WO2017123766A1 - Composés et compositions pour le traitement d'une maladie - Google Patents

Composés et compositions pour le traitement d'une maladie Download PDF

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WO2017123766A1
WO2017123766A1 PCT/US2017/013201 US2017013201W WO2017123766A1 WO 2017123766 A1 WO2017123766 A1 WO 2017123766A1 US 2017013201 W US2017013201 W US 2017013201W WO 2017123766 A1 WO2017123766 A1 WO 2017123766A1
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Prior art keywords
compound
heterocyclyl
alkyl
optionally substituted
heteroalkyl
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PCT/US2017/013201
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English (en)
Inventor
Radhakrishnan P. Iyer
Anjaneyulu Sheri
Seetharamaiyer Padmanabhan
Rayormand H. GIMI
Dillon CLEARY
Santosh KHEDKAR
Sreerupa CHALLA
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Sperovie Biosciences, Inc.
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Publication of WO2017123766A1 publication Critical patent/WO2017123766A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/20—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom

Definitions

  • This invention relates to compounds and compositions for use in inhibition of PDE4 as well as the prevention and treatment of a PDE4-mediated disease in a subject, in particular a neurodegenerative disease or an inflammatory disease.
  • Cyclic dinucleotide phosphodiesterases are a class of enzymes responsible for the hydrolysis and resulting inactivation of cyclic dinucleotide second messengers, particularly cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP). These enzymes are largely distributed throughout the mammalian central nervous system and immune system, and play a critical role in regulating intracellular signaling cascades by controlling second messenger concentration.
  • cAMP cyclic adenosine monophosphate
  • cGMP cyclic guanine monophosphate
  • PDE4 is widely expressed in various tissues including the central nervous system and is encoded by four genes (PDE4A-PDE4D) that result in over 20 different variants of the enzyme.
  • the common feature of all PDE4 isoforms is the ability to hydrolyze cAMP through a conserved catalytic domain comprising a tripartite structure (Houslay, M.D. et al. Circ Res (2007) 100:950- 966).
  • the specific function of each PDE4 isoform within the larger context of cellular homeostasis is still unclear, the activity of each isoform has been shown to be regulated by a number of kinases and phosphatases, suggesting that each carries out an important role in various aspects of controlling intracellular cAMP concentration. Due to the far-reaching effects of PDE4 enzymes, development of PDE4 inhibitors is currently an active area of research in relation to treatment and prevention of a number of diseases, particularly neurodegenerative and
  • Described herein are compounds and compositions useful for modulating the family of PDE4 enzymes.
  • the present invention further provides methods of preventing and treating a PDE4-mediated disease in a subject, e.g., neurodegenerative disease or an inflammatory disease.
  • the present invention features a com ound of Formula (I):
  • the present invention features a compound of Formula (II):
  • the present invention features a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient or carrier.
  • a pharmaceutical composition described herein includes a therapeutically effective amount of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may be useful for preventing or treating preventing a neurodegenerative disease or an inflammatory disease.
  • the present invention features a method for inhibiting PDE4 activity in a cell or in a subject (e.g., PDE4B 1 activity), comprising contacting the cell or administering to a subject an effective amount of a compound or a pharmaceutical composition described herein (e.g., a composition comprising a compound of Formula (I) or Formula (II) or a
  • the present invention features method for the treatment of a
  • neurodegenerative disease or disorder comprising administering to a subject an effective amount of a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition thereof.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • the neurodegenerative disease or disorder comprises Alzheimer's disease, Huntington's disease, Parkinson's disease, dementia, amyotrophic lateral sclerosis, or motor neuron disease.
  • the present invention features a method for the treatment of an inflammatory disease or disorder comprising administering to a subject an effective amount of a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition thereof.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • the inflammatory disease or disorder comprises COPD, an allergy, asthma, dermatitis, psoriasis, irritable bowel syndrome, or ulcerative colitis.
  • the present invention features a kit comprising a container with a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a kits described herein further includes instructions for administering the compound of Formula (I) or Formula (II) or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.
  • the present disclosure relates to compounds, compositions, and methods directed to the inhibition of a PDE4 isoform (e.g., PDE4B 1).
  • a PDE4-mediated disorder such as a neurodegenerative disease or an inflammatory disease.
  • the articles “a” and “an” refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.
  • “About” and “approximately” generally refer to an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
  • the term "acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity (e.g. , a sample, e.g. , blood sample or liver biopsy specimen), or a value, e.g. , a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value.
  • Directly acquiring means performing a process (e.g. , an analytical method) to obtain the physical entity or value.
  • “Indirectly acquiring” refers to receiving the physical entity or value from another party or source (e.g. , a third party laboratory that directly acquired the physical entity or value).
  • Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g. , performing an analytical process which includes a physical change in a substance, e.g. , a sample, performing an analytical method, e.g. , a method as described herein, e.g. , by sample analysis of bodily fluid, such as blood by, e.g. , mass spectroscopy (e.g. LC-MS), or PCR (e.g., RT-PCR).
  • bodily fluid such as blood by, e.g. , mass spectroscopy (e.g. LC-MS), or PCR (e.g., RT-PCR).
  • an amount of a compound, conjugate, or substance effective to treat a disorder refers to an amount of the compound, substance, or composition which is effective, upon single or multiple dose administration(s) to a subject, in treating a subject, or in curing, alleviating, relieving or improving a subject with a disorder (e.g. , a neurodegenerative or inflammatory disease mediated by PDE4) beyond that expected in the absence of such treatment.
  • a disorder e.g. , a neurodegenerative or inflammatory disease mediated by PDE4
  • the terms “prevent” or “preventing” as used in the context of a disorder or disease refer to administration of an agent to a subject, e.g. , the administration of a compound of the present invention (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, e.g., as described herein) to a subject, such that the onset of at least one symptom of the disorder or disease is delayed as compared to what would be seen in the absence of administration of said agent.
  • a compound of the present invention e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, e.g., as described herein
  • the term "subject” is intended to include human and non-human animals.
  • exemplary human subjects include a human patient having a disorder, e.g. , a disorder described herein (e.g., a neurodegenerative disease or an inflammatory disease), or a normal subject.
  • a disorder described herein e.g., a neurodegenerative disease or an inflammatory disease
  • non-human animals includes all vertebrates, e.g. , non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g. , sheep, dogs, cats, cows, pigs, etc.
  • the terms "treat” or “treating" a subject having a disorder or disease refer to subjecting the subject to a regimen, e.g. , the administration of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, such that at least one symptom of the disorder or disease is cured, healed, alleviated, relieved, altered, remedied, ameliorated, or improved. Treating includes administering an amount effective to alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or disease, or the symptoms of the disorder or disease. The treatment may inhibit deterioration or worsening of a symptom of a disorder or disease.
  • ranges e.g., ranges for the amount of a drug administered per day, are provided herein.
  • the range includes both endpoints.
  • the range excludes one or both endpoints.
  • the range can exclude the lower endpoint.
  • a range of 100 to 1000 mg/day, excluding the lower endpoint would cover an amount greater than 100 that is less than or equal to 1000 mg/day.
  • Co-administration refers to administration at the same time, administration of one therapy before (e.g., immediately before, less than about 5, about 10, about 15, about 30, about 45, about 60 minutes, about 1, about 2, about 3, about 4, about 6, about 8, about 10, about 12, about 16, about 20, about 24, about 48, about 72 or more hours before) administration of a secondary therapy.
  • a course of therapy can comprise one or more cycles of a therapeutic agent.
  • a "cycle”, as used herein in the context of a cycle of administration of a drug, refers to a period of time for which a drug is administered to a patient. For example, if a drug is
  • the periodic administration e.g., daily or twice daily, is given for 4 weeks.
  • a drug can be administered for more than one cycle.
  • the first and second or subsequent cycles are the same in terms of one or both of duration and periodic administration.
  • a first and second or subsequent cycle differs in terms of one or both of duration and periodic administration.
  • Rest periods may be interposed between cycles.
  • a rest cycle may be about 1, about 2, about 4, about 6, about 8, about 10, about 12, about 16, about 20, or about 24 hours; or about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days; or about 1, about 2, about 3, about 4 or more weeks in length.
  • Ci_6 alkyl is intended to encompass, Ci, C 2 , C 3 , C 4 , C5, C 6 , Ci_ 6 , Q-5, Ci ⁇ , Ci_ 3 , Ci_ 2 , C 2 _6, C 2 5, C 2 ⁇ , C 2 _ 3 , C 3 _6, C 3 _5, C 3 ⁇ , C4_6, C4_5, and Cs_ 6 alkyl.
  • each variable can be a different moiety selected from the Markush group defining the variable.
  • the two R groups can represent different moieties selected from the Markush group defined for R.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, and can have a number of carbon atoms as optionally designated ⁇ i.e., Ci-C 6 refers to an alkyl chain comprising one to six carbons).
  • saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, homologs and isomers of, for example, n-pentyl, n-hexyl, and the like.
  • alkenyl can be a straight or branched hydrocarbon chain, containing at least one double bond, and having from two to six carbon atoms (i.e. C 2 -C 6 alkenyl).
  • alkenyl groups include, but are not limited to, groups such as ethenyl (i.e., vinyl), prop- l-enyl (i.e., allyl), but-l-enyl, pent- l-enyl, penta-l,4-dienyl, and the like.
  • alkoxy is be a straight chain or branched alkyl group bound to an oxygen atom.
  • alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, or hexyloxy, and the like.
  • alkynyl can be a straight or branched hydrocarbon chain, containing at least one triple bond, having from two to six carbon atoms (i.e. C 2 -C 6 alkynyl).
  • alkynyl groups include, but are not limited to, groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • amine and “amino” refer to the radical -NH 2 .
  • amino substituted amino
  • R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or an amino protecting group, wherein at
  • each R is independently selected from hydrogen, Ci-C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 6 -Cio aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 3 -C 10 cycloalkyl, -(CH 2 ) t (C 6 -Cio aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -Cio cycloalkyl), or -(CH 2 ) t (4-10 membered heterocyclyl),
  • t is an integer between 0 and 8
  • R groups are joined to form an ring, e.g., a 3-8 membered ring (e.g., a 3-8 membered heterocyclyl or 3-8 membered heteroaryl ring).
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6 -i 4 aryl”).
  • an aryl group has six ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("Ci 4 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and
  • alkoxy refers to -O-(alkyl), wherein the alkyl moiety is as defined herein.
  • arylalkyl refers to an (aryl)alkyl— radical wherein aryl and alkyl moieties are as disclosed herein.
  • aryloxy refers to -O-(aryl), wherein the aryl moiety is as defined herein.
  • cyano refers to a -CN radical
  • cyclyl and cycloalkyl refer to a monocyclic or polycyclic non-aromatic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. C3-C 10 cycloalkyl).
  • Exemplary C 3 _ 6 cycloalkyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _ 8 cycloalkyl groups include, without limitation, the aforementioned C 3 _ 6 cycloalkyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _io cycloalkyl groups include, without limitation, the aforementioned C 3 _ 8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (Cio), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated.
  • Cycloalkyl or “cyclyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system.
  • halo or halogen
  • halo independently or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • halide by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom.
  • haloalkyl and haloalkoxy refers to alkyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • heteroalkyl refers to an alkyl that has one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range may be given, e.g. Ci-C 6 heteroalkyl which refers to the number of carbons in the chain, which in this example includes 1 to 6 carbon atoms.
  • a -CH 2 OCH 2 CH 3 radical is referred to as a "C 3 " heteroalkyl. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain.
  • heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl").
  • heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom ⁇ e.g., 2-indolyl) or the ring that does not contain a heteroatom ⁇ e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5- membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • heterocyclyl and “heterocycloalkyl” refer to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, furanosyl, ribosyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5- membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, and 5,6- dihydropyrimidinyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl,
  • hydroxy or “hydroxyl” refers to a -OH radical.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et ah,
  • an "S" form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the "R” form.
  • enantiomeric ally pure or “pure
  • enantiomer denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound.
  • the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound.
  • a pharmaceutical composition comprising
  • enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • the enantiomerically pure S- compound in such compositions can, for example, comprise, at least about 95% by weight S- compound and at most about 5% by weight R-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • Compound described herein may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • O may be in any isotopic form, including 16 0 and ls O; and the like.
  • the present invention features compounds and compositions for the inhibition of PDE4 and the treatment and prevention of PDE4-mediated disorders, such as a neurodegenerative disease or an inflammatory disease.
  • the present invention features a compound of Formula (I):
  • Z is O or NR 5 ;
  • R 1 is H, Ci-C 6 alkyl, or Q-
  • R 2 is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, C(0)R A , C(0)OR B , C(0)NR c R D , NR C R D , NR c C(0)R A , NR c S(0) p R E , S(0) p NR c R D , S(0) p R E , halo, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-5 R 6 ; R 3 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, C(0)R
  • R is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, C(0)R B , C(0)OR A , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is
  • R is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, OR A , C(0)R B , C(0)OR A , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-5 R 8 ; or wherein R 4 and R 5 may be taken together to form a ring optionally
  • each of R and R is independently Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, OR A , C(0)R B , C(0)OR A , C(0)NR c R D , NR C R D , NR c C(0)R B , NR c S(0) p R E , S(0) p NR c R D , S(0) p R E , halo, oxo, cyano, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6
  • R 9 is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, OR A , C(0)R B , C(0)OR A , C(0)NR c R D , NR C R D , NR c C(0)R B , NR c S(0) p R E , S(0) p NR c R D , S(0) p R E , halo, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted optionally substituted with 1-5 R 9 ; each of R A , R B , R c , R D , and R E is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2
  • R 1 is H or Ci-C 6 alkyl. In some embodiments, R 1 is H. In some embodiments, R 1 is Ci-C 6 alkyl (e.g., CH 3 ).
  • R 2 is Ci-C 6 alkyl, C(0)NR c R D , NR C R D , NR c C(0)R B ,
  • R 2 is NR C R D , NR c S(0) p R E , S(0) p NR c R D , S(0) p R E , halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • R 2 is S(0) p R E , RE is Ci-C 6 alkyl (e.g., CH 3 ), and p is 2.
  • R 2 is NR C R D , one of R C and RD is H and the other of R C and RD is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6-dihydropyrimidinyl), optionally substituted with 1-5 R 9.
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6-dihydropyrimidinyl
  • one of R C and RD is H
  • the other of RC and R D is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ) or heterocyclyl (e.g., 5,6- dihydropyrimidinyl)
  • R 9 if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 2 is heterocyclyl, optionally substituted with 1-5 R 6 .
  • R is a nitrogen-containing heterocyclyl, (e.g., a 5- or 6-membered nitrogen- containing heterocyclyl, e.g., pyrrolidinyl, piperidinyl, piperazinyl, e.g., pyrrolidinyl), each of which is optionally substituted with 1-5 R 6 .
  • R is halo (e.g., chloro). 2
  • R is aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl), each of which is optionally substituted with 1-5 R 6 .
  • R is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C(0)R , S(0) p R , halo, hydroxyl, or oxo, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 R 7.
  • R 3 is hydroxyl or oxo.
  • R 3 is hydroxyl or oxo and n is 3 or 4.
  • R is hydroxyl or oxo, n is 3 or 4, and m is 1.
  • Z is O. In some embodiments, Z is O and R 4 is Ci-C 6 alkyl (CH 2 ) or heterocyclyl (e.g., cyclopentyl), optionally substituted with 1-5 R .
  • R 4 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8. In some embodiments, R 4 is H or Ci-C 6 alkyl (e.g., H or CH 3 ).
  • Z is NR 5 .
  • Z is NR 5 and R 5 is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, aryl, or heteroaryl is optionally substituted with 1-5 R 8.
  • Z is NR 5 and R 5 is Ci-C 6 alkyl (e.g., -
  • Z is NR and R is Ci-C 6 alkyl
  • R 8 is heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl is optionally substituted optionally substituted with 1-5
  • R 8 is heteroaryl (e.g., monocyclic or bicyclic heteroaryl).
  • R is a bicyclic heteroaryl (e.g., a nitrogen-containing bicyclic heteroaryl, e.g., benzothiazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, indolyl, or benzoimidazolyl).
  • R is benzothiazolyl.
  • Z is NR 5 and R 4 and R 5 are taken together to form a heterocyclyl ring (e.g., a 5-membered heterocyclyl ring, e.g., pyrrolidinyl).
  • a heterocyclyl ring e.g., a 5-membered heterocyclyl ring, e.g., pyrrolidinyl.
  • the compound is a compound of Formula (la):
  • R C", R D", R E , m, n, and p are defined as for Formula (I), R 8' is heteroaryl, and q is 0, 1, 2, or 3.
  • R 1 is H or Ci-C 6 alkyl. In some embodiments, R 1 is H. In some embodiments, R 1 is Ci-C 6 alkyl (e.g., CH 3 ).
  • R 2 is Ci-C 6 alkyl, C(0)NR c R D , NR C R D , NR c C(0)R B ,
  • R 2 is NR C R D , NR c S(0) p R E , S(0) p NR c R D , S(0) p R E , halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • R 2 is S(0) p R E , RE is Ci-C 6 alkyl (e.g., CH 3 ), and p is 2.
  • R 2 is NR C R D , one of R C and RD is H and the other of R C and RD is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6-dihydropyrimidinyl), optionally substituted with 1-5 R 9.
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6-dihydropyrimidinyl
  • one of R C and RD is H
  • the other of RC and R D is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ) or heterocyclyl (e.g., 5,6- dihydropyrimidinyl)
  • R 9 if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 2 is heterocyclyl, optionally substituted with 1-5 R 6 .
  • R is a nitrogen-containing heterocyclyl, (e.g., a 5- or 6-membered nitrogen- containing heterocyclyl, e.g., pyrrolidinyl, piperidinyl, piperazinyl, e.g., pyrrolidinyl), each of which is optionally substituted with 1-5 R 6 .
  • R is halo (e.g., chloro).
  • R is aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl), each of which is optionally substituted with 1-5 R 6 .
  • R is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C(0)R , S(0) p R , halo, hydroxyl, or oxo, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 R 7.
  • R 3 is hydroxyl or oxo.
  • R 3 is hydroxyl or oxo and m is 3 or 4.
  • R 4 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8.
  • R 4 is H or Ci-C 6 alkyl (e.g., H or CH 3 ).
  • q is 1 or 2. In some embodiments, q is 1. In some embodiments, R 8' is heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl is optionally substituted optionally substituted with 1-5 R 9. In some embodiments, R 8' is heteroaryl (e.g., monocyclic or bicyclic heteroaryl). In some embodiments, R 8' is a bicyclic heteroaryl (e.g., a nitrogen-containing bicyclic heteroaryl, e.g., benzothiazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, indolyl, or benzoimidazolyl). In some embodiments, R 8' is benzothiazolyl.
  • the compound is a compound of Formula (lb):
  • R D", R E , m, and p are defined as for Formula (I), and R 8' is a nitrogen-containing bicyclic heteroaryl.
  • R 2 is Ci-C 6 alkyl, C(0)NR c R D , NR C R D , NR c C(0)R B ,
  • R 2 is NR C R D , NR c S(0) p R E , S(0) p NR c R D , S(0) p R E , halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • R 2 is S(0) p R E , RE is Ci-C 6 alkyl (e.g., CH 3 ), and p is 2.
  • R 2 is NR C R D , one of R C and RD is H and the other of R C and RD is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6-dihydropyrimidinyl), optionally substituted with 1-5 R 9.
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6-dihydropyrimidinyl
  • one of R C and RD is H
  • the other of RC and R D is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ) or heterocyclyl (e.g., 5,6- dihydropyrimidinyl)
  • R 9 if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 2 is heterocyclyl, optionally substituted with 1-5 R 6 .
  • R is a nitrogen-containing heterocyclyl, (e.g., a 5- or 6-membered nitrogen - containing heterocyclyl, e.g., pyrrolidinyl, piperidinyl, piperazinyl, e.g., pyrrolidinyl), each of which is optionally substituted with 1-5 R 6 .
  • R is halo (e.g., chloro).
  • R is aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl), each of which is optionally substituted with 1-5 R 6 .
  • R is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C(0)R , S(0) p R , halo, hydroxyl, or oxo, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 R 7.
  • R 3 is hydroxyl or oxo. In some embodiments, R 3 is hydroxyl or oxo and m is 1.
  • R 4 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8. In some embodiments, R 4 is H or Ci-C 6 alkyl (e.g., H or CH 3 ).
  • R 8' is heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl is optionally substituted optionally substituted with 1-5 R 9.
  • R 8' is heteroaryl (e.g., monocyclic or bicyclic heteroaryl).
  • R 8' is a bicyclic heteroaryl (e.g., a nitrogen-containing bicyclic heteroaryl, e.g., benzothiazolyl, benzofuranyl, benzoxazolyl, benzothiophenyl, indolyl, or benzoimidazolyl).
  • R 8' is benzothiazolyl.
  • the compound is a compound of Formula (Ic):
  • R D", R E , m, and p are defined as for Formula (I), X is O, NH, CH 2 , or S, and Y is N or CH.
  • R 2 is Ci-C 6 alkyl, C(0)NR c R D , NR C R D , NR c C(0)R B ,
  • R 2 is NR C R D , NR c S(0) p R E , S(0) p NR c R D , S(0) p R E , halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • R 2 is S(0) p R E , RE is Ci-C 6 alkyl (e.g., CH 3 ), and p is 2.
  • R 2 is NR C R D , one of R C and RD is H and the other of R C and RD is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6-dihydropyrimidinyl), optionally substituted with 1-5 R 9.
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6-dihydropyrimidinyl
  • one of R C and RD is H
  • the other of RC and R D is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ) or heterocyclyl (e.g., 5,6- dihydropyrimidinyl)
  • R 9 if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 2 is heterocyclyl, optionally substituted with 1-5 R 6 .
  • R is a nitrogen-containing heterocyclyl, (e.g., a 5- or 6-membered nitrogen- containing heterocyclyl, e.g., pyrrolidinyl, piperidinyl, piperazinyl, e.g., pyrrolidinyl), each of which is optionally substituted with 1-5 R 6 .
  • R is halo (e.g., chloro).
  • R is aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl), each of which is optionally substituted with 1-5 R 6 .
  • R is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C(0)R , S(0) p R , halo, hydroxyl, or oxo, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 R 7.
  • R 3 is hydroxyl or oxo. In some embodiments, R 3 is hydroxyl or oxo and m is 1.
  • X is O. In some embodiments, X is NH. In some embodiments, X is CH 2 . In some embodiments, X is S. In some embodiments, Y is N. In some embodiments, Y is CH. In some embodiments, X is S and Y is N.
  • the compound is a compound of Formula (Id):
  • each R 3 , R 6 , R 7 , R 9 , R 10 , R A , R B , R c , R D , R , m, and p are defined as for Formula (I), X is O, NH, CH 2 , or S, and Y is N or CH.
  • R is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C(0)R , S(0) p R , halo, hydroxyl, or oxo, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 R 7.
  • R 3 is hydroxyl or oxo. In some embodiments, R 3 is hydroxyl or oxo and m is 1.
  • X is O. In some embodiments, X is NH. In some embodiments, X is CH 2 . In some embodiments, X is S. In some embodiments, Y is N. In some embodiments, Y is CH. In some embodiments, X is S and Y is N.
  • the compound is a compound of Formula (Ie):
  • each R 3, R 7, R 9, R 10 , R A, R B, R C, R D, R E, m, and p are defined as for Formula (I).
  • R is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C(0)R , S(0) p R , halo, hydroxyl, or oxo, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 R 7.
  • R 3 is hydroxyl or oxo.
  • R 3 is hydroxyl or oxo and m is 1.
  • the compound is a compound of Formula (If)
  • each R 3 , R 7 , R 9 , R 10 , and m are defined as for Formula (I).
  • R is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C(0)R , S(0) p R , halo, hydroxyl, or oxo, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 R 7.
  • R 3 is hydroxyl or oxo. In some embodiments, R 3 is hydroxyl or oxo and m is 1.
  • R 9 is heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 . In some embodiments, R 9 is oxo. In some embodiments, R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • the present invention features a compound of Formula (II):
  • R 1 is H, Ci-C 6 alkyl, or Ci- C 6 heteroalkyl
  • R 2 is Ci-C 6 heteroalkyl, C(0)R A , C(0)OR B , C(0)NR c R D , NR C R D , NR c C(0)R A , halo, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-5 R 6 ;
  • R 3 is H, Ci-C 6 alkyl, or Q-
  • R 4 is H, Ci-C 6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-5 R 8 ;
  • R 5 is H, Ci-C 6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-5
  • each of R 6 and R 7 is independently Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, OR A , C(0)R B , C(0)OR A , C(0)NR c R D , NR C R D , NR c C(0)R B , NR c S(0) p R E , S(0) p NR c R D , S(0) p R , halo, cyano, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
  • R is H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, OR A , C(0)R B , C(0)OR A , C(0)NR c R D , NR C R D , NR c C(0)R B , NR c S(0) p R E , S(0) p NR c R D , S(0) p R , halo, oxo, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted optionally substituted with 1-5 R 9 ; each of R A , R B , R c , R D , and R E is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl
  • Z is N. In some embodiments, Z is CH.
  • R 1 is H or Ci-C 6 alkyl. In some embodiments, R 1 is H. In some embodiments, R 1 is Ci-C 6 alkyl (e.g., CH 3 ).
  • R 2 is Ci-C 6 heteroalkyl, NR C R D , NR c C(0)R B , halo, cycloalkyl, or heterocyclyl.
  • R 2 is NR C R D .
  • R 2 is NR C R D and R C and R D are each independently H, Ci-C 6 alkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with 1-5 R 9.
  • R 2 is NR C R D and R C and R D are each
  • R c and R D are each independently H, Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydro yrimidinyl), optionally substituted with 1-5 R 9 .
  • R c and R D are each independently H, Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl), and R 9 , if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), halo (e.g., fluoro), or hydroxyl.
  • R 2 is NR C R D , one of R C and RD is H and the other of R C and RD is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6-dihydropyrimidinyl), optionally substituted with 1-5 R 9.
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6-dihydropyrimidinyl
  • one of R C and RD is H
  • the other of RC and R D is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl)
  • R 9 if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 2 is heterocyclyl optionally substituted with 1-5 R 6 .
  • R is a nitrogen-containing heterocyclyl (e.g., a 6-membered nitrogen-containing heterocyclyl, e.g., piperazinyl, piperidinyl, morphilinyl), each of which is optionally substituted
  • R e.g., C(0)R D , oxo
  • R is C(0)R or oxo
  • R is Ci-C 6 heteroalkyl (e.g., methoxy).
  • R is halo (e.g., chloro).
  • R is H, Ci-C 6 alkyl (e.g., CH 2 ), or Ci-C 6 heteroalkyl (e.g., CH 2 CH 2 OCH 3 or CH 2 CH 2 N-), substituted with 0-2 R 7 (e.g., -(C(0)OCH 3 ) 2 ).
  • R 3 is H.
  • R 3 is Ci-C 6 alkyl (e.g., CH 2 ) substituted with 1 R 7 .
  • R 3 is Ci-C 6 heteroalkyl (e.g., CH 2 CH 2 OCH 3 or CH 2 CH 2 N-) substituted with 0-2 R 7' (e.g., -(C(0)OCH 3 ) 2 ).
  • R 7 is heteroaryl. In some embodiments, R 7 is a bicyclic heteroaryl. In some embodiments, R 7 is a bicyclic heteroaryl (e.g., a nitrogen-containing bicyclic heteroaryl, e.g., benzothiazolyl, benzoxazolyl). In some embodiments, R is benzothiazolyl (e.g., 2-benzothiazolyl) or benzoxazolyl (2-benzoxazolyl). In some embodiments, R 7 is benzothiazolyl (e.g., 2-benzothiazolyl). In some embodiments, R 7 is benzoxazolyl (2-benzoxazolyl).
  • R 4 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8 .
  • R 4 is H.
  • R 4 is heterocyclyl (e.g., 5,6-dihydropyrimidinyl) optionally substituted with 1-5 R .
  • R is oxo or heterocyclyl (e.g., tetrahydrofuranyl) optionally substituted with 1-5 R 9 .
  • R 9 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 5 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8.
  • R 5 is H.
  • R 5 is heterocyclyl (e.g., 5,6-dihydropyrimidinyl) optionally substituted with 1-5 R .
  • R is oxo or heterocyclyl (e.g., tetrahydrofuranyl) optionally substituted with 1-5 R 9 .
  • R 9 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 4 is H and R 5 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8.
  • R 8 is oxo or heterocyclyl (e.g., tetrahydrofuranyl) optionally substituted with 1-5 R 9 .
  • R 9 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 4 and R 5 are taken together to form a ring optionally substituted with 1-5 R 8°. In some embodiments, R 4 and R 5 are taken together to form a heterocyclyl ring (e.g., pyrrolidinyl) optionally substituted with 1-5 R .
  • a heterocyclyl ring e.g., pyrrolidinyl
  • the com ound of Formula (II) is a compound of Formula (Ila):
  • each R 1 , R 2 , R 9 , R 10 , R c , and R D are defined as for Formula (I), and R 7' is heteroaryl.
  • R 1 is H or Ci-C 6 alkyl. In some embodiments, R 1 is H. In some embodiments, R 1 is Ci-C 6 alkyl (e.g., CH 3 ).
  • R 2 is Ci-C 6 heteroalkyl, NR C R D , NR c C(0)R B , halo, cycloalkyl, or heterocyclyl. In some embodiments, R 2 is NR C R D . In some embodiments, R 2 is NR C R D and R C and R D are each independently H, Ci-C 6 alkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with 1-5 R 9.
  • R 2 is NR C R D and R C and R D are each independently H, Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl), optionally substituted with 1-5 R 9 .
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6- dihydropyrimidinyl
  • R c and R D are each independently H, Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl), and R 9 , if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), halo (e.g., fluoro), or hydroxyl.
  • R 2 is NR C R D , one of R C and RD is H and the other of R C and RD is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6-dihydropyrimidinyl), optionally substituted with 1-5 R 9.
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6-dihydropyrimidinyl
  • one of R C and RD is H
  • the other of RC and R D is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl)
  • R 9 if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 2 is heterocyclyl optionally substituted with 1-5 R 6 .
  • R is a nitrogen-containing heterocyclyl (e.g., a 6-membered nitrogen-containing heterocyclyl, e.g., piperazinyl, piperidinyl, morphilinyl), each of which is optionally substituted
  • R e.g., C(0)R D , oxo
  • R is C(0)R or oxo
  • R is Ci-C 6 heteroalkyl (e.g., methoxy).
  • R is halo (e.g., chloro).
  • R 4 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8 .
  • R 4 is H.
  • R 4 is heterocyclyl (e.g., 5,6-dihydropyrimidinyl) optionally substituted with 1-5 R .
  • R is oxo or heterocyclyl (e.g., tetrahydrofuranyl) optionally substituted with 1-5 R 9 .
  • R 9 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 5 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8.
  • R 5 is H.
  • R 5 is heterocyclyl (e.g., 5,6-dihydropyrimidinyl) optionally substituted with 1-5 R .
  • R is oxo or heterocyclyl (e.g., tetrahydrofuranyl) optionally substituted with 1-5 R 9 .
  • R 9 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 4 is H and R 5 is H, Ci-C 6 alkyl, cycloalkyl or heterocyclyl, each optionally substituted with 1-5 R 8.
  • R 8 is oxo or heterocyclyl (e.g., tetrahydrofuranyl) optionally substituted with 1-5 R 9 .
  • R 9 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 4 and R 5 are taken together to form a ring optionally substituted with 1-5 R 8°. In some embodiments, R 4 and R 5 are taken together to form a heterocyclyl ring (e.g., pyrrolidinyl) optionally substituted with 1-5 R .
  • a heterocyclyl ring e.g., pyrrolidinyl
  • R 7' is heteroaryl. In some embodiments, R 7' is a bicyclic heteroaryl. In some embodiments, R 7' is a bicyclic heteroaryl (e.g., a nitrogen-containing bicyclic heteroaryl, e.g., benzothiazolyl, benzoxazolyl). In some embodiments, R 7' is benzothiazolyl (e.g., 2-benzothiazolyl) or benzoxazolyl (2-benzoxazolyl). In some
  • R 7' is benzothiazolyl (e.g., 2-benzothiazolyl). In some embodiments, R 7' is benzoxazolyl (2-benzoxazolyl).
  • the compound of Formula (II) is a compound of Formula (lib):
  • R 2 , R 3 , R 9 , R 10 , R C , and R D are defined as for Formula (II), and m is 1, 2, 3, 4, or 5.
  • R 1 is H or Ci-C 6 alkyl. In some embodiments, R 1 is H. In some embodiments, R 1 is Ci-C 6 alkyl (e.g., CH 3 ).
  • R 2 is Ci-C 6 heteroalkyl, NR C R D , NR c C(0)R B , halo, cycloalkyl, or heterocyclyl.
  • R 2 is NR C R D .
  • R 2 is NR C R D and R C and R D are each independently H, Ci-C 6 alkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with 1-5 R 9.
  • R 2 is NR C R D and R C and R D are each
  • R c and R D are each independently H, Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydro yrimidinyl), optionally substituted with 1-5 R 9 .
  • R c and R D are each independently H, Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl), and R 9 , if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), halo (e.g., fluoro), or hydroxyl.
  • R 2 is NR C R D , one of R C and RD is H and the other of R C and RD is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6-dihydropyrimidinyl), optionally substituted with 1-5 R 9.
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6-dihydropyrimidinyl
  • one of R C and RD is H
  • the other of RC and R D is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl)
  • R 9 if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 2 is heterocyclyl optionally substituted with 1-5 R 6 .
  • R is a nitrogen-containing heterocyclyl (e.g., a 6-membered nitrogen-containing heterocyclyl, e.g., piperazinyl, piperidinyl, morphilinyl), each of which is optionally substituted
  • R e.g., C(0)R D , oxo
  • R is C(0)R or oxo
  • R is Ci-C 6 heteroalkyl (e.g., methoxy).
  • R is halo (e.g., chloro).
  • R is H, Q-C 6 alkyl (e.g., CH 2 ), or Ci-C 6 heteroalkyl (e.g., CH 2 CH 2 OCH 3 or CH 2 CH 2 N(C(0)OCH 3 ) 2 ), substituted with 0-2 R 7 .
  • R 3 is
  • R 7 is heteroaryl.
  • R 7 is a bicyclic heteroaryl.
  • R 7 is a bicyclic heteroaryl (e.g., a nitrogen-containing bicyclic heteroaryl, e.g., benzothiazolyl, benzoxazole).
  • R is benzothiazolyl (e.g., 2-benzothiazolyl) or benzoxazole (2-benzoxazole). In some embodiments, R is benzothiazolyl (e.g., 2-benzothiazolyl) or bennzoxazole (2- benzoxazole). In some embodiments, R is benzothiazolyl (e.g., 2-benzothiazolyl).
  • n is 2, 3, or 4. In some embodiments, m is 2. In some embodiments,
  • m is 3 or 4. In some embodiments, m is 3. In some embodiments, m is 4.
  • the compound of Formula (II) is a compound of Formula (lie):
  • R 2 , R 3 , R 9 , R 10 , R C , and R D are defined as for Formula (I), and m is 1, 2, 3, 4, or 5.
  • R 1 is H or Ci-C 6 alkyl. In some embodiments, R 1 is H. In some embodiments, R 1 is Ci-C 6 alkyl (e.g., CH 3 ).
  • R 2 is Ci-C 6 heteroalkyl, NR C R D , NR c C(0)R B , halo, cycloalkyl, or heterocyclyl.
  • R 2 is NR C R D .
  • R 2 is NR C R D and R C and R D are each independently H, Ci-C 6 alkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with 1-5 R 9.
  • R 2 is NR C R D and R C and R D are each
  • R c and R D are each independently H, Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl), optionally substituted with 1-5 R 9 .
  • R c and R D are each independently H, Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl), and R 9 , if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), halo (e.g., fluoro), or hydroxyl.
  • R 2 is NR C R D , one of R C and RD is H and the other of R C and RD is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6-dihydropyrimidinyl), optionally substituted with 1-5 R 9.
  • Ci-C 6 alkyl e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3
  • heterocyclyl e.g., 5,6-dihydropyrimidinyl
  • one of R C and RD is H
  • the other of RC and R D is Ci-C 6 alkyl (e.g., CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 ), or heterocyclyl (e.g., 5,6- dihydropyrimidinyl)
  • R 9 if present, is oxo or heterocyclyl (e.g., tetrahydrofuranyl), optionally substituted with 1-5 R 10 .
  • R 10 is Ci-C 6 heteroalkyl (e.g., methoxy), Ci-C 6 hydroxyalkyl (e.g., CH 2 OH), halo (e.g., fluoro), or hydroxyl.
  • R 2 is heterocyclyl optionally substituted with 1-5 R 6 .
  • R is a nitrogen-containing heterocyclyl (e.g., a 6-membered nitrogen-containing heterocyclyl, e.g., piperazinyl, piperidinyl, morphilinyl), each of which is optionally substituted 6 B 6 B B with 1-5 R" (e.g., C(0)R D , oxo).
  • R is C(0)R or oxo
  • R is Ci-C 6 heteroalkyl (e.g., methoxy).
  • R is halo (e.g., chloro).
  • R is H, Ci-C 6 alkyl (e.g., CH 2 ), or Ci-C 6 heteroalkyl (e.g., CH2CH2OCH3 or CH 2 CH 2 N(C(0)OCH 3 )2), substituted with 0-2 R 7 .
  • R 3 is H, Ci-C 6 alkyl (e.g., CH 2 ), or Ci-C 6 heteroalkyl (e.g., CH2CH2OCH3 or CH 2 CH 2 N(C(0)OCH 3 )2), substituted with 0-2 R 7 .
  • R 3 is H, Ci-C 6 alkyl (e.g., CH 2 ), or Ci-C 6 heteroalkyl (e.g., CH2CH2OCH3 or CH 2 CH 2 N(C(0)OCH 3 )2), substituted with 0-2 R 7 .
  • R 3 is
  • C C 6 alkyl e.g., CH 2
  • R is heteroaryl
  • R is a bicyclic heteroaryl.
  • R is a bicyclic heteroaryl (e.g., a nitrogen-containing bicyclic heteroaryl, e.g., benzothiazolyl, benzoxazole).
  • a bicyclic heteroaryl e.g., a nitrogen-containing bicyclic heteroaryl, e.g., benzothiazolyl, benzoxazole.
  • R is benzothiazolyl (e.g., 2-benzothiazolyl) or benzoxazole (2-benzoxazole). In some embodiments, R is benzothiazolyl (e.g., 2-benzothiazolyl) or bennzoxazole (2- benzoxazole). In some embodiments, R is benzothiazolyl (e.g., 2-benzothiazolyl).
  • n is 2, 3, or 4. In some embodiments, m is 2. In some embodiments,
  • m is 3 or 4. In some embodiments, m is 3. In some embodiments, m is 4.
  • Table 1 summarizes exemplary compounds of the invention (e.g., a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof).
  • the compounds provided herein may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included within the scope. Unless otherwise indicated when a compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
  • the compounds provided herewith may also contain linkages (e.g., carbon-carbon bonds, phosphorus-oxygen bonds, or phosphorus-sulfur bonds) or substituents that can restrict bond rotation, e.g. restriction resulting from the presence of a ring or double bond.
  • PDE4 is a member of the class of cyclic dinucleotide phosphodiesterases that catalyzes the hydrolysis of cyclic AMP (cAMP), thus terminating the downstream signaling of this second messenger.
  • cAMP cyclic AMP
  • PDE4A PDE4A
  • PDE4B PDE4B
  • PDE4C PDE4C
  • PDE4D PDE4D
  • PDE4 family of enzymes has been shown to be widely distributed throughout different mammalian tissues and are present in all major organs including the brain. However, each of the four gene families of PDE4 (PDE4A, PDE4B, PDE4C, and PDE4D) has been shown to exhibit a distinct pattern of expression throughout tissues and cells. For example, while PDE4A is distributed widely, PDE4C is abundant in neuronal tissue and skeletal muscle largely absent from immune and inflammatory cells. Likewise, PDE4B is expressed throughout the nervous system, lungs, heart, and muscular tissue, while PDE4D is largely localized to the lungs, immune cells, and cerebellum (Bao, Z. et al. Oncol Rep (2014) 32:250-60; Eskandari, N. et al. Res Pharm Pract (2015) 4: 175-181). The PDE4 subtype PDE4B
  • a compound or composition for the inhibition of PDE4 is specific to one gene family of PDE4.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to one of PDE4A, PDE4B, PDE4C, or PDE4D.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to more than one of PDE4A, PDE4B, PDE4C, or PDE4D.
  • composition described herein is specific to one of PDE4A, PDE4B, PDE4C, or PDE4D, with at least about a 1.5-fold, about a 2-fold, about a 3- fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50- fold, about a 100-fold, or greater selectively of one of PDE4A, PDE4B, PDE4C, or PDE4D over another of PDE4A, PDE4B, PDE4C, or PDE4D.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to PDE4A or a variant or isoform thereof with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4B, PDE4C, or PDE4D or a variant or isoform thereof.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to PDE4B or a variant or isoform thereof with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4A, PDE4C, or PDE4D or a variant or isoform thereof.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to PDE4C or a variant or isoform thereof with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4A, PDE4B, or PDE4D or a variant or isoform thereof.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to PDE4D or a variant or isoform thereof with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4A, PDE4B, or PDE4C or a variant or isoform thereof.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4A or a variant or isoform thereof, e.g., PDE4A1, PDE4A4, PDEA6, PDEA7, PDEA8, PDEA10, or PDEA11.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific for more than one PDE4A or a variant or isoform thereof, e.g., PDE4A1, PDE4A4, PDE4A6, PDE4A7, PDEA8, PDEAIO, or PDEAl 1.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4A1 with at least about a 1.5-fold, about a 2-fold, about a 3- fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50- fold, about a 100-fold, or greater selectively over PDE4A4, PDE4A6, PDE4A7, PDEA8, PDEAIO, or PDEAl 1.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4A4 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100- fold, or greater selectively over PDE4A1, PDE4A6, PDE4A7, PDEA8, PDEAIO, or PDEAl 1.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to PDE4A6 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4A1, PDE4A4, PDE4A7, PDEA8, PDEAIO, or PDEAl 1.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a
  • a compound e.g., a compound of Formula (I) or Formula (II) or a
  • PDE4A10 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4A1, PDE4A4, PDE4A6, PDEA7, PDEA8, or PDEA11.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a
  • PDE4A11 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4A1, PDE4A4, PDE4A6, PDEA7, PDEA8, or PDEA10.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to PDE4B or a variant or isoform thereof, e.g., PDE4B 1, PDE4B2, PDE4B3, PDE4B4, or PDE4B5.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific for more than one PDE4B or a variant or isoform thereof, e.g., PDE4B 1, PDE4B2, PDE4B3, PDE4B4, or PDE4B5.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4B 1 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4B2, PDE4B3, PDE4B4, or PDE4B5.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4B2 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4B 1, PDE4B3, PDE4B4, or PDE4B5.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4B3 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100- fold, or greater selectively over PDE4B 1, PDE4B2, PDE4B4, or PDE4B5.
  • PDE4B3 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100- fold, or greater selectively over PDE4B 1, PDE4B2, PDE4B4, or PDE4B5.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a
  • PDE4B4 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4B 1, PDE4B2, PDE4B3, or PDE4B5.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4B5 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4B 1, PDE4B2, PDE4B3, or PDE4B4.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4C or a variant or isoform thereof, e.g., PDE4C1, PDE4C2, PDE4C3, PDE4C4, PDE4C5, PDE4C6, or PDE4C7.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific for more than one PDE4C or a variant or isoform thereof, e.g., PDE4C1, PDE4C2, PDE4C3, PDE4C4, PDE4C5, PDE4C6, or PDE4C7.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4C1 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4C2, PDE4C3, PDE4C4, PDE4C5, PDE4C6, or PDE4C7.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4C2 with at least about a 1.5-fold, about a 2-fold, about a 3- fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50- fold, about a 100-fold, or greater selectively over PDE4C1, PDE4C3, PDE4C4, PDE4C5, PDE4C6, or PDE4C7.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4C3 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100- fold, or greater selectively over PDE4C1, PDE4C2, PDE4C4, PDE4C5, PDE4C6, or PDE4C7.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein is specific to PDE4C4 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4C1, PDE4C2, PDE4C3, PDE4C5, PDE4C6, or PDE4C7.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a
  • a compound e.g., a compound of Formula (I) or Formula (II) or a
  • PDE4C7 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4C1, PDE4C2, PDE4C3, PDE4C4, PDE4C5, or PDE4C6.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4D or a variant or isoform thereof, e.g., PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8, or PDE4D9.
  • a compound or composition described herein e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • a compound or composition described herein is specific for more than one PDE4D or a variant or isoform thereof, e.g., PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a
  • PDE4D1 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5-fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4D2 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D1, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described is specific to PDE4D3 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D1, PDE4D2, PDE4D4, PDE4D5, PDE4D6, PDE4D7, PDE4D8, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4D4 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D1, PDE4D2, PDE4D3, PDE4D5, PDE4D6, PDE4D7, PDE4D8, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4D5 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D6, PDE4D7, PDE4D8, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4D6 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4D7 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4D8 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, or PDE4D9.
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is specific to PDE4D9 with at least about a 1.5-fold, about a 2-fold, about a 3-fold, about a 4-fold, about a 5- fold, about a 7.5-fold, about a 10-fold, about a 20-fold, about a 50-fold, about a 100-fold, or greater selectively over PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D7, or PDE4D8.
  • the present invention features compounds and composition for the inhibition of PDE4 (e.g., compounds described herein, e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof).
  • the compounds and compositions described herein may be used to treat or prevent a disease or disorder involving aberrant function of PDE4, or a specific variant or isoform thereof (e.g., a specific isoform of PDE4A, PDE4B, PDE4C, or PDE4D).
  • Exemplary conditions that may be treated with the compounds and compositions described herein include, but are not limited to, inflammatory diseases and neurodegenerative diseases.
  • the present invention features compounds and compositions (e.g., compounds and compositions described herein, e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) that may be used for the treatment or prevention of an inflammatory disease or an autoimmune disease.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein may be administered prior to the onset of, at the onset of, or after the initiation of symptoms of said inflammatory or autoimmune disease.
  • inflammatory conditions include, but are not limited to, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, degenerative joint disease, spondoulo-arthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulin dependent diabetes mellitus or juvenile onset diabetes), menstrual cramps, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis (acute or chronic), multiple organ injury syndrome (e.g., secondary to septicemia or trauma), myocardial infarction, atherosclerosis, stroke, rep
  • inflammatory conditions of the skin include, for example, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, and dermatosis with acute inflammatory
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • composition described herein is used to treat or prevent allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • a compound e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • exemplary autoimmune diseases include, but are not limited to, organ-tissue autoimmune diseases (e.g., Raynaud's syndrome), scleroderma, myasthenia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), and Grave's disease.
  • organ-tissue autoimmune diseases e.g., Raynaud's syndrome
  • scleroderma myasthenia gravis
  • transplant rejection transplant rejection
  • endotoxin shock sepsis
  • psoriasis eczema
  • the present invention features compounds and compositions (e.g., compounds and compositions described herein, e.g., a compound of Formula (I) or
  • a neurodegenerative disease may involve a central nervous system (CNS) disorder, a peripheral nervous (PNS) disorder, a neuromuscular disorder, or other disease or condition involving any aspect of the nervous system.
  • a compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) or composition described herein may be administered prior to the onset of, at the onset of, or after the initiation of symptoms of said neurodegenerative disease.
  • exemplary neurodegenerative diseases include, but are not limited to, a myelopathy, an encephalopathy, central nervous system (CNS) infection, encephalitis (e.g., viral encephalitis, bacterial encephalitis, parasitic
  • meningitis e.g., spinal meningitis, bacterial meningitis, viral meningitis, fungal meningitis
  • Huntington's disease Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, a mental health disorder (e.g.,
  • brain tumors e.g., intra-axial tumors, extra-axial tumors
  • adult brain tumors e.g., glioma, glioblastoma
  • pediatric brain tumors e.g., medulloblastoma
  • cognitive impairment e.g., genetic disorders (e.g., Huntington's disease, neurofibromatosis type 1, neurofibromatosis type 2, Tay-Sachs disease, tuberous sclerosis), headache (e.g., tension headache, migraine headache, cluster headache, meningitis headache, cerebral aneurysm and subarachnoid hemorrhage headache, brain tumor headache), stroke (e.g., cerebral ischemia or cerebral infarction, transient ischemic attack, hemorrhagic (e.g., aneurysmal subarachnoid hemorrhage, hypertensive hemorrhage, other sudden hemorrhage)), epilepsy, spinal disease (e.g., degenerative spinal disease (
  • the present invention features compounds and compositions (e.g., compounds and compositions described herein, e.g., a compound of Formula (I) or Formula (II) or a
  • the subject is further administered an additional agent or treatment in conjunction with a compound of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.
  • the additional agent may be an agent for inhibition of PDE4, or an agent for treating an inflammatory disease, an autoimmune disease, or a neurodegenerative disease.
  • the additional agent is an anti-PDE4 agent, e.g., rolipram, AN2728, E6005, roflumilast, piclamilast, mesembrenone, luteolin, ibudilast, diazepam, cilomilast, or apremilast.
  • the additional agent is an agent for treatment of an inflammatory or autoimmune disease, e.g., a steroid (e.g., prednisone) or a NSAID (e.g., naproxen or ibuprofen).
  • the additional agent is an agent for treatment of a neurodegenerative disease, e.g., a neurotransmitter (e.g., dopamine, L-dopa, acetylcholine) or a GABA agonist.
  • a neurodegenerative disease e.g., a neurotransmitter (e.g., dopamine, L-dopa, acetylcholine) or a GABA agonist.
  • the additional agent is one that targets a symptom of an inflammatory disease, an autoimmune disease, or a neurodegenerative disease, e.g., an anti-nausea medication, a skin cream, a steroid, etc.
  • exemplary additional agents may include, but are not limited to, a beta-adrenergic agonist (e.g., a beta2-agonist (e.g., salbutamol, epinephrine, ritodrine, procaterol, pirbuterol, isoetarine, clenbuterol, terbutaline, metaproterenol, isoproterenol, formoterol, fenoterol, or levosalbutamol)), an anticholinergic agent (e.g., an antimuscarinic agent (e.g., atropine, benzatropine, tropicamide, solifenacin, trihexyphenidyl, tiotropium, tolterodine, oxybutynin, oxitropium, orphenadrine, ipratropium, hydroxyzine, glycopyrrolate, doxylamine, diphenhydramine, dimenhydrinate, dicyclomine, chlorpheniramine
  • the combination of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof and the additional agent has a synergistic or additive effect.
  • additive refers to an outcome wherein when two agents are used in combination, the combination of the agents acts in a manner equal to but not greater than the sum of the individual anti-PDE4 activity of each agent.
  • the terms “synergy” or “synergistic” refer to an outcome wherein when two agents are used in combination, the combination of the agents acts so as to require a lower concentration of each individual agent than the concentration required to be efficacious in the absence of the other agent.
  • a synergistic effect results in a reduced in a reduced minimum inhibitory concentration of one or both agents, such that the effect is greater than the sum of the effects.
  • a synergistic effect is greater than an additive effect.
  • the agents in the composition herein may exhibit a synergistic effect, wherein the anti-PDE4 activity at a particular concentration is greater than at least about 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 10, 12, 15, 20, 25, 50, or 100 times the anti-PDE4 activity of either agent alone.
  • the present invention features compounds (e.g., compounds of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) and compositions for the inhibition of PDE4, as well as methods of treating and preventing a PDE4-mediated disease, such as an inflammatory or neurodegenerative disease.
  • methods for treating a subject suffering from a PDE4-mediated disease comprise administering a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to the subject.
  • the methods described herein may further comprise administration of a composition of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof combined with one or more pharmaceutically acceptable diluents, excipients, or carriers.
  • the compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine.
  • the compounds included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof).
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into a pharmaceutically acceptable dosage form such as described below or by other conventional methods known to those of skill in the art.
  • compositions as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in the pharmaceutical compositions, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions.
  • compositions comprising a therapeutically effective amount or prophylactic aly effective amount of a composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • pharmaceutically acceptable carriers additives
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for oral or parenteral administration, for example, by oral dosage, or by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension.
  • the subject compounds may be simply dissolved or suspended in sterile water.
  • the pharmaceutical preparation is non-pyrogenic, i.e., does not elevate the body temperature of a patient.
  • systemic administration means the administration of the compound other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, oral, intranasal, or subcutaneous administration.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, stabilizing agent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, stabilizing agent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide, such
  • certain embodiments of the compounds described herein may contain a basic functional group, such as an amine, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts without limitation include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, trifluoroacetate, and laurylsulphonate salts and the like (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1- 19).
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of the compound of the present invention (e.g., a compound of Formula (I) or Formula (II)). These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine,
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated
  • hydroxyanisole BHA
  • butylated hydroxytoluene BHT
  • lecithin propyl gallate
  • metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • EDTA ethylenediamine tetraacetic acid
  • the pharmaceutically acceptable carriers, as well as wetting agents, emulsifiers, lubricants, coloring agents, release agents, coating agents, sweetening, flavoring agents, perfuming agents, preservatives, antioxidants, and other additional components may be present in an amount between about 0.001% and 99% of the composition described herein.
  • said pharmaceutically acceptable carriers as well as wetting agents, emulsifiers, lubricants, coloring agents, release agents, coating agents, sweetening, flavoring agents, perfuming agents, preservatives, antioxidants, and other additional components may be present from about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 85%, about 90%, about 95%, or about 99% of the composition described herein.
  • compositions of the present invention may be in a form suitable for oral administration, e.g., a liquid or solid oral dosage form.
  • the liquid dosage form comprises a suspension, a solution, a linctus, an emulsion, a drink, an elixir, or a syrup.
  • the solid dosage form comprises a capsule, tablet, pill, dragee, powder, or microencapsulated dose form.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • compositions may comprise, in addition to the compounds described herein (e.g., a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and may optionally further comprise one or more pharmaceutically acceptable excipients, such as, for example, stabilizers (e.g., a binder, e.g., polymer, e.g., a precipitation inhibitor, diluents, binders, and lubricants.
  • stabilizers e.g., a binder, e.g., polymer, e.g., a precipitation inhibitor, diluents, binders, and lubricants.
  • the composition described herein comprises a liquid dosage form for oral administration, e.g., a solution or suspension.
  • the composition described herein comprises a solid dosage form for oral administration capable of being directly compressed into a tablet.
  • said tablet may include other medicinal or pharmaceutical agents, carriers, and or adjuvants.
  • Exemplary pharmaceutical compositions include compressed tablets (e.g., directly compressed tablets), e.g., comprising compounds of the present invention (e.g., a compound of Formula (I) or Formula (II)) or pharmaceutically acceptable salts thereof.
  • the composition described herein comprises a liquid dosage form for inhalation or intranasal administration, e.g., a spray, a solution, a nebulized formulation, or a suspension.
  • the composition provided for inhalation or intranasal administration is provided as a solid dosage form (e.g., a powder) for inhalation or intranasal administration, which may be combined with a liquid prior to administration by a subject.
  • said formulations may include other medicinal or pharmaceutical agents, carriers, and or adjuvants to provide certain desired properties, e.g., to aid in absorption by the lungs or nasal passages, enhance stability of the composition, or aid in solubility of the active agents in a liquid prior to administration.
  • Formulations of the present invention include those suitable for parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • compositions of this invention suitable for parenteral administration comprise compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacterio stats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • a composition comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • delayed absorption of a parenterally administered form of the compound of the present invention is accomplished by dissolving or suspending compound in an oil vehicle.
  • compositions of the present invention may be advantageous to administer the compound (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof) and compositions of the present invention in a sustained fashion.
  • a sustained absorption profile may be used.
  • sustained absorption may be achieved by combining a compound of the present invention with other pharmaceutically acceptable ingredients, diluents, or carriers that slow its release properties into systemic circulation.
  • compositions used in the methods described herein may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • routes of administration include topical, enteral, or parenteral applications.
  • Topical applications include but are not limited to epicutaneous, inhalation, enema, eye drops, ear drops, and applications through mucous membranes in the body.
  • Enteral applications include oral administration, rectal administration, vaginal administration, and gastric feeding tubes.
  • Parenteral administration includes
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • compositions described herein comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof are administered orally.
  • the compositions described herein comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof are administered intravenously.
  • the compositions described herein comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof are administered intranasally (e.g., by administration into the nasal passage).
  • the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition. Long-term absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • the choice of the route of administration will depend on whether a local or systemic effect is to be achieved.
  • the composition can be formulated for topical administration and applied directly where its action is desired.
  • the composition can be formulated for enteral administration and given via the digestive tract.
  • the composition can be formulated for parenteral administration and given by routes other than through the digestive tract.
  • a composition described herein e.g., a composition of comprising a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • the composition may be provided as a nebulized formulation with a suitable device to enable local delivery into the lungs or nasal passage (e.g., through a spray device or an inhaler).
  • compositions of the present invention are formulated into acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the compositions of the present invention e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of absorption of the particular agent being employed, the duration of the treatment, other drugs, substances, and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the composition required. For example, the physician or veterinarian can start doses of the substances of the invention employed in the composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a composition of the invention will be that amount of the substance which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of a therapeutic composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • Preferred therapeutic dosage levels are between about 0.1 mg/kg to about 1000 mg/kg (e.g. , about 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg) of the composition per day administered (e.g., orally) to a subject afflicted with the disorders described herein (e.g.
  • Preferred prophylactic dosage levels are between about 0.1 mg/kg to about 1000 mg/kg (e.g. , about 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg) of the composition per day administered (e.g., orally) to a subject.
  • the dose may also be titrated (
  • the frequency of treatment may also vary.
  • the subject can be treated one or more times per day (e.g., once, twice, three, four or more times) or every so-many hours (e.g., about every 2, 4, 6, 8, 12, or 24 hours).
  • the composition can be administered 1 or 2 times per 24 hours.
  • the time course of treatment may be of varying duration, e.g., for two, three, four, five, six, seven, eight, nine, ten, or more days, two weeks, 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, or more than one year.
  • the treatment can be twice a day for three days, twice a day for seven days, twice a day for ten days.
  • Treatment cycles can be repeated at intervals, for example weekly, bimonthly or monthly, which are separated by periods in which no treatment is given.
  • the treatment can be a single treatment or can last as long as the life span of the subject (e.g., many years).
  • a patient and/or subject can be selected for treatment using a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof by first evaluating the patient and/or subject to determine whether the subject is suffering from a disease or symptom of a disease described herein (e.g., an inflammatory or neurodegenerative disease).
  • a disease or symptom of a disease described herein e.g., an inflammatory or neurodegenerative disease
  • a subsequent step may entail a determination of the severity of the symptoms of the disease using standard diagnostic protocols and methods known in the art.
  • the subject can also be monitored, for example, subsequent to administration of a composition described herein (e.g., a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof).
  • the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject has been diagnosed with a disease or disorder. In some embodiments, the subject is diagnosed with an inflammatory disease (e.g., an inflammatory disease described herein). In other embodiments, the subject is diagnosed with an autoimmune disease (e.g., an autoimmune disease described herein). In still other embodiments, the subject is diagnosed with a neurodegenerative disease (e.g., a neurodegenerative disease described herein).
  • a disease or disorder e.g., the subject is diagnosed with an inflammatory disease (e.g., an inflammatory disease described herein). In other embodiments, the subject is diagnosed with an autoimmune disease (e.g., an autoimmune disease described herein). In still other embodiments, the subject is diagnosed with a neurodegenerative disease (e.g., a neurodegenerative disease described herein).
  • the subject is treatment naive.
  • the subject has previously been treated for a disease or disorder described herein (e.g., an inflammatory, autoimmune, or neurodegenerative disease).
  • the subject is suffering from a relapsed disease or disorder described herein (e.g., an inflammatory, autoimmune, or neurodegenerative disease).
  • the subject has been treated with an antiinflammatory agent other than a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof and is suffering from a relapsed or worsening of an inflammatory disease.
  • the subject has been treated with an anti-autoimmune agent other than a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof and is suffering from a relapsed or worsening of an autoimmune disease.
  • the subject has been treated with an agent known to mitigate the effects of a neurodegenerative disease other than a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof and is suffering from a relapsed or worsening of a neurodegenerative disease.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in Greene et ah, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • Example 1 Synthesis of (lS,2S)-2-(6-((benzo[d]thiazol-2-ylmethyl)amino)-2- (methylsulfonyl)-9H-purin-9-yl)cyclohexan-l-ol (Compound 5), (lS,2R)-2-(6- ((benzo[d]thiazol-2-ylmethyl)amino)-2-(pyrrolidin-l-yl)-9H-purin-9-yl)cyclohexan-l-ol (Compound 6), (S)-2-(6-((benzo[d]thiazol-2-ylmethyl)amino)-2-(methylsulfonyl)-9H-purin- 9-yl)cyclohexan-l-one (Compound 9) and (S)-2-(6-((benzo[d]thiazol-2-ylmethyl)amino)-2- (pyrrolidin-l-yl)-9H-purin
  • Example 2 Synthesis of (lS,2S)-2-(6-((benzo[d]thiazol-2-ylmethyl)amino)-2- (methylsulfonyl)-9H-purin-9-yl)cyclohexan-l-ol (Compound 7), (lS,2S)-2-(6- ((benzo[d]thiazol-2-ylmethyl)amino)-2-(pyrrolidin-l-yl)-9H-purin-9-yl)cyclohexan-l-ol (Compound 8), (S)-2-(6-((benzo[d]thiazol-2-ylmethyl)amino)-2-(methylsulfonyl)-9H-purin- 9-yl)cyclohexan-l-one (Compound 11), (S)-2-(6-((benzo[d]thiazol-2-ylmethyl)amino)-2- (pyrrolidin-l-yl)-9H-purin-9
  • reaction mixture was then diluted with DCM (25 mL) and washed with water (3 x 20 mL) and brine (20 mL), and the combined organic layers were dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to give a crude residue, that was purified by silica gel column chromatography (60% EtOAc in DCM) to give 70 mg of pure intermediate 16 as white solid.
  • Compound 49 (i.e., intermediate 3) was used for further nucleophilic substitution with different amines at the 2 position on the bicyclic core as shown in Scheme 11 below to provide exemplary compounds of the invention, e.g., 9-(benzo[d]thiazol-2-ylmethyl)-N-methyl-6-(pyrrolidin-l-yl)- 9H-purin-2- amine (Compound 48, Intermediate 4a), 4-(9-(benzo[d]thiazol-2-ylmethyl)-6- (pyrrolidin-l-yl)-9H-purin-2-yl)morpholine (Compound 50, Intermediate 4b), 4-(9- (benzo[d]thiazol-2-ylmethyl)-6-(pyrrolidin-l-yl)-9H-purin-2-yl)piperazin-2-one (Compound 39, Intermediate 4c), 9-(benzo[d]thiazol-2-ylmethyl)-N,N-dimethyl-6-(pyrrolidin-
  • Example 12 Synthesis of 4-(9-(benzo[d]thiazol-2-ylmethyl)-6-(pyrrolidin-l-yl)-9H-purin-2- yl)piperazin-2-one (Compound 39), Intermediate 4c, and 9-(benzo[d]thiazol-2-ylmethyl)- N,N-dimethyl-6-(pyrrolidin-l-yl)-9H-purin-2-amine (Compound 51), Intermediate 4d
  • Example 14 Synthesis of 2-Chloro-6-(Pyrrolidin-l-yl)-7-Deazapurine (Compound 57) To a solution of 2, 6-dichloro-7-deazapurine (200 mg, 1 mmol) 1-butanol (5ml) was added at room temperature, followed by the slow addition of stirring pyrrolidine (0.2 ml, 2.3 mmol). The reaction was stirred for 3 h at room temperature until TLC analysis (DCM: EtOAc 7:3) indicated it was complete. The reaction mixture was concentrated, co-evaporated with acetonitrile, and treated with hexanes.
  • the phosphodiesterase inhibition assay is performed using the PDE-Glo Phosphodiesterase Assay kit (Promega; Cat. No. V1361) and PDE4B 1 enzyme ((BPS Bioscience, 60041 ).
  • the assay is designed to evaluate the inhibitory effects of compounds on PDE reaction between pure PDE4B 1 and a cyclic nucleotide substrate (cAMP).
  • the principle of the assay is based on the assumption that remaining cAMP after PDE reaction can bind and release an active Protein kinase A subunit which then catalyzes phosphorylation of the PKA substrate leading to a reduction in ATP level (present in the detection buffer).
  • lucif erase activity can be measured by adding Kinase-Glo reagent where luminescent signal produced is indirectly related to the activity of PDE4B 1.
  • the IC 50 was then determined by plotting the results in XLfit.
  • L refers to a value greater than 85%
  • M refers to a value between 60% and 85%
  • N refers to a value between 35% and 60%
  • O refers to a value between 15% to 35%
  • P refers to a value between 0% and 15%. In both cases, “ND” refers to a value that was not determined.
  • IC 50 values of exemplary compounds of the invention were determined to gauge selectivity of the compounds against various PDE4 isoforms in comparison with a control.
  • Table 3 summarizes the results of these assays, using the same grading scheme as that outlined above for Table 2.
  • PBMCs Peripheral Blood Mononuclear Cells
  • RPMI complete medium RPMI 1640, 10 % fetal bovine serum, 100 U-mL "1 penicillin, 100 mg
  • Example 18 Metabolic stability in liver microsomes and S9 fractions
  • M liver microsomes
  • S9 fractions S9 fractions
  • the reactions were initiated with 20mM NADPH and quenched with addition of 1ml acetonitrile. The supernatant was collected after snap freezing and centrifuging @ 4°C for 5 min followed by analysis in HPLC. The data was plotted and the half-life values (Ti /2 ) were calculated in Xlfit and are summarized in Table 5 below.
  • A refers to a T 2 of greater than 6 hrs;
  • B refers to Ti /2 of less than 6 hrs and more than 1 hr;
  • C refers to a T 2 of less than 1 hr and more than 0.5 hr;
  • D refers to a T 2 of less than 0.5 hr.
  • Exemplary compounds were incubated with either rabbit, rat, or mouse serum for various time periods at 37°C. The reactions were quenched with addition of 1ml acetonitrile. The supernatant was collected after snap freezing and centrifuging @ 4°C for 5 min followed by analysis in HPLC. The data was plotted and the half-life values (Ti /2 ) were calculated in Xlfit.

Abstract

La présente invention concerne des composés (par exemple, un composé de Formule (I) ou de Formule (II) ou un sel pharmaceutiquement acceptable de celui-ci) et des compositions destinées à être utilisées pour moduler le PDE4 ainsi que pour prévenir et traiter une maladie à médiation par le PDE4 chez un sujet.
PCT/US2017/013201 2016-01-12 2017-01-12 Composés et compositions pour le traitement d'une maladie WO2017123766A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020116971A1 (fr) * 2018-12-06 2020-06-11 한국화학연구원 Composés ayant une activité inhibitrice de pde9a et leurs utilisations pharmaceutiques
RU2788147C2 (ru) * 2018-12-06 2023-01-17 Корея Рисерч Институт Оф Кемикал Текнолоджи Соединения, обладающие ингибирующей активностью по отношению к pde9a, и их фармацевтическое применение

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6228859B1 (en) * 1997-12-12 2001-05-08 Euro-Celtique S.A. Purine derivatives having phosphodiesterase IV inhibition activity
US6319928B1 (en) * 1998-11-30 2001-11-20 Euro-Celtique, S.A. Purine derivatives having phosphodiesterase IV inhibition activity
US20080125446A1 (en) * 2001-10-30 2008-05-29 Conforma Therapeutics Corporation Purine analogs having HSP90-inhibiting activity
US20080280926A1 (en) * 2003-12-16 2008-11-13 Palle Venkata P Phosphodiesterase Inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6228859B1 (en) * 1997-12-12 2001-05-08 Euro-Celtique S.A. Purine derivatives having phosphodiesterase IV inhibition activity
US6319928B1 (en) * 1998-11-30 2001-11-20 Euro-Celtique, S.A. Purine derivatives having phosphodiesterase IV inhibition activity
US20080125446A1 (en) * 2001-10-30 2008-05-29 Conforma Therapeutics Corporation Purine analogs having HSP90-inhibiting activity
US20080280926A1 (en) * 2003-12-16 2008-11-13 Palle Venkata P Phosphodiesterase Inhibitors

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM [O] NCBI; 25 October 2006 (2006-10-25), XP055401875, Database accession no. 10060615 *
DATABASE PUBCHEM [O] NCBI; 30 November 2012 (2012-11-30), XP055401868, Database accession no. 68455742 *
DATABASE PUBCHEM [O] NCBI; 8 February 2007 (2007-02-08), XP055401874, Database accession no. 12777820 *
DATABASE PUBCHEM NCBI; 11 February 2007 (2007-02-11), XP055401886, Database accession no. 117084947 *
DATABASE PUBCHEM NCBI; 25 October 2006 (2006-10-25), XP055401884, Database accession no. 10586466 *
DATABASE PUBCHEM NCBI; 26 March 2005 (2005-03-26), XP055401865, Database accession no. 95121 *
DATABASE PUBCHEM NCBI; 7 December 2009 (2009-12-07), XP055401879, Database accession no. 44475537 *
DATABASE PUBCHEM NCBI; 8 February 2007 (2007-02-08), XP055401870, Database accession no. 12918096 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020116971A1 (fr) * 2018-12-06 2020-06-11 한국화학연구원 Composés ayant une activité inhibitrice de pde9a et leurs utilisations pharmaceutiques
CN113166161A (zh) * 2018-12-06 2021-07-23 韩国化学研究院 具有pde9a抑制活性的化合物及其药物用途
EP3892623A4 (fr) * 2018-12-06 2022-07-06 Korea Research Institute of Chemical Technology Composés ayant une activité inhibitrice de pde9a et leurs utilisations pharmaceutiques
RU2788147C2 (ru) * 2018-12-06 2023-01-17 Корея Рисерч Институт Оф Кемикал Текнолоджи Соединения, обладающие ингибирующей активностью по отношению к pde9a, и их фармацевтическое применение
CN113166161B (zh) * 2018-12-06 2023-10-27 韩国化学研究院 具有pde9a抑制活性的化合物及其药物用途

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