (2012)), a subpopulation of T cells that restricts the activity of effector T cells. Selective deletion of Helios in regulatory T cells resulted in both loss of suppressive activity and acquisition of effector T cell functions (Najagawa et al., Proc. Natl. Acad. Sci. USA 113:6248-6253 (2016); Yates et al., Proc. Natl. Acad. Sci. USA 115:2162-2167 (2016)).
• Helios is a critical factor in restricting T cell effector function in Tregs.
• Helios expression has also been reported to be upregulated in ‘exhausted’ T cells, in the settings of both chronic viral infections (Crawford et al., Immunity 40:289-302 (2014), Doering et al., Immunity 371130-1144 (2012); Scott-Browne et al., Immunity 45:1327-1340 (2016)) and tumors (Martinez et al., Immunity 42:265-278 (2015); Mognol et al., Proc. Natl. Acad. Sci. USA 114:E2776-E2785 (2017); Pereira et al., J. Leukoc.
• a first aspect of the present invention is directed to a compound having a structure represented by formula (I): wherein R 1a , R 1b , R 1a ’, R 1b ’, R2, R3, R 4 , R 4 ’, R5, R5’, R6, and n1 are as defined herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
• a second aspect of the present invention is directed to a compound having a structure represented by formula (II): wherein R 1a , R 1b , R 1a ’, R 1b ’, R2, R 4 , R 4 ’, R5, R5’, R21, and n1 are as defined herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
• 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 (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
• the pharmaceutical composition comprises a co-crystal of a compound of formula (I) or (II).
• a further aspect of the present invention is directed to methods of treating diseases or disorders that would benefit from IKZF2 (Helios) degradation.
• the disease or disorder is cancer.
• the cancer is T cell leukemia, T cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, or carcinoid.
• NSCLC non-small cell lung cancer
• TNBC triple-negative breast cancer
• NPC nasopharyngeal cancer
• mssCRC microsatellite stable colorectal cancer
• thymoma thymoma
• carcinoid thymoma
• inventive compounds may enhance an anti-tumor immune response by converting regulatory T cells into effector T cells, and by rescuing effector T cell function in exhausted T cells or CAR-T cells.
• DETAILED DESCRIPTION OF THE INVENTION [0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention.
• alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical.
• the alkyl radical is a C 1 -C18 group. In other embodiments, the alkyl radical is a C 0 -C 6 , C 0 -C 5 , C 0 -C 3 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 or C 1 -C 3 group (wherein C 0 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.
• an alkyl group is a C 1 -C 3 alkyl group. In some embodiments, an alkyl group is a C 1 -C 2 alkyl group, or a methyl group.
• 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 (C 1 -C 8 alkylene). In other embodiments, an alkylene group contains one to 5 carbon atoms (C 1 -C 5 alkylene). In other embodiments, an alkylene group contains one to 4 carbon atoms (C 1 -C 4 alkylene). In other embodiments, an alkylene contains one to three carbon atoms (C 1 -C 3 alkylene). In other embodiments, an alkylene group contains one to two carbon atoms (C 1 -C 2 alkylene). In other embodiments, an alkylene group contains one carbon atom (C 1 alkylene).
• 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 C 2 -C18 group.
• the alkenyl radical is a C 2 -C 12 , C 2 - C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 group.
• alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond.
• the alkynyl radical is a C 2 -C18 group.
• the alkynyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 - C 6 or C 2 -C 3 .
• Examples include ethynyl prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.
• alkoxyl or “alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto, and which is the point of attachment. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
• ether is two hydrocarbyl groups 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.
• 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.
• carbocyclyl includes 3 to 15 carbon atoms (C 3 -C 15 ).
• carbocyclyl includes 3 to 12 carbon atoms (C 3 - C 12 ).
• carbocyclyl includes C 3 -C 8 , C 3 -C 10 or C 5 -C 10 .
• carbocyclyl, as a monocycle includes C 3 -C 8 , C 3 -C 6 or C 5 -C 6 .
• carbocyclyl, as a bicycle includes C 7 -C 12 .
• carbocyclyl, as a spiro system includes C 5 -C 12 .
• monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-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[2.2.1]heptane, bicyclo[2.2.2]
• 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.
• 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 “aroxyalkyl” 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, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H- indenyl, naphthyridinyl, 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.
• cyclic groups e.g., carbocyclic rings or heterocyclic rings
• the structure of any aryl group that is capable of having double bonds positioned differently is considered so as to embrace any and all such resonance structures.
• aryl embraces aralkyl groups (e.g., benzyl) 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.
• 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(O) 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 C 3 -C 8 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 and oxygen.
• heterocyclyl includes 4- to 6- membered monocycles having one or more heteroatoms selected from nitrogen, sulfur and 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, SO 2 ), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR 4 ] + Cl-, [NR 4 ] + OH-).
• heterocyclyls include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H- pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, homo
• 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 1,3,4- thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl.
• Example 5-membered ring heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl.
• imidazolyl such as imidazol-2-yl
• triazolyl such as 1,3,4-triazol-5-yl
• 1,2,3-triazol-5-yl 1,2,4-triazol-5-yl
• tetrazolyl such as 1H-tetrazol-5-yl.
• 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 1,3,4-triazin-2-yl and 1,3,5-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 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl
• 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 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-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.
• Representative examples of 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.
• heteroaryl used alone or as part of a larger moiety (e.g., “heteroarylalkyl” (also “heteroaralkyl”), or “heteroarylalkoxy” (also “heteroaralkoxy”), 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 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, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl,
• 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.
• cyclic e.g., carbocyclyl, or heterocyclyl
• Nonlimiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3- b]-1,4-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.
• the structure of any heteroaryl group that is capable of having double bonds positioned differently is considered so as to embrace any and all such resonance structures.
• 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, wherein 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.
• 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 include alkyl, substituted alkyl (e.g., C 1 -C 6 , C 1 -C 5 , C 1 -C 4, C 1 -C 3 , C 1 -C 2 , C 1 ), alkoxy (e.g., C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 1 ), substituted alkoxy (e.g., C 1 - C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 1 ), haloalkyl (e.g., CF 3 ), alkenyl (e.g., C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 2 ), substituted
• each R 1a , R 1b , R 1a ’ and R 1b ’ is independently hydrogen or (C 1 -C 6 )alkyl, or R 1a and R 1a ’, together with the same carbon atom to which they are attached, form a spiro (C 3 -C 7 )cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 1a and R 1a ’, when on different carbon atoms, together with the atoms to which they are attached, form a (C 3 -C 7 )cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 1b and R 1b ’ form a spiro (C 3 -C 7 )cyclo
• R7 is selected from the group consisting of: R8 is selected from the group consisting of (C 6 -C 10 )aryl, and monocyclic and bicyclic 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is further optionally and independently substituted by one or more identical or different R 15 groups; each R 9 is independently selected from the group consisting of hydrogen, (C 1- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, 4- to 7-membered heterocycloalkyl, (C 6 -C 10 )aryl, and monocyclic and bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted by one or more identical or different R 15 groups; each R11 and R11’ is independently selected from the group consisting of hydrogen, (C 1 - C 6 )al
• each R 1a , R 1b , R 1a’ and R 1b’ is hydrogen; each R 2 is independently selected from the group consisting of hydrogen, halo, and (C 1 -C 6 )alkyl; R3 is selected from the group consisting of hydrogen, amino, hydroxyl, cyano, halogen, (C 1 - C 6 )alkyl, and (C 1 -C 6 )haloalkyl, wherein said alkyl, is further optionally and independently substituted by one or more identical or different R 15 groups; each R 4 and R 4 ’ is independently selected from the group consisting of hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )hydroxyalkyl, wherein said alkyl is further optionally and independently substituted by one or more identical or different R 15 groups, or R 4 and R
• R 7 is selected from the group consisting of: R8 is selected from the group consisting of (C 6 -C 10 )aryl, and monocyclic and bicyclic 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is further optionally and independently substituted by one or more identical or different R 15 groups; each R 9 is independently selected from the group consisting of hydrogen, (C 1- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, 4- to 7-membered heterocycloalkyl, (C 6 -C 10 )aryl, and monocyclic and bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally and independently substituted by one or more identical or different R 15 groups; each R11 and R11’ is independently selected from the group consisting of hydrogen, (C 1 - C 6 )al
• compounds are represented by formula I, wherein R 6 is , wherein R 6 is further optionally and independently substituted with one or more groups selected from (C 1 -C 6 )alkyl, halo, and cyano; and each R11 and R11’ is independently hydrogen or (C 1 -C 6 )alkyl.
• R 8 is selected from: , wherein R 8 is further optionally and independently substituted with one or more R 15 .
• compounds are represented by formula I, R8 is selected from: , wherein R8 is further optionally and independently substituted with one or more R 15 .
• a second aspect of the present invention is directed to a compound having a structure represented by formula (II): , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: each R 1a , R 1b , R 1a ’ and R 1b ’ is independently hydrogen or (C 1 -C 6 )alkyl, or R 1a and R 1a ’, together with the same carbon atom to which they are attached, form a spiro (C 3 -C 7 )cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 1a and R 1a ’, when on different carbon atoms, together with the atoms to which they are attached, form a (C 3 -C 7 )cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 1b and R 1b ’ form a spiro (C 3
• compounds are represented by formula II, wherein R 21 is selected from: , , , , , , and wherein R 21 is optionally and independently substituted with one or more (C 1- C 6 )alkyl, halo, and cyano.
• R8 is selected from: , , , , , , , , and , wherein R8 is further optionally and independently substituted with one or more R 15 .
• R 8 is selected from: wherein R8 is further optionally and independently substituted with one or more R 15 .
• compounds of the invention are represented by formula IIa, IIb, IIc, IId, or IIe:
• each R2 is independently selected from the group consisting of hydrogen and halo
• R 8 is selected from the group consisting of (C 6 -C 10 )aryl, and monocyclic and bicyclic 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is further optionally and independently substituted by one or more identical or different R 15 groups
• each R 15 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy haloalkoxy aryloxy heteroaryloxy aralkyloxy alkyenyloxy alkynyloxy amino, alkylamino, cycloalkylamino, heterocycloalkylamino, ary
• R8 is selected from: and , wherein R8 is further optionally and independently substituted with one or more R 15 .
• R8 is selected from: , , , , , , , , and , wherein R8 is further optionally and independently substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, cyano, halo, and one or more groups selected from R 15 ; and R16’ is selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl.
• Representative compounds of the invention have the following structures:
• the term "pharmaceutically acceptable” in the context of a salt refers to a salt of the compound that does not abrogate the biological activity or properties of the compound, and is relatively non- toxic, i.e., the compound in salt form 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 other 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
• Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.
• Suitable base salts include aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.
• Compounds of the present invention may have at least one chiral center and thus 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.
• 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 compound 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.
• Compounds of the present invention may also be in the form of N-oxides, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, prodrugs, tautomers, and unsolvated as well as solvated (e.g., hydrated) forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, of the compounds.
• the compounds of the present invention may be prepared by crystallization under different conditions and may exist as one or a combination of polymorphs of the compound.
• polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization, by performing crystallizations at different temperatures, or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other known techniques.
• the pharmaceutical composition comprises a co-crystal of an inventive compound.
• co-crystal refers to a stoichiometric multi-component system comprising a compound of the invention and a co-crystal former wherein the compound of the invention and the co-crystal former are connected by non- covalent interactions.
• co-crystal former refers to compounds which can form intermolecular interactions with a compound of the invention and co-crystallize with it.
• co-crystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2- hexanoic acid, 2-hydroxycaproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicyclic acid, maleic acid, saccharin, 4,4’-bipyridine p-aminosalicyclic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etofylline, and phenobarbital.
• the present invention is directed to a method for making an inventive compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
• inventive compounds or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer 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 described in various working examples and which illustrate non- limiting methods by which the compounds of the invention may be prepared.
• compositions [0058] Another aspect of the present invention is directed to a pharmaceutical composition that includes a therapeutically effective amount of an inventive compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer 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 also include one or more pharmaceutically acceptable excipients.
• compounds of the invention and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers 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.), and intrasternal injection
• intra-ocular, intra-arterial, intramedullary intrathecal, intraventricular, transdermal, interderma
• the most appropriate route of administration will depend upon a variety of factors including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
• 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.
• the compounds are formulated for oral or intravenous administration (e.g., systemic intravenous injection).
• compounds of the 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 elixi
• 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 tapi
• 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 invention may be formulated in a hard or soft gelatin capsule.
• 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, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• 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,
• Oral compositions may also include an excipients such as wetting agents, suspending agents, coloring, sweetening, flavoring, and perfuming agents.
• injectable preparations for parenteral administration 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 1,3-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 the invention 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. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. [0067] The compositions may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges and gels. [0068] The compounds of the invention may be formulated for administration by inhalation.
• 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 may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• a powder mix of the compound may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• suitable powder base such as lactose or starch.
• Compounds of the invention may be formulated for topical administration which as used herein, refers to administration intradermally by invention of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.
• Representative examples of carriers useful in formulating compounds 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 corneum 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.
• aloe compositions e.g., aloe-vera gel
• ethyl alcohol isopropyl alcohol
• octolyphenylpolyethylene glycol oleic acid
• polyethylene glycol 400 propylene glycol
• N- decylmethylsulfoxide e.g., isopropyl myristate, methyl laur
• 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 glycerin, 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.
• terapéuticaally effective amount refers to an amount of an inventive compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof that is effective in producing the desired therapeutic response in a patient suffering from a disease or disorder involving IKZF2 (Helios) and would benefit from IKZF2 degradation.
• terapéuticaally effective amount thus includes the amount of the inventive compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer 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 cells, or reduces the amounts of IKZF2 in diseased 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 following: the disease or disorder being treated and the severity thereof (e.g., its present status); the activity of the 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 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, Hardman et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, 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 1000 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, from about 5 to about 40 mg per day, and in yet other embodiments from about 10 to about 30 mg per day.
• Individual dosages 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).
• the compound may be administered at a dose in range from about 0.01 mg to about 200 mg/kg of body weight per day.
• a dose of from 0.1 to 100, e.g., from 1 to 30 mg/kg per day in one or more dosages per day may be effective.
• a suitable dose for oral administration may be in the range of 1-30 mg/kg of body weight per day, and a suitable dose for intravenous administration may be in the range of 1-10 mg/kg of body weight per day.
• the present invention is directed to methods of treating diseases or disorders involving IKZF2, that entails administration of a therapeutically effective amount of a compound of formula (I) and/or (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a subject in need thereof.
• the diseases or disorders that may be amenable to treatment with compounds of the present invention involve IKZF2 or otherwise functionally abnormal IKZF2 activity relative to a non-pathological state.
• 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 subject’s state of health.
• compounds of formula (I) and (II) may be useful in the treatment of cell proliferative diseases and disorders (e.g., cancer or benign neoplasms).
• the term “cell proliferative disease or disorder” refers to the conditions characterized by deregulated or abnormal cell growth, or both, including noncancerous conditions such as neoplasms, precancerous conditions, benign tumors, and cancer.
• the term “subject” (or “patient”) as used herein includes all members of the animal kingdom prone to or suffering from the indicated disease or disorder. In some embodiments, 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.
• Exemplary types of non-cancerous (e.g., cell proliferative) 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 ectodermal 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 ratoid arthritis,
• 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) such as 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 adrenocortical 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, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma), breast cancer, bronchial carcinoma, AIDS-related cancer
• 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) and mesenchymous or mixed mesodermal tumor (mixed connective tissue types).
• bone e.g.,
• methods of the present invention entail treatment of subjects having cell proliferative diseases or disorders of the hematological system, liver, brain, lung, colon, pancreas, prostate, ovary, breast, skin, and endometrium.
• “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), 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 lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macro
• 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.
• liver cancer e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma
• precancer or precancerous condition of the liver benign growths or lesions of the liver
• 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, dysplasia of the liver, hepatocellular carcinoma, intrahepatic cholangiocarcinoma (bile duct cancer), angiosarcoma, hemangiosarcoma, hepatoblastoma, and secondary liver cancer (metastatic liver cancer).
• “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, glioblastomas, meningiomas, pituitary adenomas, vestibular schwannomas, and primitive neuroectodermal tumors (medulloblastomas)), 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, precancer and precancerous conditions of the lung, benign growths or lesions of the lung, hyperplasia, metaplasia, and dysplasia 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).
• a compound of the present invention may be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC harboring ROS1 Rearrangement, Lung Adenocarcinoma, and Squamous Cell Lung Carcinoma).
• non-metastatic or metastatic lung cancer e.g., NSCLC, ALK-positive NSCLC, NSCLC harboring ROS1 Rearrangement, Lung Adenocarcinoma, and Squamous Cell Lung Carcinoma.
• cell proliferative diseases or disorders of the colon include all forms of cell proliferative disorders affecting colon cells, including colon cancer, a precancer or precancerous conditions of the colon, adenomatous polyps of the colon and metachronous lesions of the colon.
• 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.
• Cell proliferative disorders of the colon may also 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, 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 un
• 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 disorders of the ovary may include hyperplasia, metaplasia, and dysplasia of 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 disorders of the breast may include hyperplasia, metaplasia, and dysplasia of 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 cells of the endometrium.
• Cell proliferative disorders of the endometrium may include a precancer or precancerous condition of the endometrium, benign growths or lesions of the endometrium, endometrial cancer, 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.
• a compound of the present invention may be used to treat T cell leukemia or T cell lymphoma.
• a compound of the present invention may be used to treat Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
• a compound of the present invention may be used to treat myeloid leukemia.
• a compound of the present invention may be used to treat non-small cell lung cancer (NSCLC).
• NSCLC non-small cell lung cancer
• a compound of the present invention may be used to treat melanoma.
• a compound of the present invention may be used to treat triple-negative breast cancer (TNBC).
• TNBC triple-negative breast cancer
• NPC nasopharyngeal cancer
• a compound of the present invention may be used to treat microsatellite stable colorectal cancer (mssCRC).
• a compound of the present invention may be used to treat thymoma.
• a compound of the present invention may be used to treat carcinoid.
• a compound of the present invention may be used to treat gastrointestinal stromal tumor (GIST).
• GIST gastrointestinal stromal tumor
• Therapy may be "front/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 unsuccessful, or partially successful but who became non-responsive or 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 prior therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy or any combination thereof.
• prior 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 an inventive compound or a pharmaceutical composition 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.
• the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments entails at least one 28-day cycle which includes daily administration for 3 weeks (21 days) followed by a 7-day off period.
• the compound may be dosed twice a day (BID) over the course of two and a half days (for a total of 5 doses) or once a day (QD) over the course of two days (for a total of 2 doses).
• the compound may be dosed once a day (QD) over the course of five days.
• Combination Therapy [00112]
• the compounds of the present invention and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers may be used in combination or concurrently 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 terms “in combination” and “concurrently” in this context mean that the agents are co-administered, which includes substantially contemporaneous administration, by way of the same or separate dosage forms, and by the same or different modes of administration, or sequentially, e.g., as part of the same treatment regimen, or by way of successive treatment regimens.
• the first of the two agents 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 agents 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 the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in combination with one or more additional therapeutic agents known for use in treating the disease or disorder (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 Basis Of Therapeutics, 10th 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.
• additional anti-cancer agents and treatment regimens include radiation therapy, chemotherapeutics (e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, 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), immune- modulators, therapeutic antibodies (e.g., mono-specific and bispecific antibodies) and CAR-T therapy.
• chemotherapeutics e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, 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
• immune- modulators e.g
• the compound of the invention and the additional anticancer therapeutic agent 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 anticancer therapeutics may be administered within the same patient visit.
• the compound of the present invention and the additional therapeutic agent e.g., an anti-cancer therapeutic
• 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.
• the compound of the present invention may be used in combination with at least one other anti- cancer agents such as Paclitaxel (e.g., ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer), Topotecan (e.g., ovarian cancer and lung cancer), Irinotecan (e.g., colon cancer, and small cell lung cancer), Etoposide (e.g., testicular cancer, lung cancer, lymphomas, and non-lymphocytic leukemia), Vincristine (e.g., leukemia), Leucovorin (e.g., colon cancer), Altretamine (e.g., ovarian cancer), Daunorubicin (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma), Trast
• Paclitaxel e.g., ovarian cancer,
• 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 the present invention or a pharmaceutical composition which contains the compound and a pharmaceutically acceptable carrier wherein the compound and the carrier may be disposed in the same or separate containers.
• the kits or pharmaceutical systems of the invention may also include printed instructions for using the compounds and compositions.
• Example 1 Synthesis of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6- dione [00121] tert-Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate [00122] A mixture of 3-(6-bromo-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (3.0 g, 9.3 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
• Example 3 Synthesis of 3-(1-oxo-5-(1-((5-oxo-4-phenyl- 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)methyl)piperidin-4-yl)isoindolin-2- yl)piperidine-2,6-dione (1)
• 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6- dione 98 mg, 0.3 mmol
• sodium triacetoxyborohydride (191 mg, 0.9 mmol) in DMF (5 mL) was stirred at rt for 16 hours.
• Example 4 Synthesis of 4-oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-2-carbaldehyde [00137] Diethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylate [00138] To a stirred solution of diethyl 1H-pyrazole-3,5-dicarboxylate (2.0 g, 9.43 mmol) and tert-butyl (2-bromoethyl) carbamate (2.7 g, 12.2 mmol) in DMF (20 mL), was added K2CO3 (2.6 g, 18.8 mmol).
• Ethyl 4-oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate Under nitrogen, a solution of ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-2-carboxylate (1.15 g, 5.5 mmol), phenylboronic acid (1.05 g, 8.25 mmol), Cu(OAc)2 (995 mg, 5.5 mmol), and triethylamine (1.1 g, 11.0 mmol) in dichloromethane (DCM) (10 mL) was stirred at rt for 2 hours.
• DCM dichloromethane
• Example 5 Synthesis of 3-(1-oxo-5-(1-((4-oxo-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5a]pyrazin-2-yl)methyl)piperidin-4-yl)isoindolin-2- yl)piperidine-2,6-dione (8) [00148] A solution of 4-oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2- carbaldehyde (150 mg, 0.62 mmol), 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6- dione (203 mg, 0.62 mmol), and NaBH(OAc)3 (254 mg, 1.2 mmol) in DMF (5 mL) was stirred at rt for 16 hours.
• Example 6 Synthesis of 3-(5-(1-(3-((1-Methyl-2-oxo-1,2-dihydropyridin-3- yl)amino)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (12) [00150] 3-((3-(Hydroxymethyl)phenyl)amino)-1-methylpyridin-2(1H)-one [00151] A solution of 3-bromo-1-methylpyridin-2(1H)-one (400 mg, 2.2 mmol) in 10 mL of anhydrous DMF under nitrogen atmosphere was treated with (3-aminophenyl)methanol (320 mg, 2.6 mmol), Pd(OAc)2 (24 mg, 0.11 mmol), Xantphos (64 mg, 0.11 mmol) and K3PO4 (552 mg, 2.6 mmol), and the reaction mixture stirred
• Phenyl-6-vinyl-indolin-2-one [00160] To a solution of 6-bromo-1-phenyl-indolin-2-one (2.8 g, 9.72 mmol) in dioxane (32 mL) and H 2 O (4 mL) was added potassium vinyl trifluoroborate (2.60 g, 19.44 mmol), Pd(dppf)Cl 2 (711.04 mg, 0.972 mmol), and K 2 CO 3 (4.03 g, 29.15 mmol). The mixture stirred at 110°C for 12 hours.
• reaction mixture was then cooled to -75°C and a solution of 4-bromo-3-fluorobenzoic acid (15.0 g, 68.5 mmol) in THF (30 mL) was added dropwise.
• the reaction mixture was stirred for 40 min, then DMF (10.0 g, 137 mmol) in THF (15 mL) was added dropwise at -75 °C and the resulting mixture was stirred for an additional 2 h.
• the reaction mixture was quenched with 5 M HCl (10 mL) and was diluted with brine solution (50 mL).
• the resulting mixture was extracted with DCM (2 x 100 mL) and the combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered.
• reaction mixture was stirred for 30 min, then sodium triacetoxyborohydride (5.15 g, 24.3 mmol) was added and the resulting mixture was stirred for 18 h at rt.
• the reaction mixture was quenched with brine (15 mL) and the aqueous layer was extracted with EtOAc (2 ⁇ 100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and filtered.
• reaction mixture was stirred at 100°C for 15 h. Excess solvent was removed under reduced pressure to afford a crude residue that was dissolved in ACN (5 mL)/MTBE (5 mL) and stirred for 10 min to afford the title compound as a white solid which was isolated by filtration, washed with excess MTBE, and dried by vacuum (1.30 g, 72%).
• tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine- 1-carboxylate To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin- 5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.500 g, 1.13 mmol) in DMF (10 mL) was added Pd/C (10-50% wet, 0.120 g, 0.113 mmol) at rt under N2 atmosphere and the mixture was stirred for 60 h under a hydrogen atmosphere.
• reaction mixture was filtered through Celite® and was washed with THF (50 mL x 2). The solvent was removed under reduced pressure to afford a crude residue that was dissolved in ACN (5 mL)/MTBE (5 mL) and stirred for 10 min to afford the title compound as a white solid which was isolated by filtration, washed with excess MTBE, and dried by vacuum (0.380 g, 73%).
• reaction mixture was concentrated under reduced pressure to afford a crude residue that was dissolved in ACN (5 mL)/MTBE (5 mL) and stirred for 10 min to afford the title compound as an off-white solid which was isolated by filtration, washed with excess MTBE, and dried by vacuum (0.32 g, 91%).
• Example 12 Synthesis of 6-methyl-3-(6-(trifluoromethyl)pyridin-2-yl)quinazolin- 4(3H)-one
• 6-methylquinazolin-4(3H)-one (0.500 g, 3.12 mmol) in 1,4- dioxane (10 mL) at 25°C was added 2-bromo-6-(trifluoromethyl)pyridine (1.13 g, 4.99 mmol), cesium carbonate (3.05 g, 9.36 mmol) and 1,2-dimethylethylenediamine (DMEDA, 0.549 g, 6.24 mmol).
• DMEDA 1,2-dimethylethylenediamine
• reaction mixture was degassed with N2 for 10 min before copper(I) iodide (0.297 g, 1.56 mmol) was added at rt and the reaction mixture was heated at 120°C for 24 h. The reaction mixture was cooled to rt and the volatiles were evaporated under reduced pressure. The crude material was purified by reverse phase chromatography purification using 10 mM ammonium acetate in water and ACN followed by lyophilization to afford the title compound as an off-white solid (130 mg, 33%).
• Example 13 Synthesis of 3-(6-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile [00222] To a solution of 6-methylquinazolin-4(3H)-one (1.00 g, 6.24 mmol) in DCM (20 mL) were added 3 ⁇ molecular sieves (2.00 g, 6.24 mmol), (3-cyanophenyl)boronic acid (1.84 g, 12.5 mmol), pyridine (1.01 ml, 12.5 mmol) and copper (II) acetate (1.13 g, 6.24 mmol) at 25°C. The reaction mixture was stirred at rt under a balloon filled with air for 14 h.
• reaction mixture was filtered through a pad of Celite® and was washed with ethyl acetate (50 mL). The filtrate was evaporated under reduced pressure to give a solid (1.5 g) which was purified by silica gel column chromatography using ethyl acetate-hexanes to afford the title compound as an off-white solid (0.300 g, 17%).
• Example 14 Synthesis of 5-fluoro-6-methyl-3-(pyridin-2-yl)quinazolin-4(3H)-one [00224] To the solution of 6-amino-2-fluoro-3-methylbenzoic acid (0.500 g, 2.96 mmol) in triethyl orthoformate (5 mL) was added pyridin-2-amine (0.278 g, 2.96 mmol) at rt. The resulting reaction mixture was stirred at 140°C for 24 h.
• Example 15 Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(6-(trifluoromethyl)pyridin-2- yl)-3,4-dihydroquinazolin-6-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (64) [00226] 6-(Bromomethyl)-3-(6-(trifluoromethyl) pyridin-2-yl) quinazolin-4(3H)-one [00227] To a stirred solution of 6-methyl-3-(6-(trifluoromethyl)pyridin-2-yl)quinazolin- 4(3H)-one (0.250 g, 0.819 mmol) in ACN (10 mL) were added N-bromosuccinimide (NBS, 0.292 g, 1.64 mmol) and azobisisobutyronitrile (AIBN,
• Example 17 Synthesis of 6-bromo-2-methyl-3-(pyridin-2-yl)quinazolin-4(3H)-one
• Example 18 Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyridin-3-yl)-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (67) [00235] 3-(Pyridin-3-yl)-6-vinylquinazolin-4(3H)-one [00236] To a solution of 6-bromo-3-(pyridin-3-yl)quinazolin-4(3H)-one (700 mg, 2.32 mmol) in 1,4-dioxane (8 mL) were added potassium vinyltrifluoroborate (310 mg, 2.32 mmol) followed by a solution of cesium carbonate (2 M in water, 1.16 mL, 2.32 mmol) and PdCl 2 (dppf) 2 -CH 2 Cl 2 adduct (1.
• reaction mixture was stirred at 85°C for 18 h.
• Ethyl acetate 50 mL was added to reaction mixture and the mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to obtain a crude product that was purified by silica gel column chromatography using ethyl acetate and hexane as eluents to afford the title compound as a pale yellow solid (475 mg, 71%).
• the reaction mixture was warmed to 25°C and stirred for 3 h. During progress of the reaction, a large amount of solid formation was observed.
• the reaction mixture was filtered and the solid residue was washed with ethyl acetate.
• the filtrate was concentrated under reduced pressure to give the crude residue that was purified by silica gel column chromatography using ethyl acetate in hexane (45-95%) as an eluent to afford the title compound as a light yellow solid (225 mg, 45 %).
• the reaction mixture was stirred at 85°C for 14 h.
• the reaction mixture was filtered through a pad of Celite® and washed with ethyl acetate.
• the combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 and filtered.
• the solvent was removed under reduced pressure to afford the title compound as a pale brown solid (3.50 g, 79%).
• reaction mixture was quenched with ice- cold brine (100 mL) before it was extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered. The solvent was removed under reduced pressure to afford a crude residue that was purified by silica gel column chromatography using 40-60% ethyl acetate in hexane as an eluent to afford the title compound as a yellow solid (250 mg, 25%).
• reaction mixture was stirred at rt for 30 min before sodium triacetoxyhydroborate (238 mg, 1.13 mmol) was added at rt and the mixture was stirred for 15 h.
• the reaction mixture was diluted with cold water (2 x 30 mL) and was extracted with 10% MeOH/DCM (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford a crude residue that was purified by preparative HPLC [(Column : X select (150 mm*19) 5 ⁇ m, Mobile phase A: 0.1% HCOOH in H 2 O, Mobile phase B: acetonitrile, flow rate: 15 mL/min)].
• reaction mixture was stirred at rt for 30 min before it was cooled to 0°C and sodium triacetoxyborohydride (0.242 g, 1.143 mmol) was added portion-wise.
• the resulting reaction mixture was allowed to stir under nitrogen atmosphere at rt for 20 h.
• the reaction mixture was concentrated under reduced pressure to afford a crude residue that was purified using reverse phase column chromatography, eluting with 0.1% HCOOH in water:acetonitrile. The acetonitrile/water was removed by lyophilization to afford the title compound as a white solid (0.074 g, 30%).
• the reaction mixture was irradiated under microwave at 140°C for 4 h.
• the reaction mixture was concentrated under reduced pressure to afford a crude residue that was purified by reverse phase column chromatography 4% ACN in water as an eluent to afford the title compound (30 mg).
• the isolated compound was further purified by prep-HPLC [Method info: column: X select (150mm ⁇ 19) 5 ⁇ m, 0.1% HCl in H 2 O and ACN, flow rate: 15 mL/min].
• the vial was flushed with nitrogen and then heated at 80°C. After 4 hours, the mixture was cooled to rt before tri-n-butylphosphine (1.77 mL, 7.17 mmol) was added. The resulting mixture was heated at 80°C for 16 hr overnight. The mixture was cooled to rt, diluted with ethyl acetate (4 mL) and washed with sat. aq. ammonium chloride solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography on a C18 reverse-phase column, eluting with 20-100% acetonitrile in water containing 0.1% formic acid.
• Example 27 Synthesis of 3-(6-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-1-yl)methyl)-4-oxoquinazolin-3(4H)-yl)benzonitrile (61) [00281]
• Example 31 Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(thiazol-5-yl)-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (66) [00289] Compound 66 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 34 Synthesis of 3-(5-(1-((3-(2,6-dimethylpyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70) [00295] Compound 70 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 35 Synthesis of 3-(5-(1-((3-(6-isopropylpyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (71) [00297] Compound 71 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 36 Synthesis of 3-(5-(1-((3-(2-isopropylpyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (72) [00299] Compound 72 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 38 Synthesis of 3-(5-(1-((3-(6-methoxypyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (74) [00303] Compound 74 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 40 Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyridazin-3-yl)-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (76) [00307] Compound 76 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 41 Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyrazin-2-yl)-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (77) [00309] Compound 77 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 42 Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyridin-4-yl)-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (78) [00311] Compound 78 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 43 Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(2-oxo-1,2-dihydropyridin-3-yl)- 3,4-dihydroquinazolin-6-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (79)
• Compound 79 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 44 Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(6-oxo-1,6-dihydropyridin-2-yl)- 3,4-dihydroquinazolin-6-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (80) [00315] Compound 80 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 45 Synthesis of 3-(5-(1-((3-(1-methyl-1H-imidazol-5-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (81) [00317] Compound 81 is prepared according to similar procedures as described in Example 8.
• Example 54 Synthesis of 3-(5-(1-((7-fluoro-4-oxo-3-(pyridin-3-yl)-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90) [00335] Compound 90 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 55 Synthesis of 3-(5-(1-((5-fluoro-4-oxo-3-(pyridin-3-yl)-3,4- dihydroquinazolin-6-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (91) [00337] Compound 91 is prepared according to similar procedures as described in Examples 16 and 18.
• Example 57 Synthesis of 3-(1-oxo-5-(1-((2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-6- yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (93) [00341] Compound 93 is prepared according to similar procedures as described in Example 9.
• Example 58 Synthesis of 3-(1-oxo-5-(1-((2-(pyridin-2-yl)-2H-indazol-6- yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (94) [00343] Compound 94 is prepared according to similar procedures as described in Example 24.
• Example 61 Liquid Chromatography Mass Spectrometry (LCMS) Data
• Reaction monitoring and final compound characterization were done using Shimadzu LC-20AD series (binary pump and diode array detector) with Luna®-C18 column (3 ⁇ m, 2.0 ⁇ 30 mm).
• Mobile phase A: 0.04% Trifluoroacetic acid in water (v/v), B: 0.02% Trifluoroacetic acid in MeCN (v/v).
• Flow Rate 1 mL/min (0.00-1.80 min) and 1.2 mL/min (1.81-2.00 min) at 25°C.
• Example 63 HiBiT Protocol
• the HiBiT protein tagging system was applied to MOLT4 cells via a CRISPR/Cas – mediated insertion of the HiBiT peptide tag (PromegaTM) to the N-terminus of the IKZF2 gene locus (NeonTM Transfection System).
• the resulting HiBiT-Helios stable cell line was treated with the following inventive compounds in triplicates following a 13-point concentration scheme ranging from 10 ⁇ M to 0.00026 ⁇ M.
• the Nano-Glo® HiBiT Lytic Detection system (PromegaTM) was utilized for detecting bioluminescence of the HiBiT tag in treated cells: the abundance of the tag is proportionate to the level of luminescence.
• dose-response curves were plotted (GraphPad Prism) to determine the concentration points at which 50% of HiBiT-Helios degradation was achieved by each compound. The extent of degradation (range of luminescence) from the highest to lowest concentration points was calculated to determine Dmax. The results are shown in Table 3. VIA EFS Attorney Docket No.52095-710001WO Date of Deposit: October 15, 2021 Table 3.
• Example 64 MOLT4 IKZF2 HiBit Assay Protocol
• This protocol uses MOLT4 cells that were engineered using CRISPR/Cas9-mediated genomic insertion of HiBit, tagged to the N terminus of the IKZF2 coding sequence.
• Day 1. Created a 10-point dose response starting from 30 ⁇ M down to 1 nM using a Tecan D300e.

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