WO2011139273A1 - Pyrazolopyrimidines 4-substituées pouvant être employées en tant qu'inhibiteurs de pkc-thêta - Google Patents

Pyrazolopyrimidines 4-substituées pouvant être employées en tant qu'inhibiteurs de pkc-thêta Download PDF

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WO2011139273A1
WO2011139273A1 PCT/US2010/033711 US2010033711W WO2011139273A1 WO 2011139273 A1 WO2011139273 A1 WO 2011139273A1 US 2010033711 W US2010033711 W US 2010033711W WO 2011139273 A1 WO2011139273 A1 WO 2011139273A1
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independently
compound
halogen
optionally
aliphatic
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PCT/US2010/033711
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Juan-Miguel Jimenez
Andrew Miller
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Vertex Pharmaceuticals Incorporated
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Priority to CN201080030395XA priority Critical patent/CN102471342A/zh
Priority to CA2761074A priority patent/CA2761074A1/fr
Priority to JP2013509037A priority patent/JP2013525481A/ja
Priority to EP10721216A priority patent/EP2566866A1/fr
Priority to AU2010352577A priority patent/AU2010352577A1/en
Priority to MX2011011712A priority patent/MX2011011712A/es
Priority to PCT/US2010/033711 priority patent/WO2011139273A1/fr
Priority to US13/289,300 priority patent/US20120172379A1/en
Publication of WO2011139273A1 publication Critical patent/WO2011139273A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/00—Drugs for dermatological disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • protein kinases mediate intracellular signaling by affecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g. shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a), and growth factors (e.g.
  • environmental and chemical stress signals e.g. shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2
  • cytokines e.g. interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a
  • growth factors e.g.
  • GM-CSF granulocyte macrophage-colony stimulating factor
  • FGF fibroblast growth factor
  • kinases may be categorized into families by the substrates they phosphorylate (e.g.
  • PKC-theta protein kinase C-theta
  • PKC-theta Upon antigen stimulation of T cells, PKC-theta, but not other PKC isoforms, rapidly translocates from the cytoplasm to the site of cell contact between the T cell and antigen-presenting cell (APC), where it localizes with the T cell receptor (TCR) in a region termed the central supramolecular activation cluster (cSMAC) (Monks et al., 1997, Nature, 385: 83-86; Monks et al., 1998, Nature, 395: 82-86).
  • APC antigen-presenting cell
  • PKC-theta catalytic domain-Lck membrane-binding domain chimera was able to reconstitute signaling (Bi et al., 2001, Nat. Immunol., 2:556-563).
  • PKC-theta-deficient mice More recently, studies in PKC-theta-deficient mice have indicated a role for PKC-theta in the development of mouse models of autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA) and irritable bowel disease (IBD) (Salek-Ardakani et al., 2006; Tan et al., 2006; Healy et al., 2006; Anderson et al, 2006). In these models, PKC-theta-deficient mice exhibited a marked reduction in disease severity that was associated with a profound defect in the development and effector function of autoreactive T cells.
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • IBD irritable bowel disease
  • PKC-theta In addition to its role in T cell activation, PKC-theta is reported to mediate the phorbol ester-triggered survival signal that protects T cells from Fas- and UV-induced apoptosis (Villalba et al., 2001, J. Immunol. 166: 5955-5963; Berttolotto et al., 2000, 275: 37246-37250).
  • PKC-theta deficient mice elicit normal Thl and cytotoxic T cell-mediated responses to several viral infections and the protozoan parasite, Leishmania major and effectively clear these infections (Marsland et al., 2004; Berg-Brown et al., 2004; Marsland et al., 2005;
  • mice are unable to wage normal Th2 T cell responses against the parasite Nippostrongylus brasiliensis and certain allergens (Marsland et al., 2004; Salek-Ardakani et al., 2004) and are unable to clear Listeria monocytogenes infection (Sakowicz-Burkiewicz et al., 2008).
  • PKC-theta in T cell activation can be bypassed and this is likely to involve the provision of additional signals to T cells, either from cells of the innate immune system, or directly from the pathogen in the form of pathogen associated molecular patterns (PAMPs) (Marsland et al., 2007).
  • PAMPs pathogen associated molecular patterns
  • PKC-theta-deficient mice exhibited a marked reduction in disease severity that was associated with a profound defect in the development of a newly discovered class of T cells, Thl7 cells (Salek-Ardakani et al., 2006; Tan et al., 2006; Healy et al., 2006; Anderson et al., 2006; Nagahama et al., 2008).
  • PKC-theta therefore appears to be essential for the development of pathogenic auto-reactive Thl 7 cells in the context of autoimmunity. These observations support the notion that targeting PKC-theta will provide a way to target autoimmune T cell responses, leaving many T cell responses (e.g., to viral infections) intact.
  • This invention provides, in general, compounds that are useful as kinase inhibitors.
  • the compounds of the present invention are represented by a structural formula a I or IA:
  • a and A' are independently -N- or -C(R + )-.
  • Ring B is five- or six-membered saturated carbocyclic or heterocyclic ring.
  • Ri is halogen, -CN, -N0 2 , or -Tl-Ql.
  • Tl is absent or a Cl-10 aliphatic wherein one or more methylene units of Tl are optionally and independently replaced by G wherein G is -0-, -S(0) p -, -N(R')-, or -C(O)-; and Tl is optionally and independently substituted with one or more JTI .
  • Ql is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, or an 8-12 membered saturated, partially saturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from the group consisting of 0, N, and S, wherein Ql is optionally and independently substituted with one or more JQI; wherein when Ri is Tl-Ql, then TI and Ql are not both absent.
  • R 2 is -H, -(CR" 2 ) procurC(0)N(R*) 2 , -(CR ++ 2 ) n OR*, -(CR ++ 2 ) n N(R*) 2 ,
  • Each R3 and R4 independently are -H, halogen, Cl-10 aliphatic, heterocyclyl,
  • R3 and R4 are optionally and independently substituted with one or more selected from the group consisting of Cl-10 alkyl, halogen, -CN, -N0 2 , -N(R*) 2 , -S(0) p R ⁇ -S(0) p NR*, -C(0)N(R * ) 2 , -NR*C(0), -OC(0)N(R*) 2 , -N(R*)C(0)OR*,
  • Each R5 is independently -H, halogen, Cl-10 haloaliphatic, or Cl-10 aliphatic.
  • Each R7 is independently Cl-10 haloaliphatic, Cl-10 aliphatic, halogen, -N0 2 ,
  • Each JTI is independently halogen, -OR , -N(R") 2 , or -CN.
  • Each JQI is independently halogen, Cl-10 alkyl, Cl-10 haloalkyl, -OR", -N(R")2, -CN, - N0 2 , -S(0) p R “ , -S(0) p NR “ , -C(O) N(R")2, -N(R")C(0)R", acyl, carbalkoxyalkyl, or acetoxyalkyl.
  • Each R + is independently -H, halogen, or Cl-10 alkyl optionally and independently substituted with up to five halogen groups.
  • Each is independently -H or halogen.
  • Each R' is independently -H or Cl-10 alkyl optionally and independently substituted with up to five halogen groups.
  • Each R" is independently -H, Cl-10 alkyl, or aralkyl wherein each R * is optionally and independently substituted with up to five halogen groups.
  • Each R" is independently -H or Cl-10 alkyl optionally and independently substituted with up to five halogen groups.
  • Each R* is independently -H or C-10 alkyl or aralkyl optionally and independently substituted with up to five halogen groups.
  • Each R* * is independently -H or Cl-10 alkyl optionally and independently substituted with up to five halogen groups.
  • x is 0 or 1.
  • Each n is independently 0, or 1-10.
  • Each p is independently 0, 1, or 2.
  • the present invention is a method of treating or preventing protein kinase-mediated condition in a subject, comprising administering to the subject an effective amount of a compound or composition of the present invention.
  • the present invention is the manufacture of a compound or composition of the present invention for use in treating or preventing a protein kinase-mediated condition in a subject.
  • the compounds and compositions of the present invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of hew kinase inhibitors.
  • This invention relates to compounds and compositions (such as, pharmaceutical compositions) useful as protein kinase inhibitors.
  • the compounds and compositions of the present invention are effective as inhibitors of P Ctheta.
  • the compounds of the present invention are represented by a structural formula I and IA as described above.
  • the compounds of the present invention are represented by Formula I.
  • the compounds of the present invention are represented by Formula IA.
  • A is -N- or -C(R + )-; and A' is -C(R + )- and the remainder of the variables are as described above.
  • Tl is absent or a C 1-10 aliphatic wherein up to three methylene units of Tl are optionally and independently replaced by G wherein G is -0-, -N(R')-, or -C(O)-; and Tl is optionally and independently substituted with one or more JTI.
  • Ql is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of 0, N, and S, wherein Ql is optionally and independently substituted with one or more JQI and the remainder of the variables are as described above for the fourth embodiment.
  • each R3 and R4 independently is -H, Cl-10 aliphatic, cycloalkylalkyl, wherein R 3 and R4 are optionally and independently substituted with one or more selected from the group consisting of halogen, -CN, -NO2, -N(R * ) 2 , and -OR * ; or
  • R 2 is -H, - (CR ++ 2 ) n OR*, -(CR ++ 2 ) n N(R*) 2 , or Cl-3 aliphatic optionally substituted with one or more halogen and the remainder of the variables are as described above for the tenth embodiment.
  • R.2 is -H, -(CR ++ 2) n CN, - (CR ++ 2) n OR*, -(CR ++ 2 ) n N(R*) 2 , or Cl-3 aliphatic optionally substituted with one or more halogen.
  • R ⁇ is -H, -(CR ++ 2) n CN, - -(CR ++ 2)nN(R*) 2 , or Cl-3 aliphatic optionally substituted with one or more halogen.
  • R3 and R 4 taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and
  • R2 is -H, -(CR ++ 2) n CN, - (CR ++ 2 )nOR*, -(CR ++ 2) n N(R*)2, or Cl-3 aliphatic optionally substituted with one or more halogen.
  • R 2 is -H, -(CR ++ 2 ) n CN, -(CR ⁇ OR*, -(CR ++ 2 )nN(R*) 2 , or Cl-3 aliphatic optionally substituted with one or more halogen.
  • Each R3 and R4 independently is -H, Cl-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R3 and R4 are optionally and independently substituted with one or more selected from the group consisting of halogen, -CN,
  • IA and IC R5 is -H, CI, CI -4 haloalkyl, or CI -4 alkyl and the remainder of the variables are as described above for the fifteenth, sixteenth or seventeenth embodiments.
  • IA and IC R5 is -H, CI, trifluoromethyl, methyl, ethyl, or cyclopropyl and the remainder of the variables are as described above for the eighteenth embodiment.
  • IA and IC R5 is trifluoromethyl and the remainder of the variables are as described above for the nineteenth embodiment.
  • ring B is five- or six-membered saturated carbocyclic ring and the remainder of the variables are as described above for the sixth embodiment.
  • A is -C(R + )-.
  • JTI is -OR * .
  • Each J Q ) is independently Cl-10 alkyl, -OR", -N(R") 2 , or acyl.
  • Ring B is five-membered saturated carbocyclic ring and the remainder of the variables are as described above for the twenty second embodiment.
  • one or more means, for example, that all substitutable carbon atoms can be substituted, for example, up to 6 carbons atoms, up to 5 carbon atoms, up to 3 carbon atoms, up to 2 carbon atoms, or one carbon atom can be substituted.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, recovery, storage, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched), branched, or cyclic hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation but is non-aromatic. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms.
  • aliphatic groups may be linear or branched.
  • alkyl as used herein means a saturated straight, branched or cyclic hydrocarbon.
  • alkenyl as used herein means a straight or branched chain hydrocarbon comprising one or more double bonds.
  • alkynyl as used herein means a straight or branched chain hydrocarbon comprising one or more triple bonds.
  • alkyl, alkenyl and alkynyl groups contain 1-20 carbon atoms. In some embodiments, alkyl, alkenyl and alkynyl groups contain 1-10 carbon atoms. In other embodiments, alkyl, alkenyl and alkynyl groups contain 1-8 carbon atoms. In still other embodiments, alkyl, alkenyl and alkynyl groups contain 1-6 carbon atoms, and in yet other embodiments alkyl, alkenyl and alkynyl groups contain 1-4 carbon atoms.
  • cycloaliphatic refers to a non-aromatic monocyclic or polycyclic carbon containing ring which can be saturated or contain one or more units of unsaturation, having three to fourteen ring carbon atoms.
  • the term includes polycyclic fused, spiro or bridged carbocyclic ring systems wherein the radical or point of attachment is on the carbocyclic ring.
  • the term also includes polycyclic ring systems in which the carbocyclic ring can be attached to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the carbocyclic ring.
  • Fused bicyclic ring systems comprise two rings which share two adjoining ring atoms
  • bridged bicyclic group comprise two rings which share three or four adjacent ring atoms
  • spiro bicyclic ring systems share one ring atom.
  • Examples of cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropentyl, and cyclobutyl.
  • heterocyclic refers to a non-aromatic monocyclic or polycyclic ring which can be saturated or contain one or more units of unsaturation, having three to fourteen ring atoms in which one or more ring carbons is replaced by a heteroatom such as, N, S, or O.
  • heteroatom such as, N, S, or O.
  • the term includes polycyclic fused, spiro or bridged heterocyclic ring systems wherein the radical or point of attachment is on the heterocyclic ring.
  • the term also includes polycyclic ring systems in which the heterocyclic ring can be attached to one or more non- aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring.
  • heterocycles include, but are not limited to, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azetidinylazocanyl, diazocanyl, triazocanyl, oxazolidinyl, oxetenyl, isoxazolidinyl, thiazolidinyl, imidazolinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrofuranyl,
  • tetrahydrothiophenyl tetrahydropyranyl, tetrahydrothiophenyl, morpholirio, including, for example, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1- pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3- tetrahydropiperazinyl, 1 -piperidinyl, 2-piperidinyl, 3 -piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4- pyrazolinyl, 5-pyrazolinyl, 1 -piperidinyl, 2-piperidinyl, 3 -piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1
  • alkoxy refers to an alkyl group, as defined herein, attached to the molecule through an oxygen (“alkoxy” e.g., -O-alkyl) or sulfur (“thioalkyl” e.g., -S-alkyl) atom.
  • haloalkyl haloalkenyl
  • '3 ⁇ 4aloaliphatic haloalkenyl
  • 'Tialoalkoxy haloalkoxy
  • aminoalkyl '3 ⁇ 4ydroxyalkyl
  • haloalkyl mean alkyl, alkenyl, aliphatic, or alkoxy, as the case may be, substituted with one or more halogen atoms (or amino or hydroxy).
  • haloalkyl etc. include, mono- di- and tri- halo substituted groups. In particular, these terms include perfluorinated alkyl groups, such as -CF 3 and -CF 2 CF 3 .
  • acyl group means -C(0)R wherein R is an aliphatic groups as defined herein, or an aryl group as defined herein.
  • Bicyclic 6,5 heteroaromatic ring as used herein, for example, is a six membered heteroaromatic ring fused to a second five membered ring, wherein the radical or point of attachment is on the six membered ring.
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, for example, 2-furanyl, 3- furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-oxadiazolyl, 5 -oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolylj 4- pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyr
  • isoquinolinyl e.g., 1 -isoquinolinyl, 3 -isoquinolinyl, or 4-isoquinolinyl.
  • aralkyl refers to alkyl groups as defined herein substituted with aryl, heteroaryl, cycloaliphatic, or heterocyclic groups respectively.
  • a protecting group and “protective group” as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites.
  • a protecting group has one or more, or preferably all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound.
  • the reagents may also react with other reactive groups in the compound.
  • protecting groups are detailed in Greene, T.W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book), the entire contents of which are hereby incorporated by reference.
  • nitrogen protecting group refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound.
  • Preferred nitrogen protecting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • a methylene unit of an aliphatic group or alkyl group is optionally replaced with another atom or group.
  • the replacement atom is bound to an H on the terminal end.
  • the replacement atom is bound to an H on the terminal end.
  • the resulting compound could be - ⁇ 0 ⁇ 2 (%, -CH 2 OCH 3 , or
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric, conformational, and rotational) forms of the structure.
  • isomeric e.g., enantiomeric, diastereomeric, geometric, conformational, and rotational
  • the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention.
  • a substituent can freely rotate around any rotatable bonds.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Therefore, where it is not indicated that a compound or group is substituted, it is understood that the group is not substituted. That is, if the terms "optionally substituted” or “substituted” is not present in an instance of the definition of a compound or group it is understood that the compound or group is not substituted in that instance.
  • Ri is alkyl
  • Rii is optionally substituted alkyl
  • Riiii is alkyl optionally substituted with halo
  • a "substitutable ring atom" in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom.
  • the hydrogen can be optionally replaced with a suitable substituent group.
  • substituted ring atom does not include ring nitrogen or carbon atoms which are shared when two rings are fused.
  • substituted ring atom does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen, or when the structure depicts they are already bound by a hydrogen.
  • An optionally substituted aryl group as defined herein contains one or more substitutable ring atoms, which may be optionally bonded to one or more suitable substituent.
  • suitable substituents on a substitutable ring carbon atom of an aryl group includes Rk.
  • Rk is -Ra, - Br, -CI, -I, -F, -ORa, -SRa, -O-CORa, -CORa, -CSRa, -CN, -N0 2 , -NCS, -S0 3 H, -N(RaRb), - COORa, -NRcNRcCORa, -NRcNRcC0 2 Ra, -CHO, -CON(RaRb), -OC(0)N(RaRb), -CSN(RaRb), -NRcCORa, -NRcCOORa, -NRcCSRa, -NRcCON(RaRb), -NRcNRcC(0)N(RaRb),
  • Ra-Rd are each independently -H, an aliphatic group, aromatic group, non-aromatic carbocyclic or heterocyclic group or -N(RaRb), taken together, form a non-aromatic heterocyclic group.
  • the aliphatic, aromatic and non-aromatic heterocyclic group represented by Ra-Rd and the non-aromatic heterocyclic group represented by -N(RaRb) are each optionally and independently substituted with one or more groups represented by RJ.
  • Ra-Rd are unsubstituted.
  • R m is -H, a C1-C4 alkyl group, a monocyclic aryl group, a non-aromatic carbocyclic or heterocyclic group each optionally substituted with unsaubsituted alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, -CN, -N0 2 , amine, alkylamine or dialkylamine.
  • R m is unsubstituted.
  • An optionally substituted aliphatic or a non-aromatic heterocyclic or carbocyclic group as defined herein contains one or more substitutable atoms which may optionally be bonded to one or more suitable substituents.
  • suitable substituents for an aliphatic group or a ring carbon of a non-aromatic heterocyclic group is Rn.
  • Each Ro is independently selected from hydrogen, an unsubstituted alkyl group or a substituted alkyl group.
  • substituents on the alkyl group represented by Ro include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
  • Preferably Ro is unsubstituted.
  • heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted as indicated herein.
  • nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.
  • non-aromatic nitrogen-containing heterocyclic group or heteroaryl groups are optionally substituted at the nitrogen ring atom.
  • substituents on the group represented by R A include alkyl, haloalkoxy, haloalkyl, alkoxyalkyl, sulfonyl, alkylsulfonyl, halogen, nitro, cyano, hydroxy, aryl, carbocyclic or heterocyclic ring, oxo, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, carboxy, alkoxycarbonyl, or alkylcarbonyl.
  • R A is not substituted.
  • Non-aromatic nitrogen containing heterocyclic rings and heteroaryl that are substituted on a ring nitrogen and attached to the remainder of the molecule at a ring carbon atom are said to be N substituted.
  • an N alkyl piperidinyl group is attached to the remainder of the molecule at the two, three or four position of the piperidinyl ring and substituted at the ring nitrogen with an alkyl group.
  • Non-aromatic nitrogen containing heterocyclic rings such as piperazdnyl that are substituted on a ring nitrogen and attached to the remainder of the molecule at a second ring nitrogen atom are said to be N' substituted-N-heterocycles.
  • an N' acyl N-piperazinyl group is attached to the remainder of the molecule at one ring nitrogen atom and substituted at the second ring nitrogen atom with an acyl group.
  • an optionally substituted aralkyl can be substituted on both the alkyl and the aryl portion. In certain embodiments, optionally substituted aralkyl is optionally substituted on the aryl portion.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • the compounds of this invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt.
  • the term "pharmaceutically acceptable salt” refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et ai, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1- 19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds. Acid addition salts can be prepared by 1) reacting the purified compound in its free-based form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate ⁇ laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, ox
  • Base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N + (Ci -4 alkyl)4 salts.
  • alkali metal e.g., sodium, lithium, and potassium
  • alkaline earth metal e.g., magnesium and calcium
  • ammonium and N + (Ci -4 alkyl)4 salts e.g., sodium, lithium, and potassium
  • alkaline earth metal e.g., magnesium and calcium
  • ammonium and N + (Ci -4 alkyl)4 salts e.g., sodium, lithium, and potassium
  • ammonium and N + (Ci -4 alkyl)4 salts e.g., sodium, lithium, and potassium
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • Other acids and bases while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid or base addition salts.
  • compositions to treat or prevent the herein identified disorders.
  • pharmaceutically acceptable solvates e.g., hydrates
  • clathrates of the compounds of this invention may also be employed in compositions to treat or prevent the herein identified disorders.
  • solvate is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds the invention.
  • solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • hydrate means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces.
  • compositions to treat or prevent the herein identified disorders.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include derivatives of compounds of the invention that comprise -NO, -N02, -ONO, or - ON02 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).
  • a "pharmaceutically acceptable derivative” is an adduct or derivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.
  • a "pharmaceutically acceptable derivative or prodrug” includes any
  • compositions of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
  • side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia,
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • the present invention is a pharmaceutical composition comprising an effective amount of compound of the present invention and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.
  • the pharmaceutically acceptable carrier, adjuvant, or vehicle includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin
  • buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, pre
  • the protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to a subject as defined herein.
  • compositions which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are another embodiment of the present invention.
  • the present invention is a method of treating or preventing a protein kinase-mediated disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound composition or a pharmaceutically acceptable salt of the present invention as described herein.
  • the present invention is the use of an effective amount of a compound, composition or a pharmaceutically acceptable salt described herein for treating or preventing a disease or disorder, described herein, in a subject in need thereof.
  • the present invention is the use of an effective amount of a compound, composition or a pharmaceutically acceptable salt described herein for treating a disease or disorder, described herein, in a subject in need thereof.
  • the present invention is the use of an effective amount of a compound, composition or a pharmaceutically acceptable salt described herein for the manufacture of a medicament method for the treatment or prevention of a disease or disorder, described herein, in a subject in need thereof. In yet another embodiment, the present invention is the use of an effective amount of a compound, composition or a
  • the protein kinase mediated disease is a protein kinase C (PKC) mediated disease.
  • PDC protein kinase C
  • the protein kinase mediated disease is a protein kinase C theta (PKCtheta)- mediated disease.
  • the terms “subject”, “patient” and “mammal” are used interchangeably.
  • the terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human.
  • a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
  • a primate e.g., a monkey, chimpanzee and a human
  • the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit).
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit
  • an "effective amount" refers to an amount sufficient to elicit the desired biological response.
  • the desired biological response is to reduce or ameliorate the severity, duration, progression, or onset of a protein kinase-mediated condition, prevent the advancement of a protein kinase-mediated condition, cause the regression of a protein kinase-mediated condition, prevent the recurrence, development, onset or progression of a symptom associated with a protein kinase-mediated condition, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • the precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs.
  • an effective amount of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used. In cases where no amount is expressly noted, an effective amount should be assumed.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a protein kinase-mediated condition, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a protein kinase-mediated condition resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of the invention).
  • the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a protein kinase-mediated condition.
  • treatment and “treating” refer to the inhibition of the progression of a protein kinase-mediated condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of a protein kinase-mediated condition.
  • a compound of the invention is administered as a preventative measure to a patient, preferably a human, having a genetic predisposition to any of the conditions, diseases or disorders described herein.
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where a protein kinase is implicated in the disease state. In another aspect, the present invention provides a method for treating or lessening the severity of a kinase disease, condition, or disorder where inhibition of enzymatic activity is implicated in the treatment of the disease. In another aspect, this invention provides a method for treating or lessening the severity of a disease, condition, or disorder with compounds that inhibit enzymatic activity by binding to the protein kinase.
  • Another aspect provides a method for treating or lessening the severity of a kinase disease, condition, or disorder by inhibiting enzymatic activity of the kinase with a protein kinase inhibitor.
  • said protein kinase inhibitor is a PKCtheta inhibitor.
  • protein kinase-mediated condition means any disease or other deleterious condition in which a protein kinase plays a role.
  • Such conditions include, without limitation, autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, immuno-deficiency disorders, immunomodulatory or immunosuppressive disorder, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone related diseases, diabetes, allergies, asthma, and
  • the protein-kinase mediated condition is a P C-mediated condition.
  • PKC-mediated condition means any disease or other deleterious condition in which PKC plays a role.
  • Such conditions include, without limitation, those listed above, and in particular, T-cell mediated diseases, including without limitation autoimmune diseases, chronic or acute inflammatory diseases, and proliferative and hyperproliferative diseases.
  • the PKC-mediated condition is a PKCtheta-mediated condition
  • PKCtheta-mediated condition means any disease or other deleterious condition in which PKCtheta plays a role.
  • Such conditions include, without limitation, those listed above, and in particular, autoimmune diseases, chronic or acute inflammatory diseases, and proliferative and hyperproliferative diseases.
  • inflammatory disease refers to pathological states resulting in inflammation, typically caused by leukocyte infiltration.
  • disorders include inflammatory skin diseases, including, without limitation, psoriasis and atopic dermatitis; systemic scleroderma and sclerosis; responses associated with inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative colitis); ischemic reperfusion disorders including surgical tissue reperfusion injury, myocardial ischemic conditions such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery and constriction after percutaneous transluminal coronary angioplasty, stroke, and abdominal aortic aneurysms; cerebral edema secondary to stroke; cranial trauma, hypovolemic shock; asphyxia; adult respiratory distress syndrome; acute-lung injury; Behcet's Disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; mening
  • inflammations of the lung including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse
  • panbronchiolitis hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis; etc.
  • Proliferative or hyperproliferative diseases are characterized by excessive or abnormal cell proliferation. Such diseases include, without limitation, cancer and myeloproliferative disorders.
  • cancers includes, but is not limited to, the following cancers: epidermoid Oral: Cardiac: Lung: Gastrointestinal: Genitourinary tract: Liver: Bone: Nervous system:
  • Hematologic cancers include: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell; lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, arposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and psoriasis.
  • the term "cancerous cell” as provided herein includes a cell afflicted by any one of the above- identified conditions.
  • myeloproliferative disorders includes disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, hypereosinophilic syndrome, juvenile myelomonocytic leukaemia, systemic mast cell disease, and hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia (APL), and acute lymphocytic leukemia (ALL).
  • AML acute-myelogenous leukemia
  • CML chronic-myelogenous leukemia
  • APL acute-promyelocytic leukemia
  • ALL acute lymphocytic leukemia
  • neurodegenerative diseases include, without limitation, Alzheimer' s disease Huntington's disease, Parkinson's disease, AIDS-associated dementia, and bipolar disorder.
  • the PKCtheta mediated disease includes, without limitation, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritic conditions, multiple sclerosis (MS), asthma, systemic lupus
  • IBD inflammatory bowel disease
  • the PKCtheta mediated disease includes, diseases such as, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, joint inflammation, lupus, multiple sclerosis, asthma, psoriasis, cancer, T-cell lymphomas, leukaemia,diabetes type I or II, and inflammatory bowel diseases, transplant rejection, Crohn's disease and colitis.
  • diseases such as, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, joint inflammation, lupus, multiple sclerosis, asthma, psoriasis, cancer, T-cell lymphomas, leukaemia,diabetes type I or II, and inflammatory bowel diseases, transplant rejection, Crohn's disease and colitis.
  • autoimmune diseases include, without limitation, multiple sclerosis, rheumatoid arthritis and irritable bowel disease.
  • compositions of this invention can be any pharmaceutically acceptable compositions of this invention.
  • intravaginally intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating ⁇ excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating ⁇ excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined . with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene,
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, ben ⁇ yl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the dosage regimen utilizing the compounds of Structural Formula I, IA, and IC can be selected in accordance with a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of
  • Dosages of the compounds of Structural Formula I, IA, and IC can range from between about 0.01 to about 100 mg/kg body weight/day, about 0.01 to about 50 mg/kg body weight day, about 0.1 to about 50 mg kg body weight/day, or about 1 to about 25 mg/kg body weight/day. It is understood that the total amount per day can be administered in a single dose or can be administered in multiple dosings such as twice, three or four times per day.
  • the compounds for use in the method of the invention can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
  • An effective amount can be achieved in the method or pharmaceutical composition of the invention employing a compound of Structural Formula I, IA, and IC or a pharmaceutically acceptable salt or solvate (e.g., hydrate) thereof alone or in combination with an additional suitable therapeutic agent, for example, a cancer-therapeutic agent.
  • an effective amount can be achieved using a first amount of a compound of Structural Formula I, LA, and IC or a pharmaceutically acceptable salt or solvate (e.g., hydrate) thereof and a second amount of an additional suitable therapeutic agent.
  • the compound of Structural Formula I, LA, and IC and the additional therapeutic agent are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone).
  • the compound of Structural Formula I, LA, and IC and the additional therapeutic agent are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose).
  • the compound of Structural Formula I, LA, and IC can be administered in an effective amount, while the additional therapeutic agent is administered in a subtherapeutic dose.
  • the compound of Structural Formula I, IA, and IC can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer-therapeutic agent is administered in an effective amount.
  • the terms “in combination” or “coadministration” can be used interchangeably to refer to the use of more than one therapies (e.g., one or more prophylactic and/or therapeutic agents).
  • therapies e.g., prophylactic and/or therapeutic agents
  • the use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.
  • the compounds are administered sufficiently close in time to have the desired therapeutic effect.
  • the period of time between each administration which can result in the desired therapeutic effect can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile.
  • a compound of Structural Formula I, IA, and IC and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound of the invention
  • a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent) to a subject.
  • a second therapy e.g., a prophylactic or therapeutic agent such as an anti-cancer agent
  • the method of coadministration of a first amount of a compound of Structural Formula I, IA, and IC and a second amount of an additional therapeutic agent can result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect that would result from separate administration of the first amount of the compound of Structural Formula I, IA, and IC and the second amount of the additional therapeutic agent.
  • the term "synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject.
  • the ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention, management or treatment of a disorder.
  • a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disorder.
  • a synergistic effect of a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • Suitable methods include, for example, the Sigmoid-Emax equation (Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T.C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)).
  • Each equation referred to above can be applied with experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
  • the corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.
  • said additional therapeutic agent is selected from a cancer- therapeutic agent, such as, an anti-cancer agent, an anti-proliferative agent, or a chemotherapeutic agent.
  • said additional therapeutic agent is selected from camptothecin, the ME inhibitor: U0126, a SP (kinesin spindle protein) inhibitor, adriamycin, interferons, and platinum derivatives, such as Cisplatin.
  • said additional therapeutic agent is selected from taxanes; inhibitors of bcr-abl (such as Gleevec, dasatinib, and nilotinib); inhibitors of EGFR (such as Tarceva and Iressa); DNA damaging agents (such as cisplatin, oxaliplatin, carboplatin, topoisomerase inhibitors, and anthracyclines); and antimetabolites (such as AraC and 5-FU).
  • bcr-abl such as Gleevec, dasatinib, and nilotinib
  • inhibitors of EGFR such as Tarceva and Iressa
  • DNA damaging agents such as cisplatin, oxaliplatin, carboplatin, topoisomerase inhibitors, and anthracyclines
  • antimetabolites such as AraC and 5-FU.
  • said additional therapeutic agent is selected from camptothecin, doxorubicin, idarubicin, Cisplatin, taxol, taxotere, vincristine, tarceva, the MEK inhibitor, U0126, a KSP inhibitor, vorinostat, Gleevec, dasatinib, and nilotinib.
  • said additional therapeutic agent is selected from Her-2 inhibitors (such as Herceptin); HDAC inhibitors (such as vorinostat), VEGFR inhibitors (such as Avastin), c-KIT and FLT-3 inhibitors (such as sunitinib), BRAF inhibitors (such as Bayer's BAY 43-9006) MEK inhibitors (such as Pfizer's PD0325901); and spindle poisons (such as Epothilones and paclitaxel protein-bound particles (such as Abraxane®)-
  • Her-2 inhibitors such as Herceptin
  • HDAC inhibitors such as vorinostat
  • VEGFR inhibitors such as Avastin
  • c-KIT and FLT-3 inhibitors such as sunitinib
  • BRAF inhibitors such as Bayer's BAY 43-9006
  • MEK inhibitors such as Pfizer's PD0325901
  • spindle poisons such as Epothilones and paclitaxel protein-bound particles (such
  • therapies or anticancer agents that may be used in combination with the inventive agents of the present invention include surgery, radiotherapy (in but a few examples, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile,
  • Gemcitabine spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), GleevecTM, adriamycin,
  • dexamethasone and cyclophosphamide.
  • a compound of the instant invention may also be useful for treating cancer in combination with any of the following therapeutic agents: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukiri®); Alemtuzumabb (Campath®); alitretinoin (Panretin®);
  • cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Daunorubicin, daunomycin
  • etoposide phosphate Etopophos®
  • etoposide, VP- 16 Vepesid®
  • exemestane Aromasin®
  • Filgrastim Neurogen®
  • floxuridine Intraarterial
  • FUDR® Fluorouracil
  • 5-FU Adrucil®
  • fulvestrant Faslodex®
  • gefitinib Iressa®
  • gemcitabine Gemzar®
  • gemtuzumab ozogamicin Mylotarg®; goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (Ce
  • mercaptopurine 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pega
  • Tositumomab I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA
  • Vesanoid® Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); zoledronate (Zometa®) and vorinostat (Zolinza®).
  • agents the compounds of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept ® and Excelon ® ; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex ® and Rebif ® ), Copaxone ® , and mitoxantrone; treatments for asthma such as albuterol and Singulair ® ; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory agents such as cortico
  • immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
  • neurotrophic factors such as acetylcho
  • the compounds and compositions of this invention are also useful in biological samples.
  • One aspect of the invention relates to inhibiting protein kinase activity in a biological sample, which method comprises contacting said biological sample with a compound of Formula I, IA, and IC or a composition comprising said compound.
  • biological sample means an in vitro or an ex vivo sample, including, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of protein kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, and biological specimen storage.
  • Another aspect of this invention relates to the study of protein kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such protein kinases; and the comparative evaluation of new protein kinase inhibitors.
  • uses include, but are not limited to, biological assays such as enzyme assays and cell-based assays.
  • the activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of the activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with the kinase bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention are set forth in the Examples below.
  • Another aspect of the invention provides a method for modulating enzyme activity by contacting a compound of Formula I, IA, and IC with a protein kinase.
  • the compounds of this invention are represented in Table 1.
  • variables used herein such as x, y, A, A', R.2, R3, R4, R5, R 7 , are as defined in Table 1.
  • the compounds of this invention may be prepared in light of the specification using steps generally known to those of ordinary skill in the art. Those compounds may be analyzed by known methods, including but not limited to LCMS (liquid chromatography mass spectrometry) HPLC and NMR (nuclear magnetic resonance). It should be understood that the specific conditions shown below are only examples, and are not meant to limit the scope of the conditions that can be used for making compounds of this invention. Instead, this invention also includes conditions that would be apparent to those skilled in that art in light of this specification for making the compounds of this invention. Unless otherwise indicated, all variables in the following schemes are as defmed herein. General Schemes:
  • Reagents and conditions a) 2 C0 3 , [B(OR 7 )2]2, Pd(dppf) 2 Cl 2 .DCM, DME, 100°C; b) Na 2 C0 3 , Pd[P(tBu) 3 ] 2 , dioxane, 70°C.
  • Scheme I above describes another general synthetic route for preparing compounds of Formula I, IA, and IC of this invention where x, A, A', Rj, R 2 , R 3 and R4 are as described herein (it is understood that R5 and Re can also be present and that ring B substituted with (R 7 )y can replace the CR 2 R 3 R4 group).
  • Starting materials for 1 are either commercially available or can be prepared by reactions well known in the art (e.g. nochel, Buchwald). Boronation of derivative 1, followed by Suzuki-Miyaura cross-coupling reaction with intermediate 3 leads to compounds 4 of this invention.
  • Reagents and conditions a) B(OR 7 ) 2 (OMe), 'PrMgCl.LiCl, THF, -20°C; b) Na 2 C0 3 , Pd[P(tBu) 3 ] 2 , dioxane, 70°C; c) R 1 B(OH) 2 , Na 2 C0 3 , Pd(PPh 3 ) 4 , DME, mwave irradiations, 150°C.
  • Reagents and conditions a) LDA, THF, aldehyde, ' 78°C; b) Cr0 3 , acetone, 0°C ; c) NH 2 NH 2 , THF, pressure tube, 90°C; d) Na 2 C0 3 , Pd(PPh 3 ) , dioxane, mwave irradiation, 150°C; e) deprotection conditions.
  • Scheme 4 above shows another general synthetic route for preparing compounds of Formula I, IA, and IC of this invention where x, A, A', Ri, R 2 , R3, and R5 are as described herein (it is understood that Re can also be present).
  • Intermediate 12 was transformed to the alcohol 13 and then oxidized to ketone 14. This was cyclised using hydrazine to give 15 which was coupled with intermediate 16 using Suzuki-Miyaura cross-coupling reactions to yield compounds 17.
  • Compounds 18 of this invention were finally obtained after deprotection.
  • Reagents and conditions a) NaOEt, EtOOCCF 3 , RT; b) tBuNHNH 2 , TFA, dimethylcarbonate 80°C; c) (CH 3 ) 2 NC(OMe) 2 , MeCN, 50°C; d) NH3, MeOH, 100°C in a sealed tube; e) S(0)C1 2 , DMF, 77°C, overnight; f) Na 2 C0 3 , [P(tBu ) 3 ] 2 , dioxane, 60°C; g) deprotection conditions.
  • Scheme 5 above shows another general synthetic route for preparing compounds of Formula I, IA, and IC of this invention where x, A, A', Ri, R2 and R 3 are as described herein (it is understood that Re can also be present).
  • Intermediate 19 was prepared by two-step process that involves condensation reaction and cyclazation using hydrazine. The intermediate 19 was cyclazed to produce intermediate 21 by condensing 19 with NN, dimethylformamide dimethylacetal and then treated with ammonia under pressurize conditions. Intermediate 21 was transformed in a chloro derivative using thionyl chloride. Compounds of formula 21 then underwent a Suzuki- iyaura cross-coupling reaction with intermediate 23 to lead to compounds 24. Compounds 25 of this invention were finally obtained after deprotection.
  • Reagents and conditions a) 2-triphenylphosphoranylideneacetate, DCM, 0°C - RT; b) i)3-bromo- phenyl boronic acid, [Rh(cod)Cl]2 , dioxane, KOH, ethyl 2-(oxetan-3-ylidene) acetate, ii) NaOH, MeOH, 0°C; c) DPPA, triethylamine, tBuOH, 80°C; d) B(OR 7 ) 2 (OMe), Pd[dppf)]Cl 2 .DCM, dioxane, KOAc, 90°C; e) Na 2 C0 3 , [P(tBu 3 )3] 2 , dioxane, 60°C; f) deprotection conditions.
  • Scheme 6 above shows another general synthetic route for preparing compounds of Formula I, IA, and IC of this invention where x, A, A', and R 1 are as described herein it is understood that Re can also be present).
  • Intermediate 26 was converted to 27 under Wittig reaction conditions and then coupled to form 28, using Rh as catalyst.
  • a Curtius reaction gave 29, which was converted to the boronate 30 and then underwent a Suzuki-Miyaura cross-coupling reaction with intermediate 31 to lead to compounds 32.
  • Final compounds 33 were obtained after deprotection.
  • Mass spec samples were analyzed on a MicroMass Quattro Micro mass spectrometer operated in single MS mode with electrospray ionization. Samples were introduced into the mass spectrometer using chromatography. Mobile phase for all mass spec, analyses consisted of lOmM pH 7 ammonium acetate and a 1 : 1 acetonitrile-methanol mixture. Column gradient conditions were 5%-100% acetonitrile-methanol over 3.5 mins gradient time and 4.8 mins run time on an ACE5C8 3.0 x 75mm column. Flow rate was 1.2 ml/min.
  • Rt(min) refers to the LCMS retention time, in minutes, associated with the compound. Unless otherwise indicated, the LCMS method utilized to obtain the reported retention time is as detailed above.
  • Step 3 4-chloro-3-cyclopropyl-lH-pyrazolo[3,4-c3 ⁇ 4pyrimidine
  • Step 4 l-(3-(3-cyclopropyl-lH-pyrazolo[3,4-i ⁇ pyrimidin-4-yl)phenyl) cyclopropanecarbonitrile
  • a solution of 4-chloro-3-cyclopropyl-lH-pyrazolo[3,4-d]pyrimidine (290 mg, 1.490 mmol) in dioxane (30 mL) was treated with l-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]cyclopropanecarbonitrile (445.6 mg, 1.490 mmol) and sodium carbonate (2.235 mL of 2 M, 4.470 mmol).
  • the reaction mixture was degassed (vacuum/nitrogen cycles) and then treated with Pd[P(tBu) 3 ]2 (114.2 mg, 0.2235 mmol) and the reaction heated at 70°C for a total of 7 hours.
  • the mixture was allowed to cool to RT and diluted with EtOAc/I ⁇ O.
  • the organics were separated, washed with saturated NaCl, dried (MgSC ), passed through a short Si02 pad and concentrated to give an oil. This was purified by column chromatography (ISCO CompanionTM, 120g column, 0- 6% MeOH / DCM) to give the required product (54.2mg, 12% Yield).
  • Step 1 4-chloro-lH-pyrazolo[3,4-i/]pyrimidine
  • Step 2 l-(3-(lH-pyrazolo[3,4- ⁇ flpyrimidin-4-yl)phenyl)cyclopropanecarbonitrile
  • Step 2 l-(3-(3-ethyl-l-trityl-lH-pyrazolo[3,4-i/]pyrimidin-4-yl)phenyl) cyclopropanecarbonitrile
  • the reaction mixture was degassed (vacuum/nitrogen cycles) and then treated with Pd[P(tBu) 3 ] 2 (50 mg, 0.09784 mmol) and heated at 70°C for 3 hours.
  • the reaction was allowed to cool to RT and diluted with EtOAc/3 ⁇ 40.
  • the organics were separated, washed with saturated NaCl, dried (MgSC ⁇ ), and concentrated in vacuo.
  • the resultant residue was purified by column chromatography (ISCO CompanionTM, 40g column, EtOAc / Petroleum ether) to give the required product (209mg, 65% Yield).
  • Step 3 (l-(3-(3-ethyl-l-trityl-lH-pyrazolo[3,4-i ⁇ pyrimidin-4-yl)phenyl)cyclopropyl) meth an amine l-[3-(3-ethyl-l-trityl-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl]cyclopropanecarbonitrile (208 mg, 0.3912 mmol) was dissolved in dry THF (30 mL) and cooled in an ice-bath.
  • Step 4 (l-(3-(3-ethyl-lH-pyraz»lo[3,4- ⁇ f]pyrimidin-4-yl)phenyl)cyclopropyl) methanamine
  • Step 1 Sodium 3-cyano-4-ethoxy-l,l,l-trifluoro-4-oxobutan-2-olate
  • Step 3 Ethyl l-/e ⁇ butyl-5-((dimemylammo)methyleneamino)-3-(trifluoromethyl)-lH-pyrazole 4-carboxylate
  • MeCN MeCN
  • ⁇ , ⁇ -dimethylforamide dimethyl acetal 7.595 g, 8.467 mL, 63.74 mmol
  • Step 4 l-/er butyl-3-(trifluoromethyl)-lH-pyraz»lo[3,4-i/]pyrimidin-4-ol
  • Step 5 l-ter butyl-4-chloro-3-(trifluoromethyl)-lH-pyrazolo[3,4-cflpyrimidine
  • reaction mixture was degassed (nitrogen/vacuum cycles) and then treated with Pd[P(tBu) 3 ]2 (65.47 mg, 0.1281 mmol) and allowed to heat at 67°C for 5 hours.
  • the reaction was allowed to cool and diluted with EtOAc/water and the two layers separated. The organics were washed with saturated NaCl, dried (MgSO- , filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO CompanionTM, 120g column, EtOAc/ Petroleum ether) to give the required product (226mg, 69% Yield).
  • Step 7 l-(3-(3-(trifluoromethyl)-lH-pyrazolo[3,4-iflpyrimidin-4-yl)phenyl)
  • cyclopropanecarbonitnle (225 mg, 0.5838 mmol) was treated with methane sulfonic acid (7.406 g, 5.001 mL, 77.06 mmol) and the reaction allowed to heat at 60°C for 2 hours. The mixture was allowed to cool to RT, poured onto ice and made basic (pH 8) by addition of solid NaHC0 3 . This was treated with EtOAc/water and the two layers separated. The organics were washed with water followed by saturated NaCl, dried (MgSC ), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO CompanionTM, 40g column, DCM/MeOH) to give the required product (72mg, 36% Yield).
  • Step 1 Tert-butyl (l-(3-(3-ethyl-l-trityl-lH-pyrazolo[3,4-c/lpyrimidin-4-yl)-5- fluorophenyl)cyclobutyl)methylcarbamate
  • the reaction mixture was degassed (nitrogen/vacuum cycles) and then treated with Pd[P(tBu) 3 ] 2 (180.4 mg, 0.3530 mmol) and heated at 67°C for 24 hours. The mixture was allowed to cool and diluted with EtOAc/water and the two layers separated. The organics were washed with saturated NaCl, dried (MgS04), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO CompanionTM, 120g column, EtOAc/ Petroleum ether) to give the required product (1.407g, 90% Yield).
  • Step 2 (l-(3-(3-ethyl-lH-pyrazolo[3,4-i/]pyrimidin-4-yl)-5-fluorophenyl)cyclobutyl) meth an amine
  • reaction mixture was then allowed to warm to RT overnight, concentrated in vacuo and purified by column chromatography (ISCO CompanionTM, 80g column, 95:5:1 DCM/MeOH NH40H) to give the required product (385mg, 53% Yield).
  • Table 2 below depicts data for certain exemplary compounds made in general by a similar route to that outlined in the Examples above.
  • An assay buffer solution was prepared which consisted of 100 mM HEPES (pH 7.5), 10 mM MgCl 2 , 25 mM NaCl, 0.1 mM EDTA and 0.01% Brij.
  • An enzyme buffer containing reagents to final assay concentrations of 0.00001% Triton X-100, 200 ⁇ g/mL Phosphatidylserine, 20 pg/mL Diacylglycerol, 360 ⁇ NADH, 3 mM phosphoenolpyruvate, 70 ⁇ g/mL pyruvate kinase, 24 pg/mL lactate dehydrogenase, 2 mM DTT, 100 ⁇ substrate peptide (ERMRPRKRQGSVRRRV SEQ ID NO.
  • B compounds are: 1 and 6.
  • Ki values were calculated from initial rate data by non-linear regression using the Prism software package (Prism 4.0a, Graphpad Software, San Diego, CA).
  • PKC Alpha [00198 ] An assay buffer solution was prepared which consisted of 100 mM HEPES (pH 7.5), 10 mM MgCl 2 , 25 mM NaCl, 0.1 mM EDTA, 100 ⁇ CaCl 2 and 0.01% Brij.
  • Triton X-100 100 ⁇ g/mL Phosphatidylserine, 20 ⁇ g/mL Diacylglycerol, 360 ⁇ NADH, 3 mM phosphoenolpyruvate, 70 ⁇ g mL pyruvate kinase, 24 ⁇ g/mL lactate dehydrogenase, 2 mM DTT, 150 ⁇ substrate peptide (RR RRKGSF PvKA SEQ ID NO. 3) and 4.5 nM PKC alpha kinase was prepared in assay buffer.
  • Triton X-100 100 ⁇ g/mL Phosphatidylserine, 20 ⁇ g/mL Diacylglycerol, 360 ⁇ NADH, 3 mM phosphoenolpyruvate, 70 ⁇ g mL pyruvate kinase, 24 ⁇ g/mL lactate dehydrogenase, 2 mM DTT, 150 ⁇
  • Ki values were calculated from initial rate data by non-linear regression using the Prism software package (Prism 4.0a, Graphpad Software, San Diego, CA).

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Abstract

La présente invention concerne des composés de formule (I) et (IA) pouvant être employés en tant qu'inhibiteurs de protéine kinases. La présente invention concerne également des compositions de qualité pharmaceutique comprenant lesdits composés, et des méthodes d'emploi des compositions dans le traitement de diverses maladies, divers états pathologiques ou divers troubles. La présente invention concerne en outre des procédés de synthèse des composés selon l'invention.
PCT/US2010/033711 2009-05-06 2010-05-05 Pyrazolopyrimidines 4-substituées pouvant être employées en tant qu'inhibiteurs de pkc-thêta WO2011139273A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CN201080030395XA CN102471342A (zh) 2010-05-05 2010-05-05 用作PKC-θ抑制剂的4取代的吡唑并吡啶类
CA2761074A CA2761074A1 (fr) 2010-05-05 2010-05-05 Pyrazolopyrimidines 4-substituees pouvant etre employees en tant qu'inhibiteurs de pkc-theta
JP2013509037A JP2013525481A (ja) 2010-05-05 2010-05-05 ＰＫＣ−θインヒビターとして有用な４置換ピラゾロピリミジン
EP10721216A EP2566866A1 (fr) 2010-05-05 2010-05-05 Pyrazolopyrimidines 4-substituées pouvant être employées en tant qu'inhibiteurs de pkc-thêta
AU2010352577A AU2010352577A1 (en) 2010-05-05 2010-05-05 4 substituted pyrazolopyrimidines useful as PKC-theta inhibitors
MX2011011712A MX2011011712A (es) 2009-05-06 2010-05-05 Pirazolopirimidinas 4-sustituidas utiles como inhibidores de pkc-theta.
PCT/US2010/033711 WO2011139273A1 (fr) 2010-05-05 2010-05-05 Pyrazolopyrimidines 4-substituées pouvant être employées en tant qu'inhibiteurs de pkc-thêta
US13/289,300 US20120172379A1 (en) 2009-05-06 2011-11-04 4 substituted pyrazolopyrimidines

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US9840503B2 (en) 2015-05-11 2017-12-12 Incyte Corporation Heterocyclic compounds and uses thereof
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US10053465B2 (en) 2015-08-26 2018-08-21 Incyte Corporation Pyrrolopyrimidine derivatives as TAM inhibitors
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