WO2013024427A1 - Nouveaux dérivés d'urée en tant qu'inhibiteurs de kinase tec et leurs utilisations - Google Patents

Nouveaux dérivés d'urée en tant qu'inhibiteurs de kinase tec et leurs utilisations Download PDF

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WO2013024427A1
WO2013024427A1 PCT/IB2012/054126 IB2012054126W WO2013024427A1 WO 2013024427 A1 WO2013024427 A1 WO 2013024427A1 IB 2012054126 W IB2012054126 W IB 2012054126W WO 2013024427 A1 WO2013024427 A1 WO 2013024427A1
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amino
benzimidazol
carbamoyl
cyanophenyl
hydroxy
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PCT/IB2012/054126
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English (en)
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Sachin Sundarlal Chaudhari
Abraham Thomas
Bharat Gangadhar Adik
Sachin Vasantrao Dhone
Prashant Dilip WADEKAR
Neelima Khairatkar-Joshi
Daisy Manish Shah
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Glenmark Pharmaceuticals S.A.
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Publication of WO2013024427A1 publication Critical patent/WO2013024427A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present patent application relates to urea derivatives for use as inhibitors of Tec kinases and more specifically inhibitors of interleukin-2 inducible T-cell kinase (ITK).
  • ITK interleukin-2 inducible T-cell kinase
  • Protein kinases are enzymes which modulate fundamental cellular processes via protein phosphorylation. Protein kinases play a critical role in mediating the signaling events which control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines. Kinases are classified in two general groups, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues [S. K. Hanks and T. Hunter, FASEB. J., 1995, 9 pages 576-596].
  • Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue located on a protein substrate.
  • the tyrosine kinases include membrane- spanning growth factor receptors such as the epidermal growth factor receptor (EGFR), Insulin receptor (INSR), Platelet derived growth factor receptor etc and cytosolic non-receptor kinases such as Src family kinases (Lck and Lyn), the Syk family kinases (ZAP-70 and Syk) and the Tec family kinases (e.g. ITK).
  • the Tec family kinase include ITK [expressed mainly in T cells; Gibson, S. et al., Blood 82, 1561 1572 (1993)], Txk [T-cell expressed kinase; Haire, R. N. et al., Hum. Mol. Genet. 3, 897 901 (1994)], Tec [tyrosine kinase expressed in hepatocellular carcinoma cells; Mano et al., Oncogene 5, 1781 1786 (1990)], Btk [Bruton's tyrosine kinase; Vetrie, D.
  • ITK or Tsk T-cell- specific tyrosine kinase is expressed solely in inflammation cells such as T cells, natural killer (NK) cells, and mast cells with a prominent role of T cell proliferation and production of critical cytokines such as IL2, IL4, IL5, IL10 and IL13.
  • T cell activation via T cell receptor (TCR) CD3 and CD28 interaction a cascade of signal transduction events is trigerred including Lck activation followed by ZAP70 and ITK phosphorylation, ITK subsequently activates phospholipase C ⁇ (PLC- ⁇ ) that fruther cleaves phospotidylinositol biphosphate to yield diacylgycerol (DAG) and inositol triphosphate (IP3).
  • PLC- ⁇ phospholipase C ⁇
  • DAG diacylgycerol
  • IP3 inositol triphosphate
  • mice lacking ITK have decreased numbers of mature thymocytes, especially CD4+ T cells.
  • the T cells isolated from such mice are compromised in their proliferative response to allogeneic MHC stimulation, and to anti-TCR/CD3 cross- linking [Liao X. C. and Littman, D. R., Immunity 3, 757 769 (1995)] .
  • These T cells also exhibit defective PLCyl tyrosine phosphorylation, inositol triphosphate production, Ca 2+ moblization, and cytokine production (such as IL-2 and IFNy) in response to TCR cross- linking [Schaeffer, E. M.
  • mice are unable to establish functional Th2 cells (the IL-4 producing cells) and such mice are unable to clear parasitic infections depending upon a Th2 response [Fowell, D. J. et al., Immunity 11, 399 409 (1999)] .
  • ITK deficient mice have drastically reduced lung inflammation, eosinophil infiltration, and mucous production in response to OVA induced allergic asthma [Mueller, C, ; August, A., J. Immunol. 2003, 170, 5056]]. These studies support a key role for ITK in the activation of T cells, thus inhibitors of ITK should be useful as immunosuppressive or anti-inflammatory agents.
  • WO2002050071 relates to inhibitors of the Tec family tyrosine kinases, particularly, inhibitors of Emt [expressed mainly in T cells] as immunosuppressive, anti-inflammatory, anti-allergic & anti-cancer agents.
  • WO2003041708, WO2004016600, WO2004016609, WO2004016610, WO2004016611, WO2004016270, WO2004016615, WO2004014905, WO2005026175, WO2005056785, WO2005066335, WO2005070420, WO2005079791, WO2007058832, WO2008025820, and WO2008025822 disclose certain ITK inhibitors for the treatment of inflammation, immunological disorders, and allergic disorders.
  • WO2010106016 describe certain ITK inhibitors for the treatment of disorders such as respiratory diseases; allergic diseases; autoimmune diseases; transplant rejection; graft versus host disease; inflammatory disorders; HIV; aplastic anemia; and pain.
  • WO2005095406, WO2006065946, WO2007027528, WO2007027594, WO2007027729, and WO2007076228 describe certain compounds as Tec family kinase inhibitors.
  • WO2007136790 describe certain compounds as ITK and BTK kinase inhibitors, and WO2008025821 disclose certain compounds as ITK or PI3K inhibitors.
  • an object of the present patent application is to provide a new class of compounds as kinase inhibitors, especially as ITK inhibitors, which may be effective in the treatment or prophylaxis of disorders associated with ITK, such as respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and bronchitis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases including rheumatoid arthritis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, T cell mediated hypersensitivities, Guillain-Barre Syndrome and Hashimoto's thyroiditis; transplant rejection; graft versus host disease; inflammatory disorders including conjunctivitis, contact dermatitis, inflammatory bowel disease and chronic inflammation; proliferative disorders; immunological disorders; HIV; aplastic anemia; and pain including inflammatory pain.
  • respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and bronchitis
  • allergic diseases
  • X is selected from -(CH 2 ) P -, -0-, -C(O)-, -(CH 2 ) p NR a -, -C(0)NR ⁇ -NR a C(0)-, N(R a )CSN(R b ) and -NR a -;
  • Y is selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyl
  • R is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
  • U is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
  • V is selected from hydrogen, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalky
  • Z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylal
  • R a is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; at each occurrence, R b , and R c which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or un
  • R x and R y which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl; or R x and R y together with the atom to which they are attached, may form cyclic ring; substituted or unsubstituted; the cyclic ring may optionally contain one or more hetero atoms selected from O, NR a or S; and
  • 'p' is an integer ranging from 0 to 6, both inclusive.
  • the compounds of formula (I) are inhibitors of kinase activity, in particular ITK activity. Therefore, said compounds are useful for the treatment of diseases and/or disorders, in which the inappropriate activity of ITK contributes to the pathology or symptoms of the disease.
  • the compound of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, claim or any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (I) as defined above wherein U is substituted or unsubstituted aryl (according to an embodiment defined below), R is hydrogen (according to another embodiment defined below) and X is - (CH 2 ) p NR a - (according to yet another embodiment defined below).
  • X is -NR a C(0)- and -(CH 2 ) p NR a -;
  • Y is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C3- 12 cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted aryl;
  • R is hydrogen or substituted or unsubstituted C 1-6 alkyl
  • U is substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl
  • V is selected from hydrogen, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
  • Z is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and - C(0)NR x R y ;
  • R a is hydrogen or substituted or unsubstituted C 1-6 alkyl
  • R x and R y which may be the same or different, are independently selected from hydrogen and substituted or unsubstituted C 1-6 alkyl;
  • 'p' is an integer ranging from 0 to 3, both inclusive.
  • R a is hydrogen or substituted or unsubstituted C 1-6 alkyl (e.g. methyl or ethyl).
  • R a is hydrogen or substituted or unsubstituted C 1-6 alkyl (e.g. methyl or ethyl).
  • 'p' is 1.
  • Y is selected from substituted or unsubstituted C 1-6 alkyl (e.g. ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, 3-pentyl, 1,1- dimethylbutyl or 3,3-dimethyl-2-butyl), substituted or unsubstituted C 3-12 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclohexyl or adamantyl) and substituted or unsubstituted cycloalkylalkyl (e.g. methylcyclopentyl).
  • C 1-6 alkyl e.g. ethyl, propyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, 3-pentyl, 1,1- dimethylbutyl or 3,3-dimethyl-2-
  • Y is substituted or unsubstituted aryl (e.g. phenyl), wherein substituents are halogen (e.g. F or CI) or C 1-6 alkyl (e.g. methyl).
  • aryl e.g. phenyl
  • substituents are halogen (e.g. F or CI), cyano, C 1-6 alkyl (e.g. methyl), alkoxy (e.g. methoxy), haloalkyl (e.g. trifluoromethyl) and haloalkoxy (e.g. trifluoromethoxy).
  • U is substituted or unsubstituted heteroaryl (e.g. thiophenyl, pyridinyl, benzothiazolyl or oxazolyl), wherein substituents are halogen (e.g. F or CI), cyano and C 1-6 alkyl (e.g. methyl).
  • substituents are halogen (e.g. F or CI), cyano and C 1-6 alkyl (e.g. methyl).
  • U is unsubstituted or mono-, di- or trisubstituted aryl (e.g. phenyl), wherein substituents are halogen (e.g. F or CI), cyano, C 1-6 alkyl (e.g. methyl), alkoxy (e.g. methoxy), haloalkyl (e.g. trifluoromethyl) and haloalkoxy (e.g. trifluoromethoxy).
  • substituents are halogen (e.g. F or CI), cyano, C 1-6 alkyl (e.g. methyl), alkoxy (e.g. methoxy), haloalkyl (e.g. trifluoromethyl) and haloalkoxy (e.g. trifluoromethoxy).
  • U is unsubstituted or mono-, di- or trisubstituted heteroaryl (e.g. thiophenyl, pyridinyl, benzothiazolyl or oxazolyl), wherein substituents are halogen (e.g. F or CI), cyano and C 1-6 alkyl (e.g. methyl).
  • substituents are halogen (e.g. F or CI), cyano and C 1-6 alkyl (e.g. methyl).
  • V is substituted or unsubstituted aryl (e.g. phenyl), wherein substituents are halogen (e.g. F or CI), cyano, C 1-6 alkyl (e.g. methyl) and haloalkoxy (e.g trifluoromethoxy) .
  • substituents are halogen (e.g. F or CI), cyano, C 1-6 alkyl (e.g. methyl) and haloalkoxy (e.g trifluoromethoxy) .
  • V is substituted or unsubstituted heteroaryl (e.g. pyrazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl), wherein substituents are halogen (e.g. F or CI), cyano and Ci-6 alkyl (e.g. methyl).
  • V is unsubstituted or mono-, di- or trisubstituted aryl (e.g. phenyl), wherein substituents are halogen (e.g. F or CI), cyano, C 1-6 alkyl (e.g. methyl) and haloalkoxy (e.g. trifluoromethoxy).
  • substituents are halogen (e.g. F or CI), cyano, C 1-6 alkyl (e.g. methyl) and haloalkoxy (e.g. trifluoromethoxy).
  • V is unsubstituted or mono-, di- or trisubstituted heteroaryl (e.g. pyrazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl), wherein substituents are halogen (e.g. F or CI), cyano and C 1-6 alkyl (e.g. methyl).
  • heteroaryl e.g. pyrazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl
  • substituents are halogen (e.g. F or CI), cyano and C 1-6 alkyl (e.g. methyl).
  • R is selected from hydrogen and C 1-6 alkyl (e.g. methyl or ethyl).
  • compounds of formula is selected from heterocyclylalkyl, preferably and and 'p' is 0.
  • the present invention also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions described herein are useful for inhibiting ITK activity.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of ITK, which is believed to be related to a variety of disease states.
  • the invention is still further directed to methods of inhibiting ITK activity and treatment of disorders associated therewith using a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention is yet further directed towards processes for the preparation of the compounds of the invention.
  • the present patent application further provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment of one or more conditions selected from the group consisting of immunological, inflammatory, allergic disorders, proliferative disorders and other diseases and disorders associated with ITK, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.
  • the present patent application further provides a new class of compounds as kinase inhibitors, especially as ITK inhibitors, which may be effective in the treatment or prophylaxis of disorders associated with ITK, such as respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and bronchitis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases including rheumatoid arthritis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, T cell mediated hypersensitivities, Guillain-Barre Syndrome and Hashimoto's thyroiditis; transplant rejection; graft versus host disease; inflammatory disorders including conjunctivitis, contact dermatitis, inflammatory bowel disease and chronic inflammation; proliferative disorders; immunological disorders; HIV; aplastic anemia; and pain including inflammatory pain.
  • respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and bronchitis
  • allergic diseases including allergic r
  • halogen or halo means fluorine, chlorine, bromine, or iodine.
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C 1-8 alkyl), and which is attached to the rest of the molecule by a single bond.
  • Ci_ 6 alkyl is an alkyl group that has from 1 to 6 carbon atoms.
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (t-butyl) and 2,2-dimethylpropyl.
  • alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), zsopropenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.
  • all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred).
  • Non-limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above.
  • Example of such alkoxyalkyl moiety includes, but are not limited to, -CH 2 OCH 3 and -CH 2 OC 2 H 5 .
  • all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkyl refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above.
  • haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms.
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups.
  • Examples of hydroxyalkyl moiety include, but are not limited to -CH 2 OH and -C 2 H 4 OH.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms (i.e. C 3-12 cycloalkyl), such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group.
  • the cycloalkenylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H5 and -C 2 H 4 C 6 Hs . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroaryl unless otherwise specified refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, pyrazolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, p
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compound described in the present patent application may form salts.
  • Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I) the present patent application extends to these stereoisomeric forms and to mixtures thereof.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, ,lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinyl pyrrolidone.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch and/or potato starch. A syrup or elixir is used in cases where a sweetened vehicle is employed.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, eye ointments, eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the pharmaceutical forms suitable for injectable or infusing use include sterile aqueous solutions, suspensions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable or infusing solutions, suspension or dispersions.
  • compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects.
  • the daily dosage of the ⁇ inhibitors can range from about 0.1 to about 200.0 mg/Kg.
  • Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
  • the present invention provides compounds and pharmaceutical compositions which inhibit Tec family tyrosine kinases, especially ITK and are thus useful in the treatment or prevention of Tec family tyrosine kinase associated disorders particularly ITK associated disorder.
  • Compounds and pharmaceutical compositions of the present invention selectively inhibit ⁇ and are thus useful in the treatment or prevention of a range of disorders associated with the activation of ITK (for e.g. immunological, inflammatory or allergic disorders and cancer).
  • the compounds and pharmaceutical compositions of the invention are also effective inhibitors of Tec family kinases other than ITK including Txk, Tec, Btk, and Bmx and would thus be useful in treating preventing diseases associated with the activity of one or more of these Tec family kinases.
  • the compounds of the present invention may be used to prevent or treat airways diseases including chronic obstructive pulmonary disease (COPD) such as irreversible COPD; asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (for example, late asthma and airways hyper- responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idi
  • the compounds of the present invention are useful for the treatment of cancer such as, but are not limited to breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, non- small cell lung cancer, brain cancer, cancer of the larynx, gall bladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, and kidney cancer, basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, myeloma, giant cell tumor, small-cell lung tumor, islet cell tumor, primary brain tumor, lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, ovarian tumor, cervical dysplasia, neuroblastoma, retinoblastoma, soft tissue sarcoma,
  • Compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions may have potential utility in combination with other therapies for the treatment of immune, inflammatory, proliferative, and allergic disorders.
  • Example includes but not limited to co-administration with steroids, leukotriene antagonists, histamines, cyclosporine, or rapamycin.
  • Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.
  • An appropriately substituted 2-amino benzimidazole of general formula (1) can be coupled with a suitable phenylcarbamate derivative of general formula (2) (wherein, Ar is phenyl) using suitable base such as, but not limited to triethylamine, sodium hydride or potassium carbonate to give the benzimidazole urea derivative of formula (I).
  • a substituted 2-aminobenzimidazole of general formula (1) can be coupled with an appropriately substituted azide derivative of formula (3) using toluene at reflux temperature to give the benzimidazole urea derivative of formula (I).
  • a detailed synthesis for the preparation of benzimidazole derivatives of the general formula (la) (where R can be hydrogen or alkyl) is described in scheme 3 [wherein R a , R b , Z, U, V and p are as defined in compound of formula (I)].
  • the reduction of nitro group of intermediate (10) under palladium catalysis can give the diamine of general formula (11).
  • the reaction of diamine (11) with cyanogen bromide in ethanol can afford 2-aminobenzimidazole derivative of general formula (12).
  • the intermediate (12) can be coupled with the phenyl carbamate of general formula (2) (wherein, Ar is phenyl) under basic condition to give the benzimidazole urea derivative of formula (la).
  • the coupling of intermediate (12) with a suitable azide of formula (3) using toluene at reflux temperature can afford compound of the general formula (la).
  • the triisopropyl silyl group of formula (19) can be cleaved using hydrochloric acid to afford the free alcohol intermediate of formula (20).
  • the hydroxyl group of intermediate (20) can be oxidized to the formyl derivative of formula (21) using manganese dioxide in acetone.
  • the formyl intermediate (21) on reductive amination with the amine of general formula (22) in presence of sodium triacetoxyborohydride can afford the benzimidazole urea derivative of general formula (Id).
  • DMSO- ⁇ hexadeuterodimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • 1H NMR Proton Nuclear Magnetic Resonance
  • MS Mass Spectrum
  • CDC1 3 Deuterated chloroform
  • THF Tetrahydrofuran
  • / coupling constant in units of Hz
  • RT or rt room temperature (22-26°C);
  • h hour(s)
  • DMSO Dimethyl sulfoxide
  • EDTA Ethylenediaminetetraacetic acid
  • DIPEA N,N-Diisopropylethylamine.
  • Step 1 N-(4-Fluoro-3-nitrophenyl)propanamide: To a stirred solution of 4-fluoro-3- nitroaniline (14.5 g, 92.877 mmol) in THF (25 ml) was added pyridine (14.88 ml, 185.75 mmol) followed by propanoyl chloride (9.72 ml, 111.98 mmol) and the resultant mixture was stirred at room temperature overnight. The reaction mixture was quenched with ethyl acetate (50 ml). The mixture was washed with IN hydrochloride acid (250 ml) followed by saturated aqueous solution of sodium bicarbonate (250 ml) and brine (150 ml). The organic layer was dried over Na 2 S0 4 and concentrated under reduced pressure to yield 17.0 g of N-(4-fluoro-3- nitrophenyl)propanamide as an off-white solid.
  • N-(4-fluoro-3-nitrophenyl)propanamide can be prepared by the procedure described below.
  • reaction mixture was extracted with ethyl acetate and washed with IN hydrochloric acid, bicarbonate solution, brine, dried over Na 2 S0 4 and concentrated under reduced pressure.
  • the crude residue was purified by column chromatography to yield N-(4-fluoro-3- nitrophenyl)propanamide as a yellow solid.
  • Step 2 N-(4-Fluoro-3-nitrophenyl)-N-methylpropanamide: To a solution of step 1 intermediate (13.0 g, 61.268 mmol) in DMSO (20 ml) was added lithium bis(trimethylsilyl)amide (110.3ml, 110.283 mmol) drop wise and the mixture was stirred for 30 min at room temperature. To this mixture was added methyl iodide (11.37 ml, 183.80 mmol) and the resultant mixture was stirred at room temperature overnight. The reaction mixture was quenched with ethyl acetate (75 ml).
  • Step 3 N- ⁇ 4-[(3-Ethoxypropyl)amino]-3-nitrophenyl ⁇ -N-methylpropanamide: To a well stirred solution of step 2 intermediate (1.0 g, 4.420 mmol) in dimethyl formamide (5 ml) were added 3-ethoxypropan-l -amine (0.343 g, 7.703 mmol) followed by diisopropyl ethylamine (0.804 ml, 4.605 mmol) and the resultant mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue obtained was diluted with water (200 ml).
  • reaction mixture was extracted with ethyl acetate (3 x 100 ml).
  • the combined organic layer was washed with water (150 ml), dried over Na 2 S0 4 and concentrated under reduced pressure to obtain 1.55 g of N- ⁇ 4-[(3- ethoxypropyl)amino]-3-nitrophenyl ⁇ -N-methylpropanamide as a yellow solid.
  • Step 4 N- ⁇ 3-Amino-4-[(3-ethoxypropyl)amino]phenyl ⁇ -N-methylpropanamide: To a solution of step 3 intermediate (1.5 g, 4.84 mmol) in ethanol (20 ml) were added ammonium formate (3.52 g, 35.76 mmol) followed by 10 % Pd-C (0.5 g) at room temperature and stirred for 3 h. The reaction mixture was filtered and washed with ethanol (10 ml) and concentrated to give brown solid. The residue was diluted with water (50 ml). The aqueous layer was extracted with dichloromethane (2 x 50 ml).
  • Step 5 N- ⁇ 2- Amino- 1 -(3-ethoxypropyl)- lH-benzimidazol-5-yll -N-methylpropanamide: To a solution of step 4 intermediate (1.4 g, 5.011 mmol) in ethanol (10 ml) was added cyanogen bromide (0.796 g, 7.516 mmol) and the reaction mixture was stirred overnight. The reaction mixture was concentrated to brown solid. The residue was then diluted with ethyl acetate (100 ml) and washed with sodium bicarbonate solution (50 ml). The aqueous layer was extracted with ethyl acetate (150 ml x 2).
  • Step 1 ((4-Fluoro-3-nitrobenzyl)oxy)triisopropylsilane: To a stirred solution of (4-fluoro-3- nitrophenyl)methanol (5.0 g, 29.217 mmol) in dichloromethane (100 ml) was added 2,6- lutidine (3.57 g, 35.061 mmol) followed by triisopropylsilyltrifluoromethanesulfonate (8.669 ml, 32.317 mmol) and stirred at room temperature overnight. The reaction mixture was washed with water (150 ml) and the aqueous layer was extracted with dichloromethane (2 x 150 ml).
  • Step 2 2-Methyl-l-((2-nitro-4-(((triisopropylsilyl)oxy)methyl)phenyl)amino)propan-2-ol: The coupling reaction of step 1 intermediate (7.0 g, 21.376 mmol) with l-amino-2- methylpropan-2-ol (2.096 g, 23.513 mmol) in dimethyl formamide (50 ml) using diisopropyl ethylamine (7.447 ml, 42.752 mmol) as described in Intermediate 1 step 3 yields 2.7 g of 2- methyl-l-((2-nitro-4-(((triisopropylsilyl)oxy)methyl)phenyl)amino)propan-2-ol as a pale yellow oil.
  • Step 3 l-((2-Arrdno-4-(((triisopropylsilyl)oxy)methyl)phenyl)amino)-2-methylpropan-2-ol: The reaction of step 2 intermediate (2.7 g, 6.807 mmol) with ammonium formate (4.936 g, 78.290 mmol) in presence of 10 % palladium carbon (1.0 g) in ethanol (25 ml) as described in Intermediate 1 step 4 yields 2.5 g of l-((2-amino-4- (((triisopropylsilyl)oxy)methyl)phenyl)amino)-2-methylpropan-2-ol as a pale yellow oil.
  • Step 4 1 - ⁇ 2- Amino-5- [( ⁇ triisopropylsilyl ⁇ oxy)methyl] - lH-benzo [d] imidazol- 1 -yl ⁇ -2- methylpropan-2-ol:
  • the reaction of step 3 intermediate (2.5 g, 6.818 mmol) with cyanogen bromide (1.083 g, 10.227 mmol) in ethanol (25 ml) as described in Intermediate 1 step 5 yields 1.7 g of the title product as a off-white solid.
  • Method B A solution of aryl azide (1 equiv.) in toluene (5 vol) was heated to reflux for 1 h. The solution was cooled at room temperature. To this solution was added appropriate 2- aminobenzimidazole derivative (1 equiv.) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, water, dried over Na 2 S0 4 and concentrated under reduced pressure. The crude residue was purified by column chromatography to yield the desired benzimidazole urea derivative.
  • Example 84 (s, 3H), 4.11-4.18 (m, 2H), 7.05-7.12 (m, 1H), 7.29 (s,
  • Example 143 1.98-2.10 (m, 3H), 3.14 (s, 3H), 4.17 (br s, 2H), 4.56
  • Example 150 2.63 (m, 2H), 3.32-3.42 (m, IH), 3.60-3.70 (m, 2H),
  • Table 4 Structure, chemical name, 1H NMR and MS data of examples 174-197.
  • Step 1 N-(l-(2-Hydroxy-2-methylpropyl)-2-(3-(5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-
  • Step 2 N-[l-(2-Hydroxy-2-methylpropyl)-2-( ⁇ [5-(lH-pyrazol-4-yl)thiophen-2- yl]carbamoyl ⁇ amino)-lH-benzimidazol-5-yl]-N,3,3-trimethylbutanamide: To a stirred solution of step 1 intermediate (40 mg) in ethyl acetate (2 ml) was added saturated solution of ethyl acetate in hydrochloric acid (2 ml) at room temperature and the resultant mixture was stirred at same temperature for 2 h. The reaction mixture was diluted with ethyl acetate (75 ml) and water (75 ml).
  • Step 1 N- (2- (3 -(4-Cyanophenyl)ureido)- 1 - (3 -methoxypropyl)- 1 H-benzo [d] imidazol-5-yl)-N- methylisobutyramide:
  • the coupling reaction of Intermediate 7 (150 mg, 0.496 mmol) with phenyl(4-cyanophenyl)carbamate (130 mg, 0.546 mmol) using triethylamine (139.4 mg, 0.992 mmol) in DMF (5 ml) as described in Example 1 yields 153 mg of N-(2-(3-(4- Cyanophenyl)ureido)-l-(3-methoxypropyl)-lH-benzo[d]imidazol-5-yl)-N- methylisobutyramide as an off-white solid.
  • Step 2 N-[2- ⁇ [(4-Cyanophenyl)carbamoyl] amino ⁇ - 1 -(3-hydroxypropyl)- lH-benzimidazol-5- yl]-N,2-dimethylpropanamide: To a stirred suspension of step 1 intermediate (150 mg, 0.334 mmol) in dichloromethane (7 ml) at -78 °C was added solution of boron tribromide (3.3 ml, 3.348 mmol) in dichloromethane (3 ml) and the reaction was first stirred at -78 °C for 2 h and then at room temperature for 1 h.
  • reaction mixture was diluted with ethyl acetate (80 ml), washed with water (80 ml), saturated solution of bicarbonate (75 ml), brine (75 ml), dried over Na 2 S0 4 and concentrated under reduced pressure.
  • the crude residue was purified by column chromatography to yield 74 mg of the title product as an off-white solid.
  • the examples 200-222 were obtained in the same manner as described above in example 199.
  • the structural formulas, chemical names, 1H NMR and MS data are provided in Table 5.
  • Table 5 Structure, chemical name, 1H NMR and MS data of examples 200-222.
  • Step 1 l-(4-Cyanophenyl)-3-(l-(2-hydroxy-2-methylpropyl)-5-
  • Step 2 l-(4-Cyanophenyl)-3-[l-(2-hydroxy-2-methylpropyl)-5-(hydroxymethyl)-lH- benzo[JJimidazol-2-yl]urea: To a suspension of step 1 intermediate (700 mg, 1.306 mmol) in dioxane (20 ml) was added 0.01 N HCl (20 ml) and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled at room temperature and concentrated under reduced pressure. The solid obtained was triturated with ethyl acetate.
  • Step 3 l-(4-Cyanophenyl)-3-[5-formyl-l-(2-hydroxy-2-methylpropyl)-lH-benzo[ ⁇ i]imidazol- 2-yl]urea: To the step 2 intermediate (200 mg, 0.527 mmol) in acetone (25 ml) was added manganese dioxide (458 mg, 5.271 mmol) and the reaction mixture was stirred at 80 °C overnight. The black suspension formed in the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure.
  • Step 4 ( l S')-l-(4-Cyanophenyl)-3- ⁇ 5-[(3,3-dimethylbutan-2-yl)amino]methyl ⁇ -l-(2-hydroxy- 2-methylpropyl)-lH-benzo[d]midazol-2-yl]urea: To the step 3 intermediate (35 mg, 0.092 mmol) in ethylene dichloride (10 ml) were added glacial acetic acid (0.007 ml, 0.139 mmol), (S)-(+)-3,3-dimethyl-2-butylamine (10 mg, 0.102 mmol) followed by sodium triacetoxy borohydride (29 mg, 0.139 mmol) and the reaction mixture was stirred at room temperature overnight.
  • reaction mixture was diluted with ethyl acetate (75 ml) and washed with bicarbonate solution (100 ml), brine (100 ml) and dried over Na 2 S0 4 .
  • the solvent was concentrated under reduced pressure and the crude mass obtained was purified by column chromatography to yield 8.0 mg of the title product as an off-white solid.
  • Step 2 l-(l-(2-Hydroxy-2-methylpropyl)-5-(hydroxymethyl)-lH-benzo[d]imidazol-2-yl)-3- (5-(3-methyl-l,2,4-oxadiazol-5-yl)thiophen-2-yl)urea:
  • This intermediate was prepared by deprotection reaction of step 1 intermediate (225 mg) using 0.01 N HCl (10 ml) in dioxane (10 ml) as described in Step 2 of Example 223 to yield 190 mg of product as an off-white solid.
  • Step 3 l-(5-Formyl-l-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-2-yl)-3-(5-(3- methyl-l,2,4-oxadiazol-5-yl)thiophen-2-yl)urea: To a stirred solution of step 2 intermediate (190 mg, 0.429 mmol) in dry THF (10 ml) was added Dess-Martin periodinane (273 mg, 0.644 mmol) and the reaction mixture was stirred at room temperature for 3 h.
  • reaction mixture was diluted with ethyl acetate (75 ml) and washed with bicarbonate solution (100 ml), brine (100 ml) and dried over Na 2 S0 4 .
  • the solvent was concentrated under reduced pressure and the crude mass obtained was purified by column chromatography to yield 200 mg of l-(5-formyl-l-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-2-yl)-3-(5-(3- methyl-l,2,4-oxadiazol-5-yl)thiophen-2-yl)urea as an off-white solid.
  • Step 4 l-[5-( ⁇ [(2 l S')-3,3-Dimethylbutan-2-yl]amino ⁇ methyl)-l-(2-hydroxy-2-methylpropyl)- lH-benzimidazol-2-yl]-3-[5-(3-methyl-l,2,4-oxadiazol-5-yl)thiophen-2-yl]urea:
  • the reductive amination reaction of step 3 intermediate 70 mg, 0.159 mmol
  • (S)-(+)-3,3- dimethyl-2-butylamine (322 mg, 3.181 mmol) in presence of sodium triacetoxy borohydride (67 mg, 0.318 mmol) and glacial acetic acid (0.013 ml, 0.238 mmol in methylene dichloride (5 ml) as described in Step 4 of Example 223 yields 10 mg of the title product as an off-white solid.
  • reaction mixture was diluted with ethyl acetate (75 ml ) and washed with bicarbonate solution (100 ml ), brine (100 ml ) and dried over Na 2 S0 4 .
  • the solvent was concentrated under reduced pressure and the crude mass obtained was purified by column chromatography to yield 13 mg of the title product as an off-white solid.
  • Step 1 Ethyl 3-(5-[benzoyl(methyl)amino]-2- ⁇ [(4-cyanophenyl)carbamoyl] amino ⁇ - 1H- benzimidazol-l-yl)propanoate:
  • the coupling reaction of Intermediate 43 (1.5 g, 4.093 mmol) with phenyl(4-cyanophenyl)carbamate (1.072 g, 4.503 mmol) using triethylamine (1.141 ml, 8.186 mmol) in DMF (10 ml) as described in Example 1 yields 700 mg of ethyl 3-(5- [benzoyl(methyl)amino] -2- ⁇ [(4-cyanophenyl)carbamoyl] amino ⁇ - lH-benzimidazol- 1 - yl)propanoate as an off-white solid.
  • Step 2 3-(5-[Benzoyl(methyl)amino]-2- ⁇ [(4-cyanophenyl)carbamoyl]amino ⁇ -lH- benzimidazol-l-yl)propanoic acid: To a well stirred mixture of step 1 intermediate (100 mg, 0.195 mmol) in methanol (5 ml) and water (5 ml) was added sodium hydroxide (23.4 mg, 0.587 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH 2-3 using dilute HCl solid was precipitated.
  • Step 3 N-(2- ⁇ [(4-Cyanophenyl)carbamoyl]amino ⁇ -l-[3-(methylamino)-3-oxopropyl]-lH- benzimidazol-5-yl)-N-methylbenzamide: To a well stirred solution of step 2 intermediate (80 mg, 0.165 mmol) in tetrahydrofuran (10 ml) were added methylamine hydrochloride (12.31 mg, 0.182 mmol), triethylamine (0.231 ml, 1.658 mmol) followed by benzotriazol-l-yl-oxy- tris-(dimethylamino)-phosphonium hexafluorophosphate (87 mg, 0.198 mmol) and the resultant mixture was stirred at room temperature overnight under nitrogen atmosphere.
  • methylamine hydrochloride (12.31 mg, 0.182 mmol
  • triethylamine 0.231 ml, 1.658 m
  • In-vitro ITK inhibition assay of compounds of the invention The compounds of the present invention were evaluated as inhibitors of human recombinant ITK using TR-FRET (time resolved fluorescence resonance energy transfer) based LANCE Ultra assay.
  • TR-FRET time resolved fluorescence resonance energy transfer
  • the ITK assay utilized recombinant human ITK fused with GST (Glutathione S- transferase). The assay was carried out in the 384 well white optiplates on the automated robotic system. 2.5 ⁇ of test compounds (or controls at final 1% DMSO concentration) were added to 384 well plate, followed by 2.5 ⁇ of ITK enzyme in the kinase assay buffer and the reaction was started by adding 5 ⁇ of ATP / peptide substrate mix in the kinase assay buffer.
  • the kinase assay components contained 50 mM Hepes pH 7.5, 5 mM MgCl 2 , 1 mM EGTA (Ethylene glycol tetraacetic acid), 2 mM DTT (Dithiothreitol), 0.01% Tween 20, 0.75 nM ITK enzyme, 100 nM Ulight-VolyGT substrate and 3 ⁇ ATP in 10 ⁇ volume. Incubation was carried out at 23 °C for 15 minutes on the shaker. The assay was stopped by adding EDTA (Ethylenediaminetetraacetic acid). This was followed by the addition of detection reagent Europium anti-phospho-substrate antibody. The fluorescence was measured at 665/620 nm on htrf reader after incubation for 1 hour at RT. IC 50 values were calculated from non-linear regression analysis of the initial rate data using the GraphpadPrism software.
  • IC 50 (nM) values of the compounds are set forth in Table 6, wherein "A” refers to an IC 50 value of less than 50 nM, “B” refers to an IC 50 value in the range of 50.01 to 200.0 nM and “C” refers to IC 50 value of greater than 200 nM.
  • the compounds which were active in the ITK biochemical assay were further tested in the cell based assay for IL2 inhibition in Jurkat cells.
  • Jurkat cells ( Clone E6-1, ATCC) at a density of 0.2 million / well / 200 ⁇ final volume were preincubated with different concentrations of the test compounds for 30 minutes in RPMI - 1640 medium (Sigma) containing 2% FBS. After preincubation, the cells were transferred to anti human CD3 (Clone UCHT1, BD Pharmingen, 10 ⁇ g/ml) coated round bottom 96 well plate. A mixture of anti human CD28 (Clone CD28.2, Biolegend, 2 ⁇ g/ml) and PMA (Sigma, 5 ng/ml) was added to each well and after extensive mixing, the plate was incubated at 37°C for 20 hours in 5% C0 2 incubator.
  • the plate was spun at 4°C at 1200 rpm for 12 minutes and supernatants were separated. The supernatants were analysed for IL2 cytokine according to manufacturer's instructions using Human Quantikine IL2 ELISA kits.
  • EC 50 was calculated from dose response curve by non linear regression analysis using GraphPadPRISM software.
  • the compounds of the present invention were tested in IL2 assay using Jurkat cells and were shown to inhibit IL2 production.
  • the EC 50 (nM) values of the compounds are set forth in Table 6, wherein "A” refers to an EC 50 value of less than 1000 nM, "B” refers to an EC 50 value in the range of 1000.01 to 2000.0 nM and "C” refers to EC 50 value of greater than 2000 nM.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés d'urée de formule (I) en tant qu'inhibiteurs de kinase Tec, en particulier inhibiteurs d'ITK (tyrosine kinase inductible par l'interleukine-2). La présente invention concerne également des procédés de préparation des composés décrits, des intermédiaires utilisés dans leur synthèse, des compositions pharmaceutiques de ceux-ci, et des méthodes de traitement ou de prévention de maladies, d'états et/ou de troubles à médiation par ITK.
PCT/IB2012/054126 2011-08-16 2012-08-14 Nouveaux dérivés d'urée en tant qu'inhibiteurs de kinase tec et leurs utilisations WO2013024427A1 (fr)

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IN2311MU2011 2011-08-16
IN2311/MUM/2011 2011-08-16
US201161531070P 2011-09-05 2011-09-05
US61/531,070 2011-09-05

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US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
WO2018010514A1 (fr) * 2016-07-13 2018-01-18 南京天印健华医药科技有限公司 Composé hétérocyclique utilisé en tant qu'inhibiteur de fgfr
CN109983009A (zh) * 2016-08-17 2019-07-05 Gb005股份有限公司 含有螺环的化合物及其药物用途
US10710981B2 (en) 2016-09-19 2020-07-14 Beijing Innocare Pharma Tech Co., Ltd. Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use thereof

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WO2003074515A1 (fr) * 2002-03-01 2003-09-12 Smithkline Beecham Corporation Diamino-pyrimidines et leurs utilisations en tant qu'inhibiteurs de l'angiogenese

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WO2003074515A1 (fr) * 2002-03-01 2003-09-12 Smithkline Beecham Corporation Diamino-pyrimidines et leurs utilisations en tant qu'inhibiteurs de l'angiogenese

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10508077B2 (en) 2015-03-13 2019-12-17 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US11919839B2 (en) 2015-03-13 2024-03-05 Valo Health, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10988441B2 (en) 2015-03-13 2021-04-27 Valo Early Discovery, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10266487B2 (en) 2015-03-13 2019-04-23 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
CN108349896B (zh) * 2016-07-13 2021-06-01 南京天印健华医药科技有限公司 作为fgfr抑制剂的杂环化合物
US10590109B2 (en) 2016-07-13 2020-03-17 Nanjing Innocare Pharma Tech Co., Ltd. Heterocyclic compounds used as FGFR inhibitors
RU2742485C2 (ru) * 2016-07-13 2021-02-08 Нанцзин Иннокэар Фарма Тек Ко., Лтд. Гетероциклическое соединение, используемое как ингибитор fgfr
CN108349896A (zh) * 2016-07-13 2018-07-31 南京天印健华医药科技有限公司 作为fgfr抑制剂的杂环化合物
AU2017295628B2 (en) * 2016-07-13 2021-05-13 Nanjing Innocare Pharma Tech Co., Ltd. Heterocyclic compound used as FGFR inhibitor
CN107619388A (zh) * 2016-07-13 2018-01-23 南京天印健华医药科技有限公司 作为fgfr抑制剂的杂环化合物
WO2018010514A1 (fr) * 2016-07-13 2018-01-18 南京天印健华医药科技有限公司 Composé hétérocyclique utilisé en tant qu'inhibiteur de fgfr
CN109983009A (zh) * 2016-08-17 2019-07-05 Gb005股份有限公司 含有螺环的化合物及其药物用途
US10710981B2 (en) 2016-09-19 2020-07-14 Beijing Innocare Pharma Tech Co., Ltd. Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use thereof
US11059805B2 (en) 2016-09-19 2021-07-13 Beijing Innocare Pharma Tech Co., Ltd. Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use thereof
US11572353B2 (en) 2016-09-19 2023-02-07 Beijing Innocare Pharma Tech Co., Ltd. Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use thereof

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