WO2014024119A1 - Heterocyclic amides as itk inhibitors - Google Patents

Heterocyclic amides as itk inhibitors Download PDF

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WO2014024119A1
WO2014024119A1 PCT/IB2013/056409 IB2013056409W WO2014024119A1 WO 2014024119 A1 WO2014024119 A1 WO 2014024119A1 IB 2013056409 W IB2013056409 W IB 2013056409W WO 2014024119 A1 WO2014024119 A1 WO 2014024119A1
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Prior art keywords
carboxamide
indole
methylcyclohexanecarboxamido
thiophene
carboxamido
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PCT/IB2013/056409
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French (fr)
Inventor
Sukeerthi Kumar
Abraham Thomas
Rajendra Prakash Chikhale
Nayan Taterao Waghmare
Nanasaheb KADLAG
Neelima Khairatkar-Joshi
Daisy Manish Shah
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Glenmark Pharmaceuticals S.A.
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Publication of WO2014024119A1 publication Critical patent/WO2014024119A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D409/02—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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present patent application relates to heterocyclic amide compounds which are inhibitors of kinase activity, in particular ITK (interleukin-2 inducible tyrosine kinase) activity, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders.
  • ITK interleukin-2 inducible tyrosine 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, 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), and platelet derived growth factor receptor, 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 includes ITK (IL2-inducible T-cell kinase, Gibson, S. et al, Blood, 1993, 82, 1561-1572), Txk (T-cell expressed kinase; Haire, R. N. et al, Hum. Mol. Genet., 1994, 3, 897-901), Tec (tyrosine kinase expressed in hepatocellular carcinoma cells; Mano et al, Oncogene, 1990, 5, 1781-1786), Btk (Bruton's tyrosine kinase; Vetrie, D.
  • ITK IL2-inducible T-cell kinase, Gibson, S. et al, Blood, 1993, 82, 1561-1572
  • Txk T-cell expressed kinase; Haire, R. N. et al, Hum. Mol. Genet., 1994, 3, 897-901
  • Tec tyrosine kinase expressed in
  • 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 triggered including Lck activation followed by ZAP70 and ITK phosphorylation.
  • ITK subsequently activates phospholipase C ⁇ (PLC- ⁇ ) that further cleaves phosphotidyli-nositol 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, 1995, 3, 757-769). These T cells also exhibit defective PLCyl tyrosine phosphorylation, inositol triphosphate production, Ca 2+ mobilization, and cytokine production (such as IL-2 and IFNy) in response to TCR cross- linking (Schaeffer, E. M.
  • ITK activity plays a requisite role in TCR signal transduction; and selective inhibition of ITK should have immunosuppressive, anti-inflammatory, and anti-pro liferative effects.
  • 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, WO2005079791, WO2007058832, WO2008025820, WO2007076228 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.
  • an object of the present invention is to provide novel compounds which are inhibitors of kinase activity, in particular ITK activity.
  • Compounds of the present invention may be useful in the treatment of disorders associated with inappropriate kinase activity, in particular inappropriate ITK activity, for example in the treatment and prevention of disorders mediated by ITK mechanisms.
  • Such disorders include 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, 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 rhinitis and atopic dermatitis
  • autoimmune diseases including rheumatoid arthritis, multiple sclerosis, psoriasis, type I diabetes, T cell mediated hypersen
  • the present invention relates to compound of formula (I)
  • P is selected form phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and indazolyl each optionally being substituted with one or more substituents selected from halogen, cyano, Ci_ 8 alkyl, haloCi_ 8 alkyl, haloCi_ 8 alkoxy and - NR a R b ;
  • Q is selected from hydrogen, imidazolyl, pyrazolyl and pyridyl;
  • L is selected from -(CH 2 ) n CR a R b -, -C(O)-, -C(0)NR a -, -(CH 2 ) n C(0)NR a -, - C(0)(CH 2 ) n C(0)-, and -(CR a R b ) n O-;
  • M is selected from hydrogen, cyano, Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, haloCi_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3 _i 2 cycloalkylCi_ 8 alkyl and C 6 _i 4 aryl;
  • R 1 is Ci_ 8 alkyl
  • R 2 is selected from Ci_ 8 alkyl, Ci_ 8 alkoxyCi_ 8 alkyl, hydroxyCi_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3 _i 2 cycloalkylalkyl, C6 -14 aryl, 3- to 15- membered heterocyclylCi_ 8 alkyl, 5- to 14- heteroaryl and -(CH 2 ) n NR b C(0)R c ;
  • R 3 is Ci_ 8 alkyl
  • R 4 is Ci_ 8 alkyl
  • R 5 is Ci_ 8 alkyl
  • R 6 is selected from Ci_ 8 alkyl and C 3 _i 2 cycloalkyl
  • R 7 is C 3 _i 2 cycloalkyl
  • R 8 is Ci_ 8 alkyl
  • R 9 is C 3 _i 2 cycloalkyl
  • R 10 is Ci_ 8 alkyl
  • R n is Ci_ 8 alkyl
  • R 12 is C 3 _i 2 cycloalkyl
  • R 13 is Ci_ 8 alkyl
  • R 14 is C 3 _i 2 cycloalkyl
  • R a is independently selected from hydrogen and Ci_ 8 alkyl; at each occurrence, R b is independently selected from hydrogen and Ci_ 8 alkyl; at each occurrence, R c is independently selected from hydrogen and Ci_ 8 alkyl; and 'n' is an integer ranging from 1 to 6, both inclusive.
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) include compounds of formula (la), (lb), (Ic), (Id) and (Ie) as described hereinafter. 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein Q is hydrogen (according to an embodiment defined below) and n is 1 or 2 (according to another embodiment defined below).
  • R 1 is Ci_ 4 alkyl (e.g. methyl or ethyl).
  • R 2 is -(CH 2 ) consultNR b C(0)R c .
  • R b is Ci.galkyl (e.g.methyl);
  • R c is Ci_ 8 alkyl (e.g.methyl or ethyl) and n is 1.
  • R 2 is -(CH 2 ) consultNR b C(0)R c .
  • R b is methyl;
  • R c is methyl or ethyl and n is 1.
  • R 3 is Ci_ 4 alkyl (e.g. methyl).
  • R 5 is Ci_ 4 alkyl (e.g. methyl).
  • C 3 _i 2 cycloalkyl e.g. cyclohexyl
  • R 7 is C 3 _i 2 cycloalkyl (e.g. cyclohexyl).
  • R 8 is Ci_ 4 alkyl (e.g. methyl).
  • R 9 is C 3 _i 2 cycloalkyl (e.g. cyclohexyl).
  • R 10 is Ci_ 4 alkyl (e.g. methyl).
  • R a and R b are Ci_ 8 alkyl (e.g. methyl).
  • compounds of formula (I) in which P is phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl or indazolyl each optionally being substituted with one or more substituents selected from CI, F, cyano, methyl, trifluoroalkyl, trifluoromethoxy and
  • -L- is -(CH 2 ) compassionCR a R b -, -C(O)-, -C(0)NR a -, -(CH 2 ) compassionC(0)NR a -, - C(0)(CH 2 ) n C(0)-, and -(CR a R b ) n O-.
  • R a is hydrogen or Ci_ 4 alkyl (e.g. methyl)
  • R b is hydrogen or Ci_ 4 alkyl (e.g. methyl) and n is 1 or 2.
  • -L- is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -,-CH 2 CH 2 C(CH 3 ) 2 -, -C(O)-, - C(0)NH-, -C(0)N(CH 3 )-, -CH 2 CH 2 -C(0)NH- or -CH 2 CH 2 -C(0)N(CH 3 )-.
  • M is hydrogen, cyano, Ci_ 4 alkyl (e.g. methyl, ethyl, propyl or isopropyl), Ci_ 4 alkoxy (e.g. methoxy or ethoxy), Ci_ 4 alkoxyCi_ 4 alkyl (e.g. methoxymethyl, 2- methoxyethyl, 3-methoxypropyl), hydroxyCi_ 4 alkyl (e.g. 2-hydroxy-2-methyl-propyl), haloCi_ 4 alkyl (e.g. trifluoroethyl), C 3 _i 2 cycloalkyl (e.g. cyclopropyl, cyclopentyl or cyclohexyl) or C 3 _ i 2 cycloalkylCi_ 4 alkyl (e.g. cyclopropylmethyl).
  • Ci_ 4 alkyl e.g. methyl, ethyl, propyl or isopropyl
  • M is hydrogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-hydroxy-2-methyl-propyl, trifluoroethyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclopropylmethyl.
  • M is C 6 -i 4 aryl optionally substituted with halogen (e.g. 4-chlorophenyl).
  • M is hydrogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-hydroxy-2-methyl-propyl, trifluoroethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or 4-chlorophenyl.
  • compounds of formula (I) with an IC 50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
  • the invention also provides a compound of formula (la), which is an embodiment of a compound of formula (I).
  • P is selected form phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and indazolyl each optionally being substituted with one or more substituents selected from halogen, cyano, Ci_salkyl, haloCi_salkyl, haloCi_salkoxy and - NR a R b ;
  • Q is selected from hydrogen, imidazolyl, pyrazolyl and pyridyl;
  • L is selected from -(CH 2 ) compassionCR a R b -, -C(O)-, -C(0)NR a -, -(CH 2 ) disregardC(0)NR a -, - C(0)(CH 2 ) n C(0)-, and -(CR a R b ) n O-;
  • M is selected from hydrogen, cyano, Ci_salkyl, Ci_salkoxy, Ci_ 8 alkoxyCi_salkyl, hydroxyCi_salkyl, haloCi_salkyl, C 3 _i 2 cycloalkyl, C 3 _i 2 cycloalkylCi_salkyl and C 6 -i 4 aryl;
  • R 1 is Ci_ 8 alkyl
  • R is selected from Ci_salkyl, Ci_ 8 alkoxyCi_salkyl, hydroxyCi_salkyl, C 3 _i 2 cycloalkyl, C 3 _i 2 cycloalkylalkyl, C 6 -i 4 aryl, 3- to 15- membered heterocyclylCi-salkyl, 5- to 14- heteroaryl, and -(CH 2 ) n NR b C(0)R c ; at each occurrence, R a is independently selected from hydrogen and Ci_salkyl; at each occurrence, R b is independently selected from hydrogen and Ci_salkyl; at each occurrence, R c is independently selected from hydrogen and Ci_salkyl; and
  • 'n' is an integer ranging from 1 to 6, both inclusive.
  • the compounds of formula (la) 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 of 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 (la) as defined above wherein R 1 is methyl or ethyl (according to an embodiment defined below) and Q is hydrogen (according to another embodiment defined below).
  • R 1 is Ci_ 4 alkyl (e.g. methyl or ethyl).
  • R 2 is -(CH 2 ) n NR b C(0)R c .
  • R b is Ci_ 8 alkyl (e.g.methyl);
  • R c is Ci_salkyl (e.g.methyl or ethyl) and n is 1.
  • compounds of formula (la) in which R 2 is -(CH 2 ) n NR b C(0)R c .
  • R b is methyl;
  • R c is methyl or ethyl and n is 1.
  • R a and R b are Ci_ 8 alkyl (e.g. methyl).
  • compounds of formula (la) in which P is phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl or indazolyl each optionally being substituted with one or more substituents selected from CI, F, cyano, methyl, trifluoroalkyl, trifluoromethoxy and
  • -L- is -(CH 2 ) n CR a R b -, -C(O)-, -C(0)NR a -, -(CH 2 ) n C(0)NR a -, - C(0)(CH 2 ) n C(0)-, and -(CR a R b ) n O-.
  • R a is hydrogen or Ci_ 4 alkyl (e.g. methyl)
  • R b is hydrogen or Ci_ 4 alkyl (e.g. methyl) and n is 1 or 2.
  • -L- is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -,-CH 2 CH 2 C(CH 3 ) 2 -, -C(O)-, - C(0)NH-, -C(0)N(CH 3 )-, -CH 2 CH 2 -C(0)NH-, or -CH 2 CH 2 -C(0)N(CH 3 )-.
  • M is hydrogen, cyano, Ci_ 4 alkyl (e.g. methyl, ethyl, propyl or isopropyl), Ci_ 4 alkoxy (e.g. methoxy or ethoxy), Ci_ 4 alkoxyCi_ 4 alkyl (e.g. methoxymethyl, 2- methoxyethyl, 3-methoxypropyl), hydroxyCi_ 4 alkyl (e.g. 2-hydroxy-2-methyl-propyl), haloCi_ 4 alkyl (e.g. trifluoroethyl), C 3 -i 2 cycloalkyl (e.g. cyclopropyl, cyclopentyl or cyclohexyl) or C 3 _ i 2 cycloalkylCi_ 4 alkyl (e.g. cyclopropylmethyl).
  • Ci_ 4 alkyl e.g. methyl, ethyl, propyl or isopropyl
  • M is hydrogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-hydroxy-2-methyl-propyl, trifluoroethyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclopropylmethyl.
  • M is hydrogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-hydroxy-2-methyl-propyl, trifluoroethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and 4-chlorophenyl.
  • compounds of formula (la) with an IC 50 value of less than 2000 11M, preferably less than 1000 11M, more preferably less than 500 11M, with respect to ITK activity.
  • the invention also provides a compound of formula (lb), which is an embodiment of a compound of formula (I).
  • P is selected from thienyl and pyridyl
  • Q is hydrogen or pyrazolyl
  • L is -C(0)NH-
  • M is C 3 _i 2 cycloalkyl
  • R is Ci_ 8 alkyl
  • R 4 is Ci_ 8 alkyl.
  • the compounds of formula (lb) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (lb) as defined above wherein P is
  • M is C 3 _i 2 cycloalkyl (e.g. cyclopropyl).
  • M is cyclopropyl
  • R is methyl
  • IC 50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
  • the invention also provides a compound of formula (Ic), which is an embodiment of a compound of formula (I).
  • P is thienyl
  • Q is hydrogen or pyrazolyl
  • L is -C(0)NH-
  • M is selected from Ci_salkyl and C 3 _i 2 cycloalkyl
  • R 5 is Ci_ 8 alkyl
  • R 6 is selected from Ci_salkyl and C 3 _i 2 cycloalkyl.
  • the compounds of formula (Ic) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (Ic) as defined above wherein R 5 is methyl (according to an embodiment defined below) and Q is hydrogen (according to another embodiment defined below).
  • R 5 is Ci_ 4 alkyl (e.g. methyl).
  • R 6 is C 3 -i 2 cycloalkyl (e.g. cyclohexyl) or Ci_salkyl (e.g.
  • M is ethyl or cyclopropyl
  • R 5 is methyl
  • the invention also provides a compound of formula (Id), which is an embodiment of a compound of formula (I).
  • P is selected from thiazolyl, thienyl and pyridyl
  • Q is hydrogen or pyrazolyl
  • L is -C(0)NH-
  • M is selected from Ci_salkyl and C 3 _i 2 cycloalkyl
  • R 7 is C 3 -i 2 cycloalkyl
  • R 8 is Ci_ 8 alkyl.
  • the compounds of formula (Id) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (Id) as defined above wherein M is ethyl or cyclopropyl (according to an embodiment defined below) and R is methyl (according to another embodiment defined below).
  • M is Ci_salkyl (e.g. ethyl) or C 3 _i 2 cycloalkyl (e.g. cyclopropyl).
  • R 7 is C 3 _i 2 cycloalkyl (e.g. cyclohexyl).
  • R is Ci_ 4 alkyl (e.g. methyl).
  • M is ethyl or cyclopropyl
  • R 7 is cyclohexyl
  • R is methyl. According to an embodiment, specifically provided are compounds of formula (Id) with an IC 50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
  • the invention also provides a compound of formula (Ie), which is an embodiment of a compound of formula (I).
  • P is selected from thiazolyl, thienyl and pyridyl each being optionally substituted with one or more substituents selected from -NR a R b ;
  • Q is hydrogen or pyrazolyl
  • L is -C(0)NR a -
  • M is C 3 _i 2 cycloalkyl
  • R 9 is C 3 _i 2 cycloalkyl
  • R 10 is Ci_ 8 alkyl
  • R a is hydrogen or Ci_salkyl
  • R b is Ci-galkyl
  • the compounds of formula (Ie) 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 of 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 (Ie) as defined above wherein M is cyclopropyl (according to an embodiment defined below) and R 10 is methyl (according to another embodiment defined below). According to one embodiment, specifically provided are compounds of formula (Ie), in hich P is
  • M is C 3 _i 2 cycloalkyl (e.g. cyclopropyl).
  • R 9 is C 3 -i 2 cycloalkyl (e.g. cyclohexyl).
  • R 10 is Ci_ 4 alkyl (e.g. methyl).
  • -L- is -C(0)NH-
  • M is cyclopropyl
  • R 9 is cyclohexyl
  • R 10 is methyl
  • compounds of formula (Ie) with an IC 50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
  • the present invention also provides a pharmaceutical composition that includes at least one compound described herein or a pharmaceutically acceptable salt thereof 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 kinase activity, in particular ITK activity.
  • 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 diseases, conditions and/or disorders selected from the group consisting of respiratory diseases, allergic diseases, autoimmune diseases, inflammatory disorders, proliferative disorders, transplant rejection, graft versus host disease, HIV, aplastic anemia, pain including inflammatory pain 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.
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • alkyl refers to a straight or branched 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. Ci_salkyl), and which is attached to the rest of the molecule by a single bond.
  • Ci_salkyl carbon atoms
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 2-methylpropyl (isobutyl), n-pentyl, 1,1-dimethylethyl (t-butyl), and 2,2- dimethylpropyl. Unless set forth or recited to the contrary, all 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 (i.e. C 2-10 alkenyl) and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z ' sopropenyl, 2- methyl-l-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, 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 i.e. C 2-10 alkynyl).
  • 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 (i.e. Ci_salkoxy). Representative examples of such groups are -OCH3 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 (i.e. Ci_ 8 alkoxyCi_salkyl or Ci_ 8 alkyloxyCi_ 8 alkyl).
  • alkoxyalkyl moiety includes, but are not limited to, - CH 2 OCH 3 and -CH 2 OC 2 H 5 . Unless set forth or recited to the contrary, 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 (i.e. haloCi_salkyl).
  • haloalkyl moiety include, but are not limited to, trifluoromethyl, trifluoroethyl, 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 (i.e. haloCi_salkoxy).
  • 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.
  • hydroxy alkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi_ 8 alkyl).
  • hydroxyalkyl moiety include, but are not limited to -CH 2 OH, -C 2 H 4 OH and -CH(OH)C 2 H 4 OH.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, for example C 3 _i 2 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, for example C 3 _ 8 cycloalkylCi_ 8 alkyl.
  • 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, for example C 3 _ 8 cycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclop entenyl. 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, for example C 3 _ 8 cycloalkenylCi_ 8 alkyl.
  • 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 (i.e. C 6- i 4 aryl), 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.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C 6 -i 4 aryloxy).
  • 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.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C 6 _i 4 arylCi_ 8 alkyl, such as -CH 2 C 6 H 5 and -C 2 H 4 C 6 H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclyl or “heterocyclic ring” 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 olefmic 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 (i.e. heterocyclylCi.salkyl).
  • 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. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroaryl 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, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazol
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. heterarylCi-salkyl).
  • 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.
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
  • 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.
  • 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. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present patent application may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated. It is also to be understood that compounds of the invention may exist in solvated forms (such as hydrates) as well as unsolvated forms, and that the invention encompasses all such forms.
  • compositions 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. Typically, 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 ITK 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 kinase activity, particularly ITK activity and are thus useful in the treatment or prevention of disorders associated with ITK.
  • Compounds and pharmaceutical compositions of the present invention selectively inhibit ITK and are thus useful in the treatment or prevention of a range of disorders associated with the activation of ITK which includes, but are not limited to respiratory diseases, allergic diseases, autoimmune diseases, inflammatory disorders, immunological disorders, proliferative disorders, transplant rejection, graft versus host disease, HIV, aplastic anemia, pain including inflammatory pain and other diseases and disorders associated with ITK.
  • 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, anti-histamines, anti-cancer agents, protein kinase inhibitors, 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.
  • reaction conditions for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention.
  • the compounds obtained using the general reaction sequences may be of insufficient purity.
  • These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.
  • a general approach for the preparation of compound of formula (I) of the present invention (where A, x, y, L, M, P and Q are as defined compound of formula (I)) can be prepared as depicted in Scheme 1.
  • An appropriately substituted heteroaryl amine of formula (1) can be coupled with a suitable acid halide of general formula (2) (wherein X is halogen) using a suitable base such as, but not limited to triethylamine, pyridine or diisopropylethylamine to give the compound of formula (I).
  • a suitable coupling agent such as, but not limited to 1- ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI
  • the indole derivatives of the formula (la) (where R , R , M, P and Q are as defined in compound of formula (la)) can be prepared by following the synthetic steps depicted in scheme 2.
  • a general apparoach for the synthesis of thieno[2,3-b]pyrrole amide derivative of formula (Ie- 1) (where R 9 , R 10 , M and P are as defined in compound of formula (Ie)) is as shown in scheme 13.
  • work-up implies the following operations: distribution of the reaction mixture between the organic and aqueous phase, separation of layers, drying the organic layer over sodium sulphate, filtration and evaporation of the organic solvent.
  • Purification implies purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.
  • Step 1 iert-Butyl(4-fluoro-3-nitrophenyl)carbamate: A solution of di-iert-butyl dicarbonate (6.14 g, 28.185 mmol) in iert-butanol (20 ml) was added drop wise to a solution of 4-fluoro- 3-nitroaniline (4 g, 25.622 mmol) in ie/t-butanol (18 ml) at 0 °C and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was evaporated under reduced pressure and the residue obtained was purified by column chromatography to yield 5.6 g of product as a yellow solid.
  • Step 2 ieri-Butyl(4-fluoro-3-nitrophenyl)methylcarbamate: To a solution of step 1 intermediate (5.5 g, 21.484 mmol) in dry N,N-dimethylformamide (71 ml), sodium hydride (950 mg, 23.632 mmol) was added at 0 °C and the reaction mixture was stirred for 30 min at room temperature. To the reaction mixture, methyl iodide (6.71 ml, 107.42 mmol) was added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2 x 100 ml).
  • Step 3 4-Fluoro-N-methyl-3-nitroaniline: To a stirred solution of step 2 intermediate (5.5 g, 20.370 mmol) in dichloromethane (50 ml), trifluoroacetic acid (12.5 ml) was added at 0 °C and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was evaporated under reduced pressure and to the residue aqueous saturated solution of sodium bicarbonate (50 ml) was added. The mixture was extracted with dichloromethane (2 x 75 ml). The combined organic layer was washed with brine (100 ml) and dried over sodium sulphate.
  • Step 4 2,2,2-Trifluoro-N-(4-fluoro-3-nitrophenyl)-N-methylacetamide: To a stirred solution of step 3 intermediate (1.0 g, 5.882 mmol) in dichloromethane (20 ml), triethylamine (0.826 ml, 5.882 mmol) was added followed by addition of trifluoroacetic anhydride (0.817 ml, 5.88 mmol) at 0 °C and the reaction mixture was stirred for 45 min at the same temperature. The reaction mixture was quenched with water (50 ml). The mixture was extracted with dichloromethane (2 x 75 ml).
  • Step 5 N- ⁇ 4-[l-Cyano-2-(cyclopropylamino)-2-oxoethyl]-3-nitrophenyl ⁇ -2,2,2-trifluoro-N- methylacetamide: To a stirred solution of 2-cyano-N-cyclopropylacetamide (1.034 g, 8.345 mmol) in dry tetrahydrofuran (12 ml), sodium hydride (333 mg, 8.345 mmol) was added at 0 °C and the reaction mixture was stirred at same temperature for 30 min. The step 4 intermediate (1.1 1 g, 4.172 mmol) was added to reaction mixture and the reaction mixture was stirred overnight at room temperature.
  • Step 6 2-Amino-N-cyclopropyl-6-[methyl(trifluoroacetyl)amino]-lH-indole-3-carboxamide: To a stirred solution of step 5 intermediate (650 g, 1.756 mmol) in dry N,N- dimethylformamide (8 ml), ferric chloride (854 mg, 5.268 mmol) was added followed by the addition of zinc dust (1.1 16 g, 17.560 mmol) and the reaction mixture was first stirred at room temperature for 30 min and then stirred at 100 °C for 1 h.
  • reaction mixture was cooled at room temperature, quenched with saturated solution of sodium bicarbonate (50 ml) and extracted with ethyl acetate (75 ml x 2). The combined organic layer was washed with water (100 ml) and dried over sodium sulphate. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain 421 mg of the title compound as an off-white solid.
  • Step 1 N-(4-Fluoro-3-nitrophenyl)cyclohexanecarboxamide: To a stirred solution of 4-fluoro- 3-nitroaniline (25.0 g, 160.13 mmol) and dry pyridine (25 ml, 0.310 mmol) in dry tetrahydrofuran (250 ml), cyclohexanecarbonyl chloride (23.6 ml, 176.15 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture, hydrochloric acid (1 N, 100 ml) was added and the mixture was extracted with ethyl acetate (2 x 300 ml).
  • Step 2 N-(4-Fluoro-3 -nitrophenyl)-N-methylcyclohexanecarboxamide :
  • This intermediate was prepared by reaction of step 1 intermediate (35.0 g, 131.57 mmol) with methyl iodide (12.34 ml, 197.30 mmol) using sodium hydride (7.89 g, 197.30 mmol) in dry tetrahydrofuran (350 ml) as described in step 2 of intermediate 1 to yield 31.4 g of product as a yellow solid.
  • Step 3 N-(4-(l-Cyano-2-(cyclopropylamino)-2-oxoethyl)-3-nitrophenyl)-N- methylcyclohexanecarboxamide:
  • This intermediate was prepared by displacement reaction of step 2 intermediate (31.0 g, 1 10.71 mmol) with 2-cyano-N-cyclopropylacetamide (27.45 g, 221.43 mmol) using sodium hydride (8.85 g, 221.42 mmol) in dry tetrahydrofuran (310 ml) as described in step 5 of intermediate 1 to afford 42.1 g of product as pale yellow oil.
  • Step 4 2-Amino-N-cyclopropyl-6-(N-methylcyclohexanecarboxamido)-lH-indole-3- carboxamide:
  • the title compound was prepared by reductive cyclization of step 3 intermediate (42.0 g, 109.375 mmol) using ferric chloride (53.22 g, 328.125 mmol) and zinc dust (69.52 g, 1093.37 mmol) in dry N,N-dimethylformamide (420 ml) as described in step 6 of intermediate 1 to obtain 27.1 g of title compound as a pale yellow solid.
  • Step 1 N-(4-Fluorobenzyl)-3,3-dimethylbutanamide: To a stirred solution of 3,3- dimethylbutanoic acid (7.63 ml, 159.93 mmol), catalytic amount of N,N-dimethylformamide (1.2 ml) in dichloromethane (60 ml), oxalyl chloride (7.0 ml, 79.9 mmol) was added drop wise at 0 °C and the reaction mixture was stirred for 3 h at room temperature and then evaporated under reduced pressure.
  • Step 2 N-(4-Fluorobenzyl)-N,3,3-trimethylbutanamide: The N-methylation reaction of step 1 intermediate (7.0 g, 31.346 mmol) using methyl iodide (3.0 ml, 47.02 mmol) in presence of sodium hydride (1.9 g, 47.02 mmol) in dry tetrahydrofuran (90 ml) as described in step 2 of intermediate 1 yields 8.0 g of product as a yellow solid.
  • Step 3 N-(4-Fluoro-3-nitrobenzyl)-N,3,3-trimethylbutanamide: Concentrated sulphuric acid (98 %, 15 ml) was added to concentrated nitric acid (70 %, 31 ml) at 0-5 °C and stirred for 15 min at same temperature. This nitrating mixture was drop-wise added to a solution of step 2 intermediate (7.5 g, 31.604 mmol) in concentrated sulfuric acid (7 ml) at 0-5 ° C and the reaction mixture was stirred for 1 h at same temperature. The reaction mixture was quenched with ice-cooled water (75 ml) and the mixture was extracted with ethyl acetate (2 x 150 ml).
  • Step 4 N-(4-(l-Cyano-2-(cyclopropylamino)-2-oxoethyl)-3-nitrobenzyl)-N,3,3- trimethylbutanamide:
  • step 3 intermediate 5.0 g, 17.73 mmol
  • 2-cyano- N-cyclopropylacetamide 4.39 g, 35.46 mmol
  • sodium hydride (1.42 g, 35.46 mmol
  • step 5 of intermediate 1 affords 3.55 g of product as pale yellow oil.
  • Step 5 2-Amino-N-cyclopropyl-6-((N,3,3-trimethylbutanamido)methyl)-lH-indole-3- carboxamide:
  • step 4 intermediate 3-(9.067 mmol) with ferric chloride (4.412 g, 27.20 mmol) in presence of zinc dust (5.92 g, 90.67 mmol) in dry N,N- dimethylformamide (35 ml) as described in step 6 of intermediate 1 yields 1.6 g of the title product as a light pink solid.
  • Table 1 Structure, chemical name and spectral data of Intermediates 4-55. Structure Chemical name and Spectral data
  • Step 1 N- ⁇ 2-[(4-Fluoro-3-nitrophenyl)amino]-2-oxoethyl ⁇ -N-methylpropanamide: To a stirred solution of 4-fluoro-3-nitroaniline (7.0 g, 44.837 mmol) and [methyl(propanoyl)amino] acetic acid (6.5 g, 44.837 mmol) in dry 1 ,2-dichloroethane (224 ml), HOBt (2.3 g, 16.589 mmol), N-methyl morpholine (5.8 ml, 52.01 mmol) and EDCI (10 g, 52.01 mmol) were added and the reaction mixture was stirred at room temperature overnight.
  • 4-fluoro-3-nitroaniline 7.0 g, 44.837 mmol
  • [methyl(propanoyl)amino] acetic acid 6.5 g, 44.837 mmol
  • HOBt 2.3 g, 16.589 m
  • reaction mixture was concentrated under reduced pressure, diluted with water (150 ml) and extracted with ethyl acetate (2 x 250 ml). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 6.75 g of product as an off-white solid.
  • Step 2 N- ⁇ 2-[(4-Fluoro-3-nitrophenyl)(methyl)amino]-2-oxoethyl ⁇ -N-methylpropanamide:
  • the N-methylation reaction of step 1 intermediate (6.7 g, 23.674 mmol) using methyl iodide (2.22 ml, 35.512 mmol) in presence of sodium hydride (1.42 g, 35.512 mmol) in dry tetrahydrofuran (68 ml) as described in step 2 of intermediate 1 yields 7.0 g of product as a brown oil.
  • Step 3 N-(2-((4-(l-Cyano-2-(cyclopropylamino)-2-oxoethyl)-3-nitrophenyl)(methyl)amino)- 2-oxoethyl)-N-methylpropionamide:
  • the displacement reaction of step 2 intermediate (3.0 g, 10.101 mmol) with 2-cyano-N-cyclopropylacetamide (2.5 g, 20.202 mmol) using sodium hydride (808 mg, 20.202 mmol) in dry tetrahydrofuran (30 ml) as described in step 5 of intermediate 1 affords 3.45 g of product as yellow solid.
  • Step 4 2- Amino-N-cyclopropyl-6-(N-methy l-2-(N-methylpropionamido)acetamido)- 1 H- indole-3-carboxamide:
  • the reductive cyclization of step 3 intermediate (3.4 g, 8.478 mmol) using ferric chloride (4.12 g, 25.436 mmol) and zinc dust (5.54 g, 84.78 mmol) in dry N,N- dimethylformamide (34 ml) as described in step 6 of intermediate 1 affords 1.0 g of the title compound as a brown solid.
  • Step 1 N-Cyclohexyl-4-fluoro-N-methyl-3-nitrobenzamide: This intermediate was prepared by reaction of 4-fluoro-3-nitrobenzoic acid (5.5 g, 27.02 mmol) with N-methyl cyclohexyl amine (3.5 ml, 27.02 mmol) using HOBt (1.34 g, 9.997 mmol) and EDCI (6.0 g, 31.34 mmol) in presence of N-methyl morpholine (3.45 ml, 31.33 mmol) in dry 1 ,2-dichloroethane (135 ml) as described in step 1 of intermediate 56 to obtain 5.8 g of product as a yellow solid.
  • Step 2 4-( 1 -Cyano-2-(ethylamino)-2-oxoethyl)-N-cyclohexyl-N-methyl-3 -nitrobenzamide :
  • the displacement reaction of step 1 intermediate (5.7 g, 20.35 mmol) with 2-cyano-N- ethylacetamide (4.5 g, 40.71 mmol) in presence of sodium hydride (1.6 g, 40.71 mmol) in dry tetrahydrofuran (57 ml) as described in step 5 of intermediate 1 affords 9.0 g of product as a pale yellow oil.
  • Step 3 2-Amino-N 6 -cyclohexyl-N 3 -ethyl-N 6 -methyl-lH-indole-3,6-dicarboxamide:
  • the reaction of step 2 intermediate (1.0 g, 2.68 mmol) with ferric chloride (1.30 g, 7.97 mmol) in presence of zinc dust (1.75 g, 26.85 mmol) in dry N,N-dimethylformamide (10 ml) as described in step 6 of intermediate 1 affords 400 mg of the title compound as an off-brown solid.
  • This intermediate is prepared in 4 steps (i) The coupling reaction of 4-fluoro-3-nitrobenzoic acid (5 g, 27.01 mmol) with (2S)-3,3-dimethylbutan-2-amine (3.67 ml, 27.01 mmol) using HOBt (1.34 g, 9.997 mmol) and EDCI (6.0 g, 31.34 mmol) in presence of N-methyl morpholine (3.45 ml, 31.33 mmol) as described in step 1 of intermediate 56 (ii) The N- methylation of N-[(2 l S , )-3,3-dimethylbutan-2-yl]-4-fluoro-3-nitrobenzamide (6.5 g, 24.22 mmol) using methyl iodide (2.27 ml, 36.33 mmol) in presence of sodium hydride (1.45 g, 36.33 mmol) as described in step 2 of intermediate 1 ; (iii) The fluoro displacement of
  • Step 1 N-(4-Fluoro-3-nitrophenyl)-3,3-dimethylbutanamide: This intermediate was prepared by reaction of 3,3-dimethylbutanoic acid (18.3 ml, 144.1 1 mmol) with 4-fluoro-3-nitroaniline (15.0 g, 96.07 mmol) using oxalyl chloride (16.6 ml, 192.14 mmol) and pyridine (15 ml) in dry tetrahydrofuran (90 ml) and N,N-dimethylformamide (1.5 ml) as described in step 1 of intermediate 3 to obtain 21.56 g of product as off white solid.
  • Step 2 N-(4-Fluoro-3-nitrophenvl)-N,3,3-trimethylbutanamide:
  • the step 1 intermediate (21.5 g, 84.64 mmol) undergoes N-methylation using methyl iodide (7.9 ml, 126.96 mmol) in presence of sodium hydride (5.0 g, 126.96 mmol) in dry tetrahydrofuran (215 ml) as described in step 2 of intermediate 1 to yield 20.45 g of product as a yellow solid.
  • Step 3 Ethyl cyano ⁇ 4-[(3,3-dimethylbutanoyl)(methyl)amino]-2-nitrophenyl ⁇ acetate: The displacement reaction of step 2 intermediate (8.0 g, 29.850 mmol) with ethyl cyano acetate (6.36 ml, 59.701 mmol) in the presence of sodium hydride (2.4 g, 59.709 mmol) in dry tetrahydrofuran (80 ml) as described in step 5 of intermediate 1 affords 8.05 g of product as a pale yellow oil.
  • Step 4 N-[4-(Cyanomethyl)-3-nitrophenyl]-N,3,3-trimethylbutanamide: To a stirred solution of step 3 intermediate (8.0 g 45.17 mmol) in dimethyl sulfoxide (41 ml) was added saturated brine solution (17.3 ml) and the reaction mixture was heated at 120 °C overnight. The reaction was cooled to room temperature, diluted with water (150 ml), extracted with ethyl acetate (100 ml x 3) and washed with brine (150 ml). The mixture was evaporated and the residue obtained was purified by column chromatography to give 3.7 g of product as yellow oil.
  • Step 5 N-[4-( 1 -Cyano-3 -methoxy-2-oxopropyl)-3 -nitrophenyl] -N,3 ,3 -trimethylbutanamide : Triethyl amine ( 4.1 ml, 29.18 mmol) was added to a solution of step 4 intermediate (3.67 g, 12.69 mmol) in dry dichloromethane (37 ml) followed by 4-(dimethyl amino pyridine) (155 mg, 1.269 mmol) at 0 °C. To this mixture methoxyacetyl chloride (1.22 ml, 13.33 mmol) was added over 10-15 min.
  • the reaction mixture was warmed to room temperature, stirred for 2 h and concentrated under reduced pressure.
  • the residue obtained was diluted with water and extracted with ethyl acetate (75 ml x 3), washed with saturated solution of sodium bicarbonate (75 ml), aqueous hydrochloric acid (75 ml) and brine (75 ml).
  • the crude residue after evaporation of mixture was purified by column chromatography to afford 3.95 g of product as a brown solid.
  • Step 6 N-[2-Amino-3-(methoxyacetyl)-lH-indol-6-yl]-N,3,3-trimethylbutanamide: Step 5 intermediate (3.9 g, 10.78 mmol) undergoes reaction with ferric chloride (5.2 g, 32.36 mmol) and zinc dust (7.0 g, 107.8 mmol) in dry N,N-dimethylformamide (40 ml) as described in step 6 of intermediate 1 to afford 1.87 g of the title compound as a yellow solid.
  • Step 1 Ethyl 2-cyano-2-(4-(N-methylcyclohexanecarboxamido)-2-nitrophenyl)acetate: The reaction of N-(4-Fluoro-3-nitrophenyl)-N-methylcyclohexanecarboxamide (step 2 of intermediate-2) (20.0 g, 71.42 mmol) with ethyl cyano acetate (15.3 ml, 142.82 mmol) in the presence of sodium hydride (5.7 g, 142.82 mmol) in dry tetrahydrofuran (200 ml) as described in step 5 of intermediate 1 affords 25.0 g of product as a pale yellow oil.
  • Step 2 N-(4-(Cyanomethyl)-3 -nitrophenyl)-N-methylcyclohexanecarboxamide :
  • This intermediate is prepared by reaction of step 1 intermediate (25.0 g 67.02 mmol) with saturated solution of brine (50 ml) in dimethyl sulfoxide (132 ml) as described in step 4 of intermediate 63 to give 14.2 g of product as yellow oil.
  • Step 3 N-(4-( 1 -Cyano-3 -methoxy-2-oxopropyl)-3 -nitrophenyl)-N-methylcyclohexane carboxamide:
  • This intermediate was prepared by reaction of step 2 intermediate (3.0 g, 9.96 mmol) with methoxyacetyl chloride (962 ⁇ , 10.46 mmol) in presence of triethyl amine ( 3.2 ml, 22.9 mmol) and 4-(dimethyl amino pyridine) (121 mg, 0.99 mmol) in dry dichloromethane (30 ml) as described in step 5 of intermediate 63 to afford 3.675 g of product as a brown solid.
  • Step 4 N-(2- Amino-3 -(2-methoxyacetyl)- 1 H-indol-6-yl)-N-methylcyclohexanecarboxamide : Step 3 intermediate (3.67 g, 9.82 mmol) undergoes reaction with ferric chloride (4.8 g, 29.47 mmol) and zinc dust (6.5 g, 98.25 mmol) in dry N,N-dimethylformamide (40 ml) as described in step 6 of intermediate 1 to obtain 1.5 g of the title compound as a yellow solid.
  • Step 1 Methyl 5 -cyano-5 -(4-(N-methylcyclohexanecarboxamido)-2-nitrophenyl)-4- oxopentanoate: The coupling reaction of N-(4-(cyanomethyl)-3-nitrophenyl)-N- methylcyclohexanecarboxamide (Step 2 intermediate of 64) (3.0 g, 9.93 mmol) with methyl 4-chloro-4-oxobutyrate (1.57 g, 10.43 mmol) in the presence of triethyl amine (2.31 g, 3.20 ml, 22.84 mmol) and 4-(dimethylamino)pyridine (121 mg, 0.933 mmol) in dry dichloromethane (300 ml) as described in step 5 of intermediate 63 affords 5.00 g of product as a brown oil which was directly used in next step without purification.
  • Step 2 Methyl 4-(2-amino-6-(N-methylcyclohexanecarboxamido)- lH-indol-3-yl)-4- oxobutanoate: Step 1 intermediate (4.4 g, 10.57 mmol) undergoes reaction with ferric chloride (5.10 g, 31.72 mmol) and zinc dust (6.90 g, 105.74 mmol) in dry N,N- dimethylformamide (44 ml) as described in step 6 of intermediate 1 to obtain 1.80 g of the title compound as an off-white solid.
  • Step 1 tert-Butyl 2-cyano-2-(2-nitro-4-(N,3,3-trimethylbutanamido)phenyl)acetate: The displacement reaction of N-(4-Fluoro-3-nitrophenyl)-N,3,3-trimethylbutanamide (step 2 intermediate 63) (29.1 g, 108.45 mmol) with tert-butyl cyanoacetate (31.25 ml, 216.9 mmol) in presence of sodium hydride (8.67 g, 216.9 mmol) in dry tetrahydrofuran (290 ml) as described in step 5 of intermediate 1 to afford 40.6 g of product as a pale yellow oil.
  • Step 2 tert-Butyl 2-amino-6-(N,3,3-trimethylbutanamido)-lH-indole-3-carboxylate: the step 1 intermediate (40.3 g, 103.4 mmol) undergoes reaction with ferric chloride (50.51 g, 310.2 mmol) and zinc dust (67.59 g, 1034.9 mmol) in dry N,N-dimethylformamide (403 ml) as described in step 6 of intermediate 1 to yield 31.3 g of product as an off-white solid.
  • Step 1 5-Chloro-N-cyclohexyl-N-methyl-4-nitrothiophene-2-carboxamide: 5-Chloro-4- nitrothiophene-2-carboxylic acid (7.2 g, 34.782 mmol) in thionyl chloride (30 ml) was stirred at reflux temperature for 4 h. The reaction mixture concentrated under reduced pressure and diluted with dry tetrahydrofuran (50 ml).
  • Step 2 5-[ 1 -Cyano-2-(cyclopropylamino)-2-oxoethyl]-N-cyclohexyl-N-methyl-4- nitrothiophene-2-carboxamide:
  • This intermediate is prepared by reaction of step 1 intermediate (1.2 g, 3.973 mmol) with 2-cyano-N-cyclopropylacetamide (985 mg, 7.947 mmol) in presence of sodium hydride (318 mg, 7.947 mmol) in dry tetrahydrofuran (12 ml) as described in step 5 of intermediate 1 to afford 1.65 g of product as brown oil.
  • Step 3 5-Amino-N 2 -cyclohexyl-N 6 -cyclopropyl-N 2 -methyl-4H-thieno[3,2-b]pyrrole-2,6- dicarboxamide:
  • This intermediate is prepared by reaction of step 2 intermediate (1.6 g, 4.107 mmol) with ferric chloride (2.0 g, 12.323 mmol) and zinc dust (2.68 g, 41.07 mmol) in dry N,N-dimethylformamide (16 ml) as described in step 6 of intermediate 1 to yield 370 mg of product as a brown solid.
  • Step 1 5-[ 1 -Cyano-2-(ethylamino)-2-oxoethyl]-N-cyclohexyl-N-methyl-4-nitrothiophene-2- carboxamide:
  • This intermediate was prepared by displacement reaction of 5-chloro-N- cyclohexyl-N-methyl-4-nitrothiophene-2-carboxamide (4.0 g, 13.245 mmol) with 2-cyano-N- ethylacetamide (3.0 g, 26.49 mmol) in presence of sodium hydride (1.05 g, 56.49 mmol) in dry tetrahydrofuran (40 ml) as described in step 5 of intermediate 1 to afford 3.0 g of product as brown oil.
  • Step 2 5-Amino-N 2 -cyclohexyl-N 6 -ethyl-N 2 -methyl-4H-thieno[3,2-b]pyrrole-2,6- dicarboxamide:
  • the title compound was prepared by reductive cyclization of step 1 intermediate (3 g, 7.947 mmol) using ferric chloride (3.86 g, 23.84 mmol) and zinc dust (5.2 g, 79.47 mmol) in dry N,N-dimethylformamide (30 ml) as described in step 6 of intermediate 1 to obtain 650 mg of product as a brown solid.
  • Step 1 4-Chloro-5-nitrothiophene-2-carbaldehyde: Concentrated sulfuric acid (55 ml) was drop wise added to concentrated nitric acid (96 ml) and the mixture was stirred at -10 to -5 °C for 1 h. To this mixture 4-chlorothiophene-2-carbaldehyde (24 g, 165.51 mmol) was added in portions at -5 °C and the reaction mixture was stirred for 1 h at same temperature. The reaction was quenched by adding ice cooled water (1 lit.) and the mixture was extracted with chloroform (2 x 500 ml). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 16.09 g of product as an off white solid. 1H NMR (300 MHz, CDC1 3 ): ⁇ 7.66 (s, 1H), 9.93 (s, 1H).
  • Step 2 4-Chloro-5-nitrothiophene-2-carboxylic acid: To a stirred solution of step 1 intermediate (9.5 g, 49.738 mmol) in acetone (250 ml), sulfamic acid (9.7 g, 99.47 mmol) was added followed by drop wise addition of aqueous solution of sodium chlorite (50 ml, 6.8 g, 74.60 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, residue obtained was treated with hydrochloric acid (I N, 100 ml) and the mixture was stirred for 30 min.
  • sulfamic acid 9.7 g, 99.47 mmol
  • sodium chlorite 50 ml, 6.8 g, 74.60 mmol
  • Step 3 4-Chloro-N-cyclohexyl-N-methyl-5-nitrothiophene-2-carboxamide: This intermediate was prepared by coupling reaction of step 2 intermediate (4 g, 19.32 mmol) with N- methylcyclohexanamine (3 ml, 23.18 mmol) in presence of dry pyridine (3 ml, 0.03 mmol) in dry tetrahydrofuran (100 ml) as described in step 1 of intermediate 72 to yield 4.81 g of product as a yellow solid.
  • Step 4 4-[l-Cyano-2-(cyclopropylamino)-2-oxoethyl]-N-cyclohexyl-N-methyl-5- nitrothiophene-2-carboxamide:
  • This intermediate was prepared by displacement reaction of step 3 intermediate (2.8 g, 9.27 mmol) with 2-cyano-N-cyclopropylacetamide (2.3 g, 18.54 mmol) in presence of sodium hydride (742 mg, 18.54 mmol) in dry tetrahydrofuran (28 ml) as described in step 5 of intermediate 1 to afford 3.1 g of product as brown oil.
  • 1H NMR 300 MHz, CDCI3: ⁇ 1.03-2.00 (m, 10H), 3.02 (s, 3H), 3.70-3.77 (m, 1H), 7.14 (br s, 1H).
  • Step 5 5-Amino-N 2 -cyclohexyl-N 4 -cyclopropyl-N 2 -methyl-6H-thieno[2,3-b]pyrrole-2,4- dicarboxamide:
  • the title compound was prepared by reductive cyclization of step 4 intermediate (1.6 g, 7.702 mmol) using ferric chloride (3.7 g, 23.106 mmol) and zinc dust (5 g, 77.02 mmol) in dry N,N-dimethylformamide (30 ml) as described in step 6 of intermediate 1 to obtain 780 mg of product as a brown solid.
  • heteroaryl and aromatic carboxylic acids viz. thiazole-4-carboxylic acid, 5- bromothiophene-2-carboxylic acid, 2-bromo-l,3-thiazole-4-carboxylic acid, 6-bromopyridine- 2-carboxylic acid, 5-(4-fluorophenyl)thiophene-2-carboxylic acid, pyridine-2-carboxylic acid, 5-(pyridin-4-yl)thiophene-2-carboxylic acid, 2-(pyridin-4-yl)-l ,3-thiazole-4-carboxylic acid, picolinic acid, 4-fluoro-3-nitroaniline and lH-pyrazole-4-boronic acid pinacol ester were used in the preparation of the compounds of the present invention are commercially available and can be prepared by the person skilled in the art.
  • 2-(Dimethylamino)thiazole-4-carboxylic acid was prepared by hydrolysis of commercially available ethyl 2-(dimethylamino)-l ,3-thiazole-4- carboxylate (CAS No: 630423-58-4).
  • Method A A mixture of substituted aryl or heterocyclic carboxylic acid (1.0 equiv.) and thionyl chloride (15 vol.) was stirred at reflux temperature for 3-5 h. The reaction mixture was concentrated under reduced pressure and the acid chloride obtained was directly used in the next step.
  • Method B To a stirred solution of substituted aryl or heterocyclic carboxylic acid (1.0 equiv.) in dichloromethane (10 vol.) was added catalytic amount of N,N-dimethylformamide (2-3 drops) followed by drop wise addition of oxalyl chloride (2 equiv.) at 0 °C and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was evaporated under reduced pressure and the acid chloride obtained was directly used in the next step.
  • Step 2 Coupling of acid chloride with amine: To a stirred solution of amino indole (1.0 equiv) in dry tetrahydrofuran (10 vol.), dry pyridine (2.5 equiv.) was added at room temperature. This reaction mixture was drop wise added to a solution of acid chloride (1.5 equiv.) in dry tetrahydrofuran (10 vol) at 0-5 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with hydrochloric acid (1 N), extracted thrice with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulphate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield desired product.
  • Step 1 2-(6-(N-Methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)-lH-indole-3- carboxamido)ethyl thiophene-2-carboxylate:
  • This intermediate was prepared by reaction of intermediate 38 (250 mg, 0.696 mmol) with thiophene-2-carbonyl chloride (75 ⁇ , 0.696 mmol) using dry pyridine (250 ⁇ , 0.002 mmol) in dry tetrahydrofuran (4 ml) as described in general procedure to yield 125 mg of the title compound as an off-white solid.
  • Step 2 N-(2-Hydroxyethyl)-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2- carboxamido)-lH-indole-3-carboxamide:
  • the step 1 intermediate (1 15 mg) was stirred in methanolic ammonia (7 ml) at room temperature overnight.
  • the reaction mixture was evaporated under reduced pressure, diluted with water (10 ml), solid obtained was collected by Alteration and dried to yield 90 mg of an off-white solid.
  • reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (2 x 25 ml), dried over sodium sulphate and concentrated uneder reduced pressure. The residue was purified by column chromatography to yield 50 mg of product as white solid.
  • Step 1 5-Bromothiophene-2-carbonyl chloride: The title compound was obtained from 5- bromothiophene-2-carboxylic acid (702 mg, 3.389 mmol) and thionyl chloride (7 ml) as described in general procedure (Method A).
  • Step 2 2-(5-Bromothiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylcyclohexanecarboxamido)-l H-indole-3 -carboxamide:
  • Step 3 N-Cyclopropyl-6-(N-methylcyclohexanecarboxamido)-2-(5-(l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazol-4-yl)thiophene-2-carboxamido)-lH-indole-3-carboxamide:
  • the step 2 intermediate (700 mg, 1.289 mmol) was dissolved in dry N,N-dimethylformamide (30 ml) and degassed for 10 min.
  • the aqueous solution of potassium carbonate (10.5 ml) was added to it and the reaction mixture was degassed for 90 min.
  • Step 4 2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylcyclohexanecarboxamido)-lH-indole-3-carboxamide:
  • step 3 intermediate 100 mg, 0.163 mmol
  • methanol 5 ml
  • step 3 intermediate 100 mg, 0.163 mmol
  • methanol 5 ml
  • step 3 intermediate 100 mg, 0.163 mmol
  • methanol 5 ml
  • step 3 intermediate 100 mg, 0.163 mmol
  • methanol 5 ml
  • step 3 intermediate 100 mg, 0.163 mmol
  • methanol 5 ml
  • the reaction mixture was evaporated under reduced pressure.
  • the residue was cooled and basified ( ⁇ pH 9) using aqueous ammonia solution, precipitated solid obtained was collected by Alteration and washed with water (50 ml).
  • the solid was dried and purified by column chromatography to yield 60 mg of product as a yellow solid.
  • step 3 intermediate (1 equiv.) in ethanol (10 vol.)
  • p-toluene sulphonic acid (2 equiv.) was added and the reaction mixture was stirred at reflux temperature for 1 h.
  • the reaction mixture was concentrated under reduced pressure and the residue thus obtained was basified by addition of aqueous saturated solution of sodium bicarbonate.
  • the precipitated solid collected by filtration, washed and dried. The solid was purified by column chromatography to yield the title compound.
  • Step 1 6-(2-(Benzyloxy)-N-methylacetamido)-2-(5-bromothiophene-2-carboxamido)-N- cyclopropyl-1 H-indole-3 -carboxamide:
  • This intermediate was prepared by the reaction of intermediate 55 (1.0 g, 2.548 mmol) with 5-bromothiophene-2-carbonyl chloride (791 mg, 3.822 mmol) in presence of dry pyridine (1 ml) in dry tetrahydrofuran (14.15 ml) as described in general procedure yields 810 mg of product as yellow solid.
  • Step 2 6-(2-(Benzyloxy)-N-methylacetamido)-N-cyclopropyl-2-(5-(l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazol-4-yl)thiophene-2-carboxamido)-l H-indole-3 -carboxamide:
  • This intermediate was prepared by Suzuki coupling reaction of step 1 intermediate (800 mg, 1.3757 mmol) with l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan- 2-yl)-lH-pyrazole (474 mg, 1.705 mmol) using tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.023 mmol) in presence of 1.6M potassium carbonate (1 1.84 ml) in N,N- dimethylformamide (38 ml) as described in step 3
  • Step 3 2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-6-(2-(benzyloxy)-N- methylacetamido)-N-cyclopropyl-l H-indole-3 -carboxamide:
  • This intermediate was prepared by reaction of step 2 intermediate (240 mg, 0.367 mmol) using hydrochloric acid (6 N, 4.8 ml) in methanol (12 ml) as described in step 4 (Method A) of example 1 10 to yield 150 mg of the title product as a yellow solid.
  • APCI-MS (m/z): 569.1 1 (M+H) + .
  • Step 4 2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(2-hydroxy-N- methylacetamido)-lH-indole-3-carboxamide: To a stirred solution of step 3 intermediate (140 mg, 0.214 mmol) in dichloromethane (3 ml) was added iodotrimethylsilane (61 ⁇ , 0.428 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with water (50 ml) and extracted with ethyl acetate (2 x 50 ml).
  • Example 1 12-158 were obtained in the same manner as described above in Example 1 10.
  • 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 1 12-158.
  • Example 128 0.74 (s, 2H), 0.96 (br s, 9H), 1.25 (s, 2H), 2.06 (s, 2H), 3.07
  • Example 132 1.69 (m, 2H), 1.98 (s, 2H), 3.17 (s, 2H), 3.33 (s,merged with
  • Example 138 DMSO-Jg: ⁇ 0.65-1.62 (m, 15H), 2.17-2.25 (m, 1H), 3.14 (s,
  • Example 139 d 6 ⁇ 0.70-1.58 (m, 14H), 2.10-2.16 (m, 1H), 2.95-3.95 (m,
  • Example 140 1.63 (m, 10H), 2.13-2.20 (m, 1H), 2.85-2.93 (m, 1H), 3.13 (s,
  • Example 141 2.30 (m, 1H), 3.02-3.09 (m, 1H), 3.29 (s, 3H), 6.15 (s, 1H),
  • Step 1 ie/t-Butyl 2-(2-methylthiazole-4-carboxamido)-6-(N,3,3-trimethylbutanamido)-lH- indole-3-carboxylate: The coupling reaction of intermediate 66 (2.5 g, 6.963 mmol) with 2- methyl-l ,3-thiazole-4-carbonyl chloride (1.5 g, 10.445 mmol) using dry pyridine (2.5 ml, 0.025 mmol) in dry tetrahydrofuran (39 ml) as described in general procedure yields 2.05 g of product as a yellow solid.
  • Step 2 2-(2-Methylthiazole-4-carboxamido)-6-(N,3,3-trimethylbutanamido)-lH-indole-3- carboxylic acid: To a stirred solution of step 1 intermediate (2.0 g) in dry dichloromethane (32 ml), trifluoroacetic acid (8.2 ml) was added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure followed by treatment with saturated solution of sodium bicarbonate (75 ml) and the solid obtained was collected by Alteration to yield 1.82 g of product as a brown solid.
  • Step 3 2-Methyl-N-(6-(N,3,3-trimethylbutanamido)-lH-indol-2-yl)thiazole-4-carboxamide: To a solution of step 2 intermediate (1.8 g, 4.20 mmol) in dry toluene (53 ml), triethylamine (17.7 ml, 126.02 mmol) was added and heated to 130 °C for 18 h. The reaction mixture was evaporated under reduced pressure, 1 N hydrochloric acid (50 ml) was added and extracted with ethyl acetate (2 x 100 ml).
  • Step 4 N-(3 -(3 -Methoxypropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-2- methylthiazole-4-carboxamide: To a solution of step 3 intermediate (270 mg, 0.702 mmol) and freshly prepared 3-methoxypropanal (93 mg, 1.053 mmol) in dry dichloromethane (12 ml), triethyl silane (336 ⁇ , 2.106 mmol) was added at 0 °C followed by trifluroacetic acid (156 ⁇ , 2.106 mmol). After being stirred at 0 °C for 1 h, the reaction mixture was warmed to room temperature overnight.
  • Example 162-165 were obtained in the same manner as described above in Example 161.
  • the structure, chemical names, 1H NMR and MS data are provided in table 6.
  • Step 1 5-Bromo-N-(3-(2-methoxyacetyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiophene-2-carboxamide:
  • the coupling of intermediate 64 (1 g, 2.915 mmol) with 5- bromothiophene-2-carbonyl chloride (905 mg, 4.373 mmol) in presence of dry pyridine (1 ml, 0.01 mmol) in dry tetrahydrofuran (16 ml) as described in general procedure yields 1.28 g of product as an off-white solid.
  • Step 2 5 -Bromo-N-(3 -(2-methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)thiophene-2-carboxamide: To a solution of step 1 intermediate (1.26 g, 2.366 mmol) in triethylsilane (12 ml), trifluoroacetic acid (12 ml) was added and reaction mixture was heated at 70-80 °C overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and extracted with ethyl acetate (2 x 100 ml).
  • Step 3 N-(3-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)thiophene-2-carboxamide:
  • step 2 intermediate (600 mg, 1.15 mmol) with l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (399 mg, 1.436 mmol) using [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.96 mg, 0.019 mmol) in presence of aqueous solution of potassium carbonate (9 ml) in N,N-dimethylformamide
  • Step 4 N-(3-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(lH- pyrazol-4-yl)thiophene-2-carboxamide:
  • the deprotection reaction of step 3 intermediate 125 mg, 0.212 mmol) using hydrochloric acid (6 N, 1.95 ml) in methanol (6.25 ml) as described in step 4 of example 1 10 (Method A) yields 30 mg of the title compound as a yellow solid.
  • Step 1 N-(3-(2-Methoxyacetyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiophene-2-carboxamide:
  • the coupling reaction of intermediate 64 (300 mg, 0.874 mmol) with thiophene-2-carbonyl chloride (103 ⁇ , 0.962 mmol) using dry pyridine (300 ⁇ , 0.003 mmol) in dry tetrahydrofuran (3 ml) as described in general procedure affords 210 mg of product as a pale yellow solid.
  • Step 2 N-(3-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiophene-2-carboxamide:
  • This intermediate was prepared by reductive deoxyegenation of step 1 intermediate (180 mg) using triethyl silane (5 ml) and trifluoroacetic acid (5 ml) as described in step 2 of example 166 to yield 97 mg of product as a pale yellow solid.
  • Table 7 Structure, chemical name, 1H NMR and MS data of Examples 168-173.
  • Example 172 ⁇ 0.90-1.69 (m, 10H), 2.20-2.28 (m, 1H), 2.82 (s, 3H), 3.27
  • Example 173 2.90-2.99 (m, 2H), 3.15 (s, 3H), 3.25-3.35 (m, 3H), 3.50-3.60
  • Step 1 2-(Pyridin-4-yl)-l,3-thiazole-4-carbonyl chloride: The title compound was obtained by the reaction of 2-(pyridin-4-yl)-l,3-thiazole-4-carboxylic acid (832 mg, 4.038 mmol) in presence of oxalyl chloride (470 ⁇ , 5.384 mmol) in dichloromethane (10 ml) as described in general procedure (Method B).
  • Step 2 tert-Butyl 6-(N-methylcyclohexanecarboxamido)-2-(2-(pyridin-4-yl)thiazole-4- carboxamido)-lH-indole-3-carboxylate: The coupling reaction of intermediate 69 (1 g, 2.692 mmol) with 2-(pyridin-4-yl)-l,3-thiazole-4-carbonyl chloride using dry pyridine (2 ml, 0.002 mmol) and catalytic amoumt of N,N-dimethylformamide (2 drops) in dry tetrahydrofuran (14.9 ml) as described in general procedure yields 220 mg of product as a pale yellow solid.
  • Step 3 6-(N-Methylcyclohexanecarboxamido)-2-(2-(pyridin-4-yl)thiazole-4-carboxamido)- lH-indole-3-carboxylic acid:
  • This intermediate was prepared by the reaction of step 2 intermediate (215 mg, 0.384 mmol) with trifluoroacetic acid (0.8 ml) in dichloromethane (3.2 ml) as described in step 2 of example 161 to yield 170 g of product as a pale yellow solid.
  • Step 4 N-(6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-2-(pyridin-4-yl)thiazole-4- carboxamide:
  • This intermediate was prepared by reaction of step 3 intermediate (160 mg, 3.18 mmol) with triethylamine (1.34 ml, 9542.7 mmol) in dry toluene (4 ml) as described in step 3 of example 161 to yield 136 mg of product as an off-white solid.
  • Step 5 N-(3-(3-Amino-3-oxopropyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 2-(pyridin-4-yl)thiazole-4-carboxamide: To a stirred solution of step 4 intermediate (127 mg, 0.276 mmol) in dry acetonitrile (3 ml), aluminium chloride (1 10 mg, 0.829 mmol) was added at 0 °C followed by addition of acrylamide (40 mg, 0.553 mmol) and the reaction mixture was refluxed for 3 h.
  • Step 1 N-(6-(N-Methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(pyridin-4-yl)thiophene- 2-carboxamide:
  • the intermediate was prepared in three steps (i) by coupling reaction of intermediate 69 (1.5 g, 4.043 mmol) with 5-(pyridin-4-yl)thiophene-2-carboxylic acid (996 mg, 4.851 mmol) using TBTU (0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 5.2 g, 16.461 mmol) in presence of N,N-diisopropylethylamine (3.5 ml, 20.21 mmol) as described in example 108; (ii) deprotection of tertiary butyl group using trifluoroacetic acid (5 ml) described in step
  • Step 2 N-(3-(3-Amino-3-oxopropyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 5-(pyridin-4-yl)thiophene-2-carboxamide:
  • the title compound was prepared by reaction of step 1 intermediate (250 mg, 0.5451 mmol) with acrylamide (43 mg, 0.599 mmol) using aluminium chloride (145 mg, 1.09 mmol) in dry acetonitrile (5 ml) as described in step 5 of example 174 to yield 55 mg of the title compound a yellow solid.
  • Table 8 Structure, chemical name, 1H NMR and MS data of Examples 175-184.
  • Step 1 5-bromothiophene-2-carbonyl chloride: The title compound was obtained from 5- bromothiophene-2-carboxylic acid (13.8 g, 66.852 mmol) and thionyl chloride (150 ml) as described in general procedure (Method A).
  • Step 2 tert-Butyl 2-(5-bromothiophene-2-carboxamido)-6-(N,3,3-trimethylbutanamido)-lH- indole-3-carboxylate:
  • This intermediate was prepared by reaction of intermediate 66 (16 g, 44.568 mmol) with 5-bromothiophene-2-carbonyl chloride (step 1 intermediate) in the presence of dry pyridine (16 ml) in dry tetrahydrofuran (160 ml) as described in general procedure to yield 8.8 g of product as yellow solid.
  • Step 3 2-(5-Bromothiophene-2-carboxamido)-6-(N,3,3-trimethylbutanamido)-lH-indole-3- carboxylic acid:
  • This intermediate was prepared by reaction of a step 2 intermediate (15.9 g, 28.98 mmol) with trifluoroacetic acid (57.9 ml) in dichloromethane (241.5 ml) as described in step 2 of example 161 to yield 13.61 g of product as a yellow solid.
  • This intermediate was prepared by reaction of step 3 intermediate (13.6 mg, 27.620 mmol) with triethylamine (1 16.4 ml, 828.61 mmol) in dry toluene (345.2 ml) as described in step 3 example 161 to yield 8.14 g of product as yellow solid.
  • Step 5 N-(3 -(3 -Amino-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-5 - bromothiophene-2-carboxamide:
  • This compound was prepared by reaction of step 4 intermediate (8.1 g, 18.060 mmol) with acrylamide (1.41 g, 19.866 mmol) using aluminium chloride (4.816 g, 36.121 mmol) in dry acetonitrile (125 ml) as described in step 5 of example 174 to yield 4.34 g of product as yellow solid;
  • 1H NMR 300 MHz, DMSO-J 6 ): ⁇ 0.94 (s, 9H), 2.04 (s, 2H), 2.65-2.75 (m, 2H), 3.01-3.12 (m, 2H), 3.26 (s, 3H), 5.50 (s, 1H), 5.62 (s, 1H), 6.87 (d,
  • Step 6 N-(3-(3-Amino-3-oxopropyl)-6-(N,3,3-trimethylbutanamido)-lH-indol-2-yl)-5-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)thiophene-2-carboxamide:
  • This intermediate was prepared by coupling reaction of step 5 intermediate (4.2 g, 8.078 mmol) with l-(tetrahydro- 2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (2.78 g, 10.017 mmol) using [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (131.8 mg, 0.161 mmol) in presence of aqueous soution of potassium carbonate (65.8
  • Step 7 N-(3 -(3 -amino-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-5 -( 1 H- pyrazol-4-yl)thiophene-2-carboxamide:
  • the title compound was prepared by deprotection reaction of step 6 intermediate (4.8 g, 8.125 mmol) using p-toluene sulphonic acid (3.09 g, 16.250 mmol) in ethanol (102 ml) as described in step 4 (Method B) of example 1 10 to yield 1.5 g of product as yellow solid.
  • the title compound is prepared by coupling reaction of intermediate 72 (200 mg, 0.556 mmol) with l ,3-thiazole-4-carbonyl chloride (108 mg, 0.834 mmol) using dry pyridine (200 ⁇ , 0.002 mmol) in dry tetrahydrofuran (3 ml) as described in general procedure to yield 370 mg of the title compound as a pale yellow solid.
  • Step 1 5-bromothiophene-2-carbonyl chloride: The title compound was obtained from 5- bromothiophene-2-carboxylic acid (950 mg, 4.589 mmol) and thionyl chloride (10 ml) as described in general procedure (Method A).
  • Step 2 5-(5-Bromothiophene-2-carboxamido)-N 2 -cyclohexyl-N 6 -cyclopropyl-N 2 -methyl-4H- thieno[3,2-b]pyrrole-2,6-dicarboxamide:
  • This intermediate was prepared by coupling of intermediate 72 (1.1 g, 3.059 mmol) with 5-bromothiophene-2-carbonyl chloride (step 1 intermediate) in presence of dry pyridine (1.1 ml, 0.01 mmol) in dry tetrahydrofuran (17 ml) as described in general procedure to yield 600 mg of product as a yellow solid.
  • Step 3 N 2 -Cyclohexyl-A ⁇ -cyclopropyl-N 2 -methyl-5 -(5 -( 1 -(tetrahydro-2H-pyran-2-yl)- 1 H- pyrazol-4-yl)thiophene-2-carboxamido)-4H-thieno[3,2-b]pyrrole-2,6-dicarboxamide:
  • This intermediate is prepared by Suzuki coupling reaction of step 2 intermediate (600 mg, 1.093 mmol) with l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-pyrazole (378 mg, 1.355 mmol) using ⁇ , - bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (16 mg, 0.018 mmol) in presence of potassium carbon
  • Step 4 5-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N 2 -cyclohexyl-N 6 -cyclopropyl-N 2 - methyl-4H-thieno[3,2-b]pyrrole-2,6-dicarboxamide:
  • the title compound is preparded by deprotection step 3 intermediate (103 mg) using hydrochloric acid (6 N, 3 ml) in methanol (6 ml) as described in step 4 of example 1 10 (Method A) to afford 40 mg of product as a yellow solid.
  • Step 1 5-bromothiophene-2-carbonyl chloride: The title compound was obtained from 5- bromothiophene-2-carboxylic acid (492 mg, 2.378 mmol) and thionyl chloride (5 ml) as described in general procedure (Method A).
  • Step 2 5-(5-Bromothiophene-2-carboxamido)-N 2 -cyclohexyl-N 4 -cyclopropyl-N 2 -methyl-6H- thieno[2,3-b]pyrrole-2,4-dicarboxamide:
  • This intermediate was prepared by coupling of intermediate 74 (570 mg, 1.585 mmol) with 5-bromothiophene-2-carbonyl chloride (step 1 intermediate) in the presence of dry pyridine (600 ⁇ ) in dry tetrahydrofuran (9 ml) as described in general procedure to yield 475 mg of product as a yellow solid.
  • Step 3 N 2 -Cyclohexyl-A ⁇ -cyclopropyl-N 2 -methyl-5 -(5 -( 1 -(tetrahydro-2H-pyran-2-yl)- 1 H- pyrazol-4-yl)thiophene-2-carboxamido)-6H-thieno[2,3-b]pyrrole-2,4-dicarboxamide:
  • This intermediate is prepared by Suzuki coupling reaction of step 2 intermediate (470 mg, 0.856 mmol) with l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-pyrazole (295 mg, 1.062 mmol) using ⁇ , -
  • Step 4 5-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N 2 -cyclohexyl-N 4 -cyclopropyl-N 2 - methyl-6H-thieno[2,3-b]pyrrole-2,4-dicarboxamide:
  • the title compound was prepared by deprotection of step 3 intermediate (70 mg, 0.1 13 mmol) using hydrochloric acid (6 N, 1.1 ml) in methanol (3.7 ml) as described in step 4 of example 1 10 to afford 26 mg of product as a yellow solid.
  • 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.
  • the excited europium chelate donor dye transfers its energy to the nearby ULight acceptor dye molecule that will in turn emit light at 665 nm.
  • the intensity of light emission is proportional to the level of the ULight peptide phosphorylation.
  • 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 MgC12, 1 mM EGTA (Ethylene glycol tetraacetic acid), 2 mM DTT (Dithiothreitol), 0.01% Tween 20, 0.75 nM ITK enzyme, 100 nM U light-Poly GT 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 10 wherein "A” refers to an IC 50 value of less than 50 nM, “B” refers to IC 50 value in range of 50.01 to 100 nM, “C” refers to an IC 50 value in range of 100.01 - 500 nM and “D” refers to an IC 50 value of more than 500 nM.

Abstract

The present invention is directed to heterocyclic amide compounds of formula (I) as Tec kinase inhibitors, in particular ITK (interleukin-2 inducible tyrosine kinase) inhibitors. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders mediated by ITK.

Description

HETEROCYCLIC AMIDES AS ITK INHIBITORS
Related Applications
This application claims benefit of Indian provisional application No(s). 2257/MUM/2012 filed on August 6, 2012; 2888/MUM/2012 filed on October 1, 2012; 762/ MUM/2013 filed on March 13, 2013 and US provisional application No(s). 61/696,439 filed on September 4, 2012; 61/717,224 filed on October 23, 2012. All of which are hereby incorporated by reference in their entirety.
Technical Field of the Invention
The present patent application relates to heterocyclic amide compounds which are inhibitors of kinase activity, in particular ITK (interleukin-2 inducible tyrosine kinase) activity, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders.
Background of the Invention
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, 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), and platelet derived growth factor receptor, 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 includes ITK (IL2-inducible T-cell kinase, Gibson, S. et al, Blood, 1993, 82, 1561-1572), Txk (T-cell expressed kinase; Haire, R. N. et al, Hum. Mol. Genet., 1994, 3, 897-901), Tec (tyrosine kinase expressed in hepatocellular carcinoma cells; Mano et al, Oncogene, 1990, 5, 1781-1786), Btk (Bruton's tyrosine kinase; Vetrie, D. et al, Nature, 1993, 361, 226-233), and Bmx (bone marrow kinase, X-linked; Tamagnon, L. et al., Oncogene, 1994, 9, 3683-3688). 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. During T cell activation via T cell receptor (TCR) CD3 and CD28 interaction, a cascade of signal transduction events is triggered including Lck activation followed by ZAP70 and ITK phosphorylation. ITK subsequently activates phospholipase C γ (PLC-γ) that further cleaves phosphotidyli-nositol biphosphate to yield diacylgycerol (DAG) and inositol triphosphate (IP3). Finally these two components activate NFKB and NFAT pathways leading to cytokine production, T cell-proliferation and subsequent differentiation. Disruption of T cell signal transduction by inhibition of ITK in the cascade would attenuate T cell mediated inflammation responses, especially in the pathological stage.
The study of genetically manipulated mice in which the gene encoding the ITK protein is deleted reveal that 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, 1995, 3, 757-769). These T cells also exhibit defective PLCyl tyrosine phosphorylation, inositol triphosphate production, Ca2+ mobilization, and cytokine production (such as IL-2 and IFNy) in response to TCR cross- linking (Schaeffer, E. M. et al, Science, 1999, 284, 638-641) This genetic evidence indicates that ITK activity plays a requisite role in TCR signal transduction; and selective inhibition of ITK should have immunosuppressive, anti-inflammatory, and anti-pro liferative effects. Recent studies have shown that 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, WO2005079791, WO2007058832, WO2008025820, WO2007076228 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.
Thus, an object of the present invention is to provide novel compounds which are inhibitors of kinase activity, in particular ITK activity. Compounds of the present invention may be useful in the treatment of disorders associated with inappropriate kinase activity, in particular inappropriate ITK activity, for example in the treatment and prevention of disorders mediated by ITK mechanisms. Such disorders include 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, 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.
Summary of the Invention
In one aspect, the present invention relates to compound of formula (I)
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein,
Ring A is
Figure imgf000005_0002
wherein x and y represent the point of attachment;
P is selected form phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and indazolyl each optionally being substituted with one or more substituents selected from halogen, cyano, Ci_8alkyl, haloCi_8alkyl, haloCi_8alkoxy and - NRaRb;
Q is selected from hydrogen, imidazolyl, pyrazolyl and pyridyl;
L is selected from -(CH2)nCRaRb-, -C(O)-, -C(0)NRa-, -(CH2)nC(0)NRa-, - C(0)(CH2)nC(0)-, and -(CRaRb)nO-;
M is selected from hydrogen, cyano, Ci_8alkyl, Ci_8alkoxy, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, haloCi_8alkyl, C3_i2cycloalkyl, C3_i2cycloalkylCi_8alkyl and C6_i4aryl;
R1 is Ci_8alkyl;
R2 is selected from Ci_8alkyl, Ci_8alkoxyCi_8alkyl, hydroxyCi_8alkyl, C3_i2cycloalkyl, C3_i2cycloalkylalkyl, C6-14aryl, 3- to 15- membered heterocyclylCi_8alkyl, 5- to 14- heteroaryl and -(CH2)nNRbC(0)Rc;
R3 is Ci_8alkyl;
R4 is Ci_8alkyl;
R5 is Ci_8alkyl;
R6 is selected from Ci_8alkyl and C3_i2cycloalkyl;
R7 is C3_i2cycloalkyl;
R8 is Ci_8alkyl;
R9 is C3_i2cycloalkyl;
R10 is Ci_8alkyl;
Rn is Ci_8alkyl;
R12 is C3_i2cycloalkyl;
R13 is Ci_8alkyl;
R14 is C3_i2cycloalkyl;
at each occurrence, Ra is independently selected from hydrogen and Ci_8alkyl; at each occurrence, Rb is independently selected from hydrogen and Ci_8alkyl; at each occurrence, Rc is independently selected from hydrogen and Ci_8alkyl; and 'n' is an integer ranging from 1 to 6, both inclusive.
The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (la), (lb), (Ic), (Id) and (Ie) as described hereinafter. 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein Q is hydrogen (according to an embodiment defined below) and n is 1 or 2 (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (I), in which R1 is Ci_4alkyl (e.g. methyl or ethyl).
According to anothet embodiment, specifically provided are compounds of formula (I), in which R1 is methyl or ethyl.
According to yet another another embodiment, specifically provided are compounds of
.g.methyl,
Figure imgf000007_0001
C i_8alkoxyC i_salkyl
Figure imgf000007_0002
hydroxyCi.galkyl
Figure imgf000007_0003
C3-i2cycloalkyl
Figure imgf000007_0004
C3_i2cycloalkylalkyl
Figure imgf000007_0005
3- to 15- membered heterocyclylCi-salkyl
Figure imgf000007_0006
- to 14- heteroaryl
Figure imgf000007_0007
According to yet another another embodiment, specifically provided are compounds of formula (I), in which R is methyl,
Figure imgf000008_0001
According to yet another another embodiment, specifically provided are compounds of formula (I), in which R2 is -(CH2)„NRbC(0)Rc. In this embodiment, Rb is Ci.galkyl (e.g.methyl); Rc is Ci_8alkyl (e.g.methyl or ethyl) and n is 1.
According to yet another another embodiment, specifically provided are compounds of formula (I), in which R2 is -(CH2)„NRbC(0)Rc. In this embodiment, Rb is methyl; Rc is methyl or ethyl and n is 1.
According to yet another another embodiment, specifically provided are compounds of formula (I), in which R2 is methyl,
Figure imgf000008_0002
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is Ci_galkyl
Figure imgf000008_0003
According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is
Figure imgf000009_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R6 is Ci.galkyl (e.g.
Figure imgf000009_0002
or C3_i2cycloalkyl (e.g. cyclohexyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R6 is
Figure imgf000009_0003
or cyclohexyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R7 is C3_i2cycloalkyl (e.g. cyclohexyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R7 is cyclohexyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R8 is Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R8 is methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R9 is C3_i2cycloalkyl (e.g. cyclohexyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R9 is cyclohexyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which ring A is
Figure imgf000010_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which ring A is
Figure imgf000010_0002
According to yet another embodiment, specifically provided are compounds of formula (I), in which ring A is
Figure imgf000011_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which P is phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl or indazolyl each optionally being substituted with one or more substituents selected from halogen (e.g. CI or F), cyano, Ci.galkyl (e.g. methyl), haloCi.galkyl (e.g. trifluoroalkyl), haloCi-salkoxy (e.g. trifluoromethoxy) and -NRaRb, in this embodiment Ra and Rb are Ci_8alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which P is phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl or indazolyl each optionally being substituted with one or more substituents selected from CI, F, cyano, methyl, trifluoroalkyl, trifluoromethoxy and
According to yet another embodiment, specifically provided are compounds of formula (I), in which P is
Figure imgf000011_0002
According to yet another embodiment, specifically provided are compounds of formula (I), in which Q is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which Q is
Figure imgf000012_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which Q is hydrogen,
Figure imgf000012_0002
According to yet another embodiment, specifically provided are compounds of formula (I), in which -L- is -(CH2)„CRaRb-, -C(O)-, -C(0)NRa-, -(CH2)„C(0)NRa-, - C(0)(CH2)nC(0)-, and -(CRaRb)nO-. In this embodiment, Ra is hydrogen or Ci_4alkyl (e.g. methyl), Rb is hydrogen or Ci_4alkyl (e.g. methyl) and n is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (I), in which -L- is -CH2CH2-, -CH2CH2CH2-,-CH2CH2C(CH3)2-, -C(O)-, - C(0)NH-, -C(0)N(CH3)-, -CH2CH2-C(0)NH- or -CH2CH2-C(0)N(CH3)-.
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is hydrogen, cyano, Ci_4alkyl (e.g. methyl, ethyl, propyl or isopropyl), Ci_4alkoxy (e.g. methoxy or ethoxy), Ci_4alkoxyCi_4alkyl (e.g. methoxymethyl, 2- methoxyethyl, 3-methoxypropyl), hydroxyCi_4alkyl (e.g. 2-hydroxy-2-methyl-propyl), haloCi_ 4alkyl (e.g. trifluoroethyl), C3_i2cycloalkyl (e.g. cyclopropyl, cyclopentyl or cyclohexyl) or C3_ i2cycloalkylCi_4alkyl (e.g. cyclopropylmethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is hydrogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-hydroxy-2-methyl-propyl, trifluoroethyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclopropylmethyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is C6-i4aryl optionally substituted with halogen (e.g. 4-chlorophenyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is 4-chlorophenyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which M is hydrogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-hydroxy-2-methyl-propyl, trifluoroethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or 4-chlorophenyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which -L-M is
Figure imgf000013_0001
NH,
,OC¾ O O x or CN
According to an embodiment, specifically provided are compounds of formula (I) with an IC50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
Further embodiments relating to groups ring A, L, M, P and Q (and groups defined therein) are described hereinafter in relation to the compounds of formula (la), (lb), (Ic), (Id) or (Ie). It is to be understood that these embodiments are not limited to use in conjunction with formula (la), (lb), (Ic), (Id) or (Ie), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (la), (lb), (Ic), (Id) or (Ie), wherein Q is hydrogen and consequently there is also provided a compound of formula (I), wherein L is - C(0)NH-.
The invention also provides a compound of formula (la), which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (la)
Figure imgf000013_0002
or a pharmaceutically acceptable salt thereof, wherein,
P is selected form phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and indazolyl each optionally being substituted with one or more substituents selected from halogen, cyano, Ci_salkyl, haloCi_salkyl, haloCi_salkoxy and - NRaRb;
Q is selected from hydrogen, imidazolyl, pyrazolyl and pyridyl;
L is selected from -(CH2)„CRaRb-, -C(O)-, -C(0)NRa-, -(CH2)„C(0)NRa-, - C(0)(CH2)nC(0)-, and -(CRaRb)nO-;
M is selected from hydrogen, cyano, Ci_salkyl, Ci_salkoxy, Ci_8alkoxyCi_salkyl, hydroxyCi_salkyl, haloCi_salkyl, C3_i2cycloalkyl, C3_i2cycloalkylCi_salkyl and C6-i4aryl;
R1 is Ci_8alkyl;
R is selected from Ci_salkyl, Ci_8alkoxyCi_salkyl, hydroxyCi_salkyl, C3_i2cycloalkyl, C3_i2cycloalkylalkyl, C6-i4aryl, 3- to 15- membered heterocyclylCi-salkyl, 5- to 14- heteroaryl, and -(CH2)nNRbC(0)Rc; at each occurrence, Ra is independently selected from hydrogen and Ci_salkyl; at each occurrence, Rb is independently selected from hydrogen and Ci_salkyl; at each occurrence, Rc is independently selected from hydrogen and Ci_salkyl; and
'n' is an integer ranging from 1 to 6, both inclusive.
The compounds of formula (la) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (la) as defined above wherein R1 is methyl or ethyl (according to an embodiment defined below) and Q is hydrogen (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (la), in which R1 is Ci_4alkyl (e.g. methyl or ethyl).
According to anothet embodiment, specifically provided are compounds of formula (la), in which R1 is methyl or ethyl.
According to yet another another embodiment, specifically provided are compounds of
.g.methyl,
Figure imgf000014_0001
C i_8alkoxyC i_salkyl
Figure imgf000015_0001
hydroxyCi_8alkyl
Figure imgf000015_0002
C3_i2cycloalkylalkyl
(e.g. CT^ ),
C6-i4aryl
Figure imgf000015_0003
3- to 15- membered heterocyclylCi-salkyl
(e.g. CP' or eft ), or
5- to 14- heteroaryl
Figure imgf000015_0004
According to yet another another embodiment, specifically provided are compounds of formula (la), in which R is methyl,
Figure imgf000015_0005
According to yet another another embodiment, specifically provided are compounds of formula (la), in which R2 is -(CH2)nNRbC(0)Rc. In this embodiment, Rb is Ci_8alkyl (e.g.methyl); Rc is Ci_salkyl (e.g.methyl or ethyl) and n is 1. According to yet another another embodiment, specifically provided are compounds of formula (la), in which R2 is -(CH2)nNRbC(0)Rc. In this embodiment, Rb is methyl; Rc is methyl or ethyl and n is 1.
According to yet another another embodiment, specifically provided are compounds of
Figure imgf000016_0001
According to yet another embodiment, specifically provided are compounds of formula (la), in which P is phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl or indazolyl each optionally being substituted with one or more substituents selected from halogen (e.g. CI or F), cyano, Ci_salkyl (e.g. methyl), haloCi_salkyl (e.g. trifluoroalkyl), haloCi-salkoxy (e.g. trifluoromethoxy) and -NRaRb, in this embodiment Ra and Rb are Ci_8alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which P is phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl or indazolyl each optionally being substituted with one or more substituents selected from CI, F, cyano, methyl, trifluoroalkyl, trifluoromethoxy and
According to yet another another embodiment, specifically provided are compounds of formula (la), in which P is
Figure imgf000016_0002
Figure imgf000017_0001
According to yet another embodiment, specifically provided are compounds of formula (la), in which Q is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (la), in which Q is
Figure imgf000017_0002
According to yet another embodiment, specifically provided are compounds of formula (la), in which Q is hydrogen,
Figure imgf000017_0003
According to yet another embodiment, specifically provided are compounds of formula (la), in which -L- is -(CH2)nCRaRb-, -C(O)-, -C(0)NRa-, -(CH2)nC(0)NRa-, - C(0)(CH2)nC(0)-, and -(CRaRb)nO-. In this embodiment, Ra is hydrogen or Ci_4alkyl (e.g. methyl), Rb is hydrogen or Ci_4alkyl (e.g. methyl) and n is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (la), in which -L- is -CH2CH2-, -CH2CH2CH2-,-CH2CH2C(CH3)2-, -C(O)-, - C(0)NH-, -C(0)N(CH3)-, -CH2CH2-C(0)NH-, or -CH2CH2-C(0)N(CH3)-.
According to yet another embodiment, specifically provided are compounds of formula (la), in which M is hydrogen, cyano, Ci_4alkyl (e.g. methyl, ethyl, propyl or isopropyl), Ci_4alkoxy (e.g. methoxy or ethoxy), Ci_4alkoxyCi_4alkyl (e.g. methoxymethyl, 2- methoxyethyl, 3-methoxypropyl), hydroxyCi_4alkyl (e.g. 2-hydroxy-2-methyl-propyl), haloCi_ 4alkyl (e.g. trifluoroethyl), C3-i2cycloalkyl (e.g. cyclopropyl, cyclopentyl or cyclohexyl) or C3_ i2cycloalkylCi_4alkyl (e.g. cyclopropylmethyl).
According to yet another embodiment, specifically provided are compounds of formula (la), in which M is hydrogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-hydroxy-2-methyl-propyl, trifluoroethyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclopropylmethyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which M is C6-i4aryl (e.g. 4-chlorophenyl). According to yet another embodiment, specifically provided are compounds of formula (la), in which M is 4-chlorophenyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which M is hydrogen, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-hydroxy-2-methyl-propyl, trifluoroethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and 4-chlorophenyl.
According to yet another embodiment, specifically provided are compounds of formula (la), in which -L-M is
Figure imgf000018_0001
Figure imgf000018_0002
According to an embodiment, specifically provided are compounds of formula (la) with an IC50 value of less than 2000 11M, preferably less than 1000 11M, more preferably less than 500 11M, with respect to ITK activity.
The invention also provides a compound of formula (lb), which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (lb)
Figure imgf000018_0003
or a pharmaceutically acceptable salt thereof, wherein,
P is selected from thienyl and pyridyl;
Q is hydrogen or pyrazolyl; L is -C(0)NH-;
M is C3_i2cycloalkyl;
R is Ci_8alkyl; and
R4 is Ci_8alkyl.
The compounds of formula (lb) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (lb) as defined above wherein P is
Figure imgf000019_0001
(according to an embodiment defined below) and Q is hydrogen (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (lb), in hich P is
Figure imgf000019_0002
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Q is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Q is
Figure imgf000019_0003
According to yet another embodiment, specifically provided are compounds of formula (lb), in which Q is hydrogen or
Figure imgf000019_0004
According to yet another embodiment, specifically provided are compounds of formula (lb), in which M is C3_i2cycloalkyl (e.g. cyclopropyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which M is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R is methyl.
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R4 is Ci_salkyl
Figure imgf000020_0001
According to yet another embodiment, specifically provided are compounds of formula (lb), in which R4 is
Figure imgf000020_0002
According to yet another embodiment, specifically provided are compounds of formula (lb), in which:
P is
Figure imgf000020_0003
Q is hydrogen or
N I
NH
M is cyclopropyl;
R is methyl and
4 is
Figure imgf000020_0004
According to an embodiment, specifically provided are compounds of formula (lb) with an IC50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
The invention also provides a compound of formula (Ic), which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (Ic)
Figure imgf000021_0001
(Ic) or a pharmaceutically acceptable salt thereof, wherein,
P is thienyl;
Q is hydrogen or pyrazolyl;
L is -C(0)NH-;
M is selected from Ci_salkyl and C3_i2cycloalkyl;
R5 is Ci_8alkyl; and
R6 is selected from Ci_salkyl and C3_i2cycloalkyl.
The compounds of formula (Ic) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (Ic) as defined above wherein R5 is methyl (according to an embodiment defined below) and Q is hydrogen (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (Ic), in which P is
Figure imgf000021_0002
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Q is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Q is
Figure imgf000021_0003
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which Q is hydrogen or According to yet another embodiment, specifically provided are compounds of formula (Ic), in which M is Ci_salkyl (e.g. ethyl) or C3_i2cycloalkyl (e.g. cyclopropyl).
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which M is ethyl or cyclopropyl.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R5 is Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R5 is methyl.
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R6 is C3-i2cycloalkyl (e.g. cyclohexyl) or Ci_salkyl (e.g.
Figure imgf000022_0001
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which R6 is cyclohexyl or
Figure imgf000022_0002
According to yet another embodiment, specifically provided are compounds of formula (Ic), in which:
Figure imgf000022_0003
s hydrogen or
Figure imgf000022_0004
M is ethyl or cyclopropyl;
R5 is methyl and
6 is cyclohexyl or
Figure imgf000022_0005
According to an embodiment, specifically provided are compounds of formula (Ic) with an IC50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
The invention also provides a compound of formula (Id), which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (Id)
Figure imgf000023_0001
(Id) or a pharmaceutically acceptable salt thereof, wherein,
P is selected from thiazolyl, thienyl and pyridyl;
Q is hydrogen or pyrazolyl;
L is -C(0)NH-;
M is selected from Ci_salkyl and C3_i2cycloalkyl;
R7 is C3-i2cycloalkyl; and
R8 is Ci_8alkyl.
The compounds of formula (Id) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (Id) as defined above wherein M is ethyl or cyclopropyl (according to an embodiment defined below) and R is methyl (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (Id), in hich P is
Figure imgf000023_0002
According to yet another embodiment, specifically provided are compounds of formula (Id), in which Q is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (Id), in which Q is
Figure imgf000024_0001
According to yet another embodiment, specifically provided are compounds of formula (Id), in which Q is hydrogen or
Figure imgf000024_0002
According to yet another embodiment, specifically provided are compounds of formula (Id), in which M is Ci_salkyl (e.g. ethyl) or C3_i2cycloalkyl (e.g. cyclopropyl).
According to yet another embodiment, specifically provided are compounds of formula (Id), in which M is ethyl or cyclopropyl.
According to yet another embodiment, specifically provided are compounds of formula (Id), in which R7 is C3_i2cycloalkyl (e.g. cyclohexyl).
According to yet another embodiment, specifically provided are compounds of formula (Id), in which R7 is cyclohexyl.
According to yet another embodiment, specifically provided are compounds of formula (Id), in which R is Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (Id), in which R is methyl.
According to yet another embodiment, specifically provided are compounds of formula (Id), in which:
P is
Figure imgf000024_0003
is hydrogen or
Figure imgf000024_0004
M is ethyl or cyclopropyl;
R7 is cyclohexyl and
R is methyl. According to an embodiment, specifically provided are compounds of formula (Id) with an IC50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
The invention also provides a compound of formula (Ie), which is an embodiment of a compound of formula (I).
Accordingly the invention provides a compound of formula (Ie)
Figure imgf000025_0001
(Ie) or a pharmaceutically acceptable salt thereof, wherein,
P is selected from thiazolyl, thienyl and pyridyl each being optionally substituted with one or more substituents selected from -NRaRb;
Q is hydrogen or pyrazolyl;
L is -C(0)NRa-;
M is C3_i2cycloalkyl;
R9 is C3_i2cycloalkyl;
R10 is Ci_8alkyl;
Ra is hydrogen or Ci_salkyl; and
Rb is Ci-galkyl.
The compounds of formula (Ie) 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 of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (Ie) as defined above wherein M is cyclopropyl (according to an embodiment defined below) and R10 is methyl (according to another embodiment defined below). According to one embodiment, specifically provided are compounds of formula (Ie), in hich P is
Figure imgf000026_0001
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which Q is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which Q is
Figure imgf000026_0002
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which Q is hydrogen or
Figure imgf000026_0003
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which -L- is -C(0)NRa. In this embodiment Ra is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which -L- is -C(0)NH-.
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which M is C3_i2cycloalkyl (e.g. cyclopropyl).
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which M is cyclopropyl.
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which R9 is C3-i2cycloalkyl (e.g. cyclohexyl).
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which R9 is cyclohexyl.
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which R10 is Ci_4alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which R10 is methyl.
According to yet another embodiment, specifically provided are compounds of formula (Ie), in which:
P is
Figure imgf000027_0001
Q is hydrogen or
Figure imgf000027_0002
-L- is -C(0)NH-;
M is cyclopropyl;
R9 is cyclohexyl and
R10 is methyl.
According to an embodiment, specifically provided are compounds of formula (Ie) with an IC50 value of less than 2000 nM, preferably less than 1000 nM, more preferably less than 500 nM, with respect to ITK activity.
It should be understood that the formulas (I), (la), (lb), (Ic), (Id) and (Ie) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, pharmaceutically acceptable salts and solvates including hydrates that may be contemplated from the chemical structure of the genera described herein.
The present invention also provides a pharmaceutical composition that includes at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, 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 kinase activity, in particular ITK activity.
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.
In another aspect, 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 diseases, conditions and/or disorders selected from the group consisting of respiratory diseases, allergic diseases, autoimmune diseases, inflammatory disorders, proliferative disorders, transplant rejection, graft versus host disease, HIV, aplastic anemia, pain including inflammatory pain 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.
Detailed Description
Terms and Definitions:
The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
The term "alkyl" refers to a straight or branched 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. Ci_salkyl), 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, 2-methylpropyl (isobutyl), n-pentyl, 1,1-dimethylethyl (t-butyl), and 2,2- dimethylpropyl. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C2-10 alkenyl) and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z'sopropenyl, 2- methyl-l-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
The term "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 i.e. C2-10 alkynyl). 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.
The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci_salkoxy). Representative examples of such groups are -OCH3 and - OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted. The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci_8alkoxyCi_salkyl or Ci_8alkyloxyCi_8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, - CH2OCH3 and -CH2OC2H5. Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "haloalkyl" refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi_salkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, trifluoroethyl, 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.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi_salkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "hydroxy alkyl" refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi_8alkyl). Examples of hydroxyalkyl moiety include, but are not limited to -CH2OH, -C2H4OH and -CH(OH)C2H4OH.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, for example C3_i2cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of 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.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group, for example C3_8cycloalkylCi_8alkyl. 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. The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, for example C3_8cycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclop entenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
The term "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, for example C3_8cycloalkenylCi_8alkyl. 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.
The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6- i4aryl), 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.
The term "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C6-i4aryloxy). 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.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C6_i4arylCi_8alkyl, such as -CH2C6H5 and -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "heterocyclyl" or "heterocyclic ring" 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. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefmic bond(s). Examples of such 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, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The 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.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclylCi.salkyl). 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. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "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. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, pyrazolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. heterarylCi-salkyl). 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.
Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyl alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COORx, -C(0)Rx, -C(S)RX, -C(0)NRxRy, - C(0)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)S02Ry, -NRxC(0)ORy, -NRxRy, - NRxC(0)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, -S02NRxRy, -ORx, -OC(0)NRyRz, - OC(0)ORy, -OC(0)Rx, -OC(0)NRxRy, -SRX, -SORx, -S02Rx and -ON02, wherein Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" can be unsubstituted alkenyl but cannot be "substituted alkenyl".
The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.
The term "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.
The term "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).
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. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present patent application may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated. It is also to be understood that compounds of the invention may exist in solvated forms (such as hydrates) as well as unsolvated forms, and that the invention encompasses all such forms.
Pharmaceutical Compositions 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. Typically, 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.
Examples of 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.
The pharmaceutical 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.
For parenteral application, particularly suitable are 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.
The pharmaceutical compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th 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. For example, the daily dosage of the ITK 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.
Methods of Treatment
The present invention provides compounds and pharmaceutical compositions which inhibit kinase activity, particularly ITK activity and are thus useful in the treatment or prevention of disorders associated with ITK. Compounds and pharmaceutical compositions of the present invention selectively inhibit ITK and are thus useful in the treatment or prevention of a range of disorders associated with the activation of ITK which includes, but are not limited to respiratory diseases, allergic diseases, autoimmune diseases, inflammatory disorders, immunological disorders, proliferative disorders, transplant rejection, graft versus host disease, HIV, aplastic anemia, pain including inflammatory pain and other diseases and disorders associated with ITK.
In particular, 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 idiopathic interstitial pneumonia; sinusitis, chronic rhinosinusitis, nasosinusal polyposis; pulmonary fibrosis; inflammatory bowel disease; Guillain-Barre syndrome, acute or chronic inflammation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis; psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermitides, sebonhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythema, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis; Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, for example, migraine, rhinitis and eczema; multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, type II diabetes, nephritic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; tuberculosis; organ and bone marrow transplant rejection; graft-versus-host disease.
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, malignant carcinoid, topical skin lesion, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma, malignant hypercalcemia, renal cell tumor, adenocarcinoma, glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, and epidermoid carcinomas.
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, anti-histamines, anti-cancer agents, protein kinase inhibitors, cyclosporine, or rapamycin.
Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses 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.
General Methods of Preparation
The compounds described herein, including compounds of general formula (I), (la), (lb), (Ic), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Id), (Ie), (Id-1), (Ie-1) and specific examples can be prepared using techniques known to one skilled in the art through the reaction sequences depicted in schemes 1-13 as well as by other methods. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, solvents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.
The starting materials used herein are commercially available or were prepared by methods known in the art to those of ordinary skill or by methods disclosed herein. In general, the intermediates and compounds of the present invention may be prepared through the reaction scheme as follows.
A general approach for the preparation of compound of formula (I) of the present invention (where A, x, y, L, M, P and Q are as defined compound of formula (I)) can be prepared as depicted in Scheme 1. An appropriately substituted heteroaryl amine of formula (1) can be coupled with a suitable acid halide of general formula (2) (wherein X is halogen) using a suitable base such as, but not limited to triethylamine, pyridine or diisopropylethylamine to give the compound of formula (I). Alternatively, the coupling reaction of appropriately substituted amine of formula (1) with an acid of the formula (2) (wherein X = OH) in the presence of a suitable coupling agent such as, but not limited to 1- ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), O-(Benzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU) and a base (such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine) in a suitable solvent (such as 1,2- dichloroethane, N,N-dimethylformamide or tetrahydrofuran) affords the compound of formula
(I)-
Scheme 1:
Figure imgf000038_0001
(1) (I)
1 2
The indole derivatives of the formula (la) (where R , R , M, P and Q are as defined in compound of formula (la)) can be prepared by following the synthetic steps depicted in scheme 2. The 4-Fluoro-3-nitroaniline (3) undergoes reaction with appropriately substituted acid (X = OH) or acid chloride (X = CI) of formula (4) under suitable reaction condition to afford the corresponding amide, which on N-alkylation using alkyl halide (X = halogen) of formula (5) gives intermediate (6). The aromatic nucleophilic substitution of fluorine of intermediate (6) with an appropriately substituted cyanoacetamide (7) in the presence of suitable base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as tetrahydrofuran, acetonitrile or N,N-dimethylformamide affords 2-substituted nitro compound of formula (8). The reductive cyclization of intermediate (8) affords the 2- amino indole derivative of formula (9). The coupling of intermediate (9) with appropriate acid chloride (X is CI) of formula (2) using a suitable base furnishes compound of the general formula (la).
Scheme 2: reductive cyclization
Figure imgf000039_0001
An approach for the synthesis of indole derivatives of formula (lb) (where R , R , M, P and Q are as defined in compound of formula (lb)) is described in scheme 3. The acylation of l-(4- fluorobenzyl)amine (10) with appropriately substituted acyl halide (11) followed by N- alkylation using an alkyl halide (12) gives intermediate (13). The intermediate (13) on nitration under standard procedure gives nitro amide intermediate (14). The displacement of fluorine of intermediate (14) with an appropriately substituted cyanoacetamide (7) in the presence of a suitable base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as tetrahydrofuran, acetonitrile or N,N-dimethylformamide affords intermediate (15). The reductive cyclization of intermediate (15) using an appropriate reagent such as ferric chloride and zinc dust in suitable solvent such as N,N-dimethylformamide affords 2-amino indole derivative of formula (16). The coupling reaction of intermediate (16) with appropriate acid chloride (X is CI) of formula (2) furnishes the desired compound of the general formula (lb).
Scheme 3:
Figure imgf000039_0002
An approach for the synthesis of indole carboxamides of formula (Ic) (where R , R , M, P and Q are as defined in compound of formula (Ic)) is depicted in scheme 4. The coupling reaction of 4-fluoro-3-nitrobenzoic acid (17) with an amine of the formula (18) gives the corresponding amide of the formula (19). The displacement of fluorine of intermediate (19) with appropriately substituted cyanoacetamide (7) in the presence of a suitable base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as tetrahydrofuran, acetonitrile or N,N-dimethylformamide affords intermediate (20). The reductive cyclization of intermediate (20) is accomplished as described above in scheme 2 to afford 2-amino indole derivative (21). The coupling reaction of 2-amino indole (21) with an appropriate acid chloride (where X is CI) of formula (2) in the presence of a suitable base furnishes the compound of the general formula (Ic).
Scheme 4:
reductive cyclization
Figure imgf000040_0001
1 2
A general approach for synthesis of indole derivatives of formula (Ia-1) (where R , R , M and P are as defined in compound of formula (la)) is depicted in scheme 5. The coupling of compound of formula (9) with an acid chloride of the formula (22, where X = CI and X' = Br or I) where P is a halogen substituted heteroaryl ring (e.g. thiophene, thiazole, benzene, pyridine) affords the corresponding halo amide derivative (23). The Suzuki-Miyaura coupling reaction of halo amide (23, where X' is Br or I) with THP-protected pyrazole boronic ester (24) using palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) or [Ι, - bis(diphenylphosphino) ferrocene] dichloropalladium(II) in presence of suitable base such as potassium carbonate, cesium fluoride or cesium carbonate in suitable solvent such as tetrahydrofuran, N,N-dimethylformamide or 1,4-dioxane affords pyrazole amide (25). The deprotection of THP group of intermediate (25) under acidic conditions affords compounds of the general formula (Ia-1).
Scheme 5:
Figure imgf000041_0001
(25) (Ia-1)
1 2
An approach for the synthesis of indole derivatives of formula (Ia-2) (where R , R , M, P and Q are as defined in compound of formula (la)) is depicted in scheme 6. The nucleophilic aromatic substitution of fluorine of compound (6) with ethyl cyanoacetate (26) in the presence of suitable base affords the intermediate (27). The intermediate (27) on deethoxycarbonylation using DMSO/NaCl/water under Krapcho reaction conditions affords phenyl acetonitrile derivative (28). The reaction of intermediate (28) with an appropriately substituted acid chloride of formula (29) in the presence of a suitable base affords ketone (30). The reductive cyclization of intermediate (30) as described in scheme 2 affords the 2- aminoindole derivative of formula (31). The coupling reaction of intermediate (31) with intermediate of the formula (2) (where X is CI) by using a suitable base gives the compound of formula (Ia-2). The reductive deoxygenation of compound (Ia-2) using appropriate reagent such as lithium aluminium hydride or triethyl silane in the presence of trifluoroacetic acid using suitable solvent affords compound of the general formula (Ia-3).
Scheme 6:
Figure imgf000041_0002
(Ia-3) 1 2
An approach for the synthesis of indole derivatives of general formula (Ia-4) (where R , R , M and P are as defined in compound of formula (la)) is depicted in scheme 7. The coupling of amine (31) with an acid chloride of the formula (22, where X = CI and X' = Br or I) affords halo intermediate (32). The reductive deoxygenation of halo intermediate (32) using appropriate reagent such as lithium aluminium hydride or triethyl silane in the presence of trifluoroacetic acid in the presence of suitable solvent gives halo indole derivative. The halo indole derivative on Suzuki-Miyaura coupling reaction with THP -protected pyrazole boronic ester (24) using suitable palladium catalyst in presence of suitable base gives pyrazole derivative (33). The deprotection of pyrazole (33) under acidic conditions affords compounds of the general formula (Ia-4).
Scheme 7:
Figure imgf000042_0001
1 2
An approach for the synthesis of indole derivatives of general formula (Ia-5) (where R , R , Ra, M, P and Q are as defined in compound of formula (la)) is depicted in scheme 8. The displacement of fluorine of compound of formula (6) with tert-butyl cyanoacetate (34) in the presence of suitable base affords the intermediate (35). The reductive cyclization of (35) using the same procedure as described in scheme 2 provides tert-butyl amino indole derivative of formula (36). The coupling reaction of intermediate (36) with suitable acid chloride (2, where X is CI) in the presence of a suitable base affords compound of formula (37). The ester hydrolysis of intermediate (37) followed by decarboxylation affords the indole amide derivative of formula (38). Michael addition of intermediate (38) with an acrylamide derivative of the formula (39) in presence of Lewis acid such as aluminium chloride or weak acid such as acetic acid furnishes compound of the general formula (Ia-5).
Scheme 8:
Figure imgf000043_0001
A general approach for the synthesis of indole derivatives of general formula (Ia-6) (where R1, R2, Ra, M and P are as defined in compound of formula (la)) can be prepared as depicted in scheme 9. The coupling reaction of 2-aminoindole derivative (36) with suitable acid chloride of the formula (22) (where X = CI and X' = Br or I) affords the corresponding halo indole amide of the formula (40). The hydrolysis of tertiary butyl ester group of halo indole amide (40) gives the corresponding acid (41). Decarboxylation of intermediate (41) in the presence of suitable base and solvent gives halo indole amide (42). Michael addition of halo indole amide derivative (42) with acrylamide derivative of formula (39) using Lewis acid such as aluminium chloride in suitable solvents such as acetonitrile affords intermediate (43). Suzuki-Miyaura coupling reaction of aryl halide (43) with THP-protected pyrazole boronic ester (24) using suitable palladium catalyst in presence of suitable base and solvent affords pyrazole amide derivative which on deprotection under acidic condition affords compounds of the general formula (Ia-6). Also, when M and Ra are hydrogen atoms, the reaction of (Ia-6) with trifluoroacetic anhydride in presence of suitable base such as triethylamine gives the coressponding nitrile derivative (Ia-7).
Scheme 9:
Figure imgf000044_0001
An approach for the synthesis of thieno[3,2-b]pyrrole carboxamide derivatives of formula (Id)
7 8
(where R , R , M, P and Q are as defined in compound of formula (Id)) is depicted in scheme 10. The coupling reaction of 5-chloro-4-nitro-thiophene-2-carboxylic acid (44) with appropriately substituted amine (45) affords the corresponding 2-chloro-3-nitro thiophene amide (46). The displacement reaction of 2-chloro-3-nitro thiophene amide (46) with an appropriately substituted cyanoacetamide (7) in the presence of suitable base affords intermdiate (47). The reductive cyclization of intermediate (47) by using same procedure as described in scheme 2 affords the desired 5-amino-4H-thieno[3,2-b]pyrrole of formula (48). Coupling reaction of 5-amino pyrrole of formula (48) with appropriate acid chloride of formula (2, where X is CI) using a suitable base such as pyridine, triethylamine or N,N- diisopropylethylamine, etc gives compound of the general formula (Id).
Scheme 10:
Figure imgf000044_0002
An approach for the synthesis of thieno[2,3-b]pyrrole derivatives of formula (Ie) (where R , R10, M, P and Q are as defined in compound of formula (Ie)) is described in scheme 11. The known 4-chloro-5-nitrothiophene-2-carbaldehyde (50) is prepared by nitration of commercially available 4-chlorothiophene-2-carbaldehyde (49) using a mixture of nitric acid and sulfuric acid. Pinnick oxidation of formyl group of intermediate (50) using sodium chlorite gives 4-chloro-5-nitrothiophene-2-carboxylic acid (51). The coupling reaction of 4- chloro-5-nitrothiophene carboxylic acid (51) with appropriately substituted amine of the formula (52) affords corresponding thiophene amide (53). The displacement reaction of (53) with an appropriately substituted cyanoacetamide (7) in the presence of suitable base affords intermdiate (54). The reductive cyclization of intermediate (54) is accomplished as described in synthetic scheme 2 to afford desired 5-amino-6H-thieno[2,3-b]pyrrole (55). The coupling of compound (55) with appropriate acid chloride (2, where X is CI) using a suitable base furnishes compound of the general formula (Ie).
Scheme 11:
Figure imgf000045_0001
(55) (Ie)
A general approach for the synthesis of thieno[3,2-b]pyrrole amide derivative of formula (Id-
7 8
1) (where R , R°, M and P are as defined in compound of formula (Id)) is depicted in scheme 12. The coupling reaction of 5-amino-4H-thieno[3,2-b]pyrrole (48) with a appropriately functionalized halo acid chloride of formula (22) (where X = CI and X' = Br or I) by using suitable base gives halo thienopyrrole amide (56). The reaction of aryl halide (56) with ΤΗΡ- protected pyrazole boronic ester (24) by Suzuki-Miyaura coupling reaction using palladium catalyst such as [l, -bis(diphenylphosphino)ferrocene] dichloropalladium(II) in presence of suitable base such as potassium carbonate, cesium fluoride, cesium carbonate etc in suitable solvent such as tetrahydrofuran, N,N-dimethylformamide, etc affords pyrazole amide (57). The deprotection of pyrazole (57) under acidic conditions furnishes compounds of the general formula (Id-1).
Scheme 12:
(24)
Figure imgf000046_0001
(57) (Id-1)
A general apparoach for the synthesis of thieno[2,3-b]pyrrole amide derivative of formula (Ie- 1) (where R9, R10, M and P are as defined in compound of formula (Ie)) is as shown in scheme 13. The coupling reaction of 5-amino-6H-thieno[2,3-b]pyrrole (55) with appropriately functionalized acid chloride of formula (22) (where X = CI and X' = Br or I) using suitable base gives thienopyrrole amide (58). Suzuki-Miyaura coupling reaction of aryl halide (58) with ΤΗΡ -protected pyrazole boronic ester (24) by using palladium catalyst such as [Ι , - bis(diphenylphosphino) ferrocene] dichloropalladium(II) in presence of suitable base affords pyrazole amide (59). The deprotection of pyrazole (59) under acidic conditions furnishes compounds of the general formula (Ie-1).
Sch me 13:
Figure imgf000046_0002
Experimental
Unless otherwise stated, work-up implies the following operations: distribution of the reaction mixture between the organic and aqueous phase, separation of layers, drying the organic layer over sodium sulphate, filtration and evaporation of the organic solvent. Purification, unless otherwise mentioned, implies purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. The following abbreviations are used in the text: DMSO-<i6: hexadeuterodimethyl sulfoxide; DMF: N,N-dimethylformamide, 1H NMR: Proton Nuclear Magnetic Resonance; MS: Mass Spectrum; Ex.: Example; CDC13: Deuterated chloroform; THF: Tetrahydrofuran; /: coupling constant in units of Hz; RT or rt: room temperature (22- 26°C); h: hour(s); min: minute(s); DMSO: Dimethyl sulfoxide; EDTA: Ethylenediaminetetraacetic acid; HOBt: Hydroxybenzotriazole; EDCI: l-ethyl-3-(3- dimethylaminopropyl) carbodiimide, TBTU: (0-(Benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate, THP: Tetrahydropyranyl.
Intermediate 1
2-Amino-N-cyclopropyl-6-[methyl(trifluoroacetyl)amino]-lH-indole-3-carboxamide
Figure imgf000047_0001
Step 1 : iert-Butyl(4-fluoro-3-nitrophenyl)carbamate: A solution of di-iert-butyl dicarbonate (6.14 g, 28.185 mmol) in iert-butanol (20 ml) was added drop wise to a solution of 4-fluoro- 3-nitroaniline (4 g, 25.622 mmol) in ie/t-butanol (18 ml) at 0 °C and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was evaporated under reduced pressure and the residue obtained was purified by column chromatography to yield 5.6 g of product as a yellow solid. 1H NMR (300 MHz, CDC13): δ 1.52 (br s, 9H), 6.66 (br s, 1H), 7.15-7.27 (m, 1H), 7.56-7.63 (m, 1H), 8.11-8.18 (m, 1H).
Step 2: ieri-Butyl(4-fluoro-3-nitrophenyl)methylcarbamate: To a solution of step 1 intermediate (5.5 g, 21.484 mmol) in dry N,N-dimethylformamide (71 ml), sodium hydride (950 mg, 23.632 mmol) was added at 0 °C and the reaction mixture was stirred for 30 min at room temperature. To the reaction mixture, methyl iodide (6.71 ml, 107.42 mmol) was added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with brine (100 ml) and dried over sodium sulphate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield 5.6 g of product as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 1.48 (br s, 9H), 3.29 (s, 3H), 7.20-7.30 (m, 1H), 7.52-7.61 (m, 1H), 7.93-8.00 (m, 1H). Step 3 : 4-Fluoro-N-methyl-3-nitroaniline: To a stirred solution of step 2 intermediate (5.5 g, 20.370 mmol) in dichloromethane (50 ml), trifluoroacetic acid (12.5 ml) was added at 0 °C and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was evaporated under reduced pressure and to the residue aqueous saturated solution of sodium bicarbonate (50 ml) was added. The mixture was extracted with dichloromethane (2 x 75 ml). The combined organic layer was washed with brine (100 ml) and dried over sodium sulphate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield 3.8 g of product as a red solid. 1H NMR (300 MHz, CDC13): δ 2.86 (s, 3H), 6.74-6.82 (m, 1H), 7.03-7.15 (m, 2H).
Step 4: 2,2,2-Trifluoro-N-(4-fluoro-3-nitrophenyl)-N-methylacetamide: To a stirred solution of step 3 intermediate (1.0 g, 5.882 mmol) in dichloromethane (20 ml), triethylamine (0.826 ml, 5.882 mmol) was added followed by addition of trifluoroacetic anhydride (0.817 ml, 5.88 mmol) at 0 °C and the reaction mixture was stirred for 45 min at the same temperature. The reaction mixture was quenched with water (50 ml). The mixture was extracted with dichloromethane (2 x 75 ml). The combined organic layer was washed with brine (75 ml) and dried over sodium sulphate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield 1.4 g of product as a yellow solid. 1H NMR (300 MHz, CDC13): δ 3.39 (s, 3H), 7.40 (d, / = 9.3 Hz, 1H), 7.52-7.59 (m, 1H), 7.99-8.07 (m, 1H). Step 5 : N- {4-[l-Cyano-2-(cyclopropylamino)-2-oxoethyl]-3-nitrophenyl}-2,2,2-trifluoro-N- methylacetamide: To a stirred solution of 2-cyano-N-cyclopropylacetamide (1.034 g, 8.345 mmol) in dry tetrahydrofuran (12 ml), sodium hydride (333 mg, 8.345 mmol) was added at 0 °C and the reaction mixture was stirred at same temperature for 30 min. The step 4 intermediate (1.1 1 g, 4.172 mmol) was added to reaction mixture and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with 1 N hydrochloric acid (100 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to give residue. The residue was purified by column chromatography to afford 660 mg of product as pale yellow oil. 1H NMR (300 MHz, CDC13): δ 0.60-0.69 (m, 2H), 0.79-0.88 (m, 2H), 1.21-1.29 (m, 1H), 2.71-2.78 (m, 1H), 3.45 (s, 3H), 6.47 (s, 1H), 7.63-7.80 (m, 1H), 7.88 (d, / = 8.1 Hz, 1H), 8.1 1 (s, 1H).
Step 6: 2-Amino-N-cyclopropyl-6-[methyl(trifluoroacetyl)amino]-lH-indole-3-carboxamide: To a stirred solution of step 5 intermediate (650 g, 1.756 mmol) in dry N,N- dimethylformamide (8 ml), ferric chloride (854 mg, 5.268 mmol) was added followed by the addition of zinc dust (1.1 16 g, 17.560 mmol) and the reaction mixture was first stirred at room temperature for 30 min and then stirred at 100 °C for 1 h. The reaction mixture was cooled at room temperature, quenched with saturated solution of sodium bicarbonate (50 ml) and extracted with ethyl acetate (75 ml x 2). The combined organic layer was washed with water (100 ml) and dried over sodium sulphate. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain 421 mg of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-J6): δ 0.63-0.70 (m, 2H), 0.85 (d, / = 5.7 Hz, 2H), 2.83-2.90 (m, 1H), 3.35 (s, 3H), 5.97 (s, 1H), 6.92-7.00 (m, 3H), 7.17-7.27 (m, 2H), 9.60-9.67 (m, 1H). APCI-MS (m z): 340.99 (M+H)+.
Intermediate 2
2-Amino-N-cyclopropyl-6-(N-methylcyclohexanecarboxamido)- 1 H-indole-3 -carboxamide
Figure imgf000049_0001
Step 1 : N-(4-Fluoro-3-nitrophenyl)cyclohexanecarboxamide: To a stirred solution of 4-fluoro- 3-nitroaniline (25.0 g, 160.13 mmol) and dry pyridine (25 ml, 0.310 mmol) in dry tetrahydrofuran (250 ml), cyclohexanecarbonyl chloride (23.6 ml, 176.15 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture, hydrochloric acid (1 N, 100 ml) was added and the mixture was extracted with ethyl acetate (2 x 300 ml). The combined organic layer was washed with brine (250 ml) and dried over sodium sulphate. The mixture was concentrated under reduced pressure, residue obtained was stirred in hexane (300 ml) and precipitated solid was collected by filtration to yield 45 g of product as off white solid. 1H NMR (300 MHz, CDC13): δ 1.28-1.38 (m, 4H), 1.48-1.60 (m, 2H), 1.83-1.93 (m, 4H), 2.23-2.32 (m, 1H), 7.23-7.30 (m, 1H), 7.57-7.63 (m, 1H), 7.87- 7.95 (m, 1H), 8.26 (d, / = 5.4 Hz, 1H).
Step 2 : N-(4-Fluoro-3 -nitrophenyl)-N-methylcyclohexanecarboxamide : This intermediate was prepared by reaction of step 1 intermediate (35.0 g, 131.57 mmol) with methyl iodide (12.34 ml, 197.30 mmol) using sodium hydride (7.89 g, 197.30 mmol) in dry tetrahydrofuran (350 ml) as described in step 2 of intermediate 1 to yield 31.4 g of product as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.81-0.88 (m, 1H), 1.00-1.12 (m, 2H), 1.20-1.28 (m, 2H), 1.50- 1.62 (m, 6H), 3.27 (s, 3H), 7.36 (t, / = 9.6 Hz, 1H), 7.43-7.50 (m, 1H), 7.89-7.96 (m, 1H).
Step 3 : N-(4-(l-Cyano-2-(cyclopropylamino)-2-oxoethyl)-3-nitrophenyl)-N- methylcyclohexanecarboxamide: This intermediate was prepared by displacement reaction of step 2 intermediate (31.0 g, 1 10.71 mmol) with 2-cyano-N-cyclopropylacetamide (27.45 g, 221.43 mmol) using sodium hydride (8.85 g, 221.42 mmol) in dry tetrahydrofuran (310 ml) as described in step 5 of intermediate 1 to afford 42.1 g of product as pale yellow oil. H NMR
(300 MHz, CDCI3): δ 0.60-0.68 (m, 2H), 0.83 (d, J = 6.60 Hz, 2H), 1.12-1.80 (m, 10H), 2.20- 2.38 (m, 1H), 2.70-2.79 (m, 1H), 3.33 (s, 3H), 5.48 (s, 1H), 6.51 (br s, 1H), 7.58 (d, / = 8.7 Hz, 1H), 7.81 (d, / = 8.4 Hz, 1H), 8.02 (s, 1H).
Step 4: 2-Amino-N-cyclopropyl-6-(N-methylcyclohexanecarboxamido)-lH-indole-3- carboxamide: The title compound was prepared by reductive cyclization of step 3 intermediate (42.0 g, 109.375 mmol) using ferric chloride (53.22 g, 328.125 mmol) and zinc dust (69.52 g, 1093.37 mmol) in dry N,N-dimethylformamide (420 ml) as described in step 6 of intermediate 1 to obtain 27.1 g of title compound as a pale yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.60-0.71 (m, 2H), 0.87 (d, / = 5.70 Hz, 2H), 0.93-1.70 (m, 10H), 2.16-2.28 (m, 1H), 2.85-2.93 (m, 1H), 3.24 (s, 3H), 5.93 (s, 1H), 6.33 (s, 2H), 6.90 (s, 2H), 7.19-7.27 (m, 1H), 9.74 (br s, 1H). APCI-MS (m/z): 355.21 (M+H)+.
Intermediate 3
2-Amino-N-cyclopropyl-6-((N,3,3-trimethylbutanamido)methyl)-lH-indole-3-carboxamide
Figure imgf000050_0001
Step 1 : N-(4-Fluorobenzyl)-3,3-dimethylbutanamide: To a stirred solution of 3,3- dimethylbutanoic acid (7.63 ml, 159.93 mmol), catalytic amount of N,N-dimethylformamide (1.2 ml) in dichloromethane (60 ml), oxalyl chloride (7.0 ml, 79.9 mmol) was added drop wise at 0 °C and the reaction mixture was stirred for 3 h at room temperature and then evaporated under reduced pressure. The residue obtained was diluted withdry tetrahydrofuran (25 ml) and was added to a solution of l-(4-fluorophenyl)methanamine (5.0 g, 39.95 mmol) and dry pyridine (5 ml) in dry tetrahydrofuran (25 ml) at 0 °C. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (200 ml), washed with hydrochloric acid (1 N, 100 ml) and water (100 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain 7.05 g of product as a white solid. 1H NMR (300 MHz, CDCI3): δ 1.03 (s, 9H), 2.08 (s, 2H), 4.39 (d, / = 5.4 Hz, 2H), 5.70 (br s, 1H), 7.00 (t, / = 8.1 Hz, 2H), 7.20-7.29 (m, 2H).
Step 2: N-(4-Fluorobenzyl)-N,3,3-trimethylbutanamide: The N-methylation reaction of step 1 intermediate (7.0 g, 31.346 mmol) using methyl iodide (3.0 ml, 47.02 mmol) in presence of sodium hydride (1.9 g, 47.02 mmol) in dry tetrahydrofuran (90 ml) as described in step 2 of intermediate 1 yields 8.0 g of product as a yellow solid. 1H NMR (300 MHz, CDC13): δ 1.07 (s, 9H), 2.33 (s, 2H), 2.95 (s, 3H), 4.57 (s, 2H), 6.96-7.13 (m, 2H), 7.20-7.29 (m, 2H).
Step 3 : N-(4-Fluoro-3-nitrobenzyl)-N,3,3-trimethylbutanamide: Concentrated sulphuric acid (98 %, 15 ml) was added to concentrated nitric acid (70 %, 31 ml) at 0-5 °C and stirred for 15 min at same temperature. This nitrating mixture was drop-wise added to a solution of step 2 intermediate (7.5 g, 31.604 mmol) in concentrated sulfuric acid (7 ml) at 0-5 ° C and the reaction mixture was stirred for 1 h at same temperature. The reaction mixture was quenched with ice-cooled water (75 ml) and the mixture was extracted with ethyl acetate (2 x 150 ml). The combined organic layer was washed with aqueous saturated sodium carbonate solution (150 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography to yield 8.0 g of product as yellow oil. 1H NMR (300 MHz, CDC13): δ 1.08 (s, 9H), 2.33 (s, 2H), 3.02 (s, 3H), 4.62 (s, 2H), 7.20-7.30 (m, 1H), 7.54-7.64 (m, 1H), 7.94 (d, / = 6.9 Hz, 1H).
Step 4: N-(4-(l-Cyano-2-(cyclopropylamino)-2-oxoethyl)-3-nitrobenzyl)-N,3,3- trimethylbutanamide: The reaction of step 3 intermediate (5.0 g, 17.73 mmol) with 2-cyano- N-cyclopropylacetamide (4.39 g, 35.46 mmol) using sodium hydride (1.42 g, 35.46 mmol) in dry tetrahydrofuran (25 ml) as described in step 5 of intermediate 1 affords 3.55 g of product as pale yellow oil. 1H NMR (300 MHz, CDC13): δ 0.56-0.64 (m, 2H), 0.78-0.85 (m, 2H), 1.04-1.1 1 (m, 9H), 2.36 (s, 1H), 2.69-2.75 (m, 1H), 3.06 (s, 2H), 3.35 (s, 3H), 4.69 (s, 1H), 6.36 (br s, 1H), 7.58-7.64 (m, 1H), 7.69-7.76 (m, 1H), 7.95-8.03 (m, 1H).
Step 5 : 2-Amino-N-cyclopropyl-6-((N,3,3-trimethylbutanamido)methyl)-lH-indole-3- carboxamide: The reaction of step 4 intermediate (3.50 g, 9.067 mmol) with ferric chloride (4.412 g, 27.20 mmol) in presence of zinc dust (5.92 g, 90.67 mmol) in dry N,N- dimethylformamide (35 ml) as described in step 6 of intermediate 1 yields 1.6 g of the title product as a light pink solid. 1H NMR (300 MHz, CDC13): δ 0.55-0.65 (m, 4H), 1.00 (s, 9H), 2.29 (s, 2H), 2.75-2.81 (m, 1H), 2.86 (s, 3H), 4.56 (s, 2H), 6.61-6.80 (m, 2H), 6.81 (d, / = 8.1 Hz, 1H), 6.91 (s, 1H), 6.99 (s, 1H), 7.32-7.40 (m, 1H), 10.56 (s, 1H). ESI-MS (m/z): 357.23 (M+H)+.
The intermediates 4-55 were obtained in the same manner as described above in intermediate 2. The structural formulas, chemical names and spectral data are provided in table 1.
Table 1 : Structure, chemical name and spectral data of Intermediates 4-55.
Figure imgf000052_0001
Structure Chemical name and Spectral data
2- Amino-N-cyclopropyl-6-(3 -methoxy-N,3 - dimethylbutanamido)-lH-indole-3-carboxamide. 1H NMR (300 MHz, DMSO-Je): δ 0.56-0.67 (m, 4H), 1.14 (s, 6H),
Figure imgf000053_0001
2.21 (s, 2H), 2.74-2.81 (m, 1H), 2.90 (s, 3H), 3.12 (s, 3H),
Intermediate 9
6.75-6.81 (m, 4H), 6.96 (s, 1H), 7.44 (d, / = 8.4 Hz, 1H), 10.66 (s, 1H). APCI-MS (m z): 359.06 (M+H)+.
2- Amino-N-ethyl-6- [methyl(2-methylpropanoyl)amino] - lH-indole-3-carboxamide: 1H NMR (300 MHz, CDC13): δ
Figure imgf000053_0002
1.00 (d, / = 6.3 Hz, 6H), 1.24-1.34 (m, 3H), 2.53-2.64 (m,
Intermediate 10 1H), 3.27 (s, 3H), 3.44-3.59 (m, 2H), 5.72-5.74 (m, 1H),
6.28 (s, 2H), 6.91-6.95 (m, 2H), 7.31 (d, / = 8.1 Hz, 1H), 9.90 (br s, 1H). APCI-MS (m z): 303.15 (M+H)+.
2-Amino-N-cyclopropyl-6-[methyl(2- methylpropanoyl)amino]- lH-indole-3-carboxamide' lH NMR (300 MHz, CDCI3): δ 0.63-0.71 (m, 2H), 0.8-0.90
Figure imgf000053_0003
(m, 2H), 0.99 (d, / = 6.9 Hz, 6H), 2.00 (m, 2H), 2.51-2.64
Intermediate 11
(m, 1H), 2.84-2.90 (m, 1H), 3.26 (s, 3H), 5.95 (s, 3H), 6.44 (s, 1H), 6.85-6.95 (m, 1H), 7.21 (d, / = 7.8 Hz, 1H), 10.37 (s, 1H). APCI-MS (m z): 315.09 (M+H)+.
2-Amino-N-cyclopropyl-6-[ethyl(2- methylpropanoyl)amino]- lH-indole-3-carboxamide: 1H NMR (300 MHz, CDCI3): δ 0.59-0.70 (m, 4H), 0.80-0.90
Figure imgf000053_0004
(m, 3H), 0.96-1.00 (m, 3H), 1.04-1.10 (m, 3H), 2.41-2.50
Intermediate 12 (m, 1H), 2.84-2.92 (m, 1H), 3.73 (q, / = 6.6 Hz, 2H), 5.96
(s, 1H), 6.42 (s, 2H), 6.83-6.90 (m, 2H), 7.17-7.28 (m, 1H), 10.43 (br s, 1H). APCI-MS (m z): 329.11 (M+H)+.
2-Amino- V-cyclopropyl-6-[(2,2- dimethylpropanoyl)(methyl)amino] - 1 H-indole-3 - carboxamide: 1H NMR (300 MHz, CDCI3): δ 0.63-0.71
Figure imgf000053_0005
(m, 2H), 0.81-0.90 (m, 2H), 1.04 (s, 9H), 2.83-2.91 (m,
Intermediate 13
1H), 3.23 (s, 3H), 5.93 (s, 1H), 6.32 (s, 2H), 6.94 (s, 2H), 7.18 (d, / = 7.8 Hz, 1H), 9.81 (s, 1H). APCI-MS (m z): Structure Chemical name and Spectral data
329.32 (M+H)+.
2-Amino-6-(N,3-dimethylbutanamido)-N-ethyl-lH- indole-3-carboxamide. 1H NMR (300 MHz, CDC13): δ
Figure imgf000054_0001
0.80 (d, / = 6.6 Hz, 6H), 1.19-1.33 (m, 3H), 1.98 (d, / =
Intermediate 14 6.6 Hz, 2H), 2.06-2.14 (m, 1H), 3.28 (s, 3H), 3.46-3.57
(m, 2H), 5.69-5.76 (m, 1H), 6.29 (s, 2H), 6.87-6.92 (m, 2H), 7.30 (d, / = 9.0 Hz, 1H), 9.91 (br s, 1H). APCI-MS (m/z): 317.19 (M+H)+.
2- Amino-N-cyclopropyl-6- [methyl(3 - methylbutanoyl)amino]- lH-indole-3-carboxamide: 1H NMR (300 MHz, DMSO-J6): δ 0.51-0.66 (m, 4H), 0.74
Figure imgf000054_0002
(d, / = 6.3 Hz, 6H), 1.87 (d, / = 6.3 Hz, 2H), 1.90-1.99
Intermediate 15
(m, 1H), 2.72-2.80 (m, 1H), 3.13 (s, 3H), 6.72-6.80 (m, 4H), 6.95 (s, 1H), 7.45 (d, / = 8.4 Hz, 1H), 10.66 (s, 1H); APCI-MS (m/z) 329.49 (M+H)+.
2-Amino-6-[(3,3-dimethylbutanoyl)(methyl)amino]-N- ethyl-lH-indole-3-carboxamide: 1H NMR (300 MHz, CDCI3): δ 0.94 (s, 9H), 1.30 (t, / = 7.2 Hz, 3H), 2.05 (s,
Figure imgf000054_0003
Intermediate 16 2H), 3.27 (s, 3H), 3.48-3.57 (m, 2H), 5.73 (br s, 1H),
6.05-6.19 (m, 2H), 6.86-6.93 (m, 2H), 7.28-7.34 (m, 1H), 9.52 (br s, 1H). APCI-MS (m z): 331.18 (M+H)+.
2-Amino-N-cyclopropyl-6-(N,3,3-trimethylbutanamido)- lH-indole-3-carboxamide: 1H NMR (300 MHz, CDC13): δ
0 0.63-0.73 (m, 2H), 0.81-0.89 (m, 1 1H), 2.10 (s, 2H),
2.84-2.92 (m, 1H), 3.26 (s, 3H), 5.93 (s, 1H), 6.29 (br s,
Intermediate 17
2H), 6.85-6.92 (m, 2H), 7.16-7.25 (m, 1H), 9.55-9.62 (m, 1H). APCI-MS (m/z): 343.19 (M+H)+.
2-Amino-6-[(3,3-dimethylbutanoyl)(methyl)amino]-N,N- dimethyl-lH-indole-3-carboxamide: 1H NMR (300 MHz, cTN' DMSO-Je): δ 0.88 (s, 9H), 1.95 (s, 2H), 2.94 (s, 6H),
Intermediate 18 3.12 (s, 3H), 6.20 (s, 2H), 6.75 (d, / = 7.8 Hz, 1H), 6.95
(s, 1H), 7.12 (d, / = 8.4 Hz, 1H), 10.60 (s, 1H). APCI-MS Structure Chemical name and Spectral data
(m/z) 331.32 (M+H)
2-Amino-N-propyl-6-(N,3,3-trimethylbutanamido)-lH- indole-3-carboxamide: 1H NMR (300 MHz, DMSO-J6): δ 0.94 (s, 9H), 1.02 (t, / = 7.5 Hz, 3H), 1.65-1.75 (m, 2H),
Figure imgf000055_0001
2.06 (s, 2H), 3.27 (s, 3H), 3.47 (q, / = 6.3 Hz, 2H), 5.80
Intermediate 19
(s, 1H), 6.24 (s, 2H), 6.88 (s, 2H), 7.26 (s, 1H), 9.76 (s, 1H). APCI-MS (m/z) 345.43 (M+H)+. APCI-MS (m/z): 345.20 (M+H)+.
2-Amino-N-ethyl-6-(N- methylcyclopropanecarboxamido)- 1 H-indole-3 - carboxamide: 1H NMR (300 MHz, CDC13): δ 0.58 (d, / =
Intermediate 20 6.6 Hz, 2H), 0.95-1.13 (m, 2H), 1.23-1.33 (m, 3H), 1.40- 1.47 (m, 1H), 3.30 (s, 3H), 3.48-3.57 (m, 2H), 5.72 (s, 1H), 6.21 (s, 2H), 7.01-7.06 (m, 1H), 7.31 (d, / = 8.7 Hz, 1H), 9.64 (s, 1H). APCI-MS (m/z): 301.18 (M+H)+.
2-Amino-N-ethyl-6-(N-methylcyclopentanecarboxamido)- lH-indole-3-carboxamide. 1H NMR (300 MHz, CDC13): δ 1.24-1.83 (m, 1 1H), 2.57-2.66 (m, 1H), 3.27 (s, 3H), 3.48-
Intermediate 21 3.59 (m, 2H), 5.69-5.76 (m, 1H), 6.28 (s, 2H), 6.90-6.94
(m, 2H), 7.30 (d, / = 9.0 Hz, 1H), 9.92 (br s, 1H). APCI- MS (m/z): 329.25 (M+H)+.
2-Amino-6-(2-cyclopentyl-N-methylacetamido)-N-ethyl- lH-indole-3-carboxamide. 1H NMR (300 MHz, CDC13): δ
Figure imgf000055_0004
0.95-2.30 (m, 1 1H), 1.20-1.33 (m, 3H), 2.12 (d, / = 6.9
Intermediate 22 Hz, 2H), 3.28 (s, 3H), 3.51-3.59 (m, 2H), 5.71-5.79 (m,
1H), 6.88-6.95 (m, 2H), 7.24-7.33 (m, 1H), 9.50 (br s, 1H). APCI-MS (m/z): 343.22 (M+H)+.
2-Amino-6-(2-cyclopentyl-N-methylacetamido)-N- cyclopropyl-lH-indole-3-carboxamide. lH NMR (300 MHz, CDCI3): δ 0.65-2.30 (m, 14H), 2.83-2.91 (m, 2H),
Figure imgf000055_0005
3.26 (s, 3H), 5.95 (s, 1H), 6.39 (s, 2H), 6.85-6.93 (m, 2H),
Intermediate 23
7.15-7.28 (m, 1H), 10.08 (br s, 1H). APCI-MS (m/z):
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
} - Hz,
.
(s,
Figure imgf000062_0001
Intermediate 56
- Amino-N-cyclopropyl-6-(N-methyl-2-(N-methylpropionamido)acetamido)- 1 H-indole-3 - carboxamide
Figure imgf000063_0001
Step 1 : N- {2-[(4-Fluoro-3-nitrophenyl)amino]-2-oxoethyl}-N-methylpropanamide: To a stirred solution of 4-fluoro-3-nitroaniline (7.0 g, 44.837 mmol) and [methyl(propanoyl)amino] acetic acid (6.5 g, 44.837 mmol) in dry 1 ,2-dichloroethane (224 ml), HOBt (2.3 g, 16.589 mmol), N-methyl morpholine (5.8 ml, 52.01 mmol) and EDCI (10 g, 52.01 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (150 ml) and extracted with ethyl acetate (2 x 250 ml). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 6.75 g of product as an off-white solid. 1H NMR (300 MHz, CDCI3): δ 1.19 (t, / = 7.5 Hz, 3H), 2.48 (q, / = 7.2 Hz, 2H), 3.21 (s, 3H), 4.14 (s, 2H), 7.1 1 (t, / = 9.3 Hz, 1H), 7.56-7.63 (m, 1H), 8.21-8.26 (m, 1H), 9.58 (br s, 1H).
Step 2: N- {2-[(4-Fluoro-3-nitrophenyl)(methyl)amino]-2-oxoethyl} -N-methylpropanamide: The N-methylation reaction of step 1 intermediate (6.7 g, 23.674 mmol) using methyl iodide (2.22 ml, 35.512 mmol) in presence of sodium hydride (1.42 g, 35.512 mmol) in dry tetrahydrofuran (68 ml) as described in step 2 of intermediate 1 yields 7.0 g of product as a brown oil. 1H NMR (300 MHz, CDC13): δ 1.13 (t, / = 7.2 Hz, 3H), 2.39 (q, / = 6.6 Hz, 2H), 3.1 1 (s, 3H), 3.31 (br s, 3H), 3.82 (br s, 2H), 7.38 (t, / = 9.0 Hz, 1H), 7.70-7.77 (m, 1H), 7.98- 8.05 (m, 1H).
Step 3 : N-(2-((4-(l-Cyano-2-(cyclopropylamino)-2-oxoethyl)-3-nitrophenyl)(methyl)amino)- 2-oxoethyl)-N-methylpropionamide: The displacement reaction of step 2 intermediate (3.0 g, 10.101 mmol) with 2-cyano-N-cyclopropylacetamide (2.5 g, 20.202 mmol) using sodium hydride (808 mg, 20.202 mmol) in dry tetrahydrofuran (30 ml) as described in step 5 of intermediate 1 affords 3.45 g of product as yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.61(s, 2H), 0.80 (t, / = 7.2 Hz, 2H), 1.14 (t, / = 7.2 Hz, 3H), 2.38-2.44 (m, 2H), 2.71-2.80 (m, 1H), 3.10 (s, 3H), 3.35 (s, 3H), 3.97-4.05 (m, 2H), 5.44 (s, 1H), 7.68-7.79 (m, 2H), 8.06 (s, 1H).
Step 4: 2- Amino-N-cyclopropyl-6-(N-methy l-2-(N-methylpropionamido)acetamido)- 1 H- indole-3-carboxamide: The reductive cyclization of step 3 intermediate (3.4 g, 8.478 mmol) using ferric chloride (4.12 g, 25.436 mmol) and zinc dust (5.54 g, 84.78 mmol) in dry N,N- dimethylformamide (34 ml) as described in step 6 of intermediate 1 affords 1.0 g of the title compound as a brown solid. 1H NMR (300 MHz, CDC13): δ 0.60-0.70 (m, 2H), 0.83-0.91 (m, 3H), 1.12 (t, / = 7.5 Hz, 3H), 2.41 (q, / = 7.2 Hz, 2H), 2.85-2.96 (m, 2H), 3.04 (s, 3H), 3.16 (s, 3H), 5.88 (s, 1H), 6.50-6.59 (m, 2H), 6.85-6.96 (m, 2H), 7.16 (d, / = 8.4 Hz, 1H), 9.98 (s, 1H). APCI-MS (m/z): 370.19 (M-H)".
The intermediates 57-60 were obtained in the same manner as described above in intermediate 56. The structural formulas, chemical names and 1H NMR data are provided in table 2.
Table 2: Structure, chemical name and 1H NMR data of Intermediates 57-60.
Figure imgf000064_0001
Figure imgf000065_0001
Intermediate 61
2-Amino-N6-cyclohexyl- 3-ethyl-N6-methyl-lH-indole-3,6-dicarboxamide
Figure imgf000065_0002
Step 1 : N-Cyclohexyl-4-fluoro-N-methyl-3-nitrobenzamide: This intermediate was prepared by reaction of 4-fluoro-3-nitrobenzoic acid (5.5 g, 27.02 mmol) with N-methyl cyclohexyl amine (3.5 ml, 27.02 mmol) using HOBt (1.34 g, 9.997 mmol) and EDCI (6.0 g, 31.34 mmol) in presence of N-methyl morpholine (3.45 ml, 31.33 mmol) in dry 1 ,2-dichloroethane (135 ml) as described in step 1 of intermediate 56 to obtain 5.8 g of product as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 1.07-1.89 (m, 1 1H), 2.83-2.99 (m, 3H), 7.35 (d, / = 9.3 Hz, 1H), 7.65-7.72 (m, 1H), 8.10 (d, / = 6.3 Hz, 1H).
Step 2: 4-( 1 -Cyano-2-(ethylamino)-2-oxoethyl)-N-cyclohexyl-N-methyl-3 -nitrobenzamide : The displacement reaction of step 1 intermediate (5.7 g, 20.35 mmol) with 2-cyano-N- ethylacetamide (4.5 g, 40.71 mmol) in presence of sodium hydride (1.6 g, 40.71 mmol) in dry tetrahydrofuran (57 ml) as described in step 5 of intermediate 1 affords 9.0 g of product as a pale yellow oil. 1H NMR (300 MHz, CDCI3): δ 0.85-0.91 (m, 3H), 1.14-2.00 (m, 1 1H), 3.32- 3.39 (m, 5H), 5.56 (s, 1H), 6.43-6.53 (m, 1H), 7.70-7.79 (m, 1H), 7.84 (d, / = 7.8 Hz, 1H), 8.15 (s, 1H).
Step 3 : 2-Amino-N6-cyclohexyl-N3-ethyl-N6-methyl-lH-indole-3,6-dicarboxamide: The reaction of step 2 intermediate (1.0 g, 2.68 mmol) with ferric chloride (1.30 g, 7.97 mmol) in presence of zinc dust (1.75 g, 26.85 mmol) in dry N,N-dimethylformamide (10 ml) as described in step 6 of intermediate 1 affords 400 mg of the title compound as an off-brown solid. 1H NMR (300 MHz, CDCI3): δ 1.08-1.70 (m, 1 1H), 1.27 (t, / = 7.2 Hz, 3H), 2.95 (s, 3H), 3.44-3.55 (m, 2H), 5.63-5.70 (m, 1H), 6.25 (s, 2H), 7.05-7.27 (m, 3H), 10.10 (br s, APCI-MS (m/z): 343.23 (M+H)+.
Intermediate 62
(S)-2-Amino-N3-cyclopropyl-N6-(3,3-dimethylbutan-2-yl)-N6-methyl-lH-indole-3,6- dicarboxamide
Figure imgf000066_0001
This intermediate is prepared in 4 steps (i) The coupling reaction of 4-fluoro-3-nitrobenzoic acid (5 g, 27.01 mmol) with (2S)-3,3-dimethylbutan-2-amine (3.67 ml, 27.01 mmol) using HOBt (1.34 g, 9.997 mmol) and EDCI (6.0 g, 31.34 mmol) in presence of N-methyl morpholine (3.45 ml, 31.33 mmol) as described in step 1 of intermediate 56 (ii) The N- methylation of N-[(2lS,)-3,3-dimethylbutan-2-yl]-4-fluoro-3-nitrobenzamide (6.5 g, 24.22 mmol) using methyl iodide (2.27 ml, 36.33 mmol) in presence of sodium hydride (1.45 g, 36.33 mmol) as described in step 2 of intermediate 1 ; (iii) The fluoro displacement of Λ^-[(25)- 3,3-dimethylbutan-2-yl]-4-fluoro-N-methyl-3-nitrobenzamide (6.5 g, 23.020 mmol) with 2- cyano-N-cyclopropylacetamide (5.71 g, 46.04 mmol) using sodium hydride (1.84 g, 46.04 mmol) in dry tetrahydrofuran as described in step 5 of intermediate 1 ; (iv) The reductive cyclization using ferric chloride (6.94 g, 14.23 mmol) and zinc dust (9.3 g, 142.3 mmol) as described in step 6 of intermediate 1 to yield 1.9 g of product as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.55-0.70 (m, 2H), 0.75-0.90 (m, 9H), 0.99-1.10 (m, 2H), 1.23 (t, / = 7.2 Hz, 3H), 3.00 (s, 3H), 3.85-3.95 (m, 1H), 4.75-4.86 (m, 1H), 5.85 (s, 1H), 6.15-6.25 (m, 2H), 7.07-7.15 (m, 3H), 10.32-1.43 (m, 1H). APCI-MS (m z): 357.24 (M+H)+.
Intermediate 63
N- [2-Amino-3 -(methoxyacet l)- 1 H-indol-6-yl] -N,3 ,3 -trimethylbutanamide
Figure imgf000066_0002
Step 1 : N-(4-Fluoro-3-nitrophenyl)-3,3-dimethylbutanamide: This intermediate was prepared by reaction of 3,3-dimethylbutanoic acid (18.3 ml, 144.1 1 mmol) with 4-fluoro-3-nitroaniline (15.0 g, 96.07 mmol) using oxalyl chloride (16.6 ml, 192.14 mmol) and pyridine (15 ml) in dry tetrahydrofuran (90 ml) and N,N-dimethylformamide (1.5 ml) as described in step 1 of intermediate 3 to obtain 21.56 g of product as off white solid. 1H NMR (300 MHz, CDC13): δ 1.1 1 (s, 9H), 2.25 (s, 2H), 7.20-7.34 (m, 2H), 7.83-7.90 (m, 1H), 8.19-8.26 (m, 1H).
Step 2: N-(4-Fluoro-3-nitrophenvl)-N,3,3-trimethylbutanamide: The step 1 intermediate (21.5 g, 84.64 mmol) undergoes N-methylation using methyl iodide (7.9 ml, 126.96 mmol) in presence of sodium hydride (5.0 g, 126.96 mmol) in dry tetrahydrofuran (215 ml) as described in step 2 of intermediate 1 to yield 20.45 g of product as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 1.00 (s, 9H), 2.01-2.07 (m, 2H), 3.27-3.37 (m, 3H), 7.35 (t, / = 9.3 Hz, 1H), 7.45-7.52 (m, 1H), 7.87-7.94 (m, 1H).
Step 3 : Ethyl cyano {4-[(3,3-dimethylbutanoyl)(methyl)amino]-2-nitrophenyl}acetate: The displacement reaction of step 2 intermediate (8.0 g, 29.850 mmol) with ethyl cyano acetate (6.36 ml, 59.701 mmol) in the presence of sodium hydride (2.4 g, 59.709 mmol) in dry tetrahydrofuran (80 ml) as described in step 5 of intermediate 1 affords 8.05 g of product as a pale yellow oil. 1H NMR (300 MHz, CDCI3): δ 1.02 (s, 9H), 1.34 (d, / = 6.9 Hz, 3H), 2.18 (s, 2H), 3.35 (s, 3H), 4.33 (q, / = 7.2 Hz, 2H), 5.67 (s, 1H), 7.60 (d, / = 6.9 Hz, 1H), 7.82 (d, / = 8.1 Hz, 1H), 8.06 (s, 1H).
Step 4: N-[4-(Cyanomethyl)-3-nitrophenyl]-N,3,3-trimethylbutanamide: To a stirred solution of step 3 intermediate (8.0 g 45.17 mmol) in dimethyl sulfoxide (41 ml) was added saturated brine solution (17.3 ml) and the reaction mixture was heated at 120 °C overnight. The reaction was cooled to room temperature, diluted with water (150 ml), extracted with ethyl acetate (100 ml x 3) and washed with brine (150 ml). The mixture was evaporated and the residue obtained was purified by column chromatography to give 3.7 g of product as yellow oil. 1H NMR (300 MHz, CDCI3): δ 1.01 (s, 9H), 2.12-2.20 (m, 2H), 3.33 (s, 3H), 4.23 (s, 2H), 7.57 (d, / = 7.8 Hz, 1H), 7.79 (d, / = 8.1 Hz, 1H), 8.04 (s, 1H).
Step 5 : N-[4-( 1 -Cyano-3 -methoxy-2-oxopropyl)-3 -nitrophenyl] -N,3 ,3 -trimethylbutanamide : Triethyl amine ( 4.1 ml, 29.18 mmol) was added to a solution of step 4 intermediate (3.67 g, 12.69 mmol) in dry dichloromethane (37 ml) followed by 4-(dimethyl amino pyridine) (155 mg, 1.269 mmol) at 0 °C. To this mixture methoxyacetyl chloride (1.22 ml, 13.33 mmol) was added over 10-15 min. The reaction mixture was warmed to room temperature, stirred for 2 h and concentrated under reduced pressure. The residue obtained was diluted with water and extracted with ethyl acetate (75 ml x 3), washed with saturated solution of sodium bicarbonate (75 ml), aqueous hydrochloric acid (75 ml) and brine (75 ml). The crude residue after evaporation of mixture was purified by column chromatography to afford 3.95 g of product as a brown solid. 1H NMR (300 MHz, CDCI3): δ 1.00 (s, 9H), 2.12-2.19 (m, 2H), 3.28-3.36 (m, 4H), 3.42-3.50 (m, 2H), 3.54 (s, 3H), 4.20-4.35 (m, 2H), 7.40-7.47 (m, 1H), 7.55-7.65 (m, 1H), 7.75-7.85 (m, 1H).
Step 6: N-[2-Amino-3-(methoxyacetyl)-lH-indol-6-yl]-N,3,3-trimethylbutanamide: Step 5 intermediate (3.9 g, 10.78 mmol) undergoes reaction with ferric chloride (5.2 g, 32.36 mmol) and zinc dust (7.0 g, 107.8 mmol) in dry N,N-dimethylformamide (40 ml) as described in step 6 of intermediate 1 to afford 1.87 g of the title compound as a yellow solid. 1H NMR (300 MHz, CDCls): δ 0.96 (br s, 9H), 2.08 (s, 2H), 3.29 (s, 3H), 3.64 (s, 3H), 4.73 (s, 2H), 6.88- 6.95 (m, 2H), 7.29-7.35 (m, 1H), 7.38-7.45 (m, 2H), 10.70 (br s, 1H).
Intermediate 64
N-(2- Amino-3 -(2-methoxyacet - 1 H-indol-6-yl)-N-methylcyclohexanecarboxamide
Figure imgf000068_0001
Step 1 : Ethyl 2-cyano-2-(4-(N-methylcyclohexanecarboxamido)-2-nitrophenyl)acetate: The reaction of N-(4-Fluoro-3-nitrophenyl)-N-methylcyclohexanecarboxamide (step 2 of intermediate-2) (20.0 g, 71.42 mmol) with ethyl cyano acetate (15.3 ml, 142.82 mmol) in the presence of sodium hydride (5.7 g, 142.82 mmol) in dry tetrahydrofuran (200 ml) as described in step 5 of intermediate 1 affords 25.0 g of product as a pale yellow oil. H NMR
(300 MHz, CDCI3): δ 0.95-1.99 (m, 10H), 2.05-2.36 (m, 1H), 3.33 (s, 3H), 4.15-4.41 (m, 2H), 5.61 (br s, 1H), 7.45-8.38 (m, 3H).
Step 2: N-(4-(Cyanomethyl)-3 -nitrophenyl)-N-methylcyclohexanecarboxamide : This intermediate is prepared by reaction of step 1 intermediate (25.0 g 67.02 mmol) with saturated solution of brine (50 ml) in dimethyl sulfoxide (132 ml) as described in step 4 of intermediate 63 to give 14.2 g of product as yellow oil. 1H NMR (300 MHz, CDC13): δ 1.08-1.73 (m, 10H), 2.20-2.35 (m, 1H), 3.33 (s, 3H), 4.25 (s, 2H), 7.58 (d, / = 8.4 Hz, 1H), 7.80 (d, / = 8.4 Hz, 1H), 8.06 (s, 1H).
Step 3 : N-(4-( 1 -Cyano-3 -methoxy-2-oxopropyl)-3 -nitrophenyl)-N-methylcyclohexane carboxamide: This intermediate was prepared by reaction of step 2 intermediate (3.0 g, 9.96 mmol) with methoxyacetyl chloride (962 μΐ, 10.46 mmol) in presence of triethyl amine ( 3.2 ml, 22.9 mmol) and 4-(dimethyl amino pyridine) (121 mg, 0.99 mmol) in dry dichloromethane (30 ml) as described in step 5 of intermediate 63 to afford 3.675 g of product as a brown solid. 1H NMR (300 MHz, CDCI3): δ 0.85-1.73 (m, 10H), 2.10-2.38 (m, 1H), 3.29-3.36 (m, 3H), 3.47-3.56 (m, 5H), 5.99 (br s, 1H), 7.44-7.66 (m, 1H), 7.76-7.82 (m, 1H), 8.07 (d, / = 7.8 Hz, 1H).
Step 4: N-(2- Amino-3 -(2-methoxyacetyl)- 1 H-indol-6-yl)-N-methylcyclohexanecarboxamide : Step 3 intermediate (3.67 g, 9.82 mmol) undergoes reaction with ferric chloride (4.8 g, 29.47 mmol) and zinc dust (6.5 g, 98.25 mmol) in dry N,N-dimethylformamide (40 ml) as described in step 6 of intermediate 1 to obtain 1.5 g of the title compound as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.90-1.67 (m, 10H), 2.20-2.38 (m, 2H), 3.37 (s, 3H), 3.63 (s, 3H), 4.71 (s, 2H), 6.91-6.97 (m, 2H), 7.25-7.40 (m, 3H), 10.59 (br s, 1H). APCI-MS (m z): 344.26 (M+H)+.
Intermediate 65
Methyl 4-(2-amino-6-(N-methylcyclohexanecarboxamido)-lH-indol-3-yl)-4-oxobutanoate
Figure imgf000069_0001
Step 1 : Methyl 5 -cyano-5 -(4-(N-methylcyclohexanecarboxamido)-2-nitrophenyl)-4- oxopentanoate: The coupling reaction of N-(4-(cyanomethyl)-3-nitrophenyl)-N- methylcyclohexanecarboxamide (Step 2 intermediate of 64) (3.0 g, 9.93 mmol) with methyl 4-chloro-4-oxobutyrate (1.57 g, 10.43 mmol) in the presence of triethyl amine (2.31 g, 3.20 ml, 22.84 mmol) and 4-(dimethylamino)pyridine (121 mg, 0.933 mmol) in dry dichloromethane (300 ml) as described in step 5 of intermediate 63 affords 5.00 g of product as a brown oil which was directly used in next step without purification.
Step 2: Methyl 4-(2-amino-6-(N-methylcyclohexanecarboxamido)- lH-indol-3-yl)-4- oxobutanoate: Step 1 intermediate (4.4 g, 10.57 mmol) undergoes reaction with ferric chloride (5.10 g, 31.72 mmol) and zinc dust (6.90 g, 105.74 mmol) in dry N,N- dimethylformamide (44 ml) as described in step 6 of intermediate 1 to obtain 1.80 g of the title compound as an off-white solid. 1H NMR (300 MHz, CDCI3): δ 0.85-1.65 (m, 10H), 2.20-2.36 (m, 1H), 2.77-2.84 (m, 2H), 2.93 (s, 5H), 3.73 (s, 3H), 6.86-6.95 (m, 4H), 7.53 (d, / = 8.1 Hz, 1H), 9.77 (br s, 1H). APCI-MS (m z): 386.19 (M+H)+.
Intermediate 66
tert-Butyl 2-amino-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indole-3 -carboxylate
Figure imgf000069_0002
Step 1 : tert-Butyl 2-cyano-2-(2-nitro-4-(N,3,3-trimethylbutanamido)phenyl)acetate: The displacement reaction of N-(4-Fluoro-3-nitrophenyl)-N,3,3-trimethylbutanamide (step 2 intermediate 63) (29.1 g, 108.45 mmol) with tert-butyl cyanoacetate (31.25 ml, 216.9 mmol) in presence of sodium hydride (8.67 g, 216.9 mmol) in dry tetrahydrofuran (290 ml) as described in step 5 of intermediate 1 to afford 40.6 g of product as a pale yellow oil. 1H NMR (300 MHz, CDCI3): δ 1.10-1.75 (m, 19H), 2.25-2.34 (m, 1H), 3.33 (s, 3H), 5.58 (s, 1H), 7.60 (d, / = 6.3 Hz, 1H), 7.82 (d, / = 8.1 Hz, 1H), 8.08 (s, 1H).
Step 2: tert-Butyl 2-amino-6-(N,3,3-trimethylbutanamido)-lH-indole-3-carboxylate: the step 1 intermediate (40.3 g, 103.4 mmol) undergoes reaction with ferric chloride (50.51 g, 310.2 mmol) and zinc dust (67.59 g, 1034.9 mmol) in dry N,N-dimethylformamide (403 ml) as described in step 6 of intermediate 1 to yield 31.3 g of product as an off-white solid. 1H NMR (300 MHz, CDCI3): δ 0.84-1.68 (m, 19H), 2.24-2.35 (m, 1H), 3.26 (s, 3H), 6.02 (br s, 2H), 6.83 (s, 1H), 6.90 (d, / = 8.7 Hz, 1H), 7.75 (d, / = 8.1 Hz, 1H), 9.55-9.63 (m, 1H). APCI-MS (m/z): 360.21 (M+H)+.
The Intermediates 67-71 were obtained in the same manner as described above in Intermediate 66. The structural formulas, chemical names and lH NMR data are provided in
Table 3: Structure, chemical name and 1H NMR data of Intermediates 67-71
Figure imgf000070_0001
Structure Chemical name, 1H NMR ans MS data
iert-Butyl 2-amino-6-[(cyclohexylcarbonyl)(methyl)amino]-
0 XX N H2 lH-indole-3-carboxylate: 1H NMR (300 MHz, CDC13): δ
0.84-1.68 (m, 19H), 2.24-2.35 (m, 1H), 3.26 (s, 3H), 6.02 (br s, 2H), 6.83 (s, 1H), 6.90 (d, / = 8.7 Hz, 1H), 7.75 (d, / = 8.1
Intermediate 69
Hz, 1H), 9.55-9.63 (m, 1H). APCI-MS (m/z): 372.16.
iert-Butyl 2-amino-6-[methyl(phenylcarbonyl)amino]- 1H- indole-3-carboxylate: 1H NMR (300 MHz, CDC13): δ 1.61 (s, 9H), 3.45 (s, 3H), 5.78 (br s, 2H), 6.54 (s, 1H), 6.85 (d, / = 6.3 Hz, 1H), 7.08-7.11 (m, 3H), 7.24-7.30 (m, 2H), 7.60 (d, / =
Intermediate 70
5.1 Hz, 1H), 8.97 (s, 1H). APCI-MS (m z): 366.18 (M+H)+. iert-Butyl 2-amino-6-{[(4- fluorophenyl)carbonyl](methyl)amino} - lH-indole-3- carboxylate: 1H NMR (300 MHz, CDC13): δ 1.61 (s, 9H), 3.44 (s, 3H), 5.82 (br s, 2H), 6.53 (s, 1H), 6.74-6.87 (m, 3H), 7.21-
Intermediate 71 7.31 (m, 2H), 7.60 (d, / = 8.7 Hz, 1H), 8.95 (s, 1H). APCI-MS
(m/z): 384.41 (M+H)+.
Intermediate 72
5-Amino-N2-cyclohexyl-N6-cyclopropyl-N2-methyl-4H-thieno[3,2-b]pyrrole-2,6- dicarboxamide
Figure imgf000071_0001
Step 1 : 5-Chloro-N-cyclohexyl-N-methyl-4-nitrothiophene-2-carboxamide: 5-Chloro-4- nitrothiophene-2-carboxylic acid (7.2 g, 34.782 mmol) in thionyl chloride (30 ml) was stirred at reflux temperature for 4 h. The reaction mixture concentrated under reduced pressure and diluted with dry tetrahydrofuran (50 ml). This solution was drop wise added to a stirred mixture of N-methylcyclohexanamine (4.54 ml, 34.812 mmol), dry pyridine (4.5 ml, 0.04 mmol) and dry tetrahydrofuran (140 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with hydrochloric acid (1 N, 100 ml), extracted with ethyl acetate (2 x 75 ml). The combined organic layer was washed with brine (75 ml) and dried over sodium sulphate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield 10.8 g of product as a yellow solid. 1H MR (300 MHz, CDC13): δ δ 1.05-1.93 (m, 11H), 3.08 (s, 3H), 7.72 ( br s, 1H). ESI (m/z) 303.02 (M+H)+.
Step 2: 5-[ 1 -Cyano-2-(cyclopropylamino)-2-oxoethyl]-N-cyclohexyl-N-methyl-4- nitrothiophene-2-carboxamide: This intermediate is prepared by reaction of step 1 intermediate (1.2 g, 3.973 mmol) with 2-cyano-N-cyclopropylacetamide (985 mg, 7.947 mmol) in presence of sodium hydride (318 mg, 7.947 mmol) in dry tetrahydrofuran (12 ml) as described in step 5 of intermediate 1 to afford 1.65 g of product as brown oil. 1H NMR (300 MHz, CDCI3): δ 0.55-2.07 (m, 14H), 2.70-2.80 (m, 1H), 3.00-3.09 (m, 2H), 3.35 (s, 3H), 5.65 (s, 1H), 7.77 (s, 1H).
Step 3 : 5-Amino-N2-cyclohexyl-N6-cyclopropyl-N2-methyl-4H-thieno[3,2-b]pyrrole-2,6- dicarboxamide: This intermediate is prepared by reaction of step 2 intermediate (1.6 g, 4.107 mmol) with ferric chloride (2.0 g, 12.323 mmol) and zinc dust (2.68 g, 41.07 mmol) in dry N,N-dimethylformamide (16 ml) as described in step 6 of intermediate 1 to yield 370 mg of product as a brown solid. 1H NMR (300 MHz, DMSO-J6): δ 1.05-1.93 (m, 16H), 3.08 (s, 3H), 4.10-4.36 (m, 2H), 7.72 (br s, 1H), 8.31 (s, 1H), 10.57 (s, 1H). APCI-MS (m z): 361.21 (M+H)+.
Intermediate 73
5-Amino-N2-cyclohexyl-N6-ethyl-N2-methyl-4H-thieno[3,2-b]pyrrole-2,6-dicarboxamide
Figure imgf000072_0001
Step 1 : 5-[ 1 -Cyano-2-(ethylamino)-2-oxoethyl]-N-cyclohexyl-N-methyl-4-nitrothiophene-2- carboxamide: This intermediate was prepared by displacement reaction of 5-chloro-N- cyclohexyl-N-methyl-4-nitrothiophene-2-carboxamide (4.0 g, 13.245 mmol) with 2-cyano-N- ethylacetamide (3.0 g, 26.49 mmol) in presence of sodium hydride (1.05 g, 56.49 mmol) in dry tetrahydrofuran (40 ml) as described in step 5 of intermediate 1 to afford 3.0 g of product as brown oil. 1H NMR (300 MHz, DMSO-J6): δ 0.95-2.10 (m, 14H), 2.91-3.08 (m, 3H), 3.27- 3.36 (m, 2H), 6.12-6.20 (m, 1H), 6.57-6.65 (m, 1H), 7.76 (br s, 1H).
Step 2 5-Amino-N2-cyclohexyl-N6-ethyl-N2-methyl-4H-thieno[3,2-b]pyrrole-2,6- dicarboxamide: The title compound was prepared by reductive cyclization of step 1 intermediate (3 g, 7.947 mmol) using ferric chloride (3.86 g, 23.84 mmol) and zinc dust (5.2 g, 79.47 mmol) in dry N,N-dimethylformamide (30 ml) as described in step 6 of intermediate 1 to obtain 650 mg of product as a brown solid. 1H NMR (300 MHz, DMSO-J6): δ 1.10 (d, / = 7.5 Hz, 3H), 1.14-1.85 (m, 11H), 3.00 (s, 3H), 3.17-3.29 (m, 2H), 6.49 (s, 2H), 7.18 (s, 1H), 8.31 (s, 1H), 10.58 (s, 1H). ESI-MS (m z): 348.94 (M+H)+.
Intermediate 74
5-Amino-N2-cyclohexyl-N4-cyclopropyl-N2-methyl-6H-thieno[2,3-b]pyrrole-2,4- dicarboxamide
Figure imgf000073_0001
Step 1 : 4-Chloro-5-nitrothiophene-2-carbaldehyde: Concentrated sulfuric acid (55 ml) was drop wise added to concentrated nitric acid (96 ml) and the mixture was stirred at -10 to -5 °C for 1 h. To this mixture 4-chlorothiophene-2-carbaldehyde (24 g, 165.51 mmol) was added in portions at -5 °C and the reaction mixture was stirred for 1 h at same temperature. The reaction was quenched by adding ice cooled water (1 lit.) and the mixture was extracted with chloroform (2 x 500 ml). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 16.09 g of product as an off white solid. 1H NMR (300 MHz, CDC13): δ 7.66 (s, 1H), 9.93 (s, 1H).
Step 2: 4-Chloro-5-nitrothiophene-2-carboxylic acid: To a stirred solution of step 1 intermediate (9.5 g, 49.738 mmol) in acetone (250 ml), sulfamic acid (9.7 g, 99.47 mmol) was added followed by drop wise addition of aqueous solution of sodium chlorite (50 ml, 6.8 g, 74.60 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, residue obtained was treated with hydrochloric acid (I N, 100 ml) and the mixture was stirred for 30 min. The precipitated solid was collected by Alteration, washed with water (100 ml) and dried to yield 9.2 g of product as an off-white solid. 1H NMR (300 MHz, DMSO-J6): δ 7.87 (s, 1H), 14.15 (br s, 1H).
Step 3: 4-Chloro-N-cyclohexyl-N-methyl-5-nitrothiophene-2-carboxamide: This intermediate was prepared by coupling reaction of step 2 intermediate (4 g, 19.32 mmol) with N- methylcyclohexanamine (3 ml, 23.18 mmol) in presence of dry pyridine (3 ml, 0.03 mmol) in dry tetrahydrofuran (100 ml) as described in step 1 of intermediate 72 to yield 4.81 g of product as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.59-2.00 (m, 15H), 2.69-2.77 (m, 1H), 3.04 (s, 3H), 5.58 (s, 1H), 6.51 (s, 1H), 7.43 (brs, 1H). Step 4: 4-[l-Cyano-2-(cyclopropylamino)-2-oxoethyl]-N-cyclohexyl-N-methyl-5- nitrothiophene-2-carboxamide: This intermediate was prepared by displacement reaction of step 3 intermediate (2.8 g, 9.27 mmol) with 2-cyano-N-cyclopropylacetamide (2.3 g, 18.54 mmol) in presence of sodium hydride (742 mg, 18.54 mmol) in dry tetrahydrofuran (28 ml) as described in step 5 of intermediate 1 to afford 3.1 g of product as brown oil. 1H NMR (300 MHz, CDCI3): δ 1.03-2.00 (m, 10H), 3.02 (s, 3H), 3.70-3.77 (m, 1H), 7.14 (br s, 1H).
Step 5 : 5-Amino-N2-cyclohexyl-N4-cyclopropyl-N2-methyl-6H-thieno[2,3-b]pyrrole-2,4- dicarboxamide: The title compound was prepared by reductive cyclization of step 4 intermediate (1.6 g, 7.702 mmol) using ferric chloride (3.7 g, 23.106 mmol) and zinc dust (5 g, 77.02 mmol) in dry N,N-dimethylformamide (30 ml) as described in step 6 of intermediate 1 to obtain 780 mg of product as a brown solid. 1H NMR (300 MHz, DMSO-J6): δ 1.05-1.93 (m, 14H), 2.62-2.70 (m, 1H), 3.03 (s, 3H), 4.16-4.26 (m, 1H), 6.41 (s, 2H), 6.89 (s, 1H), 7.54 (s, 1H), 10.80 (s, 1H). APCI-MS (m z): 361.15 (M+H)+.
Preparation of THP protected lH-pyrazole-4-boronic acid
Intermediate 75
l-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5 -tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole
Figure imgf000074_0001
To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.76 mmol) in dry dichloroethane (128 ml), 3,4-dihydro-2H-pyran (4.71 ml, 51.52 mmol) was added followed by p-toluenesulfonic acid (490 mg, 2.576 mmol) and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with aqueous saturated solution of sodium bicarbonate (75 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic layer was washed with brine (100 ml) and dried over sodium sulphate. The mixture was evaporated under reduced pressure and residue obtained was purified by column chromatography to yield 5.04 g of product as a white solid. 1H NMR (300 MHz, CDCI3): δ
I .31 (s, 12H), 1.54-1.70 (m, 3H), 1.98-2.20 (m, 3H), 3.68 (t, / = 10.2 Hz, 1H), 4.04 (d, / =
I I .7 Hz, 1H), 5.35-5.45 (m, 1H), 7.82 (s, 1H), 7.93 (s, 1H).
Various heteroaryl and aromatic carboxylic acids viz. thiazole-4-carboxylic acid, 5- bromothiophene-2-carboxylic acid, 2-bromo-l,3-thiazole-4-carboxylic acid, 6-bromopyridine- 2-carboxylic acid, 5-(4-fluorophenyl)thiophene-2-carboxylic acid, pyridine-2-carboxylic acid, 5-(pyridin-4-yl)thiophene-2-carboxylic acid, 2-(pyridin-4-yl)-l ,3-thiazole-4-carboxylic acid, picolinic acid, 4-fluoro-3-nitroaniline and lH-pyrazole-4-boronic acid pinacol ester were used in the preparation of the compounds of the present invention are commercially available and can be prepared by the person skilled in the art. 2-(Dimethylamino)thiazole-4-carboxylic acid was prepared by hydrolysis of comercially available ethyl 2-(dimethylamino)-l ,3-thiazole-4- carboxylate (CAS No: 630423-58-4).
Examples
General procedure for the preparation of compounds of present invention
Step 1 : Preparation of acid chloride:
Method A: A mixture of substituted aryl or heterocyclic carboxylic acid (1.0 equiv.) and thionyl chloride (15 vol.) was stirred at reflux temperature for 3-5 h. The reaction mixture was concentrated under reduced pressure and the acid chloride obtained was directly used in the next step.
Method B: To a stirred solution of substituted aryl or heterocyclic carboxylic acid (1.0 equiv.) in dichloromethane (10 vol.) was added catalytic amount of N,N-dimethylformamide (2-3 drops) followed by drop wise addition of oxalyl chloride (2 equiv.) at 0 °C and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was evaporated under reduced pressure and the acid chloride obtained was directly used in the next step.
Step 2: Coupling of acid chloride with amine: To a stirred solution of amino indole (1.0 equiv) in dry tetrahydrofuran (10 vol.), dry pyridine (2.5 equiv.) was added at room temperature. This reaction mixture was drop wise added to a solution of acid chloride (1.5 equiv.) in dry tetrahydrofuran (10 vol) at 0-5 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with hydrochloric acid (1 N), extracted thrice with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulphate. The mixture was concentrated under reduced pressure and purified by column chromatography to yield desired product.
The examples 1-106 were obtained as described above in the general procedure. The structural formulas, chemical names, 1H NMR and MS data are provided in table 4.
Table 4: Structure, chemical name, 1H NMR and MS data of Examples 1-106.
Structure Chemical name, 1H NMR and MS data Structure Chemical name, 1H NMR and MS data
N-(3-(Cyclopropylcarbamoyl)-6-(N- methylcyclohexanecarboxamido)-lH-indol-2-yl)thiazole-4- carboxamide: 1H NMR (300 MHz, CDC13): δ 0.70-1.69 (m,
Figure imgf000076_0001
14H), 2.01-2.09 (m, 1H), 2.98-3.05 (m, 1H), 3.28 (s, 3H), 6.15
Example 1
(s, 1H), 7.05 (d, / = 6.9 Hz, 1H), 7.45 (d, / = 8.4 Hz, 1H), 8.35 (s, 1H), 8.94 (s, 1H), 11.10 (s, 1H), 12.86 (s, 1H); APCI-MS (m/z): 466.03 (M+H)+.
N-Cyclopropyl-2-(picolinamido)-6-(2,2,2-trifluoro-N- methylacetamido)-l H-indole-3 -carboxamide: 1H NMR (300 MHz, DMSO-Je): δ 0.65-0.75 (m, 2H), 0.95 (d, / = 5.7 Hz,
Figure imgf000076_0002
2H), 2.96-3.08 (m, 1H), 3.41 (s, 3H), 6.15 (s, 1H), 7.11 (d, / =
Example 2
8.4 Hz, 1H), 7.32 (s, 1H), 7.44-7.58 (m, 2H), 7.94 (t, / = 7.8 Hz, 1H), 8.27 (d, / = 7.2 Hz, 1H), 8.81 (s, 1H), 11.30 (s, 1H), 13.15 (s, 1H); ESI-MS (m z): 446.00 (M+H)+.
N-Cyclopropyl-6-(N-ethylacetamido)-2-(picolinamido)-lH- indole-3-carboxamide: 1H NMR (300 MHz, DMSO-J6): δ 0.65-0.90 (m, 4H), 1.03 (t, / = 6.6 Hz, 3H), 1.71 (s, 3H), 2.85-
Figure imgf000076_0003
2.93 (m, 1H), 3.66 (q, / = 7.8 Hz, 2H), 7.03 (d, / = 8.4 Hz,
Example 3 1H), 7.49 (s, 1H), 7.59 (s, 1H), 7.71-7.85 (m, 2H), 8.17 (t, / =
7.8 Hz, 1H), 8.27 (d, / = 7.8 Hz, 1H), 8.85 (d, / = 4.5 Hz, 1H), 12.28 (s, 1H), 13.13 (s, 1H); ESI-MS (m z): 406.32 (M+H)+.
N-Cyclopropyl-6-(N-ethylacetamido)-2-(6- methylpicolinamido)-l H-indole-3 -carboxamide: 1H NMR (300 MHz, DMSO-Jg): δ 0.67-0.85 (m, 2H), 0.90-0.98 (m,
Figure imgf000076_0004
2H), 1.14 (t, / = 7.2 Hz, 3H), 1.85 (s, 3H), 2.77 (s, 3H), 2.99-
Example 4
3.06 (m, 1H), 3.82 (q, / = 6.9 Hz, 2H), 6.14 (s, 1H), 7.03 (d, / = 8.4 Hz, 1H), 7.17-7.27 (m, 1H), 7.40 (d, / = 7.8 Hz, 1H), 7.47 (d, / = 8.4 Hz, 1H), 7.81 (t, / = 7.5 Hz, 1H), 8.08 (d, / = 7.2 Hz, 1H), 11.31 (s, 1H), 13.04 (s, 1H); APCI-MS (m/z): 420.13 (M+H)+.
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Structure Chemical name, 1H NMR and MS data
N-(3-(Cyclopropylcarbamoyl)-6-(N,3,3-trimethylbutanamido)- lH-indol-2-yl)thiazole-4-carboxamide: 1H NMR (300 MHz, CDCI3): δ 0.67-0.75 (m, 2H), 0.95 (s, 11H), 2.05 (s, 2H), 2.94-
Figure imgf000080_0001
3.01 (m, 1H), 3.29 (s, 3H), 6.14 (s, 1H), 7.03 (d, / = 8.4 Hz,
Example 17
1H), 7.20-7.29 (m, 1H), 7.44 (d, / = 8.4 Hz, 1H), 8.36 (s, 1H), 8.93 (s, 1H), 11.09 (br s, 1H), 12.85 (br s, 1H); APCI-MS (m/z): 454.02 (M+H)+.
N-(3-(Cyclopropylcarbamoyl)-6-(N,3,3-trimethylbutanamido)- lH-indol-2-yl)-2-methylthiazole-4-carboxamide: lH NMR
Figure imgf000080_0002
(300 MHz, DMSO-Je): δ 0.70-0.77 (m, 2H), 0.90-.097 (m,
Example 18 11H), 2.05 (s, 2H), 2.84 (s, 3H), 2.96-3.07 (m, 1H), 3.29 (s,
3H), 6.15 (s, 1H), 7.02 (d, / = 7.5 Hz, 1H), 7.19-7.28 (m, 1H), 7.44 (d, / = 7.8 Hz, 1H), 8.15 (s, 1H), 11.19 (s, 1H), 12.54 (s, 1H); APCI-MS (m z): 467.98 (M+H)+.
H3C N-(3-(Cyclopropylcarbamoyl)-6-(N,3,3-trimethylbutanamido)- lH-indol-2-yl)-2-(dimethylamino)thiazole-4-carboxamide: 1H NMR (300 MHz, CDC13): δ 0.65-0.75 (m, 4H), 0.89-0.97 (m, 9H), 2.04 (s, 2H), 2.85-2.92 (m, 1H), 3.23 (s, 6H), 3.28 (s,
Example 19
3H), 6.02-6.10 (m, 1H), 7.00 (d, / = 7.8 Hz, 1H), 7.18 (s, 1H), 7.42 (d, / = 8.4 Hz, 1H), 7.49 (s, 1H), 11.18 (s, 1H), 12.38 (s, 1H); APCI-MS (m z): 497.11 (M+H)+.
N-Cyclopropyl-2-(picolinamido)-6-((N,3,3- trimethylbutanamido)methyl)- lH-indole-3-carboxamide: 1H NMR (300 MHz, DMSO-J6): δ 0.64-0.71 (m, 4H), 0.99 (s,
Figure imgf000080_0003
9H), 2.26 (s, 2H), 2.86-2.94 (m, 4H), 4.53-4.65 (m, 2H), 6.90-
Example 20
7.03 (m, 1H), 7.45-7.53 (m, 1H), 7.65-7.72 (m, 2H), 8.11 (t, / = 7.5 Hz, 1H), 8.24 (d, / = 7.8 Hz, 1H), 8.81 (d, / = 4.5 Hz, 1H), 12.10-12.18 (m, 2H), 13.12 (s, 1H); APCI-MS (m/z): 462.05 (M+H)+.
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Structure Chemical name, 1H NMR and MS data
Figure imgf000089_0001
Figure imgf000090_0001
Structure Chemical name, 1H NMR and MS data
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(pyrazine-2- carboxamido)-lH-indole-3-carboxamide
1H NMR (300 MHz, CDC13): δ 0.87-1.70 (m, 10H), 1.35 (t, /
Figure imgf000091_0001
= 7.5 Hz, 3H), 2.16-2.26 (m, 1H), 3.30 (s, 3H), 3.58-3.68 (m,
Example 62
2H), 5.98-6.06 (m, 1H), 7.10 (d, / = 8.4 Hz, 1H), 7.23-7.30
(m, 1H), 7.58 (d, / = 8.4 Hz, 1H), 8.80 (s, 1H), 8.85 (s, 1H),
9.50 (s, 1H), 1 1.12 (s, 1H), 13.18 (s, 1H).
6-(N-Methylcyclohexanecarboxamido)-2-(picolinamido)-N- (2,2,2-trifluoroethyl)-lH-indole-3-carboxamide: 1H NMR (300 MHz, CDCI3): δ 0.90-1.68 (m, 10H), 2.19-2.27 (m, 1H),
Figure imgf000091_0002
3.29 (s, 3H), 4.22-4.35 (m, 2H), 6.18-6.23 (m, 1H), 7.12 (d, /
Example 63
= 9.3 Hz, 1H), 7.24-7.30 (m, 1H), 7.50-7.59 (m, 2H), 7.95 (t, / = 6.9 Hz, 1H), 8.30 (d, / = 7.8 Hz, 1H), 8.81-8.87 (m, 1H), 1 1.31 (s, 1H), 12.97 (s, 1H); APCI-MS (m z): 500.30 (M-H)".
N,N-Dimethyl-6-(N-methylcyclohexanecarboxamido)-2- (thiophene-2-carboxamido)- lH-indole-3-carboxamide: 1H
CTN NMR (300 MHz, CDC13): δ 0.85-0.92 (m, 2H), 1.10-1.19 (m,
CH3
2H), 1.52-1.62 (m, 6H), 2.18-2.25 (m, 1H), 3.20 (s, 6H), 3.28
Example 64
(s, 3H), 7.01 (d, / = 8.1 Hz, 1H), 7.16-7.24 (m, 2H), 7.46 (d, / = 8.7 Hz, 1H), 7.66 (d, / = 4.8 Hz, 1H), 7.79 (d, / = 3.9 Hz, 1H), 10.98 (br s, 1H), 1 1.27 (br s, 1H); APCI-MS (m z): 453.26 (M+H)+.
6-(N-Methylcyclohexanecarboxamido)-N-propyl-2- (thiophene-2-carboxamido)- lH-indole-3-carboxamide: 1H NMR (300 MHz, CDCI3): δ 0.85-1.80 (m, 15H), 2.19-2.25 (m,
Figure imgf000091_0003
Example 65 1H), 3.28 (s, 3H), 3.53 (q, / = 6.6 Hz, 2H), 6.00-6.08 (m, 1H),
7.07 (d, / = 8.4 Hz, 1H), 7.15-7.27 (m, 2H), 7.51 (d, / = 7.8 Hz, 1H), 7.66 (d, / = 5.1 Hz, 1H), 7.86 (d, / = 4.5 Hz, 1H), 1 1.01 (s, 1H), 12.40 (s, 1H); APCI-MS (m z): 467.14 (M+H)+.
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Structure Chemical name, 1H NMR and MS data
(M+H)
4-Cyano-N-(3 -(3 -methoxypropanoyl)-6-(N- methylcyclohexanecarboxamido)- 1 H-indol-2-yl)benzamide :
Figure imgf000098_0001
1H NMR (300 MHz, CDC13): δ 0.89-0.98 (m, 2H), 1.17-1.26
Example 91 (m, 2H), 1.57-1.69 (m, 6H), 2.19-2.26 (m, 1H), 3.29 (s, 3H),
3.37 (t, / = 6.0 Hz, 2H), 3.45 (s, 3H), 3.93 (t, / = 6.3 Hz, 2H), 7.12 (d, / = 6.0 Hz, 1H), 7.80-7.90 (m, 4H), 8.20 (d, / = 7.8 Hz, 2H), 11.20 (s, 1H), 12.92 (s, 1H); ESI-MS (m z): 487.21 (M+H)+.
Ethyl 6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2- carboxamido)-lH-indole-3-carboxylate: 1H NMR (300 MHz, CDC13): δ 0.84-0.92 (m, 2H), 1.24-1.68 (m, 8H), 1.52 (t, / =
Figure imgf000098_0002
6.9 Hz, 3H), 2.15-2.30 (m, 1H), 3.29 (s, 3H), 4.49 (q, / = 6.9
Example 92
Hz, 2H), 7.06 (d, / = 8.4 Hz, 1H), 7.18-7.28 (m, 2H), 7.70 (d, / = 6.0 Hz, 1H), 7.84 (d, / = 4.2 Hz, 1H), 7.94 (d, / = 8.4 Hz, 1H), 10.98 (s, 1H), 11.36 (s, 1H); APCI-MS (m z): 454.05 (M+H)+.
Methyl 4-(6-(N-methylcyclohexanecarboxamido)-2- (thiophene-2-carboxamido)-l H-indol-3 -yl)-4-oxobutanoate: 1H NMR (300 MHz, CDC13): δ 0.86-0.98 (m, 2H), 1.05-1.30
Figure imgf000098_0003
(m, 2H), 1.55-1.68 (m, 6H), 2.15-2.28 (m, 1H), 2.86 (t, / = 6.9
Hz, 2H), 3.29 (s, 3H), 3.40 (t, / = 7.2 Hz, 2H), 3.76 (s, 3H), 7.10 (d, / = 7.2 Hz, 1H), 7.20-7.28 (m, 2H), 7.70 (d, / = 4.2 Hz, 1H), 7.80 (d, / = 7.2 Hz, 1H), 7.87 (d, / = 3.9 Hz, 1H), 11.14 (s, 1H), 12.47 (s, 1H); ESI (m z): 496.12 (M+H)+.
N-Cyclopropyl-6-(N-methyl-2-morpholinoacetamido)-2- (picolinamido)-lH-indole-3-carboxamide: lH NMR (300 MHz, DMSO-Je): δ 0.65-0.75 (m, 4H), 2.30-2.39 (m, 4H),
Figure imgf000098_0004
2.85-2.94 (m, 3H), 3.18 (s, 3H), 3.46-3.54 (m, 4H), 7.08 (d, /
Example 94
= 6.0 Hz, 1H), 7.52 (s, 1H), 7.58 (s, 1H), 7.69-7.81 (m, 2H), 8.17 (t, / = 7.8 Hz, 1H), 8.27 (d, / = 7.5 Hz, 1H), 8.84 (s, 1H), 12.31 (s, 1H), 13.14 (s, 1H); ESI-MS (m/z): 477.20 (M+H)+.
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Example 107
N-(2-Hydroxyethyl)-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)- lH-indole-3-carboxamide
Figure imgf000102_0001
Step 1 : 2-(6-(N-Methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)-lH-indole-3- carboxamido)ethyl thiophene-2-carboxylate: This intermediate was prepared by reaction of intermediate 38 (250 mg, 0.696 mmol) with thiophene-2-carbonyl chloride (75 μΐ, 0.696 mmol) using dry pyridine (250 μΐ, 0.002 mmol) in dry tetrahydrofuran (4 ml) as described in general procedure to yield 125 mg of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-Jg): δ 0.85-0.95 (m, 2H), 1.20-1.30 (m, 3H), 1.50-1.60 (m, 5H), 2.15-2.25 (m, 1H), 3.28 (s, 3H), 3.94 (q, / = 3.6 Hz, 2H), 4.58-4.66 (m, 2H), 6.50-6.60 (m, 1H), 7.05 (d, / = 7.5 Hz, 1H), 7.1 1 (t, / = 4.5 Hz, 1H), 7.14-7.23 (m, 2H), 7.59-7.68 (m, 3H), 7.82-7.90 (m, 2H), 1 1.01 (s, 1H), 12.31 (s, 1H); ESI (m/z) 579.10 (M+H)+.
Step 2: N-(2-Hydroxyethyl)-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2- carboxamido)-lH-indole-3-carboxamide: The step 1 intermediate (1 15 mg) was stirred in methanolic ammonia (7 ml) at room temperature overnight. The reaction mixture was evaporated under reduced pressure, diluted with water (10 ml), solid obtained was collected by Alteration and dried to yield 90 mg of an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 0.85-1.63 (m, 10H), 2.16-2.36 (m, 1H), 3.15 (s, 3H), 3.43-3.49 (m, 2H), 3.53-3.59 (m, 2H), 4.80 (t, / = 5.4 Hz, 1H), 7.10 (d, / = 7.8 Hz, 1H), 7.30-7.37 (m, 1H), 7.45-7.53 (m, 1H), 7.80 (d, / = 4.2 Hz, 1H), 7.95 (d, / = 9.0 Hz, 1H), 8.02 (d, / = 4.5 Hz, 1H), 8.31 (s, 1H), 12.20 (s, 1H), 12.71 (s, 1H); ESI-MS (m/z): 467.10 (M-H)".
Example 108
N-Cyclopropyl-2-( 1 H-imidazole-4-carboxamido)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indole-
3-carboxamide
Figure imgf000102_0002
To a stirred solution of lH-imidazole-4-carboxylic acid (49.12 mg, 0.4385 mmol) in dry N,N- dimethylformamide (1.5 ml), N,N-diisopropylethylamine (314 μΐ, 1.827 mmol) and TBTU (0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (469.33 mg, 1.461 mmol) were added at room temperature and the reaction mixture was stirred for 1 h. To the reaction mixture intermediate 17 (125 mg, 0.365 mmol) was added and stirred at room temperature overnight. The reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (2 x 25 ml), dried over sodium sulphate and concentrated uneder reduced pressure. The residue was purified by column chromatography to yield 50 mg of product as white solid. 1H NMR (300 MHz, DMSO-Je): δ 0.63-0.75 (m, 4H), 0.89 (s, 9H), 1.97 (s, 2H), 2.83-2.90 (m, 1H), 3.15 (s, 3H), 6.97 (d, / = 9.9 Hz, 1H), 7.43 (s, 1H), 7.47 (s, 1H), 7.76 (t, / = 8.7 Hz, 1H), 7.89 (s, 1H), 7.98 (s, 1H), 12.09 (s, 1H), 12.40 (s, 1H), 12.84 (s, 1H); APCI-MS (m z): 437.12 (M+H)+.
Example 109
N-Cyclopropyl-2-(lH-imidazole-4-carboxamido)-6-(N-methylcyclohexanecarboxamido)-lH- indole-3-carboxamide
Figure imgf000103_0001
The title compound was prepared by coupling reaction of intermediate 2 (300 mg, 0.846 mmol) with lH-imidazole-4-carboxylic acid (1 14 mg, 1.015 mmol) using TBTU O- (Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1.086 g, 3.384 mmol) and N,N-diisopropylethylamine (715 μΐ, 4.22 mmol) in dry N,N-dimethylformamide (3 ml) as described in example 108 to yield 23 mg of product as white solid. 1H NMR (300 MHz, DMSO-Je): δ 0.55-1.66 (m, 14H), 2.17-2.25 (m, 1H), 2.83-2.91 (m, 1H), 3.14 (s, 3H), 7.02 (d, / = 5.4 Hz, 1H), 7.48 (s, 2H), 7.78 (d, / = 6.3 Hz, 1H), 7.87-8.04 (m, 2H), 12.09 (s, 1H), 12.41 (s, 1H), 12.84 (s, 1H); APCI-MS (m z): 449.29 (M+H)+.
Example 1 10
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylcyclohexanecarboxamido)- 1 H-indole-3 -carboxamide
Figure imgf000103_0002
Step 1 : 5-Bromothiophene-2-carbonyl chloride: The title compound was obtained from 5- bromothiophene-2-carboxylic acid (702 mg, 3.389 mmol) and thionyl chloride (7 ml) as described in general procedure (Method A).
Step 2: 2-(5-Bromothiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylcyclohexanecarboxamido)-l H-indole-3 -carboxamide: The reaction of intermediate 2 (800 mg, 2.259 mmol) with 5-bromothiophene-2-carbonyl chloride (step 1 intermediate) in presence of dry pyridine (800 μΐ) in dry tetrahydrofuran (12.66 ml) as described in general procedure yields 1.08 g of product as a pale yellow solid. 1H NMR (300 MHz, CDC13): δ 0.70-1.65 (m, 14H), 2.15-2.21 (m, 1H), 2.90-2.97 (m, 1H), 3.28 (s, 3H), 6.18 (s, 1H), 7.06 (d, / = 8.7 Hz, 1H), 7.15 (d, / = 4.5 Hz, 1H), 7.24-7.30 (m, 1H), 7.43 (d, / = 8.4 Hz, 1H), 7.63 (d, / = 3.9 Hz, 1H), 10.94 (br s, 1H), 12.35 (s, 1H); APCI-MS (m z): 543.20 (M)+.
Step 3 : N-Cyclopropyl-6-(N-methylcyclohexanecarboxamido)-2-(5-(l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazol-4-yl)thiophene-2-carboxamido)-lH-indole-3-carboxamide: The step 2 intermediate (700 mg, 1.289 mmol) was dissolved in dry N,N-dimethylformamide (30 ml) and degassed for 10 min. The aqueous solution of potassium carbonate (10.5 ml) was added to it and the reaction mixture was degassed for 90 min. To this mixture l-(tetrahydro-2H-pyran-2- yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (444 mg, 1.59 mmol) was added followed by [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.89 mg, 0.0219 mmol) and the reaction mixture was stirred at 90 °C overnight. The reaction mixture was cooled at room temperature, diluted with water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with brine (150 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography to yield 200 mg of product as a yellow solid. 1H NMR (300 MHz, CDC13): δ 0.70-2.15 (m, 22H), 2.91-2.99 (m, 1H), 3.28 (s, 3H), 3.71-3.79 (m, 1H), 4.09 (d, / = 1 1.7 Hz, 1H), 6.17 (s, 1H), 7.05 (d, / = 7.5 Hz, 1H), 7.12 (d, / = 3.9 Hz, 1H), 7.20-7.28 (m, 1H), 7.42 (d, / = 8.4 Hz, 1H), 7.78-7.86 (m, 2H), 7.93 (s, 1H), 1 1.05 (s, 1H), 12.26 (s, 1H); APCI-MS (m/z): 615.15 (M+H)+.
Step 4: 2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylcyclohexanecarboxamido)-lH-indole-3-carboxamide:
Method A: ΤΗΡ deprotection using hydrochloric acid
Hydrochloric acid (6 N, 1.5 ml) was added to a stirred suspension of step 3 intermediate (100 mg, 0.163 mmol) in methanol (5 ml) and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was evaporated under reduced pressure. The residue was cooled and basified (~ pH 9) using aqueous ammonia solution, precipitated solid obtained was collected by Alteration and washed with water (50 ml). The solid was dried and purified by column chromatography to yield 60 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO-J6): δ 0.65-1.77 (m, 14H), 2.15-2.23 (m, 1H), 2.86-2.93 (m, 1H), 3.14 (s, 3H), 7.05 (d, / = 9.0 Hz, 1H), 7.39-7.46 (m, 2H), 7.62 (s, 1H), 7.75 (s, 1H), 7.84 d, / = 7.8 Hz, 1H), 7.96 (s, 1H), 8.35 (s, 1H), 12.19 (s, 1H), 12.58 (s, 1H), 13.24 (s, 1H); APCI-MS (m/z): 531.15 (M+H)+.
Method B: THP group deprotection using p-toluene sulphonic acid
To a stired solution of step 3 intermediate (1 equiv.) in ethanol (10 vol.), p-toluene sulphonic acid (2 equiv.) was added and the reaction mixture was stirred at reflux temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was basified by addition of aqueous saturated solution of sodium bicarbonate. The precipitated solid collected by filtration, washed and dried. The solid was purified by column chromatography to yield the title compound.
Example 1 1 1
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(2-hydroxy-N- methylacetamido)- 1 H-indole-3 -carboxamide
Figure imgf000105_0001
Step 1 : 6-(2-(Benzyloxy)-N-methylacetamido)-2-(5-bromothiophene-2-carboxamido)-N- cyclopropyl-1 H-indole-3 -carboxamide: This intermediate was prepared by the reaction of intermediate 55 (1.0 g, 2.548 mmol) with 5-bromothiophene-2-carbonyl chloride (791 mg, 3.822 mmol) in presence of dry pyridine (1 ml) in dry tetrahydrofuran (14.15 ml) as described in general procedure yields 810 mg of product as yellow solid. APCI-MS (m z): 583.01 (M)+. Step 2: 6-(2-(Benzyloxy)-N-methylacetamido)-N-cyclopropyl-2-(5-(l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazol-4-yl)thiophene-2-carboxamido)-l H-indole-3 -carboxamide: This intermediate was prepared by Suzuki coupling reaction of step 1 intermediate (800 mg, 1.3757 mmol) with l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan- 2-yl)-lH-pyrazole (474 mg, 1.705 mmol) using tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.023 mmol) in presence of 1.6M potassium carbonate (1 1.84 ml) in N,N- dimethylformamide (38 ml) as described in step 3 of Example 1 10 to yield 200 mg of product as a yellow solid. APCI-MS (m z): 653.17 (M+H)+.
Step 3 : 2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-6-(2-(benzyloxy)-N- methylacetamido)-N-cyclopropyl-l H-indole-3 -carboxamide: This intermediate was prepared by reaction of step 2 intermediate (240 mg, 0.367 mmol) using hydrochloric acid (6 N, 4.8 ml) in methanol (12 ml) as described in step 4 (Method A) of example 1 10 to yield 150 mg of the title product as a yellow solid. APCI-MS (m/z): 569.1 1 (M+H)+. Step 4: 2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(2-hydroxy-N- methylacetamido)-lH-indole-3-carboxamide: To a stirred solution of step 3 intermediate (140 mg, 0.214 mmol) in dichloromethane (3 ml) was added iodotrimethylsilane (61 μΐ, 0.428 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer washed with water (3 x 50 ml) and was dried over sodium sulphate and concentrated reduced pressure. The residue was purified by column chromatography to yield 12.7 mg of product as yellow solid. 1H NMR (300 MHz, DMSO-dg): δ 0.65-0.73 (m, 2H), 1.16-1.23 (m, 2H), 2.85-2.93 (m, 1H), 3.21 (s, 3H), 3.70 (s, 2H), 4.57 (s, 1H), 7.07 (d, / = 6.6 Hz, 1H), 7.37-7.49 (m, 2H), 7.61 (s, 1H), 7.74 (d, / = 3.6 Hz, 1H), 7.85 (d, / = 7.8 Hz, 1H), 8.29-8.36 (m, 2H), 12.21 (s, 1H), 12.58 (s, 1H). 13.20 (s, 1H); ESI-MS (m/z): 479.38 (M+H)+.
The Examples 1 12-158 were obtained in the same manner as described above in Example 1 10. 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 1 12-158.
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Structure Chemical name, 1H NMR and MS data
(m/z): 505.41 (M-H)~.
2-(5 -( 1 H-Imidazol- 1 -yl)thiophene-2-carboxamido)-N- cyclopropyl-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indole-3 -
Figure imgf000110_0001
carboxamide: 1H NMR (300 MHz, DMSO-J6): δ 0.65-0.77
Example 126 (m, 4H), 0.89 (s, 9H), 1.97 (s, 2H), 2.85-2.92 (m, 1H), 3.16
(s, 3H), 7.02 (d, / = 9.3 Hz, 1H), 7.17 (s, 1H), 7.41 (s, 1H), 7.51 (d, / = 4.5 Hz, 1H), 7.65 (s, 1H), 7.74-7.90 (m, 3H), 8.35 (s, 1H), 12.19 (s, 1H), 12.66 (s, 1H); APCI-MS (m z): 519.45 (M+H)+.
H Q Λ arboxamido)-N- ¾ NH 5 2-(5-(lH-Pyrazol-4-yl)thiophene-2-c
cyclopropyl-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indole-3 - carboxamide: 1H NMR (300 MHz, CDC13): δ 0.74 (s, 2H),
Example 127 0.95 (s, 9H), 1.25 (s, 2H), 2.04 (s, 2H), 2.93-3.00 (m, 1H),
3.03 (s, 3H), 6.18 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 7.11-7.27 (m, 3H), 7.42 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.90 (s, 2H), 11.06 (s, 1H), 12.27 (s, 1H); ESI-MS (m z): 519.19 (M+H)+.
1 H O N-(3-(Cyclopropylcarbamoyl)-6-(N,3,3- u NH N trimethy lbutanamido)- 1 H-indol-2-yl)-2-(pyridin-4- yl)thiazole-4-carboxamide: 1H NMR (300 MHz, CDC13): δ
Example 128 0.74 (s, 2H), 0.96 (br s, 9H), 1.25 (s, 2H), 2.06 (s, 2H), 3.07
(br s, 1H), 3.30 (s, 3H), 6.16 (s, 1H), 7.00-7.09 (m, 1H), 7.20- 7.30 (m, 1H), 7.40-7.49 (m, 1H), 8.00 (s, 2H), 8.40 (s, 1H), 8.81 (s, 2H), 11.14 (s, 1H), 12.77 (s, 1H); APCI-MS (m/z): 531.14 (M+H)+.
N-Cyclopropyl-2-(5 -(pyridin-3 -yl)thiophene-2- carboxamido)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indole-3 -
Figure imgf000110_0002
carboxamide: 1H NMR (300 MHz, DMSO-J6): δ 0.65-0.72
Example 129 (m, 4H), 0.87 (s, 9H), 1.95 (s, 2H), 2.87-2.93 (m, 1H), 3.14
(s, 3H), 6.95-7.05 (m, 1H), 7.39 (s, 1H), 7.44-7.52 (m, 1H), 7.60-7.72 (m, 1H), 7.81-7.90 (m, 3H), 8.14-8.20 (m, 1H), 8.55- 8.63 (m, 1H), 9.02 (s, 1H), 12.20 (s, 1H), 12.67 (s, 1H); APCI-MS (m/z): 530.30 (M+H)+. Structure Chemical name, 1H NMR and MS data
2-(6-( 1 H-Pyrazol-4-yl)picolinamido)-N-cyclopropyl-6- (N,3 ,3 -trimethylbutanamido)- 1 H-indole-3 -carboxamide : 1H
Figure imgf000111_0001
NMR (300 MHz, CDC13): δ 0.69-0.76 (m, 4H), 0.79 (s, 9H),
Example 130 1.99 (s, 2H), 2.97-3.07 (m, 1H), 3.17 (s, 3H), 7.02 (d, / = 7.2
Hz, 1H), 7.46 (s, 1H), 7.60 (s, 1H), 7.83 (d, / = 6.3 Hz, 1H), 7.94-8.15 (m, 3H), 8.48 (s, 1H), 8.75 (s, 1H) 12.25 (s, 1H), 13.26 (s, 1H); 13.59 (s, 1H); APCI-MS (m/z): 514.08 (M+H)+.
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N,N- dimethyl-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indole-3 -
Figure imgf000111_0002
carboxamide: 1H NMR (300 MHz, DMSO-J6): δ 0.90 (m,
Example 131
9H), 1.98 (s, 2H), 3.04 (s, 6H), 3.17 (s, 3H), 6.91-7.01 (m, 1H), 7.30-7.37 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.93 (s, 1H), 8.30 (s, 1H), 1 1.05 (s, 1H), 1 1.99 (s, 1H), 13.21 (s, 1H); ESI-MS (m/z): 507.77 (M+H)+.
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-propyl- 6-(N,3 ,3-trimethylbutanamido)- 1 H-indole-3 -carboxamide : 1H
Figure imgf000111_0003
NMR (300 MHz, DMSO-J6): δ 0.85-1.10 (m, 12H), 1.53-
Example 132 1.69 (m, 2H), 1.98 (s, 2H), 3.17 (s, 2H), 3.33 (s,merged with
DMSO peak, 3H), 7.04 (d, / = 7.8 Hz, 1H), 7.37-7.45 (m, 2H), 7.57-7.65 (m, 1H), 7.71 (d, / = 3.9 Hz, 1H), 7.95 (d, / = 7.8 Hz, 2H), 8.33 (s, 1H), 12.17 (s, 1H), 12.70 (s, 1H), 13.22 (s, 1H); ESI-MS (m z): 521.42 (M+H)+.
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-
V ) NH S
cyclopropyl-6-((N,3,3-trimethylbutanamido)methyl)-lH- indole-3-carboxamide: 1H NMR (300 MHz, CDCI3): δ 0.72
Example 133
(s, 2H), 0.91-1.00 (m, 2H), 1.09 (s, 9H), 2.33 (s, 2H), 2.92- 3.00 (m, 3H), 4.69 (s, 2H), 6.16 (s, 1H), 7.00-7.06 (m, 1H), 7.10-7.18 (m, 2H), 7.78-7.88 (m, 3H), 10.99 (s, 1H), 12.24 (s, 1H) +NH; APCI-MS (m z): 533.0 (M+H)+.
Figure imgf000112_0001
Structure Chemical name, 1H NMR and MS data
(M+H)+.
N-(3-(Cyclopropylcarbamoyl)-6-(N- methylcyclohexanecarboxamido)-lH-indol-2-yl)-2-(lH-
°
Figure imgf000113_0001
pyrazol-4-yl)thiazole-4-carboxamide: 1H NMR (300 MHz,
Example 138 DMSO-Jg): δ 0.65-1.62 (m, 15H), 2.17-2.25 (m, 1H), 3.14 (s,
3H), 7.05 (d, / = 7.8 Hz, 1H), 7.49-7.57 (m, 2H), 7.82 (d, / = 8.4 Hz, 1H), 8.26-8.36 (m, 2H), 8.50 (s, 1H), 12.20 (s, 1H), 12.72 (s, 1H), 13.35 (s, 1H); APCI-MS (m z): 532.20 (M+H)+.
N-(3-(Cyclopropylcarbamoyl)-6-(N- o XJ NH methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-2-(pyridin-
° h 4-yl)thiazole-4-carboxamide: 1H NMR (300 MHz, DMSO-
Example 139 d6): δ 0.70-1.58 (m, 14H), 2.10-2.16 (m, 1H), 2.95-3.95 (m,
1H), 3.15 (s, 3H), 7.06 (d, / = 9.0 Hz, 1H), 7.50 (s, 1H), 7.58 (s, 1H), 7.84 (d, / = 8.4 Hz, 1H), 8.04 (d, / = 5.7 Hz, 2H), 8.80-8.90 (m, 3H), 12.24 (s, 1H), 12.86 (s, 1H); APCI-MS (m/z): 543.13 (M+H)+.
2-(4-(lH-Pyrazol-4-yl)benzamido)-N-cyclopropyl-6-(N- methylcyclohexane carboxamido)- 1 H-indole-3 -carboxamide :
° ^ 1H NMR (300 MHz, DMSO-J6): δ 0.65-0.99 (m, 4H), 1.17-
Example 140 1.63 (m, 10H), 2.13-2.20 (m, 1H), 2.85-2.93 (m, 1H), 3.13 (s,
3H), 7.04 (d, / = 7.2 Hz, 1H), 7.45 (s, 1H), 7.60 (s, 1H), 7.79- 7.99 (m, 5H), 8.01-8.09 (m, 1H), 8.31-8.39 (m, 1H), 12.27 (s, 1H), 12.78 (s, 1H), 13.12 (br s, 1H); ESI-MS (m z): 525.28 (M+H)+.
2-(6-(lH-Pyrazol-4-yl)picolinamido)-N-cyclopropyl-6-(N- methylcyclohexanecarboxamido)-l H-indole-3 -carboxamide:
0 -NH NH 1H NMR (300 MHz, CDC13): δ 0.72-2.00 (m, 14H), 2.20-
Example 141 2.30 (m, 1H), 3.02-3.09 (m, 1H), 3.29 (s, 3H), 6.15 (s, 1H),
7.05 (d, / = 8.1 Hz, 1H), 7.48 (d, / = 8.4 Hz, 2H), 7.73 (d, / = 7.2 Hz, 1H), 7.92 (d, / = 8.4 Hz, 2H), 8.07 (d, / = 7.8 Hz, 1H), 8.51 (s, 2H), 1 1.12 (s, 1H), 13.48 (s, 1H); ESI-MS (m/z):
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Example 159
N-Cyclopropyl-6-(3 -hydroxy- V,3 -dimethylbutanamido)-2-(picolinamido)- 1 H-indole-3 - carboxamide
Figure imgf000118_0002
To a stirred solution of example 8 (90 mg, 0.194 mmol) in dichloromethane (9 ml), solution of boron tribromide (0.29 ml, 0.291 mmol) in dichloromethane (9 ml) was added at 0 °C. The reaction mixture was first stirred at -10 °C for 1 h and then at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and residue thus obtained was treated with saturated solution of sodium bicarbonate. The precipitated solid obtained was filtered, dried and purified by column chromatography to yield 30 mg of product as yellow solid. 1H NMR (300 MHz, CDC13): δ 0.73 (s, 2H), 0.91-1.00 (m, 2H), 1.16 (s, 6H), 2.22 (s, 2H), 3.01 (s, 3H), 3.34 (s, 1H), 5.44 (s, 1H), 6.15 (s, 1H), 7.03 (d, / = 7.2 Hz, 1H), 7.24-7.30 (m, 1H), 7.53-7.60 (m, 2H), 7.94 (t, / = 7.2 Hz, 1H), 8.28 (d, / = 8.1 Hz, 1H), 8.81 (d, / = 3.6 Hz, 1H), 1 1.29 (s, 1H), 13.16 (s, 1H); ESI-MS (m z): 450.10 (M+H)+.
Example 160
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(3-hydroxy-N,3- dimethylbutanamido)- 1 H-indole-3 -carboxamide
Figure imgf000118_0003
The title compound was prepared by reaction of example 135 (165 mg, 0.308 mmol) with boron tribromide (0.47 ml, 0.463 mmol) in dichloromethane (3.3 ml) as described in example 159 to yield 24 mg of product as yellow solid. 1H NMR (300 MHz, CDC13): δ 0.70-0.76 (m, 2H), 0.93-1.00 (m, 2H), 1.15 (s, 6H), 2.20 (s, 2H), 2.91-2.98 (m, 1H), 3.33 (s, 3H), 3.93 (s, 1H), 6.15 (s, 1H), 7.02 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.18-7.26 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 3.9 Hz, 1H), 7.89 (s, 2H), 1 1.10 (s, 1H), 12.26 (s, 1H), 13.25 (s, 1H), ; ESI-MS (m/z): 519.19 (M-H)~.
Example 161
N-(3-(3-Methoxypropyl)-6-(N,3,3-trimethylbutanamido)-lH-indol-2-yl)-2-methylthiazole-4- carboxamide
Figure imgf000119_0001
Step 1 : ie/t-Butyl 2-(2-methylthiazole-4-carboxamido)-6-(N,3,3-trimethylbutanamido)-lH- indole-3-carboxylate: The coupling reaction of intermediate 66 (2.5 g, 6.963 mmol) with 2- methyl-l ,3-thiazole-4-carbonyl chloride (1.5 g, 10.445 mmol) using dry pyridine (2.5 ml, 0.025 mmol) in dry tetrahydrofuran (39 ml) as described in general procedure yields 2.05 g of product as a yellow solid. 1H NMR (300 MHz, CDC13): δ 0.92 (t, / = 8.7 Hz, 9H), 1.73 (s, 9H), 2.00-2.1 1 (m, 2H), 2.81 (s, 3H), 3.29 (s, 3H), 7.01 (d, / = 6.9 Hz, 1H), 7.14 (s, 1H), 7.95- 8.06 (m, 1H), 8.16 (s, 1H), 1 1.1 1 (s, 1H), 1 1.63 (br s, 1H).
Step 2: 2-(2-Methylthiazole-4-carboxamido)-6-(N,3,3-trimethylbutanamido)-lH-indole-3- carboxylic acid: To a stirred solution of step 1 intermediate (2.0 g) in dry dichloromethane (32 ml), trifluoroacetic acid (8.2 ml) was added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure followed by treatment with saturated solution of sodium bicarbonate (75 ml) and the solid obtained was collected by Alteration to yield 1.82 g of product as a brown solid. 1H NMR (300 MHz, CDCI3): δ 0.96 (s, 9H), 2.08 (s, 2H), 2.84 (s, 3H), 3.31 (s, 3H), 7.07 (d, / = 7.5 Hz, 1H), 7.18-7.28 (m, 1H), 8.05 (d, / = 8.4 Hz, 1H), 8.20 (s, 1H), 1 1.19 (s, 1H), 1 1.90 (s, 1H), 12.67 (s, 1H); APCI-MS (m/z): 427.04 (M-H)".
Step 3 : 2-Methyl-N-(6-(N,3,3-trimethylbutanamido)-lH-indol-2-yl)thiazole-4-carboxamide: To a solution of step 2 intermediate (1.8 g, 4.20 mmol) in dry toluene (53 ml), triethylamine (17.7 ml, 126.02 mmol) was added and heated to 130 °C for 18 h. The reaction mixture was evaporated under reduced pressure, 1 N hydrochloric acid (50 ml) was added and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was dried over sodium sulphate, concentrated under erduced pressure and purified by column chromatography to yield 1.17 g of product as a yellow solid. 1H NMR (300 MHz, DMSO-J6): δ 0.89 (s, 9H), 1.97 (s, 2H), 2.79 (s, 3H), 3.12-3.20 (m, 3H), 6.53 (s, 1H), 6.81 (d, / = 8.4 Hz, 1H), 7.28 (s, 1H), 7.45 (d, / = 8.4 Hz, 1H), 8.34 (s, 1H), 10.59-1 1.07 (m, 2H); APCI-MS (m/z): 385.04 (M+H)+.
Step 4: N-(3 -(3 -Methoxypropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-2- methylthiazole-4-carboxamide: To a solution of step 3 intermediate (270 mg, 0.702 mmol) and freshly prepared 3-methoxypropanal (93 mg, 1.053 mmol) in dry dichloromethane (12 ml), triethyl silane (336 μΐ, 2.106 mmol) was added at 0 °C followed by trifluroacetic acid (156 μΐ, 2.106 mmol). After being stirred at 0 °C for 1 h, the reaction mixture was warmed to room temperature overnight. The reaction was then quenched with saturated solution of sodium bicarbonate (50 ml), extracted with dichloromethane (2 x 75 ml). The combined organic layer was washed with brine (50 ml) and dried over sodium sulphate. The recation mixture was evaporated and residue obtained was purified by column chromatography to give 29 mg of the title compound as yellow solid. 1H NMR (300 MHz, CDC13): δ 0.96 (br s, 9H), 1.92-2.00 (m, 2H), 2.08 (s, 2H), 2.80 (s, 3H), 2.85-2.95 (m, 2H), 3.25-3.42 (m, 8H), 6.87 (d, / = 5.4 Hz, 1H), 7.12 (s, 1H), 7.45 (d, / = 7.8 Hz, 1H), 8.10 (s, 1H), 10.17 (s, 1H), 10.50 (s, 1H); ESI-MS (m z): 455.21 (M-H)~.
The Examples 162-165 were obtained in the same manner as described above in Example 161. The structure, chemical names, 1H NMR and MS data are provided in table 6.
Table 6: Structure, chemical name, 1H NMR and MS data of Examples 162-165.
Figure imgf000120_0001
Figure imgf000121_0001
Example 166
N-(3-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(lH-pyrazol- 4-yl)thiophene-2-carboxamide
Figure imgf000121_0002
Step 1 : 5-Bromo-N-(3-(2-methoxyacetyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiophene-2-carboxamide: The coupling of intermediate 64 (1 g, 2.915 mmol) with 5- bromothiophene-2-carbonyl chloride (905 mg, 4.373 mmol) in presence of dry pyridine (1 ml, 0.01 mmol) in dry tetrahydrofuran (16 ml) as described in general procedure yields 1.28 g of product as an off-white solid. 1H NMR (300 MHz, DMSO-J6): δ 0.85-1.65 (m, 10H), 2.15- 2.23 (m, 1H), 3.14 (s, 3H), 3.45 (s, 3H), 4.72 (s, 2H), 7.15 (d, / = 7.8 Hz, 1H), 7.45-7.56 (m, 2H), 7.65-7.75 (m, 2H), 8.31 (s, 1H), 12.44 (s, 1H); ESI-MS (m z): 534.21 (M+H)+.
Step 2: 5 -Bromo-N-(3 -(2-methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)thiophene-2-carboxamide: To a solution of step 1 intermediate (1.26 g, 2.366 mmol) in triethylsilane (12 ml), trifluoroacetic acid (12 ml) was added and reaction mixture was heated at 70-80 °C overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with saturated solution of sodium bicarbonate (200 ml) and dried over sodium sulphate. The residue after evaporation of solvent was purified by column chromatography to yield 615 mg of product as a pale yellow solid. 1H NMR (300 MHz, CDC13): δ 0.80-1.72 (m, 10H), 2.24-2.31 (m, 1H), 3.04 (t, / = 4.2 Hz, 2H), 3.27 (s, 3H), 3.52 (s, 3H), 3.81 (t, / = 4.5 Hz, 2H), 6.90 (d, / = 6.9 Hz, 1H), 7.10-7.17 (m, 2H), 7.35-7.45 (m, 2H), 10.47 (s, 1H), 10.60 (s, 1H); ESI-MS (m z): 518.21 (M)+.
Step 3 : N-(3-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)thiophene-2-carboxamide: The coupling reaction of step 2 intermediate (600 mg, 1.15 mmol) with l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (399 mg, 1.436 mmol) using [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.96 mg, 0.019 mmol) in presence of aqueous solution of potassium carbonate (9 ml) in N,N-dimethylformamide (30 ml) as described in step 3 of example 1 10 yields 135 mg of product as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.84-2.15 (m, 18H), 2.24-2.31 (m, 1H), 3.01-3.08 (m, 2H), 3.27 (s, 3H), 3.53 (s, 3H), 3.74-3.85 (m, 2H), 5.00-5.09 (m, 1H), 6.90 (d, / = 7.8 Hz, 1H), 7.12 (s, 2H), 7.40 (d, / = 6.9 Hz, 1H), 7.55 (d, / = 3.9 Hz, 1H), 7.63-7.69 (m, 1H), 7.80 (s, 1H), 7.89 (s, 1H), 10.57 (s, 1H); ESI-MS (m z): 590.18 (M+H)+.
Step 4: N-(3-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(lH- pyrazol-4-yl)thiophene-2-carboxamide: The deprotection reaction of step 3 intermediate (125 mg, 0.212 mmol) using hydrochloric acid (6 N, 1.95 ml) in methanol (6.25 ml) as described in step 4 of example 1 10 (Method A) yields 30 mg of the title compound as a yellow solid. 1H NMR (300 MHz, CDC13): δ 0.89-1.67 (m, 10H), 2.23-2.30 (m, 1H), 3.05 (s, 2H), 3.28 (s, 3H), 3.54 (s, 3H), 3.82 (s, 2H), 6.90 (d, / = 8.7 Hz, 1H), 7.14 (d, / = 10.2 Hz, 2H), 7.40 (d, / = 8.4 Hz, 1H), 7.58 (s, 1H), 7.88 (s, 2H), 10.59 (br s, 2H), 12.42 (s, 1H); ESI-MS (m/z): 506.31 (M+H)+.
Example 167
N-(3 -(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)thiophene-2- carboxamide
Figure imgf000123_0001
Step 1 : N-(3-(2-Methoxyacetyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiophene-2-carboxamide: The coupling reaction of intermediate 64 (300 mg, 0.874 mmol) with thiophene-2-carbonyl chloride (103 μΐ, 0.962 mmol) using dry pyridine (300 μΐ, 0.003 mmol) in dry tetrahydrofuran (3 ml) as described in general procedure affords 210 mg of product as a pale yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.93-1.00 (m, 3H), 1.19-1.26 (m, 2H), 1.50-1.60 (m, 5H), 2.20-2.26 (m, 1H), 3.28 (s, 3H), 3.63 (s, 3H), 4.75 (s, 2H), 7.10 (d, / = 7.2 Hz, 1H), 7.23-7.35 (m, 2H), 7.60 (d, / = 7.2 Hz, 1H), 7.72 (d, / = 4.2 Hz, 1H), 7.90 (d, / = 3.9 Hz, 1H), 1 1.19 (s, 1H), 12.57 (s, 1H); APCI-MS (m z): 454.22 (M+H)+.
Step 2: N-(3-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiophene-2-carboxamide: This intermediate was prepared by reductive deoxyegenation of step 1 intermediate (180 mg) using triethyl silane (5 ml) and trifluoroacetic acid (5 ml) as described in step 2 of example 166 to yield 97 mg of product as a pale yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.84-0.95 (m, 2H), 1.25-1.59 (m, 8H), 2.20-2.35 (m, 1H), 3.05 (t, / = 4.8 Hz, 2H), 3.27 (s, 3H), 3.52 (s, 3H), 3.81 (t, / = 4.8 Hz, 2H), 6.90 (d, / = 7.2 Hz, 1H), 7.13 (s, 1H), 7.18 (t, / = 4.5 Hz, 1H), 7.41 (d, / = 8.4 Hz, 1H), 7.61 (d, / = 5.1 Hz, 1H), 7.66 (d, / = 3.9 Hz, 1H), 10.56 (s, 1H), 10.63 (s, 1H); APCI-MS (m z): 440.26 (M+H)+.
The examples 168-172 were obtained in the same manner as described above in example 167 and the example 173 was obtained in the same manner as described above in example 166. The structural formulas, chemical names, 1H NMR and MS data are provided in table 7.
Table 7: Structure, chemical name, 1H NMR and MS data of Examples 168-173.
Structure Chemical name, 1H NMR and MS data
Figure imgf000124_0001
Structure Chemical name, 1H NMR and MS data
(m, 3H), 8.02 (d, / = 8.1 Hz, 2H), 10.63 (s, 1H), 10.83 (s, 1H); ESI-MS (m z): 518.28 (M+H)+.
N-(3-(2-Amino-2-oxoethyl)-6-(N- methylcyclohexanecarboxamido)-lH-indol-2-yl)-2-
NH2 methylthiazole-4-carboxamide: 1H NMR (300 MHz, CDC13):
Example 172 δ 0.90-1.69 (m, 10H), 2.20-2.28 (m, 1H), 2.82 (s, 3H), 3.27
(s, 3H), 3.76 (s, 2H), 5.47 (br s, 1H), 5.85 (br s, 1H), 6.95 (d, J = 6.9 Hz, 1H), 7.18 (s, 1H), 7.45 (d, / = 8.4 Hz, 1H), 8.12 (s, 1H), 10.78 (s, 2H); ESI-MS (m/z): 454.06 (M+H)+.
N-(3 -(2-Methoxyethyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H- indol-2-yl)-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H
Figure imgf000125_0001
NMR (300 MHz, DMSO-Jg) : δ 0.89 (s, 9H), 1.98 (s, 2H),
Example 173 2.90-2.99 (m, 2H), 3.15 (s, 3H), 3.25-3.35 (m, 3H), 3.50-3.60
(m, 2H), 6.83 (d, / = 8.1 Hz, 1H), 7.16 (s, 1H), 7.34 (s, 1H), 7.51 (d, / = 8.4 Hz, 1H), 7.85-7.96 (m, 2H), 8.25 (s, 1H), 10.33 (s, 1H), 11.30 (s, 1H), 13.17 (br s, 1H); APCI-MS (m/z): 494.31 (M+H)+.
Example 174
N-(3-(3-Amino-3-oxopropyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-2-
(pyridin-4-yl)thiazole-4-carboxamide
Figure imgf000125_0002
Step 1 : 2-(Pyridin-4-yl)-l,3-thiazole-4-carbonyl chloride: The title compound was obtained by the reaction of 2-(pyridin-4-yl)-l,3-thiazole-4-carboxylic acid (832 mg, 4.038 mmol) in presence of oxalyl chloride (470 μΐ, 5.384 mmol) in dichloromethane (10 ml) as described in general procedure (Method B).
Step 2: tert-Butyl 6-(N-methylcyclohexanecarboxamido)-2-(2-(pyridin-4-yl)thiazole-4- carboxamido)-lH-indole-3-carboxylate: The coupling reaction of intermediate 69 (1 g, 2.692 mmol) with 2-(pyridin-4-yl)-l,3-thiazole-4-carbonyl chloride using dry pyridine (2 ml, 0.002 mmol) and catalytic amoumt of N,N-dimethylformamide (2 drops) in dry tetrahydrofuran (14.9 ml) as described in general procedure yields 220 mg of product as a pale yellow solid. 1H NMR (300 MHz, CDC13): δ 1.45-1.80 (m, 19H), 2.21-2.30 (m, 1H), 3.28 (s, 3H), 7.05 (d, / = 6.0 Hz, 1H), 7.19 (s, 1H), 7.89-8.00 (m, 3H), 8.41 (s, 1H), 8.82 (d, / = 5.1 Hz, 1H), 10.99 (s, 1H), 12.16 (s, 1H); APCI-MS (m z): 560.51 (M+H)+.
Step 3 : 6-(N-Methylcyclohexanecarboxamido)-2-(2-(pyridin-4-yl)thiazole-4-carboxamido)- lH-indole-3-carboxylic acid: This intermediate was prepared by the reaction of step 2 intermediate (215 mg, 0.384 mmol) with trifluoroacetic acid (0.8 ml) in dichloromethane (3.2 ml) as described in step 2 of example 161 to yield 170 g of product as a pale yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.85-1.65 (m, 10H), 2.15-2.24 (m, 1H), 3.15 (s, 3H), 7.06 (d, / = 6.0 Hz, 1H), 7.48 (s, 1H), 7.83 (d, / = 6.0 Hz, 1H), 8.03 (d, / = 4.2 Hz, 1H), 8.75-8.91 (m, 3H), 12.33 (s, 1H), 12.44 (s, 1H), 12.97 (s, 1H); APCI-MS (m z): 504.13 (M+H)+.
Step 4: N-(6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-2-(pyridin-4-yl)thiazole-4- carboxamide: This intermediate was prepared by reaction of step 3 intermediate (160 mg, 3.18 mmol) with triethylamine (1.34 ml, 9542.7 mmol) in dry toluene (4 ml) as described in step 3 of example 161 to yield 136 mg of product as an off-white solid. 1H NMR (300 MHz, CDCI3): δ 0.89-1.70 (m, 10H), 2.23-2.34 (m, 1H), 3.29 (s, 3H), 6.19 (s, 1H), 6.92 (d, / = 7.8 Hz, 1H), 7.14-7.26 (m, 1H), 7.53 (d, / = 7.8 Hz, 1H), 7.92 (s, 2H), 8.40 (s, 1H), 8.78-8.87 (m, 2H), 9.74 (s, 1H), 10.64 (s, 1H); APCI-MS (m z): 460.62 (M+H)+.
Step 5 : N-(3-(3-Amino-3-oxopropyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 2-(pyridin-4-yl)thiazole-4-carboxamide: To a stirred solution of step 4 intermediate (127 mg, 0.276 mmol) in dry acetonitrile (3 ml), aluminium chloride (1 10 mg, 0.829 mmol) was added at 0 °C followed by addition of acrylamide (40 mg, 0.553 mmol) and the reaction mixture was refluxed for 3 h. The reaction was cooled to room temperature and quenched with saturated solution of sodium bicarbonate (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was dried over sodium sulphate, concentrated under reduced pressure and purified by column chromatography to yield 30 mg of the title compound a yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.85-1.75 (m, 10H), 2.25-2.36 (m, 1H), 2.73-2.80 (m, 2H), 3.13-3.21 (m, 2H), 3.28 (s, 3H), 5.43 (br s, 2H), 6.92 (d, / = 7.8 Hz, 1H), 7.16 (s, 1H), 7.45 (d, / = 7.8 Hz, 1H), 8.06 (s, 2H), 8.35 (s, 1H), 8.75-8.85 (m, 2H), 10.44 (s, 1H), 1 1.33 (s, 1H); APCI-MS (m/z): 531.23 (M+H)+.
Example 175 N-(3-(3-Amino-3-oxopropyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-
(pyridin-4-yl)thiophene-2-carboxamide
Figure imgf000127_0001
Step 1 : N-(6-(N-Methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(pyridin-4-yl)thiophene- 2-carboxamide: The intermediate was prepared in three steps (i) by coupling reaction of intermediate 69 (1.5 g, 4.043 mmol) with 5-(pyridin-4-yl)thiophene-2-carboxylic acid (996 mg, 4.851 mmol) using TBTU (0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 5.2 g, 16.461 mmol) in presence of N,N-diisopropylethylamine (3.5 ml, 20.21 mmol) as described in example 108; (ii) deprotection of tertiary butyl group using trifluoroacetic acid (5 ml) described in step 3 of example 174 and (iii) decarboxylation using triethylamine (8.4 ml, 59.67 mmol) in dry toluene (25 ml) as described in step 4 of example 174 afforded 530 mg of yellow solid. 1H NMR (300 MHz, CDC13): δ 0.85-1.75 (m, 10H), 2.2.20-2.33 (m, 1H), 3.30 (s, 3H), 6.15 (s, 1H), 6.92 (d, / = 6.6 Hz, 1H), 7.16 (s, 1H), 7.45- 7.53 (m, 4H), 7.83 (d, / = 3.9 Hz, 1H), 8.68 (d, / = 6.3 Hz, 2H), 9.44-9.52 (m, 1H), 10.61 (s, 1H); ESI-MS (m/z): 457.26 (M-H)~.
Step 2: N-(3-(3-Amino-3-oxopropyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 5-(pyridin-4-yl)thiophene-2-carboxamide: The title compound was prepared by reaction of step 1 intermediate (250 mg, 0.5451 mmol) with acrylamide (43 mg, 0.599 mmol) using aluminium chloride (145 mg, 1.09 mmol) in dry acetonitrile (5 ml) as described in step 5 of example 174 to yield 55 mg of the title compound a yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.93-1.65 (m, 10H), 2.24-2.33 (m, 1H), 2.71-2.80 (m, 2H), 3.05-3.13 (m, 2H), 3.27 (s, 3H), 5.49-5.63 (m, 2H), 6.90 (d, / = 6.6 Hz, 1H), 7.13 (s, 1H), 7.42 (d, / = 8.7 Hz, 1H), 7.55 (d, / = 4.5 Hz, 3H), 8.09 (s, 1H), 8.66 (d, / = 4.5 Hz, 2H), 10.39 (s, 1H), 10.97 (s, 1H); ESI-MS (m/z): 530.26 (M+H)+.
The examples 176-184 were obtained in the same manner as described above in example The structural formulas, chemical names, 1H NMR and MS data are provided in table 8.
Table 8: Structure, chemical name, 1H NMR and MS data of Examples 175-184.
Structure Chemical name, 1H NMR and MS data
Figure imgf000128_0001
H-
(d,
= (s,
/ =
Figure imgf000129_0001
Figure imgf000130_0001
Example 185
N-( -(3 - Amino-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-5 -( 1 H-pyrazol-
4-yl)thiophene-2-carboxamide
Figure imgf000130_0002
Step 1 : 5-bromothiophene-2-carbonyl chloride: The title compound was obtained from 5- bromothiophene-2-carboxylic acid (13.8 g, 66.852 mmol) and thionyl chloride (150 ml) as described in general procedure (Method A).
Step 2: tert-Butyl 2-(5-bromothiophene-2-carboxamido)-6-(N,3,3-trimethylbutanamido)-lH- indole-3-carboxylate: This intermediate was prepared by reaction of intermediate 66 (16 g, 44.568 mmol) with 5-bromothiophene-2-carbonyl chloride (step 1 intermediate) in the presence of dry pyridine (16 ml) in dry tetrahydrofuran (160 ml) as described in general procedure to yield 8.8 g of product as yellow solid. 1H NMR (300 MHz, DMSO-J6): δ 0.95 (s, 9H), 1.69 (s, 9H), 2.05 (s, 2H), 3.29 (s, 3H), 7.01 (d, / = 8.1 Hz, 1H), 7.09 (s, 1H), 7.17 (s, 1H), 7.59 (d, / = 3.9 Hz, 1H), 7.87 (d, / = 8.1 Hz, 1H), 10.85 (s, 1H), 1 1.39 (br s, 1H).
Step 3 : 2-(5-Bromothiophene-2-carboxamido)-6-(N,3,3-trimethylbutanamido)-lH-indole-3- carboxylic acid: This intermediate was prepared by reaction of a step 2 intermediate (15.9 g, 28.98 mmol) with trifluoroacetic acid (57.9 ml) in dichloromethane (241.5 ml) as described in step 2 of example 161 to yield 13.61 g of product as a yellow solid. 1H NMR (300 MHz, CDCI3): δ 0.95 (s, 9H), 2.08 (m, 2H), 3.29 (s, 3H), 6.06 (s, 1H), 6.87 (d, / = 8.4 Hz, 1H), 7.04-7.19 (m, 2H), 7.43-7.52 (m, 2H), 8.55 (s, 1H), 10.47 (s, 1H). Step 4: 5-Bromo-N-(6-(N,3,3-trimethylbutanam
This intermediate was prepared by reaction of step 3 intermediate (13.6 mg, 27.620 mmol) with triethylamine (1 16.4 ml, 828.61 mmol) in dry toluene (345.2 ml) as described in step 3 example 161 to yield 8.14 g of product as yellow solid. 1H NMR (300 MHz, DMSO-J6): δ 0.95 (s, 9H), 2.01-2.10 (m, 2H), 3.29 (s, 3H), 6.13 (s, 1H), 6.88 (d, / = 8.4 Hz, 1H), 7.04 (s, 1H), 7.13 (d, / = 3.9 Hz, 1H), 7.44-7.59 (m, 2H), 9.08 (s, 1H), 10.47 (s, 1H).
Step 5 : N-(3 -(3 -Amino-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-5 - bromothiophene-2-carboxamide: This compound was prepared by reaction of step 4 intermediate (8.1 g, 18.060 mmol) with acrylamide (1.41 g, 19.866 mmol) using aluminium chloride (4.816 g, 36.121 mmol) in dry acetonitrile (125 ml) as described in step 5 of example 174 to yield 4.34 g of product as yellow solid; 1H NMR (300 MHz, DMSO-J6): δ 0.94 (s, 9H), 2.04 (s, 2H), 2.65-2.75 (m, 2H), 3.01-3.12 (m, 2H), 3.26 (s, 3H), 5.50 (s, 1H), 5.62 (s, 1H), 6.87 (d, / = 9.6 Hz, 1H), 7.08 (s, 1H), 7.13 (d, / = 3.9 Hz, 1H), 7.39 (d, / = 8.1 Hz, 1H), 7.83 (d, / = 3.9 Hz, 1H), 10.32 (s, 1H), 10.84 (s, 1H).
Step 6: N-(3-(3-Amino-3-oxopropyl)-6-(N,3,3-trimethylbutanamido)-lH-indol-2-yl)-5-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)thiophene-2-carboxamide: This intermediate was prepared by coupling reaction of step 5 intermediate (4.2 g, 8.078 mmol) with l-(tetrahydro- 2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (2.78 g, 10.017 mmol) using [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (131.8 mg, 0.161 mmol) in presence of aqueous soution of potassium carbonate (65.8 ml) in N,N- dimethylformamide (224 ml) as described in step 3 of example 1 10 to yield 1.8 g of product as a yellow solid. 1H NMR (300 MHz, DMSO-J6): δ 0.95 (s, 9H), 1.63-1.76 (m, 4H), 2.01- 2.19 (m, 5H), 2.65-2.76 (m, 2H), 3.04-3.13 (m, 2H), 3.27 (s, 3H), 3.69-375 (m, 1H), 4.04- 4.13 (m, 1H), 5.35-5.44 (m, 1H), 5.50-5.63 (m, 2H), 6.81-6.89 (m, 1H), 7.03 (s, 1H), 7.35- 7.46 (m, 1H), 7.75 (s, 1H), 7.89 (s, 1H), 7.98 (s, 1H), 10.42 (s, 1H), 10.74 (s, 1H).
Step 7: N-(3 -(3 -amino-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-5 -( 1 H- pyrazol-4-yl)thiophene-2-carboxamide: The title compound was prepared by deprotection reaction of step 6 intermediate (4.8 g, 8.125 mmol) using p-toluene sulphonic acid (3.09 g, 16.250 mmol) in ethanol (102 ml) as described in step 4 (Method B) of example 1 10 to yield 1.5 g of product as yellow solid. 1H NMR (300 MHz, DMSO-J6): δ 0.88 (s, 9H), 1.96 (s, 2H), 2.89 (t, / = 6.0 Hz, 2H), 3.13 (s, 3H), 3.27-3.43 (m, 2H), 6.81 (d, / = 8.4 Hz, 1H), 7.16-7.25 (m, 2H), 7.34 (d, / = 3.9 Hz, 1H), 7.46 (d, / = 8.4 Hz, 1H), 7.58 (s, 1H), 7.90 (s, 1H), 7.99 (s, 1H), 8.25 (s, 1H), 10.94 (s, 1H), 1 1.27 (s, 1H), 13.16 (s, 1H); APCI (m/z) 507.42 (M+H)+. The examples 186-194 were obtained in the same manner as described above in example 185. The structural formulas, chemical names, 1H NMR and MS data are provided in table 9.
Table 9: Structure, chemical name, 1H NMR and MS data of Examples 186-194.
Figure imgf000132_0001
Figure imgf000133_0001
Structure Chemical name, 1H NMR and MS data
2H), 1 1.32 (s, 1H); APCI (m/z) 519.16 (M+H)+.
N-(3 -(3 - Amino-3 -oxopropyl)-6-(N-methylbenzamido)- 1 H- indol-2-yl)-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide: 1H
0 NH2 NMR (300 MHz, DMSO-J6): δ 2.37-2.49 (m, 2H), 2.75-2.86 Example 193 (m, 2H), 3.30-3.42 (m, 3H), 6.80 (d, / = 7.2 Hz, 1H), 7.07 (s,
1H), 7.14-7.20 (m, 4H), 7.25-7.36 (m, 4H), 7.54 (s, 1H), 7.88 (s, 1H), 7.95 (s, 1H), 8.24 (s, 1H), 10.86 (s, 1H), 1 1.1 1 (s, 1H), 13.15 (s, 1H); APCI (m/z) 513.25 (M+H)+.
N-(3 -(3 -Amino-3 -oxopropyl)-6-(4-fluoro-N- XX *» methylbenzamido)-lH-indol-2-yl)-5-(lH-pyrazol-4-
0 NH2 yl)thiophene-2-carboxamide: 1H NMR (300 MHz, DMSO- d6): δ 1.08 (d, / = 6.6 Hz, 3H), 2.35-2.42 (m, 2H), 2.81-2.90 Example 194
(m, 2H), 6.80 (d, / = 8.4 Hz, 1H), 7.02 (d, / = 8.4 Hz, 2H), 7.10 (s, 1H), 7.21 (s, 1H), 7.29-7.37 (m, 4H), 7.57 (s, 1H), 7.91 (s, 1H), 7.96 (d, / = 3.0 Hz, 1H), 8.26 (s, 1H), 10.99 (s, 1H), 1 1.16 (s, 1H), 13.18 (s, 1H); APCI (m/z) 531.39 (M+H)+.
Example 195
N-(3-(2-Cyanoethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(lH-pyrazol-4- yl)thiophene-2-carboxamide
Figure imgf000134_0001
To a stirred solution of example 192 (50 mg, 0.096 mmol) in dichloromethane (2 ml), triethylamine (54 μΐ, 0.386 mmol) was added at room temperature and the reaction mixture was cooled at 0 °C. To this cooled mixture, trifluoroacetic anhydride (20 μΐ, 0.144 mmol) was drop wise added and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated solution of sodium bicarbonate (75 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extract was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography to yield 30 mg of product as yellow solid. 1H NMR (300 MHz, CDC13): δ 0.87-1.70 (m, 10H), 2.23-2.31 (m, 1H), 2.75 (d, / = 6.6 Hz, 2H), 3.21 (t, / = 6.6 Hz, 2H), 3.28 (s, 3H), 6.94 (d, / = 7.8 Hz, 1H), 7.10-7.17 (m, 2H), 7.40 (d, / = 8.4 Hz, 1H), 7.69 (s, 1H), 7.87 (s, 2H), 8.64 (s, 1H), 10.42 (s, 1H), 12.14 (br s, 1H); APCI-MS (m z): 501.20 (M)+.
Example 196
N2-Cyclohexyl-N6-cyclopropyl-N2-methyl-5-(thiazole-4-carboxamido)-4H-thieno[3,2- b]pyrrole-2,6-dicarboxamide
Figure imgf000135_0001
The title compound is prepared by coupling reaction of intermediate 72 (200 mg, 0.556 mmol) with l ,3-thiazole-4-carbonyl chloride (108 mg, 0.834 mmol) using dry pyridine (200 μΐ, 0.002 mmol) in dry tetrahydrofuran (3 ml) as described in general procedure to yield 370 mg of the title compound as a pale yellow solid. 1H NMR (300 MHz, CDC13): δ 0.66-0.69 (m, 2H), 0.89-0.93 (m, 2H), 1.10-1.85 (m, 1 1H), 2.91-2.97 (m, 1H), 3.09 (s, 3H), 4.28-4.36 (m, 1H), 5.71 (s, 1H), 8.30 (d, / = 1.5 Hz, 1H), 8.90 (d, / = 1.2 Hz, 1H), 1 1.08 (s, 1H), 12.51 (s, 1H); APCI (m/z) 471.93 (M+H)+.
Example 197
N2-Cyclohexyl-N6-ethyl-N2-methyl-5-(thiazole-4-carboxamido)-4H-thieno[3,2-b]pyrrole-2,6- dicarboxamide
Figure imgf000135_0002
The title compound was prepared by coupling of intermediate 73 (200 mg, 0.575 mmol) with l ,3-thiazole-4-carbonyl chloride (1 12 mg, 0.863 mmol) using dry pyridine (200 μΐ, 0.002 mmol) in dry tetrahydrofuran (3.2 ml) as described in general procedure to yield 18 mg of product as a yellow solid. 1H NMR (300 MHz, CDC13): δ 1.12-1.90 (m, 10H), 1.29 (t, / = 7.5 Hz, 3H), 3.10 (s, 3H), 3.57 (q, /= 6.9 Hz, 2H), 4.31-4.38 (m, 1H), 5.51-5.58 (m, 1H), 7.25- 7.35 (m, 1H), 8.31 (s, 1H), 8.92 (s, 1H), 1 1.06 (s, 1H), 12.56 (s, 1H). APCI (m/z) 460.01 (M+H)+.
Example 198
5-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N2-cyclohexyl-N6-cyclopropyl-N2-methyl-
4H-thieno[3,2-b]pyrrole-2,6-dicarboxamide
Figure imgf000136_0001
Step 1 : 5-bromothiophene-2-carbonyl chloride: The title compound was obtained from 5- bromothiophene-2-carboxylic acid (950 mg, 4.589 mmol) and thionyl chloride (10 ml) as described in general procedure (Method A).
Step 2: 5-(5-Bromothiophene-2-carboxamido)-N2-cyclohexyl-N6-cyclopropyl-N2-methyl-4H- thieno[3,2-b]pyrrole-2,6-dicarboxamide: This intermediate was prepared by coupling of intermediate 72 (1.1 g, 3.059 mmol) with 5-bromothiophene-2-carbonyl chloride (step 1 intermediate) in presence of dry pyridine (1.1 ml, 0.01 mmol) in dry tetrahydrofuran (17 ml) as described in general procedure to yield 600 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO-Jg): δ 0.59-0.75 (m, 4H), 1.02-1.83 (m, 10H), 2.77-2.85 (m, 1H), 2.98 (s, 3H), 4.14-4.25 (m, 1H), 7.31-7.42 (m, 3H), 7.70 (d, / = 3.9 Hz, 1H), 7.92 (s, 1H), 8.29 (s, 1H), 12.02 (s, 1H), 12.1 1 (s, 1H), 13.19 (br s, 1H). APCI (m/z) 537.16 (M+H)+.
Step 3 : N2-Cyclohexyl-A^-cyclopropyl-N2-methyl-5 -(5 -( 1 -(tetrahydro-2H-pyran-2-yl)- 1 H- pyrazol-4-yl)thiophene-2-carboxamido)-4H-thieno[3,2-b]pyrrole-2,6-dicarboxamide: This intermediate is prepared by Suzuki coupling reaction of step 2 intermediate (600 mg, 1.093 mmol) with l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-pyrazole (378 mg, 1.355 mmol) using Ι , - bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (16 mg, 0.018 mmol) in presence of potassium carbonate (1.6 M, 10 ml) in N,N- dimethylformamide (40 ml) as described in step 3 of example 1 10 to afford 106 mg of yellow solid. 1H NMR (300 MHz, CDC13): δ 0.69-2.15 (m, 22H), 2.87-2.94 (m, 1H), 3.09 (s, 3H), 3.69-3.75 (m, 1H), 4.04-4.12 (m, 1H), 5.42 (t, / = 6.0 Hz, 1H), 5.72 (s, 1H), 7.12 (t, / = 3.9 Hz, 1H), 7.75 (s, 1H), 7.80 (s, 1H), 7.91 (s, 1H), 1 1.02 (s, 1H), 1 1.81 (s, 1H).
Step 4: 5-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N2-cyclohexyl-N6-cyclopropyl-N2- methyl-4H-thieno[3,2-b]pyrrole-2,6-dicarboxamide: The title compound is preparded by deprotection step 3 intermediate (103 mg) using hydrochloric acid (6 N, 3 ml) in methanol (6 ml) as described in step 4 of example 1 10 (Method A) to afford 40 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO-J6): δ 0.59-0.65 (m, 2H), 0.69 (d, / = 7.5, 2H), 1.00-1.80 (m, 10H), 2.44-2.52 (m, 1H), 2.98 (s, 3H), 4.14-4.23 (m, 1H), 7.32-7.41 (m, 3H), 7.70 (s, 1H), 7.92 (s, 1H), 8.29 (s, 1H), 12.02 (s, 1H), 12.1 1 (s, 1H), 13.19 (s, 1H). APCI (m/z) 537.16 (M+H)+.
Example 199
2 2
N -Cyclohexyl-N6-cyclopropyl- -methyl-5-(picolinamido)-4H-thieno[3,2-b]pyrrole-2,6- dicarboxamide
Figure imgf000137_0001
The title compound was prepared by coupling of intermediate 72 (190 mg, 0.530 mmol) with pyridine-2-carbonyl chloride (98 mg, 0.792 mmol) in presence of dry pyridine (190 μΐ, 0.002 mmol) in dry tetrahydrofuran (3 ml) as described in general procedure to yield 13 mg of product as a yellow solid. 1H NMR (300 MHz, CDC13): δ 0.64-0.68 (m, 2H), 0.92 (d, J = 6.0 Hz, 2H), 1.00-1.86(m, 10H), 2.92-3.00 (m, 1H), 3.09 (s, 3H), 4.29-4.35 (m, 1H), 5.74 (s, 1H), 7.25-7.29 (m, 1H), 7.47-7.58 (m, 1H), 7.92 (t, / = 7.2 Hz, 1H), 8.24 (d, / = 7.2 Hz, 1H), 8.76- 8.80 (m, 1H), 1 1.23 (s, 1H), 12.84 (s, 1H). APCI (m/z) 466.17 (M+H)+.
Example 200
5-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N2-cyclohexyl-N4-cyclopropyl-N2-methyl-
6H-th -b]pyrrole-2,4-dicarboxamide
Figure imgf000137_0002
Step 1 : 5-bromothiophene-2-carbonyl chloride: The title compound was obtained from 5- bromothiophene-2-carboxylic acid (492 mg, 2.378 mmol) and thionyl chloride (5 ml) as described in general procedure (Method A).
Step 2: 5-(5-Bromothiophene-2-carboxamido)-N2-cyclohexyl-N4-cyclopropyl-N2-methyl-6H- thieno[2,3-b]pyrrole-2,4-dicarboxamide: This intermediate was prepared by coupling of intermediate 74 (570 mg, 1.585 mmol) with 5-bromothiophene-2-carbonyl chloride (step 1 intermediate) in the presence of dry pyridine (600 μΐ) in dry tetrahydrofuran (9 ml) as described in general procedure to yield 475 mg of product as a yellow solid. 1H NMR (300 MHz, CDCI3) δ 0.64-1.87 (m, 14H), 2.85-2.96 (m, 1H), 3.06 (s, 3H), 4.24-4.32 (m, 1H), 5.96 (s, 1H), 7.1 1 (d, / = 3.9 Hz, 1H), 7.32 (s, 1H), 7.56 (d, / = 3.9 Hz, 1H), 1 1.09 (s, 1H), 1 1.89 (s, 1H). Step 3 : N2-Cyclohexyl-A^-cyclopropyl-N2-methyl-5 -(5 -( 1 -(tetrahydro-2H-pyran-2-yl)- 1 H- pyrazol-4-yl)thiophene-2-carboxamido)-6H-thieno[2,3-b]pyrrole-2,4-dicarboxamide: This intermediate is prepared by Suzuki coupling reaction of step 2 intermediate (470 mg, 0.856 mmol) with l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-pyrazole (295 mg, 1.062 mmol) using Ι , -
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (12 mg, 0.014 mmol) in presence of aqueous solution of potassium carbonate (1.6 M, 7 ml) in N,N-dimethylformamide (24 ml) as described in step 3 of example 1 10 to afford 75 mg of yellow solid. 1H NMR (300 MHz, CDC13): δ 0.64-2.15 (m, 21H), 2.84-2.93 (m, 1H), 3.06 (s, 3H), 3.69-3.75 (m, 1H), 4.06-4.14 (m, 1H), 4.26-4.35 (m, 1H), 5.39-5.46 (m, 1H), 5.94 (s, 1H), 7.09 (d, / = 3.6 Hz, 1H), 7.33 (s, 1H), 7.80 (s, 1H), 7.90 (s, 1H), 1 1.20 (s, 1H), 1 1.81 (s, 1H).
Step 4: 5-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N2-cyclohexyl-N4-cyclopropyl-N2- methyl-6H-thieno[2,3-b]pyrrole-2,4-dicarboxamide: The title compound was prepared by deprotection of step 3 intermediate (70 mg, 0.1 13 mmol) using hydrochloric acid (6 N, 1.1 ml) in methanol (3.7 ml) as described in step 4 of example 1 10 to afford 26 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO-J6): δ 0.62-0.66 (m, 2H), 0.74 (d, / = 6.6 Hz, 2H), 1.00-1.85 (m, 10H), 2.77-2.85 (m, 1H), 2.96 (s, 3H), 4.08-4.13 (m, 1H), 7.38 (d, / = 3.6 Hz, 1H), 7.61-7.73 (m, 2H), 7.79 (s, 1H), 7.94 (m, 1H), 8.32 (s, 1H), 12.24 (s, 1H), 12.30 (s, 1H), 13.21 (s, 1H). APCI (m/z) 537.23 (M+H)+.
Example 201
N2-Cyclohexyl-N4-cyclopropyl-5-(2-(dimethylamino)thiazole-4-carboxamido)-N2-methyl-6H- thieno[2,3-b]pyrrole-2,4-dicarboxamide
Figure imgf000138_0001
The title compound was prepared by coupling recation of intermediate 74 (200 mg, 0.556 mmol) with 2-(dimethylamino)-l ,3-thiazole-4-carbonyl chloride (143 mg, 0.834 mmol) in presence of dry pyridine (400 μΐ, 0.004 mmol) in dry tetrahydrofuran (3 ml) as described in general procedure to yield 36 mg of product as a yellow solid. 1H NMR (300 MHz, DMSO- <k): δ 0.58-0.65 (m, 2H), 0.70 (d, / = 6.6 Hz, 2H), 1.00-1.86 (m, 10H), 2.81-2.89 (m, 1H), 3.04 (s, 3H), 3.14 (s, 6H), 4.18-4.30 (m, 1H), 7.49 (s, 1H), 7.64 (s, 1H), 7.71 (s, 1H), 12.19 (s, 1H), 12.27 (s, 1H). APCI (m/z) 515.01 (M+H)+.
Example 202
N2-Cyclohexyl-A^-cyclopropyl-N2-methyl-5-(picolinamido)-6H-thieno[2,3-b]pyrrole-2,4- dicarboxamide
Figure imgf000139_0001
The title compound was prepared by coupling reaction of intermediate 74 (200 mg, 0.556 mmol) with pyridine -2-carbonyl chloride (103 mg, 0.834 mmol) in presence of dry pyridine (400 μΐ, 0.004 mmol) in dry tetrahydrofuran (3 ml) as described in general procedure to yield 61 mg of product as a yellow solid. 1H NMR (300 MHz, CDC13): δ 0.62-.067 (m, 2H), 0.92 (d, / = 6.0 Hz, 2H), 1.00-1.86 (m, 10H), 2.91-2.99 (m, 1H), 3.07 (s, 3H), 4.29-4.35 (m, 1H), 5.97 (s, 1H), 7.34 (s, 1H), 7.44-7.55 (m, 1H), 7.91 (t, / = 7.5 Hz, 1H), 8.24 (d, / = 7.8 Hz, 1H), 8.77 (d, / = 4.2 Hz, 1H), 11.42 (s, 1H), 12.84 (s, 1H). APCI (m/z) 466.09 (M+H)+.
Pharmacological Activity
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.
LANCE Ultra Assay Principle: The phosphorylation of an U Light peptide substrate is detected with a specific anti phospho- peptide antibody (Ab) labeled with europium chelate molecules (Eu). The binding of the Eu-antibody to the phosphorylated U Light peptide substrate brings both the donor and acceptor dye molecules into close proximity.
Upon irradiation at 320 or 340 nm, the excited europium chelate donor dye transfers its energy to the nearby ULight acceptor dye molecule that will in turn emit light at 665 nm.
The intensity of light emission is proportional to the level of the ULight peptide phosphorylation.
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 μΐ of test compounds (or controls at final 1% DMSO concentration) were added to 384 well plate, followed by 2.5 μΐ of ITK enzyme in the kinase assay buffer and the reaction was started by adding 5 μΐ of ATP / peptide substrate mix in the kinase assay buffer. The kinase assay components contained 50 mM Hepes pH 7.5, 5 mM MgC12, 1 mM EGTA (Ethylene glycol tetraacetic acid), 2 mM DTT (Dithiothreitol), 0.01% Tween 20, 0.75 nM ITK enzyme, 100 nM U light-Poly GT substrate and 3 μΜ ATP in 10 μΐ 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. IC50 values were calculated from non-linear regression analysis of the initial rate data using the GraphpadPrism software.
The compounds prepared were tested using the above assay procedure and the results obtained are given in table 10. Percentage inhibition of ITK at concentrations of 1.0 and 10.0 μΜ is given in the table 10 along with IC50 (nM) details for selected examples.
The IC50 (nM) values of the compounds are set forth in table 10 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01 to 100 nM, "C" refers to an IC50 value in range of 100.01 - 500 nM and "D" refers to an IC50 value of more than 500 nM.
Table 10: In- vitro screening results of compounds of invention
Figure imgf000140_0001
% inhibition of lTK at
Example ICso (nM)
1.0 μΜ 10.0 μΜ
14 86.51 90.19 A
15 85.52 90.02 A
16 73.66 83.61 C
17 81.66 85.15 A
18 87.48 89.66 A
19 80.24 85.91 B
20 67.3 85.0 C
21 72.32 85.26 C
22 71.66 87.55 C
23 54.54 89.9 C
24 87.08 93.65 B
25 89.93 92.27 A
26 62.33 86.38 B
27 76.46 87.3 C
28 69.12 87.87 C
29 69.54 86.79 C
30 56.44 86.64 C
31 44.75 73.2 C
32 68.35 86.94 B
33 58.38 80.43 D
34 48 75 -
35 73.94 89.77 C
36 59.94 84.86 C
37 79.61 86.67 B
38 0.27 38.44 -
39 46.53 80.68 D
40 60.44 84.21 C
41 81.14 84.64 A
42 88.4 89.78 A
43 81.7 90.47 A
44 20.4 59 - % inhibition of lTK at
Example ICso (nM)
1.0 μΜ 10.0 μΜ
45 46.7 80.04 D
46 11.3 20.8 -
47 34.05 66.48 -
48 76.43 91.02 C
49 61.51 84.85 C
50 41.84 82.81 D
51 14.47 36.77 -
52 13.9 56.3 -
53 27.58 47.84 -
54 80.94 89.52 A
55 79.1 92.8 B
56 73.31 86.94 C
57 53.73 82.29 D
58 46.63 74.07 C
59 42.82 79 C
60 64.45 91.69 C
61 64.95 88.27 C
62 68.35 89.03 C
63 65.01 84.76 A
64 23.46 61.4 -
65 67.68 87.09 C
66 55.52 82.13 C
67 53.96 88.19 C
68 75.97 86.89 A
69 89.64 90.58 A
70 86.27 92.95 A
71 87.05 88.82 A
72 38.63 -
73 83.49 88.57 A
74 86.55 91.31 A
75 67.08 82.77 C % inhibition of lTK at
Example ICso (nM)
1.0 μΜ 10.0 μΜ
76 37.9 64.1 -
77 20.05 35.05 -
78 67.22 83.71 C
79 42.04 84.78 D
80 62.36 55.35* C
81 57.27 70.97 C
82 16.6 33.8 -
83 63.04 84.16 C
84 80.8 91.53 A
85 46.16 71.48 C
86 45.34 73.27 C
87 18.15 38.54 -
88 50.54 75.71 C
89 4 41 -
90 45.84 61.81 -
91 45.02 87.87 D
92 16.4 61.6 -
93 64.07 89.31 D
94 69.7 90.3 C
95 77.08 91.60 C
96 75.68 90.34 C
97 69.73 92.39 C
98 87.94 92.39 A
99 87.51 88.13 A
100 90.28 94.08 A
101 56 72 -
102 58.44 89.95 C
103 64.56 85.35 C
104 62.65 86.89 C
105 89.7 88.33 A
106 52.43 87.8 C % inhibition of lTK at
Example ICso (nM)
1.0 μΜ 10.0 μΜ
107 71.41 87.25 C
108 55.75 85.51 D
109 54.33 81.90 D
110 93.17 89.51 A
111 90.27 89.85 A
112 93.4 92.4 A
113 80.84 90.45 C
114 91.7 91.7 A
115 84.03 88.46 A
116 88.18 88.91 A
117 88.76 86.66 A
118 90.6 89.8 A
119 88.6 88.8 A
120 91.13 89.60 A
121 81.79 86.06 A
122 90.02 89.03 A
123 86.62 87.85 A
124 86.80 87.32 A
125 88.11 87.78 A
126 72.96 85.16 C
127 92.72 91.78 A
128 92.85 92.22 A
129 64.76 83.27 C
130 85.08 90.78 A
131 80.29 89.34 B
132 88.70 91.50 A
133 88.6 91.6 A
134 89.18 86.82 A
135 95.5 95.0 A
136 84.55 85.72 A
137 74.17 90.25 C % inhibition of lTK at
Example ICso (nM)
1.0 μΜ 10.0 μΜ
138 91.2 89.29 A
139 90.4 92.08 A
140 47.19 79.46 -
141 77.34 79.26 A
142 87.75 87.91 A
143 15.2 41.1 -
144 91.91 88.77 A
145 85.5 89.6 A
146 89.94 88.09 A
147 86.98 90.04 A
148 92.65 91.32 A
149 89.5 90.3 A
150 87.56 88.83 A
151 93.87 91.48 A
152 89.25 90.69 A
153 92.95 91.03 A
154 92.8 93.1 A
155 91.1 90.4 A
156 91.3 90.6 A
157 86.40 86.36 A
158 86.50 86.57 A
159 77.3 89.9 A
160 91.6 90.6 A
161 86.36 93.84 A
162 50.36 82.11 C
163 75.64 91.35 B
164 86.43 92.9 A
165 76.53 82.28 A
166 92.29 94.1 A
167 43.58 79.91 D
168 24.77 36.62 - % inhibition of lTK at
Example ICso (nM)
1.0 μΜ 10.0 μΜ
169 81.62 80.89 A
170 42.84 88.82 D
171 7 40 -
172 83.26 90.74 B
173 90.8 90.2 A
174 95.16 91.09 A
175 76.11 91.43 C
176 78.8 89.32 B
177 71.7 88.72 B
178 83.52 89.57 B
179 90.37 93.16 A
180 73.29 91.14 C
181 92.03 90.93 A
182 86.74 88.36 A
183 89.93 90.02 A
184 84.85 89.87 A
185 91.94 93.88 A
186 82.95 87.79 A
187 93.52 92.14 A
188 88.22 90.42 A
189 83.46 90.81 B
190 69.20 86.49 C
191 55.22 82.17 D
192 89.65 90.52 A
193 88.05 89.35 A
194 87.90 91.21 A
195 77.43 91.42 C
196 78.1 98.56 B
197 66.02 73.51 C
198 90.0 91.7 A
199 62 88 -
Figure imgf000147_0001

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I)
Figure imgf000148_0001
or a pharmaceutically acceptable salt thereof, wherein,
Ring A is
Figure imgf000148_0002
and wherein x and y represent the point of attachment;
P is selected form phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and indazolyl each optionally being substituted with one or more substituents selected from halogen, cyano, Ci_salkyl, haloCi_salkyl, haloCi_salkoxy and - NRaRb;
Q is selected from hydrogen, imidazolyl, pyrazolyl and pyridyl;
L is selected from -(CH2)„CRaRb-, -C(O)-, -C(0)NRa-, -(CH2)„C(0)NRa-, - C(0)(CH2)nC(0)-, and -(CRaRb)nO-;
M is selected from hydrogen, cyano, Ci_salkyl, Ci_salkoxy, Ci_8alkoxyCi_salkyl, hydroxyCi_8alkyl, haloCi_salkyl, C3_i2cycloalkyl, C3-i2cycloalkylCi_salkyl and C6-14aryl;
R1 is Ci_8alkyl;
R is selected from Ci_salkyl, Ci_8alkoxyCi_salkyl, hydroxyCi_salkyl, C3_i2cycloalkyl, C3_i2cycloalkylalkyl, C6-14aryl, 3- to 15- membered heterocyclylCi_salkyl, 5- to 14- heteroaryl and -(CH2)nNRbC(0)Rc;
R3 is Ci_8alkyl;
R4 is Ci_8alkyl; R5 is Ci_8alkyl;
R6 is selected from Ci_salkyl and C3_i2cycloalkyl;
R7 is C3-i2cycloalkyl;
R8 is Ci_8alkyl;
R9 is C3-i2cycloalkyl;
R10 is Ci_8alkyl;
Rn is Ci_8alkyl;
R 12 is C3_i2cycloalkyl;
R13 is Ci-galkyl;
R14 is C3_i2cycloalkyl;
at each occurrence, Ra is independently selected from hydrogen and Ci.galkyl; at each occurrence, Rb is independently selected from hydrogen and Ci.galkyl; at each occurrence, Rc is independently selected from hydrogen and Ci_salkyl; and 'n' is an integer ranging from 1 to 6, both inclusive.
2. The compound according to claim 1, wherein ring A is
Figure imgf000149_0001
Figure imgf000150_0001
3. The compound according to any one of claim 1 or 2, wherein ring A is
Figure imgf000150_0002
4. The compound according to any one of claim 1 to 3, wherein ring A is
Figure imgf000150_0003
The com ound accordin to an one of claim 1 to 4 wher in P
Figure imgf000150_0004
6. The compound according to any one of claim 1 to 5, wherein Q is hydrogen,
Figure imgf000151_0001
7. The compound according to any one of claim 1 to 6, wherein -L-M is
Figure imgf000151_0002
Figure imgf000151_0003
O ^OCH3 O ^CH3 O ¾ O H ^OCH3 ^pOCH3
NH2 ^r-N
OCH3 o - O x o nrr CN
8. A compound of the formula
Figure imgf000151_0004
or a pharmaceutically acceptable salt thereof, wherein,
P is selected form phenyl, thiazolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl and indazolyl each optionally being substituted with one or more substituents selected from halogen, cyano, Ci_salkyl, haloCi_salkyl, haloCi_salkoxy and - NRaRb;
Q is selected from hydrogen, imidazolyl, pyrazolyl and pyridyl;
L is selected from -(CH2)„CRaRb-, -C(O)-, -C(0)NRa-, -(CH2)„C(0)NRa-, - C(0)(CH2)nC(0)-, and -(CRaRb)nO-;
M is selected from hydrogen, cyano, Ci_salkyl, Ci_salkoxy, Ci_8alkoxyCi_salkyl, hydroxyCi_salkyl, haloCi_salkyl, C3_i2cycloalkyl, C3_i2cycloalkylCi_salkyl and C6-14aryl;
R1 is Ci-galkyl; 2
R is selected from Ci_salkyl, Ci_8alkoxyCi_salkyl, hydroxyCi.salkyl, C3_i2cycloalkyl, C3_i2cycloalkylalkyl, C6-14aryl, 3- to 15- membered heterocyclylCi-salkyl, 5- to 14- heteroaryl, and -(CH2)„NRbC(0)Rc; at each occurrence, Ra is independently selected from hydrogen and Ci_salkyl; at each occurrence, Rb is independently selected from hydrogen and Ci_salkyl; at each occurrence, Rc is independently selected from hydrogen and Ci_salkyl; and
'n' is an integer ranging from 1 to 6, both inclusive.
9. The compound according to claim 8, wherein R1 is methyl or ethyl.
2
The compound according to any one of claim 8 or 9, wherein R is methyl,
Figure imgf000152_0001
The com ound accordin to an one of claim 8 to 10 whe P
Figure imgf000152_0002
12. The compound according to ne of claim 8 to 11, wherein Q is hydrogen,
Figure imgf000153_0001
The compound according to any one of claim 8 to 12, wherein -L-M
Figure imgf000153_0002
^^γ^3 - L\T^OH
OCH3 O ^CH3 0 o 0 H -OC¾ -OC¾
NH, ■N
.OCH, O O or CN
14. The compound of formula
Figure imgf000153_0003
(lb) or a pharmaceutically acceptable salt thereof, wherein,
P is selected from thienyl and pyridyl;
Q is hydrogen or pyrazolyl;
L is -C(0)NH-;
M is C3_i2cycloalkyl;
R is Ci_salkyl; and
R4 is Ci_8alkyl.
15. The compound according to claim 14, wherein
P is Q is hydrogen or
N I
NH _
M is cyclopropyl;
R is methyl and
4 is
Figure imgf000154_0001
16. The compound of formula (I c)
Figure imgf000154_0002
(Ic) or a pharmaceutically acceptable salt thereof, wherein,
P is thienyl;
Q is hydrogen or pyrazolyl;
L is -C(0)NH-;
M is selected from Ci_salkyl and C3_i2cycloalkyl; R5 is Ci_8alkyl; and
R6 is selected from Ci_salkyl and C3_i2cycloalkyl.
The compound according to claim 16, wherein
Figure imgf000154_0003
Q is hydrogen or
Figure imgf000154_0004
M is ethyl or cyclopropyl; R5 is methyl and
6 is cyclohexyl or
Figure imgf000155_0001
18. The compound of formula (Id)
Figure imgf000155_0002
(Id) or a pharmaceutically acceptable salt thereof, wherein,
P is selected from thiazolyl, thienyl and pyridyl; Q is hydrogen or pyrazolyl;
L is -C(0)NH-;
M is selected from Ci_salkyl and C?_i2cycloalkyl;
R7 is C3_i2cycloalkyl; and
R8 is Ci_8alkyl.
19. The compound according to claim 18, wherein
Figure imgf000155_0003
is hydrogen or
Figure imgf000155_0004
M is ethyl or cyclopropyl;
R7 is cyclohexyl and
R is methyl.
20. The compound of formula (Ie)
Figure imgf000156_0001
(Ie) or a pharmaceutically acceptable salt thereof, wherein,
P is selected from thiazolyl, thienyl and pyridyl each being optionally substituted with one or more substituents selected from -NRaRb;
Q is hydrogen or pyrazolyl;
L is -C(0)NRa-;
M is C3_i2cycloalkyl;
R9 is C3-i2cycloalkyl;
Pv10 is Ci_8alkyl;
Ra is hydrogen or Ci.galkyl; and
Rb is Ci-galkyl.
The compound according to claim 20, wherein
P is
Figure imgf000156_0002
Q is hydrogen or
Figure imgf000156_0003
-L- is -C(0)NH-;
M is cyclopropyl;
R9 is cyclohexyl and
R10 is methyl.
22. A compound selected from
N-(3-(Cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiazole-4-carboxamide; N-Cyclopropyl-2-(picolinamido)-6-(2,2,2-trifluoro
carboxamide;
N-Cyclopropyl-6-(N-ethylacetamido)-2-(picolinamido)-lH-indole-3-carboxamide; N-Cyclopropyl-6-(N-ethylacetamido)-2-(6-methylpicolinamido)- 1 H-indole-3 - carboxamide;
N-(3-(Cyclopropylcarbamoyl)-6-(N-ethylacetamido)-lH-indol-2-yl)-2-(pyridin-4- yl)thiazole-4-carboxamide;
N-Cyclopropyl-6-(2-methoxy-N-methylacetamido)-2-(picolinamido)-lH-indole-3- carboxamide;
6-(2-Methoxy-N-methylacetamido)-2-(picolinam ^
indole-3-carboxamide;
N-Cyclopropyl-6-(3 -methoxy-N,3 -dimethylbutanamido)-2-(picolinamido)- 1 H-indole-
3 - carboxamide;
N-Ethyl-6-(N-methylisobutyramido)-2-(thiophene-2-carboxamido)- 1 H-indole-3 - carboxamide;
N-( -(Cyclopropylcarbamoyl)-6-(N-methylisobutyramido)- 1 H-indol-2-yl)-2-(pyridin-
4- yl)thiazole-4-carboxamide;
N-( -(Cyclopropylcarbamoyl)-6-(N-ethylisobutyramido)- 1 H-indol-2-yl)-2-(pyridin-4- yl)thiazole-4-carboxamide;
6-(N,3-Dimethylbutanamido)-N-ethyl-2-(thiophene-2-carboxamido)-lH-indole-3- carboxamide;
N-( -(Ethylcarbamoyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)thiazole-4- carboxamide;
N-( -(Ethylcarbamoyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-2- methylthiazole-4-carboxamide;
N-( -(Ethylcarbamoyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-2- (trifluoromethyl)thiazole-4-carboxamide;
N-Cyclopropyl-2-(picolinamido)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indole-3 - carboxamide;
N-( -(Cyclopropylcarbamoyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)thiazole- 4-carboxamide;
N-( -(Cyclopropylcarbamoyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-2- methylthiazole-4-carboxamide; N-( -(Cyclopropylcarbamoyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-2- (dimethylamino)thiazole-4-carboxamide;
N-Ethyl-6-(N-methylcyclopropanecarboxamido)-2-(thiophene-2-carboxamido)-lH- indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclopentanecarboxamido)-2-(thiophene-2-carboxamido)-lH- indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclopentanecarboxamido)-2-(picolinamido)- 1 H-indole-3 - carboxamide;
N-(6-(2-Cyclopentyl-N-methylacetamido)-3 -(ethylcarbamoyl)- 1 H-indol-2-yl)thiazole- 4-carboxamide;
N-(6-(2-Cyclopentyl-N-methylacetamido)-3 -(cyclopropylcarbamoyl)- 1 H-indol-2- yl)thiazole-4-carboxamide;
6-(2-Cyclopentyl-N-methylacetamido)-N-cyclopropyl-2-(picolinamido)- 1 H-indole-3 - carboxamide;
6-(N-Methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)-lH-indole-3- carboxamide;
2-(4-Cyanobenzamido)-6-(N-methylcyclohexanecarboxamido)-lH-indole-3- carboxamide;
N-Methyl-6-(N-methylcyclohexanecarboxamido)-2-(m^
indole-3-carboxamide;
2-(5-Chlorothiophene-2-carboxamido)-N-methyl-6-(N- methylcyclohexanecarboxamido)-lH-indole-3 -carboxamide;
2-(3-Fluorobenzamido)-N-methyl-6-(N-methylcyclohexanecarboxamido)-lH-indole- 3 -carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)-lH- indole-3-carboxamide;
N-Ethyl-6-(N-ethylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)-lH- indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(5-methylthiophene-2- carboxamido)-lH-indole-3-carboxamide;
2-(5-Chlorothiophene-2-carboxamido)-N-ethyl-6-(N- methylcyclohexanecarboxamido)-lH-indole-3 -carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-( 1 H-pyrazole-5 -carboxamido)- 1 H- indole-3-carboxamide; N-Ethyl-2-( 1 -methyl- 1 H-imidazole-4-carboxamido)-6-(N- methylcyclohexanecarboxamido)- 1 H-indole-3 -carboxamide;
2-( 1 ,3 -Dimethyl- 1 H-pyrazole-5 -carboxamido)-N-ethyl-6-(N- methylcyclohexanecarboxamido)-l H-indole-3 -carboxamide;
N-( -(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)thiazole- 2-carboxamide;
N-( -(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)thiazole- 4-carboxamide;
N-( -(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-2- methylthiazole-4-carboxamide;
N-( -(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-2- (trifluoromethyl)thiazole-4-carboxamide;
N-(3-(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-2,5- dimethylthiazole-4-carboxamide;
N-( -(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-2- methylthiazole-5 -carboxamide;
N-(3-(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-2,4- dimethylthiazole-5-carboxamide;
N-( -(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-5 - methylisoxazole-3 -carboxamide;
2-(3-Cyanobenzamido)-N-ethyl-6-(N-methylcyclohexanecarboxamido)-l H-indole-3 - carboxamide;
2-(4-Cyanobenzamido)-N-ethyl-6-(N-methylcyclohexanecarboxamido)-l H-indole-3 - carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(3 -(trifluoromethyl)benzamido)- 1 H- indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(4-(trifluoromethyl) benzamido)- lH-indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(3-(trifluoromethoxy) benzamido)- lH-indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-( 1 H-pyrazole-4-carboxamido)- 1 H- indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(picolinamido)-l H-indole-3 - carboxamide; N-(2-Hydroxy-2-methylpropyl)-6-(N-methylcyclohexane carboxamido)-2- (picolinamido)-lH-indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(nicotinamido)- 1 H-indole-3 - carboxamide;
N-Ethyl-2-(3 -fluoropicolinamido)-6-(N-methylcyclohexanecarboxamido)- 1 H-indole- 3 -carboxamide
2-(5-Cyanopicolinamido)-N-ethyl-6-(N-methylcyclohexanecarboxamido)-lH-indole- 3 -carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(5-(trifluoromethyl) picolinamido)- lH-indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(pyridazine-3 -carboxamido)- 1 H- indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(pyrimidine-4-carboxamido)-lH- indole-3-carboxamide;
N-Ethyl-6-(N-methylcyclohexanecarboxamido)-2-(pyrazine-2-carboxamido)-lH- indole-3-carboxamide;
6-(N-Methylcyclohexanecarboxamido)-2-(picolinamido)-N-(2,2,2-trifluoroethyl)-lH- indole-3-carboxamide;
N,N-Dimethyl-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)- lH-indole-3-carboxamide;
6-(N-Methylcyclohexanecarboxamido)-N-propyl-2-(thiophene-2-carboxamido)-lH- indole-3 -carboxamide
N-Isopropyl-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)-lH- indole-3-carboxamide;
N-Isopropyl-6-(N-methylcyclohexanecarboxamido)-2-(picolinamido)-l H-indole-3 - carboxamide;
N-Cyclopropyl-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)- lH-indole-3-carboxamide;
N-(3-(Cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 2-methylthiazole-4-carboxamide;
N-(3-(Cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 2-(trifluoromethyl)thiazole-4-carboxamide;
N-(3-(Cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 2-(dimethylamino)thiazole-4-carboxamide; 5 -Chloro-N-(3 -(cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H- indol-2-yl)-2-(dimethylamino)thiazole-4-carboxamide;
N-( -(Cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)isoxazole-5-carboxamide;
N-Cyclopropyl-6-(N-methylcyclohexanecarboxamido)-2-(picolinamido)- 1 H-indole-3 - carboxamide;
N-Cyclopropyl-2-(5 -fluoropicolinamido)-6-(N-methylcyclohexanecarboxamido)- 1 H- indole-3-carboxamide;
N-Cyclopropyl-2-(3,5-difluoropicolinamido)-6-(N-methylcyclohexanecarboxamido)- 1 H-indole-3 -carboxamide;
N-(3-(Cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- lH-indazole-3 -carboxamide;
N-(Cyclopropylmethyl)-6-(N-methylcyclohexanecarboxamido)-2-(picolinamido)-lH- indole-3-carboxamide;
N-Cyclopentyl-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)- lH-indole-3-carboxamide;
N-(3-(Cyclopentylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiazole-4-carboxamide;
N-(3-(Cyclohexylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiazole-4-carboxamide;
N-(4-Chlorophenyl)-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2- carboxamido)-lH-indole-3-carboxamide;
N-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2- carboxamido)-lH-indole-3-carboxamide;
N-( -((3 -Methoxypropyl)carbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H- indol-2-yl)thiazole-4-carboxamide;
N-( -Methoxypropyl)-6-(N-methylcyclohexanecarboxamido)-2-(picolinamido)- 1 H- indole-3-carboxamide;
N-(3-(2-Methoxyacetyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)thiophene-2-carboxamide;
N-(3-(2-Methoxyacetyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-4- (trifluoromethyl)benzamide;
4-Cyano-N-(3-(2-methoxyacetyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2- yl)benzamide; N-(3-(2-Methoxyacetyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-4- (trifluoromethoxy)benzamide;
N-( -(3 -Methoxypropanoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)thiophene-2-carboxamide;
4-Cyano-N-(3 -(3 -methoxypropanoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H- indol-2-yl)benzamide;
Ethyl 6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)- 1 H-indole- 3-carboxylate;
Methyl 4-(6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2-carboxamido)-lH- indol-3-yl)-4-oxobutanoate;
N-Cyclopropyl-6-(N-methyl-2-morpholinoacetamido)-2-(picolinamido)-lH-indole-3- carboxamide;
(5)-N-Cyclopropyl-6-(N-methyl-2-morpholinopropanamido)-2-(picolinamido)-lH- indole-3-carboxamide;
(S)-N-methyl-6-(N-methyl-2-morpholinopropa
carboxamide;
6-(N-Methylbenzamido)-2-(thiophene-2-carboxamido)-lH-indole-3-carboxamide;
N-( -(Cyclopropylcarbamoyl)-6-(N-methylbenzamido)- 1 H-indol-2-yl)-2-(pyridin-4- yl)thiazole-4-carboxamide;
N-(3 -(Ethylcarbamoy l)-6-(4-fluoro-N-methylbenzamido)- 1 H-indol-2-yl)-2-(pyridin-4- yl)thiazole-4-carboxamide;
N-( -Carbamoyl-6-(4-fluoro-N-methylbenzamido)- 1 H-indol-2-yl)-2-(pyridin-4- yl)thiazole-4-carboxamide;
N-Ethyl-6-(4-fluoro-N-methylbenzamido)-2-(thiophene-2-carboxamido)- 1 H-indole-3 - carboxamide;
N-Ethyl-6-(4-fluoro-N-methylbenzamido)-2-(thiophene-2-carboxamido)-lH-indole-3- carboxamide;
N-( -(Ethylcarbamoyl)-6-(N-methyl-4-(trifluoromethyl)benzamido)- 1 H-indol-2- yl)thiazole-4-carboxamide;
6-(2,4-Difluoro-N-methylbenzamido)-N-ethyl-2-(thiophene-2-carboxamido)-lH- indole-3-carboxamide;
N-(3-(Cyclopropylcarbamoyl)-6-(N-methyl-2-(N-methylpropionamido)acetamido)- lH-indol-2-yl)-2-(dimethylamino)thiazole-4-carboxamide; N-Cyclopropyl-6-(N-methyl-2-(N-methylaceta
indole-3-carboxamide;
N-(2-Hydroxyethyl)-6-(N-methylcyclohexanecarboxamido)-2-(thiophene-2- carboxamido)- 1 H-indole-3 -carboxamide;
N-Cyclopropyl-2-( 1 H-imidazole-4-carboxamido)-6-(N,3 ,3 -trimethylbutanamido)- 1 H- indole-3-carboxamide;
N-Cyclopropyl-2-(lH-imidazole-4-carboxamido)-6-(N- methylcyclohexanecarboxamido)- 1 H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylcyclohexanecarboxamido)-l H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(2-hydroxy-N- methylacetamido)-l H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylacetamido)-l H-indole-3 -carboxamide;
2-(3-(lH-Pyrazol-4-yl)benzamido)-N-cyclopropyl-6-(N-ethylacetamido)-lH-indole-3- carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- ethylacetamido)-l H-indole-3 -carboxamide;
2-(6-(lH-Pyrazol-3-yl)picolinamido)-N-cyclopropyl-6-(N-ethylacetamido)-lH-indole- 3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(2-methoxy-N- methylacetamido)-l H-indole-3 -carboxamide;
N-Cyclopropyl-6-(2-methoxy-N-methylacetamido)-2-(5-(pyridin-4-yl)thiophene-2- carboxamido)-lH-indole-3-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-ethyl-6-(2-methoxy-N- methylacetamido)-l H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-6-(2-methoxy-N-methylacetamido)- N-(2,2,2-trifluoroethyl)-lH-indole-3-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylisobutyramido)-lH-indole-3-carboxamide;
2-(6-( 1 H-Pyrazol-4-yl)picolinamido)-N-cyclopropyl-6-(N-ethylisobutyramido)- 1 H- indole-3-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- ethylisobutyramido)-lH-indole-3-carboxamide; 2-(5-(lH-Imidazol-l-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylpivalamido)- 1 H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N,3- dimethylbutanamido)-lH-indole-3-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-ethyl-6-(N,3,3- trimethylbutanamido)- 1 H-indole-3 -carboxamide;
2-(5-(lH-Imidazol-l-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N,3,3- trimethylbutanamido)- 1 H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N,3,3- trimethylbutanamido)- 1 H-indole-3 -carboxamide;
N-( -(Cyclopropylcarbamoyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-2- (pyridin-4-yl)thiazole-4-carboxamide;
N-Cyclopropyl-2-(5-(pyridin-3-yl)thiophene-2-carboxamido)-6-(N,3,3- trimethylbutanamido)- 1 H-indole-3 -carboxamide;
2-(6-(lH-Pyrazol-4-yl)picolinamido)-N-cyclopropyl-6-(N,3,3-trimethylbutanamido)- lH-indole-3-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N,N-dimethyl-6-(N,3,3- trimethylbutanamido)- 1 H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-propyl-6-(N,3,3- trimethylbutanamido)- 1 H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(3-methoxy-N,3- dimethylbutanamido)-lH-indole-3-carboxamide;
2-(6-(lH-Pyrazol-4-yl)picolinamido)-N-methyl-6-(N- methylcyclohexanecarboxamido)-l H-indole-3 -carboxamide;
N-Cyclopropyl-6-(N-methylcyclohexanecarboxamido)-2-(5-(pyridin-4-yl)thiophene-2- carboxamido)-lH-indole-3-carboxamide;
N-(3-(Cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 2-(lH-pyrazol-4-yl)thiazole-4-carboxamide;
N-(3-(Cyclopropylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 2-(pyridin-4-yl)thiazole-4-carboxamide;
2-(4-(lH-Pyrazol-4-yl)benzamido)-N-cyclopropyl-6-(N-methylcyclohexane carboxamido)-lH-indole-3-carboxamide;
2-(6-(lH-Pyrazol-4-yl)picolinamido)-N-cyclopropyl-6-(N- methylcyclohexanecarboxamido)-l H-indole-3 -carboxamide; 2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-ethyl-6-(N- methylcyclohexanecarboxamido)- 1 H-indole-3 -carboxamide;
N-Ethyl-2-(5-(4-fluorophenyl)thiophene-2-carboxamido)-6-(N-methylcyclohexane carboxamido)- 1 H-indole-3 -carboxamide;
N-( -(Ethylcarbamoyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-2- (pyridin-4-yl)thiazole-4-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-6-(N- methylcyclohexanecarboxamido)-N-(2,2,2-trifluoroethyl)-lH-indole-3-carboxamide;
2-(5 -( 1 H-Pyrazol-4-yl)thiophene-2-carboxamido)-N-methyl-6-(N-methylbenzamido)- lH-indole-3-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylbenzamido)-l H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N- methylisonicotinamido)-lH-indole-3-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(4-fluoro-N- methylbenzamido)- 1 H-indole-3 -carboxamide;
2-(6-(lH-Pyrazol-4-yl)picolinamido)-N-cyclopropyl-6-(4-fluoro-N- methylbenzamido)-l H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-6-(4-fluoro-N-methylbenzamido)- N-methyl-1 H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-6-(4-fluoro-N-methylbenzamido)- N-ethyl-1 H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-6-(4-fluoro-N-methylbenzamido)- lH-indole-3-carboxamide;
(5,)-2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(N-methyl-2- morpholinopropanamido)- 1 H-indole-3 -carboxamide;
(5,)-2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-methyl-6-(N-methyl-2- morpholinopropanamido)- 1 H-indole-3 -carboxamide;
(5,)-2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-ethyl-6-(N-methyl-2- morpholinopropanamido)- 1 H-indole-3 -carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-methyl-6-(N-methyl-2- morpholinoacetamido)-lH-indole-3-carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-ethyl-6-(N-methyl-2- morpholinoacetamido)-lH-indole-3-carboxamide; N-Cyclopropyl-6-(3-hydroxy-N,3-dimethylbutanamido)-2-(picolinamido)-lH-indole-
3- carboxamide;
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-(3-hydroxy-N,3- dimethylbutanamido)-lH-indole-3-carboxamide;
N-( -(3 -Methoxypropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2 -yl)-2- methylthiazole-4-carboxamide;
N-( -(3 -Methoxypropyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)thiophene-2-carboxamide;
N-( -(3 -Methoxypropyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)thiazole-4-carboxamide;
N-( -(3 -Methoxypropyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-2- methylthiazole-4-carboxamide;
N-( -(3 -Methoxy-3 -methylbutyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)-2-methylthiazole-4-carboxamide;
N-( -(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-5 -( 1 H- pyrazol-4-yl)thiophene-2-carboxamide;
N-( -(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)thiophene-2-carboxamide;
N-( -(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-4- (trifluoromethyl)benzamide;
N-( J-(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-2- methylthiazole-4-carboxamide;
4-Cyano-N-(3 -(2-methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2- yl)benzamide;
N-( -(2-Methoxyethyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-4- (trifluoromethoxy)benzamide;
N-(3-(2-Amino-2-oxoethyl)-6-(N-methylcyclohexanecarboxamido)-l H-indol-2 -yl)-2- methylthiazole-4-carboxamide;
N-(3 -(2-Methoxyethyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-5 -( 1 H-pyrazol-
4- yl)thiophene-2-carboxamide;
N-( -(3 - Amino-3 -oxopropyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)- 2-(pyridin-4-yl)thiazole-4-carboxamide;
N-( -(3 -Amino-3 -oxopropyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2-yl)-
5- (pyridin-4-yl)thiophene-2-carboxamide; N-( -(3 -(Dimethylamino)-3 -oxopropyl)-6-(N-methylcyclohexanecarboxamido)- 1 H- indol-2-yl)-2-methylthiazole-4-carboxamide;
N- {3 -(3 -Amino-3 -oxopropyl)-6- [(eye lohexylcarbonyl)(methyl)amino] - 1 H-indol-2 - yl}thiophene-2-carboxamide;
N-( -(3 -Amino-3 -oxopropyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2 - yl)thiazole-4-carboxamide;
N-( -(3 -Amino-3 -oxopropyl)-6-(N-methylcyclohexanecarboxamido)- lH-indol-2-yl)- 2-methylthiazole-4-carboxamide;
N-( -(3 -Amino-3 -oxopropyl)-6-(N-methylcyclohexanecarboxamido)- 1 H-indol-2 - yl)picolinamide;
N-(3 -(3 -Amino-3 -oxopropyl)-6-(N-methylbenzamido)-lH-indol-2-yl)-2-(pyridin-4- yl)thiazole-4-carboxamide;
N-(3-(3-Amino-3-oxopropyl)-6-(4-fluoro-N-methylbenzamido)-lH-indol-2-yl)-2- (pyridin-4-yl)thiazole-4-carboxamide;
N-( -(3 - Amino-3 -oxopropyl)-6-(N-ethylisobutyramido)- 1 H-indol-2 -yl)-2-(pyridin-4- yl)thiazole-4-carboxamide;
N-(3 -(3 - Amino-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2 -yl)-2- methylthiazole-4-carboxamide;
N-( -(3 - Amino-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2-yl)-5 -( 1 H- pyrazol-4-yl)thiophene-2-carboxamide;
N-(3 -(3 -(Dimethylamino)-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2- yl)-5-(lH-pyrazol-4-yl)thiophene-2-carboxamide;
N-( -(3 -Amino-3 -oxopropyl)-6-(N-ethylacetamido)-lH-indol-2-yl)-5-(lH-pyrazol-4- yl)thiophene-2-carboxamide;
N-( -(3 - Amino-3 -oxopropyl)-6-(N-ethylisobutyramido)- 1 H-indol-2-yl)-5 -( 1 H- pyrazol-4-yl)thiophene-2-carboxamide;
N-(3-(3-(Dimethylamino)-3-oxopropyl)-6-(N-ethylacetamido)-lH-indol-2-yl)-5-(lH- pyrazol-4-yl)thiophene-2-carboxamide;
2-(6-(lH-Pyrazol-4-yl)picolinamido)-N-cyclopropyl-6-(N,3,3-trimethylbutanamido)- lH-indole-3-carboxamide;
N-( -(3 -(Dimethylamino)-3 -oxopropyl)-6-(N,3 ,3 -trimethylbutanamido)- 1 H-indol-2- yl)-[2,4'-bipyridine]-6-carboxamide;
N-( -(3- Amino-3 -oxopropyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)- 5-(lH-pyrazol-4-yl)thiophene-2-carboxamide; N-( -(3 - Amino-3 -oxopropyl)-6-(N-methylbenzamido)- 1 H-indol-2-yl)-5 -( 1 H-pyrazol- 4-yl)thiophene-2-carboxamide;
N-( -(3 -Amino-3 -oxopropyl)-6-(4-fluoro-N-methy lbenzamido)- 1 H-indol-2-yl)-5 -( 1H- pyrazol-4-yl)thiophene-2-carboxamide;
N-(3-(2-Cyanoethyl)-6-(N-methylcyclohexanecarboxamido)-lH-indol-2-yl)-5-(lH- pyrazol-4-yl)thiophene-2-carboxamide;
and pharmaceutically acceptable salts thereof.
23. A compound selected from
2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N-cyclopropyl-6-((N,3,3-trimethyl butanamido)methyl)- 1 H-indole-3 -carboxamide;
N-Cyclopropyl-2-(picolinamido)-6-((N,3,3-trimethylbutanamido)methyl)-lH-indole- 3 -carboxamide;
and pharmaceutically acceptable salts thereof.
24. A compound selected from
(5,)-2-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N3-cyclopropyl-N6-(3,3- dimethylbutan-2-yl)-N6-methyl-lH-indole-3,6-dicarboxamide;
N6-Cyclohexyl-N3-ethyl-N6-methyl-2-(thiophene-2-carboxamido)-lH-indole-3,6- dicarboxamide;
and pharmaceutically acceptable salts thereof.
25. A compound selected from
N2-Cyclohexyl-N6-cyclopropyl-N2-methyl-5-(thiazole-4-carboxamido)-4H-thieno[3,2- b]pyrrole-2,6-dicarboxamide;
N2-Cyclohexyl-N6-ethyl-N2-methyl-5-(thiazole-4-carboxamido)-4H-thieno[3,2- b]pyrrole-2,6-dicarboxamide;
5-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N2-cyclohexyl-N6-cyclopropyl-N2- methyl-4H-thieno[3,2-b]pyrrole-2,6-dicarboxamide;
N2-Cyclohexyl-N6-cyclopropyl-N2-methyl-5-(picolinamido)-4H-thieno[3,2-b]pyrrole- 2,6-dicarboxamide;
and pharmaceutically acceptable salts thereof.
A compound selected from 5-(5-(lH-Pyrazol-4-yl)thiophene-2-carboxamido)-N2-cyclohexyl-N4-cyclopropyl-N2- methyl-6H-thieno[2,3-b]pyrrole-2,4-dicarboxamide;
N2-Cyclohexyl-A^-cyclopropyl-5-(2-(dimethylamino)thiazole-4-carboxamido)-N2- methyl-6H-thieno[2,3-b]pyrrole-2,4-dicarboxamide;
N2-Cyclohexyl-A^-cyclopropyl-N2-methyl-5-(picolinamido)-6H-thieno[2,3-b]pyrrole- 2,4-dicarboxamide;
and pharmaceutically acceptable salts thereof.
A compound of the formula
Figure imgf000169_0001
or a pharmaceutically acceptable salt thereof.
A compound of the formula
Figure imgf000169_0002
or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 and a pharmaceutically acceptable excipient.
30. The pharmaceutical composition according to claim 29, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
31. A method of treating ITK mediated disease, disorder or syndrome in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 28.
32. A method of treatment of disorder or disease selected from the group consisting of respiratory disease, an allergic disease, an autoimmune disease, an inflammatory disorder, a proliferative disorder, diabetes, transplant rejection, graft versus host disease, HIV, aplastic anemia, and pain administering an effective amount of a compound according to any one of claims 1 to 28.
33. A method of treatment of disorder or disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, T cell mediated hypersensitivity, Guillain-Barre Syndrome, Hashimoto's thyroiditis, cancer, transplant rejection, graft versus host disease, conjunctivitis, contact dermatitis, inflammatory bowel disease, chronic inflammation, HIV, aplastic anemia, and inflammatory pain administering an effective amount of a compound according to any one of claims 1 to 28.
34. A method according to claim 33, wherein the disorder or disease is asthma or chronic obstructive pulmonary disease (COPD).
35. A method according to claim 33, wherein the disorder or disease is allergic rhinitis.
36. A method according to claim 33, wherein the disorder or disease is atopic dermatitis.
37. A method according to claim 33, wherein the disorder or disease is rheumatoid arthritis.
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