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WO2009078992A1 - Composés tricycliques linéaires utilisés comme inhibiteurs de la kinase p38 - Google Patents

Composés tricycliques linéaires utilisés comme inhibiteurs de la kinase p38 Download PDF

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Publication number
WO2009078992A1
WO2009078992A1 PCT/US2008/013785 US2008013785W WO2009078992A1 WO 2009078992 A1 WO2009078992 A1 WO 2009078992A1 US 2008013785 W US2008013785 W US 2008013785W WO 2009078992 A1 WO2009078992 A1 WO 2009078992A1
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oxo
compound
methyl
cyclopropyl
heteroatoms
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PCT/US2008/013785
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English (en)
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Fang-Tsao Hong
Andrew Tasker
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Amgen Inc.
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Publication of WO2009078992A1 publication Critical patent/WO2009078992A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates generally to the field of pharmaceutically active compounds, compositions and methods of use thereof, to treat various p38 kinase activity related disorders, including TNF- ⁇ , IL- l ⁇ , IL-6 and/or IL-8 mediated inflammatory diseases and other maladies, such as pain and diabetes.
  • Protein kinases represent a large family of enzymes, which catalyze the phosphorylation of target protein substrates.
  • the phosphorylation is a transfer reaction of a phosphate group from ATP to the protein substrate.
  • Common points of attachment for the phosphate group to the protein substrate include, for example, a tyrosine, serine or threonine residue.
  • Protein tyrosine kinases (PTKs) are enzymes, which catalyze the phosphorylation of specific tyrosine residues in cellular proteins.
  • kinases in the protein kinase family include, without limitation, abl, Akt, bcr-abl, BIk, Brk, Btk, c- kit, c-Met, c-src, c-frns, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDKlO, cRafl, CSFlR, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-IR, INS- R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PDC, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. Due to their activity
  • Protein kinases play a central role in the regulation and maintenance of a wide variety of cellular processes and cellular function. For example, kinase activity acts as molecular switches regulating inflammatory cytokine production via various pathways. Uncontrolled or excessive cytokine production has been observed in many disease states, and particularly in those related to inflammation.
  • Interleukin-1 IL-I
  • Tumor Necrosis Factor ⁇ also referred to herein as TNF- ⁇ or TNF
  • IL-I Interleukin-1
  • TNF- ⁇ Tumor Necrosis Factor ⁇
  • Elevated levels of TNF- ⁇ over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis (RA); osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease (IBD); adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type II diabetes; bone resorption diseases; graft vs.
  • RA rheumatoid arthritis
  • osteoarthritis rheumatoid spondylitis
  • gouty arthritis inflammatory bowel disease
  • IBD adult respiratory distress syndrome
  • psoriasis Crohn's disease
  • allergic rhinitis ulcerative colitis
  • anaphylaxis contact dermatitis
  • asthma muscle
  • HTV- 1, HTV-2, H ⁇ V-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-I, HSV-2), and herpes zoster are also exacerbated by TNF- ⁇ .
  • TNF- ⁇ has been reported to play a role in head trauma, stroke, and ischemia.
  • TNF- ⁇ levels increased in the contused hemisphere (Shohami et al., J. Cereb. Blood Flow Metab. 14:615 (1994)).
  • TNF- ⁇ mRNA of TNF- ⁇ increased in a rat model of ischemia wherein the middle cerebral artery was occluded.
  • TNF- ⁇ has been reported to result in significant neutrophil accumulation in capillaries and adherence in small blood vessels.
  • TNF- ⁇ promotes the infiltration of other cytokines (IL- l ⁇ , IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein, Stroke 25:1481 (1994)).
  • TNF- ⁇ appears to play a role in promoting certain viral life cycles and disease states associated therewith.
  • TNF- ⁇ secreted by monocytes induced elevated levels of HTV expression in a chronically infected T cell clone (Clouse et al., J. Immunol. 142:431 (1989)).
  • Lahdevirta et al., (Am. J. Med. 85:289 (1988)) discussed the role of TNF- ⁇ in the HTV associated states of cachexia and muscle degradation.
  • TNF- ⁇ is upstream in the cytokine cascade of inflammation.
  • elevated levels of TNF- ⁇ may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-I, IL-6, and IL-8.
  • Elevated levels of LL-I over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis; anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome.
  • Viruses sensitive to TNF- ⁇ inhibition e.g., HTV-I,
  • TNF- ⁇ has been reported to play a role in SAPHO, periodic fever, relapsing polychondritis, multicentric reticulohistiocytosis, macrophage activation syndrome, Hyper IgD syndrome, familial Hibernian fever, Pyoderma gangrenosum, Cochleovestibular disorders, Cicatrical pemphigoid, Herniated intervertebral disc diseases, amyloidosis, CINCA syndrome, myelodisplastic syndrome, alcoholic hepatitis, and endometriosis.
  • indications which have already been approved for treatment with a therapeutic agent which modulates TNF- ⁇ levels in the plasma, and/or other pro-inflammatory cytokines include without limitation, inflammatory bowel disease (IBD), psoriatis arthritis, ankylosing spondylitis and juvenile RA.
  • IBD inflammatory bowel disease
  • psoriatis arthritis psoriatis arthritis
  • ankylosing spondylitis juvenile RA.
  • TNF- ⁇ and IL-I appear to play a role in pancreatic ⁇ cell destruction and diabetes.
  • Pancreatic ⁇ cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic ⁇ cells often accompanies type I diabetes. Pancreatic ⁇ cell functional abnormalities may occur in patients with type II diabetes. Type II diabetes is characterized by a functional resistance to insulin. Further, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production.
  • Glucagon is a regulatory hormone that attenuates liver gluconeogenesis inhibition by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue.
  • glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety).
  • antagonizing the glucagon receptors it is thought that insulin responsiveness in the liver will improve, thereby decreasing gluconeogenesis and lowering the rate of hepatic glucose production.
  • IL-I is a more potent inducer of stromelysin than is TNF- ⁇ (Firestein, Am. J. Pathol.,
  • IL- 1 also appears to play a role in promoting certain viral life cycles. For example, cytokine-induced increase of HTV expression in a chronically infected macrophage line has been associated with a concomitant and selective increase in IL-I production (Folks et al., J. Immunol., 136:40 (1986)).
  • rheumatoid arthritis both IL-I and TNF- ⁇ induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints.
  • CIA collagen-induced arthritis
  • intra-articular administration of TNF- ⁇ either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11:253 (1992); and Cooper, Clin. Exp. Immunol., 898:244 (1992)).
  • IL-I and TNF-a have been implicated in pro-inflammatory mechanisms in many human diseases including inflammatory arthritis, inflammatory bowel disease sepsis syndrome and both acute and cheonis inflammation of many organs.
  • IL-6 also appears to play a role in, and therefore have applications to, proinflammatory and other malignant diseases.
  • deregulated levels of IL-6 are associated with various immunological diseases, such as RA, systemic juvenile idiopathic arthritis (sJIA), polyarticular type JIA, systemic lupus erythematosus (SLE), vasculitis syndrome, Castleman Disease and Crohn's Disease; transplantation conditions such as acute rejection and graft-versus-host disease (GVHD); respiratory diseases such as interstitial pneumonia and bronchial; asthma; bone diseases such as osteoporosis and Paget's disease, as well as various malignant disease including multiple myeloma, renal cancer, prostate cancer, cardiac mixoma, Kaposis sarcoma, Mesothelioma, Malignant lymphoma, lung cancer and gastric cancer. (Nishimoto and Kishimoto, Review, 2: 619- 625 (2006)). It follows that the reduction and/or regulation of DL-6 levels may be useful for
  • IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis.
  • IL-8 also has the ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
  • p38 ⁇ null mice are not viable, embryonic stem cells taken from these mice show a reduced capacity for EL-I induced production and activation of MAP kinase-activated protein kinase-2 (MAPKAP- 2), a downstream substrate of p38 ⁇ map kinase in response to stress (J. Exp. Med. 191, 859-869, 2000). More importantly, MAPKAP-2 deficient mice also show diminished production of IL-6 and TNF ((Kotlyarov, A.
  • MAPKAP kinase 2 is Essential for LPS-induced TNF- ⁇ Biosynthesis", Nature Cell Biology, I, 94-97, 1999). So p38 ⁇ /MAPKAP pathway is crutial to inflammatory cytokine production and signaling. Furthermore, p38 ⁇ phosphorylates a variety of transcriptional factors, some of which are responsible for transcription expression of genes encoding inflammatory cytokines (Kumar, S. et al, "p38 MAP kinases: key signaling molecules as Therapeutic targets for Inflammatory Disease", Nature Review Drug Discovery, 2, 717-726, 2003).
  • RA Rheumatoid arthritis
  • PGE2 prostaglandins E2
  • small molecule SB-203580 a traryl imidazole, was developed as a pharmacological tool to show a correlation between the binding of the compound inside the cell to inhibit the natural function of p38 ⁇ and the inhibition of cell cytokine synthesis (Nature 372, 739-746, 1994).
  • TNF- ⁇ Several approaches have been taken to block the effect of TNF- ⁇ .
  • the present invention provides a new class of compounds useful in the prophylaxis and treatment of p38 activity related diseases and disorders, including TNF- ⁇ , IL- l ⁇ , IL-6 and/or IL-8 mediated diseases and other conditions, such as pain. More particularly, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. To this end, the invention also provides pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of TNF- ⁇ , IL-I ⁇ , IL-6 and/or EL-8 mediated diseases, such as inflammatory pain, by administering the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
  • the compounds including stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, are defined by general Formula I:
  • A is a fully or partially saturated 5- or 6-membered heterocyclic ring including one carbonyl group, optionally including 1-2 additional heteroatoms selected from O, S and N and optionally fused to a benzene ring; each of B 1 and B 2 , independently, is CR 2 or N;
  • C 1 is CR 3 or N and each of C 2 , C 3 and C 4 , independently, is CR 4 or N, provided no more than two of C 1 , C 2 , C 3 and C 4 is N;
  • R 1 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, C 1-10 -alkyl, C 2 - I0 - alkenyl, C 2-10 -alkynyl, C 3-) o-cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 - dialkylamino-, C, -10 -alkoxyl, C 10 -thioalkoxyl, NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 , OC(O)R 7 , COOR 7 , OC(O)R 8 , COOR 8 , C(O)NR 7 R 7 , C(S)NR 7 R 7 , NR 7 C(O)R 7 , NR 7 C(S)R 7 , NR 7 C(O)
  • R 2 , R 3 and R 4 independently, is H, halo, haloalkyl, NO 2 , CN, OR 7 , SR 7 , NR 7 R 7 , NR 7 R 8 , C(O)R 7 , C 1-10 -alkyl, C 2-10 -alkenyl or C 2-10 -alkynyl, each of the C,.i O -alkyl, C 2-10 -alkenyl and C 2-10 -alkynyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents of R 8 or R 9 ;
  • R 5 is a C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl or a partially or fully saturated or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said ring system is substituted independently with one or more substituents of R 9 , NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 , C(O)R 7 , C(S)R 7 , C(NCN)R 7 , C(O)R 8 , C(NCN)R 8 , OC(O)R 7 , COOR 7 ,
  • R 8 is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein each ring of said ring system is optionally substituted independently with 1-3 substituents of R 9 , oxo, NR 9 R 9 , OR 9 , SR 9 , C(O)R 9 , COOR 9 , C(O)NR 9 R 9 , NR 9 C(O)R 9 , NR 9 C(O)NR 9 R 9 , OC(O)NR 9 R 9 , S(O) 2 R 9 , S(O) 2 NR 9 R 9 , NR 9 S(O) 2 R 9 , or a partially or fully saturated or unsatur
  • R 9 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, C 1-10 -alkyl, C 2-10 - alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 - dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alky
  • )0 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert- butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; m is O, 1, 2 or 3; and n is O, 1 or 2.
  • the invention provides compounds of Formula I wherein A is a fully saturated 5- or 6-membered heterocyclic ring including one carbonyl group, optionally including 1-2 additional heteroatoms selected from O, S and N and optionally fused to a benzene ring, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein A is 2-oxo-oxazolidinyl, 2-oxo-imidazolidinyl, 2-oxo-1-piperizinyl, 2-oxo-1-pyrrolidinyl or 2-oxo-1,3-benzoxazolinyl, each of which is optionally substituted as defined in the embodiment above, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein B 1 is CR 2 and B 2 is N, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein B 1 is N and B 2 is CR 2 , in conjunction with any of the above or below embodiments. In another embodiment, the invention provides compounds of Formula I wherein each of B 1 and B 2 , independently, is CR 2 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein each of B 1 and B 2 , independently, is N, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein C 1 is CR 3 and each of C 2 , C 3 and C 4 , independently, is CR 4 or N, provided no more than two of C 1 , C 2 , C 3 and C 4 is N; in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein
  • C 1 is N and each of C 2 , C 3 and C 4 , independently, is CR 4 or N, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein C 1 is CR 3 and R3 is C 1-10 -alkyl, halo, OH, CN or OCi -10 -alkyl and each of C 2 , C 3 and C 4 , independently, is CH, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein C 1 is CR 3 and R3 is methyl, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein C 1 is CR 3 and R 3 is methyl and each of C 2 , C 3 and C 4 , independently, is CH, conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein R 1 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 - alkynyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 - alkoxyl, C 1-10 -thioalkoxyl, each of which is optionally substituted independently with one or more substituents of R 7 , R 8 or R 9 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein R 1 is NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 , OC(O)R 7 , COOR 7 , OC(O)R 8 , COOR 8 ,
  • the invention provides compounds of Formula I wherein R 1 is a 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein said ring system is optionally substituted independently with one or more substituents of R 7 , R 8 or R 9 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein R 1 is a ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyrany
  • R 2 is H, halo, haloalkyl, NO 2 , CN, OR 7 , SR 7 , NR 7 R 7 , NR 7 R 8 , C(O)R 7 , C 1-10 -alkyl, C 2-10 - alkenyl or C 2-10 -alkynyl, each of the C 1-10 -alkyl, C 2-10 -alkenyl and C 2-10 -alkynyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents of R 8 or R 9 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein R 2 is H or C 1-10 -alkyl, in conjunction with any of the above or below embodiments. In another embodiment, the invention provides compounds of Formula I wherein
  • R 3 is H or C 1-10 -alkyl, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein R 3 is methyl, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein R 4 is H, halo, haloalkyl, NO 2 , CN, OR 7 , SR 7 , NR 7 R 7 , NR 7 R 8 , C(O)R 7 , C,.i O -alkyl, C 2- , 0 - alkenyl or C 2-10 -alkynyl, each of the C 1-10 -alkyl, C 2-10 -alkenyl and C 2-10 -alkynyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents of R 8 or R 9 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein each R 4 is, independently, H or C 1-10 -alkyl, in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein R 5 is C 1-10 -alkyl, C 2-10 -alkenyl or C 2-10 -alkynyl, each of which is optionally substituted independently with one or more substituents of R 9 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein R 5 is a partially or fully saturated or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said ring system is substituted independently with one or more substituents of R 9 , NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 , C(O)R 7 , C(S)R 7 , C(NCN)R 7 , C(O)R 8 , C(S)R 8 , C(NCN)R 8 , OC(O)R 7 , COOR 7 , OC(O)R 8 , COOR 8 , C(O)NR
  • the invention provides compounds of Formula I wherein R 5 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolidinyl, tetrahydrfuranyl, piperidinyl, piperizinyl or morpholinyl, each of which is optionally substituted with 1-3 substituents of R 9 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I wherein
  • B 1 is N and B 2 is CH;
  • C 1 is CR 3 and each of C 2 , C 3 and C 4 , independently, is CR 4 ;
  • R 5 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrrolidinyl, tetrahydrfuranyl, piperidinyl, piperizinyl or morpholinyl, each of which is optionally substituted with 1-3 substituents of R 9 , in conjunction with any of the above or below embodiments.
  • the invention provides compounds of Formula I-A
  • A is a fully or partially saturated 5- or 6-membered heterocyclic ring including one carbonyl group and optionally including 1 -2 additional heteroatoms selected from O, S and N; each of B 1 and B 2 , independently, is CR 2 or N; C 1 is CR 3 and each of C 2 , C 3 and C 4 , independently, is CR 4 or N, provided no more than two of C 1 , C 2 , C 3 and C 4 is N;
  • R 1 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, d -10 -alkyl, C 2-10 - alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 - dialkylamino-, C 1-]0 -alkoxyl, C 1-10 -thioalkoxyl, NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 , OC(O)R 7 , COOR 7 , OC(O)R 8 , COOR 8 , C(O)NR 7 R 7 , C(S)NR 7 R 7 , NR 7 C(O)R 7 , NR 7 C(S)R 7 , NR 7 C(O)NR 7
  • NR 7 S(O) 2 NR 7 R 8 NR 7 S(O) 2 R 8 or a 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein said C ⁇ io-alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 - cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or ring system is optionally substituted independently with one or more substituents of R 7 , R 8 Or R 9 ; each of R 2 , R 3 and R 4 , independently, is H, halo, haloalkyl
  • R 5 is a C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl or a partially or fully saturated or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said ring system is substituted independently with one or more substituents of R 9 , NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 , C(O)R 7 , C(S)R 7 , C(NCN)R 7 , C(O)R 8 , C(NCN)R 8 , OC(O)R 7 , COOR 7 ,
  • R 8 is a partially or fully saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein each ring of said ring system is optionally substituted independently with 1 -3 substituents of R 9 , oxo, NR 9 R 9 , OR 9 , SR 9 , C(O)R 9 , COOR 9 , C(O)NR 9 R 9 , NR 9 C(O)R 9 , NR 9 C(O)NR 9 R 9 , OC(O)NR 9 R 9 , S(O) 2 R 9 , S(O) 2 NR 9 R 9 , NR 9 S(O) 2 R 9 , or a partially or fully saturated or uns
  • R 9 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, C 1-10 -alkyl, C 2-10 - alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 - dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alky
  • the invention provides compounds of Formula 1-B
  • A is a fully or partially saturated 5- or 6-membered heterocyclic ring including one carbonyl group and optionally including 1-2 additional heteroatoms selected from O, S and N; each of B 1 and B 2 , independently, is CR 2 or N, provided that no more than one of B 1 and B 2 , independently, is N;
  • R 1 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, C 1-10 -alkyl, C 2-10 - alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 - dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl, NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 ,
  • each R 2 independently, is H, halo, haloalkyl, NO 2 , CN, OR 7 , SR 7 , NR 7 R 7 , NR 7 R 8 , C(O)R 7 , Ci-6-alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, each of the C 1-6 -alkyl, C 2-6 -alkenyl and C 2 - 6 -alkynyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents of R 8 or R 9 ;
  • R 3 is H, F, Cl, CH 3
  • R 7 is H, C 1-10 -alkyl, C 2-10 -alkenyl or C 2-10 -alkynyl, each of the Cj -10 -alkyl, C 2-10 - alkenyl and C 2-10 -alkynyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents OfNR 8 R 9 , NR 9 R 9 , OR 8 , SR 8 , OR 9 , SR 9 , C(O)R 8 , OC(O)R 8 , COOR 8 , C(O)R 9 , OC(O)R 9 , COOR 9 , C(O)NR 8 R 9 , C(O)NR 9 R 9 , NR 9 C(O)R 8 , NR 9 C(O)R 9 , NR 9 C(O)NR 8 R 9 , NR 9 C(O)NR 8 R 9 , NR 9 C(O)NR 8 R 9 ,
  • R 8 is a partially or fully saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein each ring of said ring system is optionally substituted independently with 1-3 substituents of R 9 , oxo, NR 9 R 9 , OR 9 , SR 9 , C(O)R 9 , COOR 9 , C(O)NR 9 R 9 , NR 9 C(O)R 9 , NR 9 C(O)NR 9 R 9 , OC(O)NR 9 R 9 , S(O) 2 R 9 , S(O) 2 NR 9 R 9 , NR 9 S(O) 2 R 9 , or a partially or fully saturated or unsatur
  • R 9 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, C 1-10 -alkyl, C 2-10 - alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 - dialkylamino-, Q.io-alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alky
  • the compounds of Formula I-A fall within the scope of the compounds of Formula I, i.e., Formula I-A is a sub-formula of Formula I. Likewise, the invention includes all sub-formulas of Formula I.
  • the invention provides the specific compounds described in the examples and tables hereinbelow.
  • C a .palkyl when used either alone or within other terms such as “haloalkyl” and “alkylamino”, embraces linear or branched radicals having ⁇ to ⁇ number of carbon atoms (such as Ci-Ci 0 ).
  • alkyl radicals include methyl (also referred to herein as CH 3 ), ethyl (also referred to herein as C 2 H 5 ), n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like.
  • alkylenyl embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.
  • alkenyl when used alone or in combination, embraces linear or branched radicals having at least one carbon-carbon double bond in a moiety having between two and ten carbon atoms. Examples of alkenyl radicals include, without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations, as appreciated by those of ordinary skill in the art.
  • alkynyl when used alone or in combination, denotes linear or branched radicals having at least one carbon-carbon triple bond and having two to ten carbon atoms.
  • alkynyl radicals include, without limitation, ethynyl, propynyl (propargyl), butynyl, and the like.
  • alkoxy or "alkoxyl”, when used alone or in combination, embraces linear or branched oxygen-containing radicals each having alkyl portions of one or more carbon atoms.
  • alkoxy radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
  • halo atoms such as fluoro, chloro or bromo
  • aryl when used alone or in combination, means a carbocyclic aromatic moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner. Every ring of an “aryl” ring system need not be aromatic, and the ring(s) fused to the aromatic ring may be partially or fully unsaturated and include one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl, benzodioxazinyl, and the like.
  • the "aryl” group may be substituted, such as with 1 to 5 substituents including lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the like. Phenyl substituted with -0-CH 2 -O- or -0-CH 2 -CH 2 -O- forms an aryl benzodioxolyl substituent.
  • cycloalkyl when used herein alone or in combination, means a partially or fully saturated ring moiety containing one ("monocyclic"), two (“bicyclic") or even three (“tricyclic") rings wherein such rings may be attached together in a fused manner and formed from carbon atoms.
  • saturated carbocyclic radicals include saturated 3 to 6-membered monocyclic groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • ring and “ring system” refer to a ring comprising the delineated number of atoms, the atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur.
  • nonaromatic ring or ring system refers to the fact that at least one, but not necessarily all, rings in a bicyclic or tricyclic ring system is nonaromatic.
  • cycloalkenyl when used alone or in combination, means a partially or fully saturated cycloalkyl containing one, two or even three rings in a structure having at least one carbon-carbon double bond in the structure.
  • cycloalkenyl groups include C 3 -C 6 rings, such as compounds including, without limitation, cyclopropene, cyclobutene, cyclopentene and cyclohexene.
  • the term also includes carbocyclic groups having two or more carbon-carbon double bonds such as "cycloalkyldienyl” compounds.
  • cycloalkyldienyl groups include, without limitation, cyclopentadiene and cycloheptadiene.
  • halo when used alone or in combination, means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl when used alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • this term includes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as a perhaloalkyl.
  • a monohaloalkyl radical for example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difiuoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perfluoroalkyl refers to alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • heteroaryl means a fully unsaturated (aromatic) ring moiety formed from carbon atoms and having one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • the ring moiety or ring system may contain one ("monocyclic"), two ("bicyclic") or even three (“tricyclic") rings wherein such rings are attached together in a fused manner. Every ring of a “heteroaryl” ring system need not be aromatic, and the ring(s) fused thereto (to the heteroaromatic ring) may be partially or fully saturated and optionally include one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl does not include rings having ring members of -O-O-,-O-S- or -S-S-.
  • unsaturated heteroaryl radicals include unsaturated 5- to 6- membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1, 2,3 -triazolyl, 2H-1,2,3- triazolyl] and tetrazole; unsaturated 7- to 10- membered heterobicyclyl groups containing 1 to 4 nitrogen atoms, including for example, quinolinyl, isoquinolinyl, quinazolinyl, isoquina
  • heterocyclic when used alone or in combination, means a partially or fully saturated ring moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner, formed from carbon atoms and including one or more heteroatoms selected from N, O or S.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • morpholinyl saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
  • heterocycle also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5- b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • heterocyclic radicals include five to ten membered fused or unfused radicals.
  • Examples of partially saturated and saturated heterocyclyl include, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1 ,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-l ,2,4- triazolo[3,4-a]is
  • alkylamino includes "N-alkylamino” where amino radicals are independently substituted with one alkyl radical.
  • alkylamino radicals include N-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and the like.
  • dialkylamino includes "N, N-dialkylamino” where amino radicals are independently substituted with two alkyl radicals. Examples of dialkylamino radicals include N,N-dimethylamino, N,N-diethylamino, and the like.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
  • An example of “alkylthio” is methylthio, (CH 3 S-).
  • pharmaceutically-acceptable when used with reference to a compound of Formula I, is intended to refer to a form of the compound that is safe for administration.
  • a salt form, a solvate, a hydrate or derivative form of a compound of Formula I which has been approved for mammalian use, via oral ingestion or other routes of administration, by a governing body or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.
  • FDA Food and Drug Administration
  • salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • salts may be formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc.
  • the nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include, without limitation, formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including, without limitation, primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, disopropylethylamine and trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formula I.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of salts can be found in Berge et al., J. Pharm. Sci., 66, 1 (1977).
  • a phosphate salt of a compound of the invention may be made by combining the desired compound free base in a desired solvent, or combination of solvents, with phosphoric acid in a desired stoichiometric amount, at a desired temperature, typically under heat (depending upon the boiling point of the solvent).
  • the salt can be precipitated upon cooling (slow or fast) and may crystallize (i.e., if crystalline in nature), as appreciated by those of ordinary skill in the art.
  • hemi-, mono-, di, tri- and poly-salt forms of the compounds of the present invention are also contemplated herein.
  • hemi-, mono-, di, tri- and poly- hydrated forms of the compounds, salts and derivatives thereof are also contemplated herein.
  • prodrug denotes a compound which upon administration to a subject or patient is capable of providing (directly or indirectly) a compound of this invention.
  • examples of prodrugs would include esterified or hydroxylated compounds where the ester or hydroxyl groups would cleave in vivo, such as in the gut, to produce a compound according to Formula I.
  • a "pharmaceutically- acceptable prodrug” as used herein denotes a prodrug which is pharmaceutically acceptable.
  • Pharmaceutically acceptable modifications to the compounds of Formula I are readily appreciated by those of ordinary skill in the art.
  • the compound(s) of Formula I may be used to treat a subject by administering the compound(s) as a pharmaceutical composition.
  • the compound(s) can be combined with one or more carriers, diluents or adjuvants to form a suitable composition, which is described in more detail herein.
  • excipient denotes any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration purposes.
  • API active pharmaceutical ingredient
  • treat refers to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy.
  • Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals.
  • ⁇ dosage amount is intended to quantify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. While it may be possible to administer a compound of the invention alone, in the methods described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition.
  • a pharmaceutical composition comprising a compound of this invention in combination with a pharmaceutically acceptable excipient, which includes diluents, carriers and the like as described herein.
  • a pharmaceutical composition of the invention may comprise an effective amount of a compound of the invention or an "effective dosage amount" of a compound of the invention.
  • An effective dosage amount of a compound of the invention includes an amount less than, equal to or greater than an effective amount of the compound; for example, a pharmaceutical composition in which two or more unit dosages, such as in tablets, capsules and the like, are required to administer an effective amount of the compound, or alternatively, a multidose pharmaceutical composition, such as powders, liquids and the like, in which an effective amount of the compound is administered by administering a portion of the composition.
  • a pharmaceutical composition in which two or more unit dosages, such as in tablets, capsules and the like, are required to administer an effective amount of the compound may be administered in less than an effective amount for one or more periods of time, for example to ascertain the effective dose for an individual subject, to desensitize an individual subject to potential side effects, to permit effective dosing readjustment or depletion of one or more other therapeutics administered to an individual subject, and/or the like.
  • LG generally refer to groups that are displaceable by a nucleophile.
  • Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH 3 ), N-hydroxsuccinimide, N- hydroxybenzotriazole, and the like.
  • Nucleophiles are species that are capable of attacking a molecule at the point of attachment of the leaving group causing displacement of the leaving group. Nucleophiles are known in the art. Examples of nucleophilic groups include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like.
  • the present invention further comprises procedures for the preparation of compounds of Formula I.
  • the compounds of Formula I and I-A can be synthesized according to the procedures described in the following Schemes 1-4, wherein the substituents are as defined for Formula I, above, except where further noted.
  • the synthetic methods described below are merely exemplary, and the compounds of the invention may also be synthesized by alternate routes as appreciated by persons of ordinary skill in the art.
  • a compound 3 of Formula I can be prepared according to the method generally described in Scheme 1. As shown, an bromo-aryl or bromo-heteroaryl (wherein either or both of B 1 and B 2 are N) boronic acid 1 can be reacted in a Suzuki reaction or under
  • Suzuki-like reaction conditions as described hereinbelow, with a suitable partner such as compound 2, wherein LG is a suitable leaving group for a Suzuki or Suzuki-like reaction, such as an Iodide for example, to afford the corresponding coupled adduct 3.
  • a suitable partner such as compound 2, wherein LG is a suitable leaving group for a Suzuki or Suzuki-like reaction, such as an Iodide for example, to afford the corresponding coupled adduct 3.
  • Intermediate 2 may be purchased commercially or prepared by conventional methods. For example, where Ll is an amide bond, methods are known to connect a benzoic acid material with a primary or secondary amine, via a reactive, activated carboxylic acid intermediate, formed from treatment of the acid with an activating reagent such as HOBT, HATU, DCC, EDCI, etc. Methods for prearing intermediates 2 are further described in scheme 3 below.
  • Suzuki, Heck and similar reactions run in the presence of a suitable base and metal, such as Pd, are well known in the art.
  • the Suzuki method is a reaction using a borane reagent, such as a dioxaborolane intermediate 1, and a suitable leaving group (LG) containing reagent, such as the bromo- or iodo-benzene 2.
  • a suitable leaving group (LG) containing reagent such as the bromo- or iodo-benzene 2.
  • Suzuki reactions also utilize a palladium catalyst.
  • Suitable palladium catalysts include Pd(PPh 3 ) 4 , Pd(OAc) 2 or Pd(dppf)Cl 2 .
  • the halide may be an iodide, a bromide or even a chloride (chloro-pyridyl or chloro- picolinyl B rings undergo suzuki reactions in the presence OfPd(OAc) 2 ).
  • Other LGs are also suitable.
  • Suzuki couplings are known to occur with a sulfonate, such as trifiuoromethanesulfonate, as the leaving group.
  • the Suzuki reaction conditions may vary.
  • Suzuki reactions are generally run in the presence of a suitable base such as a carbonate base, bicarbonate or an acetate base, in a suitable solvent such as toluene, acetonitrile, DMF or an aqueous-organic solvent combination or a biphasic system of solvents. Further, the reaction may require heat depending upon the particular substrate 2 and/or boronic acid 1, as appreciated by those skilled in the art.
  • a suitable base such as a carbonate base, bicarbonate or an acetate base
  • a suitable solvent such as toluene, acetonitrile, DMF or an aqueous-organic solvent combination or a biphasic system of solvents.
  • the boronic acid 1 may be a non cyclic boronate (not shown). In this fashion, desired aromatic R 2 groups can be installed as the core is being constructed.
  • the desired bromo boronic acid compounds 1 may generally be made by conventional methods.
  • a compound 5 of Formula I (and I- A) can be prepared according to the method generally described in Scheme 2. As shown, bromide 2 can be treated with a suitable palladium reagent, such as Pd 2 dba 3 , to form the palladium insertion intermediate which can then be reacted with the desired cyclic amine, or amide, to afford the desired product 5.
  • Product 5 may be further functionalized as desrired (not shown) by adding R 1 groups as desired, using conventional methods.
  • (R) n refers to n number of R 7 , R 8 and R 9 substitutions wherein n is an integer from 0-9
  • X refers generally to a "leaving group” such as a halide (bromine, chlorine, iodine or fluorine), alkylsulfonate and other known groups (also see definitions herein);
  • Nu- refers generally to a nucleophilic species such as a primary or secondary amine, an oxygen, a sulfur or a anionic carbon species - examples of nucleophiles include, without limitation, amines, hydroxides, alkoxides and the like; E + refers
  • the coupling of ring C and R 5 can be brought about using various conventional methods to link ring C and R 5 together.
  • an amide or a sulfonamide linkage as shown in sub-schemes 2 and 4, and 7 and 9 where the Nu- is an amine, respectively, can be made utilizing an amine on either the C or R 5 and an acid chloride or sulfonyl chloride on the other of either R 5 or the C ring.
  • the reaction proceeds generally in the presence of a suitable solvent and/or base.
  • Suitable solvents include, without limitation, generally non-nucleophilic, anhydrous solvents such as toluene, CH 2 Cl 2 , THF, DMF, DMSO, N,N-dimethylacetamide and the like, including solvent combinations thereof.
  • the solvent may range in polarity, as appreciated by those skilled in the art.
  • Suitable bases include, for example, tertiary amine bases such as DIEA, TEA, carbonate bases such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , hydrides such as NaH, KH, borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH 3 , and the like.
  • the base itself may also serve as a solvent.
  • the reaction may optionally be run neat, i.e., without any base and/or solvent.
  • These coupling reactions are generally fast and conversion occurs typically in ambient conditions. However, depending upon the particular substrate, such reactions may require heat, as appreciated by those skilled in the art.
  • carbamates as illustrated in sub-schemes 5 and 1 where Nu- is an amine anhydrides as illustrated in sub-scheme 1 where Nu- is an oxygen
  • reverse amides as generally illustrated in sub-scheme 8 where Nu- is an amine and E+ is an acid chloride ureas as illustrated in sub-scheme 3, thioamides and thioureas where the respective carbonyl oxygen is a sulfur
  • thiocarbamates where the respective carbonyl oxygen and/or carbamate oxygen is a sulfur, and the like. While the above methods are so described, they are not exhaustive, and other methods for linking ring C and R 5 together may be utilized as appreciated by those skilled in the art.
  • sub-schemes 1-9 are illustrated as having the nucleophilic and electrophilic coupling groups, such as the amino group and acid chloride groups illustrated in sub-scheme 2, directly attached to the substrate, either R 5 or the C ring, in question, the invention is not so limited. It is contemplated herein that these nucleophilic and/or electrophilic coupling groups may be tethered from their respective ring. For example, the amine group on the C ring, and/or the acid halide group on the R 5 group, as illustrated in sub-scheme 2, may be removed from direct attachment to the ring by a one or more atom spacer, such as by a methylene, ethylene spacer or the like.
  • L may be any linker generally defined in Formula I, and particularly, it includes, without limitation, an amide, a urea, a thiourea, a thioamide, a carbamate, an anhydride, a sulfonamide and the like, allowing for spacer atoms either between ring C and L and/or between R 5 and L, as described in Scheme 3 above.
  • the amine may be protected, such as with BOC-ON, while further substituents are coupled to the C ring, prior to or after coupling the C ring to an R 5 group to form the desired linker group.
  • LC-MS Method Samples were run on an Agilent model- 1100 LC-MSD system with an Agilent Technologies XDB-C 8 (3.5 ⁇ ) reverse phase column (4.6 x 75 mm) at 30 °C. The flow rate was constant and ranged from about 0.75 mL/min to about 1.0 mL/min.
  • the mobile phase used a mixture of solvent A (H 2 CVO.1% HOAc) and solvent B (ACN/0.1% HOAc) with a 9 min time period for a gradient from 10% to 90% solvent B. The gradient was followed by a 0.5 min period to return to 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) of the column.
  • solvent A H 2 CVO.1% HOAc
  • solvent B ACN/0.1% HOAc
  • Step B N-cvclopropyl-4-methyl-3-(5-(2-oxopyrrolidin- 1 -yl)pyridin-2-yl)benzamide
  • 3-(5-bromopyridin-2-yl)-N-cyclopropyl-4-methylbenzamide 62 mg, 0.188 mmol
  • Pd 2 dba 3 3.4 mg, 2% eq
  • xantphos 7.
  • Cs 2 CO 3 91 mg, 0.282 mmol
  • Step A l-(4-Methoxybenzyl)imidazolidin-2-one
  • N-Cyclopropyl-4-methyl-3-(5-(2-oxoiinidazoIidin-1-yl)pyridin-2-yl)benza ⁇ iide A mixture of 3-(5-(3-benzyl-2-oxoimidazolidin-1-yl)pyridin-2-yl)-N-cyclopropyl-4- methylbenzamide (75 mg, 0.165 mmol) and TFA (4.0 mL) was heated at 75 °C for 4h. After cooling, the resulting mixture was concentrated, and the residue was quenched with ⁇ aHCO 3 (aq) solution and the separated aqueous layer was extracted with DCM (10 mL x 3).
  • Step A 3-(6-bromopyridin-3-yl)benzordloxazol-2(3H)-one
  • a suspension of 2-bromo-pyridine-5-boronic acid (0.51 g, 2.5 mmol) and 2- benzoxaolinone (0.4 g, 1.2 mmol) in DCM (3.0 mL) was added 4 A° molecular sieves (1.0 g), Cu(OAc) 2 (45 mg, 0.25 mmol) and TEA (0.84 mL).
  • the overall dark brown mixture was stirred for 24h and the resulting slurry was charged onto silica gel, which was eluted with DCM.
  • Step B Benzyl 4-(3-(5-bromopyridin-2-yl)-2-oxoirnidazolidin-1-yl)piperidine-1- carboxylate
  • benzyl 4-(2-oxoimidazolidin-1-yl)piperidine-1- carboxylate (0.22 g, 0.73 mmol)
  • copper(I) iodide 0.0069 g, 0.036 mmol
  • 2,5- dibromopyridine (0.22 g, 0.94 mmol)
  • potassium carbonate (0.20 g, 1.5 mmol) at RT and then stirred, followed by addition of 1,4-dioxane (1.9 g, 22 mmol) and rac-trans- N/,N2-dimethylcyclohexane-1,2-diamine (0.011 mL, 0.073 mmol).
  • reaction mixture was sealed and heated at 160°C for 20 min under microwave irradiation. After cooling, the reaction mixture was filtrated through Celite and washed with EtOAc (3 x 5 mL). The overall organic phases were concentrated to give a brown oily residue, which was purified using flash column chromatography (1:5 to 1:2 EA/hexanes) to give the title compound as a white solid. MS m/e 460 (M+H) + .
  • Step C Benzyl 4-(3-(5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)pyridin-2-yl)-2- oxoimidazolidin-1-yl)piperidine-1-carboxylate
  • N-cyclopropyl-4-methyl-3-(6-(2-oxo-3-(piperidin-4- yl)imidazolidin-1-yl)pyridin-3-yl)benzamide 0.050 g, 0.1 mmol
  • methanol 4.00 mL, 125 mmol
  • Step B Benzyl 4-(3-(5-(5-(cvclopropylcarbamoyl)-2-methylphenyl)pyridin-2-yl)-2- oxoimidazolidin- 1 -yl)piperidine- 1 -carboxylate
  • Step A Benzyl 4-((2-oxoimidazolidin-1-yl)methyl)piperidine-1-carboxylate
  • the title compound was synthesized by a method analogous to that described in step A of Example 11, using potassium tert-butoxide in the second step. The crude product was used directly without further purification.
  • Step B Benzyl 4-(T3-( ' 5-bromopyridin-2-yl)-2-oxoimidazolidin-1-yl)methyl)piperidine-1- carboxvlate
  • the title compound was synthesized as a white solid by a method analogous to that described in step B of Example 11, using benzyl 4-((2-oxoimidazolidin-1- yl)methyl)piperidine-1-carboxylate with 2,5-dibromopyridine.
  • Step C Benzyl 4-(O-(5-(5-(cvclopropylcarbamoyl)-2-methylphenyl)pyridin-2-yl)-2- oxoimidazolidin- 1 -yl)methvPpiperidine- 1 -carboxylate
  • Step B Benzyl 4-(5-(5-(cvclopropylcarbamoyl)-2-methylphenyl)pyridin-2-yl)-3- oxopiperazine- 1 -carboxylate
  • Step B l-(3-Methoxybenzyl * )-3-(5-bromopyridin-2-yl)imidazolidin-2-one
  • the title compound was obtained as a pale yellow solid from l-(3- methoxybenzyl)imidazolidin-2-one and 2,5-dibromopyridine according to a method analogous to that described in Step B of Example 11.
  • MS m/e 363 (M+H) + MS m/e 363 (M+H) + .
  • Step C 3 -(6-C3 -(3 -Methoxybenzyl)-2-oxoimidazolidin- 1 -yl)pyridin-3 -yl)-N-cvclopropyl-
  • Step B 1 -(2-Methoxybenzyl)-3-(5-bromopyridin-2-yl)imidazolidin-2-one
  • the target product was synthesized as a white by a method analogous to that described in Step C of Example 1 1, using l-(2-methoxybenzyl)-3-(5-bromopyridin-2-yl)imidazolidin- 2-one with N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)benzamide. MS m/e 457 (M+H) + .
  • Step B l-(5-Bromopvridin-2-yl)-3-tosvlimidazolidin-2-one
  • the title compound was synthesized as a white solid by a method analogous to that described in Step B of Example 12, using 2,5-dibromopyrimidine and 1- tosylimidazolidin-2-one.
  • Step C N-Cvclopropy1-4-methyl-3-(6-(2-oxo-3-tosylimidazolidin-1-yl)pyridin-3- yPbenzamide
  • protecting groups may be used. Particularly, if one or more functional groups, for example carboxy, hydroxy, amino, or mercapto groups, are or need to be protected in preparing the compounds of the invention, because they are not intended to take part in a specific reaction or chemical transformation, various known conventional protecting groups may be used. For example, protecting groups typically utilized in the synthesis of natural and synthetic compounds, including peptides, nucleic acids, derivatives thereof and sugars, having multiple reactive centers, chiral centers and other sites potentially susceptible to the reaction reagents and/or conditions, may be used.
  • the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterif ⁇ cations, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they readily lend themselves, i.e. without undesired secondary reactions, to removal, typically accomplished by solvolysis, reduction, photolysis or other methods of removal such as by enzyme activity, under conditions analogous to physiological conditions. It should also be appreciated that the protecting groups should not be present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions described herein.
  • Salts of a compound of the invention having a salt-forming group may be prepared in a conventional manner or manner known to persons skilled in the art.
  • acid addition salts of compounds of the invention may be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • a salt with two acid molecules (for example a dihalogenide) may also be converted into a salt with one acid molecule per compound (for example a monohalogenide); this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from 50°C to 170°C, one molecule of the acid being expelled per molecule of the compound.
  • Acid salts can usually be converted to free-base compounds, e.g. by treating the salt with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • suitable basic agents for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • the ability of the solvent to allow and/or influence the progress or rate of the reaction is generally dependant on the type and properties of the solvent(s), the reaction conditions including temperature, pressure, atmospheric conditions such as in an inert atmosphere under argon or nitrogen, and concentration, and of the reactants themselves.
  • Suitable solvents for conducting reactions to synthesize compounds of the invention include, without limitation, water; esters, including lower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphatic ethers, e.g., Et 2 O and ethylene glycol dimethylether or cyclic ethers, e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- and t-butanol; nitriles including CH 3 CN; halogenated hydrocarbons, including CH 2 CI 2 , CHCl 3 and CCl 4 ; acid amides including DMF; sulfoxides, including DMSO; bases, including heterocyclic nitrogen bases, e.g.
  • carboxylic acids including lower alkanecarboxylic acids, e.g., AcOH
  • inorganic acids including HCl, HBr, HF, H 2 SO 4 and the like
  • carboxylic acid anhydrides including lower alkane acid anhydrides, e.g., acetic anhydride
  • cyclic, linear, or branched hydrocarbons including cyclohexane, hexane, pentane, isopentane and the like, and mixtures of these solvents, such as purely organic solvent combinations, or water-containing solvent combinations e.g., aqueous solutions.
  • solvents and solvent mixtures may also be used in "working-up" the reaction as well as in processing the reaction and/or isolating the reaction product(s), such as in chromatography.
  • the invention further encompasses "intermediate" compounds, including structures produced from the synthetic procedures described, whether isolated or not, prior to obtaining the finally desired compound. Structures resulting from carrying out steps from a transient starting material, structures resulting from divergence from the described method(s) at any stage, and structures forming starting materials under the reaction conditions are all "intermediates" included in the invention. Further, structures produced by using starting materials in the form of a reactive derivative or salt, or produced by a compound obtainable by means of the process according to the invention and structures resulting from processing the compounds of the invention in situ are also within the scope of the invention.
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to obtain the desired compound(s).
  • Starting materials of the invention are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the examples. In synthesizing starting materials, functional groups may be protected with suitable protecting groups when necessary. Protecting groups, their introduction and removal are described above.
  • Compounds of the present invention can possess, in general, one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures thereof.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base.
  • Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
  • the optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • the compounds of this invention may also be represented in multiple tautomeric forms.
  • the invention expressly includes all tautomeric forms of the compounds described herein.
  • the compounds may also occur in cis- or trans- or E- or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • Substituents on ring moieties e.g., phenyl, thienyl, etc.
  • the compounds of this invention may contain heterocyclic ring systems attached to another ring system.
  • Such heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system.
  • a compound of any of the formulas described herein may be synthesized according to any of the procedures described herein.
  • the steps may be performed in an alternate order and may be preceded, or followed, by additional protection/deprotection steps as necessary.
  • the procedures may further use appropriate reaction conditions, including inert solvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine, K 2 CO 3 , and the like), catalysts, and salt forms of the above.
  • bases e.g., LDA, DIEA, pyridine, K 2 CO 3 , and the like
  • Purification methods include, for example, crystallization, chromatography (liquid and gas phase, and the like), extraction, distillation, trituration, reverse phase HPLC and the like. Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction.
  • reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction.
  • the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing the inhibitor compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A. Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2 nd edition (2001); M. Bodanszky, A.
  • Bodanszky The Practice of Peptide Synthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2 nd edition, Wiley- VCH, (1997); and L. Paquette, editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).
  • the present invention provides a method of making a compound of Formula I, the method comprising the step of reacting a compound 3,
  • the compounds of the invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • a compound of the invention may be modified to incorporate a hydrophobic group or "greasy" moiety in an attempt to enhance the passage of the compound through a hydrophobic membrane, such as a cell wall.
  • Formula I vary with structural change, in general, activity possessed by compounds of Formula I may be demonstrated both in vitro as well as in vivo. Particularly, the pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological in vitro assays.
  • the following exemplified pharmacological assays have been carried out with the compounds according to the invention.
  • Compounds of the invention were found to inhibit the activity of various kinase enzymes, including, without limitation, p38 receptor kinase at doses less than 25 ⁇ M.
  • the following assays were used to characterize the ability of compounds of the invention to inhibit the production of TNF- ⁇ and IL- 1- ⁇ .
  • the second assay can be used to measure the inhibition of TNF- ⁇ and/or IL- 1- ⁇ in mice after oral administration of the test compounds.
  • the third assay a glucagon binding inhibition in vitro assay, can be used to characterize the ability of compounds of the invention to inhibit glucagon binding.
  • the compounds of the invention can be tested for their respective affinities for the p38 protein using a conventional p38 in-vitro enzyme activity assay.
  • a P38-alpha HTRF assay may be used to measure the protein's in-vitro phosphorylation activity, and the data analyzed using time resolved fluorimetry techniques (FRET).
  • FRET time resolved fluorimetry techniques
  • a p38 HTRF assay is as follows.
  • the kinase reaction buffer for p38 ⁇ , p38 ⁇ , p38 ⁇ and p38 ⁇ HTRF assays consists of 50 mM Tris-pH 7.5, 5 mM MgCl 2 , 0.1 mg/mL BSA, 100 ⁇ M Na 3 VO 4 and 0.5 mM DTT.
  • the HTRF detection buffer contains 100 mM HEPES-pH 7.5, 100 mM NaCl, 0.1% BSA, 0.05% Tween-20, and 10 mM EDTA. Each compound was dissolved in 100% DMSO and serially diluted (3 fold, 10 point) in a polypropylene 96- well microtiter plate (drug plate). The final starting concentration of the compound in the p38 ⁇ and p38 ⁇ enzymatic assays was about 1 ⁇ M. The final starting concentration of each compound in the p38 ⁇ and p38 ⁇ enzymatic assays was about 10 ⁇ M.
  • the p38 ⁇ , p38 ⁇ , p38 ⁇ and p38 ⁇ kinase reactions were carried out in a polypropylene 96-well black round bottom assay plate in total volume of 30 ⁇ L kinase reaction buffer.
  • Appropriate concentration of purified and activated enzyme (recombinant human) was mixed with indicated concentration of ATP and 100 nM GST-ATF2-Avitag, in the presence or absence (HI control) of each compound. In the absence of enzyme, the background was measured as LO control.
  • HI controls and LO controls contained only DMSO. The reaction was allowed to incubate for 1 hour at RT.
  • the kinase reaction was terminated and phospho-ATF2 was revealed by addition of 30 ⁇ L of HTRF detection buffer supplemented with 0.1 nM Eu-anti-pTP and 4 nM SA-APC. After 60 minutes incubation at room temperature, the assay plate was read in a Discovery Plate Reader. The wells were excited with coherent 320 nm light and the ratio of delayed (50 ms post excitation) emissions at 620 nM (native europium fluorescence) and 665 nm (europium fluorescence transferred to allophycocyanin - an index of substrate phosphorylation) was determined (Park et al. 1999).
  • % control (POC) (compound - average LO)/(average HI - average LO)* 100.
  • Homogeneous Proximity Tyrosine Kinase Assays Scintillation Proximity Assay versus Homogeneous Time-Resolved Fluorescence. Analytical Biochemistry. 1999; 269: 94-104.
  • Biological data Exemplary compounds 1-21 exhibited IC 50 values of less than or equal to 1.OuM in the p38 in-vitro enzyme assay.
  • Exemplary compounds 1, 3-16, 17b and 19-21 exhibited IC 50 values of less than or equal to 50OnM in the p38 in-vitro enzyme assay.
  • Exemplary compounds 1, 3-8, 10-16, 17b and 19-21 exhibited IC 50 values of less than or equal to 25OnM in the p38 in-vitro enzyme assay.
  • Exemplary compounds 5-8, 10-14, 16 and 19-21 exhibited IC 50 values of less than or equal to 10OnM in the p38 in-vitro enzyme assay.
  • Test compounds were evaluated in vitro for the ability to inhibit the production of TNF by monocytes activated with bacterial lipopolysaccharide (LPS).
  • Fresh residual source leukocytes (a byproduct of plateletpheresis) were obtained from a local blood bank, and peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation on Ficol-Paque Plus (Pharmacia).
  • PBMCs peripheral blood mononuclear cells
  • PBMCs peripheral blood mononuclear cells
  • Cells were plated into Falcon flat bottom, 96 well culture plates (200 ⁇ L/well) and cultured overnight at 37°C and 6% CO 2 . Non-adherent cells were removed by washing with 200 ⁇ l/well of fresh medium. Wells containing adherent cells (-70% monocytes) were replenished with 100 ⁇ L of fresh medium.
  • Test compounds were dissolved in DMZ. Compound stock solutions were prepared to an initial concentration of 10 - 50 ⁇ M. Stocks were diluted initially to 20 - 200 ⁇ M in complete media. Nine two-fold serial dilutions of each compound were then prepared in complete medium. Treatment of cells with test compounds and activation of TNF production with lipopolysaccharide.
  • Standards consisted of eleven 1.5-fold serial dilutions from a stock of 1 ng/mL recombinant human TNF (R&D Systems). Plates were incubated at room temperature for 1 h on orbital shaker (300 rpm), washed and replenished with 100 ⁇ L/well of 0.5 ⁇ g/mL goat anti-human TNF- ⁇ (R&D systems #AB-210-NA) biotinylated at a 4: 1 ratio. Plates were incubated for 40 min, washed and replenished with 100 ⁇ L/well of alkaline phosphatase-conjugated streptavidin (Jackson ImmunoResearch #016-050-084) at 0.02 ⁇ g/mL.
  • Compounds of the invention can also be shown to inhibit LPS-induced release of IL- l ⁇ , IL-6 and/or IL-8 from monocytes by measuring concentrations of IL-I ⁇ , IL-6 and/or IL-8 by methods well known to those skilled in the art.
  • compounds of this invention can also be shown to inhibit LPS induced release of IL-I ⁇ , IL-6 and/or IL-8 from monocytes by measuring concentrations of IL-I ⁇ , IL-6 and/or IL-8 by methods well known to those skilled in the art.
  • the compounds of the invention may lower elevated levels of TNF- ⁇ , IL-I, IL-6, and IL-8 levels. Reducing elevated levels of these inflammatory cytokines to basal levels or below is favorable in controlling, slowing progression, and alleviating many disease states. All of the compounds are useful in the methods of treating disease states in which TNF- ⁇ , IL- l ⁇ , IL-6, and IL-8 play a role to the full extent of the definition of TNF- ⁇ -mediated diseases described herein.
  • THPl cells are resuspended in fresh THPl media (RPMI 1640, 10% heat- inactivated FBS, IXPGS, IXNEAA, plus 30 ⁇ M ⁇ ME) at a concentration of lE6/mL.
  • THPl media RPMI 1640, 10% heat- inactivated FBS, IXPGS, IXNEAA, plus 30 ⁇ M ⁇ ME
  • concentration of lE6/mL a concentration of lE6/mL.
  • One hundred microliters of cells per well are plated in a polystyrene 96-well tissue culture.
  • One microgram per mL of bacterial LPS is prepared in THPl media and is transferred to the wells.
  • Test compounds are dissolved in 100% DMSO and are serially diluted 3 fold in a polypropylene 96-well microtiter plate (drug plate).
  • HI control and LO control wells contain only DMSO.
  • test compound from the drug plate followed by 10 ⁇ L of LPS are transferred to the cell plate.
  • the treated cells are induced to synthesize and secrete TNF- ⁇ at 37°C for 3 h.
  • Forty microliters of conditioned media are transferred to a 96-well polypropylene plate containing 110 ⁇ L of ECL buffer (5OmM Tris-HCl pH 8.0, 10OmM NaCl, 0.05% Tween 20, 0.05% NaN 3 and 1%FBS) supplemented with 0.44nM MAB610 monoclonal Ab (R&D Systems), 0.34nM ruthenylated AF210NA polyclonal Ab (R&D Systems) and 44 ⁇ g/mL sheep anti-mouse M280 Dynabeads (Dynal).
  • ECL buffer 5OmM Tris-HCl pH 8.0, 10OmM NaCl, 0.05% Tween 20, 0.05% NaN 3 and 1%FBS
  • % control (POC) (cpd - average LO)/(average HI - average LO)* 100.
  • Exemplary compounds 1-21 exhibited IC 50 activity values in the THP-cellular TNF release assay of less than or equal to 2.5uM.
  • Exemplary compounds 2- 14, 15, 17a, 19-21 exhibited IC 50 activity values in the THP-cellular TNF release assay of less than or equal to 1.OuM.
  • Exemplary compounds 3-11, 13-14, 16, 17a, 19-21 exhibited IC50 activity values in the THP-cellular TNF release assay of less than or equal to 50OnM.
  • Exemplary compounds 4, 6-8, 9, 13-14, 16, 19 and 21 exhibited IC 50 activity values in the THP-cellular TNF release assay of less than or equal to 25OnM.
  • Exemplary compounds 6-8, 10, 14 and 21 exhibited IC 50 activity values in the THP-cellular TNF release assay of less than or equal to 10OnM.
  • mice Male DBA/1LACJ mice are dosed with vehicle or test compounds in a vehicle (the vehicle consisting of 0.5% tragacanth in 0.03 N HCl) 30 minutes prior to lipopolysaccharide (2 mg/Kg, LV.) injection.
  • vehicle the vehicle consisting of 0.5% tragacanth in 0.03 N HCl
  • lipopolysaccharide 2 mg/Kg, LV.
  • ELISA ELISA for TNF- ⁇ levels.
  • Compounds of the invention may be shown to have anti-inflammatory properties in animal models of inflammation, including carageenan paw edema, collagen induced arthritis and adjuvant arthritis, such as the carageenan paw edema model (C. A. Winter et al Proc. Soc. Exp. Biol. Med. (1962) vol 111, p 544; K. F.
  • the reagents can be prepared as follows: (a) prepare fresh IM o-Phenanthroline (Aldrich) (198.2 mg/mL ethanol); (b) prepare fresh 0.5M DTT (Sigma); (c) Protease Inhibitor Mix (1000X): 5mg leupeptin, 10 mg benzamidine, 40mg bacitracin and 5mg soybean trypsin inhibitor per mL DMSO and store aliquots at -20°C; (d) 250 ⁇ M human glucagon (Peninsula): solubilize 0.5mg vial in 575 ⁇ l 0.1N acetic acid (1 ⁇ L yields 1 ⁇ M final concentration in assay for non-specific binding) and store in aliquots at -2O°C; (e) Assay Buffer: 2OmM Tris (pH 7.8), ImM DTT and 3mM o-phenanthroline; (f) Assay
  • Membrane preparations of CHO/hGLUR cells can be used in place of whole cells at the same assay volume. Final protein concentration of a membrane preparation is determined on a per batch basis. Assay
  • the determination of inhibition of glucagon binding can be carried out by measuring the reduction of I 125 -glucagon binding in the presence of compounds of Formula I.
  • the reagents are combined as follows:
  • the mixture is incubated for 60 min at 22 °C on a shaker at 275 rpm.
  • the mixture is filtered over pre-soaked (0.5% polyethylimine (PEI)) GF/C filtermat using an Innotech Harvester or Tomtec Harvester with four washes of ice-cold 2OmM Tris buffer (pH 7.8).
  • the radioactivity in the filters is determined by a gamma-scintillation counter.
  • compounds of the invention are useful for, but not limited to, the prevention or treatment of inflammation and related diseases.
  • a method of treating a disorder related to a protein kinase enzyme in a subject comprising administering to the subject an effective dosage amount of a compound of a compound of Formula I.
  • the kinase enzyme is p38.
  • the compounds of the invention are also useful in treatment and therapy of cytokine-mediated diseases.
  • these compounds can be used for the treatment of rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic ⁇ cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease (IBD), adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, chronic obstructive pulmonary disease (COPD), dental pain, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs.
  • IBD inflammatory bowel disease
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • CMV cytomegalovirus
  • synovial inflammation for example, synovitis, including any of the particular forms of synovitis, in particular bursal synovitis and purulent synovitis, as far as it is not crystal-induced.
  • synovial inflammation may for example, be consequential to or associated with disease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritis deformans.
  • the present invention is further applicable to the systemic treatment of inflammation, e.g. inflammatory diseases or conditions, of the joints or locomotor apparatus in the region of the tendon insertions and tendon sheaths.
  • Such inflammation may be, for example, consequential to or associated with disease or further (in a broader sense of the invention) with surgical intervention, including, in particular conditions such as insertion endopathy, myofasciale syndrome and tendomyosis.
  • the present invention is further applicable to the treatment of inflammation, e.g. inflammatory disease or condition, of connective tissues including dermatomyositis and myositis.
  • the compounds of the invention can also be used as active agents against such disease states as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter related diseases, fractures, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy or macular degeneration.
  • the present invention also provides methods for the treatment of protein tyrosine kinase-associated disorders, comprising the step of administering to a subject in need thereof at least one compound of the Formula I in an amount effective therefore.
  • Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods.
  • such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
  • the present invention also provides for a method for treating the aforementioned disorders such as atopic dermatitis by administration of a therapeutically effective amount of a compound of the present invention, which is an inhibitor of protein tyrosine kinase, to a patient, whether or not in need of such treatment.
  • the compounds are useful for decreasing the level of, or lowering plasma concentrations of, one or more of TNF- ⁇ , IL-I ⁇ , IL-6 and IL-8 in a subject, generally a mammal and typically a human.
  • the compounds are useful for treating a pain disorder in a subject, which is typically a human by administering to the subject an effective dosage amount of a compound according to formula I.
  • these compounds are useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • animals including horses, dogs, and cats may be treated with compounds provided by the invention.
  • Treatment of diseases and disorders herein is intended to also include therapeutic administration of a compound of the invention, or a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject ⁇ i.e., an animal, preferably a mammal, most preferably a human) which may be in need of preventative treatment, such as, for example, for pain, inflammation and the like.
  • Treatment also encompasses prophylactic administration of a compound of the invention, or a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject ⁇ i.e., an animal, preferably a mammal, most preferably a human).
  • the subject is initially diagnosed by a licensed physician and/or authorized medical practitioner, and a regimen for prophylactic and/or therapeutic treatment via administration of the compound(s) or compositions of the invention is suggested, recommended or prescribed.
  • the amount of compound(s) which is/are administered and the dosage regimen for treating TNF- ⁇ , IL-I, IL-6, and IL-8 mediated diseases, cancer, and/or hyperglycemia with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.
  • a daily dose of about 0.01 to 500 mg/kg, advantageously between about 0.01 and about 50 mg/kg, more advantageously about 0.01 and about 30 mg/kg, even more advantageously between about 0.1 and about 10 mg/kg, and even more advantageously between about 0.25 and about 1 mg/kg body weight may be appropriate, and should be useful for all methods of use disclosed herein.
  • the daily dose can be administered in one to four doses per day.
  • a pharmaceutical composition comprising a compound of this invention in combination with a pharmaceutically acceptable excipient, which includes diluents, carriers, adjuvants and the like (collectively referred to herein as "excipient" materials) as described herein, and, if desired, other active ingredients.
  • excipient includes diluents, carriers, adjuvants and the like (collectively referred to herein as "excipient" materials) as described herein, and, if desired, other active ingredients.
  • a pharmaceutical composition of the invention may comprise an effective amount of a compound of the invention or an effective dosage amount of a compound of the invention.
  • An effective dosage amount of a compound of the invention includes an amount less than, equal to or greater than an effective amount of the compound; for example, a pharmaceutical composition in which two or more unit dosages, such as in tablets, capsules and the like, are required to administer an effective amount of the compound, or alternatively, a multi- dose pharmaceutical composition, such as powders, liquids and the like, in which an effective amount of the compound is administered by administering a portion of the composition.
  • the compound(s) of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds and compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonarily such as by inhalation spray, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly intrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are tablets or capsules.
  • these may contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and typically from about 5 to 150 mg.
  • a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods and practices.
  • the active compounds of this invention are ordinarily combined with one or more "excipients" appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to form the final formulation.
  • the active compound(s) and excipient(s) may be tableted or encapsulated by known and accepted methods for convenient administration.
  • suitable formulations include, without limitation, pills, tablets, soft and hard-shell gel capsules, troches, orally-dissolvable forms and delayed or controlled-release formulations thereof.
  • capsule or tablet formulations may contain one or more control led-release agents, such as hydroxypropylmethyl cellulose, as a dispersion with the active compound(s).
  • Topical preparation of compounds of this invention In the case of psoriasis and other skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, pastes, suspensions and the like) and drops suitable for administration to the eye, ear, or nose.
  • a suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily.
  • the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation.
  • the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in- water cream base.
  • the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1, 3 -diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
  • the topical formulation may desirably include a compound, which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs.
  • transdermal device Preferably transdermal administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifler, which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • Emulsif ⁇ ers and emulsion stabilizers suitable for use in the formulation of the present invention include, for example, Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (ie. Tween 80).
  • suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (ie. Tween 80).
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water.
  • suitable carriers including saline, dextrose, or water.
  • the daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1 mg/kg.
  • the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler including dry powder aerosol.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
  • a method of manufacturing a medicament for the treatment of a variety of diseases and conditions, including but not limited to inflammation, the method comprising combining an amount of a compound according to Formula I with a pharmaceutically acceptable carrier to manufacture the medicament.
  • the compounds of the invention can be dosed or administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or in conjunction with other agents.
  • the therapeutic agents can be formulated as separate compositions that are administered simultaneously or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • co-therapy in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace coadministration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of TNF- ⁇ , IL-I, IL-6, and IL-8 mediated diseases, cancer, and/or hyperglycemia.
  • Such combination products employ the compounds of this invention within the accepted dosage ranges.
  • Compounds of Formulas I and II may also be administered sequentially with known anti-inflammatory agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, simultaneous with or after administration of the known anti- inflammatory agent.
  • the compounds of the invention may also be used in co-therapies with antineoplastic agents such as other kinase inhibitors, including p38 inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's, SOD mimics or ctv ⁇ 3 inhibitors.
  • antineoplastic agents such as other kinase inhibitors, including p38 inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's, SOD mimics or ctv ⁇ 3 inhibitors.

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Abstract

L'invention concerne une nouvelle classe de composés utilisés dans la prophylaxie et le traitement de maladies médiées par la kinase p38, y compris l'inflammation et les états associés. Les composés précités répondent à la formule générale I dans laquelle A, B1, B2, C1-4, L1, R1, R2, R5, m et n sont tels que définis dans la description. L'invention porte également sur des compositions pharmaceutiques renfermant au moins un des composés de la formule I, sur des procédés d'utilisation de ces derniers dans le traitement de maladies médiées par la kinase p38, ledit traitement consistant à administrer les composés de la formule I ou des compositions comprenant lesdits composés, et sur des intermédiaires et des procédés utiles à la préparation des composés de la formule I.
PCT/US2008/013785 2007-12-17 2008-12-16 Composés tricycliques linéaires utilisés comme inhibiteurs de la kinase p38 WO2009078992A1 (fr)

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WO2010149755A1 (fr) * 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
US8178563B2 (en) 2006-05-05 2012-05-15 Irm Llc Compounds and compositions as hedgehog pathway modulators
US9029399B2 (en) 2011-04-28 2015-05-12 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
US9056867B2 (en) 2011-09-16 2015-06-16 Novartis Ag N-substituted heterocyclyl carboxamides
JP2016530283A (ja) * 2013-08-27 2016-09-29 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｉｄｏ阻害剤
CN106061964A (zh) * 2014-01-20 2016-10-26 豪夫迈·罗氏有限公司 能够刺激神经发生的n‑苯基‑内酰胺衍生物及其在神经性病症的治疗中的用途
CN107406426A (zh) * 2015-01-09 2017-11-28 百时美施贵宝公司 作为rock抑制剂的环状脲类
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
WO2020263191A1 (fr) 2019-06-27 2020-12-30 Nanyang Technological University Composés ayant une activité antipaludéenne
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors

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Cited By (38)

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US8178563B2 (en) 2006-05-05 2012-05-15 Irm Llc Compounds and compositions as hedgehog pathway modulators
US8263635B2 (en) 2009-06-26 2012-09-11 Novartis Ag Inhibitors of CYP 17
CN102803250A (zh) * 2009-06-26 2012-11-28 诺瓦提斯公司 作为cyp17的抑制剂的1，3-二取代的咪唑烷-2-酮衍生物
USRE45173E1 (en) 2009-06-26 2014-09-30 Novartis Ag Inhibitors of CYP 17
EA021011B1 (ru) * 2009-06-26 2015-03-31 Новартис Аг 1,3-ДИЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ ИМИДАЗОЛИДИН-2-ОНА В КАЧЕСТВЕ ИНГИБИТОРОВ Cyp 17
WO2010149755A1 (fr) * 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
US9029399B2 (en) 2011-04-28 2015-05-12 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
US9339501B2 (en) 2011-04-28 2016-05-17 Novartis Ag 17a-hydroxylase/C17,20-lyase inhibitors
US9056867B2 (en) 2011-09-16 2015-06-16 Novartis Ag N-substituted heterocyclyl carboxamides
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
JP2016530283A (ja) * 2013-08-27 2016-09-29 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｉｄｏ阻害剤
CN106061964B (zh) * 2014-01-20 2019-10-25 豪夫迈·罗氏有限公司 能够刺激神经发生的n-苯基-内酰胺衍生物及其在神经性病症的治疗中的用途
CN106061964A (zh) * 2014-01-20 2016-10-26 豪夫迈·罗氏有限公司 能够刺激神经发生的n‑苯基‑内酰胺衍生物及其在神经性病症的治疗中的用途
CN107406426A (zh) * 2015-01-09 2017-11-28 百时美施贵宝公司 作为rock抑制剂的环状脲类
US10123993B2 (en) * 2015-01-09 2018-11-13 Bristol-Myers Squibb Company Cyclic ureas as inhibitors of rock
CN107406426B (zh) * 2015-01-09 2020-11-20 百时美施贵宝公司 作为rock抑制剂的环状脲类
US11858939B2 (en) 2015-07-06 2024-01-02 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10519149B2 (en) 2017-01-11 2019-12-31 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10696673B2 (en) 2017-01-11 2020-06-30 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10793567B2 (en) 2017-01-11 2020-10-06 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11987580B2 (en) 2017-01-11 2024-05-21 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11286256B2 (en) 2017-01-11 2022-03-29 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11225479B2 (en) 2017-01-11 2022-01-18 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11912702B2 (en) 2017-08-07 2024-02-27 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11479770B2 (en) 2017-10-05 2022-10-25 Fulcrum Therapeutics, Inc. Use of p38 inhibitors to reduce expression of DUX4
US10537560B2 (en) 2017-10-05 2020-01-21 Fulcrum Therapeutics. Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11814386B2 (en) 2018-10-05 2023-11-14 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
EP3990434A4 (fr) * 2019-06-27 2023-07-19 Nanyang Technological University Composés ayant une activité antipaludéenne
WO2020263191A1 (fr) 2019-06-27 2020-12-30 Nanyang Technological University Composés ayant une activité antipaludéenne

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