WO2016054807A1 - Inhibiteurs de la kinase trka, compositions en contenant et méthodes associées - Google Patents

Inhibiteurs de la kinase trka, compositions en contenant et méthodes associées Download PDF

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WO2016054807A1
WO2016054807A1 PCT/CN2014/088321 CN2014088321W WO2016054807A1 WO 2016054807 A1 WO2016054807 A1 WO 2016054807A1 CN 2014088321 W CN2014088321 W CN 2014088321W WO 2016054807 A1 WO2016054807 A1 WO 2016054807A1
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methyl
indol
acetamide
fluoro
phenyl
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PCT/CN2014/088321
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Andrew J. COOKE
Daniel Pitts
Adam Johnson
Douglas C. Beshore
Danielle Hurzy
Helen Mitchell
Mark Fraley
Casey Mccomas
Kathy Schirripa
Swati P. Mercer
Kausik Nanda
Dongfang Meng
Jane Wu
Kerim Babaoglu
Chun Sing Li
Qinghua MAO
Zhiqi QI
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Merck Sharp & Dohme Corp.
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Priority to PCT/CN2014/088321 priority Critical patent/WO2016054807A1/fr
Publication of WO2016054807A1 publication Critical patent/WO2016054807A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—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

Definitions

  • the invention is directed to a class of substituted indole compounds, their salts, pharmaceutical compositions comprising them and their use in therapy of the human body.
  • the invention is directed to a class of substituted indole compounds, which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.
  • Trk tropomyosin-related kinase
  • Trk's are high affinity binding protein kinase receptors that are activated by Neurotrophins (NT) , a group of soluble growth factors including Nerve Growth Factor (NGF) , Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin 3-5 (NT 3-5) .
  • the Trk's consist of three family members TrkA, TrkB and TrkC that bind to and mediate the signal transduction derived from the Neurotrophins.
  • NGF activates TrkA, BDNF and NT-4/5 activate TrkB and NT3 activates TrkC.
  • Inhibitors of the Trk/neutrophin pathway have been demonstrated to be highly effective in numerous pre-clinical animal models of pain.
  • Antagonistic NGF and TrkA antibodies have been shown to be efficacious in inflammatory and neuropathic pain animal models and in human clinical trials. See Woolf, C. J. et al. (1994) Neuroscience 62, 327-331; Zahn, P. K. et al. (2004) J. Pain 5, 157-163; McMahon, S. B. et al. , (1995) Nat. Med. 1, 774-780; Ma, Q. P. and Woolf, C. J. (1997) Neuroreport 8, 807-810; Shelton, D. L. et al.
  • TrkA-NGF interaction was found to be required for the survival of certain peripheral neuron populations involved in mediating pain signaling in the case of pancreatic cancer -an increase in the expression of TrkA was shown to correlate with an increase level of pain signaling (Zhu et al., Journal of Clinical oncology, 17: 2419-2428 (1999) ) .
  • Trk inhibitors that can induce apoptosis of proliferating osteoblast may be useful in treating diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis and bone metastases.
  • diseases related to an imbalance of the regulation of bone remodeling such as osteoporosis, rheumatoid arthritis and bone metastases.
  • the expression of TrkA and TrkC receptors in the bone forming area in mouse models of bone fracture and localization of NGF in almost all bone forming cells have been observed (K. Asaumi, et al. , Bone (2000) 26 (6) 625-633) . See also Exper. Opin. Ther.
  • Trk inhibitors in the treatment of inflammatory lung diseases such as asthma (Freund-Michel, V; et al. , Pharmacology &Therapeutics (2008) , 117 (1) , 52-76) , interstitial cystitis (Hu Vivian Y; et . al. , J of Urology (2005, 173 (3) , 1016-21) , inflammatory bowel disease including ulcerative colitis and Crohn's disease (Di Mola, F. F. , et al. , Gut (2000) , 46 (5) , 670-678 and inflammatory skin diseases such as atopic dermatitis (Dou, Y.C. , et. Al.
  • inflammatory lung diseases such as asthma (Freund-Michel, V; et al. , Pharmacology &Therapeutics (2008) , 117 (1) , 52-76)
  • interstitial cystitis Hu Vivian Y; et . al. , J of Urology (2005, 173 (3)
  • the compounds of the invention which are Trk inhibitors, are believed to be useful in the treatment of multiple types of acute and chronic pain including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery and bone fracture.
  • the compounds may also useful in the treatment of cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
  • the present invention is directed to compounds of generic formula (I) below or pharmaceutically acceptable salts thereof that are useful as a Trk mediator of NGF driven biological responses, an inhibitor of TrkA as well as other Tr kinases.
  • the invention is further directed to methods of treating a patient (preferably a human) for diseases or disorders in which the NGF receptor Tr kinases are involved, in particular TrkA.
  • the invention further involves use of the compounds as NGF receptor TrkA inhibitor and/or antagonist for the preparation of a medicament for the treatment and/or prevention of diseases associated with inhibiting TrkA, which includes pain, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, or a disease, disorder, or injury relating to dysmyelination or demyelination.
  • the invention is also directed to pharmaceutical compositions which include an effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.
  • the invention is directed to compounds of general formula (I)
  • R represents hydrogen, or -C1-6alkyl
  • R 1a , R 1b , R 1c , and R 2 are independently selected from the group consisting of hydrogen, CN, OH, -C1-6alkyl, and halogen;
  • R 3 is selected from the group consisting of (CHR) n C 6-10 aryl and a nitrogen containing (CHR) n C 5-10 heterocycle, said aryl, and heterocycle optionally substituted with 1 to 3 groups of R a ,
  • R 4 is selected from the group consisting of C 3-7 cycloalkyl, C 3-7 cycloalkenyl, phenyl and C 5- 10 heteroaryl, said phenyl and heteroaryl optionally substituted with 1 to 3 groups of R x ; or R 2 and R 4 can combine together with the carbon atoms to which they are attached to form a C 9- 12 membered bicyclic ring optionally interrupted with 1 to 4 heteroatoms selected from O, S, and N, said combination resulting in a C 16-19 membered tetracyclic ring structure containing at least one nitrogen atom;
  • Ra is selected from the group consisting of hydrogen, –CN, halogen, -C 1-4 haloalkyl, -C 1- 6 alkyl, -OC 1-6 alkyl, -OC 4-10 heterocycle, OH, -O-, C (O) N (R) 2 , - (CHR) n C 6-10 aryl, (CHR) n C 4-10 heterocycle, - (CH 2 ) n C (O) NHC 4-10 heterocycle, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b ;
  • R x is selected from the group consisting of halogen and -C 1-6 alkyl; and n represents 0-4.
  • An embodiment of the invention of formula I is realized when R is hydrogen.
  • An embodiment of the invention of formula I is realized when R is -C 1-6 alkyl.
  • An embodiment of the invention of formula I is realized when one or more of R 1a , R 1b , and R 1c is halogen.
  • a subembodiment of this aspect of the invention is realized when one of R 1a , R 1b , and R 1c is halogen.
  • Another subembodiment of this aspect of the invention is realized when two of R 1a , R 1b , and R 1c is halogen.
  • Another subembodiment of this aspect of the invention is realized when the halogen of R 1a , R 1b , and R 1c is selected from the group consisting fluoro, bromo, or chloro or a mixture thereof.
  • R 1a , R 1b , and R 1c are fluoro. Still another subembodiment of this aspect of the invention is realized when one of R 1a , R 1b , and R 1c is bromo. Yet another subembodiment of this aspect of the invention is realized when one of R 1a , R 1b , and R 1c is chloro.
  • R 1a , R 1b , and R 1c is hydrogen.
  • a subembodiment of this aspect of the invention is realized when one of R 1a , R 1b , and R 1c is halogen and the others are hydrogen.
  • Another embodiment of the invention of formula I is realized when one of R 1a , R 1b , and R 1c is CN.
  • Still another embodiment of the invention of formula I is realized when one of R 1a , R 1b , and R 1c is OH.
  • Yet another embodiment of the invention of formula I is realized when one or more of R 1a , R 1b , and R 1c is -C 1-6 alkyl. Yet another embodiment of the invention of formula I is realized when one of R 1a , R 1b , and R 1c is -C 1-6 alkyl and the others are hydrogen.
  • R 2 is halogen.
  • a subembodiment of this aspect of the invention is realized when R 2 is fluoro, bromo, or chloro or a mixture thereof.
  • Another subembodiment of this aspect of the invention is realized when R 2 is fluoro.
  • Still another subembodiment of this aspect of the invention is realized when R 2 is bromo.
  • Yet another subembodiment of this aspect of the invention is realized when R 2 is chloro.
  • Still another embodiment of the invention of formula I is realized when R 2 is OH.
  • Another embodiment of the invention of formula I is realized when R 3 is (CHR) n C 6-10 aryl.
  • a further aspect of this aspect of the invention is realized when R 3 is substituted (CHR) n phenyl.
  • a further aspect of this aspect of the invention is realized when R 3 is unsubstituted (CHR) n phenyl.
  • a further aspect of this aspect of the invention is realized when R 3 is substituted (CHR) n napthyl.
  • a further aspect of this aspect of the invention is realized when R 3 is unsubstituted (CHR) n napthyl.
  • R 3 is an unsubstituted or substituted nitrogen containing (CHR) n C 5-10 heterocycle.
  • Another embodiment of the invention of formula I is realized when R 3 is a substituted nitrogen containing (CHR) n C 5-10 heterocycle.
  • a subembodiment of this aspect of the invention is realized when the heterocycle of R 3 is selected from the group consisting of unsubstituted or substituted pyridyl, pyridazinyl, oxoisoindolinyl, oxodihydropyridinyl, and benzimidazolyl.
  • heterocycle of R 3 is selected from the group consisting of substituted pyridyl, pyridazinyl, oxoisoindolinyl, oxodihydropyridinyl, and benzimidazolyl. Still another subembodiment of this aspect of the invention is realized when the heterocycle of R 3 is substituted pyridyl. Another subembodiment of this aspect of the invention is realized when the heterocycle of R 3 is substituted pyridazinyl. Another subembodiment of this aspect of the invention is realized when heterocycle of R 3 is substituted benzimidazolyl.
  • Another embodiment of the invention of formula I is realized when R 4 is unsubstituted or substituted phenyl.
  • a subembodiment of this aspect of the invention is realized when R 4 is unsubstituted phenyl.
  • Another subembodiment of this aspect of the invention is realized when R 4 is substituted phenyl.
  • Another embodiment of the invention of formula I is realized when R 4 is unsubstituted or substituted C 5-10 heteroaryl.
  • a subembodiment of this aspect of the invention is realized when R 4 is unsubstituted (CHR) n C 5-10 heteroaryl.
  • Another subembodiment of this aspect of the invention is realized when R 4 is substituted C 5-10 heteroaryl.
  • Still another subembodiment of this aspect of the invention is realized when R 4 is selected from the group consisting of unsubstituted or substituted oxazolyl, thiophenyl, pyrazolyl, triazolyl, isothiazolyl, thiazolyl, pyridyl, oxadiazolyl, and thiadiazolyl.
  • R 4 is selected from the group consisting of unsubstituted oxazolyl, thiophenyl, pyrazolyl, triazolyl, isothiazolyl, thiazolyl, pyridyl, oxadiazolyl, and thiadiazolyl.
  • R 4 is selected from the group consisting of substituted oxazolyl, thiophenyl, pyrazolyl, triazolyl, isothiazolyl, thiazolyl, pyridyl, oxadiazolyl, and thiadiazolyl. Yet another subembodiment of this aspect of the invention is realized when R 4 is substituted oxazolyl. Yet another subembodiment of this aspect of the invention is realized when R 4 is unsubstituted or substituted thiophenyl. Yet another subembodiment of this aspect of the invention is realized when R 4 is substituted pyrazolyl.
  • Another embodiment of the invention of formula I is realized when R 2 and R 4 combine together with the carbon atoms to which they are attached to form a C 9-12 membered bicyclic ring optionally interrupted by 1 to 4 heteroatoms selected from O, S, and N, said combination resulting in a C 16-19 membered tetracyclic ring structure containing at least one nitrogen atom.
  • a subembodiment of this aspect of the invention is realized when R 2 and R 4 combine together with the carbon atoms to which they are attached to form pyrazolopyridoindolyl.
  • R a is selected from the group consisting of –CN, halogen, -CF 3 , -CF 2 , -C 1-6 alkyl, -OC 1-6 alkyl, OH, phenyl, -(CHR) n C 4-10 heterocycle, and - (CH 2 ) n C (O) NHC 4-10 heterocycle, wherein the heterocycle is pyranyl, dihydropyranyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, or pyrrolopyridinyl, said alkyl, phenyl, and heterocycle optionally substituted with 1 to 3 groups of R b .
  • R a is substituted with 1 to 3 groups of R b .
  • R a is selected from the group consisting of hydrogen, CN, chloro, bromo, fluoro, methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, and optionally substituted phenyl, pyranyl, dihydropyranyl, pyridyl, C (O) NHpyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, dioxido- benzoisothiazolyl, dioxido-dihydrobenzoisothiazolyl, oxo-benzooxazolyl, oxo- dihydrobenzooxazolyl, tetrahydropyridyl, and pyrrolopyridinyl
  • R 3 is substituted with at least one Ra selected from unsubstituted or substituted phenyl.
  • a subembodiment of this aspect of the invention is realized when R 3 is substituted with one R a which is substituted phenyl.
  • R 3 is substituted with at least one R a which is unsubstituted or substituted pyridyl.
  • R a which is substituted pyridyl.
  • Another embodiment of the invention of formula I is realized when R x is halogen. Another embodiment of the invention of formula I is realized when R x is -C 1-6 alkyl.
  • Another embodiment of the invention of formula I is realized when R 1a , R 1b , R 1c , and R 2 are hydrogen. Another embodiment of the invention of formula I is realized when at least one of R 1a , R 1b , and R 1c is halogen and R 2 is hydrogen. Still another embodiment of the invention of formula I is realized when R 1a , R 1b , and R 1c are hydrogen and R 2 is halogen. Yet another embodiment of the invention of formula I is realized when one of R 1a , R 1b , and R 1c is halogen and R 2 is halogen.
  • R 1 is R 1a , and R 3 and R 4 are as originally described.
  • a subembodiment of the invention of formula I” is realized when R 4 is selected from the group consisting of unsubstituted or substituted phenyl, thiophenyl, oxazolyl, pyrazolyl, triazolyl, isothiazolyl, thiazolyl, pyridyl, thiadiazolyl, and oxadiazolyl.
  • R 3 is selected from the group consisting of substituted (CHR) n phenyl, (CHR) n pyridyl, (CHR) n pyridazinyl, and (CHR) n benzimidazolyl.
  • R 3 is substituted (CHR) n pyridyl.
  • Still another subembodiment of the invention of formula I” is realized when the phenyl or heterocycle of R 3 is substituted with 1 to 3 groups of R a selected from the group consisting of –CN, halogen, -CF 3 , -CF 2 , -C 1-6 alkyl, -OC 1-6 alkyl, OH, phenyl, -(CHR) n C 4-10 heterocycle, and - (CH 2 ) n C (O) NHC 4-10 heterocycle, wherein the heterocycle is pyranyl, dihydropyranyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, tetrahydropyridyl, or pyrrolopyridinyl, said alkyl, phenyl, and heterocycle optionally substituted with 1 to 3 groups of R b .
  • R a selected from the group consisting of –CN, halogen, -CF 3 , -CF
  • Still another subembodiment of the invention of formula I” is realized when R a is selected from the group consisting of -C 1-6 alkyl, CN, and unsubstituted or substituted phenyl, and pyridyl. Yet another subembodiment of the invention of formula I” is realized when R a is substituted phenyl or pyridyl. Another subembodiment of the invention of formula I” is realized when R1 is hydrogen or halogen.
  • R 1 is R 1a
  • R a and R 4 are as originally described.
  • a subembodiment of the invention of formula I ⁇ is realized when R 4 is selected from the group consisting of unsubstituted or substituted phenyl, thiophenyl, oxazolyl, pyrazolyl, triazolyl, isothiazolyl, thiazolyl, pyridyl, thiadiazolyl, and oxadiazolyl.
  • Another subembodiment of the invention of formula I ⁇ is realized when R 4 is unsubstituted or substituted thiophenyl.
  • Another subembodiment of the invention of formula I ⁇ is realized when R 4 is unsubstituted or substituted oxazolyl. Another subembodiment of the invention of formula I ⁇ is realized when R 4 is unsubstituted or substituted pyrazolyl. Another subembodiment of the invention of formula I ⁇ is realized when R 4 is unsubstituted or substituted triazolyl.
  • Still another subembodiment of the invention of formula I ⁇ is realized when Ra selected from the group consisting of –CN, halogen, -CF 3 , -CF 2 , -C 1-6 alkyl, -OC 1-6 alkyl, OH, phenyl, - (CHR) n C 4-10 heterocycle, and - (CH 2 ) n C (O) NHC 4-10 heterocycle, wherein the heterocycle is pyranyl, dihydropyranyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, tetrahydropyridyl, or pyrrolopyridinyl, said alkyl, phenyl, and heterocycle optionally substituted with 1 to 3 groups of R b .
  • Still another subembodiment of the invention of formula I ⁇ is realized when R a is selected from the group consisting of -C 1-6 alkyl, CN, and unsubstituted or substituted phenyl, and pyridyl. Yet another subembodiment of the invention of formula I ⁇ is realized when R a selected from the group consisting of substituted phenyl or pyridyl. Yet another subembodiment of the invention of formula I ⁇ is realized when R a selected from the group consisting of substituted phenyl. Yet another subembodiment of the invention of formula I ⁇ is realized when R a selected from the group consisting of substituted pyridyl.
  • R 1 is R 1a
  • R x and R 3 are as originally described.
  • a subembodiment of the invention of formula (aa) is realized when R 3 is selected from the group consisting of unsubstituted or substituted (CHR) n phenyl, (CHR) n pyridyl, (CHR) n pyridazinyl, and (CHR) n benzimidazolyl.
  • Another embodiment of the invention of formula I is represented by structural formulas (a), (b) , (c) , (d) , (e) , (f) , (g) , (h) , or (i) :
  • R 1 is R 1a
  • R x and R 3 are as originally described.
  • An embodiment of the invention of formula I as represented by structural formula (a) , (b) , (c), (d) , (e) , (f) , (g) , (h) , (i) is realized when R 1 is selected from hydrogen and halogen, R x is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, or butyl and R 3 is selected from the group consisting of substituted (CHR) n phenyl, (CHR) n pyridyl, (CHR) n pyridazinyl, and (CHR) n benzimidazolyl.
  • R 3 is (CHR) n pyridyl substituted with 1 to 3 groups of R a selected from the group consisting of –CN, halogen, -CF 3 , -CF 2 , -C 1- 6 alkyl, -OC 1-6 alkyl, OH, phenyl, - (CHR) n C 4-10 heterocycle, and - (CH 2 ) n C (O) NHC 4-10 heterocycle, wherein the heterocycle is pyranyl, dihydropyranyl, pyridyl, pyrimidinyl, isoxazolyl, pyrazolyl, tetrahydropyridyl, or pyrrolopyridinyl, said alkyl, phenyl, and heterocycle unsubstituted or
  • Still another subembodiment of the invention of structural formula (a) , (b) , (c) , (d) , (e) , (f), (g) , (h) , or (i) is realized when Ra is selected from the group consisting of -C 1-6 alkyl, CN, and unsubstituted or substituted phenyl, and pyridyl.
  • Yet another subembodiment of the invention of structural formula (a) , (b) , (c) , (d) , (e) , (f) , (g) , (h) , or (i) is realized when R b is SOCH 3 .
  • Still another embodiment of the invention of formula I as represented by structural formula (a) , (b) , (c) , (d) , (e) , (f) , (g) , (h) , (i) is realized when R 1 is selected from hydrogen and halogen, R x is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, or butyl, and R 3 is (CHR) n pyridyl substituted with 1 to 3 groups of R a selected from the group consisting of –CN, halogen, -CF 3 , -CF 2 , -C 1-6 alkyl, -OC 1-6 alkyl, OH, phenyl, - (CHR) n C 4-10 heterocycle, and - (CH 2 ) n C (O) NHC 4-10 heterocycle, wherein the heterocycle is pyranyl, dihydropyranyl, pyridyl, pyrimidinyl
  • Another subembodiment of this aspect of the invention is realized when the invention of formula I is represented as structural formula (g) .
  • Another subembodiment of this aspect of the invention is realized when the invention of formula I is represented as structural formula (h) .
  • Another subembodiment of this aspect of the invention is realized when the invention of formula I is represented as structural formula (I) .
  • R 1 is R 1a and R 3 are as originally described.
  • An embodiment of the invention of structural formulas (j) and (k) is realized when R 1 is selected from hydrogen and halogen and R 3 is selected from the group consisting of unsubstituted or substituted (CHR) n phenyl, (CHR) n pyridyl, (CHR) n pyridazinyl, and (CHR) n benzimidazolyl.
  • the invention is also directed to methods of treating a patient (preferably a human) for diseases or disorders in which the TrkA receptor is involved, such as pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • diseases or disorders in which the TrkA receptor is involved such as pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA
  • the invention is also directed to the use of a compound of the invention for treating a disease or disorder in which the TrkA receptor is involved, such as pain, inflammation, cancer,restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA, by administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • a disease or disorder in which the TrkA receptor is involved such as pain, inflammation, cancer,restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA
  • the invention is also directed to medicaments or pharmaceutical compositions for the treatment of diseases or disorders in a patient (preferably a human) in which the TrkA receptor is involved, such as pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA, which comprise a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • NGF nerve growth factor
  • the invention is also directed to a method for the manufacture of a medicament or a pharmaceutical composition for treating diseases in which TrkA receptor is involved, such as pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA comprising combining a compound of the inventionor a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • NGF nerve growth factor
  • variable occurs more than once in any formula of the invention, or in a substituent thereof, the individual occurrences of that variable are independent of each other, unless otherwise specified. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl by itself or as part of another substituent, means a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g. , C 1-10 alkyl means an alkyl group having from one to ten carbon atoms) .
  • Preferred alkyl groups for use in the invention are C 1-6 alkyl groups, having from one to six atoms.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
  • C 0 alkyl means a bond.
  • alkenyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon double bond and the number of carbon atoms designated (e.g. , C 2-10 alkenyl means an alkenyl group having from two to ten carbon atoms) .
  • Preferred alkenyl groups for use in the invention are C 2-6 alkenyl groups, having from two to six carbon atoms.
  • Exemplary alkenyl groups include ethenyl and propenyl.
  • cycloalkyl by itself or as part of another substituent, means a saturated cyclic hydrocarbon radical having the number of carbon atoms designated (e.g., C 3-12 cycloalkyl means a cycloalkyl group having from three to twelve carbon atoms) .
  • the term cycloalkyl as used herein includes mono-, bi-and tricyclic saturated carbocycles, spirocycles, and bridged and fused ring carbocycles as well as oxo substituted cycloalkyl groups.
  • Preferred cycloalkyl groups for use in the invention are monocyclic C 3-8 cycloalkyl groups, having from three to eight carbon atoms.
  • Exemplary monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Exemplary bridged cycloalkyl groups include adamantyl and norbornyl.
  • Exemplary fused cycloalkyl groups include decahydronaphthalene.
  • heteroatom means O, S or N, selected on an independent basis.
  • aryl by itself or as part of another substituent, means an aromatic cyclic hydrocarbon radical. Preferred aryl groups have from six to ten carbons atoms. The term “aryl” includes multiple ring systems as well as single ring systems. Preferred aryl groups for use in the invention include phenyl and naphthyl.
  • aryl also includes fused cyclic hydrocarbon rings which are partially aromatic (i.e. , one of the fused rings is aromatic and the other is non-aromatic) .
  • An exemplary aryl group which is partially aromatic is indanyl.
  • heterocyclyl, heterocycle or heterocyclic represents a stable 5-to 7-membered monocyclic or stable 8-to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclyl, heterocycle or heterocyclic includes heteroaryl moieties.
  • heterocyclic elements include, but are not limited to, azepinyl, benzodioxolyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzotriazolyly, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1, 3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolyl
  • heteroaryl represents a stable 5-to 7-membered monocyclic-or stable 9-to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole,
  • Suitable heteroaryl groups are imidazopyridinyl, indazolyl, imidazothiazolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazothiadiazolyl, quinoxalinyl, and imidazopyrrolyl.
  • the substituent When a heterocyclyl group as defined herein is substituted, the substituent may be bonded to a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e. , a nitrogen, oxygen or sulfur) , which has a valence which permits substitution. Preferably, the substituent is bonded to a ring carbon atom.
  • the point of attachment may be at a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e. , a nitrogen, oxygen or sulfur) , which has a valence which permits attachment.
  • the attachment is at a ring carbon atom.
  • halo or halogen includes fluoro, chloro, bromo and iodo.
  • oxo e.g. , an annular -CH-substituted with oxo is -C (O) or carbonyl; or nitrogen atom substituted with oxo is N-oxide
  • the compounds of the invention may have one or more asymmetric centers.
  • Compounds with asymmetric centers give rise to enantiomers (optical isomers) , diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention.
  • the present invention is meant to encompass all such isomeric forms of the compounds of the invention.
  • the present invention includes all stereoisomers of formulae (I) and pharmaceutically acceptable salts thereof.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers or diastereomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art.
  • any enantiomer or diastereomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic formulae (I) .
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H) .
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic formulae (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • substantially pure means that the isolated material is at least 90%pure, and preferably 95%pure, and even more preferably 99%pure as assayed by analytical techniques known in the art.
  • Trk refers to one of Trk's high affinity binding protein kinase receptors that are activated by Neurotrophins (NT) , a group of soluble growth factors Nerve Growth Factor (NGF) , Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin 3-5 (NT 3-5) .
  • the Trk's are made up of three family members TrkA, TrkB and TrkC that bind to and mediate the signal transduction derived from the Neurotrophins. Inhibitors of the Trk/neutrophin pathway have been demonstrated to be highly effective in numerous pre-clinical animal models of pain.
  • the compounds of the invention are modulators of the Trk receptors, particularly TrkA.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • the compounds of the invention may be mono, di or tris salts, depending on the number of acid functionalities present in the free base form of the compound.
  • Free bases and salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethyl
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, para-toluenesulfonic acid, and the like.
  • the present invention is directed to the use of the compounds of formulae (I) disclosed herein as TrkA inhibitors in a patient or subject such as a mammal in need of such activity, comprising the administration of an effective amount of the compound.
  • TrkA inhibitors in a patient or subject such as a mammal in need of such activity, comprising the administration of an effective amount of the compound.
  • a variety of other mammals can be treated according to the method of the present invention.
  • the compounds of the present invention have utility in treating or ameliorating pain disorders (including pain associated with cancer, surgery, and bone fracture, acute pain, inflammatory pain and neuropathic pain) .
  • the compounds of formula I are also useful for treating cancers including neuroblastoma, ovarian, pancreatic and colorectal cancer.
  • Other conditions that may be treated by the compounds of the invention include inflammation and certain infectious diseases, interstitial cystitis, painful bladder syndrome, urinary incontinence, asthma, anorexia, atopic dermatitis, and psoriasis.
  • Treatment of demyelination and dysmyelination, by promoting myelination, neuronal survival, and oligodendrocyte differentiation via blocking Sp35-TrkA interaction may also be possible with the compounds of the present invention.
  • the compounds of formula I may also be useful in the treatment of bone-related diseases (e.g. , those involved in bone resorption) .
  • bone-related diseases include metastatic bone disease, treatment-induce bone loss, osteoporosis, rheumatoid arthritis, ankylosing spondylitis, Paget's disease, and periodontal disease.
  • Another bone disorder or disease that can be treated with the compounds of the claimed invention is metastatic tumor-induced osteolysis.
  • Cancers known to cause tumor induced osteolysis are hematological malignancies such as myeloma and lymphoma and solid tumors such as breast, prostate, lung, renal and thyroid.
  • Pain disorders for which the compounds of the invention may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias” , e.g. , vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy) ; central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system) ; postsurgical pain syndromes (e.g., postmastectomy syndrome, postthoracotomy syndrome, stump pain) ; bone and joint pain (osteoarthritis) , repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia) ; perioperative pain (general surgery, gynecological) , chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g.
  • osteoarthritis rheumatoid arthritis, rheumatic disease, teno-synovitis and gout
  • headache migraine and cluster headache
  • headache primary hyperalgesia
  • secondary hyperalgesia primary allodynia
  • secondary allodynia secondary allodynia
  • Compounds of the invention may also be used to treat or prevent dyskinesias. Furthermore, compounds of the invention may be used to decrease tolerance and/or dependence to opioid treatment of pain, and for treatment of withdrawal syndrome of e.g. , alcohol, opioids, and cocaine.
  • an aspect of the present invention is a method of treating diseases with an inhibitor of TrkA and/or TrkB comprising administering to said mammal one or more compounds of formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent said disorder.
  • a particular aspect of the invention is directed to a method of treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection by administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • Still another aspect of the present invention is directed to a method of treating osteolytic disease in a mammal by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • mammals include dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which treatment of the above noted disorders is desired.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
  • combinations of the compounds include combinations with agents for the treatment of pain, for example steroids such as dexamethasone, cortisone, and fluticasone, non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib and valdecoxib; CB-2 agonists; VR-1 antagonists; bradykinin B l receptor antagonists; sodium channel blockers and antagonists; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors) ; glycine site antagonists, including lacosamide; neuronal nicotinic agonists; NMDA antagonists
  • a GABA-A receptor agonist a GABA-A receptor agonist
  • matrix metalloprotease (MMP) inhibitors thrombolytic agents
  • chemotherapeutic agents opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene
  • neutrophil inhibitory factor (NIF) pramipexole, ropinirole
  • anticholinergics amantadine; monoamine oxidase Bl5 ( "MAO-B” ) inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists; alpha agonists; neuronal nicotinic agonists; NMDA receptor agonists or antagonists; NKI antagonists; selective serotonin reuptake inhibitors ( "SSRI” ) and/or selective serotonin and norepinephrine reuptake inhibitors
  • Another aspect of the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • Still another aspect of the present invention is directed to a compound of formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition treatable with an inhibitor of TrkA and/or TrkB, such as the disorders, conditions and/or diseases described herein.
  • Still another aspect is directed to use of a compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of pain, cancer, inflammation, neurodegenerative disease or typanosoma cruzi infection.
  • an embodiment of the instant invention relates to a method of treating a patient diagnosed with a cancer having a dysregulation of TrkA, comprising administering to the patient a therapeutically effective amount of a compound of formula I.
  • a sub-embodiment of this aspect of the invention is realized when the dysregulation of TrkA comprises overexpression of wild-type TrkA (autocrine activation) .
  • Another sub-embodiment of this aspect of the invention is realized when the dysregulation of TrkA comprises one or more chromosome translocations or inversions resulting in TrkA gene fusions.
  • Another sub-embodiment of this aspect of the invention is realized when the dysregulation of TrkA comprises one or more deletion, insertions or mutations in the TrkA protein. Another sub-embodiment of this aspect of the invention is realized when the dysregulation of TrkA comprises a deletion of one or more residues from the TrkA protein, resulting in constitutive activity of TrkA kinase. Another sub-embodiment of this aspect of the invention is realized when the dysregulation of TrkA comprises a splice variation in which the expressed protein is an alternatively spliced variant of TrkA having one or more residues deleted resulting in constitutive activity of TrkA kinase.
  • TrkA The dysregulation of TrkA has been shown to be involved with cancers such as neuroblastoma (Brodeur, G. M. , Nat. Rev. Cancer 2003, 3, 203-216) , ovarian (Davidson. B. , et al. , Clin. Cancer Res. 2003, 9, 2248-2259) , colorectal cancer (Bardelli, A. , Science 2003, 300, 949) , melanoma (Truzzi, F. , et al. , Dermato-Endocrinology 2008, 3 (1) , pp. 32-36) , head and neck cancer (Yilmaz, T. , et al. , Cancer Biology and Therapy 2010, 10 (6) , pp.
  • cancers such as neuroblastoma (BrBank, G. M. , Nat. Rev. Cancer 2003, 3, 203-216) , ovarian (Davidson. B. , et al. , Clin. Cancer Res. 2003, 9, 2248-2259) , colorec
  • non-small cell lung cancer (Vaishnavi et al. , 2013: Nature Medicine 19, 1469-1472) ; large cell neuroendocrine carcinoma (Marchetti et al. , 2008: Human Mutation 29 (5) : 609-616) ; prostate carcinoma (Papatsoris et al. , 2007, Expert Opinion on Inves. Drugs 16 (3) : 303-309) ; and pancreatic carcinoma (Zhang et al. , 2005, Oncology Reports 14: 161-171) .
  • Non-selective inhibitors of TrkA, B and C were also found to be effective in hindering tumor growth and stopping tumor metastasis in preclinical models of cancer (Nakagawara, A. (2001) Cancer Letters 169: 107-114; and Eric Adriaenssens, E. , et al., Cancer Res (2008) 68: (2) pgs. 346-351.
  • a method of treating a patient diagnosed with a cancer having a dysregulation of TrkA comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof is realized.
  • a method of treating a patient diagnosed with a cancer selected from the group consisting of non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.
  • the compounds of formula I are useful for treating cancer in combination with one or more additional therapeutic agents.
  • additional therapeutic agents are selected from the group consisting of receptor tyrosine kinase-targeted therapeutic agents, including cabozantinib, crizotinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, pertuzumab, regorafenib, sunitinib, and trastuzumab.
  • the additional therapeutic agents are selected from signal transduction pathway inhibitors, including sorafenib, trametinib, vemurafenib, everolimus, rapamycin, perifosine, temsirolimus and obataclax.
  • signal transduction pathway inhibitors including sorafenib, trametinib, vemurafenib, everolimus, rapamycin, perifosine, temsirolimus and obataclax.
  • the additional therapeutic agents are selected from cytotoxic chemotherapeutics, including arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.
  • cytotoxic chemotherapeutics including arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubi
  • Another subembodiment of this aspect of the invention is realized when the additional therapeutic agents are selected from angiogenesis-targeted therapies, including aflibercept and bevacizumab.
  • Another subembodiment of this aspect of the invention is realized when the additional therapeutic agents are selected from immune-targeted agents, including aldesleukin, ipilimumab, lambrolizumab, nivolumab, and sipuleucel-T.
  • immune-targeted agents including aldesleukin, ipilimumab, lambrolizumab, nivolumab, and sipuleucel-T.
  • Another subembodiment of this aspect of the invention is realized when the additional therapeutic agents are selected from agents active against the TrkA pathway, including NGF-targeted biopharmaceuticals such as NGF antibodies and pan Trk inhibitors.
  • NGF-targeted biopharmaceuticals such as NGF antibodies and pan Trk inhibitors.
  • the additional therapeutic agent or therapy is radiotherapy, including radioiodide therapy, external-beam radiation and radium 223 therapy.
  • Another embodiment of the invention is realized by a method of treating cancer in a patient comprising administering to said patient a compound of formula I or a pharmaceutically acceptable salt thereof in combination with at least one of the additional therapies or therapeutic agents disclosed herein.
  • the additional therapeutic agents may be administered with one or more compounds of formula I as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules.
  • compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof in combination with at least one of the additional therapies or therapeutic agents disclosed herein and optionally at least one pharmaceutically acceptable carrier.
  • composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active compound which is a compound of formulae (I)
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. , oral or parenteral (including intravenous) .
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
  • compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, or in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt%to about 10 wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can also be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual’s body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
  • oral dosage forms such as tablets, capsules, syrups, suspensions, and the like
  • injectable dosage forms such as IV, IM, or IP, and the like
  • transdermal dosage forms including creams, jellies, powders, or patches
  • buccal dosage forms inhalation powders, sprays, suspensions, and the like
  • rectal suppositories rectal suppositories.
  • an effective amount or “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e. , arresting further development of the pathology and/or symptomatology) , or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e. , reversing the pathology and/or symptomatology) .
  • compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages.
  • Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
  • compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient.
  • kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1, 400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of active agent, compounded with an appropriate and convenient amount of carrier material.
  • Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the active ingredient, typically 0.005, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.
  • the compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions hereinabove. Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the schemes and examples herein, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
  • any of the synthetic sequences it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973, and T. W. Greene &P/G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley &Sons, 1999.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the final product may be further modified, for example, by manipulation of substituents.
  • substituents may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
  • CDI 1, 1'-carbonyldiimidazole
  • BINAP 2, 2'-bis (diphenylphosphino) -1, 1'-binaphthalene
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethyluronium hexafluorophosphate
  • EDTA ethylenediaminetetraacetic acid
  • HMDS hexamethyldisilazane
  • NBS N-bromosuccinimide
  • DIBAL diisobutylaluminum hydride
  • AOP 7- (azabenzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate
  • PE petroleum ether
  • TIPS triisopropylsilyl
  • DIAD diisopropyl azodicarboxylate
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • Scheme 1 illustrates a general strategy for preparing the compounds of the present invention in which an carboxylic acid intermediate (1.1) may be activated via EDC followed by coupling to an amine (1.2) to give the desired product amide 1.3.
  • carboxylic acid intermediates such as those described herein (vide infra)
  • Scheme 2 illustrates a method of preparing the compounds of the present invention in which cross-coupling of bromide 2.1 with an aryl or heteroarylboronic ester 2.2 (or other suitable intermediate such as a boronic acid, potassium trifluoroborate, stannane, Grignard, organozinc, etc. ) is mediated by heating in an aqueous solvent mixture in the presence of a suitable catalyst and base system (e.g. , Pd (PPh 3 ) 4 and Na 2 CO 3 ) to furnish amide 1.3.
  • a suitable catalyst and base system e.g. , Pd (PPh 3 ) 4 and Na 2 CO 3
  • Scheme 3 illustrates a method of preparing the compounds of the present invention in which bromide 2.1 is converted to the aryl or heteroarylboronic ester 3.2 (or other suitable intermediate) by heating with bis (pinacolato) diboron (3.1) in the presence of a suitable catalyst and base system (e.g. , XPHOS and KOAc) to furnish 3.2.
  • a suitable catalyst and base system e.g. , XPHOS and KOAc
  • Schemes 4 through 9 illustrate the preparation of the carboxylic acid intermediates of the type 1.1 which are used to prepare compounds of the invention as described above. More specifically, Scheme 4 illustrates a method to prepare intermediates of the type 4.6. Indole acid 4.1 is converted to the acid chloride by exposure to oxalyl chloride and DMF, followed by heating with triazole 4.2 and base in sulfolane to effect rearrangement to oxazole 4.3. Alkylation of indole 4.3 with methyl chloroacetate and cesium carbonate provides ester 4.5. Saponification of the ester then affords carboxylic acid 4.6.
  • Scheme 5 illustrates a method of preparing carboxylic acids of the type 5.5 via cross-coupling of indole boronic ester 5.1 with iodide 5.2 (or other suitable intermediate such as an aryl or heteroaryl bromide, chloride, triflate, etc. ) mediated by heating in an aqueous solvent mixture in the presence of a suitable catalyst and base system (e.g. , Pd (PPh 3 ) 2 Cl 2 and Na 2 CO 3 ) to furnish indole 5.3.
  • a suitable catalyst and base system e.g. , Pd (PPh 3 ) 2 Cl 2 and Na 2 CO 3
  • Scheme 6 illustrates a method of preparing carboxylic acids of the type 6.6 via cross-coupling of indole boronic ester 6.1 with bromide 6.2 (or other suitable intermediate) mediated by heating in an aqueous solvent mixture in the presence of a suitable catalyst and base system (e.g. , Pd (PPh 3 ) 2 Cl 2 and Na 2 CO 3 ) to furnish indole 6.3.
  • a suitable catalyst and base system e.g. , Pd (PPh 3 ) 2 Cl 2 and Na 2 CO 3
  • Scheme 7 illustrates a method of preparing carboxylic acids of the type 7.8. Protection of indole 7.1 with di-tert-butyl dicarbonate in the presence of DMAP, followed by lithiation with LDA at low temperature and treatment of the anion with CBr 4 affords bromide 7.3. Cross-coupling of indole bromide 7.3 with boronic acid 7.4 (or other suitable intermediate) is mediated by heating in an aqueous solvent mixture in the presence of a suitable catalyst and base system (e.g. , Pd (PPh 3 ) 4 and Na 2 CO 3 ) to furnish indole 7.5. Removal of the Boc group is effected under acidic conditions (TFA in DCM) to afford 7.6. Alkylation of 7.6 and saponification of the intermediate ester 7.7 provides carboxylic acid 7.8.
  • a suitable catalyst and base system e.g. , Pd (PPh 3 ) 4 and Na 2 CO 3
  • Scheme 8 illustrates a method of preparing carboxylic acids of the type 8.6.
  • Ketone 8.1 is treated with hydrazine 8.2 under acidic conditions to afford tetracyclic indole 8.3.
  • Alkylation of 8.3 and saponification of intermediate ester 8.5 provides acid 8.6.
  • Scheme 9 illustrates a method of preparing carboxylic acids of the type 9.6.
  • Conversion of indole amide 9.1 to thioamide 9.2 proceeds in the presence of Lawesson’s reagent in THF, and subsequent treatment with DMF ⁇ DMA affords thio-imino acetal 9.3.
  • Cyclization of 9.3 to thiadiazole 9.4 is effected via exposure to aminooxy sulfonic acid and pyridine in ethanol. Alkylation of 9.4 and saponification of intermediate ester 9.5 provides acid 9.6.
  • Scheme 10 illustrates an analogous method of preparing carboxylic acids of type 10.5.
  • Treatment of indole amide 10.1 with DMF ⁇ DMA affords imino acetal 10.2, and cyclization with methylhydrazine furnishes 10.3.
  • Alkylation of 10.3 by treatment of 10.3 with sodium hydride followed by addition of tert-butyl bromoacetate provides 10.4.
  • Exposure of 10.4 with TFA affords the corresponding carboxylic acid 10.5.
  • Schemes 11 through 12 illustrate the preparation of the intermediate amines of the type 1.2 which are used to prepare compounds of the invention as described above. More specifically, Scheme 11 describes the preparation of amine 1.2 from amine 11.1. The amine is protected with a Boc group via exposure to di-tert-butyl dicarbonate and base to afford 11.2. Cross-coupling of bromide 11.2 with boronic acid 11.3 (or other suitable intermediate) is mediated by heating in an aqueous solvent mixture in the presence of a suitable catalyst and base system (e.g. , Pd ( (t-Bu) 3 ) 2 and Cs 2 CO 3 ) to furnish biaryl intermediate 11.4. Removal of the Boc group under acidic conditions (HCl in EtOAc) affords amine 1.2 as an HCl salt.
  • a suitable catalyst and base system e.g. , Pd ( (t-Bu) 3 ) 2 and Cs 2 CO 3
  • Scheme 12 illustrates a method of preparing the amine 1.2 in which bromide 12.1 is converted to the aryl or heteroarylboronic ester 12.2 by heating with bis(pinacolato) diboron in the presence of a suitable catalyst and base system (e.g. , Pd (dppf) Cl 2 and KOAc) .
  • a suitable catalyst and base system e.g. , Pd (dppf) Cl 2 and KOAc
  • Exposure of boronate 12.2 to an aryl or heteroaryl bromide 12.3 (or other suitable intermediate) in an aqueous solvent mixture in the presence of a suitable catalyst and base system e.g. , Pd (dppf) Cl 2 and Na 2 CO 3
  • a suitable catalyst and base system e.g. , Pd (dppf) Cl 2 and Na 2 CO 3
  • Scheme 13 illustrates a method of preparing aryl bromides of the types 13.2, 13.3 and 13.4, which are used in the Schemes described above, from aryl bromide 13.1.
  • Exposure of thiol 13.1 to mCPBA in dichloromethane affords sulfoxide 13.2.
  • 13.2 Treatment of 13.2 with sodium azide and sulfuric acid or 2, 2, 2-trifluoroacetamide, iodobenzene diacetate, magnesium oxide, and rhodium (II) acetate dimer, in cases where R is labile under strongly acidic conditions, provides sulfoximine 13.3.
  • sulfoxide 13.2 can be further oxidized with mCPBA in dichloromethane to afford sulfone 13.4.
  • Step A 2- (1H-Indol-2-yl) oxazole
  • Oxalyl chloride (14.9 mL, 29.8 mmol) was added to a solution of 1H-indole-2-carboxylic acid (4.00 g, 24.8 mmol) in DCM (6 mL) and DMF (0.192 mL, 2.48 mmol) , and the resulting mixture was stirred for 1 h, then concentrated.
  • 1H-1, 2, 3-Triazole (2.01 mL, 34.7 mmol) , potassium carbonate (6.86 g, 49.6 mmol) , and sulfolane (24.8 mL) were added to the residue, and the mixture was heated at 140 °C for 30 minutes.
  • Step B Methyl 2- (2- (oxazol-2-yl) -1H-indol-1-yl) acetate
  • Step C 2- (2- (Oxazol-2-yl) -1H-indol-1-yl) acetic acid
  • Step A 2- (5-Fluoro-1H-indol-2-yl) oxazole
  • Step B Methyl 2- (5-fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetate
  • Step C 2- (5-Fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetic acid
  • Step A 2- (1-Methyl-1H-pyrazol-5-yl) -1H-indole
  • Step B Methyl 2- (2- (1-methyl-1H-pyrazol-5-yl) -1H-indol-1-yl) acetate
  • Step C 2- (2- (1-Methyl-1H-pyrazol-5-yl) -1H-indol-1-yl) acetic acid
  • Step A 2- (5-Fluoro-1H-indol-2-yl) thiazole
  • Step B Methyl 2- (5-fluoro-2- (thiazol-2-yl) -1H-indol-1-yl) acetate
  • Step C 2- (5-Fluoro-2- (thiazol-2-yl) -1H-indol-1-yl) acetic acid
  • Step A tert-Butyl 5-fluoro-2- (isothiazol-5-yl) -1H-indole-1-carboxylate
  • Step B 5- (5-Fluoro-1H-indol-2-yl) isothiazole
  • Step C Ethyl 2- (5-fluoro-2- (isothiazol-5-yl) -1H-indol-1-yl) acetate
  • Step D 2- (5-Fluoro-2- (isothiazol-5-yl) -1H-indol-1-yl) acetic acid
  • Step A 8-Fluoro-6, 11-dihydro-5H-pyrazolo [1', 5': 1, 2] pyrido [3, 4-b] indole
  • Step B Ethyl 2- (8-fluoro-5H-pyrazolo [1', 5': 1, 2] pyrido [3, 4-b] indol-11 (6H) -yl) acetate
  • Step C 2- (8-Fluoro-5H-pyrazolo [1', 5': 1, 2] pyrido [3, 4-b] indol-11 (6H) -yl) acetic acid
  • Step A 8-Fluoro-11H-pyrazolo [1', 5': 1, 2] pyrido [3, 4-b] indole
  • Step B Ethyl 2- (8-fluoro-11H-pyrazolo [1', 5': 1, 2] pyrido [3, 4-b] indol-11-yl) acetate
  • Step C 2- (8-Fluoro-11H-pyrazolo [1', 5': 1, 2] pyrido [3, 4-b] indol-11-yl) acetic acid
  • Step B (Z) -N- ( (Dimethylamino) methylene) -5-fluoro-1H-indole-2-carbothioamide
  • Step C 5- (5-Fluoro-1H-indol-2-yl) -1, 2, 4-thiadiazole
  • Step D Ethyl 2- (5-fluoro-2- (1, 2, 4-thiadiazol-5-yl) -1H-indol-1-yl) acetate
  • Step E 2- (5-Fluoro-2- (1, 2, 4-thiadiazol-5-yl) -1H-indol-1-yl) acetic acid
  • Step A 2- (5-Fluoro-3-iodo-2- (oxazol-2-yl) -1H-indoyl) acetic acid
  • Step B 2- (3-Cyano-5-fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetic acid
  • Step A Benzyl 2- (5-fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetate
  • Step B Benzyl 2- (5-fluoro-3-formyl-2- (oxazol-2-yl) -1H-indol-1-yl) acetate
  • Step C 2- (5-Fluoro-3-methyl-2- (oxazol-2-yl) -1H-indol-1-yl) acetic acid
  • Step A tert-Butyl 5-fluoro-1H-indole-1-carboxylate
  • Step B tert-Butyl 2-bromo-5-fluoro-1H-indole-1-carboxylate
  • Step C tert-Butyl 5-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1H-indole-1-carboxylate
  • Step D 5-Fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1H-indole
  • Step E Ethyl 2- (5-fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1H-indol-1-yl) acetate
  • Step F 2- (5-Fluoro-2- (1-methyl-1H-pyrazol-5-yl) -1H-indol-1-yl) acetic acid
  • Oxalyl chloride (18.8 g, 0.149 mol) was added dropwise to a solution of 1H-indole-2- carboxylic acid (20.0 g, 0.124 mol) in a 1:1 mixture of anhydrous DCM and THF (200 mL) and catalytic amount of anhydrous DMF at 25 °C. Following the addition, the resulting mixture was stirred for 30 min, then concentrated. A solution of the residue in anhydrous THF (200 mL) was added dropwise to a solution of NH 3 gas (20.0 g, 1.17 mol) in anhydrous THF (200 mL) at - 78 °C. The resulting mixture was allowed to warm to 25 °C and stirred for 3 h.
  • Step B (E) -N- ( (Dimethylamino) methylene) -1H-indole-2-carboxamide
  • Step C 2- (1-Methyl-1H-1, 2, 4-triazol-5-yl) -1H-indole
  • Step D tert-Butyl 2- (2- (1-methyl-1H-1, 2, 4-triazol-5-yl) -1H-indol-1-yl) acetate
  • Step E 2- (2- (1-Methyl-1H-1, 2, 4-triazol-5-yl) -1H-indol-1-yl) acetic acid
  • Step A 2- (3, 5-Difluoro-1H-indol-2-yl) oxazole
  • Step B tert-Butyl 2- (3, 5-difluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetate
  • Step C 2- (3, 5-Difluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetic acid
  • Step A 1- (Tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - 1H-pyrazole
  • n-BuLi 2.5 M, 40 mL, 0.016 mol
  • 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole 2.0 g, 0.013 mol
  • the resulting mixture was stirred at -78 °C for 30 min before 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (2.7 g, 0.014 mol) was added dropwise. After addition, the reaction was held at -78 °C for 3 h.
  • Step B tert-Butyl5-fluoro-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -1H-indole-1- carboxylate
  • Step C 5-Fluoro-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -1H-indole
  • Step D tert-Butyl2- (5-fluoro-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -1H-indol- 1-yl) acetate
  • Step E 2- (5-Fluoro-2- (1H-pyrazol-5-yl) -1H-indol-1-yl) acetic acid
  • Step A Ethyl 2- (5-fluoro-1H-indol-3-yl) acetate
  • Step B Ethyl 2- (2-bromo-5-fluoro-1H-indol-3-yl) acetate
  • Step C Ethyl 2- (5-fluoro-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -1H-indol-3- yl) acetate
  • Step D 2- (5-Fluoro-2- (1-(tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -1H-indol-3-yl) ethanol
  • Step E 2- (5-Fluoro-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -1H-indol-3-yl) ethyl 4- methylbenzenesulfonate
  • Step F 8-Fluoro-6, 11-dihydro-5H-pyrazolo [1', 5': 1, 2] pyrido [3, 4-b] indole
  • Step G Ethyl 2- (8-fluoro-5H-pyrazolo[1', 5':1, 2] pyrido [3, 4-b] indol-11 (6H) -yl) acetate
  • Step H 2- (8-Fluoro-5H-pyrazolo [1', 5':1, 2] pyrido [3, 4-b] indol-11 (6H) -yl) acetic acid
  • Step A tert-Butyl 5-fluoro-2- (oxazol-2-yl) -1H-indole-1-carboxylate
  • Step B 5-Fluoro-2- (5-fluoro-1H-indol-2-yl) oxazole
  • Step C Ethyl 2- (5-fluoro-2- (5-fluorooxazol-2-yl) -1H-indol-1-yl) acetate
  • Step D 2- (5-Fluoro-2- (5-fluorooxazol-2-yl) -1H-indol-1-yl) acetic acid
  • Step A tert-Butyl ( (5-bromopyridin-2-yl) methyl) carbamate
  • Boc 2 O (1.29 g, 5.29 mmol) was added to a solution of (5-bromopyridin-2-yl) methanamine (1.26 g, 5.64 mol) and DIEA (1.03 mL, 5.92 mmol) in DCM (25 mL) , and the resulting mixture was stirred at 25 °C for 7 h.
  • the reaction mixture was neutralized with saturated aqueous NaHCO 3 solution (50 mL) and extracted with DCM (75 mL x 2) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound.
  • MS: m/z 287.1 (M + 1) .
  • Step B tert-Butyl ( (5- (4- (methylsulfonyl) phenyl) pyridin-2-yl) methyl) carbamate
  • Step C (5- (4- (Methylsulfonyl) phenyl) pyridin-2-yl) methanamine
  • Step A tert-Butyl ( (5- (4- (methylsulfinyl) phenyl) pyridin-2-yl) methyl) carbamate (isomers A and B)
  • Step B (5- (4- (Methylsulfinyl) phenyl) pyridin-2-yl) methanamine, isomer A (B2)
  • Step B (5- (4- (Methylsulfinyl) phenyl) pyridin-2-yl) methanamine, isomer B (B3)
  • Step B tert-Butyl ( (5- (4- (S-methylsulfonimidoyl) phenyl) pyridin-2-yl) methyl) carbamate
  • Step C (5- (4- (S-Methylsulfonimidoyl) phenyl) pyridin-2-yl) methanamine (isomer A, B7)
  • Step C (5- (4- (S-Methylsulfonimidoyl) phenyl) pyridin-2-yl) methanamine (isomer B, B8)
  • Step B tert-Butyl ( (5- (4- (N- (2-hydroxyethyl) -S-methylsulfonimidoyl) phenyl) pyridin-2- yl) methyl) carbamate
  • Step C (5- (4- (N- (2-Hydroxyethyl) -S-methylsulfonimidoyl) phenyl) pyridin-2-yl) methanamine
  • Step A 2- ( (4-Bromophenyl) thio) ethanol
  • Step B 2- ( (4-Bromophenyl) sulfinyl) ethanol
  • Step C (2- ( (4-Bromophenyl) sulfinyl) ethoxy) (tert-butyl) diphenylsilane
  • Step D 2- (4-Bromophenylsulfonimidoyl) ethanol
  • Step E tert-Butyl ( (5- (4- (2-hydroxyethylsulfonimidoyl) phenyl) pyridin-2-yl) methyl) carbamate
  • Step A 2- ( (4-Bromophenyl) sulfinyl) ethyl-4-methylbenzenesulfonate
  • Step B 4- (2- ( (4-Bromophenyl) sulfinyl) ethyl) morpholine
  • Step C tert-Butyl ( (5- (4- ( (2-morpholinoethyl) sulfinyl) phenyl) pyridin-2-yl) methyl) carbamate
  • Step D (5- (4- ( (2-Morpholinoethyl) sulfinyl) phenyl) pyridin-2-yl) methanamine
  • Step B tert-Butyl (2- ( (4-bromophenyl) sulfonyl) ethyl) carbamate
  • Step C 2- ( (4-Bromophenyl) sulfonyl) ethanamine
  • Step D Benzyl (2- ( (4-bromophenyl) sulfonyl) ethyl) carbamate
  • Step E Benzyl (2- ( (4- (6- ( ( (tert-butoxycarbonyl) amino) methyl) pyridin-3- yl)phenyl) sulfonyl) ethyl) carbamate
  • Step F Benzyl (2- ( (4- (6- (aminomethyl) pyridin-3-yl) phenyl) sulfonyl) ethyl) carbamate
  • Step A 5-Bromo-2-methyl-2, 3-dihydrobenzo isothiazole 1, 1-dioxide
  • Step B 5- (6- (Aminomethyl) pyridin-3-yl) -2-methyl-2, 3-dihydrobenzo isothiazole 1, 1-dioxide
  • Step A tert-Butyl 2-cyano-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzylcarbamate
  • Step B 4- (Aminomethyl) -4'- (methylsulfonyl) - [1, 1'-biphenyl] -3-carbonitrile
  • Step A 6- (4- (Methylsulfonyl) phenyl) pyridazine-3-carbonitrile
  • Step B (6- (4- (Methylsulfonyl) phenyl) pyridazin-3-yl) methanamine
  • Step A (3-Bromopropoxy) (tert-butyl) diphenyl silane
  • Step B (3- ( (4-Bromophenyl) thio) propoxy) (tert-butyl) diphenylsilane
  • Step C (3- ( (4-Bromophenyl) sulfinyl) propoxy) (tert-butyl) diphenylsilane
  • Step D (3- ( (4-Bromophenyl) sulfonyl) propoxy) (tert-butyl) diphenylsilane
  • Step E tert-Butyl ( (5- (4- ( (3- ( (tert-butyldiphenylsilyl) oxy) propyl) sulfonyl) phenyl) pyridin-2- yl) methyl) carbamate
  • Step F tert-Butyl ( (5- (4- ( (3-hydroxypropyl) sulfonyl) phenyl) pyridin-2-yl) methyl) carbamate
  • Step G 3- ( (4- (6- (Aminomethyl) pyridin-3-yl) phenyl) sulfonyl) propan-1-ol
  • Step A 1- (4-Bromophenyl) -2, 2-difluoroethanone
  • Step B 1- (4-Bromophenyl) -2, 2-difluoroethanol
  • Step C 2, 2-Difluoro-1- (4- (4, 4, 5, 5-tetramethyl-1, 3-dioxolan-2-yl) phenyl) ethanol
  • Step D tert-Butyl ( (5- (4- (2, 2-difluoro-1-hydroxyethyl) phenyl) pyridin-2-yl) methyl) - carbamate
  • Step E 1- (4- (6- (Aminomethyl) pyridin-3-yl) phenyl) -2, 2-difluoroethanol
  • Step B tert-Butyl ( (5-bromo-6-methylpyridin-2-yl) methyl) carbamate
  • Step C tert-Butyl ( (6-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) - methyl) carbamate
  • Step D tert-Butyl ( (6-methyl-5- (4- (S-methylsulfonimidoyl) phenyl) pyridin-2-yl) methyl) - carbamate
  • Step E (6-Methyl-5- (4- (S-methylsulfonimidoyl) phenyl) pyridin-2-yl) methanamine
  • Step E tert-Butyl ( (6-chloro-2-methoxypyridin-3-yl) methyl) carbamate
  • Step F tert-Butyl ( (2-methoxy-6- (4- (methylsulfonyl) phenyl) pyridin-3-yl) methyl) carbamate
  • Step G (2-Methoxy-6- (4- (methylsulfonyl) phenyl) pyridin-3-yl) methanamine
  • Step A 1- (5-Bromopyridin-2-yl) ethanamine
  • Step B tert-Butyl (1- (5-bromopyridin-2-yl) ethyl) carbamate
  • Step C tert-Butyl (1- (5- (4- (S-methylsulfonimidoyl) phenyl) pyridin-2-yl) ethyl) carbamate
  • Step D 1- (5- (4- (S-Methylsulfonimidoyl) phenyl) pyridin-2-yl) ethanamine
  • Step A tert-Butyl 4-bromo-2-fluorobenzylcarbamate
  • Step B tert-Butyl ( (3-fluoro-4'- (S-methylsulfonimidoyl) - [1, 1'-biphenyl] -4-yl) methyl) carbamate
  • Step C (3-Fluoro-4'- (S-methylsulfonimidoyl) - [1, 1'-biphenyl] -4-yl) methanamine
  • Step B tert-Butyl 4-bromo-2-methoxybenzylcarbamate
  • Step C tert-Butyl ( (3-methoxy-4'- (S-methylsulfonimidoyl) - [1, 1'-biphenyl] -4- yl)methyl) carbamate
  • Step D (3-Methoxy-4'- (S-methylsulfonimidoyl) - [1, 1'-biphenyl] -4-yl) methanamine
  • Step A Methyl 3-bromo-4'- (methylsulfonyl) - [1, 1'-biphenyl] -4-carboxylate
  • Step B 3-Bromo-4'- (methylsulfonyl) - [1, 1'-biphenyl] -4-carboxylic acid
  • Step C 3-Bromo-4'- (methylsulfonyl) - [1, 1'-biphenyl] -4-carboxamide
  • Step D (3-Bromo-4'- (methylsulfonyl) - [1, 1'-biphenyl] -4-yl) methanamine
  • Step E tert-Butyl ( (3-bromo-4'- (methylsulfonyl) - [1, 1'-biphenyl] -4-yl) methyl) carbamate
  • Step F (3-Bromo-4'- (methylsulfonyl) - [1, 1'-biphenyl] -4-yl) methanamine hydrochloride
  • Step B 1-Bromo-4- (cyclopropanesulfonimidoyl) benzene
  • Step A 3- ( (4-Bromophenyl) thio) oxetane
  • Step B 3- ( (4-Bromophenyl) sulfonyl) oxetane
  • Step A tert-Butyl (3- (4-bromophenylsulfonamido) propyl) carbamate
  • Step A (3- ( (4-Bromophenyl) sulfinyl) propoxy) (tert-butyl) diphenylsilane
  • Step B 3- (4-Bromophenylsulfonimidoyl) propyl hydrogen sulfate
  • Step D 3- (4-Bromo-N-benzylcarbamoylphenylsulfonimidoyl) propan-1-ol
  • Step E 3- (4-Bromo-N-benzylcarbamoylphenylsulfonimidoyl) propanyl-1-azide
  • Step F 3- (4-Bromo-N-benzylcarbamoylphenylsulfonimidoyl) propan-1-amine
  • Step A tert-Butyl 2- (4-bromobenzoyl) hydrazinecarboxylate
  • Step D 5- (4-bromophenyl) -1, 3, 4-thiadiazol-2 (3H) -one
  • Step B 3- (4-Bromophenyl) -1, 2, 4-oxadiazol -5 (4H) -one
  • HATU 32 mg, 0.086 mmol was added to a solution of 2- (2- (thiophen-2-yl) -1H- indol-1-yl) acetic acid (20 mg, 0.078 mmol) , 2- (aminomethyl) pyridine (0.019 mL, 0.078 mmol) and DIEA (0.008 mL, 0.23 mmol) in DCM (0.5 mL) , and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (3 mL ⁇ 3) . The organic layer was washed with brine (3 mL) , dried over sodium sulfate and concentrated.
  • the mixture was filtered and purified by preparative reverse phase HPLC (95: 9 to 5:95 water containing 0.1%TFA: acetonitrile containing 0.1%TFA) .
  • the resulting fractions were lyophilized, providing the titled compound as a TFA salt.
  • HATU (163 mg, 0.428 mmol) was added to a solution of 2- (2- (thiophen-2-yl) -1H-indol- 1-yl) acetic acid (20 mg, 0.078 mmol) , (1H-benzo [d] imidazol-2-yl) methanamine (57 mg, 0.39 mmol) and DIEA (0.20 mL, 1.2 mmol) in DMF (2 mL) , and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and purified by reverse-phase HPLC (10-60%acetonitrile in water with 0.1%trifluoroacetic acid modifier) to afford the title compound.
  • racemic (5- (4- (S-methylsulfon-imidoyl) phenyl) pyridin-2-yl) methanamine was utilized in the coupling reaction to give racemic 2- (5-fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) - N-((5- (4- (S-methylsulfonimidoyl) phenyl) pyridin-2-yl) methyl) acetamide.
  • the enantiomers were separated using the following conditions: SFC (Column: ChiralCel OJ, 250 ⁇ 50mm I.D.
  • reaction mixture was then purified by reverse-phase HPLC (Sunfire C18 30 x 150 mm column) using 5 to 80% MeCN in water (0.1% TFA modifier for the solvents) over 15 min at 35 mL flow rate to give the title compound as a TFA salt.
  • MS: m/z 522.6 (M + 1).
  • Step A 2- (4- (Cyclopropanesulfonimidoyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
  • Step B N- ( (5- (4- (Cyclopropanesulfonimidoyl) phenyl) pyridin-2-yl) methyl) -2- (5-fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetamide (isomers A and B)
  • reaction mixture was purified by reverse phase HPLC (C-18 column) , eluting with an acetonitrile/water gradient (with 0.1%TFA modifier) , to give the title compound as a racemic mixture.
  • the enantiomers were separated by chiral SFC (AS column, 45%MeOH (0.2%NH 4 OH) /CO 2 ) to afford individually isomers A and B.
  • MS: m/z 529.87 (M + 1) .
  • reaction mixture was purified by reverse phase HPLC (C-18 column) , eluting with an acetonitrile/water gradient (with 0.1% TFA modifier) , followed by preparative TLC, eluting with CH 2 Cl 2 /MeOH/NH 4 OH, to give the title compound.
  • MS: m/z 559.01 (M + 1).
  • Step A Ethyl 4- (6- ( (2- (5-fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetamido) methyl) pyridin-3- yl) benzoate
  • Step B 4- (6- ( (2- (5-Fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetamido) methyl) pyridin-3- yl) benzoic acid
  • Step C 2- (5-Fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) -N- ( (5- (4- (hydrazinecarbonyl) phenyl) pyridin-2-yl) methyl) acetamide
  • Step D 2- (5-Fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) -N- ( (5- (4- (5-oxo-4, 5-dihydro-1, 3, 4- oxadiazol-2-yl) phenyl) pyridin-2-yl) methyl) acetamide
  • Step A Ethyl-4- (6- ( (2- (5-fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetamido) methyl) pyridin-3- yl) benzoate
  • Step B 4- (6- ( (2- (5-Fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetamido) methyl) pyridin-3-yl) benzoic acid
  • Step C 4- (6- ( (2- (5-Fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetamido) methyl) pyridin-3-yl) -N- (phenylsulfonyl) benzamide
  • Step A N- ( (3-Bromo-4'- (methylsulfonyl) - [1, 1'-biphenyl] -4-yl) methyl) -2- (5-fluoro-2- (oxazol-2-yl) -1-indol-1-yl) acetamide
  • Step B N- ( (3-Cyano-4'- (methylsulfonyl) - [1, 1'-biphenyl] -4-yl) methyl) -2- (5-fluoro-2- (oxazol -2-yl) -1H-indol-1-yl) acetamide
  • Step C 4- ( (2- (5-Fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetamido) methyl) -4'- (methylsulfonyl) - [1,1'-biphenyl] -3-carboxamide
  • Step A Benzyl (2- ( (4- (6- ( (2- (5-fluoro-2- (oxazol-2-yl) -1H-indol-1-yl) acetamido) methyl) pyridin-3-yl) phenyl) sulfonyl) ethyl) carbamate

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Abstract

La présente invention concerne des composés d'indole substitués de formule (I), qui sont des inhibiteurs de protéines kinases de la famille des kinases apparentées à la tropomyosine (Trk), et, par conséquent, qui sont utiles dans le traitement de la douleur, de l'inflammation, du cancer, de la resténose, de l'athérosclérose, du psoriasis, d'une thrombose, d'une maladie, d'un trouble, d'une lésion ou d'un dysfonctionnement associé à la myélinisation ou à une démyélinisation, ou d'une maladie ou d'un trouble associé à des activités anormales du récepteur TrkA du facteur de croissance nerveux (NGF).
PCT/CN2014/088321 2014-10-10 2014-10-10 Inhibiteurs de la kinase trka, compositions en contenant et méthodes associées WO2016054807A1 (fr)

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CN107501123A (zh) * 2017-07-03 2017-12-22 华中科技大学鄂州工业技术研究院 带永久电荷肼类糖标记物的制备方法及应用
KR20200006589A (ko) * 2017-05-18 2020-01-20 이도르시아 파마슈티컬스 리미티드 N-치환된 인돌 유도체
CN113019463A (zh) * 2021-05-25 2021-06-25 江苏欣诺科催化剂有限公司 钯复合催化剂及其制备方法和应用
CN113214148A (zh) * 2021-04-30 2021-08-06 安徽国星生物化学有限公司 一种2/3-氰基吡啶的合成方法及装置
EP3889154A4 (fr) * 2018-12-29 2022-12-21 Wuhan LL Science And Technology Development Co., Ltd. Intermédiaire de composé hétérocyclique, son procédé de préparation et son utilisation
CN116283946A (zh) * 2023-03-27 2023-06-23 武汉工程大学 5-（n-取代吲哚-5-基）异噁唑-3-甲酸衍生物及其合成方法和应用

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JP7065117B2 (ja) 2017-05-18 2022-05-11 イドーシア ファーマシューティカルズ リミテッド Ｎ－置換インドール誘導体
KR20200006589A (ko) * 2017-05-18 2020-01-20 이도르시아 파마슈티컬스 리미티드 N-치환된 인돌 유도체
JP2020520359A (ja) * 2017-05-18 2020-07-09 イドーシア ファーマシューティカルズ リミテッドＩｄｏｒｓｉａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ Ｎ−置換インドール誘導体
KR102650756B1 (ko) 2017-05-18 2024-03-22 이도르시아 파마슈티컬스 리미티드 N-치환된 인돌 유도체
CN107501123B (zh) * 2017-07-03 2020-04-28 华中科技大学鄂州工业技术研究院 带永久电荷肼类糖标记物的制备方法及应用
CN107501123A (zh) * 2017-07-03 2017-12-22 华中科技大学鄂州工业技术研究院 带永久电荷肼类糖标记物的制备方法及应用
EP3889154A4 (fr) * 2018-12-29 2022-12-21 Wuhan LL Science And Technology Development Co., Ltd. Intermédiaire de composé hétérocyclique, son procédé de préparation et son utilisation
CN113214148B (zh) * 2021-04-30 2023-02-14 安徽国星生物化学有限公司 一种2/3-氰基吡啶的合成方法及装置
CN113214148A (zh) * 2021-04-30 2021-08-06 安徽国星生物化学有限公司 一种2/3-氰基吡啶的合成方法及装置
CN113019463B (zh) * 2021-05-25 2021-09-07 江苏欣诺科催化剂有限公司 钯复合催化剂及其制备方法和应用
CN113019463A (zh) * 2021-05-25 2021-06-25 江苏欣诺科催化剂有限公司 钯复合催化剂及其制备方法和应用
CN116283946A (zh) * 2023-03-27 2023-06-23 武汉工程大学 5-（n-取代吲哚-5-基）异噁唑-3-甲酸衍生物及其合成方法和应用
CN116283946B (zh) * 2023-03-27 2024-05-07 武汉工程大学 5-(n-取代吲哚-5-基)异噁唑-3-甲酸衍生物及其合成方法和应用

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