Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/438—The ring being spiro-condensed with carbocyclic or 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • 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
  • C07D471/10—Spiro-condensed systems
• • 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
  • C07D471/12—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 three hetero rings
  • C07D471/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• Migraines are experienced by approximately 35 million people in the U.S. alone every year.45% of women and 18% of men will experience migraines at some point in their lives. Not only are migraines painful, they can seriously disupt the ability of migraine sufferers to perform even the most basic functions of life. Worse still, migraines are most typical in people ages 35-45, which are often prime wage-earning and child-raising years, allowing migraines to often affect much more than just individual well-being.
• embodiments of the present disclosure provide compounds useful for the treatment of migraines, including pharmaceutically acceptable salts, stereoisomers, tautomers, and prodrugs thereof.
• the compounds have the following Structure (I): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein each of R 1a , R 1b , and R 3 are as defined herein.
• the compounds have the following Structure (II): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein, R 1a , R 1b , R 2 , X, Y, and L are as defined herein.
• the compounds have the following Structure (III): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein, R 1a , R 1b , R 1 , R 2 , R 3 , Z 1 , and Z 2 are as defined herein.
• the compounds have the following Stucture (IX):
• FIG.1 shows the analytical scale chromatogram for the first eluting peak (i.e., "Enatiomer 1 of 4ET-01-027”) from the separation of racemic mixture of 4ET-01-027 ("rac-4ET-01-027").
• FIG.2 shows the analytical scale chromatogram for the second eluting peak (i.e., "Enatiomer 2 of 4ET-01-027") from the separation of racemic mixture of 4ET-01- 027 ("rac-4ET-01-027").
• FIGs.3A and 3B show genetic inhibition of MNK partially attenuates facial hypersensitivity and hyperalgesic priming caused by dural interleukin 6 ("IL-6").
• FIGs.4A and 4B illustrate MNK1 knock out (“KO”) mice do not prime to low- dose NO donor following repeated stress.
• FIGs.5A and 5B depict how eFT508 reduces dural IL-6-induced facial hypersensitivity and prevents priming to pH 7.0.
• FIG.6 shows rac-4ET-01-027, Enatiomer 1 of 4ET-01-027, and 4ET-04-023 reduce dural IL-6-induced facial grimacing.
• the compounds of the present disclosure are capable of treating and preventing migraines and symptoms associated migraines. It has been discovered that MNK plays a key role in migraines and symptoms associated with migraines. As a result, these MNK inhibitors are useful for treating migraines and symptoms associated with migraines.
• compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
• an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.
• the present disclosure is directed to MNK inhibitors and the treatment of migraines and symptoms associated with migraines.
• the terms “about” and “approximately” mean ⁇ 20%, ⁇ 10%, ⁇ 5% or ⁇ 1% of the indicated range, value, or structure, unless otherwise indicated.
• the use of the alternative (e.g., "or”) should be understood to mean either one, both, or any combination thereof of the alternatives.
• Reference throughout this specification to "one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
• MNK mitogen-activated protein kinases
• Amino refers to the ⁇ NH 2 radical.
• Carboxy or “carboxyl” refers to the ⁇ CO 2 H radical.
• Cyano refers to the ⁇ CN radical.
• Hydroxy or “hydroxyl” refers to the ⁇ OH radical.
• “Nitro” refers to the ⁇ NO 2 radical.
• "Thiol” refers to the ⁇ SH substituent.
• Alkyl refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C 1 -C 12 alkyl), one to eight carbon atoms (C 1 -C 8 alkyl) or one to six carbon atoms (C 1 -C 6 alkyl), or any value within these ranges, such as C 4 -C 6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethyleth
• alkyl group refers to an unsaturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C 2 -C 12 alkenyl), two to eight carbon atoms (C 2 -C 8 alkenyl) or two to six carbon atoms (C 2 -C 6 alkenyl), or any value within these ranges, and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
• alkenyl group refers to unsaturated straight or branched hydrocarbon radical, having 2 to 12 carbon atoms (C 2 -C 12 alkynyl), two to nine carbon atoms (C 2 -C 9 alkynyl), or two to six carbon atoms (C 2 -C 6 alkynyl), or any value witin these ranges, and having at least one carbon-carbon triple bond.
• alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-1 -ynyl, but-2-ynyl and the like.
• the number of carbons referred to relates to the carbon backbone and carbon branching, but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.
• Alkoxy refers to a radical of the formula ⁇ OR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms (C 1 -C 12 alkoxy), one to eight carbon atoms (C 1 -C 8 alkoxy) or one to six carbon atoms (C 1 -C 6 alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.
• Amyl refers to a radical of the formula ⁇ NR a Rb, where R a is H or C 1 -C 6 alkyl and R b is C 1 -C 6 alkyl as defined above.
• aminoalkylcycloalkyl refers to a radical of the formula –R a R b NR c R d where R a is cycloalkyl as defined herein, Rb is C 1 -C 6 alkyl, Rc is H or C 1 -C 6 alkyl and Rd is C 1 - C 6 alkyl as defined above.
• the cycloalkyl and each C 1 -C 6 alkyl portion of an aminylalkylcycloalkyl group are optionally substituted unless stated otherwise.
• Aromatic ring refers to a cyclic planar molecule or portion of a molecule (i.e., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms.
• Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, and pyrimidonyl.
• an "aromatic ring” includes all radicals that are optionally substituted.
• Aryl refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms, for example 6 to 10 carbon atoms (C 6 -C 10 aryl) and at least one carbocyclic aromatic ring.
• the aryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
• Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
• Aryl as used herein, includes a fused ring system that includes non-aromatic moieties.
• aryl may have one of the following structures: Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.
• arylalkyl or “aralkyl” refers to the group –alkyl-aryl, where the alkyl and aryl groups are as defined herein.
• Aralkyl groups of the present disclosure are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.
• Cyanoalkyl refers to an alkyl group comprising at least one cyano substituent.
• the —CN substituent may be on a primary, secondary or tertiary carbon. Unless stated otherwise specifically in the specification, a cyanoalkyl group is optionally substituted.
• Carbocyclic or “carbocycle” refers to a ring system, wherein each of the ring atoms are carbon.
• Cycloalkyl refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C 3 -C 1 5 cycloalkyl), from three to ten ring carbon atoms (C 3 -C 10 cycloalkyl), or from three to eight ring carbon atoms (C 3 -C 8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C 3 -C 4 cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond.
• Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.
• Alkylcycloalkyl refers to a radical group of the formula –R a R b where R a is a cycloalkyl group and Rb is an alkyl group as defined above.
• alkylcycloalkyl group is optionally substituted.
• Fused refers to any ring structure described herein which is fused to another ring structure.
• Halo refers to bromo, chloro, fluoro or iodo.
• Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
• Halocycloalkyl refers to a cycloalkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.
• Haloalkylcycloalkyl refers to a radical group of the formula –R a R b where R a is a cycloalkyl group and Rb is a haloalkyl group as defined above. Unless otherwise stated specifically in the specification, a haloalkylcycloalkyl group is optionally substituted.
• Halocycloalkylalkyl refers to a radical group of the formula –R a R b where R a is an alkyl group and Rb is a halocycloalkyl group as defined above. Unless otherwise stated specifically in the specification, a halocycloalkylalkyl group is optionally substituted.
• Heterocyclylcycloalkyl refers to a radical group of the formula –R a R b whereR a is a cycloalkyl group and Rb is a heterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a heterocyclylcycloalkyl group is optionally substituted.
• “Hydroxylalkyl” refers to an alkyl radical, as defined above that is substituted by one or more hydroxyl radical. The hydroxyalkyl radical is joined at the main chain through the alkyl carbon atom. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.
• Heterocyclyl refers to a 3- to 18-membered, for example 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
• the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spirocyclic, and/or bridged ring systems.
• Nitrogen, carbon, and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quaternized.
• Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2- onyl (valerolactam), 2,3,4,5-
• heterocyclic units having 2 or more rings include: hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H- cycloocta[b]pyrrolyl.
• Heterocyclyl as used herein, includes a fused ring system that comprises additional non-heterocyclyl components.
• heterocyclyl may have one of the following structures: Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted. "Haloheterocyclyl” refers to a heterocyclyl group comprising at least one halo substituent. The halo substituent may be on a primary, secondary or tertiary carbon. Unless stated otherwise specifically in the specification, a haloheterocyclyl group is optionally substituted "Haloheterocyclylalkyl” refers to a radical group of the formula –R a Rb where R a is an alkyl group and R b is a haloheterocyclyl group as defined herein.
• Heterocyclylalkyl refers to a radical group of the formula –R a Rb where R a is an alkyl group and R b is a heterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a heterocyclylalkyl group is optionally substituted.
• Heteroaryl refers to a 5- to 18-membered, for example 5- to 6-membered, ring system radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
• Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
• Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
• Heteroaryl as used herein, includes a fused ring system where the heteroatom (e.g., oxygen, sulfur, nitrogen, etc.) is not part of the aryl moiety.
• heteroaryl may have the following structure: Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.
• heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3- methylpyridinyl, and 4-dimethylaminopyridinyl.
• heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H- pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H- indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.
• heteroaryl group as described above is C 1 -C 5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S).
• N nitrogen
• O oxygen
• S sulfur
• C 1 -C 5 heteroaryl examples include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol- 1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2- yl, pyridin-3-yl, and pyridin-4-yl.
• the ring when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R 2 and R 3 taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
• the ring can be saturated or partially saturated and can be optionally substituted.
• fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.
• 1,2,3,4-tetrahydroquinoline having the formula: is, for the purposes of the present disclosure, considered a heterocyclic unit.
• 6,7- Dihydro-5H-cyclopentapyrimidine having the formula: is, for the purposes of the present disclosure, considered a heteroaryl unit.
• the aryl ring will predominate and determine the type of category to which the ring is assigned.
• 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula: is, for the purposes of the present disclosure, considered a heteroaryl unit.
• a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein.
• alkyl or aryl or either of their prefix roots appear in a name of a substituent e.g., arylalkyl, alkylamino
• the name is to be interpreted as including those limitations given above for "alkyl" and "aryl.”
• substituted is used throughout the specification.
• substituted is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below.
• the substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time.
• these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit.
• a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
• a two hydrogen atom replacement includes carbonyl, oximino, and the like.
• a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
• substituted is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent.
• any number of the hydrogen atoms may be replaced.
• difluoromethyl is a substituted C 1 alkyl
• trifluoromethyl is a substituted C 1 alkyl
• 4-hydroxyphenyl is a substituted aromatic ring
• (N,N-dimethyl-5-amino)octanyl is a substituted C 8 alkyl
• 3- guanidinopropyl is a substituted C 3 alkyl
• 2-carboxypyridinyl is a substituted heteroaryl.
• variable groups defined herein e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups are so indicated.
• the substituents are selected from i) –OR x+2 ; for example, –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 CH 3 ; ii) –C(O)R x+2 ; for example, –COCH 3 , –COCH 2 CH 3 , –COCH 2 CH 2 CH 3 ; iii) –C(O)OR x+2 ; for example, –CO 2 CH 3 , –CO 2 CH 2 CH 3 , –CO 2 CH 2 CH 2 CH 3 ; iv) –C(O)N(R x+2 ) 2 ; for example, –CONH 2 , –CONHCH 3 , –CON(CH 3 ) 2 ; v) –N(R x+2 ) 2 ; for example, –NH 2 , –NHCH 3 , –N(CH 3 ) 2 , –NH(
• each R x+2 is independently hydrogen, optionally substituted C 1 -C 6 linear or branched alkyl (e.g., optionally substituted C 1 -C 4 linear or branched alkyl), or optionally substituted C 3 -C 6 cycloalkyl (e.g optionally substituted C 3 -C 4 cycloalkyl); or two R x+2 units can be taken together to form a ring comprising 3-7 ring atoms.
• each R x+2 is independently hydrogen, C 1 -C 6 linear or branched alkyl optionally substituted with halogen or C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl.
• C 1-6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 - C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 - C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 , alkyl.
• “Patient” or “Subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications.
• the subject is a mammal, and in some embodiments, the subject is human.
• Other subjects include mammals that do not tolerate opioids well or that are common pets or domesticated animals, such as dogs, cats, and horses.
• “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
• “Pharmaceutically acceptable” refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
• “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.
• “Pharmaceutically acceptable salt” includes both acid and base addition salts.
• “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
• Pharmaceutically acceptable acid addition salts which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,
• “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
• Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid.
• Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
• Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
• Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
• basic ion exchange resins such as
• Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
• Drug refers to a compound which is biologically active and provides a desired physiological effect following administration of a patient in need.
• Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compounds of Structure (I) through (XLIX)).
• prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
• a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
• the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam).
• Bundgard, H. Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam).
• a discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B.
• prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
• Prodrugs include compounds wherein a hydroxy, amino or thiol group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
• Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
• embodiments of the present disclosure may provide prodrug of an MNK inhibitor.
• a prodrug is a compound that can be transformed to an active drug.
• a prodrug is given to a patient and is then converted into a physiologically active form of the compound in vivo.
• a prodrug may have a desired physiological effect.
• the prodrug of the present disclosure may include functional groups including esters, amides, phosphate ester, sulfonamide, or its combination thereof.
• Derivative refers a compound that can be synthesized from a parent compound by replacement of one atom with another atom or group of atoms.
• “Migraine” refers to a headache or aura that results from abnormal brain activity, but is not caused by a tumor, other serious medical problem, or a viral or bacterial infection of the sinus or nasal passageways. There are currently no blood test or scans that can diagnose migraine.
• Migraine symptoms often include: moderate to severe pain; instense pain; inability to conduct activities of daily life while experiencing the headache; aura; throbbing, pounding, or pulsating sensations in the head; worsening of pain which physical activity; worsening of pain with any movement; nausea and/or vomiting; sensitivity to noise, light, or smells; and duration for more than four hours.
• Migraine is often thought of a having four phases, prodrome, aura, headache, and postdrome. Prodrome is often characterized by extreme tiredness and yawning, irritability or moodiness, difficulty concentrating, and food cravings.
• Aura is most typically visual.
• Visual aura includes flashes of light, blind spots, bright spots, wavy, zig-zag, or C-shaped lines, bright geometrical lines and/or shapes in the visual field, blurred vision, or visual hallucinations.
• Sensory aura such as tingling or numbness in a limb or the face or tongue and dysphasic aura are also sometimes observed.
• Migraines may also be diagnosed, at least in part, by their occurrence in response to triggers, such as caffeine withdrawal, hormonal changes, lack of sleep, alcohol, exercise or physical stress, loud noises, bright lights, missed meals, odors, perfumes, smoking or exposure to smoke, stress, anxiety, and/or eating common trigger foods, such as chocolate, diary, especially cheeses, MSG, foods with tyramine, especially red wine, aged cheese, smoked fish, chicken liver, figs, and beans, fruits, especially avocado, banana, or citrus, meats containing nitrates, such as bacon, hot dogs, salami, and cured meats, onions, peanuts and other nuts asn seeds, fermented foods, and pickled foods.
• triggers such as caffeine withdrawal, hormonal changes, lack of sleep, alcohol, exercise or physical stress, loud noises, bright lights, missed meals, odors, perfumes, smoking or exposure to smoke, stress, anxiety, and/or eating common trigger foods, such as chocolate, diary, especially cheeses, MSG, foods with tyramine
• Postdrome is often characterized by fatigue, body aches, trouble concentrating, dizziness and sensitivity to light. Not all patients experience prodrome and/or postdrome. In addition, not all patients experience aura, or some experience it along with headache. Some patients experience aura alone, or with prodrome and/or postdrome, but without headache. Any patient experiencing aura and/or headache is typically considered to suffer from migraines.
• effective amount or "therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
• the therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
• the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
• the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
• treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition including but not limited to a therapeutic effect and/or a prophylactic effect.
• therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
• a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
• a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
• the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
• co-administration encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time.
• Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
• pharmaceutically acceptable salts include quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide).
• quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide).
• in vivo refers to an event that takes place in a subject’s body.
• Embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Structure (I) through (XLIX). Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds.
• Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes.
• embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof.
• Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
• solvate refers to an aggregate that comprises one or more compounds of the disclosure with one or more molecules of solvent.
• the solvent is water, in which case the solvate is a hydrate.
• the solvent is an organic solvent.
• the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
• the compounds of the disclosure are a true solvate, while in other cases, the compounds of the disclosure merely retain adventitious water or is a mixture of water plus some adventitious solvent.
• "Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
• aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
• pharmaceutical composition refers to formulations of compounds of the disclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
• stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
• the present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
• the compounds of the disclosure i.e., compounds of Structure (I) through (XLIX)
• their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
• Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms.
• Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
• Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
• HPLC high pressure liquid chromatography
• Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the disclosure.
• Atropisomers which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included.
• certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.
• the compounds of Structure (I) through (XLIX) are a mixture of enantiomers or diastereomers.
• the compounds of Structure (I) through (XLIX) are substantially one enantiomer or diastereomer.
• a "tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.
• the chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD/Name Version 9.07 software program and/or ChemDraw Profesional Version 17.0.0.206 software naming program (CambridgeSoft).
• a substituent group is typically named before the group to which it attaches.
• cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.
• Compounds The present disclosure is directed to MNK inhibitors that are used for treating, preventing, or mitigating the effects of migraines and related symptoms.
• the MNK inhibitor may have the following Structure (Ia): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 1a and R 1b are each independently alkyl. In some embodiments, R 1a and R 1b are the same. In certain embodiments, R 1a and R 1b are different. R 1a or R 1b may be alkyl groups, such as a methyl, ethyl, propyl, isopropyl, or tert-butyl group. The R 1a or R 1b substituent groups may be the same alkyl group, or different alkyl groups.
• R 1a may be a methyl group, while R 1b may be an ethyl group.
• R 1a may be an isopropyl group, while R 1b may be a tert-butyl group. Any alkyl group combinations of substituents R 1a or R 1b may be used.
• R 1a and R 1b joint to form a cyclic moiety.
• the compound has the following Structure (Ib): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 1a and R 1b may join together to form ring A.
• substituents R 1a or R 1b may together form a cyclic compound indicated as cyclic moiety A.
• the cyclic moiety A of the Structure (Ib) may include a five-membered ring.
• the cyclic moiety A of the Structure (Ib) may be a non-substituted cyclic compound.
• the cyclic moiety A may be a non- substituted five-membered ring such as a cyclopentane.
• the cyclic moiety A of the Structure (Ib) may have one or more alkyl substitutions.
• the alkyl substitutions on the cyclic moiety A may include methyl, ethyl, propyl, isopropyl, cyclopropyl, or tert-butyl group. Substituted positions may be 2-, 3-, 4-, or 5- position of the cyclopentane.
• the degree of the substitutions may include mono-, di-, tri-, or tetra-substitutions.
• the cyclic moiety A may be 2,2,5,5- tetramethylcyclopentane.
• Synthetic routes may be used to install different substitution patterns on the cyclopentane ring.
• the cyclic moiety A may be 3,3,4,4- tetramethylcyclopentane.
• the cyclic moiety A may have a fused ring.
• a part of the cyclic moiety A may include a fused benzene ring.
• the cyclic moiety A may include the fused benzene ring with a cyclopentyl or cyclohexyl ring.
• the synthetic route to prepare the benzene fused cyclohexyl compound may involve the use of 1-tetralone.
• the cyclic moiety A may include a fused cyclopentyl or cyclohexyl ring with other cyclic structures.
• the cyclic moiety A may include a six-membered ring.
• the cyclic moiety A may be non-substituted cyclic moiety.
• the cyclic moiety A may be a non- substituted six-membered ring such as a cyclohexane.
• the cyclic moiety A may have one or more alkyl substitutions.
• the alkyl substitutions on the cyclic moiety A may include methyl, ethyl, propyl, isopropyl, cyclopropyl, or tert-butyl group.
• the cyclic moiety A may have one or more heteroatom-containing substituents, such as alcohols, sulfonamides, or carboxylic acids.
• Substituted positions may be 2-, 3-, 4-, 5-, or 6- position of the cyclohexane.
• the degree of the substitutions may include mono-, di-, tri-, or tetra-substitutions.
• the cyclic moiety A may be 3,5- dimethylcyclohexane.
• Synthetic routes may be used to install different substitution patterns on the cyclohexane ring.
• the cyclic moiety A may be 2,3,4,5,6- pentamethylcyclohexane.
• the cyclic moiety A may include a heterocyclic compound.
• the heterocyclic compound is a cyclic compound that has atoms of at least two different elements such as a carbon and an oxygen atom.
• the cyclic moiety A may be tetrahydropyran.
• the tetrahydropyran includes one oxygen atom and five carbon atoms in a six-membered ring.
• the heterocyclic compound may further be substituted with alkyl substituents or functional groups on various positions with various degrees of substitutions. It is noted that, while some of the structures shown in the present disclosure include an oxygen atom in a cyclic compound, such a structure is merely provided for illustrative purposes. Synthetic routes may be used to install different heteroatoms in the cyclic compounds.
• the cyclic moiety A of the structure (Ib) may include piperidine (a nitrogen atom), phosphinate (a phosphorus atom), silinane (a silicon atom), or thiane (a sulfur atom).
• the cyclic moiety A may be unsaturated.
• Unsaturated cyclic compounds may include aromatic cyclic compounds such as a benzene, pyridine, diazine, oxazine, dioxine, or thiazine.
• the cyclic moiety A may be saturated.
• the cyclic moiety A may have one or more functional group substitutions.
• the functional groups may include a hydroxyl, amine, amide, carboxylic acid, ether, or sulfonamide.
• the cyclic moiety A may include 4-hydroxyl cyclohexane, 4-carboxylic acid cyclohexane, 4-methoxyl cyclohexane, or 4-alkylsulfonamide cyclohexane.
• Substituted positions may be 2-, 3-, 4-, 5-, or 6- position of the cyclohexane.
• the degree of the substitutions may include mono-, di-, tri-, tetra-, or penta-substitutions.
• One or more functional groups may be installed on a heterocyclic compound with various substitution positions and degree.
• the substituent R 2 of the structures (Ia) and (Ib) may include a nitrogen containing functional group.
• the nitrogen containing functional group of the substituent R 2 may include amides, amidine, amines, amine oxides, azo, carbamates, carbodiimides, enamines, aromatic heterocycles, non-aromatic heterocycles, hydrazones, hydroxamic acids, imides, imines, nitriles, sulfonamide, or urea.
• the aromatic heterocyles may include pyrrole, imidazole, pyrazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine.
• the nitrogen containing functional group of substituent R 2 may be unsubstituted or substituted.
• a pyridazine may be substituted with an amine group at 3 position as shown in 4ET-004- 006 hereinafter.
• a pyridazine may be substituted with an amide containing a cyclopropyl ring at 3 position as shown in 4ET-004-003 hereinafter.
• the degree and location of substitution on the nitrogen containing functional group may differ.
• the nitrogen containing functional group of the substituent R 2 may be attached via an alkyl chain represented by -C n H 2n - where n is between zero and five.
• the nitrogen containing functional groups of the substituent R 2 and the backbone structures (Ia) and (Ib) are separated by n carbon atoms.
• Substituent R 2 of the structures (Ia) and (Ib) may include an aromatic heterocycle.
• substituent R 2 may include 4- aminopyrimidinyl moiety.
• the compound is a compound of Structure (Ic): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 3 may include an amine.
• the amine is a primary amine.
• R 3 is –NH 2 .
• R 3 may include a secondary amine.
• R 3 may further include a functional group at one end.
• the functional group may include a hydroxyl, sulfonamide, carboxylic acid, ester, amine, amide, morpholine, piperazine, or thiomorpholine.
• the secondary amine and the functional group may be attached via an alkyl chain represented by -CnH 2 n- where n is between one and five.
• the secondary amine of the substituent R 3 and the functional group may be separated by n carbon atoms.
• the secondary amine attached to a hydroxyl group separated by carbons atoms forms an aminoalcohol (HO-C 2 H4NH-), which is shown as examples 4ET-02-001, 4ET-03-004, 4ET-03-007, and 4ET-03-011 hereinafter.
• the secondary amine attached to a sulfonamide group separated by two carbon atoms forms amino sulfonamide (CH 3 SO 2 NHC 2 H 4 NH-), which is shown as examples 4ET-02-004, 4ET-03-012, 4ET- 03-013, and 4ET-03-014 hereinafter.
• the amine of substituent R 3 may include a tertiary amine.
• the tertiary amine of the substituent R 3 may be cyclic.
• the cyclic tertiary amine of the substituent R 3 may be a part of saturated five-membered ring or six-membered ring.
• the cyclic tertiary amine of the substituent R 3 in a saturated five-membered ring may be pyrrolidine, imidazolidine, or pyrazolidine.
• the cyclic tertiary amine of the substituent R 3 in a saturated six-membered ring may be piperidine or piperazine.
• the tertiary amine may further include a functional group at one end.
• the functional group may include a hydroxyl, sulfonamide, carboxylic acid, ester, amide, amine, morpholine, piperazine, or thiomorpholine.
• the tertiary amine and the functional group may be attached via an alkyl chain represented by -CnH 2 n- where n is between one and five.
• the tertiary amine of the substituent R 3 and the functional group may be separated by n carbon atoms.
• the tertiary amine of the substituent R 3 may be cyclic.
• the cyclic tertiary amine of the substituent R 3 may be a part of unsaturated five-membered ring or six-membered ring.
• the cyclic tertiary amine of the substituent R 3 in an unsaturated five- membered ring may be pyrazole, imidazole, or oxazole.
• the cyclic tertiary amine of the substituent R 3 in an unsaturated six-membered ring may be pyridine, diazine, triazine, or oxazine.
• the amine of substituent R 3 may also include an amide group.
• the amide group of substituent R 3 may further include a functional group at one end.
• the functional group may include a hydroxyl, sulfonamide, carboxylic acid, ester, amine, amide, morpholine, piperazine, or thiomorpholine.
• the amide of the substituent R 3 and the functional group may be attached via an alkyl chain represented by -CnH 2 n- where n is between zero and five.
• the amide of the substituent R 3 and the functional group may be separated by n carbon atoms.
• the amide attached to morpholine group by one methylene forms morpholine amide, which is shown as examples 4ET-02-007, 4ET-03-027, and 4ET-03-028 hereinafter.
• the amide attached to morpholine group by two methylenes forms morpholine amide, which is shown as example 4ET-02-031 hereinafter.
• the amide of the substituent R 3 may also be directly attached to one of the functional groups.
• the amide of the substituent R 3 may be directly attached to a cyclic structure.
• the amide of the substituent R 3 may be directly attached to cyclopropane. In this case, there is no carbon atom between the amide and cyclopropane.
• Structures with the amide group directly attached to cyclopropane as a part of the substituent R 3 include 4ET- 02-003, 4ET-02-009, 4ET-02-010, 4ET-02-011, 4ET-02-012, 4ET-02- 016, 4ET-03-002, 4ET-03-009, 4ET-03-017, 4ET-03-019, 4ET-03-020, 4ET-03-023, 4ET-03-026, 4ET-03-034, and 4ET-04-003 hereinafter. Cyclopropanes may be unsubstituted or substituted with one or more functional groups.
• the substituted cyclopropanes may include fluorine, hydroxyl, hydroxylmethylene, alkyl, carboxylic acid, amine, aminomethylene, ester, ether, amide, sulfonamide, morpholine, piperazine, or thiomorpholine group attached to a cyclopropane ring.
• the substituted position on the cyclopropane where the functional group is attached may be the 1-, 2-, or 3-position.
• the functional group attached to the cyclopropane may have an additional alkyl chain (-CnH 2 n-) between the functional group and the cyclopropane where n is between zero and 5.
• n When n is equal to zero, there is no methylene between the functional group and the cyclopropane. Thus, the functional group may be directly attached to the cyclopropane on the 1-, 2-, or 3-position. Similarly, when n is equal to one, there is one methylene between the functional group and the cyclopropane. In this case, the functional group is one carbon away from the cyclopropane, which gives an extra degree of freedom to the structure.
• Structures with the amide group directly attached to substituted cyclopropane as a part of the substituent R 3 include 4ET- 02- 009, 4ET-02-010, 4ET-02-011, 4ET-02-012, 4ET-02-016, 4ET-03-019, 4ET-03- 020,4ET-03-023, 4ET-03-026, and 4ET-03-034 hereinafter.
• the amide of the substituent R 3 may be directly attached to cyclobutane. In this case, there is no carbon atom between the amide and cyclobutane.
• the cyclobutane may further have a functional group.
• the functional group may include hydroxyl, alkyl, carboxylic acid, amine, ester, ether, amide, sulfonamide, morpholine, piperazine, or thiomorpholine.
• the substituted position on the cyclobutane where the functional group is attached may be the 1-, 2-, 3-, or 4-position.
• the functional group may have an additional alkyl chain (CnH 2 n) between the functional group and the cyclobutane where n is between zero and 5.
• the cyclic structure that is attached to the amide via an alkyl chain or directly may include at least one heteroatom to form a heterocyclic compound.
• the heterocyclic compound may include a three-membered ring with one heteroatom or a four- membered ring with one heteroatom.
• the three-membered ring with one heteroatom may include aziridines or ethylene oxide.
• the four-membered ring with one heteroatom may include azetidine or oxetane. Azetidine directly attached to the amide is shown for example in 4ET-02-017 hereinafter.
• functional groups may be attached to the heterocyclic compound. In the case of ethylene oxide (epoxide), Sharpless epoxidation may be used to generate chiral epoxides.
• a total of two amine groups may be attached to the cyclopropane; a first amine group may be attached to 1-position of cyclopropane, while a second amine group is attached to 2- position of cyclopropane.
• the amide of the substituent R 3 may be a reverse amide. Instead of a nitrogen atom of the amide of the substituent R 3 being directly attached to the structure (Ic), a carbon atom of the amide of the substituent R 3 may be attached to the structure (Ic).
• the reverse amide attached to the structure (Ic) is shown for example in 4ET-03-024 hereinafter.
• Embodiments of the present disclosure described above including the amide in the substituent R 3 may also be replaced with a reverse amide.
• the amide group of examples such as 4ET-02-003, 4ET-02-009, 4ET-02-010, 4ET-02-011, 4ET- 02-012, 4ET-02-016, 4ET-03-002, 4ET-03-009, 4ET-03-017, 4ET-03-019, 4ET-03- 020, 4ET-03-023, 4ET-03-026, 4ET-03-034, 4ET-04-003, 4ET-02-007, 4ET-03-027, 4ET-03-028, and 4ET-02-031 may be replaced with a reverse amide.
• the structure (Ic) may be equipped with an amide analog of the substituent R 3 .
• a thioamide group may be used instead of the amide group shown in 4ET- 02-013 hereinafter. Similar to the amide substituent, the thioamide group may be replaced with a reverse thioamide.
• a nitrogen atom of the thiamide of the substituent R 3 instead of being directly attached to the structure (Ic), a carbon atom of the thioamide of the substituent R 3 may be attached to the structure (Ic).
• other amide analogs of the substituent R 3 may be used for the structure (Ic).
• a urea group may be used instead of the amide group shown in 4ET-02-015 hereinafter.
• a thiourea group may be used instead of the amide group.
• An amide, a reverse amide, a thioamide, a reverse thioamide, a urea, and a thiourea as a part of the substituent R 3 are interchangeable in the structure (Ic).
• the 4-aminopyrimidine moiety in structure (Ic) may be modified.
• the pyrimidine moiety and the parent structure as shown in the structure (Ia) or (Ib) are connected via the amine linker (-NH-) in the structure (Ic).
• the amine linker may be extended.
• the amine linker may include additional alkyl chain (-CnH 2 n-) between the amine and pyrimidine moiety where n is between one and five.
• additional alkyl chain (-CnH 2 n-) between the amine and pyrimidine moiety where n is between one and five.
• One carbon extension which is an insertion of a methylene unit, between the amine and the pyrimidine moiety provides a benzylpyrimidine moiety.
• the amine linker may include additional alkyl chain (-C n H 2n -) between the amine and the parent structure shown as the structure (Ia) or (Ib) where n is between one and five.
• n is between one and five.
• One carbon extension which is an insertion of a methylene unit, between the amine and the structure (Ia) or (Ib) provides a methylaminopyrimidine moiety.
• methylene units may be added both sides of the amine linker of the structure (Ic).
• Amine linker extension with extra methylene units may be used in conjunction with any of the other variations of structures (Ia), (Ib), and (Ic) disclosed herein.
• the pyrimidine moiety in the structure (Ic) may be modified to substitute a different unsaturated six-membered ring with two nitrogen atoms isomer, such as 1,2-diazine (pyridazine) or 1,4-diazine (pyrazine).
• 1,2-diazine (pyridazine) may be used instead of 1,3-diazine (pyrimidine) in the structure (Ic) shown in example 4ET-04-003 and 4ET-04-006 hereinafter.
• Pyrimidine in the structure (Ic) may be replaced with a five-membered heterocyclic compound.
• Pyrimidine is a six-membered heterocyclic compound with two nitrogen atoms.
• five-membered heterocyclic compounds have different chemical and physical properties than the six-membered heterocyclic compounds.
• Some MNK inhibitors of the present disclosure may take advantage of such differences between five- and six-membered heterocyclic compounds.
• the five- membered heterocyclic compound may include nitrogen and sulfur atoms.
• the five- membered heterocyclic compound with N and S may include thiazole as shown in example 4ET-04-001 hereinafter.
• the five- membered heterocyclic compound with S may include thiophene.
• the five-membered heterocyclic compound may include nitrogen and oxygen atoms.
• the five-membered heterocyclic compound with N and O may include oxazole or isoxazole.
• the five-membered heterocyclic compound may include two nitrogen atoms.
• the five-membered heterocyclic compound with two nitrogen atoms may include imidazole or pyrazole.
• the amine linker with additional carbon atom may be attached to a pyridazine moiety and the pyridazine moiety may be connected to the pyridone scaffold with an amine or sulfonamide.
• the amine linker with additional carbon atom may be attached to a pyridazine moiety and the pyridazine moiety may be directly connected to an amino group.
• the 4-aminopyrimidine moiety and a parent structure may be attached via other nitrogen containing linkers.
• the pyrimidine moiety and the parent structure as shown in the structure (Ia) or (Ib) are connected via the amine linker (-NH-) in the structure (Ic).
• Embodiments of the present disclosure may be configured to install an amide group between the 4-aminopyrimidine moiety and the parent structure. This can be synthesized by using an amide containing starting material in Buchwald-Hartwig amination described in Example 1 – MNK inhibitor synthesis.
• the resulting MNK inhibitor may include an amide as shown in example 4ET-04-013 or a reverse amide as shown in example 4ET-04-014 hereinbelow between the 4- aminopyrimidine moiety and the parent structure.
• embodiments of the present disclosure may be configured to install a sulfonamide group between the 4-aminopyrimidine moiety and the parent structure. This can be synthesized by using a sulfonamide containing starting material in Buchwald- Hartwig amination described in Example 1 – MNK inhibitor synthesis. Another approach involves the use of a sulfonyl chloride reagent or intermediate.
• the resulting MNK inhibitor may include a sulfonamide as shown in examples 4ET-04-010 and 4ET- 04-011 or a reverse sulfonamide as shown in example 4ET-04- 012 hereinbelow between the 4-aminopyrimidine moiety and the parent structure.
• embodiments of the present disclosure may be configured to install an ether group between the 4-aminopyrimidine moiety and the parent structure. This can be synthesized by using an alcohol containing starting material in Buchwald- Hartwig amination described in Example 1 – MNK inhibitor synthesis. Another approach involves using an alcohol containing starting material in an Ullmann-type coupling reaction.
• the substituents R 1a or R 1b of the structure (Ic) may be alkyl groups, as discussed hereinabove in the structure (Ia). Alternatively, the substituents R 1a or R 1b of the structure (Ic) may together form a cyclic compound indicated as a ring structure A below.
• the detailed discussion of the ring structure A of the structure (Ib) may also apply to the structure (Id): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein: R 3 may include an amine.
• R 1a is C 1 -C 6 alkyl. In some embodiments, R 1a is methyl. In certain embodiments, R 1a is aryl. In certain embodiments, R 1a is phenyl. In certain specific embodiments, R 1b is C 1 -C 6 alkyl. In some embodiments, R 1b is methyl. In some embodiments, R 1a and R 1b , together with the carbon to which they are both attached, join to form cycloalkyl. In more specific embodiments, the cycloalkyl is cyclopentyl or cyclohexyl. In some embodiments, R 1a and R 1b , together with the carbon to which they are both attached, join to form cycloalkenyl.
• the cycloalkenyl is cyclopentenyl, cyclohexenyl, or cycloheptenyl.
• R 1a and R 1b together with the carbon to which they are both attached, join to form heterocyclyl.
• R 1a and R 1b together with the carbon to which they are both attached, join to form aryl.
• R 1a and R 1b together with the carbon to which they are both attached, join to form heteroaryl.
• the compound has one of the following structures:
• R 4 is, at each occurrence, independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, haloalkyl, hydroxyl, -NHS(O) 2 CH 3 , or -C(O)OH, or two R 4 , together with the carbon to which they are both attached, join to form a cycloalkyl;
• W is N or O;
• Z is C or O; and
• n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, or 2.
• R 2 has one of the following structures: .
• X is CH and Y is N.
• X is N and Y is CH.
• L is –NH–.
• L is –CH 2 NH–.
• R 3a is a branched C 1 -C 6 alkyl.
• R 3a is iso-propyl.
• MNK inhibitor has the following Structure (III):
• R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 hydroxyalkyl, C 3-7 branched hydroxyalkyl, cyano, C 1-6 alkoxyl, C 3-7 branched alkoxy, hydroxy, and C 3-6 cycloalkyl that is optionally substituted with 1 to 3 substituents selected from the groups consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl;
• R 3 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched
• Z 1 is selected from the groups consisting
• R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 hydroxyalkyl, C 3-7 branched hydroxyalkyl, cyano, C 1-6 alkoxyl, C 3-7 branched alkoxy, hydroxy, and C 3-6 cycloalkyl that is optionally substituted with 1 to 3 substituents selected from the groups consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl;
• R 2 is selected from the group consisting of:
• R 3 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched
• R 7 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 alkoxyl, C 3-7 branched alkoxy, and hydroxy;
• R 8 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 hydroxyalkyl, C 3-7 branched hydroxyalkyl, C 1-6 alkoxyl, C 3-7 branched alkoxy, CO(C 1-6 alkyl), CO(C 3-7 branched alkyl), SO 2 (
• R 11 is selected from the group consisting of hydrogen and C 1-6 alkyl
• R 12 is selected from the group consisting of hydrogen and C 1-6 alkyl.
• the compound has the following Structure (V): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein, R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , n, Z 1 , R 5 , R 6 and R 7 are as defined herein.
• the compound has the following Structure (VI): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , n, Z 1 , and R 6 are as defined herein.
• the compound has the following Structure (VII): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , n, Z 1 , and R 6 are as defined herein.
• the compound has the following Structure (VIII):
• R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , n, Z 1 , and R 6 are as defined herein.
• the compound has the following Structure (IX): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4d , R 4c , n, and Z 1 are as defined herein;
• R 8a is at each occurrence independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 hydroxyalkyl, C 3-7 branched hydroxyalkyl, hydroxy, C 1-6 alkoxyl, C 3-7 branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 branched alkyl),NHSO 2 (C 1-6 alkyl), and NHSO 2 (C 3-7 branched alkyl); R 8b is at each occurrence independently selected
• R 8a is at each occurrence independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 hydroxyalkyl, C 3-7 branched hydroxyalkyl, hydroxy, C 1-6 alkoxyl, C 3-7 branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 branched alkyl),NHSO 2 (C 1-6 alkyl), and NHSO 2 (C 3-7 branched alkyl); R 8b is at each occurrence independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 hydroxyalkyl, C 3-7 branched hydroxyalkyl, hydroxy, C 1-6 alkoxyl, C 3-7 branche
• the compound has the following Structure (XI): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 5 , R 6 , R 7 , and n are as defined herein; R 8a is at each occurrence independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 hydroxyalkyl, C 3-7 branched hydroxyalkyl, hydroxy, C 1-6 alkoxyl, C 3-7 branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 branched alkyl),NHSO 2 (C 1-6 alkyl), and NHSO 2 (C 3-7 branched alky
• the compound has the following Structure (XII): (XII) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , n and z are as defined herein.
• the compound has the following Structure (XIII): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n and z are as defined herein.
• Structure (XIII) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n and z are as defined herein.
• the compound has the following Structure (XIV): (XIV) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n and z are as defined herein.
• the compound has the following Structure (XV): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 5 , R 6 , R 7 , X 1 , and n are as defined herein; R 8a is at each occurrence independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl, C 3-7 branched haloalkyl, C 1-6 hydroxyalkyl, C 3-7 branched hydroxyalkyl, hydroxy, C 1-6 alkoxyl, C 3-7 branched alkoxy, NHCO(C 1-6 alkyl), NHCO(C 3-7 branched alkyl),NHSO 2 (C 1-6 alkyl), and NHSO 2 (C 3-7
• the compound has the following Structure (XVI): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n and z are as defined herein.
• the compound has the following Structure (XVII):
• R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n and z are as defined herein.
• the compound has the following Structure (XVIII): (XVIII) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , Z 1 , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n and z are as defined herein.
• the compound has the following Structure (XIX):
• R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 5 , R 6 , R 7 and n are as defined herein.
• the compound has the following Structure (XX): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , and n are as defined herein.
• Structure (XX) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , and n are as defined herein.
• the compound has the following Structure (XXI): (XXI) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , and n are as defined herein.
• the compound has the following Structure (XXII): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , and n are as defined herein.
• the compound has the following Structure (XXIII): (XXIII) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4a , R 4b , R 4d , R 4c , R 5 , R 6 , R 7 , m and n are as defined herein.
• the compound has the following Structure (XXIV): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , m and n are as defined herein.
• the compound has the following Structure (XXV): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , m and n are as defined herein.
• the compound has the following Structure (XXVI):
• R 1a , R 1b , R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , m and n are as defined herein.
• the compound has the following Structure (XXVII): (XXVII) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4d , R 4c , R 4e , R 4f , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q and z are as defined herein.
• the compound has the following Structure (XXVIII):
• the compound has the following Structure (XXIX): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4d , R 4c , R 4e , R 4f , R 8a , R 8b , R 8c , R 8d , X 1 , n, q and z are as defined herein.
• the compound has the following Structure (XXX):
• R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 8a , R 8b , R 8c , R 8d , X 1 , m, n, q and z are as defined herein.
• the compound has the following Structure (XXXI): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q and z are as defined herein.
• the compound has the following Structure (XXXII):
• the compound has the following Structure (XXXIII): (XXXIII) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q and z are as defined herein.
• the compound has the following Structure (XXXIV):
• R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , n, q and z are as defined herein.
• the compound has the following Structure (XXXV): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4a , R 4b , R 4d , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , m, n, q and z are as defined herein.
• the compound has the following Structure (XXXVI):
• the compound has the following Structure (XXXVII): (XXXVII) or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4a , R 4b , R 4d , R 4c , R 6 , R 8a , R 8b , R 8c , R 8d , R 9a , R 9b , m, n, q and z are as defined herein.
• the compound has the following Structure (XXXIX):
• the compound has the following Structure (XL): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , R 8d , X 1 , n, q and z are as defined herein.
• the compound has the following Structure (XLI):
• R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n, q and z are as defined herein.
• the compound has the following Structure (XLII): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4e , R 4f , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , n, q and z are as defined herein.
• the compound has the following Structure (XLIII):
• the compound has the following Structure (XLIV): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 1 , R 3 , R 4d , R 4c , R 4a , R 4b , R 6 , R 8a , R 8b , R 8c , R 8d , X 1 , m, n, q and z are as defined herein.
• the compound has the following Structure (XLV):
• the compound has one of the following Structures: ,
• R 1 is hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 1 is C 1-6 alkyl. In some embodiments, R 1 is C 3-7 branched alkyl. In some embodiments, R 1 is C 1-6 haloalkyl. In some embodiments, R 1 is C 3-7 branched haloalkyl. In some embodiments, R 1 is C 1-6 hydroxyalkyl. In some embodiments, R 1 is C 3-7 branched hydroxyalkyl.
• R 1 is cyano. In some embodiments, R 1 is C 1-6 alkoxyl. In some embodiments, R 1 is C 3-7 branched alkoxy. In some embodiments, R 1 is hydroxy In some embodiments, R 1 is C 3-6 cycloalkyl. In some embodiments, R 1 is C 3-6 cycloalkyl that is substituted 1 substituent selected from the groups consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl.
• R 1 is C 3-6 cycloalkyl that is substituted 2 substituents selected from the groups consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl. In some embodiments, R 1 is C 3-6 cycloalkyl that is substituted 3 substituents selected from the groups consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl. In some embodiments, In some embodiments, .
• R 3 is hydrogen. In some embodiments, R 3 is halogen. In some embodiments, R 3 is C 1-6 alkyl. In some embodiments, R 3 is C 3-7 branched alkyl. In some embodiments, R 3 is C 1-6 haloalkyl. In some embodiments, R 3 is C 3-7 branched haloalkyl. In some embodiments, R 3 is C 1-6 hydroxyalkyl. In some embodiments, R 3 is C 3-7 branched hydroxyalkyl. In some embodiments, R 3 is cyano. In some embodiments, R 3 is C 1-6 alkoxyl. In some embodiments, R 3 is C 3-7 branched alkoxy.
• R 3 is hydroxy. In some embodiments, R 3 is C 3-6 cycloakyl. In some embodiments, R 3 is C 3-6 cycloakyl that is substituted with 1 substituent selected from the groups consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl. In some embodiments, R 3 is C 3-6 cycloakyl that is substituted with 2 substituent selected from the groups consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl.
• R 3 is C 3-6 cycloakyl that is substituted with 3 substituent selected from the groups consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl.
• R 4a is hydrogen. In some embodiments, R 4a is halogen. In some embodiments, R 4a is C 1-6 alkyl. In some embodiments, R 4a is C 3-7 branched alkyl. In some embodiments, R 4a is C 1-6 haloalkyl. In some embodiments, R 4a is C 3-7 branched haloalkyl. In some embodiments, R 4a is hydroxy. In some embodiments, R 4a is C 1-6 alkoxyl.
• R 4a is C 3-7 branched alkoxy. In some embodiments, R 4a is NHCO(C 1-6 alkyl). In some embodiments, R 4a is NHCO(C 3-7 branched alkyl). In some embodiments, R 4a is NHCO(C 3-7 cycloalkyl). In some embodiments, R 4a is NHSO 2 (C 1-6 alkyl). In some embodiments, R 4a is NHSO 2 (C 3-7 branched alkyl). In some embodiments, R 4a is NHSO 2 (C 3-7 cycloalkyl). In some embodiments, R 4b is hydrogen. In some embodiments, R 4b is halogen. In some embodiments, R 4b is C 1-6 alkyl.
• R 4b is C 3-7 branched alkyl. In some embodiments, R 4b is C 1-6 haloalkyl. In some embodiments, R 4b is C 3-7 branched haloalkyl. In some embodiments, R 4b is hydroxy. In some embodiments, R 4b is C 1-6 alkoxyl. In some embodiments, R 4b is C 3-7 branched alkoxy. In some embodiments, R 4b is NHCO(C 1-6 alkyl). In some embodiments, R 4b is NHCO(C 3-7 branched alkyl). In some embodiments, R 4b is NHCO(C 3-7 cycloalkyl).
• R 4b is NHSO 2 (C 1-6 alkyl). In some embodiments, R 4b is NHSO 2 (C 3-7 branched alkyl). In some embodiments, R 4b is NHSO 2 (C 3-7 cycloalkyl). In some embodiments, R 4c is hydrogen. In some embodiments, R 4c is halogen. In some embodiments, R 4c is C 1-6 alkyl. In some embodiments, R 4c is C 3-7 branched alkyl. In some embodiments, R 4c is C 1-6 haloalkyl. In some embodiments, R 4c is C 3-7 branched haloalkyl. In some embodiments, R 4c is hydroxy.
• R 4c is C 1-6 alkoxyl. In some embodiments, R 4c is C 3-7 branched alkoxy. In some embodiments, R 4c is NHCO(C 1-6 alkyl). In some embodiments, R 4c is NHCO(C 3-7 branched alkyl). In some embodiments, R 4c is NHCO(C 3-7 cycloalkyl). In some embodiments, R 4c is NHSO 2 (C 1-6 alkyl). In some embodiments, R 4c is NHSO 2 (C 3-7 branched alkyl). In some embodiments, R 4c is NHSO 2 (C 3-7 cycloalkyl). In some embodiments, R 4d is hydrogen. In some embodiments, R 4d is halogen.
• R 4d is C 1-6 alkyl. In some embodiments, R 4d is C 3-7 branched alkyl. In some embodiments, R 4d is C 1-6 haloalkyl. In some embodiments, R 4d is C 3-7 branched haloalkyl. In some embodiments, R 4d is hydroxy. In some embodiments, R 4d is C 1-6 alkoxyl. In some embodiments, R 4d is C 3-7 branched alkoxy. In some embodiments, R 4d is NHCO(C 1-6 alkyl). In some embodiments, R 4d is NHCO(C 3-7 branched alkyl). In some embodiments, R 4d is NHCO(C 3-7 cycloalkyl).
• R 4d is NHSO 2 (C 1-6 alkyl). In some embodiments, R 4d is NHSO 2 (C 3-7 branched alkyl). In some embodiments, R 4d is NHSO 2 (C 3-7 cycloalkyl). In some embodiments, R 4e is hydrogen. In some embodiments, R 4e is halogen. In some embodiments, R 4e is C 1-6 alkyl. In some embodiments, R 4e is C 3-7 branched alkyl. In some embodiments, R 4e is C 1-6 haloalkyl. In some embodiments, R 4e is C 3-7 branched haloalkyl. In some embodiments, R 4f is hydrogen. In some embodiments, R 4f is halogen.
• R 4f is C 1-6 alkyl. In some embodiments, R 4f is C 3-7 branched alkyl. In some embodiments, R 4f is C 1-6 haloalkyl. In some embodiments, R 4f is C 3-7 branched haloalkyl. In some embodiments, R 1a and R 1b are taken together to form an optionally substituted 3 membered ring. In some embodiments, R 1a and R 1b are taken together to form an optionally substituted 4 membered ring. In some embodiments, R 1a and R 1b are taken together to form an optionally substituted 5 membered ring. In some embodiments, R 1a and R 1b are taken together to form an optionally substituted 6 membered ring.
• R 1a and R 1b are taken together to form an optionally substituted 7 membered ring. In some embodiments, R 1a and R 1b are taken together to form an optionally substituted 3 membered ring that contains an X 1 group. In some embodiments, R 1a and R 1b are taken together to form an optionally substituted 4 membered ring that contains an X 1 group. In some embodiments, R 1a and R 1b are taken together to form an optionally substituted 5 membered ring that contains an X 1 group. In some embodiments, R 1a and R 1b are taken together to form an optionally substituted 6 membered ring that contains an X 1 group.
• R 1a and R 1b are taken together to form an optionally substituted 7 membered ring that contains an X 1 group.
• X 1 is CF 2 .
• X 1 is CHCO 2 R 12 .
• X 1 is O.
• X 1 is NH.
• X 1 is NR 8 .
• X 1 is SO 2 .
• m is 0.
• m is 1.
• m is 2.
• n is 1.
• n is 2.
• n is 3.
• R 5 is hydrogen. In some embodiments, R 5 is halogen.
• R 5 is C 1-6 alkyl. In some embodiments, R 5 is C 3-7 branched alkyl. In some embodiments, R 5 is C 1-6 haloalkyl. In some embodiments, R 5 is C 3-7 branched haloalkyl. In some embodiments, R 5 is C 1-6 alkoxyl. In some embodiments, R 5 is C 3-7 branched alkoxy. In some embodiments, R 5 is hydroxy. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is NH 2 . In some embodiments, R 6 is NHR 6a . In some embodiments, R 6 is NHCH 2 CH 2 OH. In some embodiments, R 6 is NHCH 2 CH 2 NHSO 2 Me.
• R 6 is C 1-6 alkoxyl. In some embodiments, R 6 is C 3-7 branched alkoxy. In some embodiments, R 6 is hydroxy. In some embodiments, R 6a is -(CO)C 1-6 alkyl. In some embodiments, R 6a is -(CO)C 3-7 branched alkyl. In some embodiments, R 6a is -(CO)C 1-6 hydroxyalkyl.
• R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, R 6a is In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6. In some embodiments, e is 1. In some embodiments, e is 2. In some embodiments, e is 3. In some embodiments, e is 4. In some embodiments, e is 5.
• e is 6.
• X 2 is hydrogen. In some embodiments, X 2 is halogen. In some embodiments, X 2 is C 1-6 alkyl. In some embodiments, X 2 is C 3-7 branched alkyl. In some embodiments, X 2 is C 1-6 haloalkyl. In some embodiments, X 2 is C 3-7 branched haloalkyl. In some embodiments, X 2 is hydroxy. In some embodiments, X 2 is C 1-6 hydroxyalkyl. In some embodiments, X 2 is C 3-7 branched hydroxyalkyl. In some embodiments, X 2 is C 1-6 alkoxy.
• X 2 is C 3-7 branched alkoxy. In some embodiments, X 2 is C 1-6 haloalkoxy. In some embodiments, X 2 is C 3-7 branched haloalkoxy. In some embodiments, X 2 is NH 2 . In some embodiments, X 2 is NH(C 1-6 alkyl). In some embodiments, X 2 is N(C 1-6 alkyl) 2 . In some embodiments, X 2 is C 1-5 (COOH). In some embodiments, X 2 is C 1-6 (NHSO 2 Me). In some embodiments, X 3 is hydrogen. In some embodiments, X 3 is halogen. In some embodiments, X 3 is C 1-5 alkyl.
• X 3 is C 3-7 branched alkyl. In some embodiments, X 3 is C 1-5 haloalkyl. In some embodiments, X 3 is C 3-7 branched haloalkyl. In some embodiments, X 3 is hydroxy. In some embodiments, X 3 is C 1-5 hydroxyalkyl. In some embodiments, X 3 is C 3-7 branched hydroxyalkyl. In some embodiments, X 3 is C 1-5 alkoxy. In some embodiments, X 3 is C 3-7 branched alkoxy. In some embodiments, X 3 is C 1-5 haloalkoxy. In some embodiments, X 3 is C 3-7 branched haloalkoxy.
• X 3 is NH 2 . In some embodiments, X 3 is NH(C 1-6 alkyl). In some embodiments, X 3 is N(C 1-6 alkyl) 2 . In some embodiments, X 3 is COOH. In some embodiments, X 3 is C 1-5 (COOH). In some embodiments, X 3 is NHSO 2 Me. In some embodiments, X 3 is C 1-5 (NHSO 2 Me). In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is halogen. In some embodiments, R 7 is C 1-6 alkyl. In some embodiments, R 7 is C 3-7 branched alkyl. In some embodiments, R 7 is C 1-6 haloalkyl.
• R 7 is C 3-7 branched haloalkyl. In some embodiments, R 7 is C 1-6 alkoxyl. In some embodiments, R 7 is C 3-7 branched alkoxy. In some embodiments, R 7 is hydroxy. In some embodiments, R 8 is C 1-6 alkyl. In some embodiments, R 8 is C 1-6 haloalkyl. In some embodiments, R 8 is C 3-7 branched haloalkyl. In some embodiments, R 8 is C 1-6 hydroxyalkyl. In some embodiments, R 8 is C 3-7 branched hydroxyalkyl. In some embodiments, R 8 is C 1-6 alkoxyl. In some embodiments, R 8 is C 3-7 branched alkoxy.
• R 8 is CO(C 1-6 alkyl). In some embodiments, R 8 is CO(C 3-7 branched alkyl). In some embodiments, R 8 is SO 2 (C 1-6 alkyl). In some embodiments, R 8 is SO 2 (C 3-7 branched alkyl). In some embodiments, R 8a is hydrogen. In some embodiments, R 8a is halogen. In some embodiments, R 8a is C 1-6 alkyl. In some embodiments, R 8a is C 3-7 branched alkyl. In some embodiments, R 8a is C 1-6 haloalkyl. In some embodiments, R 8a is C 3-7 branched haloalkyl.
• R 8a is C 1-6 hydroxyalkyl. In some embodiments, R 8a is C 3-7 branched hydroxyalkyl. In some embodiments, R 8a is hydroxy. In some embodiments, R 8a is C 1-6 alkoxyl. In some embodiments, R 8a is C 3-7 branched alkoxy. In some embodiments, R 8a is NHCO(C 1-6 alkyl). In some embodiments, R 8a is NHCO(C 3-7 branched alkyl). In some embodiments, R 8a is NHSO 2 (C 1-6 alkyl). In some embodiments, R 8a is NHSO 2 (C 3-7 branched alkyl). In some embodiments, R 8b is hydrogen.
• R 8b is halogen. In some embodiments, R 8b is C 1-6 alkyl. In some embodiments, R 8b is C 3-7 branched alkyl. In some embodiments, R 8b is C 1-6 haloalkyl. In some embodiments, R 8b is C 3-7 branched haloalkyl. In some embodiments, R 8b is C 1-6 hydroxyalkyl. In some embodiments, R 8b is C 3-7 branched hydroxyalkyl. In some embodiments, R 8b is hydroxy. In some embodiments, R 8b is C 1-6 alkoxyl. In some embodiments, R 8b is C 3-7 branched alkoxy.
• R 8b is NHCO(C 1-6 alkyl). In some embodiments, R 8b is NHCO(C 3-7 branched alkyl). In some embodiments, R 8b is NHSO 2 (C 1-6 alkyl). In some embodiments, R 8b is NHSO 2 (C 3-7 branched alkyl). In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is C 1-6 alkyl. In some embodiments, R 8c is C 3-7 branched alkyl. In some embodiments, R 8c is C 1-6 haloalkyl. In some embodiments, R 8c is C 3-7 branched haloalkyl.
• R 8c is C 1-6 hydroxyalkyl. In some embodiments, R 8c is C 3-7 branched hydroxyalkyl. In some embodiments, R 8c is hydroxy. In some embodiments, R 8c is C 1-6 alkoxyl. In some embodiments, R 8c is C 3-7 branched alkoxy. In some embodiments, R 8c is NHCO(C 1-6 alkyl). In some embodiments, R 8c is NHCO(C 3-7 branched alkyl). In some embodiments, R 8c is NHSO 2 (C 1-6 alkyl). In some embodiments, R 8c is NHSO 2 (C 3-7 branched alkyl). In some embodiments, R 8d is hydrogen.
• R 8d is halogen. In some embodiments, R 8d is C 1-6 alkyl. In some embodiments, R 8d is C 3-7 branched alkyl, In some embodiments, R 8d is C 1-6 haloalkyl. In some embodiments, R 8d is C 3-7 branched haloalkyl. In some embodiments, R 8d is C 1-6 hydroxyalkyl. In some embodiments, R 8d is C 3-7 branched hydroxyalkyl. In some embodiments, R 8d is hydroxy. In some embodiments, R 8d is C 1-6 alkoxyl.
• R 8d is C 3-7 branched alkoxy In some embodiments, R 8d is NHCO(C 1-6 alkyl). In some embodiments, R 8d is NHCO(C 3-7 branched alkyl). In some embodiments, R 8d is NHSO 2 (C 1-6 alkyl). In some embodiments, R 8d is NHSO 2 (C 3-7 branched alkyl). In some embodiments, R 9a is hydrogen. In some embodiments, R 9a is halogen. In some embodiments, R 9a is C 1-6 alkyl. In some embodiments, R 9a is C 3-7 branched alkyl. In some embodiments, R 9a is C 1-6 haloalkyl.
• R 9a is C 3-7 branched haloalkyl. In some embodiments, R 9a is C 1-6 hydroxyalkyl. In some embodiments, R 9a is C 3-7 branched hydroxyalkyl. In some embodiments, R 9a is hydroxy. In some embodiments, R 9a is C 1-6 alkoxyl. In some embodiments, R 9a is C 3-7 branched alkoxy. In some embodiments, R 9b is hydrogen. In some embodiments, R 9b is halogen. In some embodiments, R 9b is C 1-6 alkyl. In some embodiments, R 9b is C 3-7 branched alkyl. In some embodiments, R 9b is C 1-6 haloalkyl.
• R 9b is C 3-7 branched haloalkyl. In some embodiments, R 9b is C 1-6 hydroxyalkyl. In some embodiments, R 9b is C 3-7 branched hydroxyalkyl. In some embodiments, R 9b is hydroxy. In some embodiments, R 9b is C 1-6 alkoxyl. In some embodiments, R 9b is C 3-7 branched alkoxy. In some embodiments, R 9a and R 9b are taken together to form a 3 membered ring. In some embodiments, R 9a and R 9b are taken together to form a 4 membered ring. In some embodiments, R 9a and R 9b are taken together to form a 5 membered ring.
• R 9a and R 9b are taken together to form a 6 membered ring. In some embodiments, R 9a and R 9b are taken together to form a 7 membered ring. In some embodiments, R 9a and R 9b are taken together to form an optionally substituted 3 membered ring. In some embodiments, R 9a and R 9b are taken together to form an optionally substituted 4 membered ring. In some embodiments, R 9a and R 9b are taken together to form an optionally substituted 5 membered ring. In some embodiments, R 9a and R 9b are taken together to form an optionally substituted 6 membered ring.
• R 9a and R 9b are taken together to form an optionally substituted 7 membered ring.
• q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2.
• R 10 is hydrogen In some embodiments, R 10 is C 1-6 alkyl. In some embodiments, R 10 is C 1-6 haloalkyl. In some embodiments, R 10 is C 3-7 branched haloalkyl. In some embodiments, R 10 is C 1-6 hydroxyalkyl. In some embodiments, R 10 is C 1-6 alkoxyl.
• R 10 is C 3-7 branched alkoxy. In some embodiments, R 10 is CO(C 1-6 alkyl). In some embodiments, R 10 is CO(C 3-7 branched alkyl). In some embodiments, R 10 is SO 2 (C 1-6 alkyl). In some embodiments, R 10 is SO 2 (C 3-7 branched alkyl). In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C 1-6 alkyl. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is C 1-6 alkyl.
• the compounds of Formula (I), (I’) or substructures exclude N-(6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H-dispiro[cyclopropane-1,1'- cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4- yl)cyclopropanecarboxamide; and/or 3-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2''H- dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridin]-6''- yl)amino)pyrimidin-4-yl)amino)propanoic acid.
• the compound has the following Structure (XLVII): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein m, n, R 3 and R 2 are as defined herein.
• R 2 , R 3 , m and n are set forth in Table 2, below. Table 2.
• the compound has the following Structure (XLVIII): or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof, wherein R 2 , R 3 , n, and m are as defined herein.
• R 2 , R 3 , n, and m are defined herein below in Table 3, below.
• Table 3 Exemplary moieties for R 2 , R 3 , n, and m
• Compounds of the present disclosure include compounds having the formula (XLIX) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R 3 , R 4f , and n are defined herein below in Table 4.
• the compound having the formula has the chemical name 6''-((6-aminopyrimidin-4-yl)amino)-8''-methyl-2''H- dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione.
• a compound depicted by the racemic formula for example: will stand equally well for either of the two enantiomers having the formula: or the formula: or a pharmaceutically acceptable salt, hydrate, isotopic isomer, solvate, complex, stereoisomer, tautomer, or prodrug thereof.
• a compound depicted by the racemic formula will stand equally well for either of the two enantiomers or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.
• suitable optional substituents are not intended to limit the scope of the claimed disclosure.
• the compounds of the disclosure may contain any of the substituents, or combinations of substituents, provided herein. It is understood that in the present description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.
• various compounds of the disclosure which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the disclosure can be converted to their free base or acid form by standard techniques.
• Pharmaceutical Compositions To facilitate delivery to a cell, tissue, or patient, an MNK inhibitor of the present disclosure may, in various compositions, be formulated with a pharmaceutically- acceptable carrier, excipient, or diluent.
• Suitable pharmaceutical carriers, excipients, and/or diluents for use in the present disclosure include, but are not limited to, lactose, sucrose, starch powder, talc powder, cellulose esters of alkonoic acids, magnesium stearate, magnesium oxide, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, gelatin, glycerin, sodium alginate, gum arabic, acacia gum, sodium and calcium salts of phosphoric and sulfuric acids, polyvinylpyrrolidone and/or polyvinyl alcohol, saline, and water. Specific formulations of compounds for therapeutic treatment are discussed in Hoover, J.
• the pharmaceutical composition comprises any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier.
• the pharmaceutical composition is formulated for oral administration.
• the pharmaceutical composition is formulated for injection.
• the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent. Non-limiting examples of such therapeutic agents are described herein below.
• Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
• parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
• a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound 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.
• the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with and organ-specific antibody.
• the liposomes are targeted to and taken up selectively by the organ.
• the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
• the compound described herein is administered topically.
• an effective amount of at least one compound of Structure (I) through (XLIX) is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition.
• Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
• the compounds according to the disclosure are effective over a wide dosage range.
• dosages from 10 to 5000 mg, from 100 to 5000 mg, from 1000 mg to 4000 mg per day, and from 1000 to 3000 mg per day are examples of dosages that are used in some embodiments.
• the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
• compounds of the disclosure are administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes are used as appropriate.
• a single dose of a compound of the disclosure may also be used for treatment of an acute condition.
• compounds of the disclosure are administered in multiple doses.
• dosing is about once, twice, three times, four times, five times, six times, or more than six times per day.
• dosing is about once a month, once every two weeks, once a week, or once every other day.
• compounds of the disclosure and another agent are administered together about once per day to about 6 times per day.
• the administration of compounds of the disclosure and an agent continues for less than about 7 days.
• the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year.
• continuous dosing is achieved and maintained as long as necessary. Administration of compounds of the disclosure may continue as long as necessary.
• compounds of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, compounds of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, compounds of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic migraine or for prevention of migraine. In some embodiments, compounds of the disclosure may be administered only when migraine symptoms are manifest, such as during prodrome or aura, or even during headache. In some embodiments, the compounds of the disclosure are administered in individual dosage forms. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. In some embodiments, the compounds described herein are formulated into pharmaceutical compositions.
• compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the disclosed compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
• compositions comprising one or more compounds of Structure (I) through (XLIX), and a pharmaceutically acceptable carrier.
• pharmaceutical compositions comprising one or more compounds selected from compounds of Structure (I) through (XLIX) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s).
• the compounds described are administered as pharmaceutical compositions in which one or more compounds selected from compounds of Structure (I) through (XLIX) are mixed with other active ingredients, as in combination therapy.
• the pharmaceutical compositions include one or more compounds of Structure (I) through (XLIX).
• a pharmaceutical composition, as used herein, refers to a mixture of one or more compounds selected from compounds of Structure (I) through (XLIX) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• the pharmaceutical composition facilitates administration of the compound to an organism.
• therapeutically effective amounts of one or more compounds selected from compounds of Structure (I) through (XLIX) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated.
• the mammal is a human.
• therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
• the compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.
• an MNK inhibitor as described herein may be formulated with another MNK inhibitor as described herein, another MNK inhibitor, another pain therapeutic, a neuroregeneration therapeutic, or another small molecule or biologic therapeutic, or any combinations thereof.
• Example pain therapeutics and neuroregeneration thereapeutics are described herein with respect to therapeutic methods using MNK inhibitors.
• one or more compounds selected from compounds of Structure (I) through (XLIX) are formulated in aqueous solutions.
• the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
• one or more compounds selected from compounds of Structure (I) through (XLIX) are formulated for transmucosal administration.
• transmucosal formulations include penetrants that are appropriate to the barrier to be permeated.
• appropriate formulations include aqueous or non-aqueous solutions.
• such solutions include physiologically compatible buffers and/or excipients.
• compounds described herein are formulated for oral administration.
• Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients.
• the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
• pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
• disintegrating agents are optionally added.
• Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
• concentrated sugar solutions are used for coating the dosage form.
• the sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes.
• the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
• therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms.
• Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid.
• suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
• stabilizers are optionally added.
• the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
• formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations.
• the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles.
• Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
• suspensions of one or more compounds selected from compounds of Structure (I) or (II) are prepared as appropriate oily injection suspensions.
• Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
• aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
• compositions include at least one pharmaceutically acceptable carrier, diluent or excipient, and one or more compounds selected from compounds of Structure (I) through (XLIX), described herein as an active ingredient.
• the active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
• the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
• Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
• Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
• Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
• Semi-solid compositions include, but are not limited to, gels, suspensions and creams.
• the form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
• compositions comprising one or more compounds selected from compounds of Structure (I) through (XLIX) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a suspension, a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix.
• a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents.
• Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
• Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
• Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of one or more compounds selected from compounds of Structure (I) through (XLIX).
• solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
• Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
• compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
• acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
• bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane
• buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
• Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
• Compositions also, optionally, include one or more salts in an amount required to bring os
• Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
• Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
• Compositions may include one or more surfactants to enhance physical stability or for other purposes.
• Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
• Compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
• aqueous suspension compositions are packaged in single-dose non-reclosable containers.
• multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
• other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein.
• organic solvents such as N-methylpyrrolidone are also employed.
• the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
• sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days.
• the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
• stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
• polysorbate 20 (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
• the concentration of one or more compounds selected from compounds of Structure (I) through (XLIX) provided in the pharmaceutical compositions of the present disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%,
• the concentration of one or more compounds selected from compounds of Structure (I) through (XLIX) provided in the pharmaceutical compositions of the present disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
• the amount the one or more compounds selected from compounds of Structure (I) through (XLIX) provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03
• the amount of the one or more compounds selected from compounds of Structure (I) through (XLIX) provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001- 8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
• Packaging materials for use in packaging pharmaceutical compositions described herein include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252.
• kits include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
• the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein.
• the container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
• kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.
• a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
• materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
• a set of instructions will also typically be included.
• a label is optionally on or associated with the container.
• a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
• a label is used to indicate that the contents are to be used for a specific therapeutic application.
• the label indicates directions for use of the contents, such as in the methods described herein.
• the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
• the pack for example contains metal or plastic foil, such as a blister pack.
• the pack or dispenser device is accompanied by instructions for administration.
• the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
• a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
• Such notice for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
• compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
• One embodiment of the present disclosure provides a method of treating a disease or disorder, comprising administering a therapeutically effective amount of a compound of Structure (I) through (XLIX), or the pharmaceutical composition as described herein, to a subject in need thereof.
• the disease or disorder is migraines or symptoms associated with migraines.
• Certain compounds of the present disclosure may be able to pass through the blood brain barrier. These brain penetrant compounds may be used for administration to neurons or brain tissues.
• Embodiments of the present disclosure are useful for treating migraines and symptoms associated with migraines in a host species.
• the host species or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease.
• Embodiments of the disclosure also relate to the use of compounds according to Structure (I) through (XLIX) and/or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or modulated by the mitogen-activated protein kinase-interacting kinases (MNK) activity.
• MNK mitogen-activated protein kinase-interacting kinases
• embodiments of the disclosure relate to the use of compounds according to Structure (I) through (XLIX) and/or physiologically acceptable salts thereof for the production of a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases.
• Compounds as disclosed herein may be administered as a single dose or multiple doses.
• multiple doses may be administered at intervals of 3 times per 24 hours, 2 times per 24 hours, 1 time per 24 hours, 1 time every other day, 1 time every 3 days, 1 time every 4 days, 1 time per week, 2 times per week, or 3 times per week.
• the compound may also be delivered continuously, for example via a continuous pump.
• the administration schedule may depend on dose administered, severity of disease, response to treatment, and other factors, or any combinations thereof.
• the dose may be any effective amount. However, in specific examples the dose may be 25 mg, 50 mg, 100 mg, 200 mg, or 500 mg.
• the initial dose may be greater than subsequent doses or all doses may be the same.
• the dose may depend on the administration schedule, severity of disease, response to treatment, and other factors, or any combinations thereof.
• the compound may be administered over a period of one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years or three years.
• the duration of administration may depend on the severity of diseases, response to treatment, and other factors, or any combinations thereof. For example, a less frequent administration schedule for the same dose may be adopted as the patient responds to treatment. Alternatively, the administration schedule may remain unchanged, but the dose may be decreased as the patient responds to treatment.
• the pharmaceutical compositons may be administered daily or periodically even in the absence of migraine symptoms in order to prevent migraines.
• Such administration may be particularly useful in patients who suffer from chronic migraine, patients who are severely inacapacitated by migraine, or patients whose lifestyle or occupation is severly interrupted by migraine (e.g. parents of young children, those employed to operate automotive or heavy equipment, those who perform lengthy and visually-intensive processes, such as surgeons, etc.)
• the pharmaceutical compositions may be administered when migraines are more likely (such as during certain times of the menstrual cycle in women), or when migraine symptoms are present.
• the pharmaceutical compositions may be administered prior to headache, such as at the onset of or during prodrome or aura symptoms.
• a compound according to the present disclosure may be administered in conjunction with an additional therapeutic, including another MNK inhibitor or a therapeutic that is not an MNK inhibitor, particularly another migraine therapeutic.
• Suitable additional therapeutics include both small molecules and biologics.
• a compound according to the present disclosure may be administered with any combination or combinations of additional therapeutics.
• a compound of the present disclosure may be administered with one or more other pain and/or migraine therapeutics.
• Suitable therapeutics include mild pain relievers, such as non-steroidal anti-inflammatory drugs, including ibuprofen, ketoprofen, aspirin, other salicates, and naproxen, acetaminophen; triptans, such as sumatriptan and rizatriptan; dihydroergotamine; lasmiditan; ubrogepant; rimegepant, or other CGRP antagonists; opiods; anti-nausea medications such as metoclopramide, prochlorperazine; beta blockers, such as propranolol or metoprolol tartarate; calcium channel blockers, such as verapamil; tricyclic antidepressants such as amitriptyline
• a compound according to the present disclosure may allow a reduction in the dose or administration frequency of the other pain therapeutic, or a decrease in the total duration of time the other therapeutic is administered.
• Such an administration schedule may be particularly beneficial when the additional pain therapeutic is addictive, such as an opioid.
• the agents disclosed herein or other suitable agents are administered depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure will be co-administered with other agents.
• the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two or more agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.
• a compound described herein and any additional agent can be formulated together in the same dosage form and administered simultaneously.
• a compound of the disclosure and additional agent can be simultaneously administered, wherein both the agents are present in separate formulations.
• a compound of the present disclosure can be administered just followed by an additional agent, or vice versa.
• a compound of the disclosure and additional agent are administered a few minutes apart, or a few hours apart, or a few days apart.
• the compounds of Structure (I) through (XLIX) are administered as a mono-therapy.
• the methods of embodiments of embodiments of the disclosure can be performed either in vitro or in vivo.
• the susceptibility of a particular patient, subject, or cell to treatment with the compounds of Structure (I) through (XLIX) can be particularly determined by in vitro tests, whether in the course of research or clinical application.
• EXAMPLES The examples and preparations provided below further illustrate and exemplify the compounds of the present disclosure and methods of preparing and testing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, molecules with a single stereocenter, unless otherwise noted, exist as a racemic mixture.
• reaction schemes can be modified at any step to add and/or modify a substituent or change the order of the steps as appropriate during any stage of the overall synthesis of desired compounds.
• General Reaction Scheme 1 may be modified after the step yielding compounds 7a-7f according to the following General Reaction Scheme 2, wherein X and Y are either N or C depending on the identity of the reactants used.
• a compound of the formula (3) is reacted with urea hydrogen peroxide in the presence of an acid anhydride such as trifluoroacetic anhydride, acetic anhydride, and the like, in a solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (4).
• an acid anhydride such as trifluoroacetic anhydride, acetic anhydride, and the like
• a solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (4).
• a compound of the formula (4) is reacted with an acid anhydride such as trifluoroacetic anhydride, acetic anhydride, and the like, in a solvent such as N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (5).
• an acid anhydride such as trifluoroacetic anhydride, acetic anhydride, and the like
• a compound of the formula (5) is reacted with ammonium hydroxide, optionally in the presence of a solvent such as methanol, ethanol, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (6).
• a solvent such as methanol, ethanol, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like.
• a compound of the formula (6) is reacted with a compound of the formula (7), a known compound or compound prepared by known methods, in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like, in a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, methylene chloride, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (8).
• an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like
• a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, methylene chloride, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (8).
• an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like
• a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, methylene chloride, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the
• a compound of the formula (11) is reacted with urea hydrogen peroxide in the presence of an acid anhydride such as trifluoroacetic anhydride, acetic anhydride, and the like, in a solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12).
• an acid anhydride such as trifluoroacetic anhydride, acetic anhydride, and the like
• a solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12).
• a compound of the formula (12) is reacted with an acid anhydride such as trifluoroacetic anhydride, acetic anhydride, and the like, in a solvent such as N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (13).
• an acid anhydride such as trifluoroacetic anhydride, acetic anhydride, and the like
• a solvent such as N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave i
• a compound of the formula (13) is reacted with ammonium hydroxide, optionally in the presence of a solvent such as methanol, ethanol, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (14).
• a solvent such as methanol, ethanol, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (14).
• a compound of the formula (14) is reacted with a compound of the formula (15), a known compound or compound prepared by known methods, in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like, in a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, methylene chloride, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).
• an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like
• a solvent such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, methylene chloride, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).
• a compound of the formula (16) is reacted with a compound of the formula (17), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)phos
• a compound of the formula (16) is reacted with a compound of the formula (19), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)phos
• a compound of the formula (16) is reacted with a compound of the formula (21), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)pho
• a compound of the formula (16) is reacted with a compound of the formula (23), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)pho
• a compound of the formula (16) is reacted with a compound of the formula (25), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)pho
• a compound of the formula (26) is reacted with a compound of the formula (27), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28).
• a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
• a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide
• a compound of the formula (16) is reacted with a compound of the formula (29), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)pho
• a compound of the formula (30) is reacted with a compound of the formula (31), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32).
• a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
• a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide,
• a compound of the formula (16) is reacted with a compound of the formula (33), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)pho
• a compound of the formula (34) is reacted with a compound of the formula (35), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (36).
• a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
• a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide
• a compound of the formula (16) is reacted with a compound of the formula (37), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)pho
• a compound of the formula (38) is reacted with a compound of the formula (39), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (40).
• a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
• a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide
• a compound of the formula (41) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like, optionally in the presence of ethylenediamine, optionally in the presence of water, in the presence of a solvent such methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (42).
• a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like
• ethylenediamine optionally in the presence of water
• a solvent such methanol, ethanol, isopropanol, N,N-dimethylform
• a compound of the formula (43) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like, optionally in the presence of ethylenediamine, optionally in the presence of water, in the presence of a solvent such methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (44).
• a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like
• ethylenediamine optionally in the presence of water
• a solvent such methanol, ethanol, isopropanol, N,N-dimethyl
• a compound of the formula (45) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like, optionally in the presence of ethylenediamine, optionally in the presence of water, in the presence of a solvent such methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (46).
• a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like
• ethylenediamine optionally in the presence of water
• a solvent such methanol, ethanol, isopropanol, N,N-di
• a compound of the formula (47) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like, optionally in the presence of ethylenediamine, optionally in the presence of water, in the presence of a solvent such methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (48).
• a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, and the like
• ethylenediamine optionally in the presence of water
• a solvent such methanol, ethanol, isopropanol, N,N-di
• a compound of the formula (49) is reacted with a compound of the formula (50), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenyl phosphine)palladium(II), bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone) dipalladium(0), and the like, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate.
• a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenyl phosphine)palladium(II), bis(acetonitrile)dichloro
• lithium bicarbonate triethylamine, diisopropylethylamine, pyridine, and the like, optionally in the presence of water, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethyl formamide, N,N-dimethylacetamide, methylene chloride, 1,2-dichloroethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (51).
• a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethyl formamide, N,N-dimethylacetamide, methylene chloride, 1,2-dichloroethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (51).
• a compound of the formula (52) is reacted with a compound of the formula (53), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenyl phosphine)palladium(II), bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone) dipalladium(0), and the like, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate.
• a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenyl phosphine)palladium(II), bis(acetonitrile)dichloro
• lithium bicarbonate triethylamine, diisopropylethylamine, pyridine, and the like, optionally in the presence of water, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethyl formamide, N,N-dimethylacetamide, methylene chloride, 1,2-dichloroethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (54).
• a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethyl formamide, N,N-dimethylacetamide, methylene chloride, 1,2-dichloroethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (54).
• product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
• spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
• HPLC high pressure liquid chromatography
• GC gas chromatography
• GPC gel-permeation chromatography
• TLC thin layer chromatography
• Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature.
• a given reaction can be carried out in one solvent or a mixture of more than one solvent.
• suitable solvents for a particular reaction step can be selected.
• Suitable protecting groups include, but are not limited to, hydroxy, amino, mercapto and carboxylic acid.
• suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
• Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
• Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.
• Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups are optionally added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M.
• the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
• the protected derivatives of compounds of this disclosure may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the disclosure which are pharmacologically active. Such derivatives may therefore be described as "prodrugs.” Prodrugs of compounds of this disclosure are included within the scope of embodiments of the disclosure.
• GENERAL PROCEDURE B SYNTHESIS OF CHLOROPYRIMIDINYL PYRIDONE INTERMEDIATES (9A-F)
• One of Compound 7a-7f (1 equiv), 4-amino-6-chloropyrimidine 8a (1.2 equiv), Cs2CO3 (3 equiv), Xantphos (20 mol%), and Pd(OAc) 2 (10 mol%) was combined in 1,4-dioxane (0.1M) and the mixture was purged with inert gas (nitrogen or argon) for 20 minutes. The reaction vessel was sealed and heated at 90 oC for 16 hours.
• EXAMPLE 12 S YNTHESIS OF 6'-((6-((2-H YDROXYETHYL ) AMINO ) PYRIMIDIN -4- YL ) AMINO )-8'- METHYL - 2'H- SPIRO[CYCLOHEXANE-1,3'-IMIDAZO[1,5-A]PYRIDINE]-1',5'-DIONE (4ET-02-001)
• Compound 4ET-02-001 was synthesized according to General Procedure C.
• EXAMPLE 17 S YNTHESIS OF N-(2-((6-((8'-M ETHYL -1',5'- DIOXO -1',5'- DIHYDRO -2'H- SPIRO[CYCLOHEXANE-1,3'- IMIDAZO[1,5-A]PYRIDIN]-6'-YL)AMINO)PYRIMIDIN-4- Y L ) AMINO ) ETHYL ) METHANESULFONAMIDE (4ET-02-004) Compound 4ET-02-004 was synthesized according to General Procedure C.
• the aqueous layer was extracted with CH 2 Cl 2 (3 ⁇ 15 mL), and then a few drops of 12N HCl were added to the aqueous mixture until acidic to pH paper (pH 2-4).
• the aqueous layer was extracted with 3:1 (CHCl 3 /IPA) ⁇ 3 and combined with the CH 2 Cl2 extracts, dried (Na2SO4), filtered, and concentrated under reduced pressure to generate compound 4ET-02-004 (15mg, 0.032 mmol, 63%).
• the reaction vessel was sealed and heated at 90oC for 16 hours.
• the reaction was cooled to ambient temperature and the solvent was removed under reduced pressure.
• the resulting crude material was purified by Biotage flash chromatography (gradient elution, 0% ⁇ 10% MeOH in CH 2 Cl2) and then Prep-TLC, if necessary, to afford the amidopyrimidinyl or amidopyridazinyl pyridone aminals (compound 11).
• EXAMPLE 18 S YNTHESIS OF N-(6-((3,3,8-T RIMETHYL -1,5- DIOXO -1,2,3,5- TETRAHYDROIMIDAZO [1,5- A]PYRIDIN-6- YL)AMINO)PYRIMIDIN-4-YL)CYCLOPROPANECARBOXAMIDE (4ET-03-002) Compound 4ET-03-002 was synthesized according to General Procedure D.
• GENERAL PROCEDURE E SYNTHESIS OF AMIDOPYRIMIDINYL- AND AMIDOPYRIDAZINYL PYRIDONES FROM BROMOPYRIDONES AND AMINOPYRIMIDINES/AMINOPYRIDAZINES
• N-(6-aminopyrimidin-4- yl)cyclopropanecarboxamide 8b) or N-(5-aminopyridazin-3- yl)cyclopropanecarboxamide (8c) (1.2 equiv), Cs 2 CO 3 (3 equiv), Xantphos (20 mol%), and Pd(OAc) 2 (10 mol%) was added 1,4-dioxane (0.1M), and purged the suspension with inert gas (nitrogen or argon) for 20 minutes.
• the reaction vessel was sealed and heated at 90oC for 16 hours and then cooled to ambient temperature.
• the crude material was purified using Biotage flash chromatography (gradient elution, 0% ⁇ 10% MeOH in CH 2 Cl2) to afford the amidopyrimidinyl or amidopyridazinyl pyridone aminals (compound 12).
• GENERAL PROCEDURES F1 AND F 2 S YNTHESIS OF S YNTHESIS OF AMINOPYRIMIDINYL - AND AMINOPYRIDAZINYL PYRIDONES FROM CYCLOPROPYLAMIDES
• General Procedure F1 Aqueous potassium hydroxide (12 equiv) and ethylenediamine (12 equiv) were sequentially added to a solution of cyclopropylamide 12 (1 equiv) in tetrahydrofuran and ethanol (1:1, v/v). After stirring at room temperature for 24 hours, the mixture was concentrated under reduced pressure, and the residue was diluted with dichloromethane and then washed with water.
• EXAMPLE 29 S YNTHESIS OF N-(6'-((6-A MINOPYRIMIDIN -4- YL ) AMINO )-8'- METHYL -1',5'- DIOXO -1',5'- DIHYDRO- 2'H-SPIRO[CYCLOHEXANE-1,3'-IMIDAZO[1,5-A]PYRIDIN]-4- YL)METHANESULFONAMIDE (4ET- 01-004)
• Compound 4ET-01-004 was synthesized according to General Procedure F1.
• EXAMPLE 46 SYNTHESIS OF 5-BROMO-3-METHYL-6-OXO-1,6-DIHYDROPYRIDINE-2-CARBOXAMIDE Step 1: Synthesis of ethyl 5-bromo-3-methylpicolinate. To a solution of 5- bromo-3-methylpicolinic acid (10 g, 42.3 mmol) in ethanol (37 mL) was added H 2 SO 4 (2.3 mL, 18.4 M, 42.3 mmol) at 23 °C. The reaction mixture was heated at 80 °C for 16 hours. The solvent was removed under reduced pressure and ethyl acetate (250 mL) was added.
• Step 3 Synthesis of ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2- carboxylate.
• N,N- dimethylformamide 30.5 mL
• trifluoroacetic anhydride 9.6 mL, 68.3 mmol
• the reaction mixture was stirred at 40 °C for 8 hours and diluted with water (100 mL). After extraction with ethyl acetate (100 mL ⁇ 3), the combined organic phase was washed with brine (100 mL ⁇ 5), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
• the title compound (7k) was prepared according to General Procedure G using 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (100 mg, 0.43 mmol), tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (6k, 414 mg, 1.73 mmol), H 2 SO 4 (0.012 mL, 0.22 mmol), and 1,4-dioxane (4.0 mL).6''-Bromo-8''-methyl-2''H- dispiro[azetidine-3,1'-cyclohexane-4',3''-imidazo[1,5-a]pyridine]-1'',5''-dione (7k) yield: (101 mg, 0.29 mmol, 66%).
• EXAMPLE 62 SYNTHESIS OF 6''-BROMO-8''-METHYL-2''H-DISPIRO[CYCLOPROPANE-1,1'- CYCLOHEPTANE-4',3''-IMIDAZO[1,5-A]PYRIDINE]-1'',5''-DIONE (7W) To a stirred solution of 5 (25 mg, 0.108 mmol) in dry isopropanol was added ketone 6w (18 mg, 0.130 mmol) followed by Ti(iOPr) 4 (46 mg, 0.162 mmol). The mixture was sealed and heated at 100 °C for 12 hours.
• EXAMPLE 65 S YNTHESIS OF N-(6-((8''- METHYL -1'',5''- DIOXO -1'',5''- DIHYDRO -2''H- DISPIRO[CYCLOPROPANE-1,1'-CYCLOHEXANE-4',3''-IMIDAZO[1,5-A]PYRIDIN]-6''- YL)AMINO)PYRIMIDIN-4-YL)CYCLOPROPANECARBOXAMIDE (4ET-03-029) 7g 4ET-03-029 The title compound was prepared according to the procedure of N-(6-((8''- methyl-1'',5''-dioxo-1'',5''-dihydro-2'''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''- imidazo[1,5-a]pyridin]-6''-y
• the suspension was degassed and re-purged with hydrogen gas (this process was repeated three times).
• the reaction was stirred under hydrogen atmosphere at 23 °C for 16 hours.
• the reaction was filtered through Celite and washed with 1M NH 3 /MeOH solution until full recovery of the desired product (TLC analysis 10% 1M NH 3 /MeOH in CH 2 Cl2).
• the filtrate was concentrated and purified by Biotage flash chromatography (gradient elution, 0 to 25% 3M NH 3 /MeOH in CH 2 Cl2) to obtain the desired compound 4ET-03-040 as white powders (11 mg, 0.025 mmol, 30%).
• EXAMPLE 70 S YNTHESIS OF N-(6-((8''- METHYL -1'',5''- DIOXO -1'',5''- DIHYDRO -2''H- DISPIRO [ AZETIDINE - 3,1'-CYCLOHEXANE-4',3''-IMIDAZO[1,5-A]PYRIDIN]-6''-YL)AMINO)PYRIMIDIN-4- YL)CYCLOPROPANECARBOXAMIDE (4ET-03-049) A solution of tert-butyl 6''-((6-(cyclopropanecarboxamido)pyrimidin-4- yl)amino)-8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2'''H-dispiro[azetidine-3,1'-cyclohexane- 4',3'-imidazo
• EXAMPLE 72 S YNTHESIS OF 6''-((6-A MINOPYRIMIDIN -4- YL ) AMINO )-8''- METHYL -2''H- DISPIRO[CYCLOPROPANE-1,1'-CYCLOHEXANE-4',3''-IMIDAZO[1,5-A]PYRIDINE]-1'',5''- DIONE (4ET-03-053)
• the title compound was prepared according to the procedure of 6''-((6- Aminopyrimidin-4-yl)amino)-8'''-methyl-2'''H-dispiro[cyclopropane-1,1'-cyclohexane- 3',3''-imidazo[1,5-a]pyridine]-1'',5''-dione except that N-(6-((8''-methyl-1'',5''-dioxo- 1'',5''-d
• EXAMPLE 74 S YNTHESIS OF 1-( AMINOMETHYL )-N-(6-((8''- METHYL -1'',5''- DIOXO -1'',5''- DIHYDRO -2''H- DISPIRO[CYCLOPROPANE-1,1'-CYCLOHEXANE-4',3''-IMIDAZO[1,5-A]PYRIDIN]-6''- YL)AMINO)PYRIMIDIN-4-YL)CYCLOPROPANE-1-CARBOXAMIDE (4ET-03-055-HCl) tert-butyl ((1-((6-((8''-methyl-1'',5''-dioxo-1'',5''-dihydro-2'''H- dispiro[cyclopropane-1,1'-cyclohexane-4',3''-imidazo[1,5-a]pyri
• the Boc-protected intermediate was dissolved in CH 2 Cl 2 /Methanol (v:v/1:1, 2 mL) and added HCl (0.15 mL, 4M solution in 1,4-dioxane). The reaction was diluted with diethyl ether (30 mL) upon reaction completion as determined by monitoring by HPLC/MS. The resulting precipitates were collected through filtration and washed with diethyl ether to give the title compound 4ET-03-055 as hydrochloride salt (98 mg, 0.19 mmol, 93%).
• the Boc-protected intermediate was dissolved in CH 2 Cl2/Methanol (v:v/1:1, 2 mL) and added HCl (0.15 mL, 4M solution in 1,4-dioxane).
• the reaction was diluted with diethyl ether (30 mL) upon reaction completion as determined by monitoring by HPLC/MS, the resulting precipitates were collected through filtration and washed with diethyl ether to give the title compound 4ET-03-056 as hydrochloride salt (95 mg, 0.19 mmol, 88%).
• the Boc-protected intermediate was dissolved in CH 2 Cl2/Methanol (v:v/1:1, 2 mL) and added HCl (0.15 mL, 4M solution in 1,4-dioxane).
• the reaction was diluted with diethyl ether (30 mL) upon reaction completion as determined by monitoring by HPLC/MS, the resulting precipitates were collected through filtration and washed with diethyl ether to give the title compound 4ET-03-057 as hydrochloride salt (77 mg, 0.14 mmol, 94%).
• the mixture was treated with sodium triacetoxyborohydride (9 mg, 0.138 mmol) and left to gradually warm to 23 °C. After stirring for 16 hours, the solvent was removed and the residue was taken up with trifluoroethanol (2.0 mL) and treated with sodium borohydride (6.4 mg, 0.170 mmol) in one portion at 23 °C. After 1 hour, the mixture was diluted with MeOH (3.0 mL) and subjected to a strong cation exchange (SCX) SPE cartridge (2 gram SCX) and eluted with methanol then dichloromethane then 1M NH 3 in methanol to give the title compound 4ET-03-081 (4.3 mg, 27%).
• SCX strong cation exchange
• EXAMPLE 88 S YNTHESIS OF 6''-((6- AMINOPYRIMIDIN -4- YL ) AMINO )-8''- METHYL -2''H- DISPIRO[CYCLOHEXANE-1,1'-CYCLOBUTANE-3',3''-IMIDAZO[1,5-A]PYRIDINE]-1'',5''-DIONE (4ET-01-020): The title compound was prepared according to the procedure of N-(6-((8''- methyl-1'',5''-dioxo-1'',5''-dihydro-2'''H-dispiro[cyclopropane-1,1'-cyclohexane-3',3''- imidazo[1,5-a]pyridin]-6''-yl)amino)pyrimidin-4-yl)cyclopropane carboxamide except that 6''-bromo-8''
• reaction mixture was heated to reflux for 2h. Then, t-BuOH (0.06mL, 0.605 mmol) was added and the reaction mixture was refluxed for 16 hours. The solvent was removed under reduced pressure and NaHCO 3 (50 mL) was added. After washed with ethyl acetate (50 mL ⁇ 3), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure.
• SFC method details The structures of Enantiomer 1 of 4ET-01-027 and Enatiomer 2 of 4ET-01-027 are as follows (stereochemistry is not assigned): The first eluting peak had a retention time of 3.24 minutes, a peak height of 25,518, and peak area of 1333.80 using a diode array at 254 nm (see, e.g., FIG.1). The second eluting peak had a retention time of 3.43 minutes, a peak height of 9,144, and peak area of 628.45 using a diode array at 254 nm (see, e.g., FIG.2).
• MNK inhibitors described herein to inhibit eIF4E phosphorylation at Serine 209 in the human embryonic kidney (HEK) 293 cell line was tested by exposing the cells to compound for 2 hours and then measuring eIF4E phosphorylation with a phosphorylation-specific antibody in a fluorescent plate reader. IC 50 data is provided in Table 5. These experiments were done with HEK-293 cells plated on 96 well plates. Following treatment, cells were fixed with ice cold methanol for 10 min and then washed in 1 ⁇ phosphate buffered saline (PBS) and the permeabilized with 0.02% Triton X-100 in 10% normal goat serum made up in PBS.
• PBS phosphate buffered saline
• MNK inhibitors described herein The ability of MNK inhibitors described herein to inhibit eIF4E phosphorylation at Serine 209 in Karpas 299, Human Non-Hodgkin's Ki-positive Large Cell Lymphoma cell line was tested by sandwich enzyme linked immune-absorbance assay. IC 50 data is provided in Table 5 below. The ability of MNK inhibitors described herein to inhibit eIF4E phosphorylation at Serine 209 in the human osteosarcoma (U2OS) cell line was tested by exposing the cells to compound for 2 hours and then measuring eIF4E phosphorylation with a phosphorylation-specific antibody in a fluorescent plate reader. IC 5 0 data is provided in Table 5 below. Table 5. MNK1, MNK2, HEK293 Cell, Karpas 299 Cell, and U2OS Cell IC 5 0 values for representative compounds of the disclosure
• BIOLOGICAL EXAMPLE 2 I N VIVO TESTING Animals
• Female and male MNK1 KO mice were a gift of the Sonenberg laboratory at McGill University and bred at the University of Texas at Dallas (UTD) to generate experimental animals (Ueda T, et al., MNK2 and MNK1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol Cell Biol. Aug 2004). Genotype was confirmed at weaning using DNA from ear clips.
• mice were obtained from an internally maintained C 5 7BL/6 J colony at the University of Texas at Dallas.
• ICR human-1) mice aged 6-8 weeks ( ⁇ 25- 30 g) were outbred and purchased from Envigo. All mice were housed in groups of four animals per cage on a 12-hour light-dark cycle and had access to food and water ad libitum. Upon arrival to the animal care facility, animals were allowed a minimum of 72 hours to acclimate to their new environment before being handled for experiments. All experiments were performed between the hours of 9:00 AM and 5:00 PM. All procedures were conducted with prior approval of the Institutional Animal Care and Use Committee at the University of Texas at Dallas.
• IL-6 interleukin-6
• R&D Systems human recombinant interleukin-6 (IL-6) protein (R&D Systems) stock solution (100 mg/mL) was prepared in sterile 0.1% BSA and diluted to 1 ng/mL in synthetic interstitial fluid (SIF) consisting of 135 mM NaCl, 5 mM KCl, 10 mM HEPES, 2 mM CaCl2, 10 mM glucose, 1 mM MgCl2 (pH 7.4, 310 mOsm).
• SIF synthetic interstitial fluid
• mice were given a 150 ⁇ L IP injection of 0.1 mg/kg of SNP or a 5 ⁇ L dural injection of SIF solution that was brought to a pH of 7.0, as previously described (Avona A., et al., Repetitive stress in mice causes migraine-like behaviors and CGRP-dependent hyperalgesic priming to a migraine trigger. Pain. (2020); Burgos- Vega C.C.
• MNK inhibitors were prepared for in vivo dosing by dissolution in 10% 1- methyl-2-pyrrolidinone (NMP; Sigma Cat# 328634) and 90% propylene glycol (PG; Fisher Cat# P355-1), with ⁇ 1 eq. of HCl.
• MNK inhibitors were given orally to WT mice at 10 mg/kg approximately 1 hr prior to dural IL-6 or dural pH 7.0.
• Mouse dural injections Mouse dural injections were performed as previously described (Burgos-Vega C.C. et al., Non-invasive dural stimulation in mice: A novel preclinical model of migraine. Cephalalgia. (2019)). Mice were anesthetized under isoflurane for ⁇ 2 min with ⁇ 2.5–3% isoflurane via a chamber and given a 5 ⁇ L injection via a modified internal cannula (Invivo1, part #8IC 3 13ISPCXC, Internal Cannula, standard, 28 gauge, fit to 0.5 mm).
• the inner projection of the cannula was used to inject through the soft tissue at the intersection of the lambdoidal and sagittal sutures. Using a caliper, the length of the projection was adjusted to be from 0.6 to 0.7 mm based on animal weight (25–30 g) in order to avoid puncturing the dura mater. Control mice received a 5 ⁇ L dural injection of SIF (pH 7.4, 310 mOsm). Upon completion of injections, mice were placed back into their respective cups in the testing chamber for 1 hr before testing.
• mice were stressed as previously described (Avona A., et al., Repetitive stress in mice causes migraine-like behaviors and CGRP-dependent hyperalgesic priming to a migraine trigger. Pain. (2020)). Mice were stressed between the hours of 10:00 AM to 12.00 PM for 2 hours per day for three consecutive days. Mice were placed right-side up into tail vein injection tubes (Stolting #51338) with the nose through the provided breathing hole. The slotted tail piece was tightened so as to prevent the mouse from rotating in the tube, but loose enough to allow the animal to breathe. Mice were restrained at a level that allowed for adequate respiration and care was taken to avoid any trauma caused by the restraint tube.
• mice were placed into a separate room and deprived of food and water for the same 2 hour interval for three consecutive days. Animals subjected to stress were housed separately from control mice in order to avoid potential transfer of the stress phenotype. Measuring mechanical hypersensitivity and grimace Mice were handled and conditioned for a single 5-minute session, approximately 24 hrs before habituation. Mice were habituated to paper cups (Choice 4 oz paper cups: 6.5 cm top diameter, 4.5 cm bottom diameter, 72.5 cm length) while in testing chambers for 2 hours per day and for at least 2 days before measuring a baseline. Each mouse typically used their same assigned paper cup for the remainder of the experiment. Animals were given food while in testing chambers.
• FIG.3A and 3B show genetic inhibition of MNK partially attenuates facial hypersensitivity and hyperalgesic priming caused by dural IL-6.
• FIG.4A and 4B show MNK1 KO mice do not prime to low-dose NO donor following repeated stress. Following three consecutive days of restraint stress, female and male WT and MNK1 KO mice were tested for acute facial hypersensitivity and grimace measures. Upon resolution of hypersensitivity, mice were administered a low dose of the NO donor, SNP (0.1 mg/kg) (IP), to test for the presence of priming.
• SNP 0.1 mg/kg
• FIG.5A and 5B depict eFT508 reduces dural IL-6 -induced facial hypersensitivity and prevents priming to pH 7.0.
• FIG.6 shows rac-4ET-01-027, Enatiomer 1 of 4ET-01-027, and 4ET-04-023 reduce dural IL-6 -induced facial grimacing.
• Female and male WT mice were administered 5 ⁇ L of dural IL-6 (0.1 ng) or vehicle and tested for acute facial grimacing as measured by the grimace score.
• mice Prior to IL-6, mice received 100 ⁇ L of either rac- 4ET-01-027 (10 mg/kg), Enantiomer 1 of 4ET-01-027 (10 mg/kg), 4ET-04-023 (10 mg/kg), or vehicle via oral gavage.
• mice that received either rac-4ET-01-027, Enantiomer 1 of 4ET-01-027, or 4ET-04-023, dural IL-6 induced facial grimace measures were significantly attenuated compared to the vehicle group. No sex differences were observed. Comparisons were made via two-way ANOVA followed by Bonferroni post-hoc analysis. Significance shown is between IL-6/Vehicle and IL- 6/rac-4ET-01-027, IL-6/Enantiomer 1 of 4ET-01-027, and IL-6/4ET-04-023 groups. n ⁇ 6 for all groups; *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, ****p ⁇ 0.0001.

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Pain & Pain Management (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Engineering & Computer Science (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=85154787

Family Applications (1)

Country Status (10)

Cited By (5)

Citations (4)

Family Cites Families (2)

• 2022
  • 2022-08-05 EP EP22853939.1A patent/EP4380566A4/en active Pending
  • 2022-08-05 CA CA3228265A patent/CA3228265A1/en active Pending
  • 2022-08-05 IL IL310590A patent/IL310590A/en unknown
  • 2022-08-05 WO PCT/US2022/039529 patent/WO2023014943A1/en not_active Ceased
  • 2022-08-05 KR KR1020247007155A patent/KR20240055743A/ko active Pending
  • 2022-08-05 AU AU2022324472A patent/AU2022324472A1/en active Pending
  • 2022-08-05 MX MX2024001560A patent/MX2024001560A/es unknown
  • 2022-08-05 CN CN202280062076.XA patent/CN118076354A/zh active Pending
  • 2022-08-05 US US18/294,823 patent/US20250205244A1/en active Pending
  • 2022-08-05 JP JP2024506658A patent/JP2024528982A/ja active Pending

Patent Citations (4)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events