WO2010010184A1 - [1, 2, 4]triazolo[1, 5-a]pyridines utilisées comme inhibiteurs de jak - Google Patents

[1, 2, 4]triazolo[1, 5-a]pyridines utilisées comme inhibiteurs de jak Download PDF

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WO2010010184A1
WO2010010184A1 PCT/EP2009/059595 EP2009059595W WO2010010184A1 WO 2010010184 A1 WO2010010184 A1 WO 2010010184A1 EP 2009059595 W EP2009059595 W EP 2009059595W WO 2010010184 A1 WO2010010184 A1 WO 2010010184A1
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substituted
unsubstituted
compound
alkyl
compound according
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Christel Jeanne Marie Menet
Javier Blanc
Alastair James Hodges
Roland Werner Burli
Perla Breccia
Wesley Peter Blackaby
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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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/).
  • 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.
  • Rheumatoid arthritis 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)).
  • 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.
  • grade I osteoarthritis is reached; when the tangential surface area has disappeared, grade II osteoarthritis is reached.
  • degeneration and destruction which affect the deep and the calcified cartilage layers that border with the subchondral bone.
  • 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.
  • 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 al., 2006). Taken together, no disease modifying osteoarthritic drugs are available.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • 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.
  • Another possible treatment is the transplantation of cultured autologous chondrocytes.
  • 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.
  • 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.
  • BMP bone morphogenetic protein
  • TGF- ⁇ human transforming growth factor- ⁇
  • JAKl belongs to the Janus kinase
  • JAK cytoplasmic tyrosine kinases
  • 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
  • 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).
  • 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).
  • 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.
  • leukaemias e.g. acute myeloid leukaemia
  • 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).
  • 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).
  • SLE systemic lupus erythematosus
  • targeting the JAK family may provide a therapeutic opportunity in the immuno- inflammation area.
  • 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.
  • diseases involving cartilage degradation, bone and/or joint degradation for example osteoarthritis
  • 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
  • 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.
  • diseases involving cartilage degradation, bone and/or joint degradation for example osteoarthritis
  • 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
  • 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 4 >, - CON(R 4* )-, -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 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 sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid,
  • 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 invention useful m 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
  • 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 (e.g.
  • asthma wheezing a bowel disease
  • 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, which method 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. [0035] 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 avert or treat any maladies that may be causally related thereto.
  • a still further object of this invention is 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.
  • 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.
  • 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, 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).
  • 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 carti
  • analogue means one analogue or more than one analogue.
  • 'Acyl' 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.
  • 'acyl' groups are -C(O)H, -C(O)-Ci-C 8 alkyl, -C(O)-(CH 2 ) t (C 6 -C 10 aryl), -C(O)-(CH 2 ),(5-10 membered heteroaryl), -C(O)-(CH 2 ) t (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 Acyl' refers to a radical -C(O)R 21 , wherein R 21 is independently
  • Ci-C 8 alkyl substituted with halo or hydroxy
  • 'Acylamino' refers to a radical -NR 22 C(O)R 23 , where R 22 is hydrogen, C r 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, Ci-C 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)-Ci-C 8 alkyl, -NR 21 C(O)-(CH 2 ) ⁇ C 6 -Ci 0 aryl), -NR 21 C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 21' C(O)-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -NR 21 C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 21 independently represents H or Ci-C 8 alkyl.
  • R 24 is independently
  • R 25 is independently
  • alkoxy' refers to the group -OR 26 where R 26 is Ci-C 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, C 3 -Ci 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 X(C 6 -Ci 0 aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -0-(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 Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • Particular exemplary 'substituted alkoxy' groups are OCF 3 , OCH 2 CF 3 , OCH 2 Ph, OCH 2 -cyclopropyl, OCH 2 CH 2 OH, OCH 2 CH 2 NMe 2 .
  • Alkoxycarbonyl' refers to a radical -C(O)-OR 27 where R 27 represents an Ci-C 8 alkyl, C 3 -
  • alkoxycarbonyl groups are C(O)O-Ci-Cg alkyl, -C(O)O- (CH 2 ) t (C 6 -Cio aryl), -C(O)O-(CH 2 ) f (5-10 membered heteroaryl), -C(O)O-(CH 2 ) t (C 3 -Ci 0 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 (-0-C(O)-NR 2) , aminosulfonyl,
  • 'substituted alkyl' refers to a Ci-C 8 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 “ , -
  • t is an integer from O to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • R and R independently represents H or Ci-Cs alkyl.
  • '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 33 ) 2 where each R is independently selected from:
  • Ci-C 8 alkyl substituted with halo or hydroxy
  • -N(R 33 ) 2 is an amino group.
  • exemplary 'substituted amino' groups are -NR 33' -C r C 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 -Ci 0 cycloalkyl), and -NR 33' -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 33 independently represents H or Ci- C 8 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 unsubstitute
  • 'Alkylamino' refers to the group -NHR 34 , wherein R 34 is Ci-C 8 alkyl.
  • Substituted Alkylamino' refers to the group -NHR 35 , wherein R 35 is Ci-Cg alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted
  • Ci-C 4 alkyl halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Dialkylamino' refers to the group -NR 42 R 43 , wherein each of R 42 and R 43 are independently selected from Ci-C 8 alkyl.
  • Dialkylamino' refers to the group -NR 44 R 45 , wherein each of R 44 and R 45 are independently selected from Ci-C 8 alkyl; and the alkyl group is independently substituted with halo, hydroxy, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted
  • 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:
  • Ci-C 8 alkyl C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • '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.
  • Particularly aryl groups include phenyl
  • 'Substituted Aryl' 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.
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, Ci-C 8 alkyl, Ci-C 8 haloalkyl, Ci-C 8 haloalkoxy, cyano, hydroxy, Ci-C 8 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 CpC 8 alkyl, 4-10 membered heterocycloalkyl, CpC 8 alkoxy, hetero-O- aryl, alkylamino, 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 49 and R 50 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optional
  • R 51 , and R 52 are independently hydrogen, CpC 8 alkyl, C r C 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 Ci-C 4 alkyl, halo, cyano, unsubstituted Ci-C 4 alkoxy, unsubstituted Cr 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Azido' refers to the radical -N 3 .
  • 'amido' refers to the radical -C(O)NH 2 .
  • Ci-C 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 Amido ' groups are -C(O) NR 53' -Ci-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 Ci-Ce alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4
  • '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.
  • Particular 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 54 , O and S; and R 54 is independently hydrogen, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C ⁇ -Cio aryl, and 5-10 membered heteroaryl.
  • R 54 is independently hydrogen, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C ⁇ -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, Ci-Cg alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C ⁇ -Cio 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.
  • each W is selected from CR 56 , C(R 56 ) 2 , NR 56 , O and S, and each Y is selected from NR 56 , O and S, and R 56 is independently hydrogen, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C ⁇ -Cio aryl, 5-10 membered heteroaryl,
  • These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylammo, acyloxy (-O-acyl or - OC(O)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylammo (-NR -alkoxycarbonyl or -NH-C(O)-OR 27 ), ammo, substituted ammo, ammocarbonyl (amido or -C(O)-NR 2 ), ammocarbonylamino (-NR -
  • 'Substituted' refers to a group m which one or more hydrogen atoms are each independently replaced with the same or different substituent(s)
  • each R 57 , R 58 , R 59 and R 60 are independently hydrogen, CpC 8 alkyl, C 5 -Ci 0 aryl, arylalkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, heteroarylalkyl, or • CpC 8 alkyl substituted with halo or hydroxy; or
  • 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(O)NR R “ , -NR “ R “ , -(CR R ) m OR " , wherein, each R " is independently selected from H, Ci-C 8 alkyl, -(CH 2 ) t (C 6 -Ci 0 aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 XC 3 -Ci 0 cycloalkyl), and - (CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer
  • 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 6 alkyl.
  • Substituted sulfanyF refers to the group -SR 61 , wherein R 61 is selected from:
  • Exemplary 'substituted sulfanyP groups are -S-(CpCg alkyl) and -S-(X-VCiO cycloalkyl),
  • 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.
  • 'substituted sulfanyl' includes the groups 'alkylsulfanyl' or 'alkylthio', 'substituted alkylthio' or 'substituted alkylsulfanyl', 'cycloalkylsulfanyP or 'cycloalkylthio', 'substituted cycloalkylsulfanyF or 'substituted cycloalkylthio', 'arylsulfanyF or 'arylthio' and 'heteroarylsulfanyl' or 'heteroarylthio' as defined below.
  • 'Substituted sulfmyl' refers to the group -S(O)R 68 , wherein R 68 is selected from:
  • Exemplary 'substituted sulfinyl' groups are -S(O)-(CpC 8 alkyl) and -S(O)-(C 3 -Ci 0 cycloalkyl), -S(0)-(CH 2 ),(C 6 -Cio aryl), -S(O)-(CH 2 ),(5-10 membered heteroaryl), -S(O)-(CH 2 ) t (C 3 -Ci 0 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 haloalky
  • substituted sulfinyl includes the groups 'alkylsulfmyl', 'substituted alkylsulfmyl', 'cycloalkylsuli ⁇ nyF, 'substituted cycloalkylsulfinyl', 'arylsulfinyl' and 'heteroarylsulfmyl' as defined herein.
  • 'Substituted sulfonyF refers to the group -S(O) 2 R 75 , wherein R 75 is selected from:
  • 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 ) t (C 6 -Ci 0 aryl), -S(O) 2 -(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -(CH 2 ) t (C 3 -Ci 0 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 alkyl,
  • substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
  • '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:
  • Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O) 2 -O-(Ci-C 8 alkyl) and -S(O) 2 -O-(C 3 -C 10 cycloalkyl), -S(O) 2 -O-(CHz) 1 (C 6 -C 10 aryl), -S(O) 2 -O-(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -O-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -S(O) 2 -O-(CH 2 ) ⁇ -IO 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,
  • 'Thiol' refers to the group -SH.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • '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.
  • '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, cyclop entanepropionic 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-toluenesulf
  • 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.
  • “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 anti-malarial 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.
  • Atherosclerosis Crohn's disease and ulcerative colitis
  • amyotrophic lateral sclerosis Particularly the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • 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.
  • pancreatic islets 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.
  • '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).
  • 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.
  • 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 are the Ci to Cs alkyl, C 2 -C 8 alkenyl, aryl, C 7 -
  • 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' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • '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 H/D, 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.
  • 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. Further, 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
  • PET Positron Emission Topography
  • 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'.
  • 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
  • '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 ⁇ 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.
  • 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 this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • 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):
  • 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 )C0-, or - N(R 4a )SO 2 -; each R 1 is independently selected from Ci-C 6 alkyl, substituted Ci-C 6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted Ci-C 6 alkoxy, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted sulfmyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfonic acid, sulf
  • the compound is according to Formula I, 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(R 4a )-, - CON(R 4 >, -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 6 alkyl, unsubstituted acyl, unsubstituted acylamino, unsubstituted Ci-C 6 alkoxy, unsubstituted amido, unsubstituted amino, unsubstituted aminosulfonyl, sulfonic acid, sulfonic acid ester, carboxy, cyano, unsubstituted C 3 -
  • each R 1 is independently selected from Ci-C 6 alkyl, substituted Ci-C 6 alkyl, and halo.
  • each R 1 is independently selected from H, Me, CF 3 , Cl and F.
  • ml is 0.
  • R a is independently selected from H, Ci-C 6 alkyl, and substituted Ci-C 6 alkyl.
  • R 2a is H.
  • CyI is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • CyI is substituted or unsubstituted aryl.
  • CyI is 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.
  • CyI is substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isoxazolyl, or substituted or unsubstituted isothiazolyl.
  • CyI is substituted or unsubstituted phenyl.
  • Cy2, Ll, L2, R 2c , R 3a , R 3b , m2, nl, and n2 are as described above and R 2b , and R 2d are independently H, CpC 6 alkyl, substituted CpC 6 alkyl, CpC 6 alkoxy or halo.
  • Cy2, Ll, L2, R 2c , R 3a , R 3b , m2, nl, and n2 are as described above and R 2b , and R 2d are independently H, Me, OMe, F or Cl.
  • Ll is a single bond
  • nl is 0, and R 2c is H
  • Ll is a single bond
  • nl is 0, and R 2c is
  • Ll is CONH; nl is 2 or 3; and R 2c is
  • Ll is selected from a single bond, -C(O)-, and -CON(R 4a )-; nl is 0, 1 , 2, 3, or 4; R 4a is selected from H and C r C 6 alkyl and R 2c is substituted or unsubstituted CpC 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted 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; R 4a is selected from selected from H and CpC 6 alkyl and R 2c is Me,
  • Ll is selected from a single bond, -C(O)-, - and -CON(R 4a )-; nl is 0, 1, 2, 3, or 4; R 4a is selected from selected from H and CpC 6 alkyl and R 2c 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 -C0N(R 4a )-; nl is 0, 1, 2, 3, or 4; R 4a is selected from selected from H and CpC 6 alkyl 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 Ph, substituted or unsubstituted pyridy
  • Ll is selected from a single bond and -C(O)-, nl is 0, 1, 2, 3, or 4; and R 2b is piperidinyl, niorpholinyl, piperazinyl, or pyrrolidinyl, each of which may be unsubstituted or substituted with Ci-C 6 alkyl, acyl, phenyl, or OH.
  • Ll is -CON(R 4a )-; nl is 1,
  • R 4a is selected from selected from H and Ci-C 6 alkyl and R 2c is piperidinyl, morpholinyl, piperazinyl, or pyrrolidinyl, each of which may be unsubstituted or substituted with Ci-C 6 alkyl, acyl, phenyl, or OH.
  • -Cyl-Ll-(CH 2 )ni-R 2c is selected from:
  • nl and R 2c are as described above.
  • -Cyl-Ll-(CH 2 ) n i-R c is selected from:
  • nl and R c are as described above.
  • -CyI -Ll -(CH 2 )Hi-R 20 is selected from:
  • nl and R c are as described above.
  • the -Cyl-Ll-(CH 2 ) n i-R 2c is selected from:
  • nl and R c are as described above.
  • R 2c is N-containing heterocylic or heteroaryl ring. [00153] In a particular embodiment, R 2c is:
  • R 2c is pyrazolyl, pyrrolyl, imidazolyl, or triazolyl.
  • nl is 0, 1 or 2.
  • -Cyl-Ll-(CH 2 ) n i-R 2c is selected from:
  • Cy2 is substituted or unsubstituted aryl.
  • Cy2 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • Cy2 is substituted or unsubstituted 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 pyrazolyl, substituted or unsubstituted
  • Cy2 is substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isoxazolyl, or substituted or unsubstituted isothiazolyl.
  • Cy2 is Ph; m2 is 1, 2 or 3; and each R 3a is independently Ci-C 6 alkyl, halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, or halo.
  • Cy2 is Ph; m2 is 1, 2 or 3; and each R 3a is independently Cl, F, Me, Et, OMe, CF 3 , CONH2, CONMe2, CONHMe, CN, NHCOMe,
  • L2 is selected from -O-, -
  • n2 is 0, 1, 2, 3, or 4;
  • R 4a is selected from H and C 1 -
  • R 3b is substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted 4-7 memebered heterocycloalkyl.
  • L2 is selected from -O-, -
  • n2 is 0, 1 , 2, 3, or 4;
  • R 4a is selected from H and Ci-C 6 alkyl; and
  • R 3b is Me, Et, i-Pr, l,3-dihydroxyprop-2-yl.
  • L2 is selected from -O-, -
  • R 4a is selected from H and Ci-C 6 alkyl; and R 3b is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cyclopentyl.
  • L2 is selected from -O-, -
  • R 4a is selected from H and CpC 6 alkyl; and 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 benzimidazoly
  • L2 is selected from -O-, -
  • n2 is 0, 1, 2, 3, or 4;
  • R 4a is selected from H and C 1 -
  • R 3b is piperidinyl, morpholinyl, piperazinyl, or pyrrolidinyl, each of which may be unsubstituted or substituted with Ci-C 6 alkyl, acyl, phenyl, or OH provided that when L2 is -O, S(O) 2 N(R 4a )- and -CON(R 4a )-, n2 is 1, 2, 3, or 4.
  • R 4a is H.
  • each R a is H; and the -Cy2-L2-(CH 2 ) n2 -R 3b : is selected from:
  • R 3b , and n2 are as in Formula 1 ; and Cy3 is substituted or unsubstituted 4-7 membered N containing 4-7 membered heterocycloalkyl.
  • each R 3a is H; and the -Cy2-L2-(CH 2 ) n2 -R 3b is selected from:
  • R 3b , and n2 are as in Formula 1 ; and Cy3 is substituted or unsubstituted 4-7 membered N containing 4-7 membered heterocycloalkyl.
  • the group "L2-(CH 2 ) n2 -R 3b " is R 3c ; and R 3c is Cl, F, Me, Et, OMe, OEt, O-i-Pr, CF 3 , OCF 3 , OCH 2 CN, CONH 2 , CH 2 CN, (CH 2 ) 2 CN, CONMe 2 ,
  • CONHMe SO 2 NH 2 , SO 2 NMe 2 , CN, NHCOMe, COOH, OH or COOEt.
  • R 3C is CH 2 -R 3d , CO-R 3d , CONH(CH 2 ) n3 -R 3d , NHCO-R 3d , or NHSO 2 -R 3d ; and R 3d is substituted or unsubstituted 4-7 membered heterocycloalkyl, aryl, or heteroaryl; and n3 is 1, 2, or 3.
  • the group L2-(CH 2 ) n2 -R 3b is R 3c ; and the compound is according to Formula IVa, IVb, IVc, or IVd: and wherein nl is 1, 2, or 3;
  • R 2c is substituted or unsubstituted dialkylamino, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted -O-aryl, or substituted or unsubstituted heteroaryl;
  • R 3c is Cl, F, Me, Et, OMe, OEt, O-i-Pr, CF 3 , OCF 3 , OCH 2 CN, CONH 2 , CH 2 CN, (CH 2 ) 2 CN,
  • R 3d is substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n3 is 1, 2, or 3.
  • the group L2-(CH 2 ) n2 -R 3b is R 3c ; and the compound is according to Formula IVa, IVb, IVc, or IVd; and wherein nl is 1, 2, or 3; R c is substituted or unsubstituted dialkylamino, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted -O-aryl, or substituted or unsubstituted heteroaryl; R 3c is Cl, F, Me, Et, OMe, OEt, O-i-Pr, CF 3 , OCF 3 , OCH 2 CN, CONH 2 , CH 2 CN, (CH 2 ) 2 CN,
  • R 3d CH 2 -R 3d , CO-R 3d , CONH(CH 2 ) n3 -R 3d , NHC0-R 3d , or NHSO 2 -R 3d ; where R 3d is substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n3 is 1, 2, or 3. [00177] In a particular embodiment, with respect to compounds according to Formula IVa, IVb, IVc or
  • R 2c is NMe 2 , or R 2c is substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl.
  • R 2c is substituted or unsubstituted azetidinyl, or substituted or unsubstituted thiomorpholinyl-4,4- dioxide.
  • R 2c is
  • R 2c is
  • R 2c is substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indolyl, or substituted or unsubstituted indazolyl.
  • R 3c is
  • R 3c is
  • R 3c is
  • R 3c is
  • R 3d is:
  • R 3c is CH 2 -R 3d , CO-R 3d , NHCO-R 3d , or NHSO 2 -R 3d ; and R 3d is:
  • R 3c is
  • the compound is according to Formula Via, VIb, VIc, VId, VIe or VIf: [00190] In a preferred embodiment, with respect to compounds of Formula I, the compound is according to Formula VIg, VIh, VIi, VIj, VIk, VIl, VIm or VIn:
  • the compound of the invention is not an isotopic variant.
  • 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.
  • 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.
  • 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 C % alkyl, C 2 -C 8 alkenyl, aryl, C 7 -C 12 substituted aryl, and C 7 -Ci 2 arylalkyl esters of the compounds of the invention
  • the compounds of this 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 this 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 this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, 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
  • 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.
  • 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 0 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 this 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 this 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 a 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.
  • osteoarthritis a condition associated with, or diseases involving the anabolic stimulation of chondrocytes
  • 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.
  • 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 methods comprise 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
  • 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.
  • 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 methods comprise 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 methods comprise 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 the 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.
  • 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 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 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.
  • 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.
  • 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.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds of this invention When used to prevent the onset of an inflammatory condition, the compounds of this 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.
  • 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, auranofin, 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, auranofin, 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
  • 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. anti-thymocyte globulin (ATG), anti- lymphocyte globulin (ALG)).
  • calcineurin inhibitors e.g. cyclosporin or tacrolimus (FK506)
  • mTOR inhibitors e.g. sirolimus
  • 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, zaf ⁇ rlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g.
  • 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.
  • nonspecific beta- agonists injected or inhaled
  • injected or inhaled e.g. epinephrine, isoetharine, isoproter
  • 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. methot
  • 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,
  • 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)).
  • photochemotherapy e.g. psoralen and ultraviolet A phototherapy (PUVA)
  • PUVA ultraviolet A phototherapy
  • 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 particular 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.
  • the generic gradient used was 95% water / 5% ACN for 1 min to 5% water / 95% ACN over 5 min then held at 95% ACN for 4.0 min. The solvent mixture was then returned to the initial conditions over 0.5 min. A flow rate of 20 ml/min is used.
  • the modifiers used under acidic/basic conditions were formic acid (0.1%) and ammonium bicarbonate (1OmM) respectively.
  • Some of the compounds may have gone through a second purification process in order to achieve the required purity due to complex mixtures.
  • 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 particular 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 Broker DPX 400 NMR spectrometer (400 MHz). Chemical shifts (d) for IH NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (d 0.00) or the appropriate residual solvent peak, i.e. CHC13 (d 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 NH 2 or NHAr.
  • the crude product is then purified by flash chromatography to give the corresponding 2-amino- 8-Ar-triazolopyridine derivative (2).
  • the compounds may be purified by preparative HPLC). If the compound is not soluble in EtOAc, after cooling to room temperature, the reaction mixture is diluted with CH 2 Cl 2 /MeOH/H 2 O and the mixture filtered through Celite. The organic layer is separated and concentrated in vacuo. (The compounds may be further purified by preparative HPLC). [00265] Alternatively, a mixture of 8-bromo-triazolopyridine (1 eq), the boronic ester (1.2 eq),
  • PS-Pd(PPh 3 ) 4 polymer supported Pd(PPh 3 ) 4 , 0.03 eq) and K 2 CO 3 (1 M in H 2 O, 1.2 eq) in EtOH in a sealed 10 mL tube is heated at 110 0 C for 10 min under microwave irradiation. Water is added and the mixture is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous MgSO 4 and evaporated m vacuo to yield the crude product. The crude product is then purified by flash chromatography to give the corresponding 2-amino-8-Ar-triazolopy ⁇ dme derivative (2). (The compounds may be purified by preparative HPLC).
  • the reaction mixture is diluted with CH 2 Cl 2 /MeOH/H 2 O and the mixture filtered through Celite. The organic layer is separated and concentrated in vacuo (The compounds may be further purified by preparative HPLC)
  • the reaction mixture is diluted with CH 2 Cl 2 /MeOH/H 2 O and the mixture filtered through Celite The organic layer is separated and concentrated in vacuo. The crude product is then purified by column chromatography if required to give the corresponding 2-Ar'-8-bromo- triazolopyridine derivative (2).
  • This compound may be prepared using Method A.
  • a mixture of the above 2-amino-8-Ar-triazolopyridine derivative (1) (1 eq.) and NaNO 2 in DMSO (2eq. DMSO) is treated dropwise with a solution of 57% aqueous HI (10 eq.) in DMSO at 35 0 C with agitation.
  • the mixture is stirred at 35 °C for 10 minutes or until the reaction goes to completion (monitored by LCMS), and then it is transferred to a saturated K 2 CO 3 solution.
  • the reaction 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 is then purified by flash chromatography to give the corresponding 8-Ar-2-iodo- triazolopyridine derivative (2).
  • the reaction mixture is diluted with CH 2 Cl 2 /MeOH/H 2 O and the mixture filtered through Celite. The organic layer is separated and concentrated in vacuo. The crude product is then purified by preparative HPLC to give the corresponding 2-Ar'-8-Ar-triazolopyridine derivative (3).
  • Pd(OAc) 2 Pd 2 (dba) 3 may also equally be used
  • BINAP 0.1 eq
  • Xantphos an appropriate Ar'-NH 2 derivative (1.5 eq) and toluene (or 1,4-dioxan) is sonicated for 5 minutes under nitrogen. Afterwards, the reaction is left in a sealed tube at 120 0 C 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 reaction mixture is diluted with CH 2 Cl 2 /MeOH/H 2 O and the mixture filtered through Celite. The organic layer is separated and concentrated in vacuo. The crude product is then purified by preparative HPLC to give the corresponding 2-Ar-8-Bromo-triazolopyridine derivative (3).
  • Step c [00273] The same protocol as the one described in Method A can be used.
  • Step a (8-Bromo-[l,2,4]tnazolo[l,5-a]pyridin-2-yl)-(4-nitro-phenyl)-amine [00274] This compound may be prepared using Method B.
  • Step b
  • Step c N-[4-(8-Bromo-[l,2,4]tnazolo[l,5-a]pyndin-2-ylamino)-phenyl]-acetamide [00276] Acetic anhydride (leq.) is added dropwise to a solution of N-(8-Bromo-
  • HATU 1.5 eq.
  • HOBt 1.5eq.
  • Et 3 N 2eq.
  • An appropriate amine 1.1 eq. is added to the solution and the reaction mixture is stirred at room temperature for 16hrs.
  • Water and EtOAc are added to the reaction.
  • the organic phases is isolated, dried over MgSO4, filtered and evaporated under vacuum to afford the expected product. Purification by preparative HPLC is required.
  • Step a This compound may be prepared via Method B.
  • Step b
  • This compound may be prepared via Method H.
  • This compound may be prepared via Method I.
  • This compound may be prepared via Method A.
  • This compound may be prepared via Method B using 4-iodo-benzoic acid ethyl ester.
  • Step b [00289] This compound may be prepared via Method H.
  • Step c [00290] This compound may be prepared via Method I using an appropriate amine.
  • Step d [00291] This compound may be prepared via Method A using 4-carboxyphenylboronic acid.
  • Benzoic acid derivative EDCI (or DCI or HATU) (1.5 eq.), HOBt (1.5eq.) (not used with HATU) and Et 3 N (2eq.) are mixed in DMF (or THF) 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 preparative HPLC is required.
  • Step a [00293] A mixture of 2-methyl-4-nitrobenzoic acid (l eq.) iodomethane (1.1 eq.), K 2 CO 3 (1.5 eq.), and 10 mL of DMF is stirred for 2hrs at room temperature, then poured into water and extracted with AcOEt. The extract is washed with water and brine, dried over anhydrous MgS ⁇ 4 , and evaporated to afford the expected compound in quantative yield.
  • Step b
  • Alkyl-bromide is added to a solution of 4-Bromo-lH-pyrazole (1 eq.) and K2CO3 (2eq.) in DMA at room temperature. The solution is stirred for 20hrs. The reaction mixture is poured into water and extracted with AcOEt. The extract is washed with water and brine, dried over anhydrous
  • Step b
  • ClCHF 2 is added to a solution of 4-nitro-lH-pyrazole and K 2 CO 3 in DMF. The reaction is heated at 95°C for 2hrs. The reaction mixture is allowed to cool to room temperature. EtOAc and water were added to the reaction. The organic phase is separated, dried over MgSO 4 , evaporated under reduced pressure. The crude is used without further purification.
  • Step b
  • Step b
  • reaction mixture is further degassed by sonicating under a stream of N 2 for 5 min and then it is heated for 16 h at 100 0 C.
  • the reaction mixture is diluted with CH 2 Cl 2 ZMeOH (1 :1) filtered through Celite and the filtrate is concentrated in vacuo. Purification flash column chromatography (Gradient, CH 2 Cl 2 / CH 2 Cl 2 -MeOH 15%) yields the target compound as a yellow solid (876 mg,
  • l-bromo-2-chloroethane (1.2 eq.) is added to a solution of (4-Bromo-phenyl)- acetonitrile (leq), NaOH (solution IN) and BnNEtsCl (catalytique) in H 2 O at room temperature.
  • the resulting solution is heated to 6O 0 C for 5h.
  • EtOAc is added to the reaction.
  • the organic phases are isolated, dried over MgSO 4 , filtered and evaporated under vacuum to afford the expected product. Purification by flash chromatography is required.
  • KHMDS (1.5 eq.) is added to a solution l-Boc-3-cyanoazetidine (l.Eeq) (or l-boc-4- cyanopiperidine) in toluene at 0 0 C.
  • the resulting solution is stirred for 30 min at 0 0 C.
  • 5-bromo-2- fluoro-pyridine (leq) is added to the solution at 0 0 C.
  • EtOAc and water are added to the reaction.
  • the organic phases are isolated, dried over MgSO 4 , filtered and evaporated under vacuum to afford the expected product. Purification by flash chromatography may be required.
  • Derivative 1 (leq.), bis(pinacolato)diboron (1.2 eq.), Pd(dppf)Cl 2 (5%) and KOAc (1.3 eq) are stirred in dioxane at 90 0 C for 4hrs to 16 hr. The resulting mixture was diluted in EtOAc and filtered through Celite and evaporated under vacuum to afford the expected product used without purification in the next step.
  • Step a [00310] This compound may be prepared via Method B using 4-Iodo-benzoic acid ethyl ester. Step b:
  • This compound may be prepared via Method H then Method I using 3-hydroxy- azetidine.
  • This compound may be prepared via Method A using an appropriate boronic acid or boronate ester.
  • This compound was prepared via Method C using 4-metoxyphenyl boronic acid in step a then morpholin-4-yl-pyridin-3-ylamine in step c.
  • This compound was prepared via Method C using 4-metoxyphenyl boronic acid in step a then (4-amino-phenyl)-morpholin-4-yl-methanone in step c.
  • This compound was prepared via Method C using 4-(piperidine-l- carbonyl)phenylboronic acid in step a then N-(4-amino-phenyl)-acetamide in step c.
  • This compound was prepared via Method C using 4-(piperidine-l- carbonyl)phenylboronic acid in step a then 6-morpholin-4-yl-pyridin-3-ylamin in step c.
  • This compound was prepared via Method C using 4-(piperidine-l-carbonyl)- phenylboronic acid in step a then (4-amino-phenyl)-morphohn-4-yl-methanone in step c.
  • Step b
  • This compound was prepared via Method D using naphthalen-2-yl-boronic acid.
  • This compound was prepared via Method C using 4-methoxyphenyl boronic acid in step a then 6-(4-methylpiperazin-l-yl)pyridin-3 -amine in step c.
  • This compound was prepared via Method C using 4- metoxyphenyl boronic acid in step a then N-(3-amino-phenyl)-acetamide in step c.
  • This compound was prepared via Method C using 4- metoxyphenyl boronic acid in step a then 4-amino-benzoic acid in step c, followed by Method H.
  • This compound was prepared via Method D using phenylsulfonic acid [4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-amide prepared by Method F (using phenylsulfonyl chloride).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-[l,2,4]triazol-l-ylmethyl-phenylamine in step c.
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using isopropylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using benzylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using N- methylp ip erazine) .
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using 2,3- dihydro- 1 H-isoindole).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using C- Pyridin-3-yl-methylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using 2- Pyrrolidin- 1 -yl- ethylamine) .
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 3-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using 1- methyl-piperidin-4-ylamine).
  • This compound was prepared via Method D using N,N-dimethyl-4-benzamide boronic acid.
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-imidazol-l-ylmethyl-phenylamine in step c.
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using 1- methyl-piperidin-4-ylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using C- pyridin-2-yl-methylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 3-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using C- pyridin-2-yl-methylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 3-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using N*1 *,N*1 ⁇ dimethyl-propane- 1,3-diamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 3-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using 2- pyrrolidin- 1 -yl- ethylamine) .
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 3-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using C- (l-ethyl-piperidin-4-yl)-methylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then I (using 2-phenoxy- ethylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-amino-benzoic acid methyl ester in step c followed by Method H then Method I (using 2- pyridin-3 -yl- ethylamine) .
  • This compound was prepared via Method D using lH-pyrazole-4-boronic acid.
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 3 -amino-benzoic acid methyl ester in step c followed by Method H then Method I (using C- (2,5-dimethyl-2H-pyrazol-3-yl)-methylamine).
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 3 -amino-benzoic acid methyl ester in step c followed by Method H then Method I (using 2- pyridin-3 -yl- ethylamine) .
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 3 -amino-benzoic acid methyl ester in step c followed by Method H then Method I (using 3- (4-Methyl-piperazin- 1 -yl)-propylamine).
  • Step b
  • Step a [00391] This compound was prepared via Method A using 4-methoxyphenylboronic acid.
  • Step b
  • Step c [00393] This compound was prepared via Method H.
  • Step d [00394] This compound was prepared via Method I using methylamine.
  • Step b
  • This compound was prepared via Method C using 4-methoxyphenylboronic acid in step a and 4-amino-benzonitrile in step c.
  • This compound was prepared via Method C using 5-amino-pyridine-2-carboxylic acid amide prepared by Method N using ammonia.
  • Step b
  • This compound was prepared via Method C using 4-methoxyphenylboronic acid in step a then N-methyl-4-aniinopyrazole in step c.
  • This compound was prepared via Method C using 4-methoxyphenylboronic acid in step a then 6-amino-2,3-dihydro-isoindol-l-one in step c (prepared by Method L).
  • Step b
  • This compound was prepared via Method C 1 -methyl- lH-pyrazol-4-ylamine (prepared by Method M) and [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenoxy]-acetonitrile.
  • Step a [00415] This compound was prepared via Method B using 4-iodo-benzoic acid methyl ester.
  • Step b
  • Step b
  • This compound was prepared via Method B using N-cyclopropyl-2-fluoro-4-iodo- benzamide.
  • Step c [00421] This compound was prepared via Method A 4-methoxy-phenylboronic acid.
  • Step a [00425] This compound was prepared via Method A using 4-methoxy-phenylboronic acid.
  • Step b
  • Step c [00427] This compound was prepared via Method H.
  • Step d [00428] This compound was prepared via Method I using cyclopropylamine.
  • Step a [00429] A mixture of 4-amino-2-methyl-benzoic acid methyl ester (1 eq) and NaNCh in DMSO
  • Step b
  • This compound was prepared via Method C using N,N-dimethyl-4-benzamide boronic acid in step a then 5-amino-pyridine-2-carboxylic acid methylamide (prepared by Method N) in step c.
  • This compound was prepared via Method C using N,N-dimethyl-4-benzamide boronic acid in step a then 5-amino-pyridine-2-carboxylic acid methylamide (prepared by Method N) in step c.
  • step d 4-trifluoromethoxy-phenylboronic acid in step d.
  • Step a [00437] This compound was prepared via Method a using 4-methoxy-phenylboronic acid.
  • Step b
  • This compound was prepared via Method b using 2-Hydroxy-4-iodo-benzoic acid methyl ester.
  • Step c [00439] This compound was prepared via Method H.
  • Step d [00440] This compound was prepared via Method I using cyclopropylamine.
  • This compound was prepared via Method C using N,N-dimethyl-4-benzamide boronic acid in step a then 4-(4-isopropyl-piperazin-l-yl)-phenylamine in step c.
  • Compound 103 [00444] This compound was prepared via Method M to prepare 1-cyclopropylmethyl-lH- pyrazol-4-ylamine using bromomethyl-cyclopropane, or alternatively via Method C using 1- cyclopropylmethyl-lH-pyrazol-4-ylamine in step b then 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)-phenoxy]-acetonitrile in step c.
  • This compound was prepared via Method K using 4-Iodo-2-methoxy-benzoic acid methyl ester, cyclopropylamine and 4-(cyanomethyl)phenylboronic acid pinacol ester.
  • This compound was prepared via Method K using 4-Iodo-2-trifluoromethyl-benzoic acid methyl ester, cyclopropyl amine and 4-methoxy-phenylboronic acid.
  • This compound was prepared via Method K using 4-Iodo-2-trifluoromethyl-benzoic acid methyl ester, cyclopropyl amine and 4-isopropoxy-phenylboronic acid.
  • This compound was prepared via Method K using 4-Iodo-2-trifluoromethyl-benzoic acid methyl ester, cyclopropyl amine and 4-trifluoromethoxy-phenylboronic acid.
  • This compound was prepared via Method C using 1 -Methyl- lH-pyrazol-4-ylamine then N,N-dimethyl-4-benzamide boronic acid.
  • This compound was prepared via Method C l-cyclopropylmethyl-lH-pyrazol-4- ylamine (prepared by Method M) then N,N-dimethyl-4-benzamide boronic acid.
  • This compound was prepared via Method C using 4-methoxy-phenylboronic acid in step a then 4-(4-isopropyl-piperazin-l-yl)-phenylamine.
  • This compound was prepared via Method C: using N,N-dimethyl-4-benzamide boronic acid then 5-amino-2-benzyl-2,3-dihydro-isoindol-l-one prepared by Method L.
  • This compound was prepared via Method K using N,N-dimethyl-4-benzamide boronic acid.
  • This compound was prepared via Method A using 4-methoxy-phenylborinc acid followed by Method B using 4-Iodo-benzoic acid methyl ester then Method H and Method I using azetidine.
  • This compound was prepared via Method A using 4-methoxy-phenylborinc acid followed by Method B using 4-iodo-benzoic acid methyl ester then Method H and Method I using 3- difluoro-azetidine.
  • This compound was prepared via Method A using 4-carboxybenzene boronic acid.
  • Step b
  • This compound was prepared via Method A using 4-methoxy-phenylboronic acid followed by Method B using 4-iodo-benzoic acid methyl ester, Method H and Method I using cyclopropyl-amine.
  • This compound was prepared via Method T using N,N-dimethyl-4-benzamide boronic acid.
  • This compound was prepared via Method K using cyclopropylamine and A-
  • This compound was prepared via Method T using 3-methanesulfonyl-5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridine.
  • This compound was prepared via Method T using 2-dimethylamino-pyrimidine-5- boronic acid pinacol ester.
  • This compound was prepared via Method K' using 3-hydroxy-azetidine and l-amino-2- methyl-propan-2-ol.
  • This compound was prepared via Method C using l-pyridin-2-ylmethyl-lH-pyrazol-4- ylamine prepared by Method M.
  • This compound was prepared via Method C using lH-pyrazol-4-ylamine.
  • This compound was prepared via Method K using N,N-dimethyl-4-benzamide boronic acid.
  • This compound was prepared via Method C using (5-amino-pyridin-2-yl)-morpholin-4- yl-methanone prepared by Method N.
  • Step a [00487] CSCl 2 (1.2 eq) was added to a solution of 3-Bromo-pyridin-2-ylamine (l eq) in CH 2 Cl 2 .
  • the reactrion was allowed to stir at room temperature for 1 hr. Water and DCM were added. The organic phases was separated, dried over MgSO 4 and evaporated under reduced pressure. The expected product was obtained without further purification.
  • Step b
  • Step d [00490] Trifluoroacetic anhydride (1.2 eq.) was added to the previous compound (leq.) in THF at room temperature. After completion of the reaction, the solvent was evaporated. MeOH was added to the crude mixture, followed by K 2 CO 3 , and the reaction was stirred for 15 min at room temperature. The sovent is evaporated and the finale compound was purified by flash chromatography.
  • This compound was prepared via Method A using N,N-dimethyl-4-benzamide boronic acid.
  • This compound was prepared via Method C using l-isopropyl-lH-pyrazol-4-ylamine prepared by Method M.
  • This compound was prepared via Method A using N,N-dimethyl-4-benzamide boronic acid.
  • Step b [00494] This compound was prepared via Method B using 4-iodo-benzoic acid methyl ester.
  • Step c [00495] This compound was prepared via Method H.
  • Step d [00496] This compound was prepared via Method I using C-pyridin-2-yl-methylamine.
  • Compound 148 was prepared via Method I using C-pyridin-2-yl-methylamine.
  • This compound was prepared via Method C using N,N-dimethyl-4-benzamide boronic acid then 5-amino-2,3-dihydro-isoindol-l-one prepared by Method L.
  • This compound was prepared via Method C using N,N-dimethyl-4-benzamide boronic acid then 5-amino-2-methyl-2,3-dihydro-isoindol-l-one prepared by Method L.
  • This compound was prepared via Method T using l-Difluoromethyl-4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole prepared by the following Method:
  • ClCHF 2 was added to a solution of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- lH-pyrazole and K 2 CO 3 in DMF. The reaction was heated at 6O 0 C for 2h. The reaction mixture was allowed to cool to room temperature. EtOAc and water were added to the reaction. The organic phase was separated, dried over MgSO 4 , evaporated under reduced pressure. The crude was used without further purification.
  • Step b
  • Step c [00516] This compound was prepared via Method A using 4-Carboxyphenylboronic acid.
  • 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.
  • Step b [00521] This compound was prepared via Method B using 4-iodo-benzoic acid methyl ester.
  • Step c [00522] This compound was prepared via Method H.
  • Step d [00523] This compound was prepared via Method I using dimethylamine.

Abstract

Cette invention concerne de nouveaux composés [1,2,4]triazolo[1,5-a]pyridine représentés par la formule ci-après. Les composés peuvent être préparés en tant que compositions pharmaceutiques et peuvent être utilisés dans la prévention et le traitement de différentes affections chez le mammifère, y compris l’homme, notamment les maladies articulaires et l’inflammation.
PCT/EP2009/059595 2008-07-25 2009-07-24 [1, 2, 4]triazolo[1, 5-a]pyridines utilisées comme inhibiteurs de jak WO2010010184A1 (fr)

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