WO2010010189A1 - Novel compounds useful for the treatment of degenerative and inflammatory diseases - Google Patents

Novel compounds useful for the treatment of degenerative and inflammatory diseases Download PDF

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WO2010010189A1
WO2010010189A1 PCT/EP2009/059603 EP2009059603W WO2010010189A1 WO 2010010189 A1 WO2010010189 A1 WO 2010010189A1 EP 2009059603 W EP2009059603 W EP 2009059603W WO 2010010189 A1 WO2010010189 A1 WO 2010010189A1
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unsubstituted
substituted
compound
pharmaceutically acceptable
acceptable salt
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PCT/EP2009/059603
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Christel Jeanne Marie Menet
Javier Blanc
Nolwenn Jouannigot
Alastair James Hodges
Luc Juliaan Corina Van Rompaey
Stephen Robert Fletcher
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Galapagos Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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

  • the present invention relates to compounds that are inhibitors of JAK, a family of tyrosine kinases that are involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds, methods for the prevention and/or treatment of diseases involving cartilage degradation, bone and/or joint degradation, conditions involving inflammation or immune responses, endotoxin- driven disease states, cancer, and organ transplant rejection; and/ or methods for the prevention and/or treatment of diseases involving cartilage degradation, joint degradation and/or inflammation by administering a compound of the invention.
  • Janus kinases are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors.
  • JAK family members Four JAK family members are described, JAKl, JAK2, JAK3 and TYK2.
  • JAK family members Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription.
  • JAK-STAT intracellular signal transduction serves the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, PRL Vainchenker W. et al (2008).
  • JAK3 is validated by mouse and human genetics as an immune- suppression target (O'Shea J. et al. (2004)). JAK3 inhibitors were successfully taken into clinical development, initially for organ transplant rejection but later also in other immuno-inflammatory indications such as rheumathoid arthritis (RA), psoriasis and Crohn's disease (http://clinicaltrials.gov/).
  • RA rheumathoid arthritis
  • psoriasis http://clinicaltrials.gov/.
  • TYK2 is a potential target for immuno-inflammatory diseases, being validated by human genetics and mouse knock-out studies (Levy D. and Loomis C. (2007)).
  • JAKl is a novel target in the immuno-inflammatory disease area. JAKl heterodimerizes with the other JAKs to transduce cytokine- driven pro-inflammatory signaling. Therefore, inhibition of JAKl and/or other JAKs is expected to be of therapeutic benefit for a range of inflammatory conditions as well as for other diseases driven by JAK-mediated signal transduction.
  • Cartilage is an avascular tissue of which chondrocytes are the main cellular component.
  • the chondrocytes in normal articular cartilage occupy approximately 5% of the tissue volume, while the extra- cellular matrix makes up the remaining 95% of the tissue.
  • the chondrocytes secrete the components of the matrix, mainly proteoglycans and collagens, which in turn supply the chondrocytes with an environment suitable for their survival under mechanical stress.
  • collagen type II together with the protein collagen type IX, is arranged in solid fibril-like structures which provide cartilage with great mechanical strength.
  • the proteoglycans can absorb water and are responsible for the resilient and shock absorbing properties of the cartilage.
  • cartilage degradation is caused by the secretion of proteases (e.g. collagenases) by inflamed tissues (the inflamed synovium for example).
  • cartilage degradation can also be the result of an injury of the cartilage, due to an accident or surgery, or exaggerated loading or 'wear and tear'.
  • the ability of cartilage tissue to regenerate after such insults is limited. Chondrocytes in injured cartilage often display reduced cartilage synthesizing (anabolic) activity and / or increased cartilage degrading (catabolic) activity.
  • RA Rheumatoid arthritis
  • osteoarthritis are the most prominent.
  • RA Rheumatoid arthritis
  • the aim of an RA therapy is not only to slow down the disease but to attain remission in order to stop the joint destruction.
  • the high prevalence of RA ⁇ 0.8% of the adults are affected worldwide
  • Osteoarthritis also referred to as OA, or wear-and-tear arthritis
  • OA wear-and-tear arthritis
  • the disease mainly affects hands and weight-bearing joints such as knees, hips and spines. This process thins the cartilage. When the surface area has disappeared due to the thinning, a grade I osteoarthritis is reached; when the tangential surface area has disappeared, grade II osteoarthritis is reached.
  • Osteoarthritis is difficult to treat. At present, no cure is available and treatment focuses on relieving pain and preventing the affected joint from becoming deformed. Common treatments include the use of non-steroidal anti-inflammatory drugs (NSAIDs). Although dietary supplements such as chondroitin and glucosamine sulphate have been advocated as safe and effective options for the treatment of osteoarthritis, a recent clinical trial revealed that both treatments did not reduce pain associated to osteoarthritis. (Clegg et ah,
  • chondral cellular material is taken from the patient, sent to a laboratory where it is expanded. The material is then implanted in the damaged tissues to cover the tissue's defects.
  • Another treatment includes the intra-articular instillation of Hylan G-F 20 (e.g. Synvisc®,
  • Hyalgan®, Artz® a substance that improves temporarily the rheology of the synovial fluid, producing an almost immediate sensation of free movement and a marked reduction of pain.
  • Stimulation of the anabolic processes, blocking catabolic processes, or a combination of these two, may result in stabilization of the cartilage, and perhaps even reversion of the damage, and therefore prevent further progression of the disease.
  • Various triggers may stimulate anabolic stimulation of chondrocytes.
  • IGF-I Insulin-like growth factor-I
  • BMP bone morphogenetic protein
  • TGF- ⁇ human transforming growth factor- ⁇
  • JAKl belongs to the Janus kinase (JAK) family of cytoplasmic tyrosine kinases, involved in cytokine receptor-mediated intracellular signal transduction.
  • the JAK family consists of 4 members: JAKl, JAK2, JAK3 and TYK2. JAKs are recruited to cytokine receptors, upon binding of the cytokine, followed by heterodimerization of the cytokine receptor and a shared receptor subunit (common gamma-c chain, gpl30).
  • JAKs are then activated by auto- and/or transphosphorylation by another JAK, resulting in phosphorylation of the receptors and recruitment and phosphorylation of members of the signal transducer and activator of transcription (STATs).
  • STATs signal transducer and activator of transcription
  • Phosphorylated STATs dimerize and translocate to the nucleus where they bind to enhancer regions of cytokine-responsive genes.
  • Knockout of the JAKl gene in mice demonstrated that JAKl plays essential and nonredundant roles during development: JAKl-/- mice died within 24h after birth and lymphocyte development was severely impaired.
  • JAKl -/- cells were not, or less, reactive to cytokines that use class II cytokine receptors, cytokine receptors that use the gamma-c subunit for signaling and the family of cytokine receptors that use the gpl30 subunit for signaling (Rodig et al., 1998).
  • JAK family members have been implicated in additional conditions including myeloproliferative disorders (O'Sullivan et al, 2007, MoI Immunol. 44(10):2497-506), where mutations in JAK2 have been identified. This indicates that inhibitors of JAK in particular JAK2 may also be of use in the treatment of myeloproliferative disorders. Additionally, the JAK family, in particular JAKl, JAK2 and JAK3, has been linked to cancers, in particular leukaemias e.g. acute myeloid leukaemia (O'Sullivan et al, 2007, MoI Immunol.
  • JAK3 and Tyk2 A link with autoimmune diseases has been established for JAK3 and Tyk2. Mutations in JAK3 but also in the upstream signaling components gamma-c receptor chain and IL7 receptor account in aggregate for -70% of cases of human severe combined immunodeficiency ('OShea et al., 2004). Note that JAKl cooperates with JAK3 in transducing signals from the gamma-c receptor chain. Tyk2 polymorphisms are seen in systemic lupus erythematosus (SLE) (O'Sullivan et al, 2007, MoI Immunol. 44(10):2497-506). Hence, targeting the JAK family may provide a therapeutic opportunity in the immuno-inflammation area.
  • SLE systemic lupus erythematosus
  • the current therapies are not satisfactory and therefore there remains a need to identify further compounds that may be of use in the treatment of diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g.
  • Inhibitors of JAK can also find application in the treatment of proliferative diseases.
  • the inhibitors of JAK find application in the treatment of cancers , especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer).
  • the present invention therefore provides compounds, methods for their manufacture and a pharmaceutical comprising a compound of the invention together with a suitable pharmaceutical carrier.
  • the present invention also provides for the use of a compound of the invention in the preparation of a medicament for the treatment of degenerative joint diseases.
  • the present invention is based on the discovery that inhibitors of JAK are useful for the treatment of diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g.
  • Inhibitors of JAK can also find application in the treatment of proliferative diseases.
  • the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer).
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating diseases involving cartilage degradation, joint degradation and/or inflammation by administering a compound of the invention.
  • substituted bicycloheteroaryl compounds are disclosed according to Formula (I):
  • each CyI and Cy2 is independently selected from aryl and heteroaryl; each Ll and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O) 2 -, -N(R 4a )-, - CON(R 4a )-, -SO 2 N(R 4a )-, - N(R 4a )CO-, or - N(R 4a )SO 2 -; each R 1 is independently selected from Ci-Ce alkyl, substituted Ci-C ⁇ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC 6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, s
  • R 3b is independently selected from substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted -(CpC 4 alkyl)-(4-7- membered heterocycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted -O- aryl, substituted or unsubstituted arylamino, and substituted or unsubstituted 5-10 membered heteroaryl; ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when Ll is -N(R 4a )-, -CON(R 4a )-, or -SO 2 N(R 4a )-, and R 2c is other than H, alkyl, cycloalkyl, aryl or heteroary
  • each CyI and Cy2 is independently selected from aryl and heteroaryl; each Ll and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O) 2 -, -N(R 4a )-, CON(R 4a )-, -SO 2 N(R 4a )-, - N(R 4a )CO-, or - N(R 4a )SO 2 -; each R 1 is independently selected from Ci-Ce alkyl, substituted Ci-C ⁇ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC 6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulf
  • R 3b is independently selected from substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted -O-aryl, substituted or unsubstituted arylamino, and substituted or unsubstituted 5-10 membered heteroaryl; ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when Ll is -N(R 4a )-, -CON(R 4a )-, or -SO 2 N(R 4a )-, and R 2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L2 is -N(R 4a )-, -CON(R 4
  • novel l,2,4-triazolo[l,5-a]pyridine compounds are disclosed that are capable of modulating the activity of JAK in vivo, having a Formula (I).
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition can comprise one or more of the compounds described herein.
  • the compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein are all pharmaceutically acceptable as prepared and used.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition from among those listed herein, and particularly, such condition as may be associated with aberrant JAK activity, for example diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g.
  • a condition from among those listed herein, and particularly, such condition as may be associated with aberrant JAK activity, for example diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis,
  • Inhibitors of JAK can also find application in the treatment of proliferative diseases.
  • the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer), which method comprises administering a therapeutically effective amount of a compound of the invention or a pharmaceutical composition as described herein.
  • the present invention provides a method for treating conditions selected from inflammation, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and organ transplant rejection; and cartilage, bone and/or joint degradation or degeneration, such as osteoarthritis, which method comprises administering an effective amount of one or more of the pharmaceutical compositions or compounds herein described.
  • inflammation such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endot
  • the present invention provides a method of treating a mammal susceptible to or afflicted with proliferative disorders in particular cancer, (e.g. solid tumours), leukaemias, multiple myeloma or psoriasis.
  • cancer e.g. solid tumours
  • leukaemias e.g. multiple myeloma or psoriasis.
  • the present invention provides a compound of the invention for use in the treatment or prevention of a condition selected from those listed herein, particularly such conditions as may be associated with aberrant JAK activity such as diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g.
  • a condition selected from those listed herein particularly such conditions as may be associated with aberrant JAK activity such as diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic air
  • Inhibitors of JAK can also find application in the treatment of proliferative diseases.
  • the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer).
  • the condition is selected from inflammation, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, allergic airways disease
  • osteoarthritis e.g. asthma, rhinitis
  • inflammatory bowel diseases e.g. Crohn's disease, colitis
  • endotoxin- driven disease states e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure
  • organ transplant rejection e.g. cartilage, bone and/or joint degradation or degeneration, such as osteoarthritis.
  • the present invention provides a compound of the invention for use in the treatment or prevention of proliferative disorders, in particular cancer, (e.g. solid tumours), leukaemias, multiple myeloma or psoriasis.
  • cancer e.g. solid tumours
  • leukaemias e.g. multiple myeloma or psoriasis.
  • this invention provides a method for treating a mammal susceptible to or afflicted with a condition that is causally related to abnormal JAK activity as described herein, and comprises administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions or compounds herein described.
  • the present invention provides a compound of the invention for use in the treatment or prevention of a condition that is causally related to abnormal JAK activity.
  • this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
  • a still further object of this invention is to provide pharmaceutical compositions that may be used in the treatment or prevention of a variety of disease states, including the diseases associated with JAK activity such as diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g.
  • Inhibitors of JAK can also find application in the treatment of proliferative diseases.
  • the inhibitors of JAK find application in the treatment of cancers , especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer).
  • the condition is selected from inflammation, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g.
  • asthma wheezing fever
  • rhinitis juvenile idiopathic arthritis
  • colitis inflammatory bowel diseases
  • endotoxin- driven disease states e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure
  • organ transplant rejection e.g., hematomas, hematomas, and hematomas.
  • cartilage, bone and/or joint degradation or degeneration such as osteoarthritis or cancers (e.g. solid tumours or leukaemias).
  • 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R 20 , where R 20 is hydrogen, C 1 -C 8 alkyl, C 3 -Ci 0 cycloalkyl, C 3 -Ci 0 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • Exemplary 'acyl' groups are -C(O)H, -C(O)-Ci-C 8 alkyl, -C(O)-(CH 2 ) t (C 6 -Ci 0 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 ) ⁇ C 3 -Ci 0 cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted AcyP or 'Substituted Alkanoyl' refers to a radical -C(O)R 21 , wherein R 21 is independently
  • 'Acylamino' refers to a radical -NR 22 C(O)R 23 , where R 22 is hydrogen, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R 23 is hydrogen, CpC 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein.
  • Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl- carbonylamino, benzoylamino and benzylcarbonylamino.
  • Exemplary 'acylamino' groups are -NR 21 C(O)-Cp C 8 alkyl, -NR 21 C(O)-(CH 2 X(C 6 -Ci 0 aryl), -NR 21 C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 21 C(O)-
  • each R 21 independently represents H or CpC 8 alkyl.
  • 'Substituted Acylamino' refers to a radical -NR 24 C(O)R 25 , wherein:
  • R 24 is independently
  • R 25 is independently
  • alkoxy' refers to the group -OR 26 where R 26 is CpC 8 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of "substituted” herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -Ci 0 aryl, -O-aryl, carboxyl, cyano, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thio-O-aryl, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -.
  • Exemplary 'substituted alkoxy' groups are -0-(CH 2 )t(C 6 -Cio aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 - Cio cycloalkyl), and -O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • 'Alkoxycarbonyl' refers to a radical -C(O)-OR 27 where R 27 represents an Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, C 3 -Ci 0 cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein.
  • alkoxycarbonyl groups are C(O)O-CpCg alkyl, -C(O)O- (CH 2 MC 6 -C 10 aryl), -C(O)O-(CH 2 ) t (5-10 membered heteroaryl), -C(O)O-(CH 2 MC 3 -C 10 cycloalkyl), and - C(O)O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.
  • 'Substituted Alkoxycarbonyl' refers to a radical -C(O)-OR 28 where R 28 represents:
  • 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms.
  • Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms.
  • Exemplary straight chained groups include methyl, ethyl n- propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso-butyl, t-butyl and isoamyl.
  • Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of "substituted” herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (-O-acyl or - OC(O)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH-C(O)-OR 27 ), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(O)-NR 2 ), aminocarbonylamino (-NR -C(O)- NR 2 ), aminocarbonyloxy (-O-C(O)-NR 2) , aminosulfon
  • 'substituted alkyl' refers to a CpCg alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR SO 2 R , -SO 2 NR R , -C(O)R , - C(O)OR “ , -OC(O)R “ , -NR “' C(O)R “ , -C(0)NR “ R “ , -NR “ R “ , or -(CR “' R “” ) m OR " ; wherein each R " is independently selected from H, CpCg alkyl, -(CH 2 ) t (C6-Cio aryl), -(CH 2 ) t (5-10 membered heteroaryl), - (CH 2 ) t (C3-Cio cycloalkyl), and -(CH 2 ) t (4-10 membered heterocycloalky
  • 'Amino' refers to the radical -NH 2 .
  • 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -N(R ) 2 where each R is independently selected from:
  • -N(R 33 ) 2 is an amino group.
  • exemplary 'substituted amino' groups are -NR 33' -CpC 8 alkyl, -NR 33' -(CH 2 ) t (C 6 -Ci 0 aryl), -NR 33' -(CH 2 ) t (5-10 membered heteroaryl), -NR 33' -(CH 2 ) t (C 3 -Cio cycloalkyl), and -NR 33' -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from O to 4, each R independently represents H or CpCg alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC
  • aminosulfonyl or “Sulfonamide” refers to the radical -S(O 2 )NH 2 .
  • substituted aminosulfonyl or “substituted sulfonamide” refers to a radical such as -
  • each R 48 is independently selected from:
  • Exemplary 'substituted aminosulfonyl' or 'substituted sulfonamide' groups are -S(O 2 )N(R )-
  • each R 48 independently represents H or CpCg alkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
  • 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of any aryl group present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, cyano, unsubstituted CpC 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually 6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • 'Substituted AryP refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent.
  • Aryl' refers to an aryl group substituted with one or more of groups selected from halo, CpCg alkyl, CpCg haloalkyl, CpCg haloalkoxy, cyano, hydroxy, CpCg alkoxy, and amino.
  • R 49 and R 50 may be hydrogen and at least one of R 49 and R 50 is each independently selected from CpCg alkyl, 4-10 membered heterocycloalkyl, alkanoyl, CpCg alkoxy, hetero-O- aryl, alkylamino, arylamino, heteroarylamino, NR 51 COR 52 , NR 51 SOR 52 NR 51 SO 2 R 52 , COOalkyl, COOaryl,
  • CONR 51 R 52 , CONR 51 OR 52 , NR 51 R 52 , SO 2 NR 51 R 52 , S-alkyl, SOalkyl, S0 2 alkyl, Saryl, SOaryl, S0 2 aryl; or R 49 and R 50 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S.
  • R 51 , and R 52 are independently hydrogen, CpCg alkyl, CpC 4 haloalkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, substituted aryl, 5-10 membered heteroaryl.
  • 'Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.
  • Arylalkyloxy refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, cyano, unsubstituted CpC 4 alkoxy, unsubstituted Cp 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted
  • 'Azido' refers to the radical -N 3 .
  • Carbamoyl or amido' refers to the radical -C(O)NH 2 .
  • R 53 is independently
  • Exemplary 'Substituted Amido / Carbamoyl' groups are -C(O) NR 53' -C r C 8 alkyl, -C(0)NR 53' -(CH 2 )t(C 6 -Cio aryl), -C(O)N 53' -(CH 2 ) t (5-10 membered heteroaryl), -C(0)NR 53' -(CH 2 )t(C 3 -Cio cycloalkyl), and -C(O)NR 53' - (CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 53 independently represents H or CpCg alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstitute
  • 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent.
  • 'Cyano' refers to the radical -CN.
  • 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Examples of representative aryl having hetero atoms containing substitution include the following:
  • each W is selected from C(R 54 ) 2 , NR 54 , O and S; and each Y is selected from carbonyl, NR ,5 3 4 4 , O and S; and R 54 is independently hydrogen, CpCg alkyl, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -CiO aryl, and 5-10 membered heteroaryl.
  • R 54 is independently hydrogen, CpCg alkyl, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -CiO aryl, and 5-10 membered heteroaryl.
  • Examples of representative heteroaryls include the following:
  • each Y is selected from carbonyl, N, NR 55 , O and S; and R 55 is independently hydrogen, CpCg alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl.
  • the term 'heterocycloalkyl' refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1 -pyrrolidinyl, 2- pyrrolidinyl and 3 -pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g.
  • each W is selected from CR , C(R 5t> ) 2 , NR , O and S; and each Y is selected from NR , O and S; and R , 56 is independently hydrogen, Ci-Cg alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl,
  • These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy (-O-acyl or -OC(O)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH-C(O)-OR 27 ), amino, substituted amino, aminocarbonyl (amido or -C(O)-NR 2 ), aminocarbonylamino (-NR -C(O)-NR
  • 'Nitro' refers to the radical -NO 2 .
  • 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
  • substituent group or groups are selected from: halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR “' SO 2 R “ , -SO 2 NR R “ , -C(O)R “ , -C(O)OR “ , -OC(O)R “ , - NR '” C(O)R “ , -C(0)NR “ R “' , -NR “ R '” , -(CR '” R '” ) m OR '" , wherein, each R " is independently selected from H, Cp C 8 alkyl, -(CH 2 MC 6 -C 10 aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CHDt(C 3 -C 10 cycloalkyl), and -(CH 2 ) t (4- 10 membered heterocycloalkyl), wherein t is an
  • any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • Each R independently represents H or CpC ⁇ alkyl.
  • Substituted sulfanyl refers to the group -SR 61 , wherein R 61 is selected from:
  • Exemplary 'substituted sulfanyl' groups are -S-(CpC 8 alkyl) and -S-(C 3 -Ci 0 cycloalkyl), -S-
  • t is an integer from O to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • 'Substituted sulfmyl' refers to the group -S(O)R 68 , wherein R 68 is selected from:
  • Exemplary 'substituted sulfmyl' groups are -S(O)-(CpC 8 alkyl) and -S(O)-(C 3 -Ci 0 cycloalkyl), -S(O)-(CH 2 MC 6 -C 10 aryl), -S(O)-(CH 2 ) t (5-10 membered heteroaryl), -S(O)-(CH 2 MC 3 -C 10 cycloalkyl), and -S(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstitute
  • Exemplary 'substituted sulfonyl' groups are -S(O) 2 -(CpC 8 alkyl) and -S(O) 2 -(C 3 -Ci 0 cycloalkyl), -S(O) 2 -(CH 2 MC 6 -C 10 aryl), -S(O) 2 -(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -(CH 2 MC 3 -C 10 cycloalkyl), and -S(O) 2 -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted
  • CpC 4 alkyl halo, unsubstituted CpC 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO 3 H.
  • 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(O) 2 OR 82 , wherein R 82 is selected from: • CpC 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O) 2 -O-(CpC 8 alkyl) and -
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesul,
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • 'Pharmaceutically acceptable vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • 'Solvate' encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • 'Subject' includes humans.
  • the terms 'human', 'patient' and 'subject' are used interchangeably herein.
  • 'Therapeutically effective amount means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the "therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an antimalarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • "treating" or "treatment” relates to slowing the progression of the disease.
  • condition(s) involving inflammation' refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, allergic airway disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints.
  • the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases.
  • obstructive airways disease including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantily asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term 'transplantation rejection' refers to the acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.
  • the term 'proliferative diseases' refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukaemia and acute lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, sclerodermitis or fibrosis.
  • cancer e.g. uterine leiomyosarcoma or prostate cancer
  • myeloproliferative disorders e.g. polycythemia vera, essential thrombocytosis and myelofibrosis
  • leukemia e.g. acute myeloid leukaemia and acute lymphoblastic leukemia
  • multiple myeloma psoriasis
  • restenosis sclerodermitis or fibrosis
  • the term 'cancer' refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel.
  • a cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain.
  • cancer includes both metastatic rumour cell types, such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma and types of tissue carcinoma, such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma.
  • metastatic rumour cell types such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • types of tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblast
  • leukaemia refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding.
  • leukemia refers to acute myeloid leukaemia (AML) and acute lymphoblastic leukemia (ALL).
  • osteoarthritis psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
  • the term 'congenital cartilage malformation(s)' includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.
  • the term 'disease(s) associated with hypersecretion of IL6' includes conditions such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis .
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the Ci to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -Ci 2 substituted aryl, and C 7 -Ci 2 arylalkyl esters of the compounds of the invention.
  • the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present may vary, so that for example, any hydrogen may be 2 HIO, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon- 14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
  • 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons.
  • two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • R R
  • S S
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well- known in the art.
  • the present invention is based on the discovery that inhibitors of JAK are useful for the treatment of diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g.
  • Inhibitors of JAK can also find application in the treatment of proliferative diseases.
  • the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer).
  • diseases involving cartilage degradation, bone and/or joint degradation and/or inflammation for example osteoarthritis.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating diseases involving cartilage degradation, bone and/or joint degradation and/or inflammation by administering a compound of the invention.
  • the present compounds may be inhibitors of one or more members of the JAK family; specifically they may inhibit the activity of one or more of JAKl, JAK2, JAK3 and/or TYK2.
  • substituted bicycloheteroaryl compounds are disclosed according to Formula (I): wherein each CyI and Cy2 is independently selected from aryl and heteroaryl; each L 1 and L 2 is independently selected from a single bond, -O-, -C(O)-, -S(O) 2 -, -N(R 4a )-, -CON(R 4a )- , -SO 2 N(R 4a )-, - N(R 4a )CO-, or - N(R 4a )SO 2 -; each R 1 is independently selected from CpC 6 alkyl, substituted CpC 6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted Ci-Ce alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfmyl
  • substituted bicycloheteroaryl compounds are disclosed according to
  • each CyI and Cy2 is independently selected from aryl and heteroaryl; each L 1 and L 2 is independently selected from a single bond, -O-, -C(O)-, -S(O) 2 -, -N(R 4a )-, -CON(R 4a )- , -SO 2 N(R 4a )-, - N(R 4a )CO-, or - N(R 4a )SO 2 -; each R 1 is independently selected from Ci-Ce alkyl, substituted Ci-C ⁇ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfinyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic
  • R 3b is independently selected from substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted -O-aryl, substituted or unsubstituted arylamino, and substituted or unsubstituted 5-10 membered heteroaryl; ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when L 1 is -N(R 4a )-, -CON(R 4a )-, or -SO 2 N(R 4a )-, and R 2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L 2 is -N(R 4a )-, -CON(R 4
  • each Cyi and Cy 2 is independently selected from aryl and heteroaryl; each L 1 and L 2 is independently selected from a single bond, -O-, -C(O)-, -S(O) 2 -, -N(R 4a )-, -CON(R 4a )- , -SO 2 N(R 4a )-, - N(R 4a )CO-, or - N(R 4a )SO 2 -; each R 1 is independently selected from unsubstituted Ci-C ⁇ alkyl (optionally substituted with halo), unsubstituted acyl, unsubstituted acylamino, unsubstituted Ci-C ⁇ alkoxy, unsubstituted amido, unsubstituted amino, unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, unsubstitute
  • R 3b is independently selected from -(C 1 -C 4 alkyl)-(4-7-membered heterocycloalkyl), C3-C7 cycloalkyl (optionally substituted with unsubstituted 4-7 membered heterocycloalkyl), 4-7 membered heterocycloalkyl (optionally substituted with Ci -C O alkyl (optionally substituted with unsubstituted aryl, halo), unsubstituted aryl, amido (optionally substituted with Ci-C ⁇ alkyl), acyl, cyano, halo), aryl (optionally substituted with unsubstituted Ci-C ⁇ alkoxy, cyano, halo, Ci-C ⁇ alkyl (optionally substituted with halo, unsubstituted aryl), 4-7 membered heterocycloalkyl (optionally substituted with unsubstituted Ci-C ⁇ alkyl), amino (optionally substituted with unsubstitute
  • ml is 0. In another embodiment, ml is 1 or 2. [00128] In one embodiment, with respect to Formula I, ml is 1 or 2 and each R 1 is independently selected from CpC 6 alkyl, substituted CpC 6 alkyl, and halo.
  • ml is 1 or 2 and each R 1 is independently selected from Me, CF 3 , Cl and F.
  • R 2a is independently selected from H, Ci-Ce alkyl, and substituted Ci-C 6 alkyl.
  • R 2a is H.
  • each of R 2b , and R 2d is independently H, Ci-C 6 alkyl, substituted Ci-C 6 alkyl, or halo.
  • each of R 2b , and R 2d is independently H, Me, F or Cl.
  • Ll is a single bond
  • nl is 0, and R 2c is H, Cl, F, Me, Et, OMe, CF 3 , CONH 2 , CONMe 2 , CONHMe, CN, NHCOMe, COOH, OH or COOEt.
  • Ll is a single bond
  • nl is 0, and R 2c is NHCOMe, or COOH.
  • Ll is CONH; nl is 2 or 3; and R 2c is NMe 2 , OMe, NHCOMe,
  • Ll is selected from a single bond, -C(O)-, and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; and R 2c is substituted or unsubstituted CpC 6 alkyl, substituted or unsubstituted C 6 -Ci 0 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3 -C 7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl.
  • Ll is selected from a single bond, -C(O)-, and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; and R 2c is C 1 -C 6 alkyl.
  • Ll is selected from a single bond, -C(O)-, and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; and R 2c is Me, Et, i-Pr, l,3-dihydroxyprop-2-yl.
  • Ll is selected from a single bond, -C(O)-, - and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; and R 2c is substituted or unsubstituted C 3 -C 7 cycloalkyl.
  • Ll is selected from a single bond, -C(O)-, - and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; and R 2c is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cyclopentyl.
  • Ll is selected from a single bond, -C(O)-, - and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; and R 2c is substituted or unsubstituted C 6 -Ci 0 aryl or substituted or unsubstituted 5-10 membered heteroaryl.
  • Ll is selected from a single bond, -C(O)-, and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; and R 2c is substituted or unsubstituted Ph, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted
  • Ll is selected from a single bond, -C(O)-, and -CON(R 4a )-; nl is 0, 1 , 2, 3, or 4; and R 2c is substituted or unsubstituted 4-7 membered heterocycloalkyl.
  • Ll is selected from a single bond, -C(O)-, and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; and R 2c is piperidinyl, morpholinyl, piperazinyl, or pyrrolidinyl, each of which may be unsubstituted or substituted with CpC 6 alkyl, acyl, phenyl, or OH.
  • R 4a is H.
  • Ll is CONH; and nl is O, 1, 2 or 3.
  • Ll is CONH; and nl is 0, or 1.
  • Ll is CO; and nl is
  • Ll is CO; and nl is
  • (CH 2 ) n i-R 2c is selected from:
  • nl and R 2c are as described for Formula I.
  • (CH 2 ) n i-R 2c is selected from:
  • nl and R 2c are as described for Formula I.
  • the -CyI-Ll- (CH 2 ) n i-R 2c is selected from:
  • nl and R c are as described for Formula I.
  • R c is a substituted or unsubstituted N-containing 4-7 membered heterocycloalkyl or a substituted or unsubstituted N-containing 5- 10 membered heteroaryl.
  • R 2c is: or
  • R 2c is pyrazolyl, pyrrolyl, imidazolyl, or triazolyl.
  • nl is 0, 1 or 2.
  • the -CyI-Ll- (CH 2 )ni-R 2c is selected from:
  • Cy2 is Ph; and m2 is O.
  • Cy2 is Ph; m3 is 1, 2 or 3; and each R 3a is independently CpC 6 alkyl, CpC 6 haloalkyl, CpC 6 alkoxy, or halo.
  • Cy2 is Ph; m3 is 1, 2 or 3; and each R 3a is independently Cl, F, Me, Et, OMe, CF 3 , CONH 2 , CONMe 2 , CONHMe, CN, NHCOMe, COOH, OH or COOEt.
  • R 3b is substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7- membered heterocycloalkyl.
  • L2 is selected from -O-, -C(O)-, and -CON(R 4a )-; n2 is 0, 1, 2, 3, or 4; and R 3b is substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl.
  • L2 is selected from -O-, -C(O)-, - and -CON(R 4a )-; n2 is 0, 1, 2, 3, or 4; and R 3b is substituted or unsubstituted C 3 -C 7 cycloalkyl.
  • L2 is selected from -O-, -C(O)-, - and -CON(R 4a )-; n2 is 0, 1, 2, 3, or 4; and R 3b is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl.
  • L2 is selected from -O-, -C(O)-, - and -CON(R 4a )-; n2 is 0, 1, 2, 3, or 4; and R 3b is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • L2 is selected from
  • R 3b is substituted or unsubstituted Ph, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsub
  • L2 is selected from
  • n2 is 0, 1, 2, 3, or 4; and R 3b is substituted or unsubstituted 4-7-membered heterocycloalkyl.
  • L2 is selected from
  • R 3b is piperidinyl, morpholinyl, piperazinyl, or pyrrolidinyl, unsubstituted or substituted with Ci-C ⁇ alkyl, acyl, phenyl, or OH.
  • R 4a is H.
  • (CH 2 )n2-R 3b group is at the 4-position of the phenyl ring.
  • each R 3a is H; and the -Cy2-L2-(CH 2 ) n2 -R 3b is selected from:
  • each R a is H; and the -Cy2-L2-(CH 2 ) n2 -R 3b is selected from:
  • R 3b , and n2 are as in claim 1; Cy3 is substituted or unsubstituted N containing 4-7 membered heterocycloalkyl; R 5a and R 5b are independently selected from H, or Me, or together R 5a , R 5b and the carbon to which they are attached, form an unsubstituted C3-C7 cycloalkyl. [00176] In a preferrd embodiment, R 5a and R 5b are both Me. [00177] In another preferred embodiment, R 5a is H and R 5b is Me.
  • R 5a and R 5b together with the carbon to which they are attached form a C 3 - Cv-cycloalkyl.
  • R 5a and R 5b together with the carbon to which they are attached form a cyclopropyl.
  • R 5a and R 5b are both H.
  • the compound is according to Formula IVa, IVb, IVc, IVd, or IVe:
  • n2 is 1, 2, or 3;
  • R 2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl; and
  • R 3b is substituted or unsubstituted aryl, substituted or unsubstituted arylamino, substituted or unsubstituted-O-aryl, or substituted or unsubstituted heteroaryl.
  • the compound is according to Formula IVa, IVb, IVc, IVd, IVe, or
  • n2 is 1, 2, or 3;
  • R 2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl;
  • R 3b is, 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamino, substituted or unsubstituted-O-aryl, or substituted or unsubstituted heteroaryl,
  • n2 is 1, 2 or 3. In another embodiment, n2 is 1 or 2. In yet another embodiment, n2 is 1.
  • R 3b is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl.
  • R 3b is unsubstituted phenyl or unsubstituted pyridyl.
  • R 3b is phenyl or pyridyl each of which may be substituted with one or more groups selected from Ci-C ⁇ alkyl, halo, alkoxy, amino, CpC ⁇ dialkylamino, and CpC ⁇ haloalkyl. In one embodiment the substitution is selected from Cl, F, Me, OMe, NMe 2 , or CF 3 .
  • R 3b is substituted or unsubstituted -O-aryl or arylamino.
  • R 3b is substituted or unsubstituted phenoxy or phenylamino.
  • R 3b is substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indolyl, or substituted or unsubstituted indazolyl.
  • n2 is 1, and R 3b is substituted or unsubstituted N containing 4-7 membered heterocycloalkyl.
  • the compound is according to Formula Va:
  • R 2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl; and R 3b is substituted or unsubstituted 4-7-membered heterocycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl.
  • R 3b is substituted or unsubstituted 4-7-membered heterocycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl.
  • R 2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl, - C(O)NH-C 3 -C 7 cycloalkyl; and R 3b is substituted or unsubstituted 4-7-membered heterocycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl.
  • R 3b is:
  • R 2c is H.
  • R 2c is 3-NHCOMe, or 4-NHCOMe.
  • R 2c is 3-NHC(O)NHcPr, or 4- NHC(O)NHcPr.
  • R c is 4-7 membered heterocycloalkyl. In another embodiment R c is -C(O)-4-7 membered heterocycloalkyl. In one particular embodiment, the 4-7 membered heterocycloalkyl is
  • the compound is according to Formula Via, VIb, Vic or VId:
  • R 3b is as described above.
  • R 3b is: [00201] In one embodiment the compound of the invention is not an isotopic variant.
  • the compound is selected from the compounds listed in Table 1.
  • a compound of the invention according to any one of the embodiments herein described is present as the free base.
  • a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
  • a compound of the invention according to any one of the embodiments herein described is a solvate.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt.
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the Ci to Cg alkyl, C 2 -Cg alkenyl, aryl, C7-C 12 substituted aryl, and C7-C 12 arylalkyl esters of the compounds of the invention.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds of the invention are administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of the invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • the compounds of this invention are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration
  • the compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • the compounds of this invention can also be administered by a transdermal device.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compounds of this invention may also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active amide compound per capsule).
  • a compound of the invention (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
  • a compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
  • the present compounds may be used as therapeutic agents for the treatment of conditions in mammals that are causally related or attributable to aberrant activity of JAK.
  • a compound of the invention and pharmaceutical compositions of the invention find use as therapeutics for preventing and/or treating diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g.
  • Inhibitors of JAK can also find application in the treatment of proliferative diseases.
  • the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer).
  • the conditions are selected from inflammatory conditions, conditions related to cartilage and/or joint degradation in mammals including humans.
  • the compounds and pharmaceutical compositions of the invention find use as therapeutics for preventing and/or treating proliferative disorders in mammals, including humans.
  • the compound of the invention and pharmaceutical compositions thereof find use as therapeutics for preventing and/or treating cancer in mammals including humans.
  • this invention provides methods of treating a mammal susceptible to or afflicted with condition involving an immune response or an autoimmune disease.
  • the methods comprise administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions or compound of the invention herein described.
  • the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of a condition involving an autoimmune response or an autoimmune disease.
  • the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • this invention provides a method of treatment, prevention or prophylaxis in a mammal susceptible to or afflicted with diseases involving impairment of cartilage turnover (e.g. a condition associated with, or diseases involving the anabolic stimulation of chondrocytes), for example, osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis, which method comprises administering
  • the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of diseases involving impairment of cartilage turnover (e.g. a condition associated with, or diseases involving the anabolic stimulation of chondrocytes), for example, osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
  • diseases involving impairment of cartilage turnover e.g. a condition associated with, or diseases
  • the present invention also provides a method of treatment of congenital cartilage malformations, including hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described
  • the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of congenital cartilage malformations, including hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition involving inflammation, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • this invention provides methods of treating a mammal susceptible to or afflicted with diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, allergic airway disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g.
  • the method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the condition involving inflammation is selected from rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases.
  • the methods comprise administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions or compounds herein described.
  • this invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of a condition involving inflammation.
  • the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, allergic airway disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints.
  • the condition involving inflammation is selected from rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases.
  • this invention provides methods of treating a mammal susceptible to or afflicted with a proliferative disease, in particular cancer (e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer), leukemia (e.g. AML or ALL), multiple myeloma and/or psoriasis, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • cancer e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer
  • leukemia e.g. AML or ALL
  • this invention provides methods of treating a mammal susceptible to or afflicted with cancer (e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer) and/or leukemias, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • cancer e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer
  • leukemias e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer
  • the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of a proliferative disease, in particular cancer (e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer), leukemia (e.g. AML or ALL), multiple myeloma and/or psoriasis.
  • cancer e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer
  • leukemia e.g. AML or ALL
  • multiple myeloma and/or psoriasis e.g. AML or ALL
  • the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of cancer (e.g solid tumors such as uterine leiomyosarcoma or prostate cancer) and/or leukemias.
  • cancer e.g solid tumors such as uterine leiomyosarcoma or prostate cancer
  • leukemias e.g solid tumors such as uterine leiomyosarcoma or prostate cancer
  • this invention provides methods of treating a mammal susceptible to or afflicted with diseases associated with hypersecretion of IL6, in particular Castleman's disease or mesangial proliferative glomerulonephritis, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of diseases associated with hypersecretion of IL6, in particular
  • this invention provides methods of treating a mammal susceptible to or afflicted with transplantation rejection, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the invention provides methods of treating organ transplant rejection, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of transplantation rejection.
  • the invention provides methods of treating organ transplant rejection.
  • the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
  • a particular regimen of the present method comprises the administration to a subject in suffering from a disease involving inflammation, of an effective amount of a compound of the invention for a period of time sufficient to reduce the level of inflammation in the patient, and preferably terminate, the processes responsible for said inflammation.
  • a special embodiment of the method comprises administering of an effective amount of a compound of the invention to a subject patient suffering from or susceptible to the development of rheumatoid arthritis, for a period of time sufficient to reduce or prevent, respectively, inflammation in the joints of said patient, and preferably terminate, the processes responsible for said inflammation.
  • a further particular regimen of the present method comprises the administration to a subject in suffering from a disease condition characterized by cartilage or joint degradation (e.g. osteoarthritis) of an effective amount of a compound of the present invention for a period of time sufficient to reduce and preferably terminate, the self-perpetuating processes responsible for said degradation.
  • a special embodiment of the method comprises administering of an effective amount of a compound of the present invention to a subject patient suffering from or susceptible to the development of osteoarthritis, for a period of time sufficient to reduce or prevent, respectively, cartilage degradation in the joints of said patient, and preferably terminate, the self-perpetuating processes responsible for said degradation.
  • said compounds exhibit cartilage anabolic and/or anti-catabolic properties.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with particular doses each providing from about 0.1 to about
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • a compounds of the invention When used to prevent the onset of an inflammatory condition, a compounds of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the compounds of the invention can be administered as the sole active agent or they can be administered in combination with other agents, including other compounds that demonstrate the same or a similar therapeutic activity, and that are determined to safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of a disease involving inflammation;
  • agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.
  • immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g. rheumatoid arthritis); particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofm, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and ciclosporin), and biological DMARDS (for example but without limitation Infliximab, Etanercept, Adalimumab, Rituximab, and Abatacept).
  • NSAIDS non-steroidal anti-inflammatory drugs
  • DMARDS for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofm, sodium aurothiomalate, penicillamine, chlor
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of proliferative disorders; particular agents include but are not limited to: methotrexate, leukovorin, adriamycin, prenisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti- HER2 monoclonal antibody (e.g.
  • a compound of the invention may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery.
  • the proliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of autoimmune diseases
  • agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g.
  • dactinomycin anthracyclines mitomycin C, bleomycin, and mithramycin
  • antibodies e.g., anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®
  • cyclosporin tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN- ⁇ ), TNF binding proteins (e.g. infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira)), mycophenolate, Fingolimod, Myriocin.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of transplantation rejection
  • therapeutic agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), Antibodies (e.g. monoclonal anti-IL-2R ⁇ receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD, particular agents include but are not limited to: beta 2 -adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol.), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled) Long-acting ⁇ 2 -agonists (e.g.
  • salmeterol, formoterol, bambuterol, and sustained-release oral albuterol combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine, cinnarizine, fexofenadine), vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).
  • bronchodilators e.g. fluticasone/salmeterol, budesonide/formoterol
  • a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, nonspecific beta-agonists, injected or inhaled (e.g.
  • oxygen or heliox administration ebulized salbutamol or terbutaline
  • an anticholinergic e.g. ipratropium
  • systemic steroids oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone
  • intravenous salbutamol e.g. predn
  • epinephrine isoetharine, isoproterenol, metaproterenol
  • anticholinergics IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium
  • methylxanthines theophylline, aminophylline, bamiphylline
  • inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine, intravenous magnesium sulfate.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of IBD
  • agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetis disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and ciclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
  • glucocorticoids e.g. prednisone, budesonide
  • immunomodulatory agents e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and ciclosporin
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of SLE
  • particular agents include but are not limited to: Disease- modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid; immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.
  • DMARDs Disease- modifying antirheumatic drugs
  • antimalarials e.g. plaquenil, hydroxychloroquine
  • immunosuppressants e.g.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of psoriasis
  • agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort), fluocinonide, vitamin D 3 analogues (for example, calcipotriol), Argan oiland retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologies such as Amevive, Enbrel, Humira, Remicade,
  • any means of delivering two or more therapeutic- agents to the patient as part of the same treatment regime is included any means of delivering two or more therapeutic- agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation this is not essential. The agents may be administered in different formulations and at different times.
  • the compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • IH NMR spectra were recorded on a Bruker DPX 400 NMR spectrometer (400 MHz). Chemical shifts ( ⁇ ) for IH NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane ( ⁇ 0.00) or the appropriate residual solvent peak, i.e. CHCI3 ( ⁇ 7.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) and broad (br). Coupling constants (J) are given in Hz. Electrospray MS spectra were obtained on a Micromass platform LC/MS spectrometer.
  • a compound according to the invention can be produced according to the following scheme.
  • Ar is -Cy2-(R 3a ) m2 -; and Ar'is -Cyl-Ll-(CH 2 ) n i-R 2c ; and CyI, Cy2, Ll, L2, nl, m2, R 2c , and R 3a are as described herein.
  • reaction mixture is extracted with ethyl acetate and the extracts are combined, washed with water and dried over anhyd. magnesium sulfate.
  • the organic solvent is removed under high vacuum to yield the crude product.
  • the crude product is then purified by flash chromatography to give the corresponding 5-Ar-2-iodo-triazolopyridine derivative (3).
  • Step b
  • Step b
  • HOBt (1.5 eq) (Not used with HATU) and are mixed in DMF at room temperature.
  • An appropriate amine (1.1 eq.) is added to the solution and the reaction mixture is stirred at room temperature for 16hrs. Water is added to the reaction. The organic phases is isolated, dried over MgS ⁇ 4 , filtered and evaporated under vacuum to afford the expected product. Purification by flash chromatography.
  • This compound was prepared via Method B using l-phenyl-piperidin-4-ylamine.
  • This compound was prepared via Method B using C-(2-morpholin-4-yl-pyridin-4-yl)- methylamine.
  • This compound was prepared via Method B using l-benzyl-piperidin-4-ylamine.
  • This compound was prepared via Method B using phenethylamine.
  • This compound was prepared via the method as described for Compounds 34 and 37, using benzyl bromide.
  • Step a (5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-(4-nitro-phenyl)-amine
  • Step b
  • This compound can be made made by Method C using cyclopropylamine and 4-[2-Fluoro-4-
  • This compound can be made by Method C using cyclopropylamine and 4,4-Difluoro-l-[2- fluoro-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-piperidine prepared by method D.
  • This compound can be prepared via Method C using cyclopropylamine and 4- ⁇ l-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-ethyl ⁇ -morpholine that can be prepared by the following method:
  • Step b
  • Morpholine (2 eq.) is added to a solution of l-bromo-4-(l-chloro-ethyl)-benzene (leq) and
  • This compound can be prepared via Method C using cyclopropylamine and 4-[4-(4,4,5,5-
  • This compound can be prepared via Method C using ammonia and 4-[4-(4,4,5,5-Tetramethyl-
  • Compound 63 can be prepared via Method A using 4-[4-(4,4,5,5-Tetramethyl-
  • the compound can be prepared via Method C using cyclopropylamine and N,N-dimethyl-4- benzamide boronic acid.
  • the compound can ce prepared by Method A using 4,4-difluoro-l-[4-(4,4,5,5-tetramethyl-
  • the compound can be prepared by Method A using 4-fluoro-l-[4-(4,4,5,5-tetramethyl-
  • This compound can be prepared via Method C using cyclopropylamine and 4,4-Difluoro-l-[4-
  • the compound can be prepared by Method A using 4-[4-(4,4,5,5-Tetramethyl-
  • Compound 69 can be obtained via Method C using cyclopropylamine and 4- ⁇ l-[4-(4,4,5,5-
  • Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl ⁇ -morpholine that can be prepared via the following method:
  • Step c A mixture of 4-[l-(4-bromo-phenyl)-cyclopropyl]-morpholine (leq.), bis(pinacolato)diboron
  • Compound 70 can be prepared via Method C using cyclopropylamine and 4- ⁇ 1 -Methyl- 1- [4-
  • MeLi (2eq) is added to a solution of 4-bromo-benzonitrile (leq) an CeCi3 (leq) in THF at -
  • Compound 70 is obtained via Method A using 4- ⁇ 1 -Methyl- 1-[4-(4,4,5, 5-tetramethyl-
  • This compound can be prepared via Method C using cyclopropylamine and l- ⁇ 4-[4-(4,4,5,5-
  • the compound can be prepared via Method C using cyclopropylamine and l-[4-(4,4,5,5-
  • Example 1 - in vitro assays Example 1.1 JAKl inhibition assay
  • Recombinant human JAKl catalytic domain (amino acids 850-1154; catalog number 08-144) was purchased from Carna Biosciences. 10 ng of JAKl was incubated with 12.5 ⁇ g polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (15 mM Tris-HCl pH 7.5, 1 mM DTT, 0.01% Tween-20, 10 mM MgCl 2 , 2 ⁇ M non-radioactive ATP, 0.25 ⁇ Ci 33P-gamma-ATP (GE Healthcare, catalog number AH9968) final concentrations) with or without 5 ⁇ L containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 ⁇ L, in a polypropylene 96-well plate (Greiner, V-bottom).
  • kinase reaction buffer 15 mM Tris-HCl pH 7.5, 1 mM DTT, 0.01% Tween-20, 10 mM MgCl 2
  • Percentage inhibition ((cpm determined for sample with test compound present - cpm determined for sample with positive control inhibitor) divided by (cpm determined in the presence of vehicle - cpm determined for sample with positive control inhibitor)) * 100%.
  • JAKl catalytic domain, amino acids 866-1154; catalog number PV4774
  • Recombinant human JAKl catalog number PV4774
  • 1 ng of JAKl is incubated with 20 nM Ulight-JAKl(tyrlO23) peptide (Perkin Elmer catalog number TRF0121) in kinase reaction buffer (25mM MOPS pH6.8, 0.016% Brij-35, 8.33mM MgC12, 3.33mM DTT, 7 ⁇ M ATP) with or without 4 ⁇ L containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 20 ⁇ L, in a white 384 Luminotrac 200 plate (Greiner, catalog number 781075).
  • DMSO 1% final concentration
  • Percentage inhibition 1- ((RFU determined for sample with test compound present - RFU determined for sample with positive control inhibitor) divided by (RFU determined in the presence of vehicle - RFU determined for sample with positive control inhibitor)) * 100.
  • Dose dilution series are prepared for the compounds enabling the testing of dose-response effects in the JAKl assay and the calculation of the IC50 for each compound.
  • Each compound is routinely tested at concentration of 20 ⁇ M followed by a 1/5 serial dilution, 8 points (20 ⁇ M - 4 ⁇ M - 80OnM - 16OnM - 32nM - 6.4nM - 1.28nM - 0.26nM) in a final concentration of 1% DMSO.
  • potency of compound series increases, more dilutions are prepared and/or the top concentration are lowered (e.g. 5 ⁇ M, 1 ⁇ M).
  • Recombinant human JAK2 catalytic domain (amino acids 808-1132; catalog number PV4210) was purchased from Invitrogen. 0.025mU of JAK2 was incubated with 2.5 ⁇ g polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (5 mM MOPS pH 7.5, 9 mM MgAc, 0.3mM EDTA, 0.06% Brij and 0.6 mM DTT, 1 ⁇ M non-radioactive ATP, 0.25 ⁇ Ci 33P-gamma-ATP (GE Healthcare, catalog number AH9968) final concentrations) with or without 5 ⁇ L containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 ⁇ L, in a polypropylene 96-well plate (Greiner, V-bottom).
  • DMSO 1% final concentration
  • Percentage inhibition ((cpm determined for sample with test compound present - cpm determined for sample with positive control inhibitor) divided by (cpm determined in the presence of vehicle - cpm determined for sample with positive control inhibitor)) * 100% .
  • Dose dilution series were prepared for the compounds enabling the testing of dose-response effects in the JAK2 assay and the calculation of the IC 5 O for each compound.
  • Each compound was routinely tested at concentration of 20 ⁇ M followed by a 1/3 serial dilution, 8 points (20 ⁇ M - 6.67 ⁇ M - 2.22 ⁇ M - 74OnM
  • Recombinant human JAK2 (catalytic domain, amino acids 866-1154; catalog number PV4210) is purchased from Invitrogen. 0.0125mU of JAK2 is incubated with 25 nM Ulight-JAKl(tyrlO23) peptide (Perkin Elmer catalog number TRF0121) in kinase reaction buffer (41.66mM HEPES pH7.0, 0.016% Triton X- 100, 12.5mM MgCl 2 , 3.33mM DTT, 7.5 ⁇ M ATP) with or without 4 ⁇ L containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 20 ⁇ L, in a white 384 Luminotrac 200 plate (Greiner, catalog number 781075).
  • DMSO 1% final concentration
  • Percentage inhibition 1- ((RFU determined for sample with test compound present - RFU determined for sample with positive control inhibitor) divided by (RFU determined in the presence of vehicle - RFU determined for sample with positive control inhibitor)) * 100.
  • Dose dilution series are prepared for the compounds enabling the testing of dose-response effects in the JAKl assay and the calculation of the IC50 for each compound.
  • Each compound is routinely tested at concentration of 20 ⁇ M followed by a 1/5 serial dilution, 8 points (20 ⁇ M - 4 ⁇ M - 80OnM - 16OnM - 32nM - 6.4nM - 1.28nM - 0.26nM) in a final concentration of 1% DMSO.
  • potency of compound series increases, more dilutions are prepared and/or the top concentration are lowered (e.g. 5 ⁇ M, 1 ⁇ M).
  • Recombinant human JAK3 catalytic domain (amino acids 781-1124; catalog number PV3855) was purchased from Invitrogen. 0.025mU of JAK3 was incubated with 2.5 ⁇ g polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (25 mM Tris pH 7.5, 0.5 mM EGTA, 0.5 mM Na3VO4, 5 mM b- glycerolphosphate, 0.01% Triton X-100, 1 ⁇ M non-radioactive ATP, 0.25 ⁇ Ci 33P-gamma-ATP (GE Healthcare, catalog number AH9968) final concentrations) with or without 5 ⁇ L containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 ⁇ L, in a polypropylene 96-well plate (Greiner, V-bottom).
  • DMSO 1% final concentration
  • Percentage inhibition ((cpm determined for sample with test compound present - cpm determined for sample with positive control inhibitor) divided by (cpm determined in the presence of vehicle - cpm determined for sample with positive control inhibitor)) * 100%.
  • Recombinant human TYK2 catalytic domain (amino acids 871-1187; catalog number 08-147) was purchased from Carna biosciences. 5 ng of TYK2 was incubated with 12.5 ⁇ g polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (25 mM Hepes pH 7.5, 100 mM NaCl, 0.2 mM Na3VO4, 0.1% NP-40, 0.1 ⁇ M non-radioactive ATP, 0.125 ⁇ Ci 33P-gamma-ATP (GE Healthcare, catalog number AH9968) final concentrations) with or without 5 ⁇ L containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 ⁇ L, in a polypropylene 96-well plate (Greiner, V-bottom).
  • kinase reaction buffer 25 mM Hepes pH 7.5, 100 mM NaCl, 0.2 mM Na3VO4, 0.1% NP-40, 0.1 ⁇ M
  • Percentage inhibition ((cpm determined for sample with test compound present - cpm determined for sample with positive control inhibitor) divided by (cpm determined in the presence of vehicle - cpm determined for sample with positive control inhibitor)) * 100%.
  • Example 2 Cellular assays
  • DMEM Dulbecco's Modified Eagle's Medium
  • Percentage inhibition ((fluorescence determined in the presence of vehicle - fluorescence determined for sample with test compound present) divided by (fluorescence determined in the presence of vehicle - fluorescence determined for sample without trigger)) * 100 %.
  • OSM and IL- l ⁇ were shown to synergistically upregulate MMP 13 levels in the human chondrosarcoma cell line SW1353.
  • the cells were seeded in 96 well plates at 15,000 cells/well in a volume of 120 ⁇ L DMEM (Invitrogen) containing 10% (v/v) FBS and 1% penicillin/streptomycin (InVitrogen) incubated at 37°C 5% CO 2 .
  • MMP 13 levels were measured in conditioned medium 48 hours after triggering.
  • MMP 13 activity was measured using an antibody capture activity assay.
  • 384 well plates (NUNC, 460518, MaxiSorb black) were coated with 35 ⁇ L of a 1.5 ⁇ g/mL anti-human MMP13 antibody (R&D Systems, MAB511) solution for 24 hours at 4°C.
  • Percentage inhibition ((fluorescence determined in the presence of vehicle - fluorescence determined for sample with test compound present) divided by (fluorescence determined in the presence of vehicle - fluorescence determined for sample without trigger)) * 100 %.
  • PBL Human peripheral blood lymphocytes
  • the PBL are first stimulated for 72 hrs with PHA to induce IL-2 receptor, fasted for 24 hrs to stop cell proliferation followed by IL-2 stimulation for another 72 hrs (including 24hr BrdU labeling).
  • Cells are preincubated with test compounds 1 hr before IL-2 addition.
  • Cells are cultured in RPMI 1640 containing 10% (v/v) FBS.http://www.118800.co.uk/removeme/remove.html
  • Example 3 In vivo models
  • CFA Completed Freund's adjuvant
  • IFA incomplete Freund's adjuvant
  • Bovine collagen type II CII
  • LPS lipopolysaccharide
  • Enbrel obtained from Chondrex (Isle d'Abeau, France); Sigma (P4252, L'Isle d'Abeau, France), Whyett (25mg injectable syringe, France) Acros Organics (Palo Alto, CA), respectively. All other reagents are of reagent grade and all solvents are of analytical grade.
  • DBA/1 J mice male, 7 weeks old are obtained from Centre d'Elevage et de Reproduction JANVIER (CERJ) (Laval, France). Rats and mice are kept on a 12 hours light/dark cycle (0700 - 1900). The temperature is maintained at 22°C, and food and water are provided ad libitum.
  • mice 0.1 mL of the emulsion is injected intradermally at the base of the tail of each mouse on day 1, a second booster intradermal injection (CII solution at 1 mg/mL in CFA 0.1 mL saline) is performed on day 21.
  • This immunization method is modified from published methods (David D Brand Kary A Latham, &
  • Rat 0.2 mL of the emulsion is injected intradermally at the base of the tail of each rat on day 1, a second booster intradermal injection (CII solution at 2 mg/mL in CFA 0.1 mL saline) is performed on day 9.
  • CII solution at 2 mg/mL in CFA 0.1 mL saline
  • This immunization method is modified from published methods (Sims NA et ah, (2004) Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis, Arthritis Rheum. 50 2338-2346; Jou e? ⁇ /., 2005).
  • test compounds are tested in the rat or mouse CIA model.
  • mice are randomly divided into equal groups and each group contained 10 animals. All rats are immunized on day 1 and boosted on day 9. All mice are immunized on day 1 and boosted on day 21. Therapeutic dosing last from day 16 to day 30.
  • the negative control group is treated with vehicle (MC 0,5%) and the positive control group with Enbrel (10 mg/kg, 3x week., s.c).
  • Enbrel 10 mg/kg, 3x week., s.c
  • a compound of interest is typically tested at 3 doses, e.g. 3, 10, 30 mg/kg, p.o.
  • the swelling of each of the four paws is ranked with the arthritic score as follows: 0-no symptoms; 1- mild, but definite redness and swelling of one type of joint such as the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; 2-moderate redness and swelling of two or more types of joints; 3-severe redness and swelling of the entire paw including digits; 4- maximally inflamed limb with involvement of multiple joints (maximum cumulative clinical arthritis score 16 per animal) (Nishida et al, 2004).
  • X-ray photos are taken of the hind paws of each individual animal.
  • a random blind identity number is assigned to each of the photos, and the severity of bone erosion is ranked by two independent scorers with the radiological Larsen's score system as follows: 0- normal with intact bony outlines and normal joint space; 1- slight abnormality with any one or two of the exterior metatarsal bones showing slight bone erosion; 2-defmite early abnormality with any three to five of the exterior metatarsal bones showing bone erosion; 3- medium destructive abnormality with all the exterior metatarsal bones as well as any one or two of the interior metatarsal bones showing definite bone erosions; 4-severe destructive abnormality with all the metatarsal bones showing definite bone erosion and at least one of the inner metatarsal joints completely eroded leaving some bony joint outlines partly preserved; 5-mutilating abnormality without bony outlines.
  • This scoring system is a modification from Salvemini et al, 2001; Bush et al, 2002; Sims et al, 2004; Jo
  • mice After radiological analysis, the hind paws of mice are fixed in 10% phosphate-buffered formalin (pH 7.4), decalcified with rapid bone decalcif ⁇ ant for fine histology (Laboratories Eurobio) and embedded in paraffin.
  • pH 7.4 10% phosphate-buffered formalin
  • L&E hematoxylin and eosin
  • Histologic examinations for synovial inflammation and bone and cartilage damage are performed double blind.
  • four parameters are assessed using a four-point scale. The parameters are cell infiltration, pannus severity, cartilage erosion and bone erosion. Scoring is performed as follows: 1- normal, 2-mild, 3-moderate, 4-marked. These four scores are summed together and represented as an additional score, namely the 'RA total score'.
  • Bone degradation observed in RA occurs especially at the cortical bone and can be revealed by ⁇ CT analysis (Sims NA et al, 2004; Oste L et al, ECTC Montreal 2007). After scanning and 3D volume reconstruction of the calcaneus bone, bone degradation is measured as the number of discrete objects present per slide, isolated in silico perpendicular to the longitudinal axis of the bone. The more the bone is degraded, the more discrete objects are measured. 1000 slices, evenly distributed along the calcaneus (spaced by about 10.8 ⁇ m), are analyzed.
  • LPS lipopolysaccharide
  • TNF-alpha TNF-alpha
  • mice Six BALB/cJ female mice (20 g) per group are treated at the intended dosing once, po. Thirty minutes later, LPS (15 ⁇ g/kg; E. CoIi serotype 0111 :B4) is injected ip. Ninety minutes later, mice are euthanized and blood is collected. Circulating TNF alpha levels are determined using commercially available ELISA kits. Dexamethasone (5 ⁇ g/kg) is used as a reference anti-inflammatory compound. Selected compounds are tested at one or multiple doses, e.g. 3 and/or 10 and/or 30 mg/kg, po.
  • the MAB model allows a rapid assessment of the modulation of an RA-like inflammatory response by therapeutics (Kachigian LM. Nature Protocols (2006) 2512-2516: Collagen antibody- induced arthritis).
  • DBA/J mice are injected i.v. with a cocktail of mAbs directed against collagen II.
  • compound treatment is initiated (vehicle: 10% (v/v) HP ⁇ CD).
  • mice receive an i.p. LPS injection (50 ⁇ g/mouse), resulting in a fast onset of inflammation.
  • Compound treatment is continued until 10 days after the mAb injection.
  • Inflammation is read by measuring paw swelling and recording the clinical score of each paw.
  • the cumulative clinical arthritis score of four limbs is presented to show the severity of inflammation.
  • a scoring system is applied to each limb using a scale of 0-4, with 4 being the most severe inflammation.
  • a solution of 1 mg/mL of the test compound is prepared in a 0.2M phosphate buffer pH7.4 or a
  • DMSO stock solution diluted factor 2 in DMSO (5000 ⁇ M) and then further diluted in DMSO up to 19.5 ⁇ M.
  • 3 ⁇ L of the dilution series as from 5000 ⁇ M is then transferred to a 97 ⁇ L acetonitrile-buffer mixture (50/50).
  • the final concentration range is 2.5 to 150 ⁇ M.
  • the plate is sealed with sealing mats (MA96RD-04S, www.kinesis.co.uk) and samples are measured at room temperature on LCMS (ZQ 1525 from Waters) under optimized conditions using
  • Peak areas are analyzed with the aid of Masslynx software package and peak areas of the samples are plotted against the standard curve to obtain the solubility of the compound.
  • Solubility values are reported in ⁇ M or ⁇ g/mL.
  • DMSO DMSO
  • the dilution series is transferred to a 96 NUNC Maxisorb plate F-bottom (Cat no. 442404) and 0.2M phosphate buffer pH7.4 or 0. IM citrate buffer pH3.0 at room temperature is added.
  • the final concentration ranged from 200 ⁇ M to 2.5 ⁇ M in 5 equal dilution steps.
  • DMSO concentration did not exceed 2%.
  • 200 ⁇ M Pyrene is added to the corner points of each 96 well plate and serves as a reference point for calibration of Z-axis on the microscope.
  • the assay plates are sealed and incubated for 1 hour at 37°C while shaking at 230rpm.
  • the plates are then scanned under a white light microscope, yielding individual pictures of the precipitate per concentration.
  • the precipitate is analyzed and converted into a number which is plotted onto a graph.
  • the first concentration at which the compound appears completely dissolved is the concentration reported, however the true concentration lies somewhere between this concentration and one dilution step higher.
  • a 1OmM stock solution of the compound in DMSO is diluted with a factor 5 in DMSO. This solution is further diluted in freshly thawed human, rat, mouse or dog plasma (BioReclamation INC) with a final concentration of lO ⁇ M and final DMSO concentration of 0.5% (5.5 ⁇ l in 1094.5 ⁇ l plasma in a PP- Masterblock 96well (Greiner, Cat no. 780285))
  • a Pierce Red Device plate with inserts (ThermoScientific, Cat no. 89809) is prepared and filled with 750 ⁇ L PBS in the buffer chamber and 500 ⁇ L of the spiked plasma in the plasma chamber.
  • the plate is incubated for 4 hours at 37°C while shaking at 230rpm. After incubation, 120 ⁇ L of both chambers is transferred to 360 ⁇ L acetonitrile in a 96-well round bottom, PP deep-well plates (Nunc, Cat no. 278743) and sealed with an aluminum foil lid. The samples are mixed and placed on ice for 30min. This plate is then centrifuged 30 min at 1200rcf at 4°C and the supernatant is transferred to a 96 v-bottom PP plate (Greiner,
  • the plate is sealed with sealing mats (MA96RD-04S) of www.kinesis.co.uk and samples are measured at room temperature on LCMS (ZQ 1525 from Waters) under optimized conditions using
  • the solvent gradient has a total run time of 2 minutes and ranges from 5% B to 95% B.
  • Peak area from the compound in the buffer chamber and the plasma chamber are considered to be 100% compound.
  • the percentage bound to plasma is derived from these results and was reported to the
  • Pulse v8.77 software (HEKA). Series resistance is typically less than 10 M ⁇ and compensated by greater than
  • Electrodes are manufactured from GC 150TF pipette glass (Harvard).
  • the external bathing solution contains: 135 mM NaCl, 5 mM KCl, 1.8 mM CaCl 2 , 5 mM
  • Glucose 10 mM HEPES, pH 7.4.
  • the internal patch pipette solution contains: 10OmM Kgluconate, 20 mM KCl, ImM CaCl 2 , 1 mM MgCl 2 , 5mM Na 2 ATP, 2mM Glutathione, 11 mM EGTA, 10 mM HEPES, pH 7.2.
  • Drugs are perfused using a Biologic MEV-9/EVH-9 rapid perfusion system.
  • a 1OmM stock solution of compound in DMSO was diluted 1000 fold in a 182 mM phosphate buffer pH7.4 in a 96 deep well plate (Greiner, Cat no.780285) and pre-incubated at 37°C.
  • G6PDH Glucose-6-phophate-dehydrogenase
  • liver microsomes (Xenotech) of a species of interest
  • Peak area from the parent compound at time 0 was considered to be 100% remaining.
  • the percentage remaining after 1 hour incubation was calculated from time 0 and was calculated as the percentage remaining.
  • the solubility of the compound in the final test concentration in buffer is inspected by microscope and results are reported.
  • Caco-2 assays were performed as described below. Caco-2 cells were obtained from European Collection of Cell Cultures (ECACC, cat 86010202) and used after a 21 day cell culture in 24- well Transwell plates (Fisher TKT-545-020B).
  • Test and reference compounds (propranolol and rhodaminel23 or vinblastine, all purchased from Sigma) were prepared in Hanks' Balanced Salt Solution containing 25 mM HEPES (pH7.4) and added to either the apical (125 ⁇ L) or basolateral (600 ⁇ L) chambers of the Transwell plate assembly at a concentration of
  • Lucifer Yellow (Sigma) was added to the donor buffer in all wells to assess integrity of the cell layers by monitoring Lucifer Yellow permeation. As Lucifer Yellow (LY) cannot freely permeate lipophilic barriers, a high degree of LY transport indicates poor integrity of the cell layer. [00473] After a 1 hour incubation at 37°C while shaking at an orbital shaker at 150rpm, 70 ⁇ L aliquots were taken from both apical (A) and basal (B) chambers and added to lOO ⁇ Ll 50:50 acetonitrile:water solution containing analytical internal standard (0.5 ⁇ M carbamazepine) in a 96 well plate.
  • A apical
  • B basal
  • Lucifer yellow was measured with a Spectramax Gemini XS (Ex 426nm and Em 538nm) in a clean 96 well plate containing 150 ⁇ L of liquid from basolateral and apical side.
  • V chamber volume
  • T mc incubation time.
  • Surface area 0.33cm
  • Rhodamine 123 or Vinblastine P app (A>B) value ⁇ 5 (xlO 6 cm/s) with Efflux ratio >5.
  • Lucifer yellow permeability ⁇ 100 nm/s
  • Compounds are formulated in PEG200/physiological saline or PEG400/DMSO/physiological saline mixtures for the intravenous route and in 0.5% methylcellulose or 10-30% hydroxylpropyl- ⁇ - cyclodextrine pH3 or pH7.4 for the oral route.
  • Test compounds are orally dosed as a single esophageal gavage at 5-10 mg/kg and intravenously dosed as a bolus via the caudal vein at 1 mg/kg.
  • Each group consists of 3 rats.
  • Blood samples are collected either via the jugular vein using cannulated rats or at the retro-orbital sinus with lithium heparin as anti-coagulant at the time points in the following range: 0.05 to 8 hours (intravenous route), and 0.25 to 6 or 24 hours (oral route).
  • Whole blood samples are centrifuged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20 0 C pending analysis.
  • Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive electrospray mode.
  • a 7-day oral toxicity study with test compounds was performed in Sprague-Dawley male rats to assess their toxic potential and toxicokinetics, at daily doses of 100, 300 and 500 mg/kg/day, by gavage, at the constant dosage- volume of 5 mL/kg/day.
  • test compounds were formulated in 30% (v/v) HP ⁇ CD in purified water. Each group included 5 principal male rats as well as 3 satellite animals for toxicokinetics. A fourth group was given 30%
  • Interleukin (IL)-4 and IL- 13 up-regulate monocyte chemoattractant protein- 1 expression in human bronchial epithelial cells: involvement of p38 mitogen-activated protein kinase, extracellular signal- regulated kinase 1/2 and Janus kinase-2 but not c-Jun NH2 -terminal kinase 1/ 2 signalling pathways, Clin. Exp. Immun, 162-172.
  • the JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia, Eur J Pharmaco 154-161.
  • HDAC histone deacetylase
  • any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.
  • a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

Abstract

Novel [1,2,4]triazolo[1,5-a]pyridine compounds are disclosed that have a Formula represented by the Formula (I). These compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotox in states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection) and proliferative diseases.

Description

NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND
INFLAMMATORY DISEASES
FIELD OF THE INVENTION
[0001] The present invention relates to compounds that are inhibitors of JAK, a family of tyrosine kinases that are involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation. The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds, methods for the prevention and/or treatment of diseases involving cartilage degradation, bone and/or joint degradation, conditions involving inflammation or immune responses, endotoxin- driven disease states, cancer, and organ transplant rejection; and/ or methods for the prevention and/or treatment of diseases involving cartilage degradation, joint degradation and/or inflammation by administering a compound of the invention. [0002] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members are described, JAKl, JAK2, JAK3 and TYK2. Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription. JAK-STAT intracellular signal transduction serves the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, PRL Vainchenker W. et al (2008).
[0003] The combination of genetic models and small molecule JAK inhibitor research revealed the therapeutic potential of several JAKs. JAK3 is validated by mouse and human genetics as an immune- suppression target (O'Shea J. et al. (2004)). JAK3 inhibitors were successfully taken into clinical development, initially for organ transplant rejection but later also in other immuno-inflammatory indications such as rheumathoid arthritis (RA), psoriasis and Crohn's disease (http://clinicaltrials.gov/).
[0004] TYK2 is a potential target for immuno-inflammatory diseases, being validated by human genetics and mouse knock-out studies (Levy D. and Loomis C. (2007)).
[0005] JAKl is a novel target in the immuno-inflammatory disease area. JAKl heterodimerizes with the other JAKs to transduce cytokine- driven pro-inflammatory signaling. Therefore, inhibition of JAKl and/or other JAKs is expected to be of therapeutic benefit for a range of inflammatory conditions as well as for other diseases driven by JAK-mediated signal transduction.
BACKGROUND OF THE INVENTION
[0006] Cartilage is an avascular tissue of which chondrocytes are the main cellular component. The chondrocytes in normal articular cartilage occupy approximately 5% of the tissue volume, while the extra- cellular matrix makes up the remaining 95% of the tissue. The chondrocytes secrete the components of the matrix, mainly proteoglycans and collagens, which in turn supply the chondrocytes with an environment suitable for their survival under mechanical stress. In cartilage, collagen type II, together with the protein collagen type IX, is arranged in solid fibril-like structures which provide cartilage with great mechanical strength. The proteoglycans can absorb water and are responsible for the resilient and shock absorbing properties of the cartilage.
[0007] One of the functional roles of cartilage in the joint is to allow bones to articulate on each other smoothly. Loss of articular cartilage, therefore, causes the bones to rub against each other leading to pain and loss of mobility. The degradation of cartilage can have various causes. In inflammatory arthritides, as rheumatoid arthritis for example, cartilage degradation is caused by the secretion of proteases (e.g. collagenases) by inflamed tissues (the inflamed synovium for example). Cartilage degradation can also be the result of an injury of the cartilage, due to an accident or surgery, or exaggerated loading or 'wear and tear'. The ability of cartilage tissue to regenerate after such insults is limited. Chondrocytes in injured cartilage often display reduced cartilage synthesizing (anabolic) activity and / or increased cartilage degrading (catabolic) activity.
[0008] The degeneration of cartilage is the hallmark of various diseases, among which rheumatoid arthritis and osteoarthritis are the most prominent. Rheumatoid arthritis (RA) is a chronic joint degenerative disease, characterized by inflammation and destruction of the joint structures. When the disease is unchecked, it leads to substantial disability and pain due to loss of joint functionality and even premature death. The aim of an RA therapy, therefore, is not only to slow down the disease but to attain remission in order to stop the joint destruction. Besides the severity of the disease outcome, the high prevalence of RA (~ 0.8% of the adults are affected worldwide) means a high socio-economic impact. (For reviews on RA, we refer to Smolen and Steiner (2003); Lee and Weinblatt (2001); Choy and Panayi (2001); O'Dell (2004) and Firestein (2003)). [0009] Osteoarthritis (also referred to as OA, or wear-and-tear arthritis) is the most common form of arthritis and is characterized by loss of articular cartilage, often associated with hypertrophy of the bone and pain. The disease mainly affects hands and weight-bearing joints such as knees, hips and spines. This process thins the cartilage. When the surface area has disappeared due to the thinning, a grade I osteoarthritis is reached; when the tangential surface area has disappeared, grade II osteoarthritis is reached. There are further levels of degeneration and destruction, which affect the deep and the calcified cartilage layers that border with the subchondral bone. For an extensive review on osteoarthritis, we refer to Wieland et ah, 2005. [0010] The clinical manifestations of the development of the osteoarthritis condition are: increased volume of the joint, pain, crepitation and functional disability that lead to pain and reduced mobility of the joints. When disease further develops, pain at rest emerges. If the condition persists without correction and/or therapy, the joint is destroyed leading to disability. Replacement surgery with total prosthesis is then required. [0011] Therapeutic methods for the correction of the articular cartilage lesions that appear during the osteoarthritic disease have been developed, but so far none of them have been able to mediate the regeneration of articular cartilage in situ and in vivo.
[0012] Osteoarthritis is difficult to treat. At present, no cure is available and treatment focuses on relieving pain and preventing the affected joint from becoming deformed. Common treatments include the use of non-steroidal anti-inflammatory drugs (NSAIDs). Although dietary supplements such as chondroitin and glucosamine sulphate have been advocated as safe and effective options for the treatment of osteoarthritis, a recent clinical trial revealed that both treatments did not reduce pain associated to osteoarthritis. (Clegg et ah,
2006). Taken together, no disease modifying osteoarthritic drugs are available.
[0013] In severe cases, joint replacement may be necessary. This is especially true for hips and knees.
If a joint is extremely painful and cannot be replaced, it may be fused. This procedure stops the pain, but results in the permanent loss of joint function, making walking and bending difficult.
[0014] Another possible treatment is the transplantation of cultured autologous chondrocytes. Here, chondral cellular material is taken from the patient, sent to a laboratory where it is expanded. The material is then implanted in the damaged tissues to cover the tissue's defects.
[0015] Another treatment includes the intra-articular instillation of Hylan G-F 20 (e.g. Synvisc®,
Hyalgan®, Artz®), a substance that improves temporarily the rheology of the synovial fluid, producing an almost immediate sensation of free movement and a marked reduction of pain.
[0016] Other reported methods include application of tendinous, periosteal, fascial, muscular or perichondral grafts; implantation of fibrin or cultured chondrocytes; implantation of synthetic matrices, such as collagen, carbon fiber; administration of electromagnetic fields. All of these have reported minimal and incomplete effects, resulting in a poor quality tissue that can neither support the weighted load nor allow the restoration of an articular function with normal movement.
[0017] Stimulation of the anabolic processes, blocking catabolic processes, or a combination of these two, may result in stabilization of the cartilage, and perhaps even reversion of the damage, and therefore prevent further progression of the disease. Various triggers may stimulate anabolic stimulation of chondrocytes.
Insulin-like growth factor-I (IGF-I) is the predominant anabolic growth factor in synovial fluid and stimulates the synthesis of both proteoglycans and collagen. It has also been shown that members of the bone morphogenetic protein (BMP) family, notably BMP2, BMP4, BMP6, and BMP7, and members of the human transforming growth factor-β (TGF-β) family can induce chondrocyte anabolic stimulation (Chubinskaya and
Kuettner, 2003). A compound has recently been identified that induces anabolic stimulation of chondrocytes
(US 6,500,854; EP 1 391 211). However, most of these compounds show severe side effects and, consequently, there is a strong need for compounds that stimulate chondrocyte differentiation without these side effects.
[0018] Vandeghinste et al. (WO 2005/124342) discovered JAKl as a target whose inhibition might have therapeutic relevance for several diseases including OA. JAKl belongs to the Janus kinase (JAK) family of cytoplasmic tyrosine kinases, involved in cytokine receptor-mediated intracellular signal transduction. The JAK family consists of 4 members: JAKl, JAK2, JAK3 and TYK2. JAKs are recruited to cytokine receptors, upon binding of the cytokine, followed by heterodimerization of the cytokine receptor and a shared receptor subunit (common gamma-c chain, gpl30). JAKs are then activated by auto- and/or transphosphorylation by another JAK, resulting in phosphorylation of the receptors and recruitment and phosphorylation of members of the signal transducer and activator of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus where they bind to enhancer regions of cytokine-responsive genes. Knockout of the JAKl gene in mice demonstrated that JAKl plays essential and nonredundant roles during development: JAKl-/- mice died within 24h after birth and lymphocyte development was severely impaired. Moreover, JAKl -/- cells were not, or less, reactive to cytokines that use class II cytokine receptors, cytokine receptors that use the gamma-c subunit for signaling and the family of cytokine receptors that use the gpl30 subunit for signaling (Rodig et al., 1998).
[0019] Various groups have implicated JAK-STAT signaling in chondrocyte biology. Li e? α/. (2001) showed that Oncostatin M induces MMP and TIMP3 gene expression in primary chondrocytes by activation of JAK/STAT and MAPK signaling pathways. Osaki et al. (2003) showed that interferon-gamma mediated inhibition of collagen II in chondrocytes involves JAK-STAT signaling. ILl -beta induces cartilage catabolism by reducing the expression of matrix components, and by inducing the expression of collagenases and inducible nitric oxide synthase (NOS2), which mediates the production of nitric oxide (NO). Otero et al., (2005) showed that leptin and ILl -beta synergistically induced NO production or expression of NOS2 mRNA in chondrocytes, and that that was blocked by a JAK inhibitor. Legendre et al. (2003) showed that IL6/IL6Receptor induced downregulation of cartilage-specific matrix genes collagen II, aggrecan core and link protein in bovine articular chondrocytes, and that this was mediated by JAK/STAT signaling. Therefore, these observations suggest a role for JAK kinase activity in cartilage homeostasis and therapeutic opportunities for JAK kinase inhibitors. [0020] JAK family members have been implicated in additional conditions including myeloproliferative disorders (O'Sullivan et al, 2007, MoI Immunol. 44(10):2497-506), where mutations in JAK2 have been identified. This indicates that inhibitors of JAK in particular JAK2 may also be of use in the treatment of myeloproliferative disorders. Additionally, the JAK family, in particular JAKl, JAK2 and JAK3, has been linked to cancers, in particular leukaemias e.g. acute myeloid leukaemia (O'Sullivan et al, 2007, MoI Immunol. 44(10):2497-506; Xiang et al., 2008, "Identification of somatic JAKl mutations in patients with acute myeloid leukemia" Blood First Edition Paper, prepublished online December 26, 2007; DOI 10.1182/blood-2007-05-090308) and acute lymphoblastic leukemia (Mullighan et al, 2009) or solid tumours e.g. uterine leiomyosarcoma (Constantinescu et al, 2007, Trends in Biochemical Sciences 33(3): 122-131), prostate cancer (Tarn et al., 2007, British Journal of Cancer, 97, 378 - 383) These results indicate that inhibitors of JAK, in particular of JAKl and/or JAK2, may also have utility in the treatment of cancers (leukaemias and solid tumours e.g. uterine leiomyosarcoma, prostate cancer). [0021] In addition, Castleman's disease, multiple myeloma, mesangial proliferative glomerulonephritis, psoriasis, and Kaposi's sarcoma are likely due to hypersecretion of the cytokine IL-6, whose biological effects are mediated by intracellular JAK-STAT signaling (Tetsuji Naka, Norihiro Nishimoto and Tadamitsu Kishimoto, Arthritis Res 2002, 4 (suppl 3):S233-S242). This result shows that inhibitor of JAK, may also find utility in the treatment of said diseases.
[0022] A link with autoimmune diseases has been established for JAK3 and Tyk2. Mutations in JAK3 but also in the upstream signaling components gamma-c receptor chain and IL7 receptor account in aggregate for -70% of cases of human severe combined immunodeficiency ('OShea et al., 2004). Note that JAKl cooperates with JAK3 in transducing signals from the gamma-c receptor chain. Tyk2 polymorphisms are seen in systemic lupus erythematosus (SLE) (O'Sullivan et al, 2007, MoI Immunol. 44(10):2497-506). Hence, targeting the JAK family may provide a therapeutic opportunity in the immuno-inflammation area. [0023] The current therapies are not satisfactory and therefore there remains a need to identify further compounds that may be of use in the treatment of diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection). Inhibitors of JAK can also find application in the treatment of proliferative diseases. In particular the inhibitors of JAK find application in the treatment of cancers , especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer). The present invention therefore provides compounds, methods for their manufacture and a pharmaceutical comprising a compound of the invention together with a suitable pharmaceutical carrier. The present invention also provides for the use of a compound of the invention in the preparation of a medicament for the treatment of degenerative joint diseases.
SUMMARY OF THE INVENTION
[0024] The present invention is based on the discovery that inhibitors of JAK are useful for the treatment of diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection). Inhibitors of JAK can also find application in the treatment of proliferative diseases. In particular the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer). The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating diseases involving cartilage degradation, joint degradation and/or inflammation by administering a compound of the invention.
[0025] Accordingly, in a first aspect of the invention, substituted bicycloheteroaryl compounds are disclosed according to Formula (I):
Figure imgf000007_0001
wherein each CyI and Cy2 is independently selected from aryl and heteroaryl; each Ll and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O)2-, -N(R4a)-, - CON(R4a)-, -SO2N(R4a)-, - N(R4a)CO-, or - N(R4a)SO2-; each R1 is independently selected from Ci-Ce alkyl, substituted Ci-Cβ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, hydroxyl; each R a is independently selected from Ci-Ce alkyl, substituted Ci-Cβ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC6 alkoxy, substituted or unsubstituted amido, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfanyl, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, substituted or unsubstituted heteroaryl, hydroxy, nitro, and thiol; each R2b, R2c, and R2d is independently selected from H, CpC6 alkyl, substituted CpC6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted Ci-Cβ alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, substituted or unsubstituted amido, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted CpC6 haloalkyl, hetero-O-aryl, substituted or unsubstituted 5-10 membered heteroaryl, hydroxyl, nitro, and thiol; each R2a and R4a is independently selected from H, Ci-Ce alkyl, substituted Ci-Cβ alkyl, C3-C7 cycloalkyl, or substituted C3-C7 cycloalkyl;
R3b is independently selected from substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted -(CpC4 alkyl)-(4-7- membered heterocycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted -O- aryl, substituted or unsubstituted arylamino, and substituted or unsubstituted 5-10 membered heteroaryl; ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when Ll is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L2 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R3b is other than C3-C7 cycloalkyl, aryl or 5-10 membered heteroaryl, then n2 is 1, 2, 3, or 4; or a pharmaceutically acceptable salt, or solvate thereof or a solvate of a pharmaceutically acceptable salt. In a further aspect, the invention provides substituted bicycloheteroaryl compounds accordingula (I):
Figure imgf000008_0001
wherein each CyI and Cy2 is independently selected from aryl and heteroaryl; each Ll and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O)2-, -N(R4a)-, CON(R4a)-, -SO2N(R4a)-, - N(R4a)CO-, or - N(R4a)SO2-; each R1 is independently selected from Ci-Ce alkyl, substituted Ci-Cβ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, hydroxyl; each R3a is independently selected from CpC6 alkyl, substituted CpC6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted Ci-Ce alkoxy, substituted or unsubstituted amido, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfanyl, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, substituted or unsubstituted heteroaryl, hydroxy, nitro, and thiol; each R2b, R2c, and R2d is independently selected from H, CpC6 alkyl, substituted CpC6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC6 alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfmyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, substituted or unsubstituted amido, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted CpC6 haloalkyl, hetero-O-aryl, substituted or unsubstituted 5-10 membered heteroaryl, hydroxyl, nitro, and thiol; each R2a and R4a is independently selected from H, CpC6 alkyl, substituted CpC6 alkyl, C3-C7 cycloalkyl, or substituted C3-C7 cycloalkyl;
R3b is independently selected from substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted -O-aryl, substituted or unsubstituted arylamino, and substituted or unsubstituted 5-10 membered heteroaryl; ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when Ll is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L2 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R3b is other than C3-C7 cycloalkyl, aryl or 5-10 membered heteroaryl, then n2 is 1, 2, 3, or 4; or a pharmaceutically acceptable salt, or solvate thereof or a solvate of a pharmaceutically acceptable salt.
[0027] In a further aspect of the invention, novel l,2,4-triazolo[l,5-a]pyridine compounds are disclosed that are capable of modulating the activity of JAK in vivo, having a Formula (I). [0028] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In this aspect of the invention, the pharmaceutical composition can comprise one or more of the compounds described herein. Moreover, the compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are all pharmaceutically acceptable as prepared and used.
[0029] In a further aspect of the invention, this invention provides a method of treating a mammal susceptible to or afflicted with a condition from among those listed herein, and particularly, such condition as may be associated with aberrant JAK activity, for example diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection). Inhibitors of JAK can also find application in the treatment of proliferative diseases. In particular the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer), which method comprises administering a therapeutically effective amount of a compound of the invention or a pharmaceutical composition as described herein. In a particular embodiment the present invention provides a method for treating conditions selected from inflammation, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and organ transplant rejection; and cartilage, bone and/or joint degradation or degeneration, such as osteoarthritis, which method comprises administering an effective amount of one or more of the pharmaceutical compositions or compounds herein described.
[0030] In a further aspect, the present invention provides a method of treating a mammal susceptible to or afflicted with proliferative disorders in particular cancer, (e.g. solid tumours), leukaemias, multiple myeloma or psoriasis.
[0031] In a further aspect, the present invention provides a compound of the invention for use in the treatment or prevention of a condition selected from those listed herein, particularly such conditions as may be associated with aberrant JAK activity such as diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection). Inhibitors of JAK can also find application in the treatment of proliferative diseases. In particular the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer). In a specific embodiment, the condition is selected from inflammation, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, allergic airways disease
(e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and organ transplant rejection; and cartilage, bone and/or joint degradation or degeneration, such as osteoarthritis.
[0032] In a further aspect, the present invention provides a compound of the invention for use in the treatment or prevention of proliferative disorders, in particular cancer, (e.g. solid tumours), leukaemias, multiple myeloma or psoriasis.
[0033] In yet another method of treatment aspect, this invention provides a method for treating a mammal susceptible to or afflicted with a condition that is causally related to abnormal JAK activity as described herein, and comprises administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions or compounds herein described.
[0034] In a further aspect, the present invention provides a compound of the invention for use in the treatment or prevention of a condition that is causally related to abnormal JAK activity.
[0035] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
[0036] Accordingly, it is a principal object of this invention to provide a novel series of compounds, which can modify the activity of JAK and thus prevent or treat any maladies that may be causally related thereto.
[0037] It is further an object of this invention to provide a series of compounds that can treat or alleviate maladies or symptoms of same, such as cartilage and/or bone degradation and related inflammation, and joint diseases, that may be causally related to the activity of JAK.
[0038] A still further object of this invention is to provide pharmaceutical compositions that may be used in the treatment or prevention of a variety of disease states, including the diseases associated with JAK activity such as diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection). Inhibitors of JAK can also find application in the treatment of proliferative diseases. In particular the inhibitors of JAK find application in the treatment of cancers , especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer). In a specific embodiment the condition is selected from inflammation, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and organ transplant rejection; and cartilage, bone and/or joint degradation or degeneration, such as osteoarthritis or cancers (e.g. solid tumours or leukaemias).
[0039] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.
DETAILED DESCRIPTION OF THE INVENTION Definitions
[0040] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
[0041] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein. [0042] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.
[0043] 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R20, where R20 is hydrogen, C1-C8 alkyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. Exemplary 'acyl' groups are -C(O)H, -C(O)-Ci-C8 alkyl, -C(O)-(CH2)t(C6-Ci0 aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(O)-(CH2)^C3-Ci0 cycloalkyl), and -C(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
[0044] 'Substituted AcyP or 'Substituted Alkanoyl' refers to a radical -C(O)R21, wherein R21 is independently
• CpC8 alkyl, substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted CpC4 alkyl, halo, unsubstituted Cp C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0045] 'Acylamino' refers to a radical -NR22C(O)R23, where R22 is hydrogen, Ci-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R23 is hydrogen, CpC8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein. Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl- carbonylamino, benzoylamino and benzylcarbonylamino. Exemplary 'acylamino' groups are -NR21 C(O)-Cp C8 alkyl, -NR21 C(O)-(CH2X(C6-Ci0 aryl), -NR21 C(O)-(CH2)t(5-10 membered heteroaryl), -NR21 C(O)-
(CH2)t(C3-Cio cyclo )aallkyl), and -NR21 C(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R21 independently represents H or CpC8 alkyl.
[0046] 'Substituted Acylamino' refers to a radical -NR24C(O)R25, wherein:
R24 is independently
• H, CpC8 alkyl, substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy; and
R25 is independently
• H, CpC8 alkyl, substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxyl; provided at least one of R24 and R25 is other than H.
[0047] 'Alkoxy' refers to the group -OR26 where R26 is CpC8 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
[0048] 'Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of "substituted" herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-Ci0 aryl, -O-aryl, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thio-O-aryl, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. Exemplary 'substituted alkoxy' groups are -0-(CH2)t(C6-Cio aryl), -O-(CH2)t(5-10 membered heteroaryl), -O-(CH2)t(C3- Cio cycloalkyl), and -O-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. Particular exemplary 'substituted alkoxy' groups are OCF3, OCH2CF3, OCH2Ph, OCHrcyclopropyl, OCH2CH2OH, OCH2CH2NMe2.
[0049] 'Alkoxycarbonyl' refers to a radical -C(O)-OR27 where R27 represents an Ci-C8 alkyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein. Exemplary "alkoxycarbonyl" groups are C(O)O-CpCg alkyl, -C(O)O- (CH2MC6-C10 aryl), -C(O)O-(CH2)t(5-10 membered heteroaryl), -C(O)O-(CH2MC3-C10 cycloalkyl), and - C(O)O-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4. [0050] 'Substituted Alkoxycarbonyl' refers to a radical -C(O)-OR28 where R28 represents:
• Ci-C8 alkyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, or 4-10 membered heterocycloalkylalkyl, each of which is substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C6-Ci0 aralkyl, or 5-10 membered heteroarylalkyl, each of which is substituted with unsubstituted Ci-C4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxyl.
[0051] 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms.
Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms. Exemplary straight chained groups include methyl, ethyl n- propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso-butyl, t-butyl and isoamyl.
[0052] 'Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of "substituted" herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (-O-acyl or - OC(O)R20), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH-C(O)-OR27), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(O)-NR 2), aminocarbonylamino (-NR -C(O)- NR 2), aminocarbonyloxy (-O-C(O)-NR 2), aminosulfonyl, sulfonylamino, aryl, -O-aryl, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, heteroaryl, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl,-S(O)-aryl, -S(O)2- alkyl, and -S(0)2-aryl. In a particular embodiment 'substituted alkyl' refers to a CpCg alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR SO2R , -SO2NR R , -C(O)R , - C(O)OR", -OC(O)R", -NR"'C(O)R", -C(0)NR"R ", -NR"R ", or -(CR"'R"")mOR"; wherein each R" is independently selected from H, CpCg alkyl, -(CH2)t(C6-Cio aryl), -(CH2)t(5-10 membered heteroaryl), - (CH2)t(C3-Cio cycloalkyl), and -(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from O to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. Each of R and R independently represents H or CpC8 alkyl.
[0053] 'Amino' refers to the radical -NH2.
[0054] 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -N(R )2 where each R is independently selected from:
• hydrogen, CpC8 alkyl, C6-Ci0 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C3-C10 cycloalkyl; or
• CpCg alkyl, substituted with halo or hydroxy; or
• -(CH2)t(C6-Cio aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-Ci0 cycloalkyl) or - (CH2)t(4-10 membered heterocycloalkyl) wherein t is an integer between O and 8, each of which is substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy; or
• both R33 groups are joined to form an alkylene group.
When both R33 groups are hydrogen, -N(R33)2 is an amino group. Exemplary 'substituted amino' groups are -NR33'-CpC8 alkyl, -NR33'-(CH2)t(C6-Ci0 aryl), -NR33'-(CH2)t(5-10 membered heteroaryl), -NR33'-(CH2)t(C3-Cio cycloalkyl), and -NR33'-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from O to 4, each R independently represents H or CpCg alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. [0055] "Aminosulfonyl" or "Sulfonamide" refers to the radical -S(O2)NH2. [0056] "Substituted aminosulfonyl" or "substituted sulfonamide" refers to a radical such as -
S(O2)N(R48)2 wherein each R48 is independently selected from:
• H, CpC8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• CpCg alkyl substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy; provided that at least one R48 is other than H.
[0057] Exemplary 'substituted aminosulfonyl' or 'substituted sulfonamide' groups are -S(O2)N(R )-
Ci-C8 alkyl, -S(O2)N(R48')-(CH2)t(C6-Ci0 aryl), -S(O2)N(R48')-(CH2)t(5-10 membered heteroaryl), -
S(O2)N(R48 )-(CH2)t(C3-Cio cycloalkyl), and -S(O2)N(R48 )-(CH2)t(4- 10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; each R48 independently represents H or CpCg alkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0058] 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
[0059] 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of any aryl group present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, cyano, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. [0060] 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually 6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. [0061] 'Substituted AryP refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent. Particularly, 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, CpCg alkyl, CpCg haloalkyl, CpCg haloalkoxy, cyano, hydroxy, CpCg alkoxy, and amino.
[0062] Examples of representative substituted aryls include the following
Figure imgf000017_0001
[0063] In these formulae one of R49 and R50 may be hydrogen and at least one of R49 and R50 is each independently selected from CpCg alkyl, 4-10 membered heterocycloalkyl, alkanoyl, CpCg alkoxy, hetero-O- aryl, alkylamino, arylamino, heteroarylamino, NR51COR52, NR51SOR52 NR51SO2R52, COOalkyl, COOaryl,
CONR51R52, CONR51OR52, NR51R52, SO2NR51R52, S-alkyl, SOalkyl, S02alkyl, Saryl, SOaryl, S02aryl; or R49 and R50 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S. R51, and R52 are independently hydrogen, CpCg alkyl, CpC4 haloalkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, substituted aryl, 5-10 membered heteroaryl.
[0064] 'Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.
[0065] 'Substituted Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, cyano, unsubstituted CpC4 alkoxy, unsubstituted Cp4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted
CpC4 haloalkoxy or hydroxy.
[0066] 'Azido' refers to the radical -N3.
[0067] 'Carbamoyl or amido' refers to the radical -C(O)NH2.
[0068] 'Substituted Carbamoyl or substituted amido' refers to the radical -C(O)N(R53)2 wherein each
R53 is independently
• H, CpCg alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• CpCg alkyl substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy; provided that at least one R5 is other than H.
Exemplary 'Substituted Amido / Carbamoyl' groups are -C(O) NR53'-CrC8 alkyl, -C(0)NR53'-(CH2)t(C6-Cio aryl), -C(O)N53'-(CH2)t(5-10 membered heteroaryl), -C(0)NR53'-(CH2)t(C3-Cio cycloalkyl), and -C(O)NR53'- (CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R53 independently represents H or CpCg alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. [0069] 'Carboxy' refers to the radical -C(O)OH.
[0070] 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
[0071] 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent. [0072] 'Cyano' refers to the radical -CN.
[0073] 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
[0074] 'Hetero' when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
[0075] 'Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine. Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole. Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine. [0076] Examples of representative aryl having hetero atoms containing substitution include the following:
Figure imgf000019_0001
wherein each W is selected from C(R54)2, NR54, O and S; and each Y is selected from carbonyl, NR ,5344, O and S; and R54 is independently hydrogen, CpCg alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-CiO aryl, and 5-10 membered heteroaryl. [0077] Examples of representative heteroaryls include the following:
Figure imgf000019_0002
Figure imgf000019_0003
wherein each Y is selected from carbonyl, N, NR55, O and S; and R55 is independently hydrogen, CpCg alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, and 5-10 membered heteroaryl. [0078] As used herein, the term 'heterocycloalkyl' refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1 -pyrrolidinyl, 2- pyrrolidinyl and 3 -pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4- tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Further examples include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine. Particular examples of heterocycloalkyl groups are shown in the following illustrative examples:
Figure imgf000020_0001
wherein each W is selected from CR , C(R5t>)2, NR , O and S; and each Y is selected from NR , O and S; and R , 56 is independently hydrogen, Ci-Cg alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, 5-10 membered heteroaryl, These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy (-O-acyl or -OC(O)R20), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH-C(O)-OR27), amino, substituted amino, aminocarbonyl (amido or -C(O)-NR 2), aminocarbonylamino (-NR -C(O)-NR 2), aminocarbonyloxy (-0- C(O)-NR 2), aminosulfonyl, sulfonylamino, aryl, -O-aryl, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl,-S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives. [0079] 'Hydroxy' refers to the radical -OH.
[0080] 'Nitro' refers to the radical -NO2.
[0081] 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents may be selected from the group consisting of: halogen, -R57, -0", =0, -OR57, -SR57, -S", =S, -NR57R58, =NR57, -CCl3, -CF3, -CN, -OCN, -SCN, -NO, - NO2, =N2, -N3, -S(O)2O", -S(O)2OH, -S(O)2R57, -OS(O2)O-, -OS(O)2R57, -P(O)(O )2, -P(O)(OR57)(O ), -OP(O)(OR57XOR58), -C(O)R57, -C(S)R57, -C(O)OR57, -C(O)NR57R58, -C(O)O-, -C(S)OR57, - NR59C(O)NR57R58, -NR59C(S)NR57R58, -NR60C(NR59)NR57R58 and -C(NR59)NR57R58; wherein each R57, R58, R59 and R60 are independently:
• hydrogen, CpCg alkyl, Cβ-Cio aryl, arylalkyl, C3-CiO cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, heteroarylalkyl; or
• CpCg alkyl substituted with halo or hydroxy; or
• Cβ-Cio aryl, 5-10 membered heteroaryl, Cβ-Cio cycloalkyl or 4-10 membered heterocycloalkyl substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
In a particular embodiment, substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
In a further particular embodiment the substituent group or groups are selected from: halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR"'SO2R", -SO2NR R", -C(O)R", -C(O)OR", -OC(O)R", - NR'"C(O)R", -C(0)NR"R"', -NR"R'", -(CR'"R'")mOR'", wherein, each R" is independently selected from H, Cp C8 alkyl, -(CH2MC6-C10 aryl), -(CH2)t(5-10 membered heteroaryl), -(CHDt(C3-C10 cycloalkyl), and -(CH2)t(4- 10 membered heterocycloalkyl), wherein t is an integer from O to 4; and
• any alkyl groups present, may themselves be substituted by halo or hydroxy; and
• any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. Each R independently represents H or CpCβalkyl.
[0082] 'Substituted sulfanyl' refers to the group -SR61, wherein R61 is selected from:
• CpCg alkyl, C3-CiO cycloalkyl, 4-10 membered heterocycloalkyl, Cβ-Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• CpCg alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-CiO cycloalkyl, 4-10 membered heterocycloalkyl, Cβ-Cio aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0083] Exemplary 'substituted sulfanyl' groups are -S-(CpC8 alkyl) and -S-(C3-Ci0 cycloalkyl), -S-
(CHDt(C6-C10 aryl), -S-(CH2)t(5-10 membered heteroaryl), -S-(CH2MC3-C10 cycloalkyl), and -S-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from O to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. [0084] 'Substituted sulfmyl' refers to the group -S(O)R68, wherein R68 is selected from:
• CpC8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• Ci-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0085] Exemplary 'substituted sulfmyl' groups are -S(O)-(CpC8 alkyl) and -S(O)-(C3-Ci0 cycloalkyl), -S(O)-(CH2MC6-C10 aryl), -S(O)-(CH2)t(5-10 membered heteroaryl), -S(O)-(CH2MC3-C10 cycloalkyl), and -S(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. [0086] 'Substituted sulfonyl' refers to the group -S(O)2R75, wherein R75 is selected from:
• CpC8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• CpC8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0087] Exemplary 'substituted sulfonyl' groups are -S(O)2-(CpC8 alkyl) and -S(O)2-(C3-Ci0 cycloalkyl), -S(O)2-(CH2MC6-C10 aryl), -S(O)2-(CH2)t(5-10 membered heteroaryl), -S(O)2-(CH2MC3-C10 cycloalkyl), and -S(O)2-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted
CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0088] 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO3H.
[0089] 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(O)2OR82, wherein R82 is selected from: • CpC8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• Ci-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0090] Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O)2-O-(CpC8 alkyl) and -
S(O)2-O-(C3-Ci0 cycloalkyl), -S(O)2-O-(CH2MC6-C10 aryl), -S(O)2-O-(CH2)t(5-10 membered heteroaryl), - S(O)2-O-(CH2X(C3-Ci0 cycloalkyl), and -S(O)2-O-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. [0091] 'Thiol' refers to the group -SH.
[0092] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
[0093] 'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the
Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
[0094] 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
[0095] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
[0096] 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
[0097] 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates.
Representative solvates include hydrates, ethanolates and methanolates.
[0098] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.
[0099] 'Therapeutically effective amount' means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
[00100] 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
[00101] The term 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an antimalarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
[00102] 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.
[00103] As used herein the term 'condition(s) involving inflammation' refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, allergic airway disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. Partcicularly the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases. [00104] As used herein the term 'condition(s) involving an immune response' or 'autoimmune diseases' are used interchangeably and refer to refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantily asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. Particularly the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease. [00105] As used herein the term 'transplantation rejection' refers to the acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.
[00106] As used herein the term 'proliferative diseases' refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukaemia and acute lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, sclerodermitis or fibrosis. In particular the term refers to cancer, leukemia, multiple myeloma and psoriasis. [00107] As used herein, the term 'cancer' refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain. As used herein the term cancer includes both metastatic rumour cell types, such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma and types of tissue carcinoma, such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma.
[00108] As used herein the term 'leukaemia' refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding. In particular the term leukemia refers to acute myeloid leukaemia (AML) and acute lymphoblastic leukemia (ALL).
[00109] As used herein the term 'diseases involving impairment of cartilage turnover' and specifically
'diseases involving the anabolic stimulation of chondrocytes' includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
[00110] As used herein the term 'congenital cartilage malformation(s)' includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.
[00111] As used herein the term 'disease(s) associated with hypersecretion of IL6' includes conditions such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and/or mesangial proliferative glomerulonephritis .
[00112] 'Compound(s) of the invention', and equivalent expressions, are meant to embrace compounds of the Formula(e) as hereinbefore described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
[00113] When ranges are referred to herein, for example but without limitation, CpCg alkyl, the citation of a range should be considered a representation of each member of said range.
[00114] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci to C8 alkyl, C2-C8 alkenyl, aryl, C7-Ci2 substituted aryl, and C7-Ci2 arylalkyl esters of the compounds of the invention.
[00115] As used herein, the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2HIO, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon- 14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as 11C, 18F, 15O and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[00116] All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
[00117] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'. [00118] Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'. [00119] 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
[00120] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[00121] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. [00122] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well- known in the art.
THE COMPOUNDS
[00123] The present invention is based on the discovery that inhibitors of JAK are useful for the treatment of diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection). Inhibitors of JAK can also find application in the treatment of proliferative diseases. In particular the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer). In particular diseases involving cartilage degradation, bone and/or joint degradation and/or inflammation, for example osteoarthritis. The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating diseases involving cartilage degradation, bone and/or joint degradation and/or inflammation by administering a compound of the invention. The present compounds may be inhibitors of one or more members of the JAK family; specifically they may inhibit the activity of one or more of JAKl, JAK2, JAK3 and/or TYK2.
[00124] Accordingly, in a first aspect of the invention, substituted bicycloheteroaryl compounds are disclosed according to Formula (I):
Figure imgf000029_0001
wherein each CyI and Cy2 is independently selected from aryl and heteroaryl; each L1 and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O)2-, -N(R4a)-, -CON(R4a)- , -SO2N(R4a)-, - N(R4a)CO-, or - N(R4a)SO2-; each R1 is independently selected from CpC6 alkyl, substituted CpC6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted Ci-Ce alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, hydroxyl; each R3a is independently selected from CpC6 alkyl, substituted CpC6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted Ci-Cβ alkoxy, substituted or unsubstituted amido, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfanyl, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, substituted or unsubstituted heteroaryl, hydroxy, nitro, and thiol; each R2b, R2c, and R2d is independently selected from H, CpC6 alkyl, substituted CpC6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC6 alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfmyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, substituted or unsubstituted amido, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted CpC6 haloalkyl, hetero-O-aryl, substituted or unsubstituted 5-10 membered heteroaryl, hydroxyl, nitro, and thiol; each R2a and R4a is independently selected from H, CpC6 alkyl, substituted CpC6 alkyl, C3-C7 cycloalkyl, or substituted C3-C7 cycloalkyl; R is independently selected from substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted -(CpC4 alkyl)-(4-7- membered heterocycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted -O- aryl, substituted or unsubstituted arylamino, and substituted or unsubstituted 5-10 membered heteroaryl; ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when L1 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L2 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R3b is other than C3-C7 cycloalkyl, aryl or 5-10 membered heteroaryl, then n2 is 1, 2, 3, or 4; or pharmaceutically acceptable salts or solvates, thereof or solvates of the pharmaceutically acceptable salts.
[00125] In a further embodiment, substituted bicycloheteroaryl compounds are disclosed according to
Formula (I):
Figure imgf000030_0001
wherein each CyI and Cy2 is independently selected from aryl and heteroaryl; each L1 and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O)2-, -N(R4a)-, -CON(R4a)- , -SO2N(R4a)-, - N(R4a)CO-, or - N(R4a)SO2-; each R1 is independently selected from Ci-Ce alkyl, substituted Ci-Cβ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfinyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, hydroxyl; each R3a is independently selected from C1-C6 alkyl, substituted C1-C6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted amido, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfanyl, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, substituted or unsubstituted heteroaryl, hydroxy, nitro, and thiol; each R2b, R2c, and R2d is independently selected from H, Ci-Ce alkyl, substituted Ci-Cβ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC6 alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfmyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, substituted or unsubstituted amido, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted Ci-Ce haloalkyl, hetero-O-aryl, substituted or unsubstituted 5-10 membered heteroaryl, hydroxyl, nitro, and thiol; each R2a and R4a is independently selected from H, Ci-Cβ alkyl, substituted Ci-Cβ alkyl, C3-C7 cycloalkyl, or substituted C3-C7 cycloalkyl;
R3b is independently selected from substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted -O-aryl, substituted or unsubstituted arylamino, and substituted or unsubstituted 5-10 membered heteroaryl; ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when L1 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L2 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R3b is other than C3-C7 cycloalkyl, aryl or 5-10 membered heteroaryl, then n2 is 1, 2, 3, or 4; or pharmaceutically acceptable salts or solvates, thereof or solvates of the pharmaceutically acceptable salts. ] The compound according to Formula I, wherein each Cyi and Cy2 is independently selected from aryl and heteroaryl; each L1 and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O)2-, -N(R4a)-, -CON(R4a)- , -SO2N(R4a)-, - N(R4a)CO-, or - N(R4a)SO2-; each R1 is independently selected from unsubstituted Ci-Cβ alkyl (optionally substituted with halo), unsubstituted acyl, unsubstituted acylamino, unsubstituted Ci-Cβ alkoxy, unsubstituted amido, unsubstituted amino, unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, unsubstituted C3-C7 cycloalkyl, unsubstituted 4-7 membered heterocycloalkyl, halo, hydroxyl; each R a is independently selected from unsubstituted Ci-Ce alkyl, unsubstituted acyl, unsubstituted acylamino, unsubstituted CpC6 alkoxy, unsubstituted amido, unsubstituted alkoxycarbonyl, unsubstituted arylalkyloxy, unsubstituted amino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, unsubstituted C3-C7 cycloalkyl, unsubstituted 4-7 membered heterocycloalkyl, halo, unsubstituted heteroaryl, hydroxy, nitro, and thiol; each R2b, R2c, and R2d is independently selected from H, unsubstituted Ci-Cβ alkyl, unsubstituted acyl, unsubstituted acylamino, unsubstituted Ci-Ce alkoxy, unsubstituted alkoxycarbonyl, unsubstituted arylalkyloxy, unsubstituted amino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted aminosulfonyl, unsubstituted arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, hydroxyl, nitro, thiol, unsubstituted amido, unsubstituted C3-C7 cycloalkyl, unsubstituted 4-7 membered heterocycloalkyl (optionally substituted with oxo),, unsubstituted hetero-O-aryl, unsubstituted 5-10 membered heteroaryl; each R2a and R4a is independently selected from H, unsubstituted Ci-Cβ alkyl, unsubstituted C3-C7 cycloalkyl;
R3b is independently selected from -(C1-C4 alkyl)-(4-7-membered heterocycloalkyl), C3-C7 cycloalkyl (optionally substituted with unsubstituted 4-7 membered heterocycloalkyl), 4-7 membered heterocycloalkyl (optionally substituted with Ci -CO alkyl (optionally substituted with unsubstituted aryl, halo), unsubstituted aryl, amido (optionally substituted with Ci-Cβ alkyl), acyl, cyano, halo), aryl (optionally substituted with unsubstituted Ci-Cβ alkoxy, cyano, halo, Ci-Cβ alkyl (optionally substituted with halo, unsubstituted aryl), 4-7 membered heterocycloalkyl (optionally substituted with unsubstituted Ci-Cβ alkyl), amino (optionally substituted with unsubstituted Ci-Cβ alkyl)), unsubstituted -O-aryl, unsubstituted arylamino, 5-10 membered heteroaryl (optionally substituted with unsubstituted CpC6 alkyl); ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when Li is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L2 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R3b is other than C3-C7 cycloalkyl, aryl or 5-10 membered heteroaryl, then n2 is 1, 2, 3, or 4; or pharmaceutically acceptable salts or solvates thereof, or solvates of the pharmaceutically acceptable salts. In one embodiment, with respect to Formula I, ml is 0. In another embodiment, ml is 1 or 2. [00128] In one embodiment, with respect to Formula I, ml is 1 or 2 and each R1 is independently selected from CpC6 alkyl, substituted CpC6 alkyl, and halo.
[00129] In one embodiment, with respect to Formula I, ml is 1 or 2 and each R1 is independently selected from Me, CF3, Cl and F.
[00130] In one embodiment, with respect to Formula I, R2a is independently selected from H, Ci-Ce alkyl, and substituted Ci-C6 alkyl.
[00131] In one embodiment, with respect to Formula I, R2a is H.
[00132] In one embodiment, with respect to Formula I, the compound is according to Formula II:
Figure imgf000033_0001
wherein Cy2, Ll, L2, R2b, R2c, R2d, R3a, R3b, m2, nl, and n2 are as described for Formula I. [00133] In one embodiment, with respect to Formula I, the compound is according to Formula II:
Figure imgf000033_0002
wherein Cy2, Ll, L2, R2b, R2c, R2d, R3a, R3b, m2, nl, and n2 are as described for Formula I. [00134] In one embodiment, with respect to compounds according to Formula I, II or III, each of R2b, and R2d is independently H, Ci-C6 alkyl, substituted Ci-C6 alkyl, or halo.
[00135] In one embodiment, with respect to Formulae I-III, each of R2b, and R2d is independently H, Me, F or Cl.
[00136] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is a single bond, nl is 0, and R2c is H, Cl, F, Me, Et, OMe, CF3, CONH2, CONMe2, CONHMe, CN, NHCOMe, COOH, OH or COOEt.
[00137] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is a single bond, nl is 0, and R2c is NHCOMe, or COOH.
[00138] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is CONH; nl is 2 or 3; and R2c is NMe2, OMe, NHCOMe,
[00139] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, and -CON(R4a)-; nl is 0, 1, 2, 3, or 4; and R2c is substituted or unsubstituted CpC6 alkyl, substituted or unsubstituted C6-Ci0 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl.
[00140] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, and -CON(R4a)-; nl is 0, 1, 2, 3, or 4; and R2c is C1-C6 alkyl.
[00141] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, and -CON(R4a)-; nl is 0, 1, 2, 3, or 4; and R2c is Me, Et, i-Pr, l,3-dihydroxyprop-2-yl.
[00142] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, - and -CON(R4a)-; nl is 0, 1, 2, 3, or 4; and R2c is substituted or unsubstituted C3-C7 cycloalkyl.
[00143] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, - and -CON(R4a)-; nl is 0, 1, 2, 3, or 4; and R2c is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cyclopentyl.
[00144] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, - and -CON(R4a)-; nl is 0, 1, 2, 3, or 4; and R2c is substituted or unsubstituted C6-Ci0 aryl or substituted or unsubstituted 5-10 membered heteroaryl.
[00145] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, and -CON(R4a)-; nl is 0, 1, 2, 3, or 4; and R2c is substituted or unsubstituted Ph, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.
[00146] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, and -CON(R4a)-; nl is 0, 1 , 2, 3, or 4; and R2c is substituted or unsubstituted 4-7 membered heterocycloalkyl.
[00147] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is selected from a single bond, -C(O)-, and -CON(R4a)-; nl is 0, 1, 2, 3, or 4; and R2c is piperidinyl, morpholinyl, piperazinyl, or pyrrolidinyl, each of which may be unsubstituted or substituted with CpC6 alkyl, acyl, phenyl, or OH.
[00148] In one embodiment, with respect to compounds according to Formula I, II or III, R4a is H.
[00149] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is CONH; and nl is O, 1, 2 or 3.
[00150] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is CONH; and nl is 0, or 1. [00151] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is CO; and nl is
0, 1, 2 or 3.
[00152] In one embodiment, with respect to compounds according to Formula I, II or III, Ll is CO; and nl is
0, or l.
[00153] In one embodiment, with respect to compounds according to Formula I, II or III, the -CyI-Ll-
(CH2)ni-R2c is selected from:
Figure imgf000035_0001
and wherein nl and R2c are as described for Formula I.
[00154] In one embodiment, with respect to compounds according to Formula I, II or III, the -CyI-Ll-
(CH2)ni-R2c is selected from:
Figure imgf000035_0002
and wherein nl and R2c are as described for Formula I.
[00155] In one embodiment, with respect to compounds according to Formula I, II or III, the -CyI-Ll- (CH2)ni-R2c is selected from:
Figure imgf000035_0003
and wherein nl and R c are as described for Formula I.
[00156] In one embodiment, with respect to compounds according to Formula I, II or III, R c is a substituted or unsubstituted N-containing 4-7 membered heterocycloalkyl or a substituted or unsubstituted N-containing 5- 10 membered heteroaryl. [00157] In one embodiment, with respect to compounds according to Formula I, II or III, R2c is:
Figure imgf000036_0001
or
[00158] In one embodiment, with respect to compounds according to Formula I, II or III, R2c is pyrazolyl, pyrrolyl, imidazolyl, or triazolyl.
[00159] In one embodiment, with respect to compounds according to Formula I, II or III, nl is 0, 1 or 2. [00160] In one embodiment, with respect to compounds according to Formula I, II or III, the -CyI-Ll- (CH2)ni-R2c is selected from:
Figure imgf000036_0002
[00161] In one embodiment, with respect to compounds according to Formula I, II or III, Cy2 is Ph; and m2 is O.
[00162] In one embodiment, with respect to compounds according to Formula I, II or III, Cy2 is Ph; m3 is 1, 2 or 3; and each R3a is independently CpC6 alkyl, CpC6 haloalkyl, CpC6 alkoxy, or halo.
[00163] In one embodiment, with respect to compounds according to Formula I, II or III, Cy2 is Ph; m3 is 1, 2 or 3; and each R3a is independently Cl, F, Me, Et, OMe, CF3, CONH2, CONMe2, CONHMe, CN, NHCOMe, COOH, OH or COOEt.
[00164] In one embodiment, with respect to compounds according to Formula I, II or III, R3b is substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7- membered heterocycloalkyl.
[00165] In one embodiment, with respect to compounds according to Formula I, II or III, L2 is selected from -O-, -C(O)-, and -CON(R4a)-; n2 is 0, 1, 2, 3, or 4; and R3b is substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl. [00166] In one embodiment, with respect to compounds according to Formula I, II or III, L2 is selected from -O-, -C(O)-, - and -CON(R4a)-; n2 is 0, 1, 2, 3, or 4; and R3b is substituted or unsubstituted C3-C7 cycloalkyl. [00167] In one embodiment, with respect to compounds according to Formula I, II or III, L2 is selected from -O-, -C(O)-, - and -CON(R4a)-; n2 is 0, 1, 2, 3, or 4; and R3b is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl.
[00168] In one embodiment, with respect to compounds according to Formula I, II or III, L2 is selected from -O-, -C(O)-, - and -CON(R4a)-; n2 is 0, 1, 2, 3, or 4; and R3b is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [00169] In one embodiment, with respect to compounds according to Formula I, II or III, L2 is selected from
-O-, -C(O)-, and -CON(R4a)-; n2 is 0, 1, 2, 3, or 4; and R3b is substituted or unsubstituted Ph, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.
[00170] In one embodiment, with respect to compounds according to Formula I, II or III, L2 is selected from
-O-, -C(O)-, and -CON(R4a)-; n2 is 0, 1, 2, 3, or 4; and R3b is substituted or unsubstituted 4-7-membered heterocycloalkyl.
[00171] In one embodiment, with respect to compounds according to Formula I, II or III, L2 is selected from
-O-, -C(O)-, and -CON(R4a)-; n2 is 0, 1, 2, 3, or 4; and R3b is piperidinyl, morpholinyl, piperazinyl, or pyrrolidinyl, unsubstituted or substituted with Ci-Cβalkyl, acyl, phenyl, or OH.
[00172] In one embodiment, with respect to compounds according to Formula I, II or III, R4a is H.
[00173] In one embodiment, with respect to compounds according to Formula I, II or III, the -Cy2-L2-
(CH2)n2-R3b group is at the 4-position of the phenyl ring.
[00174] In one embodiment, with respect to compounds according to Formula I, II or III, each R3a is H; and the -Cy2-L2-(CH2)n2-R3b is selected from:
Figure imgf000037_0001
wherein R , 3b , and n2 are as described for Formula I; and Cy3 is a substituted or unsubstituted N containing 4-7- membered heterocycloalkyl. [00175] In another embodiment, with respect to compounds according to Formula I, II or III, each R a is H; and the -Cy2-L2-(CH2)n2-R 3b is selected from:
Figure imgf000038_0001
wherein R3b, and n2 are as in claim 1; Cy3 is substituted or unsubstituted N containing 4-7 membered heterocycloalkyl; R5a and R5b are independently selected from H, or Me, or together R5a, R5b and the carbon to which they are attached, form an unsubstituted C3-C7 cycloalkyl. [00176] In a preferrd embodiment, R5a and R5b are both Me. [00177] In another preferred embodiment, R5a is H and R5b is Me.
[00178] In another embodiment, R5a and R5b together with the carbon to which they are attached form a C3- Cv-cycloalkyl.
[00179] In another preferred embodiment, R5a and R5b together with the carbon to which they are attached form a cyclopropyl.
[00180] In another preferred embodiment, R5a and R5b are both H.
[00181] .In one embodiment, with respect to compounds according to Formula I, II or III, the compound is according to Formula IVa, IVb, IVc, IVd, or IVe:
Figure imgf000038_0002
and wherein n2 is 1, 2, or 3; R2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl; and R3b is substituted or unsubstituted aryl, substituted or unsubstituted arylamino, substituted or unsubstituted-O-aryl, or substituted or unsubstituted heteroaryl.
[00182] In another preferred embodiment, the compound is according to Formula IVa, IVb, IVc, IVd, IVe, or
IVf:
Figure imgf000039_0001
[00183] and wherein n2 is 1, 2, or 3; R2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl; R3b is, 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamino, substituted or unsubstituted-O-aryl, or substituted or unsubstituted heteroaryl,
[00184] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe or IVf, n2 is 1, 2 or 3. In another embodiment, n2 is 1 or 2. In yet another embodiment, n2 is 1.
[00185] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe or IVf, R3b is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl.
[00186] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe or IVf, R3b is unsubstituted phenyl or unsubstituted pyridyl.
[00187] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe or IVf, R3b is phenyl or pyridyl each of which may be substituted with one or more groups selected from Ci-Cβ alkyl, halo, alkoxy, amino, CpCβ dialkylamino, and CpCβ haloalkyl. In one embodiment the substitution is selected from Cl, F, Me, OMe, NMe2, or CF3. [00188] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe or IVf, R3b is substituted or unsubstituted -O-aryl or arylamino.
[00189] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe or IVf, R3b is substituted or unsubstituted phenoxy or phenylamino.
[00190] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe or IVf, R3b is substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indolyl, or substituted or unsubstituted indazolyl. [00191] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe or IVf, n2 is 1, and R3b is substituted or unsubstituted N containing 4-7 membered heterocycloalkyl. [00192] In one embodiment, with respect to Formula I, the compound is according to Formula Va:
Figure imgf000040_0001
and wherein R2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl; and R3b is substituted or unsubstituted 4-7-membered heterocycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl. [00193] In one embodiment, with respect to Formula I, the compound is according to Formula Va:
Figure imgf000040_0002
and wherein R2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl, - C(O)NH-C3-C7 cycloalkyl; and R3b is substituted or unsubstituted 4-7-membered heterocycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl. [00194] In one embodiment, with respect to compounds according to Formula Va, R3b is:
Figure imgf000041_0001
[00195] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe IVf or
Va, R2c is H.
[00196] In one embodiment, with respect to Formula IVa, IVb, IVc, IVd, IVe IVf or Va, R2c is 3-NHCOMe, or 4-NHCOMe.
[00197] In another embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe
IVf or Va R2c is 3-NHC(O)NHcPr, or 4- NHC(O)NHcPr.
[00198] In one embodiment, with respect to compounds according to Formula IVa, IVb, IVc, IVd, IVe IVf or
Va, R c is 4-7 membered heterocycloalkyl. In another embodiment R c is -C(O)-4-7 membered heterocycloalkyl. In one particular embodiment, the 4-7 membered heterocycloalkyl is
Figure imgf000041_0002
[00199] In one embodiment, with respect to Formula I, the compound is according to Formula Via, VIb, Vic or VId:
Figure imgf000041_0003
wherein R3b is as described above.
[00200] In one embodiment, with respect to compounds according to Formula I, II, III, IVa, IVb, IVc, IVd, IVe IVf, Va, Via, VIb, VIc or VId, R3b is:
Figure imgf000042_0001
Figure imgf000042_0002
Figure imgf000042_0003
[00201] In one embodiment the compound of the invention is not an isotopic variant.
[00202] In one embodiment, with respect to Formula I, the compound is selected from the compounds listed in Table 1.
[00203] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.
[00204] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
[00205] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate.
[00206] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt.
[00207] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.
[00208] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
[00209] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cg alkyl, C2-Cg alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
PHARMACEUTICAL COMPOSITIONS
[00210] When employed as pharmaceuticals, the compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of the invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
[00211] The pharmaceutical compositions of the invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds of this invention are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration [00212] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
[00213] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[00214] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
[00215] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
[00216] The compounds of this invention can also be administered by a transdermal device.
Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
[00217] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company,
Easton, Pennsylvania, which is incorporated herein by reference.
[00218] The compounds of this invention may also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
[00219] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
Formulation 1 - Tablets
[00220] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press. Formulation 2 - Capsules
[00221] A compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active amide compound per capsule).
Formulation 3 - Liquid
[00222] A compound of the invention (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
[00223] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
Formulation 5 - Injection
[00224] A compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
Formulation 6 - Topical
[00225] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
METHODS OF TREATMENT
[00226] The present compounds may be used as therapeutic agents for the treatment of conditions in mammals that are causally related or attributable to aberrant activity of JAK. In particular, conditions related to aberrant activity of one or more of JAKl, JAK2, JAK3 and/or TYK2. Accordingly, a compound of the invention and pharmaceutical compositions of the invention find use as therapeutics for preventing and/or treating diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection). Inhibitors of JAK can also find application in the treatment of proliferative diseases. In particular the inhibitors of JAK find application in the treatment of cancers, especially leukaemias and solid tumours (e.g. uterine leiomyosarcoma, prostate cancer). In particular the conditions are selected from inflammatory conditions, conditions related to cartilage and/or joint degradation in mammals including humans. In another embodiment, the compounds and pharmaceutical compositions of the invention find use as therapeutics for preventing and/or treating proliferative disorders in mammals, including humans. In a specific embodiment the compound of the invention and pharmaceutical compositions thereof find use as therapeutics for preventing and/or treating cancer in mammals including humans.
[00227] In additional method of treatment aspects, this invention provides methods of treating a mammal susceptible to or afflicted with condition involving an immune response or an autoimmune disease. The methods comprise administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions or compound of the invention herein described. In a specific embodiment, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
[00228] In another aspect the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of a condition involving an autoimmune response or an autoimmune disease. In a specific embodiment, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
[00229] In a method of treatment aspect, this invention provides a method of treatment, prevention or prophylaxis in a mammal susceptible to or afflicted with diseases involving impairment of cartilage turnover (e.g. a condition associated with, or diseases involving the anabolic stimulation of chondrocytes), for example, osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[00230] In another aspect the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of diseases involving impairment of cartilage turnover (e.g. a condition associated with, or diseases involving the anabolic stimulation of chondrocytes), for example, osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.
[00231] The present invention also provides a method of treatment of congenital cartilage malformations, including hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described
[00232] In another aspect the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of congenital cartilage malformations, including hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.
[00233] In another aspect, this invention provides a method of treating a mammal susceptible to or afflicted with a condition involving inflammation, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In additional method of treatment aspects, this invention provides methods of treating a mammal susceptible to or afflicted with diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, allergic airway disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure),, and related diseases involving cartilage, such as that of the joints, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the condition involving inflammation is selected from rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases. The methods comprise administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions or compounds herein described.
[00234] In another aspect, this invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of a condition involving inflammation. In another aspect the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, allergic airway disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. In a specific embodiment, the condition involving inflammation is selected from rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases. [00235] In further method of treatment aspects, this invention provides methods of treating a mammal susceptible to or afflicted with a proliferative disease, in particular cancer (e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer), leukemia (e.g. AML or ALL), multiple myeloma and/or psoriasis, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In further method of treatment aspects, this invention provides methods of treating a mammal susceptible to or afflicted with cancer (e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer) and/or leukemias, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[00236] In another aspect the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of a proliferative disease, in particular cancer (e.g. solid tumors such as uterine leiomyosarcoma or prostate cancer), leukemia (e.g. AML or ALL), multiple myeloma and/or psoriasis.
In another aspect the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of cancer (e.g solid tumors such as uterine leiomyosarcoma or prostate cancer) and/or leukemias.
[00237] In further method of treatment aspects, this invention provides methods of treating a mammal susceptible to or afflicted with diseases associated with hypersecretion of IL6, in particular Castleman's disease or mesangial proliferative glomerulonephritis, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[00238] In another aspect the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of diseases associated with hypersecretion of IL6, in particular
Castleman's disease or mesangial proliferative glomerulonephritis.
[00239] In further method of treatment aspects, this invention provides methods of treating a mammal susceptible to or afflicted with transplantation rejection, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the invention provides methods of treating organ transplant rejection, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[00240] In another aspect the present invention provides a compound of the invention for use in the treatment, prevention or prophylaxis of transplantation rejection. In a specific embodiment, the invention provides methods of treating organ transplant rejection.
[00241] As a further aspect of the invention there is provided the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
[00242] A particular regimen of the present method comprises the administration to a subject in suffering from a disease involving inflammation, of an effective amount of a compound of the invention for a period of time sufficient to reduce the level of inflammation in the patient, and preferably terminate, the processes responsible for said inflammation. A special embodiment of the method comprises administering of an effective amount of a compound of the invention to a subject patient suffering from or susceptible to the development of rheumatoid arthritis, for a period of time sufficient to reduce or prevent, respectively, inflammation in the joints of said patient, and preferably terminate, the processes responsible for said inflammation.
[00243] A further particular regimen of the present method comprises the administration to a subject in suffering from a disease condition characterized by cartilage or joint degradation (e.g. osteoarthritis) of an effective amount of a compound of the present invention for a period of time sufficient to reduce and preferably terminate, the self-perpetuating processes responsible for said degradation. A special embodiment of the method comprises administering of an effective amount of a compound of the present invention to a subject patient suffering from or susceptible to the development of osteoarthritis, for a period of time sufficient to reduce or prevent, respectively, cartilage degradation in the joints of said patient, and preferably terminate, the self-perpetuating processes responsible for said degradation. In a particular embodiment said compounds exhibit cartilage anabolic and/or anti-catabolic properties.
[00244] Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about
10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
[00245] For the prevention and/or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with particular doses each providing from about 0.1 to about
10 mg/kg and especially about 1 to about 5 mg/kg.
[00246] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[00247] When used to prevent the onset of an inflammatory condition, a compounds of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition. [00248] The compounds of the invention can be administered as the sole active agent or they can be administered in combination with other agents, including other compounds that demonstrate the same or a similar therapeutic activity, and that are determined to safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
[00249] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of a disease involving inflammation; particular agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam. [00250] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g. rheumatoid arthritis); particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofm, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and ciclosporin), and biological DMARDS (for example but without limitation Infliximab, Etanercept, Adalimumab, Rituximab, and Abatacept). [00251] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of proliferative disorders; particular agents include but are not limited to: methotrexate, leukovorin, adriamycin, prenisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti- HER2 monoclonal antibody (e.g. Herceptin™), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. lressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g. Avastin™), proteasome inhibitors (e.g. Velcade™), Glivec® or hsp90 inhibitors (e.g. 17-AAG). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.
[00252] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of autoimmune diseases, particular agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies(e.g., anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-β), TNF binding proteins (e.g. infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira)), mycophenolate, Fingolimod, Myriocin.
[00253] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of transplantation rejection, particular agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), Antibodies (e.g. monoclonal anti-IL-2Rα receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti- lymphocyte globulin (ALG)). [00254] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD, particular agents include but are not limited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol.), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled) Long-acting β2-agonists (e.g. salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine, cinnarizine, fexofenadine), vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).
[00255] Additionally, a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, nonspecific beta-agonists, injected or inhaled (e.g. epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamiphylline), inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine, intravenous magnesium sulfate. [00256] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of IBD, particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetis disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and ciclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept). [00257] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of SLE, particular agents include but are not limited to: Disease- modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid; immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.
[00258] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of psoriasis, particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort), fluocinonide, vitamin D3 analogues (for example, calcipotriol), Argan oiland retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologies such as Amevive, Enbrel, Humira, Remicade, Raptiva and ustekinumab (a IL- 12 and IL-23 blocker). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to phototherapy, or photochemotherapy (e.g. psoralen and ultraviolet A phototherapy (PUVA)).
[00259] By co-administration is included any means of delivering two or more therapeutic- agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation this is not essential. The agents may be administered in different formulations and at different times.
GENERAL SYNTHETIC PROCEDURES General
[00260] The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[00261] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
[00262] The following methods are presented with details as to the preparation of representative bicycloheteroaryls that have been listed hereinabove. The compounds of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. [00263] All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 μm). Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). IH NMR spectra were recorded on a Bruker DPX 400 NMR spectrometer (400 MHz). Chemical shifts (δ) for IH NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e. CHCI3 (δ 7.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) and broad (br). Coupling constants (J) are given in Hz. Electrospray MS spectra were obtained on a Micromass platform LC/MS spectrometer. Column Used for all LCMS analysis: Waters Acquity UPLC BEH Cl 8 1.7μm, 2.1mm ID x 50mm L (Part No.186002350)). Preparative HPLC: Waters XBridge Prep C18 5μm ODB 19mm ID x 100mm L (Part No.186002978). All the methods are using MeCWH2O gradients. H2O contains either 0.1% TFA or 0.1% NH3. [00264] List of abbreviations used in the experimental section:
Figure imgf000053_0002
Figure imgf000053_0001
Figure imgf000054_0003
Figure imgf000054_0002
Synthetic Preparation of Compounds of the Invention
[00265] A compound according to the invention can be produced according to the following scheme.
General Synthetic Method
Method A
Figure imgf000054_0001
wherein Ar is -Cy2-(R3a)m2-; and Ar'is -Cyl-Ll-(CH2)ni-R2c; and CyI, Cy2, Ll, L2, nl, m2, R2c, and R3a are as described herein.
Step a. Preparation of 2-amino-5-Ar-triazolopyridine derivatives
[00266] An appropriate Ar substituted boronic acid derivative (2eq.) is added to a solution of 2-amino-
8-bromo-triazolopyridine (Commercially available, BiofocusDPI) in dioxan/water (5:1). K2CO3 (2 eq.) and PdC^dppf (5%) are added to the mixture. The resulting mixture is heated in a microwave oven at 1400C for 15-45 min or heated in an oil bath at 900C for 4 to 16 h until the reaction goes to completion (monitored by LCMS). Water is added and the mixture is extracted with ethyl acetate. The organic layers are combined, dried over anhyd. MgSO4 and evaporated in vacuo to yield the crude product. The crude product is then purified by flash chromatography to give the corresponding 2-amino-5-Ar-triazolopyridine derivative (2).
Step b. Preparation of 5-Ar-2-iodo-triazolopyridine derivatives
[00267] A mixture of the above 2-amino-5-Ar-triazolopyridine derivative (2) (0.416 mmol) and NaNU2 in DMSO (57 mg, 0.832 mmol in 250 μL of DMSO) is treated dropwise with a solution of 57% aqueous HI (273 μL, 2.08 mmol) in DMSO (250 μL) at 35 0C with agitation. The mixture is stirred at 35 0C for 10 minutes or until the reaction goes to completion (monitored by LCMS), and then it is transferred to a solution containing K2CO3 (500 mg) in 2 mL of water. The reaction mixture is extracted with ethyl acetate and the extracts are combined, washed with water and dried over anhyd. magnesium sulfate. The organic solvent is removed under high vacuum to yield the crude product. The crude product is then purified by flash chromatography to give the corresponding 5-Ar-2-iodo-triazolopyridine derivative (3).
Step c. Preparation of'2-Ar '-5-Ar-triazolopyridine derivatives
[00268] A mixture of the above 5-Ar-2-iodo-triazolopyridine derivative (3) (1 eq), CsCO3 (5eq),
Pd(O Ac)2 (0.1 eq), BINAP (0.1 eq), an appropriate Ar'-NH2 derivative (1.5 eq) and toluene is sonicated for 5 minutes under nitrogen. Afterward, the reaction is left in a sealed tube at 1200C or in a flasked equipped with a cooling system. The crude mixture is extracted with ethyl acetate and the extracts are combined, washed with water and dried over anhyd. magnesium sulfate. The organic solvent is removed under high vacuum to yield the crude product. The crude product is then purified by preparative HPLC to give the corresponding 2-Ar'-5-Ar- triazolopyridine derivative (4)
Method B
Scheme 2
Figure imgf000056_0001
Step a
[00269] A mixture of 5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2
(0.1 eq), Xantphos (0.1 eq.), iodobenzene (1.5 eq) and 1,4-dioxane is sonicated for 5 minutes under nitrogen. Afterwards, the reaction is left in a sealed tube at 1000C or in a flask equipped with a cooling system for 5 hrs. The crude mixture is extracted with ethyl acetate and the extracts are combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent is removed under high vacuum to yield the crude product. The crude product may be purified by flash chromatography.
Step b:
[00270] 4-Carboxyphenylboronic acid (1.2eq.) is added to a solution of (5-bromo-[l,2,4]triazolo[l,5- a]pyridin-2-yl)-phenyl-amine DMF/water (5:1). CsF (2 eq.) and Pd(Ph3P)2Cl2 (cat.) are added to the mixture. The resulting mixture is heated in an oil bath at 1500C for 16 h until the reaction is completed (monitored by LCMS). HCl solution is added and the mixture is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous MgSθ4 and evaporated in vacuo to yield the crude product.
Step c
[00271] 4-(2-Phenylamino-[l,2,4]triazolo[l,5-a]pyridin-5-yl)-benzoic acid (leq.), HATU (1.2 eq),
DIPEA (1.2 eq.) and an appropriate amine (1.2 eq.) are mixed in DMF at room tempretaure. The resulting mixture is stirred at room tempretaure for 16 hrs. The reaction is dissolved in DMSO, filtered and purified by preparative HPLC to afford the expected product.
Method C
Figure imgf000057_0001
Step a:
[00272] A mixture of the above 2-amino-5-bromo-triazolopyridine derivative (I) (I eq), CS2CO3 (2eq),
Pd2(dba)3 (0.03 eq), Xantphos (0.06 eq), 4-iodo-benzoic acid methyl ester (1.1 eq) and 1,4-dioxane is sonicated for 5 minutes under nitrogen. Afterwards, the reaction is heated at 900C for 16 hrs. The reaction mixture is diluted with CH2CVMeOH (1 :1) filtered through Celite and the filtrate is concentrated in vacuo. Purification by flash column chromatography yields the target compound
Step b:
[00273] 4-[5-(Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamino]-benzoic acid methyl ester and LiOH
(2eq.) are mixed together in acetone at room temperature. The reaction is heated at 700C for 16 hrs. Acetone is evaporated. Water is added and the pH is acidified to pH=l with HCl solution (IN). The precipitate is filtered, dried to afford the expected benzoic acid in quantative yield.
Step c:
[00274] 4-[5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamino]-benzoic acid, DCI (1.5 eq.) (or HATU),
HOBt (1.5 eq) (Not used with HATU) and are mixed in DMF at room temperature. An appropriate amine (1.1 eq.) is added to the solution and the reaction mixture is stirred at room temperature for 16hrs. Water is added to the reaction. The organic phases is isolated, dried over MgSθ4, filtered and evaporated under vacuum to afford the expected product. Purification by flash chromatography.
Step d:
[00275] An appropriate boronic acid (1.2eq.) is added to a solution of 5-bromo-triazolopyridine derivative in 1 ,4-dioxane/water (5:1) (or EtOH), K2CO3 (2 eq.) and PS-Pd(PPh3)4 (or Pd(PPh3)4), cat are added to the mixture. The resulting mixture is heated in an oil bath at 900C 16 h until the reaction goes to completion (monitored by LCMS). After cooling to room temperature, the solvent is removed in vacuo and the residue is dissolved in the minimum quantity of DMSO and filtered. Purification by preparative HPLC is needed in some cases to give the desired product.
Method D
Figure imgf000058_0001
[00276] To a solution of 4-bromo-2-fluorobenzyl bromide (1 eq) in CH3CN (3 mL) is added an approiate amine (1.1 eq) in a sealed tube. The reaction mixture is stirred at room temp for 16 h. After cooling to room temperature, the reaction mixture is diluted in MeOH and concentrated in vacuo. The residue is re- dissolved in DCM/H20 (1 :1) and the organic phase is extracted over a phase separator. The solvent is removed in vacuo to yield the expected compound which is used for the next step without further purification.
Figure imgf000058_0002
[00277] To a solution of the bromo derivative (leq.) in 1,4-dioxane is added Pd(dppf)Cl2 (0.03 eq),
KOAc (1.3 eq.) and bis(pinacolato)diboron (1.3 eq.) in a sealed 25 mL tube. The reaction mixture is stirred at 90 0C for 16 h. After cooling to room temperature, the reaction mixture is filtered through Celite and concentrated under reduced pressure. Purification by flash column chromatography gives the desired product.
Synthetic procedures of selected compounds of the invention
Compound 1
[00278] This compound was prepared via Method B using piperidine.
Compound 2 [00279] This compound was prepared via Method A using 4-(Piperidine-l -carbonyl)phenylboronic acid and N-(4-Amino-phenyl)-acetamide.
Compound 3
[00280] This compound was prepared via Method A using Piperidin-l-yl-[4-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-phenyl]-methanone and 6-Morpholin-4-yl-pyridin-3-ylamine
Compound 4
[00281] This compound was prepared via Method B using 2-phenoxy-ethylamine.
Compound 5
[00282] This compound was prepared via Method B using benzylamine.
Compound 6
[00283] This compound was prepared via Method B using 3 -phenyl-propylamine.
Compound 7
[00284] This compound was prepared via Method B using N*l *-Phenyl-ethane-l,2-diamine.
Compound 8
[00285] This compound was prepared via Method B using 1-phenyl-piperazine.
Compound 9
[00286] This compound was prepared via Method B using 3-methoxy-benzylamine.
Compound 10
[00287] This compound was prepared via Method B using C-pyridin-3-yl-methylamine.
Compound 11
[00288] This compound was prepared via Method B using 2-trifluoromethyl-benzylamine.
Compound 12
[00289] This compound was prepared via Method B using 4-trifluoromethyl-benzylamine.
Compound 13 [00290] This compound was prepared via Method B using 3-trifluoromethyl-benzylamine.
Compound 14
[00291] This compound was prepared via Method B using 4-methoxy-benzylamine.
Compound 15
[00292] This compound was prepared via Method B using 2-chloro-benzylamine.
Compound 16
[00293] This compound was prepared via Method B using l-phenyl-piperidin-4-ylamine.
Compound 17
[00294] This compound was prepared via Method B using (R)-l-benzyl-pyrrolidin-3-ylamine.
Compound 18
[00295] This compound was prepared via Method B using 3,4-dichloro-benzylamine.
Compound 19
[00296] This compound was prepared via Method B using 3-chloro-benzylamine.
Compound 20
[00297] This compound was prepared via Method B using 4-chloro-benzylamine.
Compound 21
[00298] This compound was prepared via Method B using (2-aminomethyl-phenyl)-dimethyl-amine.
Compound 22
[00299] This compound was prepared via Method B using (3-aminomethyl-phenyl)-dimethyl-amine.
Compound 23
[00300] This compound was prepared via Method B using 2-morpholin-4-yl-benzylamine.
Compound 24
[00301] This compound was prepared via Method B using 2-morpholin-4-ylmethyl-benzylamine. Compound 25 [00302] This compound was prepared via Method B using C-(5 -methyl- isoxazol-3-yl)-methylamine.
Compound 26
[00303] This compound was prepared via Method B using 2-(4-methyl-piperazin-l-yl)-benzylamine.
Compound 27
[00304] This compound was prepared via Method B using 3-(4-methyl-piperazin-l-yl)-benzylamine.
Compound 28
[00305] This compound was prepared via Method B using C-pyridin-3-yl-methylamine.
Compound 29
[00306] This compound was prepared via Method B using C-pyridin-4-yl-methylamine.
Compound 30
[00307] This compound was prepared via Method B using C-(2-morpholin-4-yl-pyridin-4-yl)- methylamine.
Compound 31
[00308] This compound was prepared via Method B using l-benzyl-piperidin-4-ylamine.
Compound 32
[00309] This compound was prepared via Method B using 4-aminomethyl-benzonitrile.
Compound 33
[00310] This compound was prepared via Method B using 2-pyridin-3-yl-ethylamine.
Compound 34
Step 1
Figure imgf000062_0001
[00311] A mixture of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2
(0.1 eq), Xantphos (0.1 eq.), 4-Iodo-benzoic acid methyl ester (1.5 eq) and 1,4-dioxane was sonicated for 5 minutes under nitrogen. Afterwards, the reaction was left in a sealed tube at 1000C or in a flasked equipped with a cooling system for 5 hrs. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was purified by flash chromatography.
Step 2:
[00312] 4-Hydroxyphenylboronic acid (1.2eq.) was added to a solution of 4-(5-Bromo-
[l,2,4]triazolo[l,5-a]pyridin-2-ylamino)-benzoic acid methyl esterDMF/water (5:1). CsF (2 eq.) and Pd(Ph3P)2Cl2 (cat.) were added to the mixture. The resulting mixture was heated in an oil bath at 1500C for 16 h until the reaction went to completion (monitored by LCMS). HCl solution was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgSθ4 and evaporated in vacuo to yield the crude product.
Step 3
[00313] 4-[5-(4-Hydroxy-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-ylamino]-benzoic acid methyl ester
(leq.), l-(bromomethyl)cyclopropane (1.5 eq.) and K2CO3 (1.5 eq) were mixed together in DMF. The resulting mixture was stirred at 600C for 16 hrs. Water solution was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgSθ4 and evaporated in vacuo to yield the crude product. The final product was isolated by preparative HPLC.
Compound 35
[00314] This compound was prepared via Method B using 3-morpholin-4-ylmethyl-benzylamine. Compound 36
[00315] This compound was prepared via Method B using 4-methoxy-3-trifluoromethyl-benzylamine.
Compound 37
[00316] Compound 34 (leq) was added to a solution of LiOH (2eq) in acetone.The resulting solution was heated at 500C for 1.5 hr. HCl (2N) solution was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgSC^ and evaporated in vacuo to yield the crude product. The final product was isolated by preparative HPLC.
Compound 38
[00317] This compound was prepared via Method B using 2-pyridin-2-yl-ethylamine.
Compound 39
[00318] This compound was prepared via Method B using 2-pyridin-4-yl-ethylamine.
Compound 40
[00319] This compound was prepared via Method B using 2-(3,5-dimethyl-isoxazol-4-yl)-ethylamine.
Compound 41
[00320] This compound was prepared via Method B using 2-(lH-benzoimidazol-2-yl)-ethylamine.
Compound 42
[00321] This compound was prepared via Method B using 2-(lH-indol-3-yl)-ethylamine.
Compound 43
[00322] This compound was prepared via Method A using -l-yl-[4-(4,4,5,5-tetramethyl-
[1 ,3,2]dioxaborolan-2-yl)-phenyl]-methanone and 6-methoxy-pyridin-3-ylamine.
Compound 44
[00323] This compound was prepared via Method B using phenethylamine.
Compound 45
Figure imgf000064_0001
Step α
[00324] 4-Ethoxycarbonyl-phenylboronic acid (2eq.) was added to a solution of 5-bromo-
[l,2,4]triazolo[l,5-a]pyridin-2-ylamine in dioxane/water (5:1) K2CO3 (2 eq.) and PdCl2dppf (cat.) were added to the mixture. The resultion mixture was subjected to macrowave: T: 1400C, 60 min, Wmax: 150, Pmax: 150 PSI. The crude of the reaction was diluted with water. The product was extracted with ethyl acetate (3 times). The organic layers were dried with MgSO4. The solvent was removed under high vacuum to afford a brown solid used in the next step without further purification.
Step b
[00325] 4-(2-Amino-[l,2,4]triazolo[l,5-a]pyridin-5-yl)-benzoic acid ethyl ester (leq), NaOH 2N (3eq) were mixed together in water/methanol (1 :1). After lh30, the reaction was completed (LCMS). The mixture was acidified with HCl IN, and a white precipitate was formed. The reaction was filtered and the white solid was dried under vacuum.
Step c
[00326] 4-(2-Amino-[l,2,4]triazolo[l,5-a]pyridin-5-yl)-benzoic acid (leq), EDC (1.2 eq), HOBt (1.2 eq) and Phenylethyl amine (1.2 eq) were mixed together in DMF at room temperature. The resulting mixture was stirred for 16 hrs. The crude of the reaction was dissolved in ethyl acetate and wash with sodium bicarbonate solution. The organic layer was dried over MgSO4, filtrated and removed solvent under vacuum. The compound was used in the next step without further purification. Step d
[00327] A solution of 57% aqueous HI (5eq) dissolved in DMSO (0.3 mL) was added dropwise to a solution of 4-(2-Amino-[l,2,4]triazolo[l,5-a]pyridin-5-yl)-N-phenethyl-benzamide (leq) in a mixture of NaNθ2 (4eq) in DMSO at 35 0C with agitation. The mixture was stirred at 35 0C for 10 minutes, and then it was transferred to a solution containing K2CO3 (140 mg) in 1.2 mL of water. The reaction mixture was then taken up in ethyl acetate and the extracts were washed with water and dried magnesium sulphate. The organic solvent was removed under vacuum. The product was used in the next step without further purification.
Step e
[00328] A mixture of the above 4-(2-Iodo-[l,2,4]triazolo[l,5-a]pyridin-5-yl)-N-phenethyl-benzamide
(1 eq), CsCO3 (5eq), Pd(OAc)2 (0.1 eq), BINAP (0.1 eq), N-(4-Amino-phenyl)-acetamide (1.5 eq) and toluene was sonicated for 5 minutes under nitrogen. Afterward, the reaction was left in a sealed tube at 1200C or in a flasked equipped with a cooling system. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhyd. magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was then purified by preparative HPLC to give the corresponding product.
Compound 50
[00329] This compound was prepared via Method A using piperidin-l-yl-[4-(4,4,5,5-tetramethyl-
[1 ,3,2]dioxaborolan-2-yl)-phenyl]-methanone and (4-amino-phenyl)-morpholin-4-yl-methanone.
Compound 51
[00330] This compound was prepared via the method as described for Compounds 34 and 37, using benzyl bromide.
Compound 54
[00331] Compound 34 (leq.), CDI (1.2 eq) and NH4OH (2 eq.) were mixed in DMF at room tempretaure. The resulting mixture was stirred at room tempretaure for 16 hrs. Water was added. The organics were extracted with ethyl actetate, dried over MgSO4 and evaporated under reduced pressure. The crude was purified by preparative HPLC.
Compound 55
Figure imgf000066_0001
Step a: (5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-(4-nitro-phenyl)-amine
[00332] A mixture of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2
(0.1 eq), BINAP (0.1 eq), 1 -Iodo-4-nitro-benzene (1.5 eq) and 1,4-dioxan was sonicated for 5 minutes under nitrogen. Afterwards, the reaction was left in a sealed tube at 1200C or in a flasked equipped with a cooling system for 16 hrs. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was then purified by preparative HPLC to give the corresponding (5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-(4-nitro-phenyl)-amine
Step b:
[00333] (5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-(4-nitro-phenyl)-amine (1 eq.) and SnCl2 (5eq.) were mixed together in ethanol. The reaction mixture was stirred at 800C for 4 hours. The resulting solution was filtered and the mother liquor was basified with NaOH IN and extracted with EtOAc. The organic layer was dried and evaporated to afford 800 mg of a first batch. The filtrated green solid was taken up in NaOH IN and extracted with EtOAc. The organic layer was dried over MgSθ4 and evaporated to afford the reduced compound. The compound was used in the next step without further purification.
Step c:
[00334] Acetic anhydride (leq.) was added dropwise to a solution of N-(5-bromo-[l,2,4]triazolo[l,5- a]pyridin-2-yl)-benzene-l,4-diamine (1 eq.) in THF at 00C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with a solution OfNaHCO3 sat. and extracted with EtOAc. The organic layer was dried over MgSθ4 and concentrated to afford a residue containing the expected acetamide. Water was added to the resulting solid to obtain a suspension of the title compound which was then filtered to afford N-[4-(5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamino)-phenyl]-acetamide Step d:
[00335] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-morpholine (2eq.) was added to a solution of N-[4-(5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamino)-phenyl]-acetamide in 1 ,4-dioxane/water (5: 1) (or EtOH). K2CO3 (2 eq.) and PdC^dppf (cat.) were added to the mixture. The resulting mixture was heated in an oil bath at 900C for 4 to 16 h until the reaction went to completion (monitored by LCMS). Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgSθ4 and evaporated in vacuo to yield the crude product. The crude product was then purified by flash chromatography.
Compound 56
[00336] This compound was made by Method C using cyclopropylamine and 4-[4-(4,4,5,5-
Tetramethyl- [ 1 ,3 ,2] dioxaborolan-2-yl)-benzyl] -morpholine.
Compound 57
[00337] This compound was made by Method C using cyclopropylamine and using 4-[2-Fluoro-4-
(4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-morpholine prepared by method D.
Compound 58
[00338] This compound can be made made by Method C using cyclopropylamine and 4-[2-Fluoro-4-
(4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine 1,1-dioxide prepared by method D.
Compound 59
[00339] This compound can be made by Method C using cyclopropylamine and 4,4-Difluoro-l-[2- fluoro-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-piperidine prepared by method D.
Compound 60
[00340] This compound can be prepared via Method C using cyclopropylamine and 4-{l-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-morpholine that can be prepared by the following method:
Figure imgf000068_0001
Step a:
[00341] l-(4-bromo-phenyl)-ethanol is stirred in aq. HCl at room temperature for 20 h. The excess acid is evaporated under vacuum to give the expected product in quantative yield.
Step b:
[00342] Morpholine (2 eq.) is added to a solution of l-bromo-4-(l-chloro-ethyl)-benzene (leq) and
DIPEA (2eq.) in acetonitrile. The resulting mixture is stirred at 600C for 72 h. The solvent is evaporated under reduced pressure. Water and EtOAc are added. The organic layers are separated, dried over MgSθ4 and evaporated under reduced pressure to afford the expected product in quantitative yield used in the next step without further purification.
Step c:
[00343] A mixture of 4-[l-(4-bromo-phenyl)-ethyl]-morpholine (leq.), bis(pinacolato)diboron (1.2 eq),
PdCl2(dppf) (0.03 eq.) and KOAc (1.3 eq) and 1,4-dioxane in a reaction tube is purged with nitrogen gas for 10 min. The tube is sealed under nitrogen and the mixture stirred at 100 0C for 17 h. The brown mixture is filtered through Celite, washing with EtOAc. The filtrate is concentrated and the residue is used immediately without further purification.
Compound 61
[00344] This compound can be prepared via Method C using cyclopropylamine and 4-[4-(4,4,5,5-
Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine 1,1-dioxide prepared via method D.
Compound 62
[00345] This compound can be prepared via Method C using ammonia and 4-[4-(4,4,5,5-Tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzyl]-morpholine.
Compound 63 [00346] Compound 63 can be prepared via Method A using 4-[4-(4,4,5,5-Tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzyl]-morpholine and 4-(4-Amino-phenyl)-morpholin-3-one that can be prepared by the following method:
Figure imgf000069_0001
Step a
[00347] A mixture of l-bromo-4-nitro-benzene (1 eq), CsCO3 (5eq), Pd(OAc)2 (0.1 eq), Xantphos (0.1 eq), Morpholin-3-one (1.5 eq) and 1,4-dioxane is sonicated for 5 minutes under nitrogen. Afterwards, the reaction is left in a flasked equipped with a cooling system at reflux for 16 hr. The crude mixture is extracted with ethyl acetate and the extracts are combined, washed with water and dried over anhyd. magnesium sulfate. The organic solvent is removed under high vacuum to yield the crude product. The crude product is then purified column chromatography to give the corresponding product.
Step b
[00348] A mixture of l-bromo-4-nitro-benzene (1 eq), CsCO3 (5eq), Pd(OAc)2 (0.1 eq), Xantphos (0.1 eq), Morpholin-3-one (1.5 eq) and 1,4-dioxane is sonicated for 5 minutes under nitrogen. Afterwards, the reaction is left in a flasked equipped with a cooling system at reflux for 16 hr. The crude mixture is extracted with ethyl acetate and the extracts are combined, washed with water and dried over anhyd. magnesium sulfate. The organic solvent is removed under high vacuum to yield the crude product. The crude product is then purified column chromatography to give the corresponding product.
Compound 64
[00349] The compound can be prepared via Method C using cyclopropylamine and N,N-dimethyl-4- benzamide boronic acid.
Compound 65
[00350] The compound can ce prepared by Method A using 4,4-difluoro-l-[4-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzyl]-piperidine prepared by Method D and 5-amino-pyridine-2-carboxylic acid cyclopropylamide that can be prepared by the following method:
Figure imgf000070_0001
[00351] 5-Amino-pyridine-2-carboxylic acid (leq.), HATU (1.5 eq.) and Et3N (2eq.) are mixed in DMF at room temperature. Cyclopropylamine (l.leq.) is added to the solution and the reaction mixture is stirred at room temperature for 16hrs. Water is added to the reaction. The organic phases are isolated, dried over MgSO/i, filtered and evaporated under vacuum to afford the expected product. In same cases, purification by flash chromatography is required.
Compound 66
[00352] The compound can be prepared by Method A using 4-fluoro-l-[4-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzyl]-piperidine prepared by Method D and 5-amino-pyridine-2-carboxylic acid methylamine that can be prepared by the following method:
Figure imgf000070_0002
[00353] 5-Amino-pyridine-2-carboxylic acid (leq.), HATU (1.5 eq.) and Et3N (2eq.) are mixed in DMF at room temperature, methylamine (l.leq.) is added to the solution and the reaction mixture is stirred at room temperature for 16hrs. Water is added to the reaction. The organic phases are isolated, dried over MgS O4, filtered and evaporated under vacuum to afford the expected product. In same cases, purification by flash chromatography is required.
Compound 67
[00354] This compound can be prepared via Method C using cyclopropylamine and 4,4-Difluoro-l-[4-
(4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-piperidine prepared via Method D.
Compound 68
[00355] The compound can be prepared by Method A using 4-[4-(4,4,5,5-Tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzyl]-morpholine prepared by Method D and 5-amino-pyridine-2-carboxylic acid methylamine that can be prepared by the following method:
Figure imgf000070_0003
[00356] 5-Amino-pyridine-2-carboxylic acid (leq.), HATU (1.5 eq.) and Et3N (2eq.) are mixed in DMF at room temperature, ethyllamine (l.leq.) is added to the solution and the reaction mixture is stirred at room temperature for 16hrs. Water is added to the reaction. The organic phases is isolated, dried over MgSO4, filtered and evaporated under vacuum to afford the expected product. In same cases, purification by flash chromatography is required.
Compound 69
[00357] Compound 69 can be obtained via Method C using cyclopropylamine and 4-{l-[4-(4,4,5,5-
Tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-morpholine that can be prepared via the following method:
Figure imgf000071_0001
Step a
[00358] To a solution of 4-bromo-benzonitrile (1 eq) and Ti(Oz-Pr)4 (1.1 eq.) in dry Et2O (50 mL) is added EtMgBr (2.1 eq., 3 M in Et2O) at -78 0C. The resulting yellow solution is stirred for 10 min at this temperature and allowed to warm to room temperature over 1 h. BF3. Et2O (5.1 mL, 40 mmol) is added and the reaction mixture is further stirred for 1 h. The reaction mixture is quenched with HCl (1 M in H2O) and Et2O. NaOH (wt 10% in water) is added and the aqueous layer was extracted with Et2O. The combined organic layers are dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (Gradient, zso-hexane to Et2O) gives the desired product.
Step b
[00359] To a solution of l-(4-bromo-phenyl)-cyclopropylamine (1 eq) in DMF in a 50 mL tube is added DIPEA (2 eq) and l-Bromo-2-(2-bromo-ethoxy)-ethane (1.1 eq). the reaction mixture is heated at 1000C for 16 hrs.. After cooling to room temperature, EtOAc and water are added. The combined organic layers are dried (MgSO4) and concentrated in vacuo to give the desired product.
Step c [00360] A mixture of 4-[l-(4-bromo-phenyl)-cyclopropyl]-morpholine (leq.), bis(pinacolato)diboron
(1.5 eq), Pd(dppf)Cl2 (5%) and KOAc (1.5 eq.) in 1,4-dioxane in a 25 mL tube is purged with N2 gas at room temperature for 10 min. The tube is sealed and heated to 100 0C for 20 h. After cooling to room temperature, the reaction mixture is filtered through Celite and the filtrate was concentrated in vacuo to give a brown solid which is used in the next step without further purification.
Compound 70
[00361] Compound 70 can be prepared via Method C using cyclopropylamine and 4- {1 -Methyl- 1- [4-
(4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-morpholine that can be prepared via the following method:
Figure imgf000072_0001
Step a
[00362] MeLi (2eq) is added to a solution of 4-bromo-benzonitrile (leq) an CeCi3 (leq) in THF at -
78°C. The reaction is allowed to warm to room temperature. Boc anhydride is added to the reaction. The solution is allowed to stir for 16 hrs at room temperature. Water, followed by EtOAc are added. The combined organic layers are separated, dried (MgSO/i) and concentrated in vacuo to give the desired product which is purified by column chromatography.
Step b
[00363] To a solution of [l-(4-bromo-phenyl)-l-methyl-ethyl]-carbamic acid tert-butyl ester (1 eq) in
DMF in a 50 mL tube is added DIPEA (2 eq) and l-bromo-2-(2-bromo-ethoxy)-ethane (1.1 eq). the reaction mixture is heated at 1000C for 16 hrs.. After cooling to room temperature, EtOAc and water are added. The combined organic layers are dried (MgSO/i) and concentrated in vacuo to give the desired product.
Step c
[00364] A mixture of 4-[l-(4-bromo-phenyl)-l-methyl-ethyl]-morpholine (leq.), bis(pinacolato)diboron (1.5 eq), Pd(dppf)Cl2 (5%) and KOAc (1.5 eq.) in 1,4-dioxane in a 25 mL tube is purged with N2 gas at room temperature for 10 min. The tube is sealed and heated to 100 0C for 20 h. After cooling to room temperature, the reaction mixture is filtered through Celite and the filtrate is concentrated in vacuo to give a brown solid which is used in the next step without further purification.
[00365] Compound 70 is obtained via Method A using 4- {1 -Methyl- 1-[4-(4,4,5, 5-tetramethyl-
[1 ,3,2]dioxaborolan-2-yl)-phenyl]-ethyl} -morpholine.
Compound 71
[00366] This compound can be prepared via Method C using cyclopropylamine and l-{4-[4-(4,4,5,5-
Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-piperazin-l-yl}-ethanone prepared via Method D.
Compound 72
[00367] The compound can be prepared via Method C using cyclopropylamine and l-[4-(4,4,5,5-
Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-pyrrolidine-3-carbonitrile prepared via Method D.
[00368] The exemplary compounds that have been or can be prepared according to the synthetic methods described herein are listed in Table I below. The NMR spectral data of some representative compounds of the invention is given in Table II. [00369] Table I
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Table II: NMR Data of Representative Compounds of the Invention
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Biological Examples Example 1 - in vitro assays Example 1.1 JAKl inhibition assay
1.1.1 Assay 1
[00371] Recombinant human JAKl catalytic domain (amino acids 850-1154; catalog number 08-144) was purchased from Carna Biosciences. 10 ng of JAKl was incubated with 12.5 μg polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (15 mM Tris-HCl pH 7.5, 1 mM DTT, 0.01% Tween-20, 10 mM MgCl2, 2 μM non-radioactive ATP, 0.25 μCi 33P-gamma-ATP (GE Healthcare, catalog number AH9968) final concentrations) with or without 5μL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 μL, in a polypropylene 96-well plate (Greiner, V-bottom). After 45 min at 30 0C, reactions were stopped by adding of 25 μL/well of 150 mM phosphoric acid. All of the terminated kinase reaction was transferred to prewashed (75 mM phosphoric acid) 96 well filter plates (Perkin Elmer catalog number 6005177) using a cell harvester (Perkin Elmer). Plates were washed 6 times with 300 μL per well of a 75 mM phosphoric acid solution and the bottom of the plates was sealed. 40 μL/well of Microscint-20 was added, the top of the plates was sealed and readout was performed using the Topcount (Perkin Elmer). Kinase activity was calculated by subtracting counts per minute (cpm) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from cpm obtained in the presence of vehicle. The ability of a test compound to inhibit this activity was determined as:
[00372] Percentage inhibition = ((cpm determined for sample with test compound present - cpm determined for sample with positive control inhibitor) divided by (cpm determined in the presence of vehicle - cpm determined for sample with positive control inhibitor)) * 100%.
[00373] Dose dilution series were prepared for the compounds enabling the testing of dose-response effects in the JAKl assay and the calculation of the IC5O for each compound. Each compound was routinely tested at concentration of 20μM followed by a 1/3 serial dilution, 8 points (20μM - 6.67μM - 2.22μM - 74OnM - 247nM - 82nM - 27nM - 9nM) in a final concentration of 1% DMSO. When potency of compound series increased, more dilutions were prepared and/or the top concentration were lowered (e.g. 5 μM, 1 μM). [00374] Semi-quantitative score:
* > 1001 nM
** 501-1000 nM *** 101-50OnM ****0.01-100nM
[00375] TABLE III: JAKl ICn Values of Compounds
Figure imgf000096_0001
7.7.2 Assav 2 [00376] Recombinant human JAKl (catalytic domain, amino acids 866-1154; catalog number PV4774) is purchased from Invitrogen. 1 ng of JAKl is incubated with 20 nM Ulight-JAKl(tyrlO23) peptide (Perkin Elmer catalog number TRF0121) in kinase reaction buffer (25mM MOPS pH6.8, 0.016% Brij-35, 8.33mM MgC12, 3.33mM DTT, 7μM ATP) with or without 4μL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 20 μL, in a white 384 Luminotrac 200 plate (Greiner, catalog number 781075). After 60 min at room temperature, reactions are stopped by adding of 20 μL/well of detection mixture (1 x detection buffer (Perkin Elmer, catalog number CR97-100C), 0.5nM Europium-anti- phosphotyrosine (PT66) (Perkin Elmer, catalog number AD0068), 10 mM EDTA). Readout is performed using the Envision with excitation at 320nm and measuring emission at 615 nm (Perkin Elmer). Kinase activity is calculated by subtracting relative fluorescence units (RFU) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from RFU obtained in the presence of vehicle. The ability of a test compound to inhibit this activity is determined as:
[00377] Percentage inhibition = 1- ((RFU determined for sample with test compound present - RFU determined for sample with positive control inhibitor) divided by (RFU determined in the presence of vehicle - RFU determined for sample with positive control inhibitor)) * 100.
[00378] Dose dilution series are prepared for the compounds enabling the testing of dose-response effects in the JAKl assay and the calculation of the IC50 for each compound. Each compound is routinely tested at concentration of 20μM followed by a 1/5 serial dilution, 8 points (20μM - 4μM - 80OnM - 16OnM - 32nM - 6.4nM - 1.28nM - 0.26nM) in a final concentration of 1% DMSO. When potency of compound series increases, more dilutions are prepared and/or the top concentration are lowered (e.g. 5 μM, 1 μM).
Example 1.2 JAK2 inhibition assay
1.2.1 Assay 1
[00379] Recombinant human JAK2 catalytic domain (amino acids 808-1132; catalog number PV4210) was purchased from Invitrogen. 0.025mU of JAK2 was incubated with 2.5 μg polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (5 mM MOPS pH 7.5, 9 mM MgAc, 0.3mM EDTA, 0.06% Brij and 0.6 mM DTT, 1 μM non-radioactive ATP, 0.25 μCi 33P-gamma-ATP (GE Healthcare, catalog number AH9968) final concentrations) with or without 5μL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 μL, in a polypropylene 96-well plate (Greiner, V-bottom). After 90 min at 30 0C, reactions were stopped by adding of 25 μL/well of 150 mM phosphoric acid. All of the terminated kinase reaction was transferred to prewashed (75 mM phosphoric acid) 96 well filter plates (Perkin Elmer catalog number 6005177) using a cell harvester (Perkin Elmer). Plates were washed 6 times with 300 μL per well of a 75 mM phosphoric acid solution and the bottom of the plates was sealed. 40 μL/well of Microscint-20 was added, the top of the plates was sealed and readout was performed using the Topcount (Perkin Elmer). Kinase activity was calculated by subtracting counts per minute (cpm) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from cpm obtained in the presence of vehicle. The ability of a test compound to inhibit this activity was determined as:
[00380] Percentage inhibition = ((cpm determined for sample with test compound present - cpm determined for sample with positive control inhibitor) divided by (cpm determined in the presence of vehicle - cpm determined for sample with positive control inhibitor)) * 100% .
[00381] Dose dilution series were prepared for the compounds enabling the testing of dose-response effects in the JAK2 assay and the calculation of the IC5O for each compound. Each compound was routinely tested at concentration of 20μM followed by a 1/3 serial dilution, 8 points (20μM - 6.67μM - 2.22μM - 74OnM
- 247nM - 82nM - 27nM - 9nM) in a final concentration of 1% DMSO. When potency of compound series increased, more dilutions were prepared and/or the top concentration was lowered (e.g. 5 μM, 1 μM).
[00382] Semi-quantitative score:
# > 1001 nM
## 501-1000 nM
### 101-500 nM
#### 0.01-100 nM
[00383] TABLE IV: JAK2 IC^n Values of Compounds
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000099_0002
Figure imgf000099_0001
7.2.2 Assay 2
[00384] Recombinant human JAK2 (catalytic domain, amino acids 866-1154; catalog number PV4210) is purchased from Invitrogen. 0.0125mU of JAK2 is incubated with 25 nM Ulight-JAKl(tyrlO23) peptide (Perkin Elmer catalog number TRF0121) in kinase reaction buffer (41.66mM HEPES pH7.0, 0.016% Triton X- 100, 12.5mM MgCl2 , 3.33mM DTT, 7.5μM ATP) with or without 4μL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 20 μL, in a white 384 Luminotrac 200 plate (Greiner, catalog number 781075). After 60 min at room temperature, reactions are stopped by adding of 20 μL/well of detection mixture (lxdetection buffer (Perkin Elmer, catalog number CR97-100C), 0.5nM Europium-anti- phosphotyrosine (PT66) (Perkin Elmer, catalog number AD0068), 10 mM EDTA). Readout is performed using the Envision with excitation at 320nm and measuring emission at 615 nm (Perkin Elmer). Kinase activity is calculated by subtracting relative fluorescence units (RFU) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from RFU obtained in the presence of vehicle. The ability of a test compound to inhibit this activity is determined as:
[00385] Percentage inhibition = 1- ((RFU determined for sample with test compound present - RFU determined for sample with positive control inhibitor) divided by (RFU determined in the presence of vehicle - RFU determined for sample with positive control inhibitor)) * 100.
[00386] Dose dilution series are prepared for the compounds enabling the testing of dose-response effects in the JAKl assay and the calculation of the IC50 for each compound. Each compound is routinely tested at concentration of 20μM followed by a 1/5 serial dilution, 8 points (20μM - 4μM - 80OnM - 16OnM - 32nM - 6.4nM - 1.28nM - 0.26nM) in a final concentration of 1% DMSO. When potency of compound series increases, more dilutions are prepared and/or the top concentration are lowered (e.g. 5 μM, 1 μM). Example 1.3 JAK3 inhibition assay
[00387] Recombinant human JAK3 catalytic domain (amino acids 781-1124; catalog number PV3855) was purchased from Invitrogen. 0.025mU of JAK3 was incubated with 2.5 μg polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (25 mM Tris pH 7.5, 0.5 mM EGTA, 0.5 mM Na3VO4, 5 mM b- glycerolphosphate, 0.01% Triton X-100, 1 μM non-radioactive ATP, 0.25 μCi 33P-gamma-ATP (GE Healthcare, catalog number AH9968) final concentrations) with or without 5μL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 μL, in a polypropylene 96-well plate (Greiner, V-bottom). After 105 min at 30 0C, reactions were stopped by adding of 25 μL/well of 150 mM phosphoric acid. All of the terminated kinase reaction was transferred to prewashed (75 mM phosphoric acid) 96 well filter plates (Perkin Elmer catalog number 6005177) using a cell harvester (Perkin Elmer). Plates were washed 6 times with 300 μL per well of a 75 mM phosphoric acid solution and the bottom of the plates was sealed. 40 μL/well of Microscint-20 was added, the top of the plates was sealed and readout was performed using the Topcount (Perkin Elmer). Kinase activity was calculated by subtracting counts per minute (cpm) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from cpm obtained in the presence of vehicle. The ability of atest compound to inhibit this activity was determined as:
[00388] Percentage inhibition = ((cpm determined for sample with test compound present - cpm determined for sample with positive control inhibitor) divided by (cpm determined in the presence of vehicle - cpm determined for sample with positive control inhibitor)) * 100%.
[00389] Dose dilution series were prepared for the compounds enabling the testing of dose-response effects in the JAK3 assay and the calculation of the IC5O for each compound. Each compound was routinely tested at concentration of 20μM followed by a 1/3 serial dilution, 8 points (20μM - 6.67μM - 2.22μM - 74OnM - 247nM - 82nM - 27nM - 9nM) in a final concentration of 1% DMSO. When potency of compound series increased, more dilutions were prepared and/or the top concentration was lowered (e.g. 5 μM, 1 μM). [00390] Semi-quantitative score:
+> 1001 nM
++ 501-100O nM
+++ 101-50O nM
++++ 0.01-10O nM
[00391] TABLE V: JAK3 IC^n Values of Compounds
Figure imgf000100_0001
Figure imgf000101_0001
Example 1.4 TYK2 inhibition assay
[00392] Recombinant human TYK2 catalytic domain (amino acids 871-1187; catalog number 08-147) was purchased from Carna biosciences. 5 ng of TYK2 was incubated with 12.5 μg polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (25 mM Hepes pH 7.5, 100 mM NaCl, 0.2 mM Na3VO4, 0.1% NP-40, 0.1 μM non-radioactive ATP, 0.125 μCi 33P-gamma-ATP (GE Healthcare, catalog number AH9968) final concentrations) with or without 5μL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 μL, in a polypropylene 96-well plate (Greiner, V-bottom). After 90 min at 30 0C, reactions were stopped by adding of 25 μL/well of 150 mM phosphoric acid. All of the terminated kinase reaction was transferred to prewashed (75 mM phosphoric acid) 96 well filter plates (Perkin Elmer catalog number 6005177) using a cell harvester (Perkin Elmer). Plates were washed 6 times with 300 μL per well of a 75 mM phosphoric acid solution and the bottom of the plates was sealed. 40 μL/well of Microscint-20 was added, the top of the plates was sealed and readout was performed using the Topcount (Perkin Elmer). Kinase activity was calculated by subtracting counts per minute (cpm) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from cpm obtained in the presence of vehicle. The ability of a test compound to inhibit this activity was determined as:
[00393] Percentage inhibition = ((cpm determined for sample with test compound present - cpm determined for sample with positive control inhibitor) divided by (cpm determined in the presence of vehicle - cpm determined for sample with positive control inhibitor)) * 100%.
[00394] Dose dilution series were prepared for the compounds enabling the testing of dose-response effects in the TYK2 assay and the calculation of the IC5O for each compound. Each compound was routinely tested at concentration of 20μM followed by a 1/3 serial dilution, 8 points (20μM - 6.67μM - 2.22μM - 74OnM - 247nM - 82nM - 27nM - 9nM) in a final concentration of 1% DMSO. When potency of compound series increased, more dilutions were prepared and/or the top concentration was lowered (e.g. 5 μM, 1 μM). [00395] Semi-quantitative score:
- > 1001 nM
--501-100O nM
— 101-50O nM -- 0.01-10O nM
[00396] TABLE VI: TYK2 ICn Values of Compounds
Figure imgf000102_0001
Example 2. Cellular assays Example 2.1 JAK-STA T signalling assay:
[00397] HeLa cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM) containing
10% heat inactivated fetal calf serum, 100 U/mL penicillin and 100 μg/mL streptomycin. HeLa cells were used at 70 % confluence for transfection. 20,000 cells in 87 μL cell culture medium were transiently transfected with 40 ng pSTATl(2)-luciferase reporter (Panomics), 8 ng of LacZ reporter as internal control reporter and 52 ng of pBSK using 0.32 μL Jet-PEI (Polyplus) as transfection reagent per well in 96-well plate format. After overnight incubation at 37°C, 10% CO2, transfection medium was removed. 75 μL of DMEM + 1.5% heat inactivated fetal calf serum was added. 15 μL of compound at 6.7x concentration was added for 60 min and then 10 μL of human OSM (Peprotech) at 33 ng/mL final concentration.
[00398] All compounds were tested in duplicate starting from 20 μM followed by a 1/3 serial dilution,
8 doses in total (20 μM - 6.6 μM - 2.2 μM - 740 nM - 250 nM - 82 nM - 27 nM - 9 nM) in a final concentration of 0.2% DMSO.
[00399] After overnight incubation at 37°C, 10% CO2 cells were lysed in 100 μL lysis buffer/well
(PBS, 0.9 mM CaCl2, 0.5 mM MgC12, 5% Trehalose, 0.025% Tergitol NP9, 0.15% BSA). [00400] 40 μL of cell lysate was used to read β-galactosidase activity by adding 180 μL βGal solution
(30μl ONPG 4mg/mL + 150 μL β-Galactosidase buffer (0.06 M Na2HPO4, 0.04 M NaH2PO4, 1 mM MgCl2)) for 20 min. The reaction was stopped by addition of 50 μL Na2COs 1 M. Absorbance was read at 405 nm. [00401] Lucif erase activity was measured using 40 μL cell lysate plus 40 μL of Steadylite® as described by the manufacturer (Perkin Elmer), on the Envision (Perkin Elmer). [00402] 10 μM of a pan- JAK inhibitor was used as a positive control (100% inhibition). As negative control 0.5% DMSO (0% inhibition) was used. The positive and negative controls were used to calculate z' and
'percent inhibition' (PIN) values.
[00403] Percentage inhibition = ((fluorescence determined in the presence of vehicle - fluorescence determined for sample with test compound present) divided by (fluorescence determined in the presence of vehicle - fluorescence determined for sample without trigger)) * 100 %.
[00404] PIN values were plotted for compounds tested in dose-response and EC50 values were derived.
* > 1001 nM
**501-1000 nM
*** 1-50O nM
[00405] TABLE VII: STAT signalling EC^n Values of Compounds
Figure imgf000103_0002
Figure imgf000103_0001
Example 2.2 OSM/IL-lβ signaling Assay
[00406] OSM and IL- lβ were shown to synergistically upregulate MMP 13 levels in the human chondrosarcoma cell line SW1353. The cells were seeded in 96 well plates at 15,000 cells/well in a volume of 120 μL DMEM (Invitrogen) containing 10% (v/v) FBS and 1% penicillin/streptomycin (InVitrogen) incubated at 37°C 5% CO2. Cells were preincubated with 15 μL compound in Ml 99 medium with 2% DMSO 1 hr before triggering with 15 μL OSM and IL- lβ to reach 25 ng/mL OSM and 1 ng/mL IL-I β, and MMP 13 levels were measured in conditioned medium 48 hours after triggering. MMP 13 activity was measured using an antibody capture activity assay. For this purpose, 384 well plates (NUNC, 460518, MaxiSorb black) were coated with 35 μL of a 1.5 μg/mL anti-human MMP13 antibody (R&D Systems, MAB511) solution for 24 hours at 4°C. After washing the wells 2 times with PBS + 0.05% Tween, the remaining binding sites were blocked with 100 μL 5% non-fat dry milk (Santa Cruz, sc-2325, Blotto) in PBS for 24 hours at 4°C. Next, the wells were washed 2 times with PBS + 0.05% Tween and 35 μL of 1/10 dilution of culture supernatant containing MMP13 in 100-fold diluted blocking buffer was added and incubated for 4 hours at room temperature. Next the wells were washed twice with PBS + 0.05% Tween followed by MMP13 activation by addition of 35 μL of a 1.5 mM 4- Aminophenylmercuric acetate (APMA) (Sigma, A9563) solution and incubation at 37 0C for 1 hour. The wells were washed again with PBS + 0.05% Tween and 35 μL MMP13 substrate (Biomol, P-126, OmniMMP fluorogenic substrate) was added. After incubation for 24 hours at 37°C fluorescence of the converted substrate was measured in a Perkin Elmer Wallac EnVision 2102 Multilabel Reader (wavelength excitation: 320 nm, wavelength emission: 405 nm).
[00407] Percentage inhibition = ((fluorescence determined in the presence of vehicle - fluorescence determined for sample with test compound present) divided by (fluorescence determined in the presence of vehicle - fluorescence determined for sample without trigger)) * 100 %.
* > 1001 nM
**501-1000 nM
*** l-500 nM
[00408] TABLE VIII: MMP13 EQn Values of Compounds
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000105_0001
Example 2.3 PBL Proliferation assay
[00409] Human peripheral blood lymphocytes (PBL) are stimulated with IL-2 and proliferation measured using a BrdU incorporation assay. The PBL are first stimulated for 72 hrs with PHA to induce IL-2 receptor, fasted for 24 hrs to stop cell proliferation followed by IL-2 stimulation for another 72 hrs (including 24hr BrdU labeling). Cells are preincubated with test compounds 1 hr before IL-2 addition. Cells are cultured in RPMI 1640 containing 10% (v/v) FBS.http://www.118800.co.uk/removeme/remove.html
Example 3. In vivo models Example 3.1 CIA model
3.1.1 Materials
[00410] Completed Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA) are purchased from Difco. Bovine collagen type II (CII), lipopolysaccharide (LPS), and Enbrel are obtained from Chondrex (Isle d'Abeau, France); Sigma (P4252, L'Isle d'Abeau, France), Whyett (25mg injectable syringe, France) Acros Organics (Palo Alto, CA), respectively. All other reagents are of reagent grade and all solvents are of analytical grade.
3.1.2 Animals
[00411] Dark Agouti rats (male, 7-8 weeks old) are obtained from Harlan Laboratories (Mais on- AIf ort,
France). DBA/1 J mice (male, 7 weeks old) are obtained from Centre d'Elevage et de Reproduction JANVIER (CERJ) (Laval, France). Rats and mice are kept on a 12 hours light/dark cycle (0700 - 1900). The temperature is maintained at 22°C, and food and water are provided ad libitum.
3.1.3 Collagen induced arthritis (CIA)
[00412] One day before the experiment, CII solution (2 mg/mL) is prepared with 0.05 M acetic acid and stored at 4°C. Just before the immunization, equal volumes of adjuvant (IFA) and CII are mixed by a homogenizer in a pre-cooled glass bottle in an ice water bath. Extra adjuvant and prolonged homogenization might be required if an emulsion is not formed.
[00413] Mice: 0.1 mL of the emulsion is injected intradermally at the base of the tail of each mouse on day 1, a second booster intradermal injection (CII solution at 1 mg/mL in CFA 0.1 mL saline) is performed on day 21. This immunization method is modified from published methods (David D Brand Kary A Latham, &
Edward F Rosloniec. Collagen-induced arthritis. Nature Methods 2 (5): 1269-1275, 2007).
[00414] Rat: 0.2 mL of the emulsion is injected intradermally at the base of the tail of each rat on day 1, a second booster intradermal injection (CII solution at 2 mg/mL in CFA 0.1 mL saline) is performed on day 9.
This immunization method is modified from published methods (Sims NA et ah, (2004) Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis, Arthritis Rheum. 50 2338-2346; Jou e? α/., 2005).
3.1.4 Study design
[00415] The therapeutic effects of the test compounds are tested in the rat or mouse CIA model.
Animals are randomly divided into equal groups and each group contained 10 animals. All rats are immunized on day 1 and boosted on day 9. All mice are immunized on day 1 and boosted on day 21. Therapeutic dosing last from day 16 to day 30. The negative control group is treated with vehicle (MC 0,5%) and the positive control group with Enbrel (10 mg/kg, 3x week., s.c). A compound of interest is typically tested at 3 doses, e.g. 3, 10, 30 mg/kg, p.o.
3.1.5 Clinical assessment of arthritis
[00416] Arthritis is scored according the method of Khachigian 2006, Lin et al 2007 and Nishida et al.
2004). The swelling of each of the four paws is ranked with the arthritic score as follows: 0-no symptoms; 1- mild, but definite redness and swelling of one type of joint such as the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; 2-moderate redness and swelling of two or more types of joints; 3-severe redness and swelling of the entire paw including digits; 4- maximally inflamed limb with involvement of multiple joints (maximum cumulative clinical arthritis score 16 per animal) (Nishida et al, 2004).
3.1.6 Change in body weight (%) after onset of arthritis
[00417] Clinically, body weight loss is associated with arthritis (Shelton et al., 2005; Argiles et al.,
1998; Rail, 2004; Walsmith et al., 2004). Hence, changes in body weight after onset of arthritis can be used as a non-specific endpoint to evaluate the effect of therapeutics in the rat model. The change in body weight (%) after onset of arthritis is calculated as follows:
[00418]
[00419]
Figure imgf000106_0001
3.1.7 Radiology
[00420] X-ray photos are taken of the hind paws of each individual animal. A random blind identity number is assigned to each of the photos, and the severity of bone erosion is ranked by two independent scorers with the radiological Larsen's score system as follows: 0- normal with intact bony outlines and normal joint space; 1- slight abnormality with any one or two of the exterior metatarsal bones showing slight bone erosion; 2-defmite early abnormality with any three to five of the exterior metatarsal bones showing bone erosion; 3- medium destructive abnormality with all the exterior metatarsal bones as well as any one or two of the interior metatarsal bones showing definite bone erosions; 4-severe destructive abnormality with all the metatarsal bones showing definite bone erosion and at least one of the inner metatarsal joints completely eroded leaving some bony joint outlines partly preserved; 5-mutilating abnormality without bony outlines. This scoring system is a modification from Salvemini et al, 2001; Bush et al, 2002; Sims et al, 2004; Jou et al, 2005.
3.1.8 Histology
[00421] After radiological analysis, the hind paws of mice are fixed in 10% phosphate-buffered formalin (pH 7.4), decalcified with rapid bone decalcifϊant for fine histology (Laboratories Eurobio) and embedded in paraffin. To ensure extensive evaluation of the arthritic joints, at least four serial sections (5 μm thick) are cut and each series of sections were 100 μm in between. The sections are stained with hematoxylin and eosin (H&E). Histologic examinations for synovial inflammation and bone and cartilage damage are performed double blind. In each paw, four parameters are assessed using a four-point scale. The parameters are cell infiltration, pannus severity, cartilage erosion and bone erosion. Scoring is performed as follows: 1- normal, 2-mild, 3-moderate, 4-marked. These four scores are summed together and represented as an additional score, namely the 'RA total score'.
3.1.9 Micro-computed tomography (μCT) analysis of calcaneus (heel bone):
[00422] Bone degradation observed in RA occurs especially at the cortical bone and can be revealed by μCT analysis (Sims NA et al, 2004; Oste L et al, ECTC Montreal 2007). After scanning and 3D volume reconstruction of the calcaneus bone, bone degradation is measured as the number of discrete objects present per slide, isolated in silico perpendicular to the longitudinal axis of the bone. The more the bone is degraded, the more discrete objects are measured. 1000 slices, evenly distributed along the calcaneus (spaced by about 10.8 μm), are analyzed.
Example 3.2 Septic shock model
[00423] Injection of lipopolysaccharide (LPS) induces a rapid release of soluble tumour necrosis factor
(TNF-alpha) into the periphery. This model is used to analyse prospective blockers of TNF release in vivo. [00424] Six BALB/cJ female mice (20 g) per group are treated at the intended dosing once, po. Thirty minutes later, LPS (15 μg/kg; E. CoIi serotype 0111 :B4) is injected ip. Ninety minutes later, mice are euthanized and blood is collected. Circulating TNF alpha levels are determined using commercially available ELISA kits. Dexamethasone (5 μg/kg) is used as a reference anti-inflammatory compound. Selected compounds are tested at one or multiple doses, e.g. 3 and/or 10 and/or 30 mg/kg, po.
Example 3.3 MAB model
[00425] The MAB model allows a rapid assessment of the modulation of an RA-like inflammatory response by therapeutics (Kachigian LM. Nature Protocols (2006) 2512-2516: Collagen antibody- induced arthritis). DBA/J mice are injected i.v. with a cocktail of mAbs directed against collagen II. One day later, compound treatment is initiated (vehicle: 10% (v/v) HPβCD). Three days later, mice receive an i.p. LPS injection (50 μg/mouse), resulting in a fast onset of inflammation. Compound treatment is continued until 10 days after the mAb injection. Inflammation is read by measuring paw swelling and recording the clinical score of each paw. The cumulative clinical arthritis score of four limbs is presented to show the severity of inflammation. A scoring system is applied to each limb using a scale of 0-4, with 4 being the most severe inflammation.
0 Symptom free
1 Mild, but definite redness and swelling of one type of joint such as the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits
2 Moderate redness and swelling of two or more types of joints
3 Severe redness and swelling of the entire paw including digits
4 Maximally inflamed limb with involvement of multiple joints
Example 3.4 Oncology models
[00426] In vivo models to validate efficacy of small molecules towards JAK2-driven myleoproliferative diseases are described by Wernig et al Cancer Cell 13, 311, 2008 and Geron et al Cancer Cell 13, 321, 2008.
Example 3.5 Mouse IBD model
[00427] In vitro and in vivo models to validate efficacy of small molecules towards IBD are described by Wirtz et al. 2007.
Example 3.6 Mouse Asthma model
[00428] In vitro and in vivo models to validate efficacy of small molecules towards asthma are described by Nials et al, 2008; Ip et al. 2006; Pernis et al, 2002; Kudlacz et al, 2008.
Example 4: Toxicity, DMPK and Safety Models
Example 4.1 Thermodynamic solubility
[00429] A solution of 1 mg/mL of the test compound is prepared in a 0.2M phosphate buffer pH7.4 or a
0. IM citrate buffer pH3.0 at room temperature in a glass vial.
[00430] The samples are rotated in a Rotator drive STR 4 (Stuart Scientific, Bibby) at speed 3.0 at room temperature for 24 hours.
[00431] After 24 hours, 800μL of the sample is transferred to an eppendorf tube and centrifuged 5 min at 14000rpm. 200 μL of the supernatant of the sample is then transferred to a MultiscreenR Solubility Plate
(Millipore, MSSLBPC50) and the supernatant is filtered (10-12" Hg) with the aid of a vacuum manifold into a clean Greiner polypropylene V-bottom 96well plate (Cat no.651201). 5 μL of the filtrate is diluted into 95 μL
(F20) of the same buffer used to incubate in the plate containing the standard curve (Greiner,Cat no.651201). [00432] The standard curve for the compound is prepared freshly in DMSO starting from a 1OmM
DMSO stock solution diluted factor 2 in DMSO (5000μM) and then further diluted in DMSO up to 19.5μM.
3μL of the dilution series as from 5000μM is then transferred to a 97μL acetonitrile-buffer mixture (50/50).
The final concentration range is 2.5 to 150 μM.
[00433] The plate is sealed with sealing mats (MA96RD-04S, www.kinesis.co.uk) and samples are measured at room temperature on LCMS (ZQ 1525 from Waters) under optimized conditions using
Quanoptimize to determine the appropriate mass of the molecule.
[00434] The samples are analyzed on LCMS with a flow rate of lmL/min. Solvent A is 15mM ammonia and solvent B is acetonitrile. The sample is run under positive ion spray on an XBridge Cl 8 3.5μM
(2.1 x 30mm) column, from Waters. The solvent gradient has a total run time of 2 minutes and ranges from 5%
B to 95% B.
[00435] Peak areas are analyzed with the aid of Masslynx software package and peak areas of the samples are plotted against the standard curve to obtain the solubility of the compound.
[00436] Solubility values are reported in μM or μg/mL.
Example 4.2 Aqueous Solubility
[00437] Starting from a 1OmM stock in DMSO, a serial dilution of the compound is prepared in
DMSO. The dilution series is transferred to a 96 NUNC Maxisorb plate F-bottom (Cat no. 442404) and 0.2M phosphate buffer pH7.4 or 0. IM citrate buffer pH3.0 at room temperature is added.
[00438] The final concentration ranged from 200μM to 2.5μM in 5 equal dilution steps. The final
DMSO concentration did not exceed 2%. 200μM Pyrene is added to the corner points of each 96 well plate and serves as a reference point for calibration of Z-axis on the microscope.
[00439] The assay plates are sealed and incubated for 1 hour at 37°C while shaking at 230rpm. The plates are then scanned under a white light microscope, yielding individual pictures of the precipitate per concentration. The precipitate is analyzed and converted into a number which is plotted onto a graph. The first concentration at which the compound appears completely dissolved is the concentration reported, however the true concentration lies somewhere between this concentration and one dilution step higher.
[00440] Solubility values are reported in μg/mL
Example 4.3 Plasma Protein Binding (Equilibrium Dialysis)
[00441] A 1OmM stock solution of the compound in DMSO is diluted with a factor 5 in DMSO. This solution is further diluted in freshly thawed human, rat, mouse or dog plasma (BioReclamation INC) with a final concentration of lOμM and final DMSO concentration of 0.5% (5.5μl in 1094.5μl plasma in a PP- Masterblock 96well (Greiner, Cat no. 780285)) [00442] A Pierce Red Device plate with inserts (ThermoScientific, Cat no. 89809) is prepared and filled with 750μL PBS in the buffer chamber and 500μL of the spiked plasma in the plasma chamber. The plate is incubated for 4 hours at 37°C while shaking at 230rpm. After incubation, 120μL of both chambers is transferred to 360μL acetonitrile in a 96-well round bottom, PP deep-well plates (Nunc, Cat no. 278743) and sealed with an aluminum foil lid. The samples are mixed and placed on ice for 30min. This plate is then centrifuged 30 min at 1200rcf at 4°C and the supernatant is transferred to a 96 v-bottom PP plate (Greiner,
651201) for analysis on LCMS.
[00443] The plate is sealed with sealing mats (MA96RD-04S) of www.kinesis.co.uk and samples are measured at room temperature on LCMS (ZQ 1525 from Waters) under optimized conditions using
Quanoptimize to determine the appropriate mass of the molecule.
[00444] The samples are analyzed on LCMS with a flow rate of lmL/min. Solvent A was 15mM ammonia and solvent B was acetonitrile. The sample was run under positive ion spray on an XBridge Cl 8
3.5μM (2.1 x 30mm) column, from Waters. The solvent gradient has a total run time of 2 minutes and ranges from 5% B to 95% B.
[00445] Peak area from the compound in the buffer chamber and the plasma chamber are considered to be 100% compound. The percentage bound to plasma is derived from these results and was reported to the
LIMS as percentage bound to plasma.
[00446] The solubility of the compound in the final test concentration in PBS is inspected by microscope to indicate whether precipitation is observed or not.
Example 4.4 Liability for QT prolongation
[00447] Potential for QT prolongation is assessed in the hERG patch clamp assay.
4.4.1 Conventional whole-cell patch-clamp
[00448] Whole-cell patch-clamp recordings are performed using an EPClO amplifier controlled by
Pulse v8.77 software (HEKA). Series resistance is typically less than 10 MΩ and compensated by greater than
60%, recordings are not leak subtracted. Electrodes are manufactured from GC 150TF pipette glass (Harvard).
[00449] The external bathing solution contains: 135 mM NaCl, 5 mM KCl, 1.8 mM CaCl2, 5 mM
Glucose, 10 mM HEPES, pH 7.4.
[00450] The internal patch pipette solution contains: 10OmM Kgluconate, 20 mM KCl, ImM CaCl2, 1 mM MgCl2, 5mM Na2ATP, 2mM Glutathione, 11 mM EGTA, 10 mM HEPES, pH 7.2.
[00451] Drugs are perfused using a Biologic MEV-9/EVH-9 rapid perfusion system.
[00452] All recordings are performed on HEK293 cells stably expressing hERG channels. Cells are cultured on 12 mm round coverslips (German glass, Bellco) anchored in the recording chamber using two platinum rods (Goodfellow). hERG currents are evoked using an activating pulse to +40 mV for 1000 ms followed by a tail current pulse to -50 mV for 2000 ms, holding potential was -80 mV. Pulses are applied every 20s and all experiments are performed at room temperature.
4.4.2 Data Analysis
[00453] IC5O and IC20 values are calculated for each compound tested. The fold difference between the
IC20 and the unbound Cmax concentrations of the test compound obtained at relevant therapeutic doses as determined by results obtained from the rat CIA model is calculated.
[00454] For the concentration response curves, peak tail current amplitude is measured during the voltage step to -50 mV. Curve- fitting of concentration-response data is performed using the equation: y = a + [( b -a )/ ( 1+ 10Λ ( ( logc-x ) d )]
[00455] where a is minimum response, b is maximum response and d is Hill slope, this equation can be used to calculate both IC50 (where y = 50 and c is the IC50 value) and IC20 (where y = 20 and c is the IC20 value). GraphPad® Prism® (Graphpad® Software Inc.) software was used for all curve fitting. [00456] A difference of 100 fold or greater indicates a low potential for QT prolongation
Example 4.5 Microsomal stability
[00457] A 1OmM stock solution of compound in DMSO was diluted 1000 fold in a 182 mM phosphate buffer pH7.4 in a 96 deep well plate (Greiner, Cat no.780285) and pre-incubated at 37°C.
[00458] 40μL of deionised water was added to a well of a polypropylene Matrix 2D barcode labelled storage tube (Thermo Scientific) and pre-incubated at 37°C.
[00459] A Glucose-6-phophate-dehydrogenase (G6PDH) working stock solution was prepared in
182mM phosphate buffer pH7.4 and placed on ice before use. A co-factor containing MgCl2, glucose-6- phosphate and NADP+ was prepared in deionised water and placed on ice before use.
[00460] A final working solution containing liver microsomes (Xenotech) of a species of interest
(human, mouse, rat, dog), previously described G6PDH and co-factors was prepared and this mix was incubated for no longer than 20 minutes at room temperature.
[00461] 30μL of the pre-heated compound dilution was added to 40μL of pre-heated water in the
Matrix tubes and 30μL of the microsomal mix was added. Final reaction concentrations were 3μM compound, lmg microsomes, 0.4U/mL GDPDH, 3.3mM MgCl2, 3.3mM glucose-6-phosphate and 1.3mM NADP+.
[00462] To measure percentage remaining of compound at time zero MeOH or ACN was added (1 :1) to the well before adding the microsomal mix. The plates were sealed with Matrix Sepra sealsTM (Matrix, Cat.
No.4464) and shaken for a few seconds ensure complete mixing of all components.
[00463] The samples which were not stopped are incubated at 37°C, 300rpm and after 1 hour of incubation the reaction was stopped with MeOH or ACN (1 :1). [00464] After stopping the reaction the samples were mixed and placed on ice for 30min to precipitate the proteins. The plates were then centrifuged 30 min at 1200rcf at 4°C and the supernatant was transferred to a
96 v-bottom PP plate (Greiner, 651201) for analysis on LCMS.
[00465] These plates were sealed with sealing mats (MA96RD-04S) of www.kinesis.co.uk and samples were measured at room temperature on LCMS (ZQ 1525 from Waters) under optimized conditions using
Quanoptimize to determine the appropriate mass of the parent molecule.
[00466] The samples were analyzed on LCMS with a flow rate of lmL/min. Solvent A was 15mM ammonia and solvent B was methanol or acetonitrile, depending on the stop solution used. The samples were run under positive ion spray on an XBridge Cl 8 3.5μM (2.1 x 30mm) column, from Waters. The solvent gradient had a total run time of 2 minutes and ranges from 5% B to 95% B.
[00467] Peak area from the parent compound at time 0 was considered to be 100% remaining. The percentage remaining after 1 hour incubation was calculated from time 0 and was calculated as the percentage remaining.The solubility of the compound in the final test concentration in buffer is inspected by microscope and results are reported.
[00468] The data on microsomal stability are expressed as a percentage of the total amount of compound remaining after 60 minutes.
* 0-25
** 26-50
*** 51-75
**** 76-100
N/A - not available
TABLE IX - Microsomal stability
Figure imgf000112_0001
Figure imgf000113_0001
Example 4.6 Caco2 Permeability
[00469] Bi-directional Caco-2 assays were performed as described below. Caco-2 cells were obtained from European Collection of Cell Cultures (ECACC, cat 86010202) and used after a 21 day cell culture in 24- well Transwell plates (Fisher TKT-545-020B).
[00470] 2xlO5 cells/well were seeded in plating medium consisting of DMEM + GlutaMAXI + 1%
NEAA + 10% FBS (FetalClone II) + 1% Pen/Strep. The medium was changed every 2 - 3 days.
[00471] Test and reference compounds (propranolol and rhodaminel23 or vinblastine, all purchased from Sigma) were prepared in Hanks' Balanced Salt Solution containing 25 mM HEPES (pH7.4) and added to either the apical (125μL) or basolateral (600μL) chambers of the Transwell plate assembly at a concentration of
10 μM with a final DMSO concentration of 0.25%.
[00472] 50μM Lucifer Yellow (Sigma) was added to the donor buffer in all wells to assess integrity of the cell layers by monitoring Lucifer Yellow permeation. As Lucifer Yellow (LY) cannot freely permeate lipophilic barriers, a high degree of LY transport indicates poor integrity of the cell layer. [00473] After a 1 hour incubation at 37°C while shaking at an orbital shaker at 150rpm, 70μL aliquots were taken from both apical (A) and basal (B) chambers and added to lOOμLl 50:50 acetonitrile:water solution containing analytical internal standard (0.5μM carbamazepine) in a 96 well plate.
[00474] Lucifer yellow was measured with a Spectramax Gemini XS (Ex 426nm and Em 538nm) in a clean 96 well plate containing 150μL of liquid from basolateral and apical side.
[00475] Concentrations of compound in the samples were measured by high performance liquid- chromatography/mass spectroscopy (LC-MS/MS).
[00476] Apparent permeability (Papp) values were calculated from the relationship:
Papp = [compound]acceptor fmai x Vacceptor / ([compound]donor mitiai x Vdonor) / Tmc x Vdonor / surface area x 60 x 106 cm/s
V = chamber volume Tmc = incubation time. Surface area = 0.33cm
[00477] The Efflux ratios, as an indication of active efflux from the apical cell surface, were calculated using the ratio of Papp B>A/ Papp A>B.
[00478] The following assay acceptance criteria were used:
Propranolol: Papp (A>B) value > 20(χl0~6 cm/s)
Rhodamine 123 or Vinblastine: Papp (A>B) value < 5 (xlO 6 cm/s) with Efflux ratio >5. Lucifer yellow permeability: <100 nm/s
Table X - Caco2 Efflux rate
Figure imgf000114_0001
Example 4.7 Pharmacokinetic study in rodents
4.7.1 Pharmacokinetic study
[00479] Compounds are formulated in PEG200/physiological saline or PEG400/DMSO/physiological saline mixtures for the intravenous route and in 0.5% methylcellulose or 10-30% hydroxylpropyl-β- cyclodextrine pH3 or pH7.4 for the oral route. Test compounds are orally dosed as a single esophageal gavage at 5-10 mg/kg and intravenously dosed as a bolus via the caudal vein at 1 mg/kg. Each group consists of 3 rats. Blood samples are collected either via the jugular vein using cannulated rats or at the retro-orbital sinus with lithium heparin as anti-coagulant at the time points in the following range: 0.05 to 8 hours (intravenous route), and 0.25 to 6 or 24 hours (oral route). Whole blood samples are centrifuged at 5000 rpm for 10 min and the resulting plasma samples are stored at -200C pending analysis.
4.7.2 Quantification of compound levels in plasma
[00480] Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive electrospray mode.
4.7.3 Determination of pharmacokinetic parameters
[00481] Pharmacokinetic parameters are calculated using Winnonlin® (Pharsight®, United
Example 4.8 7-Day rat toxicity study
[00482] A 7-day oral toxicity study with test compounds was performed in Sprague-Dawley male rats to assess their toxic potential and toxicokinetics, at daily doses of 100, 300 and 500 mg/kg/day, by gavage, at the constant dosage- volume of 5 mL/kg/day.
[00483] The test compounds were formulated in 30% (v/v) HPβCD in purified water. Each group included 5 principal male rats as well as 3 satellite animals for toxicokinetics. A fourth group was given 30%
(v/v) HPβCD in water only, at the same frequency, dosage volume and by the same route of administration, and acted as the vehicle control group.
[00484] The goal of the study was to determine the lowest dose that resulted in no adverse events being identified (no observable adverse effect level - NOAEL). Compounds 37 and 176 were tested in this protocol.
[00485] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, an as indiced intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognise apparent modifications and variations that may be made without departing from the spirit of the invention. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents. [00486] REFERENCES
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JAK2V617F-induced polycythemia vera, Cancer Cell 13(4), 311-320 Geron et al. (2008) Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors Cancer Cell 13 (4), 321-30 Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA. (2005). Nat Rev Drug Discov. 4:331-44.
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Arthritis Rheum. 44:2909-21. Shelton DL, Zeller J, Ho WH, Pons J, Rosenthal A. (2005) Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis. Pain. 116:8-16. Sims NA, Green JR, Glatt M, Schlict S, Martin TJ, Gillespie MT, Romas E. (2004) Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis. Arthritis Rheum., 50: 2338-46. Walsmith J, Abad L, Kehayias J, Roubenoff R. (2004) Tumor necrosis factor-alpha production is associated with less body cell mass in women with rheumatoid arthritis. J Rheumatol.; 31 :23-9. Khachigian, L. M. Collagen antibody- induced arthritis. (2006) Nature Protocols 1, 2512-6. Lin HS, Hu CY, Chan HY, Liew YY, Huang HP, Lepescheux L, Bastianelli E, Baron R, Rawadi G, Clement-
Lacroix P. (2007) Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen- induced arthritis in rodents. Br J Pharmacol. Apr;150 (7):829-31.
[00487] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
[00488] From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.
[00489] It should be understood that factors such as the differential cell penetration capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays.
[00490] At least some of the chemical names of compounds of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.
[00491] Chemical structures shown herein were prepared using either ChemDraw® or ISIS® /DRAW.
Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

Claims

WHAT IS CLAIMED IS:
1. A compound according to Formula I:
Figure imgf000120_0001
wherein each CyI and Cy2 is independently selected from aryl and heteroaryl; each Ll and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O)2-, -N(R4a)-, - CON(R4a)-, -SO2N(R4a)-, - N(R4a)CO-, or - N(R4a)SO2-; each R1 is independently selected from Ci-Ce alkyl, substituted Ci-Cβ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, hydroxyl; each R a is independently selected from Ci-Ce alkyl, substituted Ci-Cβ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted CpC6 alkoxy, substituted or unsubstituted amido, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfanyl, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, halo, substituted or unsubstituted heteroaryl, hydroxy, nitro, and thiol; each R2b, R2c, and R2d is independently selected from H, CpC6 alkyl, substituted CpC6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted Ci-Cβ alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxy, substituted arylalkyloxy, substituted or unsubstituted amino, aryl, substituted aryl, arylalkyl, substituted sulfmyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, substituted or unsubstituted amido, cyano, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted CpC6 haloalkyl, hetero-O-aryl, substituted or unsubstituted 5-10 membered heteroaryl, hydroxyl, nitro, and thiol; each R2a and R4a is independently selected from H, CpC6 alkyl, substituted CpC6 alkyl, C3-C7 cycloalkyl, or substituted C3-C7 cycloalkyl;
R3b is independently selected from substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted -(CpC4 alkyl)-(4-7- membered heterocycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted -O- aryl, substituted or unsubstituted arylamino, and substituted or unsubstituted 5-10 membered heteroaryl; ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when Ll is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L2 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R3b is other than C3-C7 cycloalkyl, aryl or 5-10 membered heteroaryl, then n2 is 1, 2, 3, or 4; or pharmaceutically acceptable salts thereof, in the treatment and./or prevention of diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin- driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection) or proliferative diseases. 2. The compound according to claim 1, wherein each CyI and Cy2 is independently selected from aryl and heteroaryl; each Ll and L2 is independently selected from a single bond, -O-, -C(O)-, -S(O)2-, -N(R4a)-, - CON(R4a)-, -SO2N(R4a)-, - N(R4a)CO-, or - N(R4a)SO2-; each R1 is independently selected from unsubstituted Ci-Ce alkyl (optionally substituted with halo), unsubstituted acyl, unsubstituted acylamino, unsubstituted CpC6 alkoxy, unsubstituted amido, unsubstituted amino, unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, unsubstituted C3-C7 cycloalkyl, unsubstituted 4-7 membered heterocycloalkyl, halo, hydroxyl; each R3a is independently selected from unsubstituted CpC6 alkyl, unsubstituted acyl, unsubstituted acylamino, unsubstituted CpC6 alkoxy, unsubstituted amido, unsubstituted alkoxycarbonyl, unsubstituted arylalkyloxy, unsubstituted amino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, unsubstituted C3-C7 cycloalkyl, unsubstituted 4-7 membered heterocycloalkyl, halo, unsubstituted heteroaryl, hydroxy, nitro, and thiol; each R2b, R2c, and R2d is independently selected from H, unsubstituted Ci-Ce alkyl, unsubstituted acyl, unsubstituted acylamino, unsubstituted CpC6 alkoxy, unsubstituted alkoxycarbonyl, unsubstituted arylalkyloxy, unsubstituted amino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted aminosulfonyl, unsubstituted arylsulfonyl, sulfonic acid, sulfonic acid ester, azido, carboxy, cyano, hydroxyl, nitro, thiol, unsubstituted amido, unsubstituted C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl (optionally substituted with oxo), , unsubstituted hetero-O-aryl, unsubstituted 5- 10 membered heteroaryl; each R2a and R4a is independently selected from H, unsubstituted CpC6 alkyl, unsubstituted C3-C7 cycloalkyl;
R3b is independently selected from -(Ci-C4 alkyl)-(4-7-membered heterocycloalkyl), C3-C7 cycloalkyl (optionally substituted with unsubstituted 4-7 membered heterocycloalkyl), 4-7 membered heterocycloalkyl (optionally substituted with Ci -CO alkyl (optionally substituted with unsubstituted aryl, halo), unsubstituted aryl, amido (optionally substituted with Ci-Cβ alkyl), acyl, cyano, halo), aryl (optionally substituted with unsubstituted Ci-Ce alkoxy, cyano, halo, Ci-Cβ alkyl (optionally substituted with halo, unsubstituted aryl), 4-7 membered heterocycloalkyl (optionally substituted with unsubstituted Ci-Cβ alkyl), amino (optionally substituted with unsubstituted Ci-Cβ alkyl)), unsubstituted -O-aryl, unsubstituted arylamino, 5-10 membered heteroaryl (optionally substituted with unsubstituted Ci-Cβ alkyl); ml is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; and each nl and n2 is independently 0, 1, 2, 3, or 4; provided that when Ll is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R2c is other than H, alkyl, cycloalkyl, aryl or heteroaryl, then nl is 1, 2, 3, or 4; and when L2 is -N(R4a)-, -CON(R4a)-, or -SO2N(R4a)-, and R3b is other than C3-C7 cycloalkyl, aryl or 5-10 membered heteroaryl, then n2 is 1,
2, 3, or 4; or a pharmaceutically acceptable salts thereof.
3. The compound, or pharmaceutically acceptable salt, according to claim 1 or 2 wherein ml is 1 or 2; and each R1 is independently selected from Ci-Cβ alkyl, substituted Ci-Cβ alkyl, and halo.
4. The compound, or pharmaceutically acceptable salt, according to claim 3, wherein each R1 is independently selected from Me, CF3, Cl and F.
5. The compound, or pharmaceutically acceptable salt, according to claim 1 or 2, wherein ml is 0.
6. The compound, or pharmaceutically acceptable salt, according to claim 5, wherein R a is independently selected from H, Ci-C6 alkyl, and substituted Ci-C6alkyl.
7. The compound, or pharmaceutically acceptable salt, according to claim 6, wherein R a is H.
8. The compound, or pharmaceutically acceptable salt, according to claim 1 or 2 wherein the compound is according to Formula II or III:
Figure imgf000123_0001
wherein Cy2, Ll, L2, R2b, R2c, R2d, R3a, R3b, m2, nl, and n2 are as in claim 1.
9. The compound, or pharmaceutically acceptable salt, according to claim 8 wherein each of R2b, and R2d is independently H, CpC6 alkyl, substituted CpC6 alkyl, or halo.
10. The compound, or pharmaceutically acceptable salt, according to claim 9 wherein each of R2b, and R2d is independently H, Me, F or Cl.
11. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-10 wherein Ll is a single bond, nl is 0, and R2c is H, Cl, F, Me, Et, OMe, CF3, CONH2, CONMe2, CONHMe, CN,
NHCOMe, COOH, OH or COOEt.
12. The compound, or pharmaceutically acceptable salt, according to claim 11 wherein R2c is NHCOMe, or
COOH.
13. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-10 wherein Ll is
CONH; nl is 2 or 3; and R2c is NMe2, OMe or NHCOMe.
14. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-10 wherein Ll is selected from a single bond, -C(O)-, and -C0N(R4a)-; nl is O, 1, 2, 3, or 4; and R2c is substituted or unsubstituted CpC6 alkyl, substituted or unsubstituted C6-CiO aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl.
15. The compound, or pharmaceutically acceptable salt, according to claim 14 wherein R c is unsubstituted
Ci-C6 alkyl.
16. The compound, or pharmaceutically acceptable salt thereof, according to claim 14 or 15, wherein R2c is Me, Et, i-Pr, l,3-dihydroxyprop-2-yl.
17. The compound, or pharmaceutically acceptable salt, according to claim 14 wherein R c is substituted or unsubstituted C3-C7 cycloalkyl.
18. The compound, or pharmaceutically acceptable salt, according to claim 17 wherein R c is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cyclopentyl.
19. The compound, or pharmaceutically acceptable salt, according to claim 14 wherein R c is substituted or unsubstituted C6-Ci0 aryl or substituted or unsubstituted 5-10 membered heteroaryl.
20. The compound, or pharmaceutically acceptable salt, according to claim 19 wherein R c is substituted or unsubstituted Ph, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.
21. The compound, or pharmaceutically acceptable salt, according to claim 14 wherein R c is substituted or unsubstituted 4-7 membered heterocycloalkyl.
22. The compound, or pharmaceutically acceptable salt, according to claim 21 wherein R c is piperidinyl, morpholinyl, piperazinyl, or pyrrolidinyl, each of which may be unsubstituted or substituted with Ci- C6alkyl, acyl, phenyl, or OH.
23. The compound, or pharmaceutically acceptable salt, according to any one of claims 14-22, wherein R4a is H.
24. The compound, or pharmaceutically acceptable salt, according to claim 23, wherein nl is 0, 1, 2 or 3.
25. The compound, or pharmaceutically acceptable salt, according to claim 24, wherein nl is 0, or 1.
26. The compound, or pharmaceutically acceptable salt, according to any one of claims 14-22, wherein Ll is CO; and nl is 0, 1, 2 or 3.
27. The compound, or pharmaceutically acceptable salt, according to claim 26, wherein nl is 0, or 1.
28. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-10 wherein the - Cyl-Ll-(CH2)ni-R2c group is selected from:
Figure imgf000125_0001
and wherein nl and R c are as in claim 1.
29. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-10, wherein the Cyl-Ll-(CH2)ni-R2c is selected from:
Figure imgf000125_0002
and wherein nl and R ,z2cc are as in claim 1.
30. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-10, wherein the Cyl-Ll-(CH2)ni-R2c is selected from:
R2=
Figure imgf000125_0003
Figure imgf000125_0004
and wherein nl and R c are as in claim 1.
31. The compound, or pharmaceutically acceptable salt, according to any one of claims 28-30, wherein R c is a substituted or unsubstituted N-containing heterocyloalkyl or a substituted or unsubstituted N- containing 5-10 member ed heteroaryl.
32. The compound, or pharmaceutically acceptable salt, according to claim 31, wherein R2c is:
Figure imgf000126_0001
33. The compound, or pharmaceutically acceptable salt, according to claim 31, wherein R c is pyrazolyl, pyrrolyl, imidazolyl, or triazolyl.
34. The compound, or pharmaceutically acceptable salt, according to any one of claims 28-33, wherein nl is 0, 1 or 2.
35. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-10, wherein the -
Cyl-Ll-(CH2)ni-R2c is selected from:
Figure imgf000126_0002
36. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-35, wherein Cy2 is Ph; and m2 is 0.
37. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-35, wherein Cy2 is Ph; m2 is 1, 2 or 3; and each R3a is independently Ci-C6 alkyl, CpC6 haloalkyl, CpC6 alkoxy, halo, CONH2, CONMe2, CONHMe, CN, NHCOMe, COOH, OH or COOEt.
38. The compound, or pharmaceutically acceptable salt, according to claim 37 wherein each R a is independently Cl, F, Me, Et, OMe, CF3, CONH2, CONMe2, CONHMe, CN, NHCOMe, COOH, OH or COOEt.
39. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-35 wherein R3b is substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl.
40. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-35 wherein L2 is selected from -0-, -C(O)-, and -C0N(R4a)-; n2 is O, 1, 2, 3, or 4; and R3b is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycloalkyl.
41. The compound, or pharmaceutically acceptable salt, according to claim 40 wherein R3b is substituted or unsubstituted C3-C7 cycloalkyl.
42. The compound, or pharmaceutically acceptable salt, according to claim 41 wherein R3b is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cyclopentyl.
43. The compound, or pharmaceutically acceptable salt, according to claim 40 wherein R3b is substituted or unsubstituted aryl or substituted or unsubstituted 5-10 membered heteroaryl.
44. The compound, or pharmaceutically acceptable salt, according to claim 43 wherein R3b is substituted or unsubstituted Ph, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.
45. The compound, or pharmaceutically acceptable salt, according to claim 40 wherein R3b is substituted or unsubstituted 4-7 membered heterocycloalkyl.
46. The compound, or pharmaceutically acceptable salt, according to claim 45 wherein R3b is piperidinyl, morpholinyl, piperazinyl, or pyrrolidinyl, each of which may be unsubstituted or substituted with Ci-
C6alkyl, acyl, phenyl, or OH.
47. The compound, or pharmaceutically acceptable salt, according to any one of claims 40-45, wherein R4a is H.
48. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-47, wherein the -
Cy2-L2-(CH2)n2-R3b group is at the 4-position of the phenyl ring.
49. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-36, wherein the -
Cy2-L2-(CH2)n2-R3b is selected from:
Figure imgf000127_0001
wherein R3b, and n2 are as in claim 1 ; Cy3 is substituted or unsubstituted N containing 4-7 membered heterocycloalkyl; R5a and R5b are independently selected from H, or Me, or together R5a, R5b and the carbon to which they are attached, form an unsubstituted C3-C7 cycloalkyl.
50. The compound, or pharmaceutically acceptable salt, according to claim 49, wherein R5a and R5b are both Me.
51. The compound, or pharmaceutically acceptable salt, according to claim 49, wherein R5a is H and R5b is
Me.
52. The compound, or pharmaceutically acceptable salt, according to claim 49, wherein R5a and R5b together with the carbon to which they are attached form a C3-C7-cycloalkyl.
53. The compound, or pharmaceutically acceptable salt, according to claim 49, wherein R5a and R5b together with the carbon to which they are attached form a cyclopropyl.
54. The compound, or pharmaceutically acceptable salt, according to claim 49, wherein R5a and R5b are both H.
55. The compound, or pharmaceutically acceptable salt, according to claim 1 or 2 wherein the compound is according to Formula IVa, IVb, IVc, IVd, IVe, or IVf:
Figure imgf000128_0001
and wherein n2 is 1, 2, or 3; R2c is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl; R3b is, 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamino, substituted or unsubstituted-O-aryl, or substituted or unsubstituted heteroaryl,
56. The compound, or pharmaceutically acceptable salt, according to claim 55, wherein the compound is according to any one of Formula IVa-IVe, and R3b is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl.
57. The compound according to claim 55, wherein the compound is according to any one of Formula IVa- IVe, and R3b is substituted or unsubstituted -O-aryl or substituted or unsubstituted arylamino.
58. The compound according to claim 54, wherein the compound is according to formula IVa-IVe, and R3b is substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indolyl, or substituted or unsubstituted indazolyl.
59. The compound according to claim 1 or 2 wherein the compound is according to Formula Va:
Figure imgf000129_0001
and wherein R > 2cc j is H, NHCOMe, 4-7 membered heterocycloalkyl, or -C(O)- 4-7 membered heterocycloalkyl, - C(O)NH-C3-C7 cycloalkyl; and R3b is substituted or unsubstituted 4-7 membered heterocycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl.
60. The compound according to any one of claims 53-59, wherein R c is H.
61. The compound according to claim 1 or 2, wherein the compound is according to Formula Via, VIb, Vic or IVd:
Figure imgf000129_0002
wherein R3b is as described in the preceeding claims.
62. The compound according to claim 55, 59 or 61, wherein R 3b is:
Figure imgf000130_0001
Figure imgf000130_0002
63. The compound according to claim 1 or 2 wherein the compound is selected from the compounds listed in Table 1
64. The compound according to any one of claims 1 to 63 wherein the disease involves inflammation.
65. The compound according to any one of claims 1 to 63, wherein the disease is a condition involving an immune response or an autoimmune disease.
66. The compound according to claim 65, wherein the disease is selected from rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases.
67. The compound according to any one of claims 1 to 63, wherein the disease is a condition involving an immune response or an autoimmune disease.
68. The compound according to claim 67, wherein the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease
69. The compound according to any one of claims 1 to 63, wherein the disease involves an impairment of cartilage turnover.
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