WO2012085176A1 - Composés pyrazinones tricycliques, leurs compositions et leurs procédés d'utilisation en tant qu'inhibiteurs de janus kinase - Google Patents

Composés pyrazinones tricycliques, leurs compositions et leurs procédés d'utilisation en tant qu'inhibiteurs de janus kinase Download PDF

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WO2012085176A1
WO2012085176A1 PCT/EP2011/073734 EP2011073734W WO2012085176A1 WO 2012085176 A1 WO2012085176 A1 WO 2012085176A1 EP 2011073734 W EP2011073734 W EP 2011073734W WO 2012085176 A1 WO2012085176 A1 WO 2012085176A1
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alkylene
oxo
halogen
alkyl
optionally substituted
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PCT/EP2011/073734
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Christopher Hurley
Janusz Kulagowski
Robert Maxey
Stuart Ward
Mark Zak
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F. Hoffmann-La Roche Ag
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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
    • C07D487/12—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 three hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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]

Definitions

  • Compounds of formula I which are inhibitors of a Janus kinase, as well as compositions containing these compounds, and methods of use including, but not limited to, in vitro, in situ and in vivo diagnosis or treatment of mammalian cells.
  • JAK Janus kinases
  • STAT signal transducer and activator of transcription
  • JAK1, JAK2 and TYK2 exhibit broad patterns of gene expression, while JAK3 expression is limited to leukocytes.
  • Cytokine receptors are typically functional as heterodimers, and as a result, more than one type of JAK kinase is usually associated with cytokine receptor complexes.
  • the specific JAKs associated with different cytokine receptor complexes have been determined in many cases through genetic studies and corroborated by other experimental evidence.
  • JAK1 was initially identified in a screen for novel kinases (Wilks A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607). Genetic and biochemical studies have shown that JAK1 is functionally and physically associated with the type I interferon (e.g., IFNalpha), type ⁇ interferon (e.g., IFNgamma), IL-2 and IL-6 cytokine receptor complexes (Kisseleva et al, 2002, gene 285:1-24; Levy et al., 2005, Nat. Rev. Mol. Cell Biol.
  • type I interferon e.g., IFNalpha
  • type ⁇ interferon e.g., IFNgamma
  • IL-2 and IL-6 cytokine receptor complexes Kisseleva et al, 2002, gene 285:1-24; Levy et al., 2005, Nat. Rev. Mol. Cell Biol.
  • JAK1 knockout mice die perinatally due to defects in LIF receptor signaling (Kisseleva et al., 2002, gene 285:1 -24; O'Shea et al., 2002, Cell, 109 (suppl): S121- S131). Characterization of tissues derived from JAK1 knockout mice demonstrated critical roles for this kinase in the IFN, IL-10, IL-2/IL-4, and IL-6 pathways.
  • a humanized monoclonal antibody targeting the IL-6 pathway was recently approved by the European Commission for the treatment of moderate-to-severe rheumatoid arthritis (Scheinecker et al, 2009, Nat. Rev. Drug Discov. 8:273-274).
  • JAK2 knockout mice die of anemia (O'Shea et al, 2002, Cell, 109 (suppl.): S121 -S131).
  • Kinase activating mutations in JAK2 e.g., JAK2 V617F
  • MPDs myeloproliferative disorders
  • JAK3 associates exclusively with the gamma common cytokine receptor chain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complexes. JAK3 is critical for lymphoid cell development and proliferation and mutations in JAK3 result in severe combined immunodeficiency (SCID) (O'Shea et al, 2002, Cell, 109 (suppl): SI 21 -SI 31).
  • SCID severe combined immunodeficiency
  • JAK3 and JAK3 -mediated pathways have been targeted for immunosuppressive indications (e.g., transplantation rejection and rheumatoid arthritis) (Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692; Changelian et al, 2003, Science 302: 875-878).
  • immunosuppressive indications e.g., transplantation rejection and rheumatoid arthritis
  • TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6, IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva et al, 2002, gene 285:1-24; Watford, W.T. & O'Shea, J. J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from a TYK2 deficient human are defective in type I interferon, IL-6, IL-10, IL-12 and IL-23 signaling.
  • a fully human monoclonal antibody targeting the shared p40 subunit of the IL-12 and 11-23 cytokines was recently approved by the European Commission for the treatment of moderate-to-severe plaque psoriasis (Krueger et al, 2007, N. Engl. J. Med. 356:580-92; Reich et al, 2009, Nat. Rev. Drug Discov. 8:355-356).
  • an antibody targeting the IL-12 and IL-23 pathways underwent clinical trials for treating Crohn's Disease (Mannon et al, 2004, N. Engl. J. Med. 351 :2069-79).
  • One aspect includes a compound of formula I: stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein X, R 1 , R 2 , R 3 and R 5 are defined herein.
  • Another aspect includes a pharmaceutical composition that includes a compound of formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Another aspect includes a method of treating or lessening the severity of a disease or condition responsive to the inhibition of JAKl kinase activity in a patient.
  • the method includes administering to the patient a therapeutically effective amount of a compound of formula I.
  • Another aspect includes a compound of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in therapy.
  • Another aspect includes use of a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, in the treatment of an immunological or inflammatory disease.
  • Another aspect includes a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, in therapy.
  • Another aspect includes the use of a compound of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease responsive to the inhibition of JAKl kinase activity.
  • Another aspect includes methods of preparing a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • kits for treating a disease or disorder responsive to the inhibition of JAKl kinase includes a first pharmaceutical composition comprising a compound of formula I and instructions for use DETAILED DESCRIPTION OF THE INVENTION
  • Acyl means a carbonyl containing substituent represented by the formula -C(0)-R in which R is hydrogen, alkyl, a cycloalkyl, a heterocyclyl, cycloalkyl -substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein.
  • Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), and heteroaroyl (e.g. pyridinoyl).
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkyl radical is one to eighteen carbon atoms (Ci-Cis).
  • the alkyl radical is Co-Ce, C0-C5, C0-C3, C1-C12, C1-C10 , Ci-Cs, Ci- Ce, C 1 -C5, C 1 -C4, or C 1 -C 3 .
  • Co alkyl refers to a bond.
  • alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (l-Pr, 1- propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-l -propyl (l-Bu, l-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, - C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH
  • alkenyl refers to linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • the alkenyl radical is two to eighteen carbon atoms (C 2 -Cis).
  • the alkenyl radical is C 2 -C 12 , C 2 -C 1 o , C 2 -Cs, C 2 -C6 or C 2 -C3.
  • alkoxy refers to a linear or branched monovalent radical represented by the formula -OR in which R is alkyl, alkenyl, alkynyl or cycloalkyl, which can be further optionally substituted as defined herein.
  • Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di- and tri-fluoromethoxy and cyclopropoxy.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkynyl radical is two to eighteen carbon atoms (C 2 -C 18 ).
  • the alkynyl radical is C 2 -C 12 , C 2 -C 1 o , C 2 -Cs, C 2 -Ce or C 2 -C3.
  • Examples include, but are not limited to, ethynyl (-C ⁇ CH), prop-l-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (propargyl, -CH 2 C ⁇ CH), but-l-ynyl, but-2-ynyl and but-3-ynyl.
  • Alkylene refers to a saturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • the divalent alkylene group is one to eighteen carbon atoms (Ci-Cis).
  • the divalent alkylene group is Co-Ce, Co-C 5 , Co-C 3 , Ci-Ci2, C1-C10 , d-Cg, Ci-C 6 , Ci-C 5 , C1-C4, or C1-C3.
  • the group C 0 alkylene refers to a bond.
  • Example alkylene groups include methylene (-CH 2 -), 1,1 -ethyl (-CH(CH 3 )-), (1,2- ethyl (-CH 2 CH 2 -), 1 ,1 -propyl (-CH(CH 2 CH 3 )-), 2,2-propyl (-C(CH 3 ) 2 -), 1,2-propyl (-CH(CH 3 )CH 2 -), 1 ,3 -propyl (-CH 2 CH 2 CH 2 -), l,l-dimethyleth-l,2-yl (-C(CH 3 ) 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkenylene refers to an unsaturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • the alkenylene group is two to eighteen carbon atoms (C 2 -Cis).
  • the alkenylene group is C 2 -C 12 , C 2 - C1 0, C 2 -Cs, C 2 -Ce or C 2 -C 3 .
  • Alkynylene refers to an unsaturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • the alkynylene radical is two to eighteen carbon atoms (C 2 -C 18 ).
  • the alkynylene radical is C 2 -C 12 , C 2 - Cio , C2-C8, C2-C6 or C2-C3.
  • Example alkynylene radicals include: acetylene (-C ⁇ C-), propargyl (-CH 2 C ⁇ C-), and 4-pentynyl (-CH 2 CH 2 CH 2 C ⁇ C-).
  • Amidine means the group -C(NH)-NHR in which R is hydrogen, alkyl, a cycloalkyl, a heterocyclyl, cycloalkyl-substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein.
  • a particular amidine is the group - NH-C(NH)-NH 2 .
  • Amino means primary (i.e., -NH 2 ) , secondary (i.e., -NRH) and tertiary (i.e., -NRR) amines, that are optionally substituted, in which R is alkyl, alkoxy, a cycloalkyl, a heterocyclyl, cycloalkyl-substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein
  • Particular secondary and tertiary amines are alkylamine, dialkylamine, arylamine, diarylamine, aralkylamine and diaralkylamine wherein the alkyl is as herein defined and optionally substituted.
  • Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and diisopropylamine.
  • amino-protecting group refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound.
  • protecting groups include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group.
  • Particular amino protecting groups are Pmb (p- Methoxybenzyl), Boc (tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz (Carbobenzyloxy). Further examples of these groups are found in T. W. Greene and P. G. M.
  • Aryl when used alone, or as part of another term, means a carbocyclic aromatic group, whether or not fused to one or more groups, having the number of carbon atoms designated, or if no number is designated, up to 14 carbon atoms.
  • One example includes aryl groups having 6-14 carbon atoms.
  • Another example inlcudes aryl groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1 ,2,3,4- tetrahydronaphthalenyl, lH-indenyl, 2,3-dihydro-lH-indenyl, and the like (see e.g.
  • aryl is phenyl.
  • Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five, for example 1 -2, 1 -3 or 1 -4 substituents chosen from groups specified herein.
  • optional substituents on aryl are selected from halogen (F, CI, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example Ci-Ce alkyl), alkoxy (for example Ci-Ce alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, optionally substituted phenyl, or other groups specified.
  • halogen F, CI, Br, I
  • alkyl for example Ci-Ce alkyl
  • substituted phenyl include a mono- or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6- dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4- bromophenyl, 3,4-dibromophenyl, 3 -chloro -4 -fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such
  • substituted phenyl represents disubstituted phenyl groups where the substituents are different, for example, 3 -methyl -4-hydroxyphenyl, 3- chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3 -hydroxy -4- nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino.
  • Particular substituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3 -ethoxy -phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3- ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4- (l -chloromethyl)benzyloxy-6-methyl sulfonyl aminophenyl groups.
  • Fused aryl rings may also be substituted with any, for example 1 , 2 or 3, of the substituents specified herein in the same manner as substituted alkyl groups.
  • cancer and “cancerous”, “neoplasm”, “tumor” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer include carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • squamous cell cancer e.g., epithelial squamous cell cancer
  • lung cancer including small- cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain, as well as head and neck cancer, and associated metastases.
  • NSCLC non-small cell lung cancer
  • chemotherapeutic agent is an agent useful in the treatment of a given disorder, for example, cancer or inflammatory disorders.
  • chemotherapeutic agents include NSAIDs; hormones such as glucocorticoids; corticosteroids such as hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate,
  • calicheamicin especially calicheamicin gammall and calicheamicin omegall (see, e.g., Nicolaou et al, Angew. Chem Intl. Ed. Engl., 33: 183-186 (1994)); CDP323, an oral alpha-4 integrin inhibitor; dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including
  • celecoxib or etoricoxib include proteosome inhibitor (e.g. PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; EGFR inhibitors (see definition below); farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
  • proteosome inhibitor
  • Additional chemotherapeutic agents as defined herein include “anti-hormonal agents” or “endocrine therapeutics” which act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer. They may be hormones themselves, including, but not limited to: anti-estrogens with mixed agonist/antagonist profile, including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs) such as SERM3; pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors such as
  • Additional chemotherapeutic agents include therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizum
  • Chemotherapeutic agents also include "EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an "EGFR antagonist.”
  • EGFR inhibitors refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity
  • Examples of such agents include antibodies and small molecules that bind to EGFR.
  • antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No.
  • EMD 55900 Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)
  • EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as El . l, E2.4, E2.5, E6.2, E6.4, E2.l l , E6. 3 and E7.6.
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001 , 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391 ,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: W098/14451 , WO98/50038, WO99/09016, and WO99/24037.
  • EGFR antagonists include OSI-774 (CP-358774, erlotimb, TARCEVA ® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]- 7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRES S A J) 4-(3 ' -Chloro-4' -fluoroanilino)-7-methoxy-6-(3 -morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX- 1382 (N8-(3-chloro-4-fluoro-phenyl)-N
  • Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the EGFR- targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitor
  • NSAID non-steroidal anti-inflammatory drug
  • NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
  • NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib.
  • acetic acid derivatives such as indomethacin
  • sulindac sulindac
  • NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to- moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to- moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • Chemotherapeutic agents also include asthma treatment agents, including inhaled corticosteroids such as fluticasone, budesonide, mometasone, flunisolide and beclomethasone; leukotriene modifiers, such as montelukast, zafirlukast and zileuton; long-acting beta agonists, such as salmeterol and formoterol; combinations of the above such as combinations of fluticasone and salmeterol, and combinations of budesonide and formoterol; theophylline; short- acting beta agonists, such as albuterol, levalbuterol and pirbuterol; ipratropium; oral and intravenous corticosteroids, such as prednisone and methylprednisolone; omalizumab; lebrikizumab; antihistamines; and decongestants; cromolyn; and ipratropium.
  • corticosteroids such as flu
  • chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.
  • Cycloalkyl refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein.
  • the cycloalkyl group is 3 to 12 carbon atoms (C 3 -C12).
  • cycloalkyl is C 3 -C 8 , C 3 -Cio or C5-C1 0 .
  • the cycloalkyl group, as a monocycle is C 3 -C 8 , C 3 -C6 or C5-C6.
  • the cycloalkyl group, as a bicycle is C 7 -C 12 .
  • the cycloalkyl group is C5- C 12 .
  • monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-l -enyl, 1 -cyclopent-2-enyl, l -cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1- cyclohex-l-enyl, 1 -cyclohex-2-enyl, l -cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
  • Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
  • Examples of spiro cycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.
  • Carboxy-protecting group refers to those groups that are stable to the conditions of subsequent reaction(s) at other positions of the molecule, which may be removed at the appropriate point without disrupting the remainder of the molecule, to give the unprotected carboxy-group.
  • carboxy protecting groups include, ester groups and heterocyclyl groups. Ester derivatives of the carboxylic acid group may be employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • ester groups include substituted arylalkyl, including substituted benzyls, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl or substituted alkyl esters such as methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl), 4- methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butyl thio
  • carboxy-protecting groups are heterocyclyl groups such as 1,3-oxazolinyl. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2 nd ed., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, “Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981 , Chapter 5.
  • protected carboxy refers to a carboxy group substituted with one of the above carboxy- protecting groups.
  • Guanidine means the group -NH-C(NH)-NHR in which R is hydrogen, alkyl, alkoxy, a cycloalkyl, a heterocyclyl, cycloalkyl -substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein.
  • a particular guanidine is the group -NH-C(NH)-NH 2 .
  • “Hydroxy-protecting group” refers to a derivative of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound.
  • protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g. TBS, TBDPS) groups. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2 nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapters 2-3; E. Haslam, "Protective Groups in Organic Chemistry", J.
  • protected hydroxy refers to a hydroxy group substituted with one of the above hydroxy -protecting groups.
  • Heterocyclic group “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” alone, and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, tricyclic or spiro, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic, ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 1 to 4 heteroatoms.
  • heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 4- to 6-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 3-membered monocycles.
  • heterocyclyl includes 4-membered monocycles.
  • heterocyclyl includes 5-6- membered monocycles.
  • the heterocyclyl group includes 0 to 3 double bonds.
  • Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g. NO, SO, S0 2 ), and any nitrogen heteroatom may optionally be quaternized (e.g. [NR 4 ] + C1 " , [NR 4 ] + OH " ).
  • Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1 ,2-dithietanyl, 1,3-difhietanyl, pyrrolidinyl, dihydro-lH-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl
  • Examples of 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including l ,3,4-thiadiazol-5-yl and 1,2,4- thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as l ,3,4-oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl.
  • Example 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as l ,3,4-triazol-5-yl; 1,2,3- triazol-5-yl, l ,2,4-triazol-5-yl, and tetrazolyl, such as lH-tetrazol-5-yl.
  • Example benzo-fused 5- membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
  • Example 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as l ,3,4-triazin-2-yl and l,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl.
  • pyridyl such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl
  • pyrimidyl such as pyrimid-2-yl and pyrimid-4-yl
  • triazinyl such as l ,3,4-triazin-2-yl and l,3,5-
  • pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl groups are other example heterocycle groups.
  • Substituents for "optionally substituted heterocycles" include hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo- substituted alkyl, amino, cyano, nitro, amidino, guanidino.
  • Heteroaryl alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic ring system where at least one ring is a 5- or, 6- membered aromatic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang 's Handbook of Chemistry, supra. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring.
  • heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen.
  • heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen.
  • Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5-b]pyridazinyl, imidazol[l ,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benz
  • heteroaryl groups are: 1 ,3-thiazol-2-yl, 4-(carboxymethyl)-5 -methyl- 1 ,3-thiazol-2-yl, 4-(carboxymethyl)-5 -methyl- 1 ,3- thiazol-2-yl sodium salt, l ,2,4-thiadiazol-5-yl, 3-methyl-l ,2,4-thiadiazol-5-yl, l ,3,4-triazol-5-yl, 2-methyl-l ,3,4-triazol-5-yl, 2-hydroxy-l ,3,4-triazol-5-yl, 2-carboxy-4-methyl-l ,3,4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-l,3,4-triazol-5-yl, l,3-oxazol-2-yl, l ,3,4-oxadiazol-5-yl, 2- methyl-l,3,4-oxadiazol-5-yl, 2-(
  • Heteroaryl groups are optionally substituted as described for heterocycles.
  • a heterocyclyl group is attached at a carbon atom of the heterocyclyl group.
  • carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azet
  • the heterocyclyl group is N-attached.
  • the nitrogen bonded heterocyclyl or heteroaryl group include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2- imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • leaving group refers to a portion of a first reactant in a chemical reaction that is displaced from the first reactant in the chemical reaction.
  • Examples of leaving groups include, but are not limited to, hydrogen, halogen atoms, alkoxy and sulfonyloxy groups.
  • Example sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (for example methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (for example /7-toluenesulfonyloxy (tosylate group) and p- nitrosulfonyloxy (nosylate group)).
  • alkylsulfonyloxy groups for example methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)
  • arylsulfonyloxy groups for example /7-toluenesulfonyloxy (tosylate group) and p- nitrosulfonyloxy (nosylate group)
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g. 0, 1, 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different.
  • an optionally substituted group has 1 substituent.
  • an optionally substituted group has 2 substituents.
  • an optionally substituted group has 3 substituents.
  • divalent groups are described generically without specific bonding configurations, for example in the group -CH 2 C(0)-. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise.
  • R x -R 2 -R 3 if the group R 2 is described as -CH 2 C(0)-, then it is understood that this group can be bonded both as R -CH 2 C(0)-R 3 , and as R -C(0)CH 2 -R 3 , unless specified otherwise.
  • Package insert is used to refer to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • “Pharmaceutically acceptable salts” include both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.
  • a "sterile" formulation is aseptic or free from all living microorganisms and their spores.
  • Stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention.
  • solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • a "subject,” “individual,” or “patient” is a vertebrate.
  • the vertebrate is a mammal.
  • Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as cats, dogs, and horses), primates, mice and rats.
  • a mammal is a human.
  • “Therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and in certain embodiments stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and in certain embodiments stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma).
  • a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of B-cells.
  • Treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology.
  • Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis.
  • compounds of the invention are used to delay development of a disease or disorder or to slow the progression of a disease or disorder.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented.
  • compound(s) of this invention and “compound(s) of the present invention”, unless otherwise indicated, include compounds of formula I and stereoisomers, tautomers, solvates, metabolites, salts (e.g., pharmaceutically acceptable salts), isotopes and prodrugs thereof. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds of formula I wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by 1 C- or 14 C-enriched carbon atom, or one or more nitrogen atoms are replaced by a 15 N nitrogen atom, or one or more sulfur atoms are replaced by a S, S or S sulfur atom, or one or more oxygen atoms are replaced by a O or 18 0 oxygen are within the scope of this invention.
  • a compound of Formula I a stereoisomer, tautomer, prodrug and pharmaceutically acceptable salts thereof, and pharmaceutical formulations thereof, are provided that are useful in the treatment of diseases, conditions and/or disorders responsive to the inhibition of JAK1.
  • Another aspect of the invention provides compounds of formula I:
  • R 1 is absent, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 3-12 cycloalkyl, C -u aryl or 3-20 membered heterocyclyl, wherein R 1 is independently optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci -3 alkylene or Ci -6 alkyl optionally substituted by oxo, -CN or halogen;
  • R 2 is absent, Ci-6 alkyl, C 2 - 6 alkenyl, C 2 -6 alkynyl, -(Ci-6 alkylene)-, -(C 2- e alkenylene)-, -(C 2 -6 alkynylene)-, -(C 0-6 alkylene)CN, -(C 0 . 3 alkylene)NR a (C 0 - 3 alkylene)-, -(C 0 . 3 alkylene)O(C 0 -3 alkylene)-, -(C 0-3 alkylene)C(O)(C 0 - 3 alkylene)-, -(C 0 .
  • alkylene)S(0)i -2 NR a (Co-3 alkylene)- or -(C 0-3 alkylene)NR a S(O)i -2 NR (C 0 -3 alkylene)-, wherein said alkyl, alkyenyl, alkynyl, alkylene, alkenylene and alkynylene are independently optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or C 1-3 alkyl optionally substituted by halogen;
  • R 3 is absent, hydrogen, Ci-6 alkyl, C 2- 6 alkenyl, C 2 - 6 alkynyl, C3-7 cycloalkyl, Ce-i4 aryl or 3-20 membered heterocyclyl, wherein R 3 is independently optionally substituted by R 6 ;
  • R 4 is hydrogen, halogen or Ci -3 alkyl
  • R 5 is hydrogen, halogen, Ci-i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, -(C 0 -3 alkylene)CN, -(Co-3 alkylene)NR a R , -(C 0 . 3 alkylene)OR a , -(C 0 . 3 alkylene)SR a , -(C 0 . 3 alkylene)C(0)R a , -(C 0 . 3 alkylene)NR a C(0)R , -(C 0 .
  • R 6 is independently oxo, halogen, -CN, -C(0)R a , -C(0)OR a , -NR a C(0)R , -C(0)NR a R , -NR a C(0)NR a R , -OC(0)NR a R , -NR a C(0)OR , -S(0)i -2 R a , -NR a S(0) 2 R , -S(0) 2 NR a R , -OR a , -SR a , -NR a R , C M alkyl, C3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocycly or Ce-u aryl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR c ,
  • each R e , R f , R g , R h are independently hydrogen or Ci-6 alkyl optionally substituted by halogen or oxo.
  • R 1 and R 2 when R 1 and R 2 are absent, one of R 3 , R 4 and R 5 is other than hydrogen.
  • R 1 , R 2 and R 3 are not absent at the same time.
  • X is CR 4 , R 1 and R 2 are absent, and R 3 and R 4 are hydrogen. In certain embodiments, X is CR 4 .
  • X is N.
  • R is absent.
  • R is absent with the proviso that R 1 , R 2 and R 3 are not all absent at the same time.
  • R is Ci-Ce alkyl optionally substituted by halogen, oxo,
  • R 1 is selected from methyl, ethyl, propyl, butyl, wherein the wavy line represents the point of attachment in formula I.
  • R 1 is a 3-20 membered heterocyclyl, wherein R 1 is independently optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci -3 alkylene or Ci -6 alkyl optionally substituted by oxo, -CN or halogen.
  • R 1 is a 3-12 membered heterocyclyl, wherein R 1 is independently optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci-3 alkylene or Ci-6 alkyl optionally substituted by oxo, -CN or halogen.
  • R 1 is a 3-7 membered heterocyclyl, wherein R 1 is independently optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci -3 alkylene or Ci -6 alkyl optionally substituted by oxo, -CN or halogen.
  • R is a 3-20 membered heterocyclyl, wherein R is independently optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci -3 alkylene or Ci -6 alkyl optionally substituted by oxo, -CN or halogen, and wherein said heterocyclyl is oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, tetrahydrothienyl, 2,3- dihydrothienyl, pyrrolidinyl, 2,3-dihydro-lH-pyrrolyl, imidazolidinyl, 2H-pyranyl, tetrahydropyranyl, morpholinyl, piperazinyl, hexahydropyrimidinyl, oxazinanyl, thiazin
  • R 1 is a 3-7 membered heterocyclyl, wherein R 1 is independently optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci -3 alkylene or Ci -6 alkyl optionally substituted by oxo, -CN or halogen, wherein said heterocyclyl is piperidinyl.
  • R 1 is (R)-piperidin-3-yl, optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci -3 alkylene or Ci -6 alkyl optionally substituted by oxo, -CN or halogen.
  • R 1 is (S)-piperidin-3-yl optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci -3 alkylene or Ci -6 alkyl optionally substituted by oxo, -CN or halogen.
  • R 1 is piperidinyl optionally substituted by -NR a R or Ci-6 alkyl optionally substituted by oxo, -CN or halogen.
  • R 1 is a C4-7 cycloalkyl, wherein R 1 is independently optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci-3 alkylene or Ci -6 alkyl optionally substituted by oxo, -CN or halogen.
  • said cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 1 is selected from
  • R 1 is cyclopentyl optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci- 3 alkylene or C 1-6 alkyl optionally substituted by oxo, -CN or halogen.
  • R 1 is cyclohexyl optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci -3 alkylene or C 1-6 alkyl optionally substituted by oxo, -CN or halogen.
  • R 1 is selected from cyclohexyl, 2-hydroxycyclohexyl, 3 -hydroxy cyclohexyl, 4-hydroxycyclohexyl, bicyclo[2.2.1 ]heptanyl, 2-methylcyclohexyl or 4,4-difluorocyclohexyl.
  • R 1 is C -u aryl optionally substituted by halogen, oxo, -CN, -OR a , -SR a , -NR a R , Ci-3 alkylene or C 1-6 alkyl optionally substituted by oxo, -CN or halogen.
  • R 1 is 4-cyanophenyl.
  • R 1 is selected from methyl, methylene, ethyl, propyl, butyl, phenyl, 4-cyanophenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohex-l - yl, 2-hydroxycyclohex-l -yl, 3-hydroxycyclohex-l -yl, 4-hydroxycyclohex-l -yl, bicyclo[2.2.1 ]heptanyl, pyrrolidinyl, piperidinyl, piperidinonyl, 2-methylpiperidin-4-yl, 3- methylpiperidin-4-yl, 4-methylpiperidin-4-yl, 2-fluoropiperidinyl, 3-fluoropiperidin-4-yl, 3,3- difluoropiperidin-4-yl, 3 -methoxypiperidin-4-yl, 2,2-dimethyltetrahydropyranyl, te
  • R 1 is selected from cyclopentyl, cyclohexyl or piperidinyl.
  • R 2 is absent. In certain embodiments, R 2 is absent with the proviso that R 1 , R 2 and R 3 are not all absent at the same time.
  • R 2 and R 3 are absent. In certain embodiments, R 2 and R 3 are absent with the proviso that R 1 , R 2 and R 3 are not all absent at the same time.
  • R 2 is Ci_6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, wherein said alkyl, alkenyl or alkynyl are independently optionally substituted by halogen, oxo, -CN, -OR c , -SR C ,
  • R 2 is selected from -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 F, -C(CH 3 ) 2 OH, -
  • R 2 is -(Ci_6 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -C -OR c , -SR C , -NR c R d or C 1-3 alkyl optionally substituted by
  • propylene or butylene optionally substituted by halogen, oxo, -CN, -OR c , -NR c R d or Ci -3 alkyl, wherein the wavy line represents the point of attachment in formula I.
  • R 2 is -(Co-e alkylene)CN, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or C 1-3 alkyl optionally substituted by halogen, and R 3 is absent.
  • R 2 is -CH 2 CN, -CH 2 CH 2 CN, -CH(CH 3 )CN or -CH(CH 3 )CH 2 CN and R 3 is absent.
  • R 2 is -(Co -3 alkylene)NR a (Co -3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or Ci -3 alkyl optionally substituted by halogen.
  • R 2 is -NH-, -NHCH 2 - or -NHCH 2 CH 2 -.
  • R 2 is -(Co -3 alkylene)0(Co -3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or Ci -3 alkyl optionally substituted by halogen.
  • R 2 is -CH 2 0-, -CH 2 C(CH 2 ) 2 0- or -(CH 2 ) 2 0-.
  • R 2 is -(C0-3 alkylene)NR a C(0)(Co-3 alkylene)- or -(C0-3 alkylene)C(0)NR a (Co-3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or C1-3 alkyl optionally substituted by halogen.
  • R 2 is -C(0)NH- -CH 2 C(0)NH- or -CH 2 C(0)N(CH 3 )-.
  • R 2 is -NHC(O)- or -NHC(0)CH 2 -.
  • R 2 is -(C0-3 alkylene)OC(0)NR a (Co-3 alkylene)- or -(C0-3 alkylene)NR a C(0)0(Co-3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or C 1-3 alkyl optionally substituted by halogen.
  • R 2 is -NHC(0)0- -N(CH 3 )C(0)0- -NHC(0)OCH 2 - or -NHC(0)OCH 2 CH 2 -.
  • R 2 is -(C0-3 alkylene)C(0)(Co- 3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or Ci -3 alkyl optionally substituted by halogen.
  • R 2 is selected from:
  • R 2 is -(C0-3 alkylene)C(0)0(Co -3 alkylene)- or -(Co -3 alkylene)OC(0)(Co-3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or C 1-3 alkyl optionally substituted by halogen.
  • R 2 is selected from -C(0)0-
  • R 2 is -(C0-3 alkylene)S(0)i -2 (Co-3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or Ci -3 alkyl optionally substituted by halogen.
  • R 2 is selected from -C(0)CH 2 S(0) 2 ,
  • R 2 is -(C0-3 alkylene)NR a S(0)i-2(Co-3 alkylene)- or -(C0-3 alkylene)S(0)i-2NR a (Co-3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR c , -SR C , -NR c R d or C1-3 alkyl optionally substituted by halogen.
  • R 2 is -NHS(0) 2 - -N(CH 3 )S(0) 2 - or -NHS(0) 2 CH 2 -.
  • R 2 is selected from absent, -NHS(0) 2 -, -N(CH3)S(0) 2 - , -NHS(0) 2 CH 2 -, -C(0)CH 2 S(0) 2 , -C(0)0-, -NHC(0)0-, -N(CH 3 )C(0)0-, -NHC(0)OCH 2 -, -NHC(0)OCH 2 CH 2 - -C(0)NH-, -CH 2 C(0)NH-, -CH 2 C(0)N(CH 3 )-, -NHC(O)-, -NHC(0)CH 2 -, -CH 2 0-, -CH 2 C(CH 2 ) 2 0-, -(CH 2 ) 2 0-, -NH- -NHCH 2 -, -NHCH 2 CH 2 -, -CH 2 CN, -CH 2 CH 2 CN, -CH(CH 3 )CN , -CH(CH 3 )CH 2 CN, methylene, ethylene,
  • R is absent, methylene, ethylene, -NHCH 2 -, ⁇ * , -C(0)0- -C(0)NH- -NHC(0)0- -NHC(0)CH 2 -, -NHC(0)CH 2 C(0)- or -NHC(0)NH-, wherein the wavy line represents the point of attachment in formula I.
  • R is absent, methylene, ethylene, -NH-, -NHCH 2 -, ⁇ vV ,
  • R 3 is absent. In certain embodiments, R 3 is hydrogen.
  • -R 2 -R 3 is -CHO.
  • R 2 is absent and R 3 is hydrogen.
  • R 1 and R 2 are absent.
  • R 3 is absent, hydrogen, Ci-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C3-7 cycloalkyl, Ce-u aryl or 3-20 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by R 6 .
  • R 3 is Ci-6 alkyl optionally substituted by 1 to 3 R 6 .
  • R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl optionally substituted by oxo, C 1-6 alkyl, halogen, -CN, -S(0) 2 (C 1-6 alkyl), -OR a or -NR a R .
  • R 3 is selected from methyl, ethyl, n-butyl, sec-butyl, t-butyl, ⁇ CF 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH(CH 2 CH 3 )CH 2 OCH 3 , -CH(CH 3 )CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 C(CF 3 ) 2 OH, -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH(CH 3 )CH 2 CN, -C(CH 3 ) 2 CN, -CH(CH 3 )CN, -CH(CH 3 )CN, -CH 2 NH 2 ,
  • R 3 is C 3-7 cycloalkyl optionally substituted by 1 to 3 R 6 . In certain embodiments, R 3 is C 3-7 cycloalkyl optionally substituted by 1 to 3 oxo, halogen, -CN, -S(0)i -2 (Ci-6 alkyl), -OR a , -SR a , -NR a R or Ci -6 alkyl optionally substituted by oxo or halogen.
  • R 3 is selected from cyclopropyl, 1-cyanocycloprop-l-yl, 1- trifluoromethylcycloprop-l-yl, 1 -methylcycloprop-l-yl, 2-fluorocyclopyrop-l-yl, 2,2- dimethylcycloprop-l-yl, 2-cyanocyclopropyl, cyclobutyl, 4-carboxyclobutyl, 1 -cyanocyclobut-l- yl, 4-aminocyclobutyl, cyclopentyl, 3-aminocyclohexyl, 4-aminocyclohexyl, 2- hydroxycyclohexyl, 3 -hydroxy eye lohexyl, 4-hydroxycyclohexyl and 2-hydroxycyclohexyl.
  • R 3 is C6-14 aryl optionally substituted by 1 to 3 R 6 .
  • R 3 is Ce-14 aryl optionally substituted by 1 to 3 Ci-6 alkyl, C 2- 6 alkenyl, C 2 - 6 alkynyl, halogen, -CN, -S(0)i -2 (Ci -6 alkyl), -OR a , -SR a or -NR a R .
  • R 3 is phenyl, 2-chloro-4-cyanophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3- methylsulfonylphenyl, 3 -fluorophenyl or 4-methoxyphenyl.
  • R 3 is 5-6 membered heteroaryl optionally substituted by 1 to 3 R 6 . In certain embodiments, R 3 is 5-6 membered heteroaryl optionally substituted by 1 to 3 oxo, Ci-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, -CN, -S(0)i -2 (Ci -6 alkyl), -OR a , -SR a or -NR a R .
  • R 3 is selected from pyridinyl, pyridin-3 -yl, 6-cyanopyridinyl, 6-trifluoromethylpyridinyl, 2-cyanopyridin-4-yl, 4-cyanopyridin-2-yl, 5-cyanopyridin-2-yl, 3- fluoropyridin-5-yl, thiazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, oxazol-2-yl, oxazol-4-yl, l -methylpyrazol-5-yl, l-methylpyrazol-4-yl, 1 -methylimidazol-2-yl , thiazol-5-yl and isothiazol-5-yl, wherein the wavy line represents the point of attachment in formula I.
  • R 3 is 3-12 membered heterocyclyl optionally substituted by 1 to 3 R 6 . In certain embodiments, R 3 is 4-7 membered heterocyclyl optionally substituted by 1 to 3 R 6 . In certain embodiments, R 3 is 4-7 membered heterocyclyl optionally substituted by 1 to 3 oxo, Ci-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, halogen, -CN, -S(0)i -2 R a , -C(0)OR a , -OR a , -SR a or -NR a R , wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, halogen, -CN, -OR c or -NR c R d .
  • R 3 is selected from oxetan-3-yl, piperidin-3-yl, piperidin-4-yl, N-methylpiperidin-2-yl, N-methylmorpholin-2-yl, 1 -methylpyrrolidin-2-yl, pyrrolidinyl, pyrrolidinonyl, piperidinonyl, 3 ,3 -difluoropyrrolidin-2-yl, 1 -isopropylpyrrolidin-2- -methylpyrrolidin-2-yl, 1 -methylcyanopyrrolidin-2-yl, 1 -cyclobutylpyrrolidin-2-yl,
  • R 3 is absent, hydrogen, methyl, ethyl, trifluoromethyl, pyrrolidinyl, phenyl, pyridyl or cyclopropyl, independently optionally substituted by oxo, Ci_6 alkyl, halogen, -CN, -S(0) 2 (Ci -6 alkyl), -OR a or -NR a R .
  • R 3 is selected from absent, hydrogen, methyl, ethyl, n-butyl, sec- butyl, t-butyl, -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH(CH 2 CH 3 )CH 2 OCH 3 , -CH(CH 3 )CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 C(CF 3 ) 2 OH, - CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 CN, -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH(CH 3 )CH 2 CN, - C(CH 3 ) 2 CN, -CH(CH 3 )CN, -CH 2 NH 2 , -CH(CH(CH 3
  • R is absent, hydrogen, methyl, ethyl, -CF 3 , -CH 2 CF 3 , -CH 2 CN, -(CH 2 ) 2 CN, -CH 2 cyclopropyl, cyclopropyl, phenyl, 3-cyanophenyl, 5-cyanopyridin- 2-yl or pyridin-3-yl.
  • R is absent, hydrogen, methyl, ethyl, t-butyl, ⁇ CF 3 , -CH 2 CF 3 , -CH 2 CN, -(CH 2 ) 2 CN, -CH 2 cyclopropyl, cyclopropyl, phenyl, 3-cyanophenyl, 5-cyanopyridin- 2-yl, N-methylpyrrolidin-2-yl or pyridin-3-yl.
  • R 4 is hydrogen, methyl or F. In certain embodiments, R 4 is hydrogen.
  • R 5 is hydrogen
  • R 5 is halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -(Co-6 alkylene)CN, -(C 0-3 alkylene)NR a R , -(C 0 . 3 alkylene)OR a , -(C 0 . 3 alkylene)SR a , -(C 0 . 3 alkylene)C(0)R a , -(C 0 . 3 alkylene)NR a C(0)R , -(C 0 . 3 alkylene)C(0)NR a R , -(C 0 . 3 alkylene)C(0)OR a , -(C 0 .
  • R 5 is halogen. In certain embodiments, R 5 is F.
  • R 5 is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, wherein said alkyl, alkenyl and alkynyl are independently optionally substituted by halogen, oxo, -(Co -3 alkylene)CN, -(C 0 - 3 alkylene)OR c , -(C 0 . 3 alkylene)NR c R d , -(C 0 - 3 alkylene)C(0)R c , -(C 0 . 3 alkylene)C(0)OR c , -(C 0 .
  • R 5 is selected from methyl, ethyl, 1 -hydroxyethyl, 2-hydroxyethyl, propyl, isopropyl, butyl, 2-methylbutyl, 3,3-difluorobut-l-yl, isobutyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH,
  • R 5 is -(C 0 -3 alkylene)CN, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c , -(C 0 -3 alkylene)NR c R d , -(C 0-3 alkylene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(Co-3 alkylene)NR c C(0)R d , -(C0-3 alkylene)OC(0)NR c R d , -(C0-3 alkylene)NR c C(0)NR c R d , -(Co-3 alkylene)NR c C(0)OR d , -(C 0-3 alkylene)S(O) 0 - 2 R
  • R 5 is selected from -CN, -C(CH3) 2 CN. In certain embodiments, R 5 is -CN.
  • R 5 is -(C 0 -3 alkylene)OR a or -(C 0 -3 alkylene)SR a , wherein said alkylene is independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c , -(C 0-3 alkylene)NR c R d , -(C 0-3 alkyl ene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)R d , -(C 0-3 alkylene)OC(0)NR c R d , -(C 0-3 alkylene)NR c C(0)NR c R d , -(C0-3 alkylene)NR c C(0)OR d ,
  • R 5 is -(C 0 -3 alkylene)NR a R , wherein said alkylene is independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c , -(Co-3 alkylene)NR c R d , -(C0-3 alkylene)C(0)R c , -(C0-3 alkylene)C(0)OR c , -(C0-3 alkylene)C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)R d , -(C 0-3 alkylene)OC(0)NR c R d , -(C 0-3 alkylene)NR c C(0)NR c R d , -(C 0 .
  • R 5 is selected -NHCH 2 CH 2 OH, -CF 2 CH 2 NH 2 , -CH 2 C(0)NH 2 ,
  • R 5 is -(Co -3 alkylene)C3-i 2 cycloalkyl, wherein said alkylene and cycloalkyl are independently optionally substituted by halogen, oxo, -(Co -3 alkylene)CN, -(Co -3 alkylene)OR c , -(C 0 . 3 alkylene)NR c R d , -(C 0 . 3 alkyl ene)C(0)R c , -(C 0 . 3 alkylene)C(0)OR c , -(C 0 . 3 alkylene)C(0)NR c R d , -(C 0 .
  • R 5 is selected from -CH 2 cyclopentyl, -CH 2 cyclopropyl, -CH 2 CH 2 cyclopropyl, cyclopropyl, 2,2-difluorocyclopropyl and cyclobutyl.
  • R 5 is -(Co -3 alkylene)C3_7 cycloalkyl. In certain embodiments, R 5 is cyclopropyl or cyclobutyl.
  • R 5 is -(Co -3 alkylene)C(0)NR a R , wherein said alkylene is independently optionally substituted by halogen, oxo, -(Co -3 alkylene)CN, -(Co -3 alkylene)OR c , -(Co-3 alkylene)NR c R d , -(C 0 . 3 alkylene)C(0)R c , -(C 0 . 3 alkylene)C(0)OR c , -(C 0 .
  • R 5 is selected from -CH 2 C(0)NH 2i -CH 2 C(0)NHcyclopentyl i -CH 2 C(0)N(CH 3 )(cyclopentyl), -CH 2 C(0)NHCH 3 , - CH(CH 3 )C(0)NHCH(CH 3 ) 2 , -CH 2 C(0)(pyrrolidin-l -yl), -CH 2 C(0)(4,4-difluorpiperidin-l -yl), -CH 2 C(0)(morpholinyl) and , wherein the wavy line represents the point of attachment in formula I.
  • R 5 is -(C 0 -3 alkylene)C(0)NR a R , wherein said alkylene is independently optionally substituted by halogen, oxo, -(C0-3 alkylene)CN, -(C0-3 alkylene)OR c , -(Co-3 alkylene)NR c R d , -(C 0-3 alkylene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)R d , -(C 0-3 alkylene)OC(0)NR c R d , -(C 0-3 alkylene)NR c C(0)NR c R d , -(C0-3 alkylene)NR c C(0)OR d , -(C0-3 alkylene)S(O) 0 -
  • R 5 is -(C 0 -3 alkylene)NR a C(0)R , wherein said alkylene is independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c ,
  • R 5 is selected from
  • R 5 is -(C0-3 alkylene)NR a S(0)i-2R , wherein said alkylene is independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c , -(Co-3 alkylene)NR c R d , -(C 0-3 alkylene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)R d , -(C 0-3 alkylene)OC(0)NR c R d , -(C 0-3 alkylene)NR c C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)OR d , -(C 0-3 alkylene)S(
  • R 5 is selected from -CH 2 NHS(0) 2 CH 3 , -CH 2 NHS(0) 2 CH 2 CH 3 , -CH 2 NHS(0) 2 CH 2 CH(CH 3 ) 2 ,
  • R 5 is -(Co -3 alkylene)5-12 membered heteroaryl, wherein said alkylene and heteroaryl are independently optionally substituted by halogen, oxo, -(Co -3 alkylene)CN, -(C 0-3 alkylene)OR c , -(C 0-3 alkylene)NR c R d , -(C 0-3 alkylene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(C0-3 alkylene)NR c C(0)R d , -(C0-3 alkylene)OC(0)NR c R d , -(C 0-3 alkylene)NR c C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)OR d , -(C 0-3 alkylene)S(0)
  • R 5 is selected from -CH 2 CH 2 triazolyl, triazolyl, pyridinyl, -CH 2 pyrazolyl,
  • R 5 is -(C 0 -3 alkylene)4-6 membered heteroaryl, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c , -(C 0 - 3 alkylene)NR c R d , -(C 0 - 3 alkyl ene)C(0)R c , -(C 0 - 3 alkylene)C(0)OR c , -(C 0 - 3 alkylene)C(0)NR c R d , -(C 0 .
  • R 5 is pyridinyl.
  • R 5 is -(C 0 -3 alkylene)3-12 membered heterocyclyl, wherein said alkylene and heterocyclyl are independently optionally substituted by halogen, oxo, -(C0-3 alkylene)CN, -(C 0-3 alkylene)OR c , -(C 0 . 3 alkylene)NR c R d , -(C 0 - 3 alkylene)C(0)R c , -(C 0 . 3 alkylene)C(0)OR c , -(C 0 .
  • R 5 is selected from oxetanyl, 1 ,1-dioxothiomorpholinyl, -CH 2 CH 2 (1,1- dioxothiomorpholinyl), -CH 2 CH 2 triazolyl, triazolyl, -CH 2 pyrazolyl, -CH 2 pyridinyl, pyridinyl, pyrrolidinyl, piperidinyl, -CH 2 (4-hydroxypiperidin-l -yl), morpholinyl, azetidinyl, 2- acetylpyrrolidin-3-yl, -CH 2 tetrahydropyranyl, -CH 2 tetrahydropyran-4-yl, tetrahydropyranyl, tetrahydrofurany
  • R is -(C 0 -3 alkylene)4-6 membered heterocyclyl, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c , -(C 0 . 3 alkylene)NR c R d , -(C 0 . 3 alkylene)C(0)R c , -(C 0 . 3 alkylene)C(0)OR c , -(C 0 . 3 alkylene)C(0)NR c R d , alkylene)NR c C(0)R d , -(C 0 .
  • R 5 is pyridin-3-yl, pyrrolidin-l -yl, pyran-4-yl, -CH 2 C(0)(pyrrolidin-l -yl), -CH 2 C(0)(4,4-difluorpiperidin-l -yl), -CH 2 ( ⁇ ), -CH 2 C(0)(m ⁇ holinyl), -CH 2 (pyrrolidin-2-on-l -yl) or , wherein the wavy line represents the point of attachment in formula I.
  • R 5 is -(C 0 -3 alkyl ene)S(0)i -2 R a , wherein said alkylene is independently optionally substituted by halogen, oxo, -(C0-3 alkylene)CN, -(C0-3 alkylene)OR c , -(Co-3 alkylene)NR c R d , -(C 0-3 alkylene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)R d , -(C 0-3 alkylene)OC(0)NR c R d , -(C 0-3 alkylene)NR c C(0)NR c R d , -(C0-3 alkylene)NR c C(0)OR d , -(C0-3 alkylene)S(O)
  • R 5 is -(C 0 -3 alkylene)C6-i 2 aryl, wherein said alkylene and aryl are independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c , -(C 0-3 alkylene)NR c R d , -(C 0-3 alkyl ene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)R d , -(C 0-3 alkylene)OC(0)NR c R d , -(C 0-3 alkylene)NR c C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)OR d , -(C 0-3
  • R 5 is -(C0-3 alkylene)phenyl, wherein said alkylene is optionally substituted by oxo or halogen, and said phenyl is optionally substituted by halogen, C 1 -3 alkyl, -OR c or -NR c R d .
  • R 5 is -(C0-3 alkylene)NR a C(0)OR , wherein said alkylene is independently optionally substituted by halogen, oxo, -(C 0 -3 alkylene)CN, -(C 0 -3 alkylene)OR c , -(Co-3 alkylene)NR c R d , -(C 0-3 alkylene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(C0-3 alkylene)NR c C(0)R d , -(C0-3 alkylene)OC(0)NR c R d , -(C0-3 alkylene)NR c C(0)NR c R d , -(C 0-3 alkylene)NR c C(0)OR d , -(C 0-3 alkylene)S(O) 0
  • R 5 is selected from -CH 2 NHC(0)OCH 2 CH 3 and -CH 2 NHC(0)OCH 3 .
  • R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyano, 2-methylbutyl, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, methylsulfonylaminomethyl, 2-(methylsulfonylamino)ethyl, cyclopropylmethyl, 2-[N-(2- propylsulfonyl)amino] ethyl, 2-[N-(cyclopropylsulfonyl)-amino]ethyl, 2-
  • R 5 is methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, cyclopropyl, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -OCH 3 or -C(0)OEt.
  • R 5 is hydrogen, methyl, isopropyl, cyclopropyl, -NH 2 ,
  • R 6 is independently oxo, halogen, -CN, -C(0)R a , -C(0)OR a , -NR a C(0)R , -C(0)NR a R , -NR a C(0)NR a R , -OC(0)NR a R , -NR a C(0)OR , -S(0)i -2 R a , -NR a S(0) 2 R , -S(0) 2 NR a R , -OR a , -SR a , -NR a R , Ci -6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocycly or Ce-i4 aryl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN,
  • Ci -6 alkyl C 3-6 cycloalkyl or 3-7 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR c , -NR c R d or Ci -6 alkyl optionally substituted by halogen.
  • R 6 is independently oxo, F, CI, -CN, -OH, -C(0)CH 3 , -CH 2 CN, -CH 2 CH 2 CN, cyclopropyl, cyclobutyl, -CF 3 , -NHS(0) 2 CH 3 , -S(0) 2 CH 3 , -C(0)OCH 3 , pyrrolidinyl or pyrro dinonyl.
  • R 3 is optionally substituted by 1 to 3 R 6 independently selected from oxo, halogen, -CN, -S(0) 2 (Ci -6 alkyl), -OR a , -NR a R and Ci -6 alkyl, and wherein said alkyl is independently optionally substituted by halogen, oxo, -CN, -OR c or -NR c R d .
  • each R a and R are independently hydrogen, Ci-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, -C 3 - 6 cycloalkyl, -3-12 membered heterocyclyl, -C(0)3-12 membered heterocyclyl or ⁇ Ce-u aryl, wherein said alkyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR e , -NR e R f , -C(0)R g , -C(0)OR g , -C(0)NR3 ⁇ 4 h , -NR g C(0)R h , -OC(0)NR g R h , -NR g C(0)NR g R h , -NR g C(0)OR h , -S(0)i -2 R g , -NR g S(0)i -2 R h
  • each R a and R are independently hydrogen, Ci-6 alkyl, C 3 - 6 cycloalkyl, 3-6 membered heterocyclyl, -C(0)3-6 membered heterocyclyl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl and phenyl are independently optionally substituted by halogen, oxo, -CN, -OR e , -NR e R f , -C(0)R g , -C(0)OR g , -C(0)NR3 ⁇ 4 h , -NR g C(0)R h , -OC(0)NR g R h , -NR g C(0)NR g R h , -NR g C(0)OR h , -S(0)i -2 R g , -NR g S(0)i -2 R h , -S(0)i -2 NR g R , -NR g S(0)i -2 R h ,
  • each R a and R are independently hydrogen, C 1-6 alkyl, C 3 - 6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl are independently optionally substituted by halogen, oxo, -CN, -OR , -NR R f or C 1-3 alkyl optionally substituted by halogen.
  • each R a and R are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, -CF 3 , -CH 2 CF 3 , -CH 2 F, -CHF 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 ) 2 , cyclopropyl, 2,2-difluorocyclopropyl, 2-fluorocyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, pyrazolyl, N-methylpyrazolyl, azetidinyl,
  • a R a and a R are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_6 alkyl or C 1-6 alkyl optionally substituted by oxo, halogen, OR g or NR g NR h .
  • a R a and a R are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_6 alkyl or Ci-6 alkyl optionally substituted by halogen.
  • said heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, piperidinonyl, morpholinyl and 1,1-dioxomorpholinyl.
  • R a and R are taken together with the atom to which they are attached to form a 4-6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, optionally substituted by oxo, halogen, -C(0)Ci_6 alkyl or Ci-6 alkyl.
  • R a and R are independently hydrogen, methyl, isopropyl, cyclopropyl or cyclopentyl.
  • each R c and R d are independently hydrogen, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 -6 alkynyl, -C3-6 cycloalkyl, -3-12 membered heterocyclyl, -C(0)3-12 membered heterocyclyl or—Ce-u aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR g , -NR g R h , -C(0)R g , -C(0)OR g , -C(0)NR3 ⁇ 4 h , -NR g C(0)R h , -OC(0)NR g R h , -NR g
  • each R c and R d are independently hydrogen, C 1-6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, -C3-6 cycloalkyl, -3-6 membered heterocyclyl, -C(0)3-6 membered heterocyclyl or phenyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and phenyl are independently optionally substituted by halogen, oxo, -CN, -OR g , -NR g R h , -C(0)R g , -C(0)OR g , -C(0)NR3 ⁇ 4 h , -NR g C(0)R h , -OC(0)NR g R h , -NR g C(0)NR g R h , -NR g C(0)OR h , -S(0)i -2 R g , -NR3 ⁇ 4(0)i
  • each R c and R d are independently hydrogen, methyl, ethyl, isopropyl, butyl, t-butyl, sec-butyl, -CF 3 , "CH 2 CF 3 , -CH 2 F, -CHF 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 N(CH 3 ) 2 , cyclopropyl, 2,2- difluorocyclopropyl, 2-fluorocyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, pyrazolyl, N- methylpyrazolyl, azetidinyl, l ,l
  • a R c and a R d are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_6 alkyl or C 1-6 alkyl optionally substituted by oxo or halogen.
  • said heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, piperidinonyl, morpholinyl and 1 ,1 -dioxomorpholinyl.
  • each R c and R d are independently hydrogen, methyl or ethyl, optionally substituted by fluoro or oxo. In certain embodiments, each R c and R d are independently hydrogen, methyl or ethyl.
  • R c , R d , R , R f , R g and R h are independently hydrogen or methyl.
  • each R , R f , R g , R h are independently hydrogen, methyl, ethyl, propyl or isopropyl, optionally substituted by halogen or oxo.
  • each R , R , R g , R h are independently hydrogen, methyl or ethyl.
  • X is CR 4 ;
  • R 1 is piperidinyl, cyclopentyl or cyclohexyl
  • R 2 absent, methylene, ethylene, -NHCH 2 - , -C(0)0-, -C(0)NH-
  • R 3 is absent, hydrogen, methyl, ethyl, -CF 3 , -CH 2 CF 3 , -CH 2 CN, -(CH 2 ) 2 CN, -CH 2 cyclopropyl, cyclopropyl, phenyl, 3-cyanophenyl, 5-cyanopyridin-2-yl or pyridin-3-yl;
  • R 4 is hydrogen, F or methyl;
  • R 5 is methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, cyclopropyl, -NH 2 , -NH(CH 3 ),
  • each R a and R are independently hydrogen, C 1-3 alkyl or C 3 - 6 cycloalkyl, wherein said alkyl and cycloalkyl are independently optionally substituted by oxo or halogen; or are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen or C 1-3 alkyl; and each R c and R d are independently hydrogen or C 1-6 alkyl; or are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, or C 1-3- alkyl, wherein the wavy line represents the point of attachment in formula I.
  • -R x -R 2 -R 3 taken together are:
  • Compounds of the invention may contain one or more asymmetric carbon atoms.
  • the compounds may exist as diastereomers, enantiomers or mixtures thereof.
  • the syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated, or enantiomerically enriched, using the same techniques or others known in the art.
  • Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.
  • prodrugs of the compounds of formula I including known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the compound of formula I under physiologic conditions.
  • a particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl (-CO-R) group, an alkoxycarbonyl (-CO-OR), an acyloxyalkyl-alkoxycarbonyl (- CO-O-R-O-CO-R) group where R is a monovalent or divalent group, for example alkyl, alkylene or aryl, or a group having the formula -C(0)-0-CPlP2-haloalkyl, where PI and P2 are the same or different and are hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or ary
  • the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of formula I.
  • Prodrugs may be prepared by reacting a compound of formula I with an activated group, such as acyl groups, to bond, for example, a nitrogen atom in the compound of formula I to the exemplary carbonyl of the activated acyl group.
  • activated carbonyl compounds are those containing a leaving group bonded to the carbonyl group, and include, for example, acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl.
  • the reactions are generally carried out in inert solvents at reduced temperatures such as -78 to about 50°C.
  • the reactions may also be carried out in the presence of an inorganic base, for example potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, trimethylamine, triethylamine, triethanolamine, or the like.
  • Compounds of formula I may be synthesized by synthetic routes described herein.
  • processes well-known in the chemical arts can be used, in addition to, or in light of, the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967- 1999 ed.), Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)), or Comprehensive Heterocyclic Chemistry, Editors Katrizky and Rees, Pergamon Press, 1984.
  • Compounds of formula I may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds of formula I.
  • Libraries of compounds of formula I may be prepared by a combinatorial split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of formula I, enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof.
  • reaction schemes 1-10 depicted below provide routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, benzyl, phenylsulfonyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, benzyl, phenylsulfonyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • BOC t-butoxycarbonyl
  • Fmoc 9-fluorenylmethyleneoxycarbonyl
  • Compounds of Formula la can be synthesized as shown in Reaction Scheme 1.
  • commercially available 4-chloroazaindole can be protected with benzenesulfonyl chloride in the presence of 4-(dimethylamino)pyridine (DMAP) and a base such as triethylamine in a suitable solvent such as dichloromethane to give sulfonamide 2.
  • DMAP 4-(dimethylamino)pyridine
  • a base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Compound 4 can be prepared by treatment of compound 3 with a suitably protected diamine such as (i?)-l-benzyl-3-aminopiperidine in the presence of a base such as diisopropylethylamine in a compatible solvent such as propan-2-ol at temperatures between ambient and 150 °C. Reduction of compound 4 can be accomplished using a suitable reducing agent such as iron in the presence of ammonium chloride in a compatible solvent such as aqueous ethanol to afford diamine compound 5.
  • a suitably protected diamine such as (i?)-l-benzyl-3-aminopiperidine
  • a base such as diisopropylethylamine
  • a compatible solvent such as propan-2-ol
  • Compounds of Formula lb can be synthesized as shown in Reaction Scheme 2.
  • compound 7 can be prepared by treatment of compound 3 with a suitably protected diamine such as 1 -benzyl-4-aminopiperidine in the presence of a base such as diisopropylethylamine in a suitable solvent such as propan-2-ol at temperatures between ambient and 150 °C.
  • Reduction of compound 7 can be accomplished using a suitable reducing agent such as iron in the presence of ammonium chloride in a solvent such as aqueous ethanol to afford diamine compound 8.
  • compound 10 can be prepared by treatment of compound 3 with a suitably protected diamine such as (R)-l-boc-3-aminopiperidine in the presence of a base such as diisopropylethylamine.
  • a suitable reducing agent such as iron in the presence of ammonium chloride in a solvent such as aqueous ethanol to afford diamine compound 11.
  • Reaction of compound 11 with a 2-oxocarboxylic such as glyoxylic acid followed by cyclisation using a suitable amide coupling reagent such as HATU and a base such as diisopropylethylamine gives compound 12.
  • Sulfonamides can be prepared from compounds of Formula le by reaction with for example a suitable sulfonyl chloride in the presence of a base such as triethylamine to give compounds of Formula
  • Amides can be prepared from compounds of Formula le by reaction with for example a suitable carboxylic acid and in the presence of a suitable coupling reagent such as HATU and base such as diisopropylethylamine to give compounds of Formula lg.
  • Compounds of Formula le can be alkylated with for example a suitable 2-substituted ethene in a suitable solvent such as ethanol at a temperature between ambient and 100 °C to give compounds of Formula lh.
  • Compounds of Formula 11 and lm can be prepared as shown in Reaction Scheme 6.
  • reaction of compound 14 with a 2-oxocarboxylic acid such as pyruvic acid followed by cyclisation using a suitable amide coupling reagent such as HATU and a base such as diisopropylethylamine gives compound 20.
  • Hydrolysis of compound 20 with aqueous sodium hydroxide in methanol gives compound 21.
  • Deprotection of compound 21 under acidic conditions such as HCl in dioxane provides compounds of Formula 11.
  • Compounds of Formula 11 can be alkylated with for example a suitable 2-substituted ethene in a suitable solvent such as ethanol at a temperature between ambient and 100 °C to give compounds of Formula lm.
  • Compound 27 can also be prepared as shown in Reaction Scheme 8. For example, halogenation, amination and deprotection gives compound 33. Derivitizing the deprotected amine and deprotection gives 27.
  • primary amine or secondary amine groups may be converted into amide groups (-NHCOR' or -NRCOR') by acylation.
  • Acylation may be achieved by reaction with an appropriate acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reaction with an appropriate carboxylic acid in the presence of a suitable coupling agent such HATU (0-(7-azabenzotriazol-l -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate) in a suitable solvent such as dichloromethane.
  • a suitable coupling agent such as HATU (0-(7-azabenzotriazol-l -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • amine groups may be converted into sulfonamide groups (-NHSO 2 R' or -NR"S0 2 R') groups by reaction with an appropriate sulfonyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane.
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Primary or secondary amine groups can be converted into urea groups (-NHCONR'R" or -NRCONR'R”) by reaction with an appropriate isocyanate in the presence or absence of a suitable base such as triethylamine, in a suitable solvent, such as dichloromethane.
  • An amine (-NH 2 ) may be obtained by reduction of a nitro (-N0 2 ) group, for example by catalytic hydrogenation, using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol.
  • the transformation may be carried out by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • amine (-CH 2 NH 2 ) groups may be obtained by reduction of nitriles (- CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, at an appropriate temperature, for example from about -78 °C to the reflux temperature of the solvent.
  • a metal catalyst for example palladium on a support such as carbon, or Raney nickel
  • Aldehyde groups may be converted to amine groups (-CH 2 NR'R")) by reductive amination employing an amine and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol such as methanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • a borohydride for example sodium triacetoxyborohydride or sodium cyanoborohydride
  • a solvent such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol such as methanol
  • Aldehyde groups may be obtained by reduction of ester groups (such as -C0 2 Et) or nitriles (-CN) using diisobutylaluminum hydride in a suitable solvent such as toluene.
  • ester groups such as -C0 2 Et
  • -CN nitriles
  • aldehyde groups may be obtained by the oxidation of alcohol groups using any suitable oxidising agent known to those skilled in the art.
  • Ester groups (-CO 2 R') may be converted into the corresponding acid group (-CO 2 H) by acid- or base-catalysed hydrolysis, depending on the nature of R. If R is /-butyl, acid-catalysed hydrolysis can be achieved for example by treatment with an organic acid such as trifluoroacetic acid in an aqueous solvent, or by treatment with an inorganic acid such as hydrochloric acid in an aqueous solvent.
  • Carboxylic acid groups may be converted into amides (CONHR' or - CONR'R") by reaction with an appropriate amine in the presence of a suitable coupling agent, such as HATU, in a suitable solvent such as dichloromethane.
  • a suitable coupling agent such as HATU
  • carboxylic acids may be homologated by one carbon (i.e. -C0 2 H to -CH 2 CO 2 H) by conversion to the corresponding acid chloride (-COC1) followed by Arndt-Eistert synthesis.
  • -OH groups may be generated from the corresponding ester (e.g. - CO 2 R'), or aldehyde (-CHO) by reduction, using for example a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol.
  • a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol.
  • an alcohol may be prepared by reduction of the corresponding acid (-CO 2 H), using for example lithium aluminium hydride in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. /7-toluenesulfonyloxy group using conditions known to those skilled in the art.
  • halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. /7-toluenesulfonyloxy group using conditions known to those skilled in the art.
  • an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.
  • a base e.g. triethylamine
  • alcohol, phenol or amide groups may be alkylated by coupling a phenol or amide with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate.
  • alkylation may be achieved by deprotonation using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkyl halide.
  • Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange by treatment with a base, for example a lithium base such as w-butyl or /-butyl lithium, optionally at a low temperature, e.g. around -78 °C, in a solvent such as tetrahydrofuran, and then quenched with an electrophile to introduce a desired substituent.
  • a base for example a lithium base such as w-butyl or /-butyl lithium
  • a solvent such as tetrahydrofuran
  • an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using N,N-dimethylformamide as the electrophile.
  • Aromatic halogen substituents may alternatively be subjected to metal (e.g.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization or trituration from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; supercritical fluid; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LD ), or the like.
  • Example separation methods include boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like.
  • One skilled in the art will apply techniques most likely to achieve the desired separation.
  • Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column or supercritical fluid chromatography.
  • a single stereoisomer, e.g. an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., J. Chromatogr., 113(3):283-302 (1975)).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • suitable method including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • Diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-P-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g.
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography W. J. Lough, Ed., Chapman and Hall, New York, (1989); Okamoto, J. of Chromatogr. 513 :375-378 (1990)).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • the absolute stereochemistry of chiral centers and enatiomers can be determined by x-ray crystallography.
  • Positional isomers for example E and Z forms, of compounds of formula I, and intermediates for their synthesis, may be observed by characterization methods such as NMR and analytical HPLC. For certain compounds where the energy barrier for interconversion is sufficiently high, the E and Z isomers may be separated, for example by preparatory HPLC.
  • compounds of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends on the particular use and the concentration of compound, and can range anywhere from about 3 to about 8.
  • a compound of formula I is formulated in an acetate buffer, at pH 5.
  • the compounds of formula I are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhaled and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, vapors, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • An example of a suitable oral dosage form is a tablet containing about 2 mg, 5 mg, 25mg, 50mg, lOOmg, 250mg, or 500mg of the compound of the present invention compounded with about 95-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30mg polyvinylpyrrolidone (PVP) K30, and about e.g., 1-10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound of the present invention, for example 5-400 mg, in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • the solution may be filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.
  • An embodiment therefore, includes a pharmaceutical composition comprising a compound of formula I, stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a compound of formula I, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Certain embodiments includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of a hyperproliferative disease. Certain embodiments includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of cancer. Certain embodiments includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of an immunological disorder.
  • Certain embodiments includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD) or asthma.
  • Certain embodiments includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, IBD and transplant rejection.
  • the compounds of Formula I inhibit the activity of JAK1 kinase. Accordingly, the compounds of Formula I inhibit the phosphorylation of signal transducers and activators of transcription (STATs) by JAK1 kinase as well as STAT mediated cytokine production.
  • STATs signal transducers and activators of transcription
  • Compounds of Formula I are useful for inhibiting JAK1 kinase activity in cells through cytokine pathways, such as IL-6, IL-15, IL-7, IL-2, IL-4, IL-9, IL-10, IL-13, IL-21 , G-CSF, IFNalpha, IFNbeta or IFNgamma pathways.
  • the compounds of Formula I can be used for the treatment of immunological disorders driven by aberrant IL-6, IL-15, IL-7, IL-2, IL-4, IL9, IL-10, IL-13, IL- 21 , G-CSF, IFNalpha, IFNbeta or IFNgamma cytokine signaling.
  • Certain embodiments includes a method of treating or lessening the severity of a disease or condition responsive to the inhibition of JAK1 kinase activity in a patient. The method includes the step of administering to a patient a therapeutically effective amount of a compound of the present invention.
  • the disease or condition is cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, CNS disorders or a myeloproliferative disorder.
  • the disease or condition is cancer.
  • the disease is a myeloproliferative disorder.
  • the myeloproliferative disorder is polycythemia vera, essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia (CML).
  • the cancer is breast, ovary, cervix, prostate, testis, penile, genitourinary tract, seminoma, esophagus, larynx, gastric, stomach, gastrointestinal, skin, keratoacanthoma, follicular carcinoma, melanoma, lung, small cell lung carcinoma, non-small cell lung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of the lung, colon, pancreas, thyroid, papillary, bladder, liver, biliary passage, kidney, bone, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, salivary gland, pharynx, small intestine, colon, rectum, anal, renal, prostate, vulval, thyroid, large intestine, endometrial, uterine, brain, central nervous system, cancer of the peritoneum, hepatocellular cancer, head cancer, neck cancer
  • the cardiovascular disease is restenosis, cardiomegaly, atherosclerosis, myocardial infarction or congestive heart failure.
  • the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or hypoxia.
  • the inflammatory diseases is rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, contact dermatitis or delayed hypersensitivity reactions.
  • the autoimmune disease is lupus or multiple sclerosis.
  • the disease or condition responsive to the inhibition of JAKl kinase is rheumatoid arthritis.
  • the disease or condition responsive to the inhibition of JAKl kinase is asthma, inflammatory bowel disease, Crohn's disease, pouchitis, microscopic colitis, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, delayed hypersensitivity reactions, lupus or multiple sclerosis.
  • the disease or condition responsive to the inhibition of JAKl kinase is rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, USD or transplant rejection.
  • Certain embodiments includes a method of treating cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • Certain embodiments includes compounds of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in therapy.
  • the therapy is the treatment of an immunological disorder, for example rheumatoid arthritis.
  • the therapy is the treatment of cancer.
  • Certain embodiments includes compounds of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in treating a disease selected from rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, USD and transplant rejection. Certain embodiments includes the use of a compound of formulas I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease described herein (e.g., cancer or immunological disorder).
  • a disease described herein e.g., cancer or immunological disorder
  • Evaluation of drug-induced immunosuppression by the compounds of the invention may be performed using in vivo functional tests, such as rodent models of induced arthritis and therapeutic or prophylactic treatment to assess disease score, T cell-dependent antibody response (TDAR), and delayed-type hypersensitivity (DTH).
  • Other in vivo systems including murine models of host defense against infections or tumor resistance (Burleson GR, Dean JH, and Munson AE. Methods in Immunotoxicology, Vol. 1. Wiley -Liss, New York, 1995) may be considered to elucidate the nature or mechanisms of observed immunosuppression.
  • the in vivo test systems can be complemented by well-established in vitro or ex vivo functional assays for the assessment of immune competence.
  • These assays may comprise B or T cell proliferation in response to mitogens or specific antigens, measurement of signaling through one or more of the Janus kinase pathways in B or T cells or immortalized B or T cell lines, measurement of cell surface markers in response to B or T cell signaling, natural killer (NK) cell activity, mast cell activity, mast cell degranulation, macrophage phagocytosis or kill activity, and neutrophil oxidative burst and/or chemotaxis.
  • NK natural killer
  • NK natural killer
  • mast cell activity mast cell activity
  • mast cell degranulation macrophage phagocytosis or kill activity
  • neutrophil oxidative burst and/or chemotaxis may be included.
  • the in vitro and ex vivo assays can be applied in both preclinical and clinical testing using lymphoid tissues and/or peripheral blood (House RV. "Theory and practice of cytokine assessment in immunotoxicology” (1999) Methods 19:17-27; Hubbard AK. "Effects of xenobiotics on macrophage function: evaluation in vitro” (1999) Methods;19:8-16; Lebrec H, et al (2001) Toxicology 158:25-29).
  • Collagen-induced arthritis is an animal model of human rheumatoid arthritis (RA). Joint inflammation, which develops in animals with CIA, strongly resembles inflammation observed in patients with rheumatoid arthritis (RA). Blocking tumor necrosis factor (TNF) is an efficacious treatment of CIA, just as it is a highly efficacious therapy in treatment of RA patients.
  • CIA is mediated by both T-cells and antibodies (B-cells). Macrophages are believed to play an important role in mediating tissue damage during disease development.
  • CIA is induced by immunizing animals with collagen emulsified in Complete Freund's Adjuvant (CFA). It is most commonly induced in the DBA/1 mouse strain, but the disease can also be induced in Lewis rats.
  • CFA Complete Freund's Adjuvant
  • the T-cell Dependent Antibody Response is An assay for immune function testing when potential immunotoxic effects of compounds need to be studied.
  • TDAR is an assay for adult exposure immunotoxicity detection in mice based on the US National Toxicology Program (NTP) database (Ml. Luster et al (1992) Fundam. Appl. Toxicol. 18:200-210).
  • NTP National Toxicology Program
  • a TDAR is dependent on functions of the following cellular compartments: (1) antigen-presenting cells, such as macrophages or dendritic cells; (2) T-helper cells, which are critical players in the genesis of the response, as well as in isotype switching; and (3) B-cells, which are the ultimate effector cells and are responsible for antibody production.
  • antigen-presenting cells such as macrophages or dendritic cells
  • T-helper cells which are critical players in the genesis of the response, as well as in isotype switching
  • B-cells which are the ultimate effector cells and are responsible for antibody production.
  • Chemically-induced changes in any one compartment can cause significant changes in the overall TDAR (M.P. Holsapple In: G.R Burleson, J.H. Dean and AE. Munson, Editors, Modern Methods in Immunotoxicology, Volume 1, Wiley-Liss Publishers, New York, NY (1995), pp. 71- 108).
  • this assay is performed either as an ELISA for measurement of soluble antibody (RJ. Smialowizc et al (2001) Toxicol. Sci. 61 :164-175) or as a plaque (or antibody) forming cell assay (L. Guo et al (2002) Toxicol. Appl. Pharmacol. 181 :219-227) to detect plasma cells secreting antigen specific antibodies.
  • the antigen of choice is either whole cells (e.g. sheep erythrocytes) or soluble protein antigens (T. Miller et al (1998) Toxicol. Sci. 42:129-135).
  • a compound of Formula I may be administered by any route appropriate to the disease or condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal.
  • routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal.
  • the routes may vary with for example the condition of the recipient. Where the compound of Formula I is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient. Where the compound of Formula I is administered parenterally, it may be formulated with a pharmaceutically acceptable parenter
  • a dose to treat human patients may range from about 5 mg to about 1000 mg of a compound of Formula I.
  • a typical dose may be about 5 mg to about 300 mg of a compound of Formula I.
  • a dose may be administered once a day (QD), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound.
  • QD once a day
  • BID twice per day
  • toxicity factors may influence the dosage and administration regimen.
  • the pill, capsule, or tablet When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.
  • the compounds of formula I may be employed alone or in combination with other chemotherapeutic agents for treatment.
  • the compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-hyperproliferative, anti- cancer, cytostatic, cytotoxic, anti-inflammatory or chemotherapeutic agent.
  • the second compound of the pharmaceutical combination formulation or dosing regimen in one example, has complementary activities to the compound of this invention such that they do not adversely affect each other.
  • Such agents are suitably present in combination in amounts that are effective for the purpose intended.
  • the compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time.
  • compounds of the present invention are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C.
  • the cytostatic compound is doxorubicin.
  • compounds of the present invention are coadministered with an anti-inflammatory agent selected from a NSAID and corticosteroid.
  • compounds of the present invention are coadministered with an anti-rheumatoid agent, in one example, RITUXAN®.
  • compounds of the present invention are coadministered with a chemotherapeutic agent selected from etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (TL-1) blockers such as anakinra (Kineret), monoclonal antibodies against B cells such as rituximab (RITUXAN®), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (TL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (XL- 13) blockers such as lebrikizumab; Interferon alpha (TEN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Mi prime; Secreted homo
  • the compounds of the present invention can be also used in combination with radiation therapy.
  • radiation therapy refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia. Radiation therapy delivers doses of radiation sufficiently high to a target area to cause death of reproducing cells, in both tumor and normal tissues.
  • the radiation dosage regimen is generally defined in terms of radiation absorbed dose (rad), time and fractionation, and must be carefully defined by the oncologist. The amount of radiation a patient receives will depend on various considerations but two of the most important considerations are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread.
  • radiotherapeutic agents are provided in Hellman, Principles of Radiation Therapy, Cancer, in Principles I and Practice of Oncology, 24875 (Devita et al, 4th ed., vol 1, 1993).
  • Alternative forms of radiation therapy include three- dimensional conformal external beam radiation, intensity modulated radiation therapy (IMRT), stereotactic radiosurgery and brachytherapy (interstitial radiation therapy), the latter placing the source of radiation directly into the tumor as implanted "seeds".
  • IMRT intensity modulated radiation therapy
  • stereotactic radiosurgery stereotactic radiosurgery
  • brachytherapy interstitial radiation therapy
  • compounds of the present invention are coadministered with any of anti-IBD agents, including but not limited to anti-inflammatory drugs, such as sulfasalazine, mesalamine or corticosteroids, such as budesonide, prednisone, cortisone or hydrocortisone, immune suppressing agents, such as azathioprine, mercaptopurine, infliximab, adalimumab, certolizumab pegol, methotrexate, cyclosporine or natalizumab, antibiotics, such as metronidazole or ciprofloxacin, anti-diarrheals, such as psyllium powder, loperamide or methylcellulose, laxatives, pain relievers, such as NSAIDs or acetaminophen, iron supplements, vitamin B supplements, vitamin D supplements and any combination of the above.
  • compounds of the present invention are administered with (e.g. before, during
  • compounds of the present invention are coadministered with any of anti-psoriasis agents, including but not limited to topical corticosteroids, vitamin D analogues, such as calcipotriene or calcitriol, anthralin, topical retinoids, such as tazarotene, calcineurin inhibitors, such as tacrolimus or pimecrolimus, salicylic acid, coal tar, NSAIDs, moisturizing creams and ointments, oral or injectible retinoids, such as acitretin, methotrexate, cyclosporine, hydroxyurea, immunomodulator drugs, such as alefacept, etanercept, infliximab or ustekinumab, thioguanine, and any combinations of the above.
  • topical corticosteroids including but not limited to topical corticosteroids, vitamin D analogues, such as calcipotriene or calcitriol, anthral
  • compounds of the present invention are administered with (e.g. before, during or after) other anti-psoriasis therapies, such as light therapy, sunlight therapy, UVB therarpy, narrow-band UVB therapy, Goeckerman therapy, photochemotherapy, such as psoralen plus ultraviolet A (PUVA), excimer and pulsed dye laser therapy, or in any combination of antipsoriasis agents and anti-psoriasis therapies.
  • compounds of the present invention are coadministered with any of anti-asthmtic agents, including but not limited to beta2-adrenergic agonists, inhaled and oral corticosteroids, leukotriene receptor antagonist, and omalizumab.
  • compounds of the present invention are coadministered with an anti-asthmtic agent selected from a NSAK), combinations of fluticasone and salmeterol, combinations of budesonide and formoterol, omalizumab, !ebrikizumab and corticosteroid selected from fluticasone, budesonide, mometasone, flunisolide and beclomethasone.
  • an anti-asthmtic agent selected from a NSAK
  • Another embodiment includes a method of manufacturing a compound of formula I.
  • the method inlcudes: (a) reacting a compound of formula i:
  • R 1 , R 2 , R 3 and X are as defined in formula I, and Z is hydrogen or an amino protecting group, with a compound of formula ii: wherein R 5 is defined in formula I and Lg is a leaving group, under conditions sufficient to form a compound of formula iii:
  • Lg is hydrogen, halogen or C 1 -3 alkyl.
  • R 5 is hydrogen or Ci- 12 alkyl optionally substituted by halogen, oxo, -(C 0-3 alkylene)CN, -(C 0-3 alkylene)OR c , -(C 0-3 alkylene)NR c R d , -(C 0-3 alkylene)C(0)R c , -(C 0-3 alkylene)C(0)OR c , -(C 0-3 alkylene)C(0)NR c R d , -(C 0-3
  • kit further includes:
  • a second pharmaceutical composition which includes a chemotherapeutic agent.
  • the instructions describe the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof.
  • the first and second compositions are contained in separate containers.
  • the first and second compositions are contained in the same container.
  • Containers for use include, for example, bottles, vials, syringes, blister pack, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container includes a compound of formula I or formulation thereof which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the container includes a composition comprising at least one compound of formula I.
  • the label or package insert indicates that the composition is used for treating the condition of choice, such as cancer.
  • the label or package inserts indicates that the composition comprising the compound of formula I can be used to treat a disorder.
  • the label or package insert may indicate that the patient to be treated is one having a disorder characterized by overactive or irregular kinase activity.
  • the label or package insert may also indicate that the composition can be used to treat other disorders.
  • the article of manufacture may comprise (a) a first container with a compound of formula I contained therein; and (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a chemotherapeutic agent.
  • the article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the first and second compounds can be used to treat patients at risk of stroke, thrombus or thrombosis disorder.
  • the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically -acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI),
  • HM-N Isolute® HM-N is a modified form of diatomaceous earth
  • Example compounds were analysed using the following conditions: Experiments performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector.
  • the spectrometer has an electrospray source operating in positive and negative ion mode.
  • This system uses an Acquity BEH CI 8 1.7um 100 x 2.1mm column, maintained at 40°C or an Acquity BEH Shield RP18 1.7 ⁇ 100 x 2.1mm column, maintained at 40°C and a ml / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.6 minutes. This was maintained for 0.8 minute before returning to 95% solvent A and 5% solvent B over the next 1.2 minutes. Total run time was 8 minutes.
  • Method B Intermediates were analysed using the following conditions: Experiments performed on a Finnigan AQA single quadrupole mass spectrometer linked to a Hewlett Packard 1050 LC system with UV diode array detector and autosampler.
  • the spectrometer has an electrospray source operating in positive ion mode. Additional detection is achieved using a Sedex 65 evaporative light scattering detector.
  • This system uses an Luna 3micron CI 8(2) 30 x 4.6mm column at ambient temperature, and a 2.0 ml / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4.0 minutes. This was maintained for 1.0 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.
  • UV wavelength 220nm and 254nm
  • HPLC Reverse Phase High Pressure Liquid Chromatography
  • Microwave experiments were carried out using a Biotage Initiator 2.0 (400 W magnetron)TM which uses a single-mode resonator and dynamic field tuning. Temperature from 40-250°C can be achieved, and pressures of up to 20 bar can be reached.
  • the catalytically active kinase domain of human JAKl, JAK2, JAK3 or TYK2 was purified from extracts of SF9 insect cells infected with a recombinant baculovirus expression vector encoding the human JAKl, JAK2, JAK3 or TYK2 kinase domains (JAKl amino acid residues N852-D1154 according to the numbering of GenBank sequence accession number P23458, JAK2 amino acid residues D812-G1132 according to the numbering of GenBank sequence accession number NP 004963.1 ; JAK3 amino acid residues S783-S1124 according to the numbering of GenBank sequence accession number P52333, and TYK2 amino acid residues N873-C1187 according to the numbering of GenBank sequence accession number P29597).
  • the activity of the JAKl, JAK2, JAK3 or TYK2 kinase domains can be measured by a number of direct and indirect methods, including quantification of phosphorylation of peptide substrates derived from the human JAK3 protein (Saltzman et al, Biochem. Biophys. Res. Commun. 246:627-633 (2004)).
  • the activity of the JAKl , JAK2, JAK3 or TYK2 kinase domains was measured in vitro by monitoring phosphorylation of JAK3 derived peptides using the Caliper LabChip technology.
  • the activity of the isolated JAKl, JAK2 or TYK2 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Val-Ala-Leu-Val-Asp-Gly-Tyr- Phe-Arg-Leu-Thr-Thr) fluorescently labeled on the N-terminus with 5-carboxyfluorescein using the Caliper LabChip technology (Caliper Life Sciences, Hopkinton, MA).
  • Ki inhibition constants
  • the activity of the isolated JAK3 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Tyr-Val-Val- Arg) fluorescently labeled on the N-terminus with 5-carboxyfluorescein using the Caliper LabChip technology (Caliper Life Sciences, Hopkinton, MA).
  • Ki inhibition constants
  • NK92 cells American Type Culture Collection (ATCC); Manassas, VA) in 384-well microtiter plates in RPMI medium at a final cell density of 50,000 cells per well and a final DMSO concentration of 0.2%.
  • Human recombinant IL-12 R&D systems; Minneapolis, MN was then added at a final concentration of 30ng/ml to the microtiter plates containing the NK92 cells and compound and the plates were incubated for 45 min at 37oC.
  • Compound-mediated effects on STAT4 phosphorylation were then measured in the lysates of incubated cells using the Meso Scale Discovery (MSD) technology (Gaithersburg, Maryland) according to the manufacturer's protocol and EC50 values were determined.
  • MSD Meso Scale Discovery
  • the activities of compounds were determined in cell-based assays that are designed to measure JAKl or JAK2- dependent signaling.
  • Compounds were serially diluted in DMSO and incubated with TF-1 cells (American Type Culture Collection (ATCC); Manassas, VA) in 384- well microtiter plates in OptiMEM medium without phenol red, 1% Charcoal/Dextran stripped FBS, 0.1 mM NEAA, lmM sodium pyruvate (Invitrogen Corp.; Carlsbad, CA) at a final cell density of 100,000 cells per well and a final DMSO concentration of 0.2%.
  • ATCC American Type Culture Collection
  • VA Manassas, VA
  • OptiMEM medium without phenol red
  • Charcoal/Dextran stripped FBS 0.1 mM NEAA
  • lmM sodium pyruvate Invitrogen Corp.; Carlsbad, CA
  • IL-6 Human recombinant IL-6 (R&D systems; Minneapolis, MN) or EPO (Invitrogen Corp.; Carlsbad, CA) was then added at a final concentration of 30 ng/ml or 10 Units/ml, respectively, to the microtiter plates containing the TF-1 cells and compound and the plates were incubated for 30 min at 37oC.
  • Compound-mediated effects on STAT3 or STAT5 phosphorylation were then measured in the lysates of cells incubated in the presence of IL-6 or EPO, respectively, using the Meso Scale Discovery (MSD) technology (Gaithersburg, Maryland) according to the manufacturer's protocol and EC50 values were determined.
  • MSD Meso Scale Discovery
  • Examples 1-56 and 58 were tested for their capacity to inhibit JAKl kinase activity.
  • the compounds of Examples 1-56 and 58 were found to have a K of about 1 ⁇ or less in a JAKl kinase activity assay (Example A).
  • Tetrabutylammonium nitrate (381 mg, 1.25 mmol) dissolved in DCM (5 ml) was added dropwise to a stirred solution of l-benzenesulfonyl-4-chloro-lH-pyrrolo[2,3-b]pyridine (293 mg, 1.00 mmol) in DCM (5 ml) at -5 °C.
  • Trifluoroacetic anhydride (180 ⁇ , 1.29 mmol) was added whilst maintaining the reaction temperature below 0 °C. The mixture was then stirred at -5 °C for 30 minutes and ambient temperature for 5 hours.
  • HATU (57.0 mg, 0.15 mmol) was added to a suspension of (R)-9-piperidin-3-yl-3,9- dihydro-3,4,6,9-tetraaza-cyclopenta[a]naphthalene-8-one (37.0 mg, 0.14 mmol), cyanoacetic acid (12.0 mg, 0.14 mmol) and diisopropylethylamine (47.0 ⁇ ⁇ , 0.27 mmol) in THF (3 mL) under argon and stirred for 18 hours.
  • the isolated solid was suspended in acetonitrile and water (1 : 1), filtered and air dried, then triturated (DCM with minimal methanol) and air dried to give [4-(8-oxo-3,8-dihydro-3,4,6,9-tetraaza-cyclopenta[a]naphthalene-9-yl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid.
  • the mixture was diluted with DCM, washed (saturated sodium bicarbonate solution, water and brine), dried (sodium sulfate) and concentrated under vacuum to leave a yellow/ orange foam. This was taken up in toluene and heated at reflux for 70 hours.
  • Example A Examples of the JAKl inhibition (Example A) are shown in the below Table 2.

Abstract

L'invention concerne de nouveaux composés de formule I ayant la formule générale (I) où X, R1, R2, R3 et R5 sont tels que décrits présentement. Selon l'invention, les composés peuvent être apportés dans des compositions pharmaceutiquement acceptables et utilisés pour le traitement de troubles immunologiques ou hyperprolifératifs.
PCT/EP2011/073734 2010-12-23 2011-12-22 Composés pyrazinones tricycliques, leurs compositions et leurs procédés d'utilisation en tant qu'inhibiteurs de janus kinase WO2012085176A1 (fr)

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